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€œThey have 180 million people, families under what he wants to do, which will basically be socialized medicine — you won’t even have a http://cz.keimfarben.de/get-seroquel-online/ choice — they want to terminate what do you need to buy seroquel 180 million plans.”President Donald Trump during the presidential debate, Oct. 22, 2020 During the final presidential debate, President Donald Trump claimed that 180 million people would lose their private health insurance to socialized medicine if the Democratic presidential nominee, former Vice President Joe Biden, is elected president.“They have 180 million people, families under what he wants to do, which will basically be socialized medicine — you won’t even have a choice — they want to terminate 180 million plans,” what do you need to buy seroquel said Trump.Trump has repeated this claim throughout the week, and we thought the linkage of Biden’s proposed health care plan with socialism was something we needed to check out. Especially since Biden opposed “Medicare for All,” the proposal by Sen. Bernie Sanders what do you need to buy seroquel (I-Vt.) that would have created a single-payer health system run completely by the federal government, and has long been attacked by Republicans as “socialist.” Email Sign-Up Subscribe to KHN’s free Morning Briefing.

The Trump campaign did not respond to our request asking where the evidence for this claim came from. Experts called it a distortion of Biden’s plan.Where the Number Comes FromExperts agreed the number of people who have private health insurance either through an employer-sponsored what do you need to buy seroquel plan or purchased on the Affordable Care Act’s health insurance marketplace is around 180 million people.KFF, a nonpartisan health policy organization, estimated in 2018 that about 157 million Americans had health insurance through their employer, while almost 20 million had insurance they purchased for themselves. Together, that adds up to about 177 million with private health insurance. (KHN is an editorially what do you need to buy seroquel independent program of KFF.)What Does Biden Support?.

Biden supports expanding the ACA through several measures, including a public option. Under his plan, this public option would be a health insurance plan run by the federal government that would be offered alongside other private health insurance plans on the insurance marketplace.“The marketplace is made what do you need to buy seroquel up of multiple insurers in areas,” said Linda Blumberg, a health policy fellow at the Urban Institute. €œSometimes there are five or more [plans]. Sometimes there is only what do you need to buy seroquel one.

Biden is talking about adding a public option in the marketplace. You could pick between these private insurers or you could pick the public option.”Getting what do you need to buy seroquel rid of the so-called employer firewall is also part of Biden’s proposal.This firewall was implemented during the rollout of the ACA. It was designed to maintain balance in the insurance risk pools by preventing too many healthy people who have work-based coverage from opting instead to move to a marketplace plan. And it all came down to who qualified for the subsidies that made these plans more affordable.Currently, those who are offered a health insurance plan through their employer that meets certain minimum federal standards aren’t eligible to receive these subsidies, which come in the what do you need to buy seroquel form of tax credits.

But that leaves many low-income workers with health care plans that aren’t as affordable or comprehensive as marketplace plans.Biden’s plan would eliminate that firewall, meaning anyone could choose to get health insurance either through their employer or through the marketplace. That’s where many Republicans argue that we could start to see leakage from private health insurance plans to the public option.“The problem is healthy people leaving employer plans,” said Joseph Antos, a scholar what do you need to buy seroquel in health care at the conservative-leaning American Enterprise Institute. That could mean the entire workplace plan’s premiums would go up. €œYou could easily imagine a plan where it spirals, the premiums go up, and then even more people start leaving the plans to go to the public option.”Blumberg, though, said that because the marketplace would still include private health insurance plans alongside the public option, it doesn’t mean everyone who chooses to leave their employer plan would go straight to the public option.She has done estimates based on a plan similar to the what do you need to buy seroquel one Biden is proposing.

She estimates that only about 10% to 12% of Americans would choose to leave their employer-sponsored plans, which translates to about 15 million to 18 million Americans. Source List: Email interview with Cynthia Cox, vice president and director for the Program on what do you need to buy seroquel the ACA at KFF, Oct. 22, 2020Email interview with Larry Levitt, executive vice president for health policy at KFF, Oct. 22, 2020Email interview with Sabrina Corlette, co-director what do you need to buy seroquel of the Center on Health Insurance Reforms at Georgetown University, Oct.

22, 2020KFF, “Health Insurance Coverage of the Total Population,” Accessed Oct. 22, 2020KFF, “Affordability in the ACA Marketplace Under a Proposal Like Joe Biden’s Health Plan,” Sept what do you need to buy seroquel. 28, 2020Phone interview with Joseph Antos, Wilson H. Taylor resident scholar in health care and retirement policy what do you need to buy seroquel at the American Enterprise Institute, Oct.

22, 2020Phone interview with Linda Blumberg, institute fellow in the Health Policy Center at the Urban Institute, Oct. 22, 2020Rev.com, what do you need to buy seroquel “Donald Trump &. Joe Biden Final Presidential Debate Transcript 2020,” Accessed Oct. 23, 2020Twitter, what do you need to buy seroquel Donald Trump tweet, Oct.

21, 2020Urban Institute, “The Healthy America Program, an Update and Additional Options,” Sept. 2019Urban Institute, “From Incremental what do you need to buy seroquel to Comprehensive Health Insurance Reform. How Various Reform Options Compare on Coverage and Costs,” Oct. 2019 KFF also did an estimate and found that 12.3 million people with employer coverage could save money by buying what do you need to buy seroquel on the exchange under the Biden plan.But “it’s not clear all of those people would choose to leave their employer coverage, though, as there are other reasons besides costs that people might want to have job-based insurance,” Cynthia Cox, vice president and director of the program on the ACA at KFF, wrote in an email.Either way, none of the estimates are anywhere close to the 180 million that Trump claimed.Is This Type of Public Option Socialism?.

Overall, experts said no, what Biden supports isn’t socialized medicine.“Socialized medicine means that the government runs hospitals and employs doctors, and that is not part of Biden’s plan,” Larry Levitt, executive vice president for health policy at KFF, wrote in an email. €œUnder Biden’s plans, doctors and hospitals would remain in the private sector just like they are today.”However, Antos said that, in his view, the definition of socialism can really vary when it comes to health care.“I would argue in one sense, we would already have socialized what do you need to buy seroquel medicine. We have massive federal subsidies for everybody, so in that sense, we’re already there,” said Antos. €œBut, if socialized medicine means the government what do you need to buy seroquel is going to dictate how doctors practice or how health care is delivered, we are obviously not in that situation.

I don’t think the Biden plan would lead you that way.”And in the end, Antos said, invoking socialism is a scare tactic that politicians have been using for years.“It’s just a political slur,” said Antos. €œIt’s meant to inflame the emotions of those who will vote for Trump and meant to annoy the people who will vote for Biden.”Our Ruling Trump said 180 million people would lose their private health insurance plans to socialized medicine under Biden.While about 180 million people do have private health insurance, there is no evidence that all of them would lose their private plans if Biden were elected president.Biden supports implementing a public option on the health insurance what do you need to buy seroquel marketplace. It would exist alongside private health insurance plans, and Americans would have the option to buy either the private plan or the public plan. While estimates show that a number of Americans would likely leave their employer-sponsored coverage for the public plan, they would be doing that by what do you need to buy seroquel choice and the estimates are nowhere near Trump’s 180 million figure.Experts also agree that the public option is not socialized medicine, and it’s ridiculous to conflate Biden’s plan with Medicare for All.We rate this claim Pants on Fire.

Victoria Knight. vknight@kff.org, @victoriaregisk Related Topics Elections Insurance The Health Law KHN what do you need to buy seroquel &. PolitiFact HealthCheck Obamacare Plans Private Insurance.

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Highlights and updates Tennessee exchange overviewTennessee is seroquel 50 among the states that have done the least to preserve the Affordable Care Act’s gains.Tennessee has a federally run exchange, so enrollees use HealthCare.gov to sign up for exchange plans. During the first five weeks of open enrollment for 2021 coverage (through December 5, 2020), 87,930 people had made plan selections through the Tennessee marketplace. At that point, there were still 10 days remaining seroquel 50 in the open enrollment period. Enrollment always increases towards the end of the enrollment window, and HealthCare.gov will process auto-renewals after December 15, for people with existing coverage who don’t return to the exchange to pick a new plan or manually renew their coverage for 2021.Last year, total enrollment during the open enrollment period for 202 coverage (including auto-renewals) reached 200,445 people.

That was down from 221,553 people who had enrolled the seroquel 50 year before, for 2019 coverage.Tennessee continues to refuse federal funding to expand its Medicaid program to cover low-income adults in the state (13 other states have also refused to expand their Medicaid programs, although some of them will expand coverage, either fully or partially, by mid-2021). As a result, there are an estimated 117,000 people in the coverage gap in Tennessee — ineligible for Medicaid, but also ineligible for premium subsidies in the exchange because their income is too low.Insurer participation in Tennessee’s exchange has been fairly volatile over the years, but there are six insurers offering plans for 2021, up from five in 2020 (UnitedHealthcare joined the exchange for 2021, after previously only offering coverage in 2016. United’s plans are available in much seroquel 50 of the central and western parts of the state for 2021). Although their coverage areas don’t all overlap, most Tennessee residents have a choice of insurers for 2021, as much of the state has at least three participating exchange insurers.Family and Children’s Service is the Tennessee Navigator organization, and brokers certified with the exchange can be found here.How are insurance premiums in Tennessee changing for 2021?.

Insurers had to seroquel 50 submit rate filings in Tennessee by July 15, 2020. Some of the rates were approved as-filed, but the Tennessee Department of Commerce and Insurance worked with some of the insurers to reduce their proposed rates for 2021, with revised rate filings submitted by some insurers in August. By the time the rate review process was complete, the following average rate changes were approved for 2021 for the state’s individual market insurers:Blue Cross Blue Shield of Tennessee. Average premium increase of 9.8 percent (BCBSTN had initially seroquel 50 proposed an average rate increase of 12.9 percent).

BCBSTN’s filing cover letter notes that they have about 93,000 members, although another area of the filing indicates 97,222 members. SERFF filing seroquel 50 number. BCTN-132455585Cigna. Average premium decrease of 6.1 percent (Cigna’s filing notes that they expect the antidepressant drugs seroquel to increase their costs by about 1 percent in 2021, so the rate increase seroquel 50 would be more significant without antidepressant drugs as a factor).

Cigna has 64,230 members. SERFF filing number seroquel 50. CCGH-132359549Oscar. Average premium increase of 9.9 percent (Oscar had initially proposed an average rate increase of 12.4 percent).

Oscar has 7,704 members seroquel 50. SERFF filing number. OHIN-132442088Bright. Average premium increase of 3 percent (Bright’s filing notes that the average rate increase would have been larger — at about 4.2 percent — without the antidepressant drugs seroquel.

Other insurers in other states have also predicted reduced overall costs in 2021 due to antidepressant drugs’s reduction in non-emergency medical services) Bright has 26,746 members. SERFF filing number. BRHP-132308159Celtic/Ambetter. Average premium decrease of 2.5 percent (Celtic had initially proposed an average premium decrease of 0.3 percent, but the approved decrease ended up being more substantial).

Celtic has 10,716 members, and has expanded into the Jackson and Tri-City areas for 2021. SERFF filing number. CELT-132409373UnitedHealthcare. New to the market for 2021, so no applicable rate change (UHC previously offered coverage in the Tennessee exchange in 2016.

The insurer is also rejoining the exchange in Maryland for 2021). UnitedHealthcare plans to offer coverage in all counties in rating areas 3, 4, 5, 6, and 8 (Figure 13 on this page shows the rating areas in map format. UHC’s plans will be available in southern/central and western Tennessee). UHC’s filing does not include a specific rate adjustment for antidepressant drugs factors, but notes that they may revise this as the summer continues and more data become available.

SERFF filing number. UHLC-132400597In Tennessee, each insurer filed a separate form to detail the anticipated impact of antidepressant drugs on 2021 claims costs. Where they had data and projections available, insurers broke it down into cost changes (either an increase or a decrease) associated with pent-up demand for elective services that were postponed this year, the cost of a antidepressant drugs treatment, the cost of treating members who are diagnosed with antidepressant drugs, and the cost changes associated with the transition of people from the employer-sponsored market to the individual market (ie, there are expected to be more people purchasing coverage in the individual market for 2021, due to job losses amid the antidepressant drugs seroquel). Premiums in the Tennessee exchange started out as some of the lowest in the country in 2014, but increased rapidly in the subsequent years.

As of 2020, the average full-price premium in Tennessee’s exchange is $641/month. That’s higher than the $595/month average across the 38 states that use HealthCare.gov. But 86 percent of Tennessee’s exchange enrollees are receiving premium subsidies in 2020, and their after-subsidy premiums average $145/month — which is exactly the same as the after-subsidy average premium across those 38 states. Here’s a summary of how full-price rates have changed in Tennessee’s exchange over the years (keeping in mind that premium subsidies are designed to keep pace with full-price premiums, so they have grown over time as well):2014.

In 2014 Tennessee had among the lowest overall average rates in the country for individual market health plans. That was the first year that ACA-compliant plans were available, and rates were essentially educated actuarial guesses, since there was no claims experience on which to base them.2015. Average rate increase of 12.5 percent (another analysis indicated a 9 percent increase for a 40-year-old non-smoker). This included an average rate increase of 19 percent for BCBSTN, 7.5 percent for Cigna, and 14.4 percent for Humana.

Tennessee was one of just eight states in a PricewaterhouseCooper analysis with double-digit average rate increases for 2015. But because Tennessee had rates so much lower than the national average in 2014, their rates were still much lower than most states in 2015, even after the rate hikes. A Kaiser Family Foundation analysis of benchmark plan (second-lowest-cost silver plan) premium changes in major metropolitan areas in all 50 states found that the Nashville area still has the fifth-lowest average benchmark premium in the country in 2015, even after an increase of nearly 8 percent.2016. Average increase of 28.2 percent.

Average premium increases ranged from just 0.4 percent for Cigna to more than 36 percent for Blue Cross Blue Shield of Tennessee (BCBSTN had 70 percent of the market share). The overall increase was substantial, but it essentially just brought Tennessee’s lower-than-average rates more in line with rates in the rest of the country. Community Health Alliance had initially proposed a rate increase of nearly 45 percent, but the CO-OP ended up shutting down at the end of 2015, so that rate increase was not applicable.2017. Average rate increase of 56 percent.

The average rate increases ranged from 44.3 percent for Humana, to 62 percent for BCBSTN.Tennessee’s individual market rate increase was roughly tied with Minnesota’s for 2017, and both states trailed only Oklahoma, which had the highest weighted average increase for 2017.Cigna and Humana had originally filed average rate increases of 23 percent and 29 percent, respectively. But in early August 2016, regulators in Tennessee agreed to allow the carriers to refile new rates, after both carriers had told the state that the rates they had originally filed wouldn’t be adequate to cover claims costs. Several carriers across the country made headlines in August and September with announcements that they would exit the exchanges at the end of 2016, but UnitedHealthcare was the only insurer to exit the Tennessee exchange altogether. The fact that regulators in Tennessee allowed new rates to be filed helped to keep the carriers in the market, but it also resulted in more significant premium hikes for 2017.

Carriers had asked to refile rates for 2016 during the summer of 2015, but state regulators would not allow them to do so. For 2017, regulators softened their stance in an effort to keep Cigna and Humana in the marketplace.2018. Average rate increase of 28.5 percent. BCBSTN increased average premiums by 21.4 percent.

Cigna increased average premiums by 36.5 percent. Silver plans became disproportionately expensive in 2018 in Tennessee (driving a significant chunk of the overall rate increase), as the Trump administration eliminated funding for cost-sharing reductions (CSRs). Although the official notice of the funding cut didn’t come until mid-October, TDCI confirmed in September that the additional premiums necessary to cover CSR in 2018 had already been added to silver plan rates for 2018 (pre-emptively, but presciently, since the funding was cut off by the federal government a few weeks later). The higher premiums for silver plans resulted in even larger premium subsidies for 2018.

So although the federal government is no longer directly reimbursing insurers for the cost of CSR, they are indirectly continuing to fund CSR, via larger premium subsidies.TDCI published a document showing average premiums for 35-year-olds and 55-year-olds in each rating area of the state, but most enrollees pay far lower premiums, as their premiums subsidies cover a large portion of the premiums.Blue Cross Blue Shield of Tennessee issued a press release in June 2017, going into great detail about their proposed rate increase for 2018. Their actuarial memo in their rate filing indicated that their average proposed rate increase was 21.4 percent, but that the majority of that was due to concerns that the Trump Administration wouldn’t continue to enforce the individual mandate, and the uncertainty surrounding ongoing funding for cost-sharing reductions (CSR).The press release from Blue Cross Blue Shield of Tennessee noted that of the 21.4 percent rate increase they proposed (which was later approved by TDCI), 14 percentage points were due to the possible lack of funding for cost-sharing subsidies, and 7 percentage points were due to concerns that the individual mandate wouldn’t be well enforced, resulting in a sicker risk pool (healthy people are the ones likely to drop coverage if the mandate isn’t enforced. Sick people will maintain their coverage regardless). So the rate increase for 2018 would apparently have been just 0.4 percent if it weren’t for the Trump administration’s refusal to commit to funding cost-sharing reductions and enforcing the individual mandate.

Instead, BCBSTN proposed an average rate increase of 21.4 percent, and state regulators had no choice but to approve it.Cigna noted that 14.1 percentage points of their rate increase was due to the fact that the Trump Administration had not committed to funding cost-sharing subsidies.2019. Average rate decrease of 12.4 percent. But the average benchmark plan premium decreased by 26 percent in 2019, which was the largest percentage decrease in the nation. The average, across all states, was a 1.5 percent decrease.

Premium subsidies are based on the cost of the benchmark plan, so subsidies decreased by a larger margin than average premiums.In August 2018, the Tennessee Insurance Department announced approved 2019 rate changes, including rate decreases for Blue Cross Blue Shield and Cigna, which had the bulk of the state’s individual market enrollees:Blue Cross Blue Shield of Tennessee. Average premium decrease of 14.9 percent (113,000 membes)Cigna. Average premium decrease of 12.8 percent (75,568 members)Oscar. Average increase of 7.2 percent to 10.84 percent (14,107 members)Bright.

New to the marketCeltic. New to the market 2020. Average rate decrease of about 1.1 percent. But benchmark premiums dropped by 7 percent, leading to some people paying higher after-subsidy premiums for their coverage in 2020.

In 2019, when Bright and Celtic joined the marketplace in Tennessee and Cigna and Oscar expanded their coverage areas, benchmark premiums decreased much more significantly than overall average premiums, resulting in smaller premium subsidies. So 2020 was the second year in a row that subsidy amounts dropped by more than the average premium amounts in Tennessee’s exchange (which could partially explain the decrease in enrollment since 2018. Plans become less affordable when subsidies decrease by more than average premiums).Tennessee’s exchange insurers implemented the following average rate changes for 2020:Blue Cross Blue Shield of Tennessee. Average premium increase of 1.4 percentCigna.

Average premium decrease of 5.7 percentOscar. Average premium decrease of 8.3 percentBright. Average premium increase of 2.93 percentCeltic. Average premium decrease of 1.6 percent Enrollment in Tennessee’s exchange.

2014 through 2020As has been the case in the majority of states that use HealthCare.gov, enrollment in Tennessee’s exchange peaked in 2016, and has declined each year since then.2014. The first open enrollment period, for 2014 coverage, was six months long and had an additional extension tacked onto the end. By April 19, 2014, total enrollment in the Tennessee exchange stood at 151,352 people.2015. Enrollment grew significantly the next year, with 231,440 people enrolling through the exchange during the open enrollment period for 2015 coverage.2016.

Enrollment peaked in the third year, with 268,867 people enrolling through the exchange in Tennessee.2017. President Trump took office just days before the end of the open enrollment period for 2017 coverage, and immediately cut HealthCare.gov’s marketing campaign. 2017 rates were also sharply higher for people who didn’t qualify for premium subsidies. So it wasn’t surprising that enrollment dropped to 234,125 people.2018.

The Trump Administration reduced the marketing and outreach budget for HealthCare.gov, rates again increased sharply for people who didn’t qualify for premium subsidies (due mostly to uncertainty over the future of the individual mandate and the Trump Administration’s decision to cut off funding for cost-sharing reductions), and open enrollment was only half as long as it had been the year before (Nov 1 to Dec 15, which is the schedule that’s currently being used). So again, it wasn’t surprising that enrollment decreased, with 228,646 people buying plans during open enrollment.2019. Although rates decreased for 2019, they’re still quite high for people who don’t qualify for premium subsidies. The GOP tax bill ended the individual mandate penalty at the end of 2018, and the Trump Administration has made it easier for people to opt for coverage under short-term health plans instead of ACA-compliant plans.

So enrollment dropped again during the open enrollment period for 2019 coverage, with 221,553 people buying plans.2020. Enrollment stood at 200,445 at the end of the open enrollment period for 2020 coverage. As noted above, benchmark premiums decreased more significantly than overall average premiums in Tennessee’s exchange, making after-subsidy premiums less affordable for many enrollees.Which insurers offer coverage in Tennessee's exchange?. There are six insurers offering coverage in Tennessee’s exchange in 2021, up from just three in 2018.

Here’s a summary of how insurer participation in the state’s exchange has changed over the years.2014. When the exchanges launched for 2014, plans were available in Tennessee’s exchange from Blue Cross Blue Shield of Tennessee, Community Health Alliance (an ACA-created CO-OP), Cigna, and Humana, although only BCBSTN offered plans statewide.2015. Time/Assurant joined the Tennessee exchange statewide in 2015, bringing the total number of participating insurers to five.2016. Four insurers offered plans.

BCBSTN, Cigna, Humana, and UnitedHealthcare. UnitedHealthcare was new to the exchange for 2016, and according to Kaiser Family Foundation’s analysis, UnitedHeathcare offered at least one of the two lowest-priced silver plans in the exchange in 73 of Tennessee’s 95 counties in 2016. But Assurant and Community Health Alliance both stopped selling plans at the end of 2015. The CO-OP’s demise was due in part to the severe shortfall in federal risk corridor funding, although the CO-OP had stopped selling 2015 plans as of January 15, 2015, noting that they had already met their enrollment goal for the year.

Community Health Alliance had planned to begin selling plans again during the 2016 open enrollment, but instead they ceased operations altogether at the end of 2015, leaving 27,000 enrollees who needed to select new coverage for 2016 from a different carrier.2017. Plans were available from Humana, Cigna, and BCBSTN. Like Assurant’s brief stint in the exchange, UnitedHealthcare’s participation was also short-lived, as they exited the entire individual market in Tennessee at the end of 2016. The Department of Commerce and Insurance confirmed that the exit applied to both the exchange (UnitedHealthcare Insurance Company) and off-exchange (UnitedHealthcare Life Insurance Company).

The state reported that 40,879 people needed to secure new coverage for 2017 as a result of United’s exit (the large majority of these enrollees had their United coverage through the exchange). 2017 was also the first year that BCBSTN opted not to offer statewide coverage. As of 2017, BCBSTN stopped offering coverage in the metro areas of Knoxville, Nashville, and Memphis, which are the three largest metropolitan areas in the state.Blue Cross Blue Shield of Tennessee had the lion’s share of the Tennessee exchange market in 2016, covering almost 69 percent of the enrollees. Because of BCBST’s exit from the three metropolitan areas, approximately 52,000 people in Nashville, 31,000 people in Knoxville, and 29,000 in Memphis had to switch to a different plan for 2017.

So although there were three insurers offering plans in Tennessee’s exchange for 2017, residents in 73 of the state’s 95 counties had only one carrier option in the exchange. Cigna offered coverage in the Memphis and Nashville areas. Humana offered coverage in the Memphis, Nashville, and Knoxville areas, and BCBSTN offered coverage in the rest of the state.2018. There was quite a bit of upheaval in the Tennessee exchange for 2018, in terms of insurer participation.

Humana stopped offering individual market coverage in any states at the end of 2017. Humana’s exit meant that residents in the Knoxville area were facing the possibility of having no exchange insurers at all in 2018. Humana insured about 40,000 people in the Knoxville area, and about 79,000 people across all three metropolitan areas in the state. State regulators scrambled to reach a solution, and succeeded.

In May 2017, Blue Cross Blue Shield of Tennessee agreed to once again offer coverage in 2018 in the Knoxville area in order to ensure that all areas of the state would have insurance plans available in the exchange.While it initially appeared that there would only be two insurers in the Tennessee exchange for 2019, Oscar Health’s entry to the market meant that three insurers offered plans:Cigna’s plans were available in a total of 22 counties in Memphis, Nashville, and the Tri-City area (the eight eastern-most counties in the state), just as they were in 2017.BCBS of Tennessee had plans available everywhere except Memphis and Nashville. They continued to offer coverage in the non-metro areas of the state where they offered plans in 2017, and expanded back into the Knoxville area.Oscar Health has plans available in nine counties in the Nashville area.Nashville and the Tri-City areas were the only parts of the state where enrollees had a choice between two insurers, with both BCBSTN and Cigna offering plans in the Tri-City area, and Oscar and Cigna offering plans in the Nashville area.Tennessee Insurance Commissioner, Julie Mix McPeak, expressed satisfaction that all areas of the state would have at least one insurer offering coverage in the exchange in 2018, but she reiterated how the uncertainty caused by the Trump Administration and Congress was damaging the individual health insurance market, noting that “the uncertainty about the future of the exchange, cost-sharing reduction payments, and enforcement of the individual mandate will likely increase carrier rate requests by 15 to 20 percent above what they would have otherwise filed. I share consumers’ frustrations about federal uncertainty and how that is impacting their ability to afford insurance.”2019. Bright Health joined the Tennessee exchange for 2019, offering coverage in 16 counties in the Knoxville area, nine counties in the Nashville area, and five counties in the Memphis area.Celtic (Centene) also joined the Tennessee exchange for 2019, with plans available in Memphis and Chattanooga.

Much of the state had multiple carrier options for 2019 coverage:Nashville. Oscar, Cigna, BrightKnoxville. BCBSTN, Bright, and CignaMemphis. Bright, Oscar, Cigna, and CelticTri-City area.

BCBSTN and CignaChattanooga area. Celtic and BCBSTN2020. Tennessee continues to have five exchange insurers in 2020, but three have larger coverage areas. Blue Cross Blue Shield of Tennessee came back to the Memphis and Nashville areas for 2020.

Celtic expanded into the Nashville and Knoxville areas, and Cigna expanded into the Chattanooga and Jackson areas.2021. UnitedHealthcare rejoined the exchange in Tennessee for 2021, after leaving at the end of 2016. That brings the state to six insurers. UnitedHealthcare’s plans are available in all counties in rating areas 3, 4, 5, 6, and 8 (southern/central and western Tennessee).

Tennessee Insurance Commissioner’s reform proposalsJulie Mix McPeak was the Insurance Commissioner for Tennessee from 2011 through mid-2019, and also served as the President of the National Association of Insurance Commissioners. In February 2017, Mix McPeak spoke before the Senate Committee on Health, Education, Labor, &. Pensions, presenting her recommendations for health care reform. Among her proposals were:Allowing states to define essential health benefits, rather than requiring all plans sold in every state to conform to the ACA’s essential health benefits (this has been part of most of the GOP proposals to repeal or change the ACA, although it has not been implemented.

As of 2019, essential health benefits are still defined at the federal level).Relaxing the age band ratio from the 3:1 level set by the ACA, to a 5:1 or 6:1 cap. The ACA limits premiums for older enrollees to no more than three times those of younger enrollees. Mix McPeak suggested that insurers should be able to charge older enrollees five or six times as much as younger enrollees, in an effort to reduce premiums for younger enrollees and incentivize them to enroll (this is another provision that was included in most of the GOP efforts to repeal or change the ACA in 2017, but none of those efforts were successful. It’s worth noting that adjusting the age rating bands would result in lower premiums for younger people, but markedly higher premiums for older people.

For those who receive premium subsidies, the subsidies would grow to offset the increase. But for those who don’t get subsidies, coverage could become unaffordable).Tighter restrictions and increased verification of eligibility for special enrollment periods (HHS finalized a market stabilization rule in April 2017 that included increased eligibility verification, and restrictions such as limiting enrollees’ ability to use a special enrollment period to switch to a plan at a different metal level).Reducing the current 90-day grace period for people with premium subsidies down to a 30-day grace period (the market stabilization rule kept the 90-day grace period, but allows insurers to apply new enrollment premiums to past-due balances from the previous 12 months if the person seeks to re-enroll after losing coverage for non-payment of premium).Senator Alexander. 2017 legislation to protect bare counties, and a plea for CSR fundingIn 2017, the U.S. Senators from Tennessee, Lamar Alexander and Bob Corker, both Republicans, introduced legislation (S.761, the Health Care Options Act of 2017) that would allow people in counties without any participating exchange insurers to use ACA subsidies for off-exchange plans.

That scenario has never come to pass, but there were concerns at that point that some areas of the country, including the Knoxville, Tennessee area, might not have had any ACA-compliant plans available.Senator Alexander also, notably, stated in early 2017 that Congress or the Trump administration should commit to funding cost-sharing reductions (CSRs) through 2019, in an effort to stabilize the individual health insurance market. CSRs lower out-of-pocket costs for low-income exchange enrollees who pick silver plans, and 57 percent of Tennessee exchange enrollees have plans that include CSRs in 2017.CSR funding was ultimately eliminated by the Trump administration in October 2017, but the uncertainty (during the rate filing season of spring/summer 2017) around whether or not the funding would continue resulted in premium proposals for 2018 that were higher than they would otherwise have been. Without a federal commitment to fund CSR, Tennessee Insurance Commissioner, Julie Mix McPeak estimated that premiums in Tennessee would be 15 to 20 percent higher than they would otherwise have been in 2018.Senator Alexander joined forces with Senator Patty Murray (D, Washington) in an effort to pass bipartisan legislation aimed at stabilizing the individual insurance markets nationwide, with a proposal that included CSR funding. However, Republican leadership in the Senate opted to push forward on their efforts to repeal the ACA (via the Graham-Cassidy legislation) and pulled the plug on Alexander and Murray’s bipartisan approach in September 2017.In the announcement about the approved rates for 2018, Mix McPeak said “I’m disappointed by yesterday’s announcement out of Washington [about Alexander and Murray’s bipartisan approach being abandoned by Senate leadership].

While Tennessee is supportive of long-term strategies such as the Graham-Cassidy Amendment introduced in Congress, I appreciate the diligent efforts of Senators Lamar Alexander and Patty Murray to find common ground in providing more immediate stabilization in the marketplace. Instead, it appears more likely that Tennesseans must prepare themselves for a round of actuarially justified rates for 2018 that are far higher than could be necessary as a result of uncertainty in Washington.” Farm Bureau plans aren’t compliance with the ACA, but they’re still allowed to be sold in TennesseeAs of 2017, there were about 73,000 people in Tennessee who were covered under Farm Bureau plans that aren’t ACA-compliant. About 50,000 of those were grandfathered plans, but the rest are medically underwritten “traditional” plans that are still available for purchase. Medical underwriting means that the insurer uses the applicant’s medical history to determine whether to offer coverage and at what price.

That practice is no longer allowed under the ACA – on or off-exchange – for any plans that are considered individual major medical health insurance.But in Tennessee, the state doesn’t consider Farm Bureau to be a licensed health insurer. That’s been the case for more than two decades – Farm Bureau plans operate outside of the regulatory structure imposed by the state (and the ACA) on health insurers. As a result, Farm Bureau’s “traditional” plans, which are less expensive than regular health insurance but only available to healthy people, are being sold to healthy people in Tennessee, effectively removing them from the ACA-compliant risk pool.People who enroll in Farm Bureau’s “traditional” plans are not in compliance with the ACA’s individual mandate, so from 2014 through 2018, they were assessed a penalty for being uninsured unless they were exempt from the individual mandate (this is the same as the rule that required people with short-term health insurance to pay the individual mandate penalty. Just like the Tennessee Farm Bureau “traditional” plans, short-term health insurance is not regulated by the ACA).

But the individual mandate penalty no longer applies in 2019 and future years, so there is no longer a penalty for relying on a Farm Bureau plan.Farm Bureau’s plans are not as robust as regular health insurance, and aren’t helpful for people with pre-existing conditions. But the fact that Tennessee has allowed them to continue to be sold outside the scope of the state’s insurance regulations could be part of the reason the state has a risk pool in the ACA-compliant market that’s sicker than most states.Iowa has decided to follow Tennessee’s lead, enacting legislation in 2018 that allows Farm Bureau to partner with Wellmark to offer non-ACA-compliant plans in Iowa.BCBSTN losses pre-2017 and rate hike request – some backgroundDuring open enrollment for 2016 coverage, 166,425 exchange enrollees (62 percent of the total) signed up with Blue Cross Blue Shield of Tennessee for 2016. This was an increase of 16 percent over BCBSTN’s exchange enrollment in 2015, despite the fact that the carrier raised its premiums by an average of 36 percent for 2016. The remaining 38 percent of the exchange enrollees selected plans from Humana, Cigna, and United Healthcare.Blue Cross Blue Shield of Tennessee had the lowest priced plans in the Tennessee exchange — and the nation — in 2014.

Although BCBSTN’s average rate increase was 19 percent for 2015 and 36 percent for 2016 (and their competitors had significantly smaller rate hikes), they still had among the lowest premiums in many areas of Tennessee in 2016. In the Memphis area, a search on Healthcare.gov indicated that the five least expensive bronze plans and the four least expensive silver plans were all offered by BCBSTN in 2016. Their lower premiums and brand-name recognition likely played a role in their outsized market share. But because enrollees have been sicker than expected, the carrier lost $300 million during 2014 and 2015, and projected total losses to reach $500 million by the end of 2016.

Losses of that magnitude are not sustainable.In order to continue working towards long-term sustainability in the ACA-compliant individual market, BCBSTN had indicated earlier in 2016 that they were expecting to propose significant rate increases for 2017, although the expectation in early 2016 was that the proposed rate increases for 2017 would be comparable to the 36 percent average increase that the carrier implemented for 2016. Ultimately, BCBSTN requested a much higher average increase – 62 percent – for 2017, and regulators approved it in order to keep the insurer in the marketplace.Joe Sullivan of The Knoxville Mercury tracked down some 2016 data that adds perspective to the rate changes for 2017, particularly in the Memphis and Nashville metropolitan areas, where Humana, Cigna, and BCBS all offered plans in the exchange in 2016:BCBS had two networks, and offered 10 silver PPO plans in Nashville and in Memphis in 2016. The plans included out-of-network coverage. BCBST did not offer plans in either area in 2017.Humana had one silver PPO plan in Nashville and in Memphis.Cigna had three silver EPO plans in Nashville (no out-of-network coverage) and three silver PPO plans in Memphis.In Memphis, all three carriers offered silver PPO plans, and BCBS had the lowest prices (BCBST stopped offering coverage in Memphis in 2017).In Nashville, Cigna’s silver prices were lower than BCBS, but the Cigna plans were EPOs, without coverage for out-of-network care (BCBST stopped offering plans in Nashville in 2017).Grandmothered/Transitional health plansTennessee has allowed transitional (grandmothered) plans to remain in force, but the Tennessee Department of Commerce and Insurance confirmed in 2017 that they no longer had any grandmothered plans remaining in the individual market, as insurers had opted to end those plans and replace them with ACA-compliant plans instead.History of the Tennessee exchangeIn December 2012, then-Gov.

Bill Haslam announced Tennessee would not develop its own health insurance exchange, citing a lack of information from the federal government.Prior to his 2012 announcement, Haslam had leaned toward a state-run exchange. He believed local state control was preferable and that the state could run the exchange more cost-effectively that the federal government.However, Republican legislators opposed the exchange, Tea Party supporters staged repeated protests, and Tennessee eventually ended up with an exchange run by HHS.Tennessee health insurance exchange linksHealthCare.gov800-318-2596State Exchange Profile. TennesseeThe Henry J. Kaiser Family Foundation overview of Tennessee’s progress toward creating a state health insurance exchange.Louise Norris is an individual health insurance broker who has been writing about health insurance and health reform since 2006.

She has written dozens of opinions and educational pieces about the Affordable Care Act for healthinsurance.org. Her state health exchange updates are regularly cited by media who cover health reform and by other health insurance experts.Key takeawaysNearly 4.3 million people in Texas have Medicare plans, but that’s only a little more than 14 percent of the state’s population.Nearly 43% Texas Medicare beneficiaries had Medicare Advantage plans (or other private Medicare plans, including Medicare Cost plans) as of 2020. Medicare Advantage plan availability ranges from eight plans to 60 plans, depending on the county.In Texas, 70 insurers offer Medigap plans and more than 873,000 Texas residents are enrolled in Medigap plans. Medigap insurers in Texas are required to offer at least Medigap Plan A to disabled beneficiaries under the age of 65.Premiums for stand-alone Part D prescription plans in Texas range from about $7 to $155 per month for 2021 coverage.

1.65 million Texas Medicare beneficiaries have stand-alone Part D plans, plus 1.54 million with Part D integrated with Medicare Advantage.Per-enrollee Original Medicare spending in Texas is the second-highest in the nation (Louisiana is the only state where average per-beneficiary spending is higher).Extended enrollment opportunity for Texas residents affected by 2020 tropical stormsThe regular annual open enrollment period for 2021 Medicare Advantage and Part D plans ended on December 7. But Texas residents who live in counties affected by tropical storms Marco and Laura have additional time to enroll in a Part D or Advantage plan for 2021. This window in Texas continues until December 31, 2020 (four calendar months after the tropical storm disaster incident in Texas).This extended enrollment opportunity applies to people who live in the counties in eastern Texas where FEMA declared a disaster, as well as those who live elsewhere but rely on a friend or family member for assistance with the enrollment process, and that person lives in one of the affected counties. If you’re eligible for the enrollment period extension and you sign up for a Part D or Medicare Advantage plan by December 31, your new coverage will take effect January 1, the same as it would have if you’d enrolled by December 7.

Medicare enrollment in TexasThe number of Medicare beneficiaries in Texas stood at 4,292,236 as of October 2020. Only Florida and California have more residents enrolled in Medicare.CMS has extended Medicare open enrollment through December 31 in 54 Texas counties in response to the natural disasters in 2020.But only a little more than 14 percent of Texas residents are enrolled in Medicare, compared with almost 19 percent of the United States population enrolled in Medicare. Texas has among the youngest populations in the country, and since most people become eligible for Medicare enrollment when they turn 65, the state’s lower median age results in a smaller percentage of its residents filing for Medicare benefits.Although most people become eligible for Medicare coverage enrollment when they turn 65, Medicare also provides coverage for people under age 65. Those who have been receiving disability benefits for 24 months, have ALS, or have end-stage renal disease are eligible for Medicare.

Fifteen percent of all Medicare beneficiaries in Texas — and nationwide — are under the age of 65.Medicare health insurance optionsIn most areas of the country, Medicare beneficiaries can choose Original Medicare or a Medicare Advantage plan.Original Medicare is provided directly by the federal government and includes Medicare Parts A and B. Medicare Part A, also called hospital insurance, helps to pay for inpatient stays at a hospital, skilled nursing facility, or hospice center. Part B, also called medical insurance, helps pay for outpatient care like physician services, kidney dialysis, preventive care, durable medical equipment, etc.Medicare Advantage plans are administered by private insurance companies that have contracts with the federal government. Medicare Advantage plans include all of the benefits of Original Medicare (albeit with different cost-sharing, as the plans set their own deductibles, coinsurance, and copays, within the limits established by the federal government), and they typically have additional benefits, such coverage for prescription drugs, dental, and vision.

But provider networks are often limited with Medicare Advantage plans, and out-of-pocket costs are typically higher than a person would have if they opted for Original Medicare plus a Medigap plan. In short, there are pros and cons either way, and no one-size-fits-all solution. Medicare Advantage in TexasMedicare Advantage plans are available in all 254 counties in Texas in 2021, but plan availability ranges from as few as nine plans some of the state’s service areas to as many as 90 plans for sale in Harris County.A little more than a third of Texas Medicare beneficiares — just slightly more than the national average — were enrolled in private Medicare plans in 2018. These were mostly Medicare Advantage plans, but some residents in Texas have Medicare Cost plans, which are another form of private coverage.

By late 2020, however, the share of Texas Medicare beneficiaries enrolled in private plans had grown to more than 43 percent. The other 57 percent of Medicare beneficiaries in Texas were enrolled in Original Medicare instead.Medicare beneficiaries can switch between Medicare Advantage enrollment and Original Medicare (and can add or drop a Medicare Part D prescription plan) during the Medicare annual election period, which runs from October 15 to December 7 each year. Medicare Advantage enrollees also have the option to switch to a different Advantage plan or to Original Medicare during the Medicare Advantage open enrollment period, which runs from January 1 to March 31.Medigap in TexasMore than half of Original Medicare beneficiaries have supplemental coverage provided by an employer-sponsored plan or Medicaid. But for those who don’t, Medigap plans (also known as Medicare supplement plans) are designed to pay some or all of the out-of-pocket costs (deductibles and coinsurance) that enrollees would otherwise have to pay themselves.

Since Original Medicare does not include a cap on out-of-pocket costs, most enrollees maintain some form of supplemental coverage, and Medigap plans are one way to do this.According to an AHIP analysis, there were 873,514 Texas Medicare beneficiaries with Medigap coverage as of 2018.There are 70 insurers licensed to sell Medigap plans in Texas.Although Medigap plans are sold by private insurers, the plans are standardized under federal rules. There are ten different plan designs (differentiated by letters, A through N), and the benefits offered by a particular plan (Plan A, Plan F, etc.) are the same from one insurer to another.Unlike other private Medicare coverage (Medicare Advantage and Medicare Part D plans), there is no annual open enrollment window for Medigap plans. Instead, federal rules provide a one-time six-month window when Medigap coverage is guaranteed-issue. This window starts when a person is at least 65 and enrolled in Medicare Part B (you have to be enrolled in both Part A and Part B to buy a Medigap plan).Although disabled Americans under the age of 65 are eligible for Medicare, federal rules do not guarantee access to Medigap plans for people who are under 65.

But the majority of the states — including Texas — have implemented rules to ensure that disabled Medicare beneficiaries have at least some access to Medigap plans. Texas law requires Medigap insurers to offer at least Medigap Plan A to disabled enrollees under age 65, during the six-month period that begins when they’re enrolled in Medicare Part B. Medigap Plan A is the least comprehensive of the Medigap plans, but it will cover the 20 percent Part B coinsurance that the enrollee would othewise have to pay out-of-pocket.Disabled Medicare beneficiaries under the age of 65 have another six-month Medigap open enrollment period when they turn 65. At that point, they have access to any of the available Medigap plans, at the standard premiums that apply to people who are enrolling in Medicare due to turning 65 (premiums are generally significantly higher for Medicare beneficiaries under age 65, since their disabilities result in more costly medical care).Medicare Advantage plans are available to anyone eligible for Medicare, except people with end-stage renal disease (starting in 2021, this limitation will no longer apply.

People with ESRD will be able to enroll in Medicare Advantage plans). So unless they have ESRD, Texas Medicare beneficiaries under the age of 65 can choose a Medicare Advantage plan instead of Medigap Plan A. Medicare Advantage plans do have a cap on out-of-pocket costs, but they also tend to have limited provider networks, which is an important consideration for people with serious health issues.Although the Affordable Care Act eliminated pre-existing condition exclusions in most of the private health insurance market, those regulations don’t apply to Medigap plans. Medigap insurers can impose a pre-existing condition waiting period of up to six months, if you didn’t have at least six months of continuous coverage prior to your enrollment.

And if you apply for a Medigap plan after your initial enrollment window closes (assuming you aren’t eligible for one of the limited guaranteed-issue rights), the insurer can look back at your medical history in determining whether to accept your application, and at what premium. Texas Medicare Part DOriginal Medicare does not cover the cost of outpatient prescription drugs. As noted above, more than half of Original Medicare beneficiaries have supplemental coverage via an employer-sponsored plan (from a current or former employer or spouse’s employer) or Medicaid, and these plans often include prescription coverage. But Medicare beneficiaries who don’t have drug coverage through Medicaid or an employer-sponsored plan need to obtain Medicare Part D prescription coverage (prior to 2006, some Medigap plans included prescription coverage.

People who still have those plans can keep them, but they have not been for sale since the end of 2005).Part D coverage can be purchased as a stand-alone plan, or as part of a Medicare Advantage plan that includes Part D prescription drug coverage.In Texas, there are 35 stand-alone Medicare Part D plans for sale for 2021, with premiums that range from about $7 to $155/month.As of late 2020, there were 1.65 million Medicare beneficiaries in Texas with stand-alone Medicare Part D plans. An additional 1.54 million Texas residents had Medicare Part D coverage integrated with their Medicare Advantage plans.Medicare Part D enrollment follows the same schedule as Medicare Advantage. Beneficiaries can enroll in Medicare Part D plans when they’re first eligible for Medicare, and there’s also an annual enrollment window (October 15 to December 7) when people can enroll or switch to a different plan. Medicare spending in TexasIn 2018, Original Medicare’s per-beneficiary spending in Texas averaged $11,627, which was 15 percent higher than the $10,096 national average.

Texas had the second-highest average per-beneficiary costs in the country. Only Louisiana had higher average costs. That’s based on data that were standardized to eliminate regional differences in payment rates, but it did not include costs for Medicare Advantage.How does Medicaid provide financial assistance to Medicare beneficiaries in Texas?. Many Medicare beneficiaries receive financial assistance through Medicaid with the cost of Medicare premiums and services Medicare doesn’t cover – such as long-term care.Our guide to financial assistance for Medicare enrollees in Texas includes overviews of these benefits, including Medicare Savings Programs, long-term care coverage, and eligibility guidelines for assistance.Helpful resources for Texas Medicare beneficiaries and their caregiversNeed help with your Medicare application in Texas, or have questions about Medicare eligibility in Texas?.

These resources provide free assistance and information.The Health Information, Counseling, and Advocacy Program (HICAP), with any questions related to Medicare coverage in Texas. Visit the website or call 1-800-252-9240.The Texas Department of Insurance has a resources page for Texas residents with Medicare coverage.Louise Norris is an individual health insurance broker who has been writing about health insurance and health reform since 2006. She has written dozens of opinions and educational pieces about the Affordable Care Act for healthinsurance.org. Her state health exchange updates are regularly cited by media who cover health reform and by other health insurance experts..

Highlights and updates Tennessee exchange overviewTennessee is look these up among the states that have done the least to preserve the Affordable Care Act’s gains.Tennessee what do you need to buy seroquel has a federally run exchange, so enrollees use HealthCare.gov to sign up for exchange plans. During the first five weeks of open enrollment for 2021 coverage (through December 5, 2020), 87,930 people had made plan selections through the Tennessee marketplace. At that point, there were what do you need to buy seroquel still 10 days remaining in the open enrollment period.

Enrollment always increases towards the end of the enrollment window, and HealthCare.gov will process auto-renewals after December 15, for people with existing coverage who don’t return to the exchange to pick a new plan or manually renew their coverage for 2021.Last year, total enrollment during the open enrollment period for 202 coverage (including auto-renewals) reached 200,445 people. That was down from 221,553 people what do you need to buy seroquel who had enrolled the year before, for 2019 coverage.Tennessee continues to refuse federal funding to expand its Medicaid program to cover low-income adults in the state (13 other states have also refused to expand their Medicaid programs, although some of them will expand coverage, either fully or partially, by mid-2021). As a result, there are an estimated 117,000 people in the coverage gap in Tennessee — ineligible for Medicaid, but also ineligible for premium subsidies in the exchange because their income is too low.Insurer participation in Tennessee’s exchange has been fairly volatile over the years, but there are six insurers offering plans for 2021, up from five in 2020 (UnitedHealthcare joined the exchange for 2021, after previously only offering coverage in 2016.

United’s plans are available in much of what do you need to buy seroquel the central and western parts of the state for 2021). Although their coverage areas don’t all overlap, most Tennessee residents have a choice of insurers for 2021, as much of the state has at least three participating exchange insurers.Family and Children’s Service is the Tennessee Navigator organization, and brokers certified with the exchange can be found here.How are insurance premiums in Tennessee changing for 2021?. Insurers had to submit rate what do you need to buy seroquel filings in Tennessee by July 15, 2020.

Some of the rates were approved as-filed, but the Tennessee Department of Commerce and Insurance worked with some of the insurers to reduce their proposed rates for 2021, with revised rate filings submitted by some insurers in August. By the time the rate review process was complete, the following average rate changes were approved for 2021 for the state’s individual market insurers:Blue Cross Blue Shield of Tennessee. Average premium increase of 9.8 percent (BCBSTN had what do you need to buy seroquel initially proposed an average rate increase of 12.9 percent).

BCBSTN’s filing cover letter notes that they have about 93,000 members, although another area of the filing indicates 97,222 members. SERFF filing what do you need to buy seroquel number. BCTN-132455585Cigna.

Average premium decrease of 6.1 percent (Cigna’s filing what do you need to buy seroquel notes that they expect the antidepressant drugs seroquel to increase their costs by about 1 percent in 2021, so the rate increase would be more significant without antidepressant drugs as a factor). Cigna has 64,230 members. SERFF filing number what do you need to buy seroquel.

CCGH-132359549Oscar. Average premium increase of 9.9 percent (Oscar had initially proposed an average rate increase of 12.4 percent). Oscar has what do you need to buy seroquel 7,704 members.

SERFF filing number. OHIN-132442088Bright. Average premium increase of 3 percent (Bright’s filing notes that the average rate increase would have been larger — at about 4.2 percent — without the antidepressant drugs seroquel.

Other insurers in other states have also predicted reduced overall costs in 2021 due to antidepressant drugs’s reduction in non-emergency medical services) Bright has 26,746 members. SERFF filing number. BRHP-132308159Celtic/Ambetter.

Average premium decrease of 2.5 percent (Celtic had initially proposed an average premium decrease of 0.3 percent, but the approved decrease ended up being more substantial). Celtic has 10,716 members, and has expanded into the Jackson and Tri-City areas for 2021. SERFF filing number.

CELT-132409373UnitedHealthcare. New to the market for 2021, so no applicable rate change (UHC previously offered coverage in the Tennessee exchange in 2016. The insurer is also rejoining the exchange in Maryland for 2021).

UnitedHealthcare plans to offer coverage in all counties in rating areas 3, 4, 5, 6, and 8 (Figure 13 on this page shows the rating areas in map format. UHC’s plans will be available in southern/central and western Tennessee). UHC’s filing does not include a specific rate adjustment for antidepressant drugs factors, but notes that they may revise this as the summer continues and more data become available.

SERFF filing number. UHLC-132400597In Tennessee, each insurer filed a separate form to detail the anticipated impact of antidepressant drugs on 2021 claims costs. Where they had data and projections available, insurers broke it down into cost changes (either an increase or a decrease) associated with pent-up demand for elective services that were postponed this year, the cost of a antidepressant drugs treatment, the cost of treating members who are diagnosed with antidepressant drugs, and the cost changes associated with the transition of people from the employer-sponsored market to the individual market (ie, there are expected to be more people purchasing coverage in the individual market for 2021, due to job losses amid the antidepressant drugs seroquel).

Premiums in the Tennessee exchange started out as some of the lowest in the country in 2014, but increased rapidly in the subsequent years. As of 2020, the average full-price premium in Tennessee’s exchange is $641/month. That’s higher than the $595/month average across the 38 states that use HealthCare.gov.

But 86 percent of Tennessee’s exchange enrollees are receiving premium subsidies in 2020, and their after-subsidy premiums average $145/month — which is exactly the same as the after-subsidy average premium across those 38 states. Here’s a summary of how full-price rates have changed in Tennessee’s exchange over the years (keeping in mind that premium subsidies are designed to keep pace with full-price premiums, so they have grown over time as well):2014. In 2014 Tennessee had among the lowest overall average rates in the country for individual market health plans.

That was the first year that ACA-compliant plans were available, and rates were essentially educated actuarial guesses, since there was no claims experience on which to base them.2015. Average rate increase of 12.5 percent (another analysis indicated a 9 percent increase for a 40-year-old non-smoker). This included an average rate increase of 19 percent for BCBSTN, 7.5 percent for Cigna, and 14.4 percent for Humana.

Tennessee was one of just eight states in a PricewaterhouseCooper analysis with double-digit average rate increases for 2015. But because Tennessee had rates so much lower than the national average in 2014, their rates were still much lower than most states in 2015, even after the rate hikes. A Kaiser Family Foundation analysis of benchmark plan (second-lowest-cost silver plan) premium changes in major metropolitan areas in all 50 states found that the Nashville area still has the fifth-lowest average benchmark premium in the country in 2015, even after an increase of nearly 8 percent.2016.

Average increase of 28.2 percent. Average premium increases ranged from just 0.4 percent for Cigna to more than 36 percent for Blue Cross Blue Shield of Tennessee (BCBSTN had 70 percent of the market share). The overall increase was substantial, but it essentially just brought Tennessee’s lower-than-average rates more in line with rates in the rest of the country.

Community Health Alliance had initially proposed a rate increase of nearly 45 percent, but the CO-OP ended up shutting down at the end of 2015, so that rate increase was not applicable.2017. Average rate increase of 56 percent. The average rate increases ranged from 44.3 percent for Humana, to 62 percent for BCBSTN.Tennessee’s individual market rate increase was roughly tied with Minnesota’s for 2017, and both states trailed only Oklahoma, which had the highest weighted average increase for 2017.Cigna and Humana had originally filed average rate increases of 23 percent and 29 percent, respectively.

But in early August 2016, regulators in Tennessee agreed to allow the carriers to refile new rates, after both carriers had told the state that the rates they had originally filed wouldn’t be adequate to cover claims costs. Several carriers across the country made headlines in August and September with announcements that they would exit the exchanges at the end of 2016, but UnitedHealthcare was the only insurer to exit the Tennessee exchange altogether. The fact that regulators in Tennessee allowed new rates to be filed helped to keep the carriers in the market, but it also resulted in more significant premium hikes for 2017.

Carriers had asked to refile rates for 2016 during the summer of 2015, but state regulators would not allow them to do so. For 2017, regulators softened their stance in an effort to keep Cigna and Humana in the marketplace.2018. Average rate increase of 28.5 percent.

BCBSTN increased average premiums by 21.4 percent. Cigna increased average premiums by 36.5 percent. Silver plans became disproportionately expensive in 2018 in Tennessee (driving a significant chunk of the overall rate increase), as the Trump administration eliminated funding for cost-sharing reductions (CSRs).

Although the official notice of the funding cut didn’t come until mid-October, TDCI confirmed in September that the additional premiums necessary to cover CSR in 2018 had already been added to silver plan rates for 2018 (pre-emptively, but presciently, since the funding was cut off by the federal government a few weeks later). The higher premiums for silver plans resulted in even larger premium subsidies for 2018. So although the federal government is no longer directly reimbursing insurers for the cost of CSR, they are indirectly continuing to fund CSR, via larger premium subsidies.TDCI published a document showing average premiums for 35-year-olds and 55-year-olds in each rating area of the state, but most enrollees pay far lower premiums, as their premiums subsidies cover a large portion of the premiums.Blue Cross Blue Shield of Tennessee issued a press release in June 2017, going into great detail about their proposed rate increase for 2018.

Their actuarial memo in their rate filing indicated that their average proposed rate increase was 21.4 percent, but that the majority of that was due to concerns that the Trump Administration wouldn’t continue to enforce the individual mandate, and the uncertainty surrounding ongoing funding for cost-sharing reductions (CSR).The press release from Blue Cross Blue Shield of Tennessee noted that of the 21.4 percent rate increase they proposed (which was later approved by TDCI), 14 percentage points were due to the possible lack of funding for cost-sharing subsidies, and 7 percentage points were due to concerns that the individual mandate wouldn’t be well enforced, resulting in a sicker risk pool (healthy people are the ones likely to drop coverage if the mandate isn’t enforced. Sick people will maintain their coverage regardless). So the rate increase for 2018 would apparently have been just 0.4 percent if it weren’t for the Trump administration’s refusal to commit to funding cost-sharing reductions and enforcing the individual mandate.

Instead, BCBSTN proposed an average rate increase of 21.4 percent, and state regulators had no choice but to approve it.Cigna noted that 14.1 percentage points of their rate increase was due to the fact that the Trump Administration had not committed to funding cost-sharing subsidies.2019. Average rate decrease of 12.4 percent. But the average benchmark plan premium decreased by 26 percent in 2019, which was the largest percentage decrease in the nation.

The average, across all states, was a 1.5 percent decrease. Premium subsidies are based on the cost of the benchmark plan, so subsidies decreased by a larger margin than average premiums.In August 2018, the Tennessee Insurance Department announced approved 2019 rate changes, including rate decreases for Blue Cross Blue Shield and Cigna, which had the bulk of the state’s individual market enrollees:Blue Cross Blue Shield of Tennessee. Average premium decrease of 14.9 percent (113,000 membes)Cigna.

Average premium decrease of 12.8 percent (75,568 members)Oscar. Average increase of 7.2 percent to 10.84 percent (14,107 members)Bright. New to the marketCeltic.

New to the market 2020. Average rate decrease of about 1.1 percent. But benchmark premiums dropped by 7 percent, leading to some people paying higher after-subsidy premiums for their coverage in 2020.

In 2019, when Bright and Celtic joined the marketplace in Tennessee and Cigna and Oscar expanded their coverage areas, benchmark premiums decreased much more significantly than overall average premiums, resulting in smaller premium subsidies. So 2020 was the second year in a row that subsidy amounts dropped by more than the average premium amounts in Tennessee’s exchange (which could partially explain the decrease in enrollment since 2018. Plans become less affordable when subsidies decrease by more than average premiums).Tennessee’s exchange insurers implemented the following average rate changes for 2020:Blue Cross Blue Shield of Tennessee.

Average premium increase of 1.4 percentCigna. Average premium decrease of 5.7 percentOscar. Average premium decrease of 8.3 percentBright.

Average premium increase of 2.93 percentCeltic. Average premium decrease of 1.6 percent Enrollment in Tennessee’s exchange. 2014 through 2020As has been the case in the majority of states that use HealthCare.gov, enrollment in Tennessee’s exchange peaked in 2016, and has declined each year since then.2014.

The first open enrollment period, for 2014 coverage, was six months long and had an additional extension tacked onto the end. By April 19, 2014, total enrollment in the Tennessee exchange stood at 151,352 people.2015. Enrollment grew significantly the next year, with 231,440 people enrolling through the exchange during the open enrollment period for 2015 coverage.2016.

Enrollment peaked in the third year, with 268,867 people enrolling through the exchange in Tennessee.2017. President Trump took office just days before the end of the open enrollment period for 2017 coverage, and immediately cut HealthCare.gov’s marketing campaign. 2017 rates were also sharply higher for people who didn’t qualify for premium subsidies.

So it wasn’t surprising that enrollment dropped to 234,125 people.2018. The Trump Administration reduced the marketing and outreach budget for HealthCare.gov, rates again increased sharply for people who didn’t qualify for premium subsidies (due mostly to uncertainty over the future of the individual mandate and the Trump Administration’s decision to cut off funding for cost-sharing reductions), and open enrollment was only half as long as it had been the year before (Nov 1 to Dec 15, which is the schedule that’s currently being used). So again, it wasn’t surprising that enrollment decreased, with 228,646 people buying plans during open enrollment.2019.

Although rates decreased for 2019, they’re still quite high for people who don’t qualify for premium subsidies. The GOP tax bill ended the individual mandate penalty at the end of 2018, and the Trump Administration has made it easier for people to opt for coverage under short-term health plans instead of ACA-compliant plans. So enrollment dropped again during the open enrollment period for 2019 coverage, with 221,553 people buying plans.2020.

Enrollment stood at 200,445 at the end of the open enrollment period for 2020 coverage. As noted above, benchmark premiums decreased more significantly than overall average premiums in Tennessee’s exchange, making after-subsidy premiums less affordable for many enrollees.Which insurers offer coverage in Tennessee's exchange?. There are six insurers offering coverage in Tennessee’s exchange in 2021, up from just three in 2018.

Here’s a summary of how insurer participation in the state’s exchange has changed over the years.2014. When the exchanges launched for 2014, plans were available in Tennessee’s exchange from Blue Cross Blue Shield of Tennessee, Community Health Alliance (an ACA-created CO-OP), Cigna, and Humana, although only BCBSTN offered plans statewide.2015. Time/Assurant joined the Tennessee exchange statewide in 2015, bringing the total number of participating insurers to five.2016.

Four insurers offered plans. BCBSTN, Cigna, Humana, and UnitedHealthcare. UnitedHealthcare was new to the exchange for 2016, and according to Kaiser Family Foundation’s analysis, UnitedHeathcare offered at least one of the two lowest-priced silver plans in the exchange in 73 of Tennessee’s 95 counties in 2016.

But Assurant and Community Health Alliance both stopped selling plans at the end of 2015. The CO-OP’s demise was due in part to the severe shortfall in federal risk corridor funding, although the CO-OP had stopped selling 2015 plans as of January 15, 2015, noting that they had already met their enrollment goal for the year. Community Health Alliance had planned to begin selling plans again during the 2016 open enrollment, but instead they ceased operations altogether at the end of 2015, leaving 27,000 enrollees who needed to select new coverage for 2016 from a different carrier.2017.

Plans were available from Humana, Cigna, and BCBSTN. Like Assurant’s brief stint in the exchange, UnitedHealthcare’s participation was also short-lived, as they exited the entire individual market in Tennessee at the end of 2016. The Department of Commerce and Insurance confirmed that the exit applied to both the exchange (UnitedHealthcare Insurance Company) and off-exchange (UnitedHealthcare Life Insurance Company).

The state reported that 40,879 people needed http://www.ec-cath-still.ac-strasbourg.fr/SITE/?dt_gallery=spectacle-de-noel-2014 to secure new coverage for 2017 as a result of United’s exit (the large majority of these enrollees had their United coverage through the exchange). 2017 was also the first year that BCBSTN opted not to offer statewide coverage. As of 2017, BCBSTN stopped offering coverage in the metro areas of Knoxville, Nashville, and Memphis, which are the three largest metropolitan areas in the state.Blue Cross Blue Shield of Tennessee had the lion’s share of the Tennessee exchange market in 2016, covering almost 69 percent of the enrollees.

Because of BCBST’s exit from the three metropolitan areas, approximately 52,000 people in Nashville, 31,000 people in Knoxville, and 29,000 in Memphis had to switch to a different plan for 2017. So although there were three insurers offering plans in Tennessee’s exchange for 2017, residents in 73 of the state’s 95 counties had only one carrier option in the exchange. Cigna offered coverage in the Memphis and Nashville areas.

Humana offered coverage in the Memphis, Nashville, and Knoxville areas, and BCBSTN offered coverage in the rest of the state.2018. There was quite a bit of upheaval in the Tennessee exchange for 2018, in terms of insurer participation. Humana stopped offering individual market coverage in any states at the end of 2017.

Humana’s exit meant that residents in the Knoxville area were facing the possibility of having no exchange insurers at all in 2018. Humana insured about 40,000 people in the Knoxville area, and about 79,000 people across all three metropolitan areas in the state. State regulators scrambled to reach a solution, and succeeded.

In May 2017, Blue Cross Blue Shield of Tennessee agreed to once again offer coverage in 2018 in the Knoxville area in order to ensure that all areas of the state would have insurance plans available in the exchange.While it initially appeared that there would only be two insurers in the Tennessee exchange for 2019, Oscar Health’s entry to the market meant that three insurers offered plans:Cigna’s plans were available in a total of 22 counties in Memphis, Nashville, and the Tri-City area (the eight eastern-most counties in the state), just as they were in 2017.BCBS of Tennessee had plans available everywhere except Memphis and Nashville. They continued to offer coverage in the non-metro areas of the state where they offered plans in 2017, and expanded back into the Knoxville area.Oscar Health has plans available in nine counties in the Nashville area.Nashville and the Tri-City areas were the only parts of the state where enrollees had a choice between two insurers, with both BCBSTN and Cigna offering plans in the Tri-City area, and Oscar and Cigna offering plans in the Nashville area.Tennessee Insurance Commissioner, Julie Mix McPeak, expressed satisfaction that all areas of the state would have at least one insurer offering coverage in the exchange in 2018, but she reiterated how the uncertainty caused by the Trump Administration and Congress was damaging the individual health insurance market, noting that “the uncertainty about the future of the exchange, cost-sharing reduction payments, and enforcement of the individual mandate will likely increase carrier rate requests by 15 to 20 percent above what they would have otherwise filed. I share consumers’ frustrations about federal uncertainty and how that is impacting their ability to afford insurance.”2019.

Bright Health joined the Tennessee exchange for 2019, offering coverage in 16 counties in the Knoxville area, nine counties in the Nashville area, and five counties in the Memphis area.Celtic (Centene) also joined the Tennessee exchange for 2019, with plans available in Memphis and Chattanooga. Much of the state had multiple carrier options for 2019 coverage:Nashville. Oscar, Cigna, BrightKnoxville.

BCBSTN, Bright, and CignaMemphis. Bright, Oscar, Cigna, and CelticTri-City area. BCBSTN and CignaChattanooga area.

Celtic and BCBSTN2020. Tennessee continues to have five exchange insurers in 2020, but three have larger coverage areas. Blue Cross Blue Shield of Tennessee came back to the Memphis and Nashville areas for 2020.

Celtic expanded into the Nashville and Knoxville areas, and Cigna expanded into the Chattanooga and Jackson areas.2021. UnitedHealthcare rejoined the exchange in Tennessee for 2021, after leaving at the end of 2016. That brings the state to six insurers.

UnitedHealthcare’s plans are available in all counties in rating areas 3, 4, 5, 6, and 8 (southern/central and western Tennessee). Tennessee Insurance Commissioner’s reform proposalsJulie Mix McPeak was the Insurance Commissioner for Tennessee from 2011 through mid-2019, and also served as the President of the National Association of Insurance Commissioners. In February 2017, Mix McPeak spoke before the Senate Committee on Health, Education, Labor, &.

Pensions, presenting her recommendations for health care reform. Among her proposals were:Allowing states to define essential health benefits, rather than requiring all plans sold in every state to conform to the ACA’s essential health benefits (this has been part of most of the GOP proposals to repeal or change the ACA, although it has not been implemented. As of 2019, essential health benefits are still defined at the federal level).Relaxing the age band ratio from the 3:1 level set by the ACA, to a 5:1 or 6:1 cap.

The ACA limits premiums for older enrollees to no more than three times those of younger enrollees. Mix McPeak suggested that insurers should be able to charge older enrollees five or six times as much as younger enrollees, in an effort to reduce premiums for younger enrollees and incentivize them to enroll (this is another provision that was included in most of the GOP efforts to repeal or change the ACA in 2017, but none of those efforts were successful. It’s worth noting that adjusting the age rating bands would result in lower premiums for younger people, but markedly higher premiums for older people.

For those who receive premium subsidies, the subsidies would grow to offset the increase. But for those who don’t get subsidies, coverage could become unaffordable).Tighter restrictions and increased verification of eligibility for special enrollment periods (HHS finalized a market stabilization rule in April 2017 that included increased eligibility verification, and restrictions such as limiting enrollees’ ability to use a special enrollment period to switch to a plan at a different metal level).Reducing the current 90-day grace period for people with premium subsidies down to a 30-day grace period (the market stabilization rule kept the 90-day grace period, but allows insurers to apply new enrollment premiums to past-due balances from the previous 12 months if the person seeks to re-enroll after losing coverage for non-payment of premium).Senator Alexander. 2017 legislation to protect bare counties, and a plea for CSR fundingIn 2017, the U.S.

Senators from Tennessee, Lamar Alexander and Bob Corker, both Republicans, introduced legislation (S.761, the Health Care Options Act of 2017) that would allow people in counties without any participating exchange insurers to use ACA subsidies for off-exchange plans. That scenario has never come to pass, but there were concerns at that point that some areas of the country, including the Knoxville, Tennessee area, might not have had any ACA-compliant plans available.Senator Alexander also, notably, stated in early 2017 that Congress or the Trump administration should commit to funding cost-sharing reductions (CSRs) through 2019, in an effort to stabilize the individual health insurance market. CSRs lower out-of-pocket costs for low-income exchange enrollees who pick silver plans, and 57 percent of Tennessee exchange enrollees have plans that include CSRs in 2017.CSR funding was ultimately eliminated by the Trump administration in October 2017, but the uncertainty (during the rate filing season of spring/summer 2017) around whether or not the funding would continue resulted in premium proposals for 2018 that were higher than they would otherwise have been.

Without a federal commitment to fund CSR, Tennessee Insurance Commissioner, Julie Mix McPeak estimated that premiums in Tennessee would be 15 to 20 percent higher than they would otherwise have been in 2018.Senator Alexander joined forces with Senator Patty Murray (D, Washington) in an effort to pass bipartisan legislation aimed at stabilizing the individual insurance markets nationwide, with a proposal that included CSR funding. However, Republican leadership in the Senate opted to push forward on their efforts to repeal the ACA (via the Graham-Cassidy legislation) and pulled the plug on Alexander and Murray’s bipartisan approach in September 2017.In the announcement about the approved rates for 2018, Mix McPeak said “I’m disappointed by yesterday’s announcement out of Washington [about Alexander and Murray’s bipartisan approach being abandoned by Senate leadership]. While Tennessee is supportive of long-term strategies such as the Graham-Cassidy Amendment introduced in Congress, I appreciate the diligent efforts of Senators Lamar Alexander and Patty Murray to find common ground in providing more immediate stabilization in the marketplace.

Instead, it appears more likely that Tennesseans must prepare themselves for a round of actuarially justified rates for 2018 that are far higher than could be necessary as a result of uncertainty in Washington.” Farm Bureau plans aren’t compliance with the ACA, but they’re still allowed to be sold in TennesseeAs of 2017, there were about 73,000 people in Tennessee who were covered under Farm Bureau plans that aren’t ACA-compliant. About 50,000 of those were grandfathered plans, but the rest are medically underwritten “traditional” plans that are still available for purchase. Medical underwriting means that the insurer uses the applicant’s medical history to determine whether to offer coverage and at what price.

That practice is no longer allowed under the ACA – on or off-exchange – for any plans that are considered individual major medical health insurance.But in Tennessee, the state doesn’t consider Farm Bureau to be a licensed health insurer. That’s been the case for more than two decades – Farm Bureau plans operate outside of the regulatory structure imposed by the state (and the ACA) on health insurers. As a result, Farm Bureau’s “traditional” plans, which are less expensive than regular health insurance but only available to healthy people, are being sold to healthy people in Tennessee, effectively removing them from the ACA-compliant risk pool.People who enroll in Farm Bureau’s “traditional” plans are not in compliance with the ACA’s individual mandate, so from 2014 through 2018, they were assessed a penalty for being uninsured unless they were exempt from the individual mandate (this is the same as the rule that required people with short-term health insurance to pay the individual mandate penalty.

Just like the Tennessee Farm Bureau “traditional” plans, short-term health insurance is not regulated by the ACA). But the individual mandate penalty no longer applies in 2019 and future years, so there is no longer a penalty for relying on a Farm Bureau plan.Farm Bureau’s plans are not as robust as regular health insurance, and aren’t helpful for people with pre-existing conditions. But the fact that Tennessee has allowed them to continue to be sold outside the scope of the state’s insurance regulations could be part of the reason the state has a risk pool in the ACA-compliant market that’s sicker than most states.Iowa has decided to follow Tennessee’s lead, enacting legislation in 2018 that allows Farm Bureau to partner with Wellmark to offer non-ACA-compliant plans in Iowa.BCBSTN losses pre-2017 and rate hike request – some backgroundDuring open enrollment for 2016 coverage, 166,425 exchange enrollees (62 percent of the total) signed up with Blue Cross Blue Shield of Tennessee for 2016.

This was an increase of 16 percent over BCBSTN’s exchange enrollment in 2015, despite the fact that the carrier raised its premiums by an average of 36 percent for 2016. The remaining 38 percent of the exchange enrollees selected plans from Humana, Cigna, and United Healthcare.Blue Cross Blue Shield of Tennessee had the lowest priced plans in the Tennessee exchange — and the nation — in 2014. Although BCBSTN’s average rate increase was 19 percent for 2015 and 36 percent for 2016 (and their competitors had significantly smaller rate hikes), they still had among the lowest premiums in many areas of Tennessee in 2016.

In the Memphis area, a search on Healthcare.gov indicated that the five least expensive bronze plans and the four least expensive silver plans were all offered by BCBSTN in 2016. Their lower premiums and brand-name recognition likely played a role in their outsized market share. But because enrollees have been sicker than expected, the carrier lost $300 million during 2014 and 2015, and projected total losses to reach $500 million by the end of 2016.

Losses of that magnitude are not sustainable.In order to continue working towards long-term sustainability in the ACA-compliant individual market, BCBSTN had indicated earlier in 2016 that they were expecting to propose significant rate increases for 2017, although the expectation in early 2016 was that the proposed rate increases for 2017 would be comparable to the 36 percent average increase that the carrier implemented for 2016. Ultimately, BCBSTN requested a much higher average increase – 62 percent – for 2017, and regulators approved it in order to keep the insurer in the marketplace.Joe Sullivan of The Knoxville Mercury tracked down some 2016 data that adds perspective to the rate changes for 2017, particularly in the Memphis and Nashville metropolitan areas, where Humana, Cigna, and BCBS all offered plans in the exchange in 2016:BCBS had two networks, and offered 10 silver PPO plans in Nashville and in Memphis in 2016. The plans included out-of-network coverage.

BCBST did not offer plans in either area in 2017.Humana had one silver PPO plan in Nashville and in Memphis.Cigna had three silver EPO plans in Nashville (no out-of-network coverage) and three silver PPO plans in Memphis.In Memphis, all three carriers offered silver PPO plans, and BCBS had the lowest prices (BCBST stopped offering coverage in Memphis in 2017).In Nashville, Cigna’s silver prices were lower than BCBS, but the Cigna plans were EPOs, without coverage for out-of-network care (BCBST stopped offering plans in Nashville in 2017).Grandmothered/Transitional health plansTennessee has allowed transitional (grandmothered) plans to remain in force, but the Tennessee Department of Commerce and Insurance confirmed in 2017 that they no longer had any grandmothered plans remaining in the individual market, as insurers had opted to end those plans and replace them with ACA-compliant plans instead.History of the Tennessee exchangeIn December 2012, then-Gov. Bill Haslam announced Tennessee would not develop its own health insurance exchange, citing a lack of information from the federal government.Prior to his 2012 announcement, Haslam had leaned toward a state-run exchange. He believed local state control was preferable and that the state could run the exchange more cost-effectively that the federal government.However, Republican legislators opposed the exchange, Tea Party supporters staged repeated protests, and Tennessee eventually ended up with an exchange run by HHS.Tennessee health insurance exchange linksHealthCare.gov800-318-2596State Exchange Profile.

TennesseeThe Henry J. Kaiser Family Foundation overview of Tennessee’s progress toward creating a state health insurance exchange.Louise Norris is an individual health insurance broker who has been writing about health insurance and health reform since 2006. She has written dozens of opinions and educational pieces about the Affordable Care Act for healthinsurance.org.

Her state health exchange updates are regularly cited by media who cover health reform and by other health insurance experts.Key takeawaysNearly 4.3 million people in Texas have Medicare plans, but that’s only a little more than 14 percent of the state’s population.Nearly 43% Texas Medicare beneficiaries had Medicare Advantage plans (or other private Medicare plans, including Medicare Cost plans) as of 2020. Medicare Advantage plan availability ranges from eight plans to 60 plans, depending on the county.In Texas, 70 insurers offer Medigap plans and more than 873,000 Texas residents are enrolled in Medigap plans. Medigap insurers in Texas are required to offer at least Medigap Plan A to disabled beneficiaries under the age of 65.Premiums for stand-alone Part D prescription plans in Texas range from about $7 to $155 per month for 2021 coverage.

1.65 million Texas Medicare beneficiaries have stand-alone Part D plans, plus 1.54 million with Part D integrated with Medicare Advantage.Per-enrollee Original Medicare spending in Texas is the second-highest in the nation (Louisiana is the only state where average per-beneficiary spending is higher).Extended enrollment opportunity for Texas residents affected by 2020 tropical stormsThe regular annual open enrollment period for 2021 Medicare Advantage and Part D plans ended on December 7. But Texas residents who live in counties affected by tropical storms Marco and Laura have additional time to enroll in a Part D or Advantage plan for 2021. This window in Texas continues until December 31, 2020 (four calendar months after the tropical storm disaster incident in Texas).This extended enrollment opportunity applies to people who live in the counties in eastern Texas where FEMA declared a disaster, as well as those who live elsewhere but rely on a friend or family member for assistance with the enrollment process, and that person lives in one of the affected counties.

If you’re eligible for the enrollment period extension and you sign up for a Part D or Medicare Advantage plan by December 31, your new coverage will take effect January 1, the same as it would have if you’d enrolled by December 7. Medicare enrollment in TexasThe number of Medicare beneficiaries in Texas stood at 4,292,236 as of October 2020. Only Florida and California have more residents enrolled in Medicare.CMS has extended Medicare open enrollment through December 31 in 54 Texas counties in response to the natural disasters in 2020.But only a little more than 14 percent of Texas residents are enrolled in Medicare, compared with almost 19 percent of the United States population enrolled in Medicare.

Texas has among the youngest populations in the country, and since most people become eligible for Medicare enrollment when they turn 65, the state’s lower median age results in a smaller percentage of its residents filing for Medicare benefits.Although most people become eligible for Medicare coverage enrollment when they turn 65, Medicare also provides coverage for people under age 65. Those who have been receiving disability benefits for 24 months, have ALS, or have end-stage renal disease are eligible for Medicare. Fifteen percent of all Medicare beneficiaries in Texas — and nationwide — are under the age of 65.Medicare health insurance optionsIn most areas of the country, Medicare beneficiaries can choose Original Medicare or a Medicare Advantage plan.Original Medicare is provided directly by the federal government and includes Medicare Parts A and B.

Medicare Part A, also called hospital insurance, helps to pay for inpatient stays at a hospital, skilled nursing facility, or hospice center. Part B, also called medical insurance, helps pay for outpatient care like physician services, kidney dialysis, preventive care, durable medical equipment, etc.Medicare Advantage plans are administered by private insurance companies that have contracts with the federal government. Medicare Advantage plans include all of the benefits of Original Medicare (albeit with different cost-sharing, as the plans set their own deductibles, coinsurance, and copays, within the limits established by the federal government), and they typically have additional benefits, such coverage for prescription drugs, dental, and vision.

But provider networks are often limited with Medicare Advantage plans, and out-of-pocket costs are typically higher than a person would have if they opted for Original Medicare plus a Medigap plan. In short, there are pros and cons either way, and no one-size-fits-all solution. Medicare Advantage in TexasMedicare Advantage plans are available in all 254 counties in Texas in 2021, but plan availability ranges from as few as nine plans some of the state’s service areas to as many as 90 plans for sale in Harris County.A little more than a third of Texas Medicare beneficiares — just slightly more than the national average — were enrolled in private Medicare plans in 2018.

These were mostly Medicare Advantage plans, but some residents in Texas have Medicare Cost plans, which are another form of private coverage. By late 2020, however, the share of Texas Medicare beneficiaries enrolled in private plans had grown to more than 43 percent. The other 57 percent of Medicare beneficiaries in Texas were enrolled in Original Medicare instead.Medicare beneficiaries can switch between Medicare Advantage enrollment and Original Medicare (and can add or drop a Medicare Part D prescription plan) during the Medicare annual election period, which runs from October 15 to December 7 each year.

Medicare Advantage enrollees also have the option to switch to a different Advantage plan or to Original Medicare during the Medicare Advantage open enrollment period, which runs from January 1 to March 31.Medigap in TexasMore than half of Original Medicare beneficiaries have supplemental coverage provided by an employer-sponsored plan or Medicaid. But for those who don’t, Medigap plans (also known as Medicare supplement plans) are designed to pay some or all of the out-of-pocket costs (deductibles and coinsurance) that enrollees would otherwise have to pay themselves. Since Original Medicare does not include a cap on out-of-pocket costs, most enrollees maintain some form of supplemental coverage, and Medigap plans are one way to do this.According to an AHIP analysis, there were 873,514 Texas Medicare beneficiaries with Medigap coverage as of 2018.There are 70 insurers licensed to sell Medigap plans in Texas.Although Medigap plans are sold by private insurers, the plans are standardized under federal rules.

There are ten different plan designs (differentiated by letters, A through N), and the benefits offered by a particular plan (Plan A, Plan F, etc.) are the same from one insurer to another.Unlike other private Medicare coverage (Medicare Advantage and Medicare Part D plans), there is no annual open enrollment window for Medigap plans. Instead, federal rules provide a one-time six-month window when Medigap coverage is guaranteed-issue. This window starts when a person is at least 65 and enrolled in Medicare Part B (you have to be enrolled in both Part A and Part B to buy a Medigap plan).Although disabled Americans under the age of 65 are eligible for Medicare, federal rules do not guarantee access to Medigap plans for people who are under 65.

But the majority of the states — including Texas — have implemented rules to ensure that disabled Medicare beneficiaries have at least some access to Medigap plans. Texas law requires Medigap insurers to offer at least Medigap Plan A to disabled enrollees under age 65, during the six-month period that begins when they’re enrolled in Medicare Part B. Medigap Plan A is the least comprehensive of the Medigap plans, but it will cover the 20 percent Part B coinsurance that the enrollee would othewise have to pay out-of-pocket.Disabled Medicare beneficiaries under the age of 65 have another six-month Medigap open enrollment period when they turn 65.

At that point, they have access to any of the available Medigap plans, at the standard premiums that apply to people who are enrolling in Medicare due to turning 65 (premiums are generally significantly higher for Medicare beneficiaries under age 65, since their disabilities result in more costly medical care).Medicare Advantage plans are available to anyone eligible for Medicare, except people with end-stage renal disease (starting in 2021, this limitation will no longer apply. People with ESRD will be able to enroll in Medicare Advantage plans). So unless they have ESRD, Texas Medicare beneficiaries under the age of 65 can choose a Medicare Advantage plan instead of Medigap Plan A.

Medicare Advantage plans do have a cap on out-of-pocket costs, but they also tend to have limited provider networks, which is an important consideration for people with serious health issues.Although the Affordable Care Act eliminated pre-existing condition exclusions in most of the private health insurance market, those regulations don’t apply to Medigap plans. Medigap insurers can impose a pre-existing condition waiting period of up to six months, if you didn’t have at least six months of continuous coverage prior to your enrollment. And if you apply for a Medigap plan after your initial enrollment window closes (assuming you aren’t eligible for one of the limited guaranteed-issue rights), the insurer can look back at your medical history in determining whether to accept your application, and at what premium.

Texas Medicare Part DOriginal Medicare does not cover the cost of outpatient prescription drugs. As noted above, more than half of Original Medicare beneficiaries have supplemental coverage via an employer-sponsored plan (from a current or former employer or spouse’s employer) or Medicaid, and these plans often include prescription coverage. But Medicare beneficiaries who don’t have drug coverage through Medicaid or an employer-sponsored plan need to obtain Medicare Part D prescription coverage (prior to 2006, some Medigap plans included prescription coverage.

People who still have those plans can keep them, but they have not been for sale since the end of 2005).Part D coverage can be purchased as a stand-alone plan, or as part of a Medicare Advantage plan that includes Part D prescription drug coverage.In Texas, there are 35 stand-alone Medicare Part D plans for sale for 2021, with premiums that range from about $7 to $155/month.As of late 2020, there were 1.65 million Medicare beneficiaries in Texas with stand-alone Medicare Part D plans. An additional 1.54 million Texas residents had Medicare Part D coverage integrated with their Medicare Advantage plans.Medicare Part D enrollment follows the same schedule as Medicare Advantage. Beneficiaries can enroll in Medicare Part D plans when they’re first eligible for Medicare, and there’s also an annual enrollment window (October 15 to December 7) when people can enroll or switch to a different plan.

Medicare spending in TexasIn 2018, Original Medicare’s per-beneficiary spending in Texas averaged $11,627, which was 15 percent higher than the $10,096 national average. Texas had the second-highest average per-beneficiary costs in the country. Only Louisiana had higher average costs.

That’s based on data that were standardized to eliminate regional differences in payment rates, but it did not include costs for Medicare Advantage.How does Medicaid provide financial assistance to Medicare beneficiaries in Texas?. Many Medicare beneficiaries receive financial assistance through Medicaid with the cost of Medicare premiums and services Medicare doesn’t cover – such as long-term care.Our guide to financial assistance for Medicare enrollees in Texas includes overviews of these benefits, including Medicare Savings Programs, long-term care coverage, and eligibility guidelines for assistance.Helpful resources for Texas Medicare beneficiaries and their caregiversNeed help with your Medicare application in Texas, or have questions about Medicare eligibility in Texas?. These resources provide free assistance and information.The Health Information, Counseling, and Advocacy Program (HICAP), with any questions related to Medicare coverage in Texas.

Visit the website or call 1-800-252-9240.The Texas Department of Insurance has a resources page for Texas residents with Medicare coverage.Louise Norris is an individual health insurance broker who has been writing about health insurance and health reform since 2006. She has written dozens of opinions and educational pieces about the Affordable Care Act for healthinsurance.org. Her state health exchange updates are regularly cited by media who cover health reform and by other health insurance experts..

What is Seroquel?

QUETIAPINE is an antipsychotic. It is used to treat schizophrenia and bipolar disorder, also known as manic-depression.

Seroquel taper

IntroductionIn recent years, many studies have been published on new diagnostic possibilities http://pupdogs.net/2015/12/20/my-last-gift-to-nina-weena-tofina/ and management approaches in cohorts of patients suspected to have a disorder/difference of sex development (DSD).1–13 Based on these studies, it has become clear that services and institutions still differ in the composition of the multidisciplinary teams that provide seroquel taper care for patients who have a DSD.11 14 Several projects have now worked to resolve this variability in care. The European Cooperation in Science and Technology (EU COST) action BM1303 ‘A systematic elucidation of differences of sex development’ has been a platform to achieve European agreement on harmonisation of clinical management and laboratory practices.15–17 Another such initiative involved an update of the 2006 DSD consensus document by an international group of professionals and patient representatives.18 These initiatives have highlighted how cultural and financial seroquel taper aspects and the availability of resources differ significantly between countries and societies, a situation that hampers supranational agreement on common diagnostic protocols. As only a few national guidelines have been published in international journals, comparison of these guidelines is difficult even though such a comparison is necessary to capture the differences and initiate actions to overcome them. Nonetheless, four DSD (expert) centres located in the Netherlands and Flanders (the Dutch-speaking Northern part of Belgium) have collaborated to produce a detailed guideline on diagnostics in DSD.19 This shows that a supranational guideline can be a reasonable approach for countries with similarly structured healthcare systems seroquel taper and similar resources. Within the guideline there is agreement that optimisation of expertise and care can be achieved through centralisation, for example, by limiting analysis of next-generation sequencing (NGS)-based diagnostic panels to only a few centres and by centralising pathological review of gonadal tissues.

International networks such as the European Reference Network for rare endocrine conditions (EndoERN), in which DSD is embedded, may facilitate the seroquel taper expansion of this kind of collaboration across Europe.This paper highlights key discussion points in the Dutch-Flemish guideline that have been insufficiently addressed in the literature thus far because they reflect evolving technologies or less visible stakeholders. For example, prenatal observation of an atypical aspect of the genitalia indicating a possible DSD is becoming increasingly common, and we discuss appropriate counselling and a diagnostic approach for these cases, including the option of using NGS-based genetic testing. So far, little attention has been paid to this process.20 21 Furthermore, informing patients and/or their parents about atypical sex development and why this seroquel taper may warrant referral to a specialised team may be challenging, especially for professionals with limited experience in DSD.22 23 Therefore, a section of the Dutch-Flemish guideline was written for these healthcare providers. Moreover, this enables DSD specialists to refer to the guideline when advising a referral. Transition from the prenatal to the postnatal team and from the paediatric to the adult team requires optimal communication between the seroquel taper specialists involved.

Application of NGS-based techniques may lead to a higher diagnostic yield, providing a molecular genetic diagnosis in previously unsolved cases.16 We address the timing of this testing and the problems associated with this technique such as the interpretation of variants of unknown clinical significance (VUS). Similarly, histopathological seroquel taper interpretation and classification of removed gonadal tissue is challenging and would benefit from international collaboration and centralisation of expertise.MethodsFor the guideline revision, an interdisciplinary multicentre group was formed with all members responsible for updating the literature for a specific part of the guideline. Literature search in PubMed was not systematic, but rather intended to be broad in order to cover all areas and follow expert opinions. This approach is more in line with the Clinical seroquel taper Practice Advisory Document method described by Burke et al24 for guidelines involving genetic practice because it is often troublesome to substantiate such guidelines with sufficient evidence due to the rapid changes in testing methods, for example, gene panels. All input provided by the group was synthesised by the chairperson (YvB), who also reviewed abstracts of papers on DSD published between 2010 and September 2017 for the guideline and up to October 2019 for this paper.

Abstracts had to be written in English and were identified using a broad range of seroquel taper Medical Subject Headings terms (eg, DSD, genetic, review, diagnosis, diagnostics, 46,XX DSD, 46,XY DSD, guideline, multidisciplinary care). Next, potentially relevant papers on diagnostic procedures in DSD were selected. Case reports were excluded, as were articles that were not open access or retrievable through seroquel taper institutional access. Based on this, a draft guideline was produced that was in line with the international principles of good diagnostic care in DSD. This draft seroquel taper was discussed by the writing committee and, after having obtained agreement on remaining points of discussion, revised into a final draft.

This version was sent to a broad group of professionals from academic centres and DSD teams whose members had volunteered to review the draft guideline. After receiving seroquel taper and incorporating their input, the final version was presented to the paediatric and genetic associations for approval. After approval by the members of the paediatric (NVK), clinical genetic (VKGN) and genetic laboratory (VKGL) associations, the guideline was published on their respective websites.19 Although Turner syndrome and Klinefelter syndrome are considered to be part of the DSD spectrum, they are not extensively discussed in this diagnostic guideline as guidelines dedicated to these syndromes already exist.25 26 However, some individuals with Turner syndrome or Klinefelter syndrome may present with ambiguous or atypical genitalia and may therefore initially follow the DSD diagnostic process.Guideline highlightsPrenatal settingPresentationThe most frequent prenatal presentation of a DSD condition is atypical genitalia found on prenatal ultrasound as an isolated finding or in combination with other structural anomalies. This usually occurs after the 20-week routine medical ultrasound for screening of congenital anomalies, but may also occur seroquel taper earlier, for example, when a commercial ultrasound is performed at the request of the parents.Another way DSD can be diagnosed before birth is when invasive prenatal genetic testing carried out for a different reason, for example, due to suspicion of other structural anomalies, reveals a discrepancy between the genotypic sex and the phenotypic sex seen by ultrasound. In certified laboratories, the possibility of a sample switch is extremely low but should be ruled out immediately.

More often, the discrepancy will be due to sex-chromosome mosaicism or a true form of DSD.A situation now occurring with increasing frequency is a discrepancy seroquel taper between the genotypic sex revealed by non-invasive prenatal testing (NIPT), which is now available to high-risk pregnant women in the Netherlands and to all pregnant women in Belgium, and later ultrasound findings. NIPT screens for CNVs in the fetus. However, depending on legal restrictions and/or ethical considerations, the X and Y chromosomes are seroquel taper not always included in NIPT analysis and reports. If the X and Y chromosomes are included, it is important to realise that the presence of a Y-chromosome does not necessarily imply male fetal development. At the time that NIPT is performed (usually 11–13 weeks), genital development cannot be reliably appreciated by ultrasound, so any discrepancy or atypical aspect of the genitalia will only be noticed later in pregnancy and should prompt further evaluation.Counselling and diagnosticsIf a DSD is suspected, first-line sonographers and obstetricians should refer the couple to their colleague prenatal specialists working seroquel taper with or in a DSD team.

After confirming an atypical genital on ultrasound, the specialist team should offer the couple a referral for genetic counselling to discuss the possibility of performing invasive prenatal testing (usually an amniocentesis) to identify an underlying cause that fits the ultrasound findings.22 23 To enable the parents to make a well-informed decision, prenatal counselling should, in our opinion, include. Information on the ultrasound findings and the limitations of this technique seroquel taper. The procedure(s) that can be followed, including the risks associated with an amniocentesis. And the type of information genetic testing can seroquel taper and cannot provide. Knowing which information has been provided and what words have been used by the prenatal specialist is very helpful for those involved in postnatal care.It is important that parents understand that the biological sex of a baby is determined by a complex interplay of chromosomes, genes and hormones, and thus that assessment of the presence or absence of a Y-chromosome alone is insufficient to assign the sex of their unborn child or, as in any unborn child, say anything about the child’s future gender identity.Expecting parents can be counselled by the clinical geneticist and the psychologist from the DSD team, although other DSD specialists can also be involved.

The clinical geneticist should be experienced in prenatal counselling and well informed about the diagnostic possibilities given the limited time span in which test results need to be available to allow parents to make a well-informed decision about whether or not seroquel taper to continue the pregnancy. Termination of pregnancy can be considered, for instance, in a syndromic form of DSD with multiple malformations, but when the DSD occurs as an apparently isolated condition, expecting parents may also consider termination of pregnancy, which, although considered controversial by some, is legal in Belgium seroquel taper and the Netherlands. The psychologist of the DSD team can support parents during and after pregnancy and help them cope with feelings of uncertainty and eventual considerations of a termination of pregnancy, as well as with practical issues, for example, how to inform others. The stress of seroquel taper not knowing exactly what the child’s genitalia will look like and uncertainty about the diagnosis, treatment and prognosis cannot be avoided completely. Parents are informed that if the postnatal phenotype is different from what was prenatally expected, the advice given about diagnostic testing can be adjusted accordingly, for example, if a hypospadias is milder than was expected based on prenatal ultrasound images.

In our experience, parents appreciate having already spoken to some members of the DSD team during pregnancy and having a contact person before birth.After expert prenatal seroquel taper counselling, a significant number of pregnant couples decline prenatal testing (personal experience IALG, MK, ABD, YvB, MC and HC-vdG). At birth, umbilical cord blood is a good source for (molecular) karyotyping and storage of DNA and can be obtained by the obstetrician, midwife or neonatologist. The terminology used in communication with parents should be carefully chosen,22 23 and midwives and staff of neonatal and delivery units should be clearly instructed to use gender-neutral and non-stigmatising vocabulary (eg, ‘your baby’) as long as sex assignment is pending.An algorithm for diagnostic evaluation of a suspected DSD in the prenatal situation seroquel taper is proposed in figure 1. When couples opt for invasive prenatal diagnosis, the genetic analysis usually involves an (SNP)-array. It was recently estimated that >30% of individuals who have a DSD have additional structural anomalies, with cardiac and neurological anomalies and seroquel taper fetal growth restriction being particularly common.27 28 If additional anomalies are seen, the geneticist can consider specific gene defects that may underlie a known genetic syndrome or carry out NGS.

NGS-based techniques have also now made their appearance in prenatal diagnosis of congenital anomalies.29 30 Panels using these techniques can be specific for genes involved in DSD, or be larger panels covering multiple congenital anomalies, and are usually employed with trio-analysis to compare variants identified in the child with the parents’ genetics.29–31 Finding a genetic cause before delivery can help reduce parental stress in the neonatal period and speed up decisions regarding gender assignment. In such cases there is seroquel taper no tight time limit, and we propose completing the analysis well before the expected delivery.Disorders/differences of sex development (DSD) in the prenatal setting. A diagnostic algorithm. *SOX9. Upstream anomalies and balanced translocations at promotor sites!.

Conventional karyotyping can be useful. NGS, next-generation sequencing." data-icon-position data-hide-link-title="0">Figure 1 Disorders/differences of sex development (DSD) in the prenatal setting. A diagnostic algorithm. *SOX9. Upstream anomalies and balanced translocations at promotor sites!.

Conventional karyotyping can be useful. NGS, next-generation sequencing.First contact by a professional less experienced in DSDWhereas most current guidelines start from the point when an individual has been referred to the DSD team,1 15 the Dutch-Flemish guideline dedicates a chapter to healthcare professionals less experienced in DSD as they are often the first to suspect or identify such a condition. Apart from the paper of Indyk,7 little guidance is available for these professionals about how to act in such a situation. The chapter in the Dutch-Flemish guideline summarises the various clinical presentations that a DSD can have and provides information on how to communicate with parents and/or patients about the findings of the physical examination, the first-line investigations and the need for prompt referral to a specialised centre for further evaluation. Clinical examples are offered to illustrate some of these recurring situations.

The medical issues in DSD can be very challenging, and the social and psychological impact is high. For neonates with ambiguous genitalia, sex assignment is an urgent and crucial issue, and it is mandatory that parents are informed that it is possible to postpone registration of their child’s sex. In cases where sex assignment has already taken place, the message that the development of the gonads or genitalia is still atypical is complicated and distressing for patients and parents or carers. A list of contact details for DSD centres and patient organisations in the Netherlands and Flanders is attached to the Dutch-Flemish guideline. Publishing such a list, either in guidelines or online, can help healthcare professionals find the nearest centres for consultations and provide patients and patient organisations with an overview of the centres where expertise is available.Timing and place of genetic testing using NGS-based gene panelsThe diagnostic workup that is proposed for 46,XX and 46,XY DSD is shown in figures 2 and 3, respectively.

Even with the rapidly expanding molecular possibilities, a (family) history and a physical examination remain the essential first steps in the diagnostic process. Biochemical and hormonal screening aim at investigating serum electrolytes, renal function and the hypothalamic-pituitary-gonadal and hypothalamic-pituitary-adrenal axes. Ultrasound screening of kidneys and internal genitalia, as well as establishing genotypic sex, should be accomplished within 48 hours and complete the baseline diagnostic work-up of a child born with ambiguous genitalia.1 16 32 3346,XX disorders/differences of sex development (DSD) in the postnatal setting. A diagnostic algorithm. NGS, next-generation sequencing.

CAH, Congenital adrenal hyperplasia. AMH, Anti-Müllerian Hormone." data-icon-position data-hide-link-title="0">Figure 2 46,XX disorders/differences of sex development (DSD) in the postnatal setting. A diagnostic algorithm. NGS, next-generation sequencing. CAH, Congenital adrenal hyperplasia.

AMH, Anti-Müllerian Hormone.46,XY disorders/differences of sex development (DSD) in the postnatal setting. A diagnostic algorithm. * SOX9. Upstream anomalies and balanced translocations at promotor sites!. Conventional karyotyping can be useful.

NGS, next-generation sequencing." data-icon-position data-hide-link-title="0">Figure 3 46,XY disorders/differences of sex development (DSD) in the postnatal setting. A diagnostic algorithm. *SOX9. Upstream anomalies and balanced translocations at promotor sites!. Conventional karyotyping can be useful.

NGS, next-generation sequencing.Very recently, a European position paper has been published focusing on the genetic workup of DSD.16 It highlights the limitations and drawbacks of NGS-based tests, which include the chance of missing subtle structural variants such as CNVs and mosaicism and the fact that NGS cannot detect methylation defects or other epigenetic changes.16 28 31 Targeted DNA analysis is preferred in cases where hormonal investigations suggest a block in steroidogenesis (eg, 11-β-hydroxylase deficiency, 21-hydroxylase deficiency), or in the context of a specific clinical constellation such as the often coincidental finding of Müllerian structures in a boy with normal external genitalia or cryptorchidism, that is, persistent Müllerian duct syndrome.33 34 Alternative tests should also be considered depending on the available information. Sometimes, a simple mouth swab for FISH analysis can detect mosaic XY/X in a male with hypospadias or asymmetric gonadal development or in a female with little or no Turner syndrome stigmata and a normal male molecular karyotyping profile or peripheral blood karyotype. Such targeted testing avoids incidental findings and is cheaper and faster than analysis of a large NGS-based panel, although the cost difference is rapidly declining.However, due to the genetic and phenotypic heterogeneity of DSD conditions, the most cost-effective next steps in the majority of cases are whole exome sequencing followed by panel analysis of genes involved in genital development and function or trio-analysis of a large gene panel (such as a Mendeliome).16 35–38 Pretest genetic counselling involves discussing what kind of information will be reported to patients or parents and the chance of detecting VUS, and the small risk of incidental findings when analysing a DSD panel should be mentioned. Laboratories also differ in what class of variants they report.39 In our experience, the fear of incidental findings is a major reason why some parents refrain from genetic testing.Timing of the DSD gene panel analysis is also important. While some patients or parents prefer that all diagnostic procedures be performed as soon as possible, others need time to reflect on the complex information related to more extensive genetic testing and on its possible consequences.

If parents or patients do not consent to panel-based genetic testing, analysis of specific genes, such as WT1, should be considered when appropriate in view of the clinical consequences if a mutation is present (eg, clinical surveillance of renal function and screening for Wilms’ tumour in the case of WT1 mutations). Genes that are more frequently involved in DSD (eg, SRY, NR5A1) and that match the specific clinical and hormonal features in a given patient could also be considered for sequencing. Targeted gene analysis may also be preferred in centres located in countries that do not have the resources or technical requirements to perform NGS panel-based genetic testing. Alternatively, participation by these centres in international collaborative networks may allow them to outsource the molecular genetic workup abroad.Gene panels differ between centres and are regularly updated based on scientific progress. A comparison of DSD gene panels used in recent studies can be found at https://www.nature.com/articles/s41574-018-0010-8%23Sec46.15 The panels currently used at the coauthors’ institutions can be found on their respective websites.

Given the pace of change, it is important to regularly consider repeating analysis in patients with an unexplained DSD, for example, when they transition into adult care or when they move from one centre to another. This also applies to patients in whom a clinical diagnosis has never been genetically confirmed. Confusion may arise when the diagnosis cannot be confirmed or when a mutation is identified in a different gene, for example, NR5A1 in someone with a clinical diagnosis of CAIS that has other consequences for relatives. Hence, new genetic counselling should always accompany new diagnostic endeavours.Class 3 variants and histopathological examinationsThe rapidly evolving diagnostic possibilities raise new questions. What do laboratories report?.

How should we deal with the frequent findings of mainly unique VUS or class 3 variants (ACMG recommendation) in the many different DSD-related genes in the diagnostic setting?. Reporting VUS can be a source of uncertainty for parents, but not reporting these variants precludes further investigations to determine their possible pathogenicity. It can also be difficult to prove variant pathogenicity, both on gene-level and variant-level.39 Moreover, given the gonad-specific expression of some genes and the variable phenotypic spectrum and reduced penetrance, segregation analysis is not always informative. A class 3 variant that does not fit the clinical presentation may be unrelated to the observed phenotype, but it could also represent a newly emerging phenotype. This was recently demonstrated by the identification of the NR5A1 mutation, R92W, in individuals with 46,XX testicular and ovotesticular DSD.40 This gene had previously been associated with 46,XY DSD.

In diagnostic laboratories, there is usually no capacity or expertise to conduct large-scale functional studies to determine pathogenicity of these unique class 3 VUS in the different genes involved in DSD. Functional validation of variants identified in novel genes may be more attractive in a research context. However, for individual families with VUS in well-established DSD genes such as AR or HSD17B3, functional analysis may provide a confirmed diagnosis that implies for relatives the option of undergoing their own DNA analysis and estimating the genetic risk of their own future offspring. This makes genetic follow-up important in these cases and demonstrates the usefulness of international databases and networks and the centralisation of functional studies of genetic variants in order to reduce costs and maximise expertise.The same is true for histopathological description, germ-cell tumour risk assessment in specific forms of DSD and classification of gonadal samples. Germ-cell tumour risk is related to the type of DSD (among other factors), but it is impossible to make risk estimates in individual cases.41–44 Gonadectomy may be indicated in cases with high-risk dysgenetic abdominal gonads that cannot be brought into a stable superficial (ie, inguinal, labioscrotal) position that allows clinical or radiological surveillance, or to avoid virilisation due to 5-alpha reductase deficiency in a 46,XY girl with a stable female gender identity.45 Pathological examination of DSD gonads requires specific expertise.

For example, the differentiation between benign germ cell abnormalities, such as delayed maturation and (pre)malignant development of germ cells, is crucial for clinical management but can be very troublesome.46 Centralised pathological examination of gonadal biopsy and gonadectomy samples in one centre, or a restricted number of centres, on a national scale can help to overcome the problem of non-uniform classification and has proven feasible in the Netherlands and Belgium. We therefore believe that uniform assessment and classification of gonadal differentiation patterns should also be addressed in guidelines on DSD management.International databases of gonadal tissues are crucial for learning more about the risk of malignancy in different forms of DSD, but they are only reliable if uniform criteria for histological classification are strictly applied.46 These criteria could be incorporated in many existing networks such as the I-DSD consortium, the Disorders of Sex Development Translational Research Network, the European Reference Network on Urogenital Diseases (eUROGEN), the EndoERN and COST actions.15–17 47Communication at the transition from paediatric to adult carePaediatric and adult teams need to collaborate closely to facilitate a well-organised transition from paediatric to adult specialist care.15 48–50 Both teams need to exchange information optimally and should consider transition as a longitudinal process rather than a fixed moment in time. Age-appropriate information is key at all ages, and an overview of topics to be discussed at each stage is described by Cools et al.15 Table 1 shows an example of how transition can be organised.View this table:Table 1 Example of transition table as used in the DSD clinic of the Erasmus Medical CenterPsychological support and the continued provision of information remains important for individuals with a DSD at all ages.15 22 In addition to the information given by the DSD team members, families and patients can benefit from resources such as support groups and information available on the internet.47 Information available online should be checked for accuracy and completeness when referring patients and parents to internet sites.Recommendations for future actionsMost guidelines and articles on the diagnosis and management of DSD are aimed at specialists and are only published in specialist journals or on websites for endocrinologists, urologists or geneticists. Yet there is a need for guidelines directed towards first-line and second-line healthcare workers that summarise the recommendations about the first crucial steps in the management of DSD. These should be published in widely available general medical journals and online, along with a national list of DSD centres.

Furthermore, DSD (expert) centres should provide continuous education to all those who may be involved in the identification of individuals with a DSD in order to enable these healthcare professionals to recognise atypical genitalia, to promptly refer individuals who have a DSD and to inform the patient and parents about this and subsequent diagnostic procedures.As DSD continues to be a rare condition, it will take time to evaluate the effects of having such a guideline on the preparedness of first-line and second-line healthcare workers to recognise DSD conditions. One way to evaluate this might be the development and use of questionnaires asking patients, carers and families and referring physicians how satisfied they were with the initial medical consultation and referral and what could be improved. A helpful addition to existing international databases that collect information on genetic variations would be a list of centres that offer suitable functional studies for certain genes, ideally covering the most frequently mutated genes (at minimum).Patient organisations can also play an important role in informing patients about newly available diagnostic or therapeutic strategies and options, and their influence and specific role has now been recognised and discussed in several publications.17 47 However, it should be kept in mind that these organisations do not represent all patients, as a substantial number of patients and parents are not member of such an organisation.Professionals have to provide optimal medical care based on well-established evidence, or at least on broad consensus. Yet not everything can be regulated by recommendations and guidelines. Options, ideas and wishes should be openly discussed between professionals, patients and families within their confidential relationship.

This will enable highly individualised holistic care tailored to the patient’s needs and expectations. Once they are well-informed of all available options, parents and/or patients can choose what they consider the optimal care for their children or themselves.15 16ConclusionThe Dutch-Flemish guideline uniquely addresses some topics that are under-represented in the literature, thus adding some key aspects to those addressed in recent consensus papers and guidelines.15–17 33 47As more children with a DSD are now being identified prenatally, and the literature on prenatal diagnosis of DSD remains scarce,20 21 we propose a prenatal diagnostic algorithm and emphasise the importance of having a prenatal specialist involved in or collaborating with DSD (expert) centres.We also stress that good communication between all involved parties is essential. Professionals should be well informed about protocols and communication. Collaboration between centres is necessary to optimise aspects of care such as uniform interpretation of gonadal pathology and functional testing of class 3 variants found by genetic testing. Guidelines can provide a framework within which individualised patient care should be discussed with all stakeholders.AcknowledgmentsThe authors would like to thank the colleagues of the DSD teams for their input in and critical reading of the Dutch-Flemish guideline.

Amsterdam University Center (AMC and VU), Maastricht University Medical Center, Erasmus Medical Center Rotterdam, Radboud University Medical Center Nijmegen, University Medical Center Groningen, University Medical Center Utrecht, Ghent University Hospital. The authors would like to thank Kate McIntyre for editing the revised manuscript and Tom de Vries Lentsch for providing the figures as a PDF. Three of the authors of this publication are members of the European Reference Network for rare endocrine diseases—Project ID 739543.IntroductionEndometrial cancer is the most common gynaecological malignancy in the developed world.1 Its incidence has risen over the last two decades as a consequence of the ageing population, fewer hysterectomies for benign disease and the obesity epidemic. In the USA, it is estimated that women have a 1 in 35 lifetime risk of endometrial cancer, and in contrast to cancers of most other sites, cancer-specific mortality has risen by approximately 2% every year since 2008 related to the rapidly rising incidence.2Endometrial cancer has traditionally been classified into type I and type II based on morphology.3 The more common subtype, type I, is mostly comprised of endometrioid tumours and is oestrogen-driven, arises from a hyperplastic endometrium, presents at an early stage and has an excellent 5 year survival rate.4 By contrast, type II includes non-endometrioid tumours, specifically serous, carcinosarcoma and clear cell subtypes, which are biologically aggressive tumours with a poor prognosis that are often diagnosed at an advanced stage.5 Recent efforts have focused on a molecular classification system for more accurate categorisation of endometrial tumours into four groups with distinct prognostic profiles.6 7The majority of endometrial cancers arise through the interplay of familial, genetic and lifestyle factors. Two inherited cancer predisposition syndromes, Lynch syndrome and the much rarer Cowden syndrome, substantially increase the lifetime risk of endometrial cancer, but these only account for around 3–5% of cases.8–10 Having first or second degree relative(s) with endometrial or colorectal cancer increases endometrial cancer risk, although a large European twin study failed to demonstrate a strong heritable link.11 The authors failed to show that there was greater concordance in monozygotic than dizygotic twins, but the study was based on relatively small numbers of endometrial cancers.

Lu and colleagues reported an association between common single nucleotide polymorphisms (SNPs) and endometrial cancer risk, revealing the potential role of SNPs in explaining part of the risk in both the familial and general populations.12 Thus far, many SNPs have been reported to modify susceptibility to endometrial cancer. However, much of this work predated genome wide association studies and is of variable quality. Understanding genetic predisposition to endometrial cancer could facilitate personalised risk assessment with a view to targeted prevention and screening interventions.13 This emerged as the most important unanswered research question in endometrial cancer according to patients, carers and healthcare professionals in our recently completed James Lind Womb Cancer Alliance Priority Setting Partnership.14 It would be particularly useful for non-endometrioid endometrial cancers, for which advancing age is so far the only predictor.15We therefore conducted a comprehensive systematic review of the literature to provide an overview of the relationship between SNPs and endometrial cancer risk. We compiled a list of the most robust endometrial cancer-associated SNPs. We assessed the applicability of this panel of SNPs with a theoretical polygenic risk score (PRS) calculation.

We also critically appraised the meta-analyses investigating the most frequently reported SNPs in MDM2. Finally, we described all SNPs reported within genes and pathways that are likely involved in endometrial carcinogenesis and metastasis.MethodsOur systematic review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) collaboration 2009 recommendations. The registered protocol is available through PROSPERO (CRD42018091907).16Search strategyWe searched Embase, MEDLINE and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases via the Healthcare Databases Advanced Search (HDAS) platform, from 2007 to 2018, to identify studies reporting associations between polymorphisms and endometrial cancer risk. Key words including MeSH (Medical Subject Heading) terms and free-text words were searched in both titles and abstracts. The following terms were used.

€œendomet*”,“uter*”, “womb”, “cancer(s)”, “neoplasm(s)”, “endometrium tumour”, “carcinoma”, “adenosarcoma”, “clear cell carcinoma”, “carcinosarcoma”, “SNP”, “single nucleotide polymorphism”, “GWAS”, and “genome-wide association study/ies”. No other restrictions were applied. The search was repeated with time restrictions between 2018 and June 2019 to capture any recent publications.Eligibility criteriaStudies were selected for full-text evaluation if they were primary articles investigating a relationship between endometrial cancer and SNPs. Study outcome was either the increased or decreased risk of endometrial cancer relative to controls reported as an odds ratio (OR) with corresponding 95% confidence intervals (95% CIs).Study selectionThree independent reviewers screened all articles uploaded to a screening spreadsheet developed by Helena VonVille.17 Disagreements were resolved by discussion. Chronbach’s α score was calculated between reviewers and indicated high consistency at 0.92.

Case–control, prospective and retrospective studies, genome-wide association studies (GWAS), and both discovery and validation studies were selected for full-text evaluation. Non-English articles, editorials, conference abstracts and proceedings, letters and correspondence, case reports and review articles were excluded.Candidate-gene studies with at least 100 women and GWAS with at least 1000 women in the case arm were selected to ensure reliability of the results, as explained by Spencer et al.18 To construct a panel of up to 30 SNPs with the strongest evidence of association, those with the strongest p values were selected. For the purpose of an SNP panel, articles utilising broad European or multi-ethnic cohorts were selected. Where overlapping populations were identified, the most comprehensive study was included.Data extraction and synthesisFor each study, the following data were extracted. SNP ID, nearby gene(s)/chromosome location, OR (95% CI), p value, minor or effect allele frequency (MAF/EAF), EA (effect allele) and OA (other allele), adjustment, ethnicity and ancestry, number of cases and controls, endometrial cancer type, and study type including discovery or validation study and meta-analysis.

For risk estimates, a preference towards most adjusted results was applied. For candidate-gene studies, a standard p value of<0.05 was applied and for GWAS a p value of <5×10-8, indicating genome-wide significance, was accepted as statistically significant. However, due to the limited number of SNPs with p values reaching genome-wide significance, this threshold was then lowered to <1×10-5, allowing for marginally significant SNPs to be included. As shown by Mavaddat et al, for breast cancer, SNPs that fall below genome-wide significance may still be useful for generating a PRS and improving the models.19We estimated the potential value of a PRS based on the most significant SNPs by comparing the predicted risk for a woman with a risk score in the top 1% of the distribution to the mean predicted risk. Per-allele ORs and MAFs were taken from the publications and standard errors (SEs) for the lnORs were derived from published 95% CIs.

The PRS was assumed to have a Normal distribution, with mean 2∑βipI and SE, σ, equal to √2∑βi2pI(1−pi), according to the binomial distribution, where the summation is over all SNPs in the risk score. Hence the relative risk (RR) comparing the top 1% of the distribution to the mean is given by exp(Z0.01σ), where Z is the inverse of the standard normal cumulative distribution.ResultsThe flow chart of study selection is illustrated in figure 1. In total, 453 text articles were evaluated and, of those, 149 articles met our inclusion criteria. One study was excluded from table 1, for having an Asian-only population, as this would make it harder to compare with the rest of the results which were all either multi-ethnic or Caucasian cohorts, as stated in our inclusion criteria for the SNP panel.20 Any SNPs without 95% CIs were also excluded from any downstream analysis. Additionally, SNPs in linkage disequilibrium (r2 >0.2) with each other were examined, and of those in linkage disequilibrium, the SNP with strongest association was reported.

Per allele ORs were used unless stated otherwise.View this table:Table 1 List of top SNPs most likely to contribute to endometrial cancer risk identified through systematic review of recent literature21–25Study selection flow diagram. *Reasons. Irrelevant articles, articles focusing on other conditions, non-GWAS/candidate-gene study related articles, technical and duplicate articles. GWAS, genome-wide association study. Adapted from.

Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The PRISMA Statement. PLoS Med 6(6). E1000097.

Doi:10.1371/journal.pmed1000097." data-icon-position data-hide-link-title="0">Figure 1 Study selection flow diagram. *Reasons. Irrelevant articles, articles focusing on other conditions, non-GWAS/candidate-gene study related articles, technical and duplicate articles. GWAS, genome-wide association study. Adapted from.

Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The PRISMA Statement. PLoS Med 6(6). E1000097.

Doi:10.1371/journal.pmed1000097.Top SNPs associated with endometrial cancer riskFollowing careful interpretation of the data, 24 independent SNPs with the lowest p values that showed the strongest association with endometrial cancer were obtained (table 1).21–25 These SNPs are located in or around genes coding for transcription factors, cell growth and apoptosis regulators, and enzymes involved in the steroidogenesis pathway. All the SNPs presented here were reported on the basis of a GWAS or in one case, an exome-wide association study, and hence no SNPs from candidate-gene studies made it to the list. This is partly due to the nature of larger GWAS providing more comprehensive and powered results as opposed to candidate gene studies. Additionally, a vast majority of SNPs reported by candidate-gene studies were later refuted by large-scale GWAS such as in the case of TERT and MDM2 variants.26 27 The exception to this is the CYP19 gene, where candidate-gene studies reported an association between variants in this gene with endometrial cancer in both Asian and broad European populations, and this association was more recently confirmed by large-scale GWAS.21 28–30 Moreover, a recent article authored by O’Mara and colleagues reviewed the GWAS that identified most of the currently known SNPs associated with endometrial cancer.31Most of the studies represented in table 1 are GWAS and the majority of these involved broad European populations. Those having a multi-ethnic cohort also consisted primarily of broad European populations.

Only four of the variants in table 1 are located in coding regions of a gene, or in regulatory flanking regions around the gene. Thus, most of these variants would not be expected to cause any functional effects on the gene or the resulting protein. An eQTL search using GTEx Portal showed that some of the SNPs are significantly associated (p<0.05) with modified transcription levels of the respective genes in various tissues such as prostate (rs11263761), thyroid (rs9668337), pituitary (rs2747716), breast mammary (rs882380) and testicular (rs2498794) tissue, as summarised in table 2.View this table:Table 2 List of eQTL hits for the selected panel of SNPsThe only variant for which there was an indication of a specific association with non-endometrioid endometrial cancer was rs148261157 near the BCL11A gene. The A allele of this SNP had a moderately higher association in the non-endometrioid arm (OR 1.64, 95% CI 1.32 to 2.04. P=9.6×10-6) compared with the endometrioid arm (OR 1.25, 95% CI 1.14 to 1.38.

P=4.7×10-6).21Oestrogen receptors α and β encoded by ESR1 and ESR2, respectively, have been extensively studied due to the assumed role of oestrogens in the development of endometrial cancer. O’Mara et al reported a lead SNP (rs79575945) in the ESR1 region that was associated with endometrial cancer (p=1.86×10-5).24 However, this SNP did not reach genome-wide significance in a more recent larger GWAS.21 No statistically significant associations have been reported between endometrial cancer and SNPs in the ESR2 gene region.AKT is an oncogene linked to endometrial carcinogenesis. It is involved in the PI3K/AKT/mTOR pro-proliferative signalling pathway to inactivate apoptosis and allow cell survival. The A allele of rs2494737 and G allele of rs2498796 were reported to be associated with increased and decreased risk of endometrial cancer in 2016, respectively.22 30 However, this association was not replicated in a larger GWAS in 2018.21 Nevertheless, given the previous strong indications, and biological basis that could explain endometrial carcinogenesis, we decided to include an AKT1 variant (rs2498794) in our results.PTEN is a multi-functional tumour suppressor gene that regulates the AKT/PKB signalling pathway and is commonly mutated in many cancers including endometrial cancer.32 Loss-of-function germline mutations in PTEN are responsible for Cowden syndrome, which exerts a lifetime risk of endometrial cancer of up to 28%.9 Lacey and colleagues studied SNPs in the PTEN gene region. However, none showed significant differences in frequency between 447 endometrial cancer cases and 439 controls of European ancestry.33KRAS mutations are known to be present in endometrial cancer.

These can be activated by high levels of KLF5 (transcriptional activator). Three SNPs have been identified in or around KLF5 that are associated with endometrial cancer. The G allele of rs11841589 (OR 1.15, 95% CI 1.11 to 1.21. P=4.83×10-11), the A allele of rs9600103 (OR 1.23, 95% CI 1.16 to 1.30. P=3.76×10-12) and C allele of rs7981863 (OR 1.16, 95% CI 1.12 to 1.20.

P=2.70×10-17) have all been found to be associated with an increased likelihood of endometrial cancer in large European cohorts.21 30 34 It is worth noting that these SNPs are not independent, and hence they quite possibly tag the same causal variant.The MYC family of proto-oncogenes encode transcription factors that regulate cell proliferation, which can contribute to cancer development if dysregulated. The recent GWAS by O’Mara et al reported three SNPs within the MYC region that reached genome-wide significance with conditional p values reaching at least 5×10–8.35To test the utility of these SNPs as predictive markers, we devised a theoretical PRS calculation using the log ORs and EAFs per SNP from the published data. The results were very encouraging with an RR of 3.16 for the top 1% versus the mean, using all the top SNPs presented in table 1 and 2.09 when using only the SNPs that reached genome-wide significance (including AKT1).Controversy surrounding MDM2 variant SNP309MDM2 negatively regulates tumour suppressor gene TP53, and as such, has been extensively studied in relation to its potential role in predisposition to endometrial cancer. Our search identified six original studies of the association between MDM2 SNP rs2279744 (also referred to as SNP309) and endometrial cancer, all of which found a statistically significant increased risk per copy of the G allele. Two more original studies were identified through our full-text evaluation.

However, these were not included here as they did not meet our inclusion criteria—one due to small sample size, the other due to studying rs2279744 status dependent on another SNP.36 37 Even so, the two studies were described in multiple meta-analyses that are listed in table 3. Different permutations of these eight original studies appear in at least eight published meta-analyses. However, even the largest meta-analysis contained <2000 cases (table 3)38View this table:Table 3 Characteristics of studies that examined MDM2 SNP rs2279744In comparison, a GWAS including nearly 13 000 cases found no evidence of an association with OR and corresponding 95% CI of 1.00 (0.97 to 1.03) and a p value of 0.93 (personal communication).21 Nevertheless, we cannot completely rule out a role for MDM2 variants in endometrial cancer predisposition as the candidate-gene studies reported larger effects in Asians, whereas the GWAS primarily contained participants of European ancestry. There is also some suggestion that the SNP309 variant is in linkage disequilibrium with another variant, SNP285, which confers an opposite effect.It is worth noting that the SNP285C/SNP309G haplotype frequency was observed in up to 8% of Europeans, thus requiring correction for the confounding effect of SNP285C in European studies.39 However, aside from one study conducted by Knappskog et al, no other study including the meta-analyses corrected for the confounding effect of SNP285.40 Among the studies presented in table 3, Knappskog et al (2012) reported that after correcting for SNP285, the OR for association of this haplotype with endometrial cancer was much lower, though still significant. Unfortunately, the meta-analyses which synthesised Knappskog et al (2012), as part of their analysis, did not correct for SNP285C in the European-based studies they included.38 41 42 It is also concerning that two meta-analyses using the same primary articles failed to report the same result, in two instances.38 42–44DiscussionThis article represents the most comprehensive systematic review to date, regarding critical appraisal of the available evidence of common low-penetrance variants implicated in predisposition to endometrial cancer.

We have identified the most robust SNPs in the context of endometrial cancer risk. Of those, only 19 were significant at genome-wide level and a further five were considered marginally significant. The largest GWAS conducted in this field was the discovery- and meta-GWAS by O’Mara et al, which utilised 12 096 cases and 108 979 controls.21 Despite the inclusion of all published GWAS and around 5000 newly genotyped cases, the total number did not reach anywhere near what is currently available for other common cancers such as breast cancer. For instance, BCAC (Breast Cancer Association Consortium) stands at well over 200 000 individuals with more than half being cases, and resulted in identification of ~170 SNPs in relation to breast cancer.19 45 A total of 313 SNPs including imputations were then used to derive a PRS for breast cancer.19 Therefore, further efforts should be directed to recruit more patients, with deep phenotypic clinical data to allow for relevant adjustments and subgroup analyses to be conducted for better precision.A recent pre-print study by Zhang and colleagues examined the polygenicity and potential for SNP-based risk prediction for 14 common cancers, including endometrial cancer, using available summary-level data from European-ancestry datasets.46 They estimated that there are just over 1000 independent endometrial cancer susceptibility SNPs, and that a PRS comprising all such SNPs would have an area under the receiver-operator curve of 0.64, similar to that predicted for ovarian cancer, but lower than that for the other cancers in the study. The modelling in the paper suggests that an endometrial cancer GWAS double the size of the current largest study would be able to identify susceptibility SNPs together explaining 40% of the genetic variance, but that in order to explain 75% of the genetic variance it would be necessary to have a GWAS comprising close to 150 000 cases and controls, far in excess of what is currently feasible.We found that the literature consists mainly of candidate-gene studies with small sample sizes, meta-analyses reporting conflicting results despite using the same set of primary articles, and multiple reports of significant SNPs that have not been validated by any larger GWAS.

The candidate-gene studies were indeed the most useful and cheaper technique available until the mid to late 2000s. However, a lack of reproducibility (particularly due to population stratification and reporting bias), uncertainty of reported associations, and considerably high false discovery rates make these studies much less appropriate in the post-GWAS era. Unlike the candidate-gene approach, GWAS do not require prior knowledge, selection of genes or SNPs, and provide vast amounts of data. Furthermore, both the genotyping process and data analysis phases have become cheaper, the latter particularly due to faster and open-access pre-phasing and imputation tools being made available.It is clear from table 1 that some SNPs were reported with wide 95% CI, which can be directly attributed to small sample sizes particularly when restricting the cases to non-endometrioid histology only, low EAF or poor imputation quality. Thus, these should be interpreted with caution.

Additionally, most of the SNPs reported by candidate-gene studies were not detected by the largest GWAS to date conducted by O’Mara et al.21 However, this does not necessarily mean that the possibility of those SNPs being relevant should be completely dismissed. Moreover, meta-analyses were attempted for other variants. However, these showed no statistically significant association and many presented with high heterogeneity between the respective studies (data not shown). Furthermore, as many studies utilised the same set of cases and/or controls, conducting a meta-analysis was not possible for a good number of SNPs. It is therefore unequivocal that the literature is crowded with numerous small candidate-gene studies and conflicting data.

This makes it particularly hard to detect novel SNPs and conduct meaningful meta-analyses.We found convincing evidence for 19 variants that indicated the strongest association with endometrial cancer, as shown in table 1. The associations between endometrial cancer and variants in or around HNF1B, CYP19A1, SOX4, MYC, KLF and EIF2AK found in earlier GWAS were then replicated in the latest and largest GWAS. These SNPs showed promising potential in a theoretical PRS we devised based on published data. Using all 24 or genome-wide significant SNPs only, women with a PRS in the top 1% of the distribution would be predicted to have a risk of endometrial cancer 3.16 and 2.09 times higher than the mean risk, respectively.However, the importance of these variants and relevance of the proximate genes in a functional or biological context is challenging to evaluate. Long distance promoter regulation by enhancers may disguise the genuine target gene.

In addition, enhancers often do not loop to the nearest gene, further complicating the relevance of nearby gene(s) to a GWAS hit. In order to elucidate biologically relevant candidate target genes in endometrial cancer, O’Mara et al looked into promoter-associated chromatin looping using a modern HiChIP approach.47 The authors utilised normal and tumoural endometrial cell lines for this analysis which showed significant enrichment for endometrial cancer heritability, with 103 candidate target genes identified across the 13 risk loci identified by the largest ECAC GWAS. Notable genes identified here were CDKN2A and WT1, and their antisense counterparts. The former was reported to be nearby of rs1679014 and the latter of rs10835920, as shown in table 1. Moreover, of the 36 candidate target genes, 17 were found to be downregulated while 19 were upregulated in endometrial tumours.The authors also investigated overlap between the 13 endometrial cancer risk loci and top eQTL variants for each target gene.47 In whole blood, of the two particular lead SNPs, rs8822380 at 17q21.32 was a top eQTL for SNX11 and HOXB2, whereas rs937213 at 15q15.1 was a top eQTL for SRP14.

In endometrial tumour, rs7579014 at 2p16.1 was found to be a top eQTL for BCL11A. This is particularly interesting because BCL11A was the only nearby/candidate gene that had a GWAS association reported in both endometrioid and non-endometrioid subtypes. The study looked at protein–protein interactions between endometrial cancer drivers and candidate target gene products. Significant interactions were observed with TP53 (most significant), AKT, PTEN, ESR1 and KRAS, among others. Finally, when 103 target candidate genes and 387 proteins were combined together, 462 pathways were found to be significantly enriched.

Many of these are related to gene regulation, cancer, obesity, insulinaemia and oestrogen exposure. This study clearly showed a potential biological relevance for some of the SNPs reported by ECAC GWAS in 2018.Most of the larger included studies used cohorts primarily composed of women of broad European descent. Hence, there are negligible data available for other ethnicities, particularly African women. This is compounded by the lack of reference genotype data available for comparative analysis, making it harder for research to be conducted in ethnicities other than Europeans. This poses a problem for developing risk prediction models that are equally valuable and predictive across populations.

Thus, our results also are of limited applicability to non-European populations.Furthermore, considering that non-endometrioid cases comprise a small proportion (~20%) of all endometrial cancer cases, much larger cohort sizes are needed to detect any genuine signals for non-endometrioid tumours. Most of the evaluated studies looked at either overall/mixed endometrial cancer subtypes or endometrioid histology, and those that looked at variant associations with non-endometrioid histology were unlikely to have enough power to detect any signal with statistical significance. This is particularly concerning because non-endometrioid subtypes are biologically aggressive tumours with a much poorer prognosis that contribute disproportionately to mortality from endometrial cancer. It is particularly important that attempts to improve early detection and prevention of endometrial cancer focus primarily on improving outcomes from these subtypes. It is also worth noting that, despite the current shift towards a molecular classification of endometrial cancer, most studies used the overarching classical Bokhman’s classification system, type I versus type II, or no histological classification system at all.

Therefore, it is important to create and follow a standardised and comprehensive classification system for reporting tumour subtypes for future studies.This study compiled and presented available information for an extensively studied, yet unproven in large datasets, SNP309 variant in MDM2. Currently, there is no convincing evidence for an association between this variant and endometrial cancer risk. Additionally, of all the studies, only one accounted for the opposing effect of a nearby variant SNP285 in their analyses. Thus, we conclude that until confirmed by a sufficiently large GWAS, this variant should not be considered significant in influencing the risk of endometrial cancer and therefore not included in a PRS. This is also true for the majority of the SNPs reported in candidate-gene studies, as the numbers fall far short of being able to detect genuine signals.This systematic review presents the most up-to-date evidence for endometrial cancer susceptibility variants, emphasising the need for further large-scale studies to identify more variants of importance, and validation of these associations.

Until data from larger and more diverse cohorts are available, the top 24 SNPs presented here are the most robust common genetic variants that affect endometrial cancer risk. The multiplicative effects of these SNPs could be used in a PRS to allow personalised risk prediction models to be developed for targeted screening and prevention interventions for women at greatest risk of endometrial cancer..

IntroductionIn recent years, many studies have been published on new diagnostic possibilities and management approaches in cohorts of patients suspected to have a disorder/difference of sex development (DSD).1–13 Based on these studies, it has become clear that services and institutions still differ in the composition of the multidisciplinary http://farmingtondragway.com/?tribe_events=firecracker-10s-one-race-top-and-footbrake-and-juniors-80-pay-back-2 teams what do you need to buy seroquel that provide care for patients who have a DSD.11 14 Several projects have now worked to resolve this variability in care. The European Cooperation in Science and Technology (EU COST) action BM1303 ‘A systematic elucidation of differences of sex development’ has been a platform to achieve European agreement on harmonisation of clinical management and laboratory practices.15–17 Another such initiative involved an update of the 2006 DSD consensus document by an international group of professionals and patient representatives.18 These initiatives have highlighted what do you need to buy seroquel how cultural and financial aspects and the availability of resources differ significantly between countries and societies, a situation that hampers supranational agreement on common diagnostic protocols. As only a few national guidelines have been published in international journals, comparison of these guidelines is difficult even though such a comparison is necessary to capture the differences and initiate actions to overcome them. Nonetheless, four DSD (expert) centres located in the Netherlands and Flanders (the what do you need to buy seroquel Dutch-speaking Northern part of Belgium) have collaborated to produce a detailed guideline on diagnostics in DSD.19 This shows that a supranational guideline can be a reasonable approach for countries with similarly structured healthcare systems and similar resources. Within the guideline there is agreement that optimisation of expertise and care can be achieved through centralisation, for example, by limiting analysis of next-generation sequencing (NGS)-based diagnostic panels to only a few centres and by centralising pathological review of gonadal tissues.

International networks such as the European Reference Network for rare what do you need to buy seroquel endocrine conditions (EndoERN), in which DSD is embedded, may facilitate the expansion of this kind of collaboration across Europe.This paper highlights key discussion points in the Dutch-Flemish guideline that have been insufficiently addressed in the literature thus far because they reflect evolving technologies or less visible stakeholders. For example, prenatal observation of an atypical aspect of the genitalia indicating a possible DSD is becoming increasingly common, and we discuss appropriate counselling and a diagnostic approach for these cases, including the option of using NGS-based genetic testing. So far, little attention has been paid to this process.20 what do you need to buy seroquel 21 Furthermore, informing patients and/or their parents about atypical sex development and why this may warrant referral to a specialised team may be challenging, especially for professionals with limited experience in DSD.22 23 Therefore, a section of the Dutch-Flemish guideline was written for these healthcare providers. Moreover, this enables DSD specialists to refer to the guideline when advising a referral. Transition from the prenatal to the postnatal team and from the paediatric to the adult team requires optimal communication between what do you need to buy seroquel the specialists involved.

Application of NGS-based techniques may lead to a higher diagnostic yield, providing a molecular genetic diagnosis in previously unsolved cases.16 We address the timing of this testing and the problems associated with this technique such as the interpretation of variants of unknown clinical significance (VUS). Similarly, histopathological interpretation and classification of removed gonadal tissue is challenging and would benefit from international collaboration and centralisation of expertise.MethodsFor the guideline revision, an interdisciplinary multicentre group was formed with all members responsible for updating the literature for a specific part of what do you need to buy seroquel the guideline. Literature search in PubMed was not systematic, but rather intended to be broad in order to cover all areas and follow expert opinions. This approach is more in line with the Clinical Practice Advisory Document method described by Burke et al24 for guidelines involving genetic practice because it is often troublesome to substantiate such guidelines with sufficient evidence due to the rapid changes in testing methods, for example, what do you need to buy seroquel gene panels. All input provided by the group was synthesised by the chairperson (YvB), who also reviewed abstracts of papers on DSD published between 2010 and September 2017 for the guideline and up to October 2019 for this paper.

Abstracts had to be written in English and were identified using a broad range of Medical Subject Headings terms (eg, DSD, genetic, review, diagnosis, what do you need to buy seroquel diagnostics, 46,XX DSD, 46,XY DSD, guideline, multidisciplinary care). Next, potentially relevant papers on diagnostic procedures in DSD were selected. Case reports were excluded, as were articles that were not open access or retrievable through institutional what do you need to buy seroquel access. Based on this, a draft guideline was produced that was in line with the international principles of good diagnostic care in DSD. This draft was discussed by the writing committee and, after having obtained agreement on remaining points of discussion, revised into a final draft what do you need to buy seroquel.

This version was sent to a broad group of professionals from academic centres and DSD teams whose members had volunteered to review the draft guideline. After receiving and incorporating their what do you need to buy seroquel input, the final version was presented to the paediatric and genetic associations for approval. After approval by the members of the paediatric (NVK), clinical genetic (VKGN) and genetic laboratory (VKGL) associations, the guideline was published on their respective websites.19 Although Turner syndrome and Klinefelter syndrome are considered to be part of the DSD spectrum, they are not extensively discussed in this diagnostic guideline as guidelines dedicated to these syndromes already exist.25 26 However, some individuals with Turner syndrome or Klinefelter syndrome may present with ambiguous or atypical genitalia and may therefore initially follow the DSD diagnostic process.Guideline highlightsPrenatal settingPresentationThe most frequent prenatal presentation of a DSD condition is atypical genitalia found on prenatal ultrasound as an isolated finding or in combination with other structural anomalies. This usually occurs after the 20-week routine medical ultrasound for screening of congenital anomalies, but may also occur earlier, for example, when a commercial ultrasound is performed at the request of the parents.Another way DSD can be diagnosed before birth what do you need to buy seroquel is when invasive prenatal genetic testing carried out for a different reason, for example, due to suspicion of other structural anomalies, reveals a discrepancy between the genotypic sex and the phenotypic sex seen by ultrasound. In certified laboratories, the possibility of a sample switch is extremely low but should be ruled out immediately.

More often, the discrepancy will what do you need to buy seroquel be due to sex-chromosome mosaicism or a true form of DSD.A situation now occurring with increasing frequency is a discrepancy between the genotypic sex revealed by non-invasive prenatal testing (NIPT), which is now available to high-risk pregnant women in the Netherlands and to all pregnant women in Belgium, and later ultrasound findings. NIPT screens for CNVs in the fetus. However, depending on legal restrictions and/or ethical considerations, the what do you need to buy seroquel X and Y chromosomes are not always included in NIPT analysis and reports. If the X and Y chromosomes are included, it is important to realise that the presence of a Y-chromosome does not necessarily imply male fetal development. At the time that NIPT is performed (usually 11–13 weeks), genital development cannot be reliably appreciated by ultrasound, so any discrepancy or atypical aspect of the genitalia will only be noticed later in pregnancy and should prompt further evaluation.Counselling and diagnosticsIf a DSD is suspected, first-line sonographers and obstetricians should refer the couple to what do you need to buy seroquel their colleague prenatal specialists working with or in a DSD team.

After confirming an atypical genital on ultrasound, the specialist team should offer the couple a referral for genetic counselling to discuss the possibility of performing invasive prenatal testing (usually an amniocentesis) to identify an underlying cause that fits the ultrasound findings.22 23 To enable the parents to make a well-informed decision, prenatal counselling should, in our opinion, include. Information on the ultrasound findings and the limitations of this technique what do you need to buy seroquel. The procedure(s) that can be followed, including the risks associated with an amniocentesis. And the what do you need to buy seroquel type of information genetic testing can and cannot provide. Knowing which information has been provided and what words have been used by the prenatal specialist is very helpful for those involved in postnatal care.It is important that parents understand that the biological sex of a baby is determined by a complex interplay of chromosomes, genes and hormones, and thus that assessment of the presence or absence of a Y-chromosome alone is insufficient to assign the sex of their unborn child or, as in any unborn child, say anything about the child’s future gender identity.Expecting parents can be counselled by the clinical geneticist and the psychologist from the DSD team, although other DSD specialists can also be involved.

The clinical geneticist should be experienced in prenatal counselling and well informed about the diagnostic possibilities given the limited time span in which test what do you need to buy seroquel results need to be available to allow parents to make a well-informed decision about whether or not to continue the pregnancy. Termination of pregnancy can be considered, for instance, in a syndromic form of DSD with multiple malformations, but when the DSD occurs as what do you need to buy seroquel an apparently isolated condition, expecting parents may also consider termination of pregnancy, which, although considered controversial by some, is legal in Belgium and the Netherlands. The psychologist of the DSD team can support parents during and after pregnancy and help them cope with feelings of uncertainty and eventual considerations of a termination of pregnancy, as well as with practical issues, for example, how to inform others. The stress of not knowing exactly what the child’s genitalia will what do you need to buy seroquel look like and uncertainty about the diagnosis, treatment and prognosis cannot be avoided completely. Parents are informed that if the postnatal phenotype is different from what was prenatally expected, the advice given about diagnostic testing can be adjusted accordingly, for example, if a hypospadias is milder than was expected based on prenatal ultrasound images.

In our what do you need to buy seroquel experience, parents appreciate having already spoken to some members of the DSD team during pregnancy and having a contact person before birth.After expert prenatal counselling, a significant number of pregnant couples decline prenatal testing (personal experience IALG, MK, ABD, YvB, MC and HC-vdG). At birth, umbilical cord blood is a good source for (molecular) karyotyping and storage of DNA and can be obtained by the obstetrician, midwife or neonatologist. The terminology used in communication with parents should be carefully chosen,22 23 and midwives and staff of neonatal and delivery units should be clearly instructed to use gender-neutral and non-stigmatising vocabulary (eg, ‘your baby’) as long as sex assignment is pending.An algorithm for diagnostic evaluation of a suspected DSD in the prenatal situation what do you need to buy seroquel is proposed in figure 1. When couples opt for invasive prenatal diagnosis, the genetic analysis usually involves an (SNP)-array. It was recently estimated that >30% of individuals who have a DSD have additional structural anomalies, with cardiac and neurological anomalies and fetal growth restriction being particularly common.27 28 If additional anomalies are seen, the geneticist can consider specific gene defects that may underlie a what do you need to buy seroquel known genetic syndrome or carry out NGS.

NGS-based techniques have also now made their appearance in prenatal diagnosis of congenital anomalies.29 30 Panels using these techniques can be specific for genes involved in DSD, or be larger panels covering multiple congenital anomalies, and are usually employed with trio-analysis to compare variants identified in the child with the parents’ genetics.29–31 Finding a genetic cause before delivery can help reduce parental stress in the neonatal period and speed up decisions regarding gender assignment. In such cases there is no tight time limit, what do you need to buy seroquel and we propose completing the analysis well before the expected delivery.Disorders/differences of sex development (DSD) in the prenatal setting. A diagnostic algorithm. *SOX9. Upstream anomalies and balanced translocations at promotor sites!.

Conventional karyotyping can be useful. NGS, next-generation sequencing." data-icon-position data-hide-link-title="0">Figure 1 Disorders/differences of sex development (DSD) in the prenatal setting. A diagnostic algorithm. *SOX9. Upstream anomalies and balanced translocations at promotor sites!.

Conventional karyotyping can be useful. NGS, next-generation sequencing.First contact by a professional less experienced in DSDWhereas most current guidelines start from the point when an individual has been referred to the DSD team,1 15 the Dutch-Flemish guideline dedicates a chapter to healthcare professionals less experienced in DSD as they are often the first to suspect or identify such a condition. Apart from the paper of Indyk,7 little guidance is available for these professionals about how to act in such a situation. The chapter in the Dutch-Flemish guideline summarises the various clinical presentations that a DSD can have and provides information on how to communicate with parents and/or patients about the findings of the physical examination, the first-line investigations and the need for prompt referral to a specialised centre for further evaluation. Clinical examples are offered to illustrate some of these recurring situations.

The medical issues in DSD can be very challenging, and the social and psychological impact is high. For neonates with ambiguous genitalia, sex assignment is an urgent and crucial issue, and it is mandatory that parents are informed that it is possible to postpone registration of their child’s sex. In cases where sex assignment has already taken place, the message that the development of the gonads or genitalia is still atypical is complicated and distressing for patients and parents or carers. A list of contact details for DSD centres and patient organisations in the Netherlands and Flanders is attached to the Dutch-Flemish guideline. Publishing such a list, either in guidelines or online, can help healthcare professionals find the nearest centres for consultations and provide patients and patient organisations with an overview of the centres where expertise is available.Timing and place of genetic testing using NGS-based gene panelsThe diagnostic workup that is proposed for 46,XX and 46,XY DSD is shown in figures 2 and 3, respectively.

Even with the rapidly expanding molecular possibilities, a (family) history and a physical examination remain the essential first steps in the diagnostic process. Biochemical and hormonal screening aim at investigating serum electrolytes, renal function and the hypothalamic-pituitary-gonadal and hypothalamic-pituitary-adrenal axes. Ultrasound screening of kidneys and internal genitalia, as well as establishing genotypic sex, should be accomplished within 48 hours and complete the baseline diagnostic work-up of a child born with ambiguous genitalia.1 16 32 3346,XX disorders/differences of sex development (DSD) in the postnatal setting. A diagnostic algorithm. NGS, next-generation sequencing.

CAH, Congenital adrenal hyperplasia. AMH, Anti-Müllerian Hormone." data-icon-position data-hide-link-title="0">Figure 2 46,XX disorders/differences of sex development (DSD) in the postnatal setting. A diagnostic algorithm. NGS, next-generation sequencing. CAH, Congenital adrenal hyperplasia.

AMH, Anti-Müllerian Hormone.46,XY disorders/differences of sex development (DSD) in the postnatal setting. A diagnostic algorithm. * SOX9. Upstream anomalies and balanced translocations at promotor sites!. Conventional karyotyping can be useful.

NGS, next-generation sequencing." data-icon-position data-hide-link-title="0">Figure 3 46,XY disorders/differences of sex development (DSD) in the postnatal setting. A diagnostic algorithm. *SOX9. Upstream anomalies and balanced translocations at promotor sites!. Conventional karyotyping can be useful.

NGS, next-generation sequencing.Very recently, a European position paper has been published focusing on the genetic workup of DSD.16 It highlights the limitations and drawbacks of NGS-based tests, which include the chance of missing subtle structural variants such as CNVs and mosaicism and the fact that NGS cannot detect methylation defects or other epigenetic changes.16 28 31 Targeted DNA analysis is preferred in cases where hormonal investigations suggest a block in steroidogenesis (eg, 11-β-hydroxylase deficiency, 21-hydroxylase deficiency), or in the context of a specific clinical constellation such as the often coincidental finding of Müllerian structures in a boy with normal external genitalia or cryptorchidism, that is, persistent Müllerian duct syndrome.33 34 Alternative tests should also be considered depending on the available information. Sometimes, a simple mouth swab for FISH analysis can detect mosaic XY/X in a male with hypospadias or asymmetric gonadal development or in a female with little or no Turner syndrome stigmata and a normal male molecular karyotyping profile or peripheral blood karyotype. Such targeted testing avoids incidental findings and is cheaper and faster than analysis of a large NGS-based panel, although the cost difference is rapidly declining.However, due to the genetic and phenotypic heterogeneity of DSD conditions, the most cost-effective next steps in the majority of cases are whole exome sequencing followed by panel analysis of genes involved in genital development and function or trio-analysis of a large gene panel (such as a Mendeliome).16 35–38 Pretest genetic counselling involves discussing what kind of information will be reported to patients or parents and the chance of detecting VUS, and the small risk of incidental findings when analysing a DSD panel should be mentioned. Laboratories also differ in what class of variants they report.39 In our experience, the fear of incidental findings is a major reason why some parents refrain from genetic testing.Timing of the DSD gene panel analysis is also important. While some patients or parents prefer that all diagnostic procedures be performed as soon as possible, others need time to reflect on the complex information related to more extensive genetic testing and on its possible consequences.

If parents or patients do not consent to panel-based genetic testing, analysis of specific genes, such as WT1, should be considered when appropriate in view of the clinical consequences if a mutation is present (eg, clinical surveillance of renal function and screening for Wilms’ tumour in the case of WT1 mutations). Genes that are more frequently involved in DSD (eg, SRY, NR5A1) and that match the specific clinical and hormonal features in a given patient could also be considered for sequencing. Targeted gene analysis may also be preferred in centres located in countries that do not have the resources or technical requirements to perform NGS panel-based genetic testing. Alternatively, participation by these centres in international collaborative networks may allow them to outsource the molecular genetic workup abroad.Gene panels differ between centres and are regularly updated based on scientific progress. A comparison of DSD gene panels used in recent studies can be found at https://www.nature.com/articles/s41574-018-0010-8%23Sec46.15 The panels currently used at the coauthors’ institutions can be found on their respective websites.

Given the pace of change, it is important to regularly consider repeating analysis in patients with an unexplained DSD, for example, when they transition into adult care or when they move from one centre to another. This also applies to patients in whom a clinical diagnosis has never been genetically confirmed. Confusion may arise when the diagnosis cannot be confirmed or when a mutation is identified in a different gene, for example, NR5A1 in someone with a clinical diagnosis of CAIS that has other consequences for relatives. Hence, new genetic counselling should always accompany new diagnostic endeavours.Class 3 variants and histopathological examinationsThe rapidly evolving diagnostic possibilities raise new questions. What do laboratories report?.

How should we deal with the frequent findings of mainly unique VUS or class 3 variants (ACMG recommendation) in the many different DSD-related genes in the diagnostic setting?. Reporting VUS can be a source of uncertainty for parents, but not reporting these variants precludes further investigations to determine their possible pathogenicity. It can also be difficult to prove variant pathogenicity, both on gene-level and variant-level.39 Moreover, given the gonad-specific expression of some genes and the variable phenotypic spectrum and reduced penetrance, segregation analysis is not always informative. A class 3 variant that does not fit the clinical presentation may be unrelated to the observed phenotype, but it could also represent a newly emerging phenotype. This was recently demonstrated by the identification of the NR5A1 mutation, R92W, in individuals with 46,XX testicular and ovotesticular DSD.40 This gene had previously been associated with 46,XY DSD.

In diagnostic laboratories, there is usually no capacity or expertise to conduct large-scale functional studies to determine pathogenicity of these unique class 3 VUS in the different genes involved in DSD. Functional validation of variants identified in novel genes may be more attractive in a research context. However, for individual families with VUS in well-established DSD genes such as AR or HSD17B3, functional analysis may provide a confirmed diagnosis that implies for relatives the option of undergoing their own DNA analysis and estimating the genetic risk of their own future offspring. This makes genetic follow-up important in these cases and demonstrates the usefulness of international databases and networks and the centralisation of functional studies of genetic variants in order to reduce costs and maximise expertise.The same is true for histopathological description, germ-cell tumour risk assessment in specific forms of DSD and classification of gonadal samples. Germ-cell tumour risk is related to the type of DSD (among other factors), but it is impossible to make risk estimates in individual cases.41–44 Gonadectomy may be indicated in cases with high-risk dysgenetic abdominal gonads that cannot be brought into a stable superficial (ie, inguinal, labioscrotal) position that allows clinical or radiological surveillance, or to avoid virilisation due to 5-alpha reductase deficiency in a 46,XY girl with a stable female gender identity.45 Pathological examination of DSD gonads requires specific expertise.

For example, the differentiation between benign germ cell abnormalities, such as delayed maturation and (pre)malignant development of germ cells, is crucial for clinical management but can be very troublesome.46 Centralised pathological examination of gonadal biopsy and gonadectomy samples in one centre, or a restricted number of centres, on a national scale can help to overcome the problem of non-uniform classification and has proven feasible in the Netherlands and Belgium. We therefore believe that uniform assessment and classification of gonadal differentiation patterns should also be addressed in guidelines on DSD management.International databases of gonadal tissues are crucial for learning more about the risk of malignancy in different forms of DSD, but they are only reliable if uniform criteria for histological classification are strictly applied.46 These criteria could be incorporated in many existing networks such as the I-DSD consortium, the Disorders of Sex Development Translational Research Network, the European Reference Network on Urogenital Diseases (eUROGEN), the EndoERN and COST actions.15–17 47Communication at the transition from paediatric to adult carePaediatric and adult teams need to collaborate closely to facilitate a well-organised transition from paediatric to adult specialist care.15 48–50 Both teams need to exchange information optimally and should consider transition as a longitudinal process rather than a fixed moment in time. Age-appropriate information is key at all ages, and an overview of topics to be discussed at each stage is described by Cools et al.15 Table 1 shows an example of how transition can be organised.View this table:Table 1 Example of transition table as used in the DSD clinic of the Erasmus Medical CenterPsychological support and the continued provision of information remains important for individuals with a DSD at all ages.15 22 In addition to the information given by the DSD team members, families and patients can benefit from resources such as support groups and information available on the internet.47 Information available online should be checked for accuracy and completeness when referring patients and parents to internet sites.Recommendations for future actionsMost guidelines and articles on the diagnosis and management of DSD are aimed at specialists and are only published in specialist journals or on websites for endocrinologists, urologists or geneticists. Yet there is a need for guidelines directed towards first-line and second-line healthcare workers that summarise the recommendations about the first crucial steps in the management of DSD. These should be published in widely available general medical journals and online, along with a national list of DSD centres.

Furthermore, DSD (expert) centres should provide continuous education to all those who may be involved in the identification of individuals with a DSD in order to enable these healthcare professionals to recognise atypical genitalia, to promptly refer individuals who have a DSD and to inform the patient and parents about this and subsequent diagnostic procedures.As DSD continues to be a rare condition, it will take time to evaluate the effects of having such a guideline on the preparedness of first-line and second-line healthcare workers to recognise DSD conditions. One way to evaluate this might be the development and use of questionnaires asking patients, carers and families and referring physicians how satisfied they were with the initial medical consultation and referral and what could be improved. A helpful addition to existing international databases that collect information on genetic variations would be a list of centres that offer suitable functional studies for certain genes, ideally covering the most frequently mutated genes (at minimum).Patient organisations can also play an important role in informing patients about newly available diagnostic or therapeutic strategies and options, and their influence and specific role has now been recognised and discussed in several publications.17 47 However, it should be kept in mind that these organisations do not represent all patients, as a substantial number of patients and parents are not member of such an organisation.Professionals have to provide optimal medical care based on well-established evidence, or at least on broad consensus. Yet not everything can be regulated by recommendations and guidelines. Options, ideas and wishes should be openly discussed between professionals, patients and families within their confidential relationship.

This will enable highly individualised holistic care tailored to the patient’s needs and expectations. Once they are well-informed of all available options, parents and/or patients can choose what they consider the optimal care for their children or themselves.15 16ConclusionThe Dutch-Flemish guideline uniquely addresses some topics that are under-represented in the literature, thus adding some key aspects to those addressed in recent consensus papers and guidelines.15–17 33 47As more children with a DSD are now being identified prenatally, and the literature on prenatal diagnosis of DSD remains scarce,20 21 we propose a prenatal diagnostic algorithm and emphasise the importance of having a prenatal specialist involved in or collaborating with DSD (expert) centres.We also stress that good communication between all involved parties is essential. Professionals should be well informed about protocols and communication. Collaboration between centres is necessary to optimise aspects of care such as uniform interpretation of gonadal pathology and functional testing of class 3 variants found by genetic testing. Guidelines can provide a framework within which individualised patient care should be discussed with all stakeholders.AcknowledgmentsThe authors would like to thank the colleagues of the DSD teams for their input in and critical reading of the Dutch-Flemish guideline.

Amsterdam University Center (AMC and VU), Maastricht University Medical Center, Erasmus Medical Center Rotterdam, Radboud University Medical Center Nijmegen, University Medical Center Groningen, University Medical Center Utrecht, Ghent University Hospital. The authors would like to thank Kate McIntyre for editing the revised manuscript and Tom de Vries Lentsch for providing the figures as a PDF. Three of the authors of this publication are members of the European Reference Network for rare endocrine diseases—Project ID 739543.IntroductionEndometrial cancer is the most common gynaecological malignancy in the developed world.1 Its incidence has risen over the last two decades as a consequence of the ageing population, fewer hysterectomies for benign disease and the obesity epidemic. In the USA, it is estimated that women have a 1 in 35 lifetime risk of endometrial cancer, and in contrast to cancers of most other sites, cancer-specific mortality has risen by approximately 2% every year since 2008 related to the rapidly rising incidence.2Endometrial cancer has traditionally been classified into type I and type II based on morphology.3 The more common subtype, type I, is mostly comprised of endometrioid tumours and is oestrogen-driven, arises from a hyperplastic buy seroquel endometrium, presents at an early stage and has an excellent 5 year survival rate.4 By contrast, type II includes non-endometrioid tumours, specifically serous, carcinosarcoma and clear cell subtypes, which are biologically aggressive tumours with a poor prognosis that are often diagnosed at an advanced stage.5 Recent efforts have focused on a molecular classification system for more accurate categorisation of endometrial tumours into four groups with distinct prognostic profiles.6 7The majority of endometrial cancers arise through the interplay of familial, genetic and lifestyle factors. Two inherited cancer predisposition syndromes, Lynch syndrome and the much rarer Cowden syndrome, substantially increase the lifetime risk of endometrial cancer, but these only account for around 3–5% of cases.8–10 Having first or second degree relative(s) with endometrial or colorectal cancer increases endometrial cancer risk, although a large European twin study failed to demonstrate a strong heritable link.11 The authors failed to show that there was greater concordance in monozygotic than dizygotic twins, but the study was based on relatively small numbers of endometrial cancers.

Lu and colleagues reported an association between common single nucleotide polymorphisms (SNPs) and endometrial cancer risk, revealing the potential role of SNPs in explaining part of the risk in both the familial and general populations.12 Thus far, many SNPs have been reported to modify susceptibility to endometrial cancer. However, much of this work predated genome wide association studies and is of variable quality. Understanding genetic predisposition to endometrial cancer could facilitate personalised risk assessment with a view to targeted prevention and screening interventions.13 This emerged as the most important unanswered research question in endometrial cancer according to patients, carers and healthcare professionals in our recently completed James Lind Womb Cancer Alliance Priority Setting Partnership.14 It would be particularly useful for non-endometrioid endometrial cancers, for which advancing age is so far the only predictor.15We therefore conducted a comprehensive systematic review of the literature to provide an overview of the relationship between SNPs and endometrial cancer risk. We compiled a list of the most robust endometrial cancer-associated SNPs. We assessed the applicability of this panel of SNPs with a theoretical polygenic risk score (PRS) calculation.

We also critically appraised the meta-analyses investigating the most frequently reported SNPs in MDM2. Finally, we described all SNPs reported within genes and pathways that are likely involved in endometrial carcinogenesis and metastasis.MethodsOur systematic review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) collaboration 2009 recommendations. The registered protocol is available through PROSPERO (CRD42018091907).16Search strategyWe searched Embase, MEDLINE and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases via the Healthcare Databases Advanced Search (HDAS) platform, from 2007 to 2018, to identify studies reporting associations between polymorphisms and endometrial cancer risk. Key words including MeSH (Medical Subject Heading) terms and free-text words were searched in both titles and abstracts. The following terms were used.

€œendomet*”,“uter*”, “womb”, “cancer(s)”, “neoplasm(s)”, “endometrium tumour”, “carcinoma”, “adenosarcoma”, “clear cell carcinoma”, “carcinosarcoma”, “SNP”, “single nucleotide polymorphism”, “GWAS”, and “genome-wide association study/ies”. No other restrictions were applied. The search was repeated with time restrictions between 2018 and June 2019 to capture any recent publications.Eligibility criteriaStudies were selected for full-text evaluation if they were primary articles investigating a relationship between endometrial cancer and SNPs. Study outcome was either the increased or decreased risk of endometrial cancer relative to controls reported as an odds ratio (OR) with corresponding 95% confidence intervals (95% CIs).Study selectionThree independent reviewers screened all articles uploaded to a screening spreadsheet developed by Helena VonVille.17 Disagreements were resolved by discussion. Chronbach’s α score was calculated between reviewers and indicated high consistency at 0.92.

Case–control, prospective and retrospective studies, genome-wide association studies (GWAS), and both discovery and validation studies were selected for full-text evaluation. Non-English articles, editorials, conference abstracts and proceedings, letters and correspondence, case reports and review articles were excluded.Candidate-gene studies with at least 100 women and GWAS with at least 1000 women in the case arm were selected to ensure reliability of the results, as explained by Spencer et al.18 To construct a panel of up to 30 SNPs with the strongest evidence of association, those with the strongest p values were selected. For the purpose of an SNP panel, articles utilising broad European or multi-ethnic cohorts were selected. Where overlapping populations were identified, the most comprehensive study was included.Data extraction and synthesisFor each study, the following data were extracted. SNP ID, nearby gene(s)/chromosome location, OR (95% CI), p value, minor or effect allele frequency (MAF/EAF), EA (effect allele) and OA (other allele), adjustment, ethnicity and ancestry, number of cases and controls, endometrial cancer type, and study type including discovery or validation study and meta-analysis.

For risk estimates, a preference towards most adjusted results was applied. For candidate-gene studies, a standard p value of<0.05 was applied and for GWAS a p value of <5×10-8, indicating genome-wide significance, was accepted as statistically significant. However, due to the limited number of SNPs with p values reaching genome-wide significance, this threshold was then lowered to <1×10-5, allowing for marginally significant SNPs to be included. As shown by Mavaddat et al, for breast cancer, SNPs that fall below genome-wide significance may still be useful for generating a PRS and improving the models.19We estimated the potential value of a PRS based on the most significant SNPs by comparing the predicted risk for a woman with a risk score in the top 1% of the distribution to the mean predicted risk. Per-allele ORs and MAFs were taken from the publications and standard errors (SEs) for the lnORs were derived from published 95% CIs.

The PRS was assumed to have a Normal distribution, with mean 2∑βipI and SE, σ, equal to √2∑βi2pI(1−pi), according to the binomial distribution, where the summation is over all SNPs in the risk score. Hence the relative risk (RR) comparing the top 1% of the distribution to the mean is given by exp(Z0.01σ), where Z is the inverse of the standard normal cumulative distribution.ResultsThe flow chart of study selection is illustrated in figure 1. In total, 453 text articles were evaluated and, of those, 149 articles met our inclusion criteria. One study was excluded from table 1, for having an Asian-only population, as this would make it harder to compare with the rest of the results which were all either multi-ethnic or Caucasian cohorts, as stated in our inclusion criteria for the SNP panel.20 Any SNPs without 95% CIs were also excluded from any downstream analysis. Additionally, SNPs in linkage disequilibrium (r2 >0.2) with each other were examined, and of those in linkage disequilibrium, the SNP with strongest association was reported.

Per allele ORs were used unless stated otherwise.View this table:Table 1 List of top SNPs most likely to contribute to endometrial cancer risk identified through systematic review of recent literature21–25Study selection flow diagram. *Reasons. Irrelevant articles, articles focusing on other conditions, non-GWAS/candidate-gene study related articles, technical and duplicate articles. GWAS, genome-wide association study. Adapted from.

Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The PRISMA Statement. PLoS Med 6(6). E1000097.

Doi:10.1371/journal.pmed1000097." data-icon-position data-hide-link-title="0">Figure 1 Study selection flow diagram. *Reasons. Irrelevant articles, articles focusing on other conditions, non-GWAS/candidate-gene study related articles, technical and duplicate articles. GWAS, genome-wide association study. Adapted from.

Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The PRISMA Statement. PLoS Med 6(6). E1000097.

Doi:10.1371/journal.pmed1000097.Top SNPs associated with endometrial cancer riskFollowing careful interpretation of the data, 24 independent SNPs with the lowest p values that showed the strongest association with endometrial cancer were obtained (table 1).21–25 These SNPs are located in or around genes coding for transcription factors, cell growth and apoptosis regulators, and enzymes involved in the steroidogenesis pathway. All the SNPs presented here were reported on the basis of a GWAS or in one case, an exome-wide association study, and hence no SNPs from candidate-gene studies made it to the list. This is partly due to the nature of larger GWAS providing more comprehensive and powered results as opposed to candidate gene studies. Additionally, a vast majority of SNPs reported by candidate-gene studies were later refuted by large-scale GWAS such as in the case of TERT and MDM2 variants.26 27 The exception to this is the CYP19 gene, where candidate-gene studies reported an association between variants in this gene with endometrial cancer in both Asian and broad European populations, and this association was more recently confirmed by large-scale GWAS.21 28–30 Moreover, a recent article authored by O’Mara and colleagues reviewed the GWAS that identified most of the currently known SNPs associated with endometrial cancer.31Most of the studies represented in table 1 are GWAS and the majority of these involved broad European populations. Those having a multi-ethnic cohort also consisted primarily of broad European populations.

Only four of the variants in table 1 are located in coding regions of a gene, or in regulatory flanking regions around the gene. Thus, most of these variants would not be expected to cause any functional effects on the gene or the resulting protein. An eQTL search using GTEx Portal showed that some of the SNPs are significantly associated (p<0.05) with modified transcription levels of the respective genes in various tissues such as prostate (rs11263761), thyroid (rs9668337), pituitary (rs2747716), breast mammary (rs882380) and testicular (rs2498794) tissue, as summarised in table 2.View this table:Table 2 List of eQTL hits for the selected panel of SNPsThe only variant for which there was an indication of a specific association with non-endometrioid endometrial cancer was rs148261157 near the BCL11A gene. The A allele of this SNP had a moderately higher association in the non-endometrioid arm (OR 1.64, 95% CI 1.32 to 2.04. P=9.6×10-6) compared with the endometrioid arm (OR 1.25, 95% CI 1.14 to 1.38.

P=4.7×10-6).21Oestrogen receptors α and β encoded by ESR1 and ESR2, respectively, have been extensively studied due to the assumed role of oestrogens in the development of endometrial cancer. O’Mara et al reported a lead SNP (rs79575945) in the ESR1 region that was associated with endometrial cancer (p=1.86×10-5).24 However, this SNP did not reach genome-wide significance in a more recent larger GWAS.21 No statistically significant associations have been reported between endometrial cancer and SNPs in the ESR2 gene region.AKT is an oncogene linked to endometrial carcinogenesis. It is involved in the PI3K/AKT/mTOR pro-proliferative signalling pathway to inactivate apoptosis and allow cell survival. The A allele of rs2494737 and G allele of rs2498796 were reported to be associated with increased and decreased risk of endometrial cancer in 2016, respectively.22 30 However, this association was not replicated in a larger GWAS in 2018.21 Nevertheless, given the previous strong indications, and biological basis that could explain endometrial carcinogenesis, we decided to include an AKT1 variant (rs2498794) in our results.PTEN is a multi-functional tumour suppressor gene that regulates the AKT/PKB signalling pathway and is commonly mutated in many cancers including endometrial cancer.32 Loss-of-function germline mutations in PTEN are responsible for Cowden syndrome, which exerts a lifetime risk of endometrial cancer of up to 28%.9 Lacey and colleagues studied SNPs in the PTEN gene region. However, none showed significant differences in frequency between 447 endometrial cancer cases and 439 controls of European ancestry.33KRAS mutations are known to be present in endometrial cancer.

These can be activated by high levels of KLF5 (transcriptional activator). Three SNPs have been identified in or around KLF5 that are associated with endometrial cancer. The G allele of rs11841589 (OR 1.15, 95% CI 1.11 to 1.21. P=4.83×10-11), the A allele of rs9600103 (OR 1.23, 95% CI 1.16 to 1.30. P=3.76×10-12) and C allele of rs7981863 (OR 1.16, 95% CI 1.12 to 1.20.

P=2.70×10-17) have all been found to be associated with an increased likelihood of endometrial cancer in large European cohorts.21 30 34 It is worth noting that these SNPs are not independent, and hence they quite possibly tag the same causal variant.The MYC family of proto-oncogenes encode transcription factors that regulate cell proliferation, which can contribute to cancer development if dysregulated. The recent GWAS by O’Mara et al reported three SNPs within the MYC region that reached genome-wide significance with conditional p values reaching at least 5×10–8.35To test the utility of these SNPs as predictive markers, we devised a theoretical PRS calculation using the log ORs and EAFs per SNP from the published data. The results were very encouraging with an RR of 3.16 for the top 1% versus the mean, using all the top SNPs presented in table 1 and 2.09 when using only the SNPs that reached genome-wide significance (including AKT1).Controversy surrounding MDM2 variant SNP309MDM2 negatively regulates tumour suppressor gene TP53, and as such, has been extensively studied in relation to its potential role in predisposition to endometrial cancer. Our search identified six original studies of the association between MDM2 SNP rs2279744 (also referred to as SNP309) and endometrial cancer, all of which found a statistically significant increased risk per copy of the G allele. Two more original studies were identified through our full-text evaluation.

However, these were not included here as they did not meet our inclusion criteria—one due to small sample size, the other due to studying rs2279744 status dependent on another SNP.36 37 Even so, the two studies were described in multiple meta-analyses that are listed in table 3. Different permutations of these eight original studies appear in at least eight published meta-analyses. However, even the largest meta-analysis contained <2000 cases (table 3)38View this table:Table 3 Characteristics of studies that examined MDM2 SNP rs2279744In comparison, a GWAS including nearly 13 000 cases found no evidence of an association with OR and corresponding 95% CI of 1.00 (0.97 to 1.03) and a p value of 0.93 (personal communication).21 Nevertheless, we cannot completely rule out a role for MDM2 variants in endometrial cancer predisposition as the candidate-gene studies reported larger effects in Asians, whereas the GWAS primarily contained participants of European ancestry. There is also some suggestion that the SNP309 variant is in linkage disequilibrium with another variant, SNP285, which confers an opposite effect.It is worth noting that the SNP285C/SNP309G haplotype frequency was observed in up to 8% of Europeans, thus requiring correction for the confounding effect of SNP285C in European studies.39 However, aside from one study conducted by Knappskog et al, no other study including the meta-analyses corrected for the confounding effect of SNP285.40 Among the studies presented in table 3, Knappskog et al (2012) reported that after correcting for SNP285, the OR for association of this haplotype with endometrial cancer was much lower, though still significant. Unfortunately, the meta-analyses which synthesised Knappskog et al (2012), as part of their analysis, did not correct for SNP285C in the European-based studies they included.38 41 42 It is also concerning that two meta-analyses using the same primary articles failed to report the same result, in two instances.38 42–44DiscussionThis article represents the most comprehensive systematic review to date, regarding critical appraisal of the available evidence of common low-penetrance variants implicated in predisposition to endometrial cancer.

We have identified the most robust SNPs in the context of endometrial cancer risk. Of those, only 19 were significant at genome-wide level and a further five were considered marginally significant. The largest GWAS conducted in this field was the discovery- and meta-GWAS by O’Mara et al, which utilised 12 096 cases and 108 979 controls.21 Despite the inclusion of all published GWAS and around 5000 newly genotyped cases, the total number did not reach anywhere near what is currently available for other common cancers such as breast cancer. For instance, BCAC (Breast Cancer Association Consortium) stands at well over 200 000 individuals with more than half being cases, and resulted in identification of ~170 SNPs in relation to breast cancer.19 45 A total of 313 SNPs including imputations were then used to derive a PRS for breast cancer.19 Therefore, further efforts should be directed to recruit more patients, with deep phenotypic clinical data to allow for relevant adjustments and subgroup analyses to be conducted for better precision.A recent pre-print study by Zhang and colleagues examined the polygenicity and potential for SNP-based risk prediction for 14 common cancers, including endometrial cancer, using available summary-level data from European-ancestry datasets.46 They estimated that there are just over 1000 independent endometrial cancer susceptibility SNPs, and that a PRS comprising all such SNPs would have an area under the receiver-operator curve of 0.64, similar to that predicted for ovarian cancer, but lower than that for the other cancers in the study. The modelling in the paper suggests that an endometrial cancer GWAS double the size of the current largest study would be able to identify susceptibility SNPs together explaining 40% of the genetic variance, but that in order to explain 75% of the genetic variance it would be necessary to have a GWAS comprising close to 150 000 cases and controls, far in excess of what is currently feasible.We found that the literature consists mainly of candidate-gene studies with small sample sizes, meta-analyses reporting conflicting results despite using the same set of primary articles, and multiple reports of significant SNPs that have not been validated by any larger GWAS.

The candidate-gene studies were indeed the most useful and cheaper technique available until the mid to late 2000s. However, a lack of reproducibility (particularly due to population stratification and reporting bias), uncertainty of reported associations, and considerably high false discovery rates make these studies much less appropriate in the post-GWAS era. Unlike the candidate-gene approach, GWAS do not require prior knowledge, selection of genes or SNPs, and provide vast amounts of data. Furthermore, both the genotyping process and data analysis phases have become cheaper, the latter particularly due to faster and open-access pre-phasing and imputation tools being made available.It is clear from table 1 that some SNPs were reported with wide 95% CI, which can be directly attributed to small sample sizes particularly when restricting the cases to non-endometrioid histology only, low EAF or poor imputation quality. Thus, these should be interpreted with caution.

Additionally, most of the SNPs reported by candidate-gene studies were not detected by the largest GWAS to date conducted by O’Mara et al.21 However, this does not necessarily mean that the possibility of those SNPs being relevant should be completely dismissed. Moreover, meta-analyses were attempted for other variants. However, these showed no statistically significant association and many presented with high heterogeneity between the respective studies (data not shown). Furthermore, as many studies utilised the same set of cases and/or controls, conducting a meta-analysis was not possible for a good number of SNPs. It is therefore unequivocal that the literature is crowded with numerous small candidate-gene studies and conflicting data.

This makes it particularly hard to detect novel SNPs and conduct meaningful meta-analyses.We found convincing evidence for 19 variants that indicated the strongest association with endometrial cancer, as shown in table 1. The associations between endometrial cancer and variants in or around HNF1B, CYP19A1, SOX4, MYC, KLF and EIF2AK found in earlier GWAS were then replicated in the latest and largest GWAS. These SNPs showed promising potential in a theoretical PRS we devised based on published data. Using all 24 or genome-wide significant SNPs only, women with a PRS in the top 1% of the distribution would be predicted to have a risk of endometrial cancer 3.16 and 2.09 times higher than the mean risk, respectively.However, the importance of these variants and relevance of the proximate genes in a functional or biological context is challenging to evaluate. Long distance promoter regulation by enhancers may disguise the genuine target gene.

In addition, enhancers often do not loop to the nearest gene, further complicating the relevance of nearby gene(s) to a GWAS hit. In order to elucidate biologically relevant candidate target genes in endometrial cancer, O’Mara et al looked into promoter-associated chromatin looping using a modern HiChIP approach.47 The authors utilised normal and tumoural endometrial cell lines for this analysis which showed significant enrichment for endometrial cancer heritability, with 103 candidate target genes identified across the 13 risk loci identified by the largest ECAC GWAS. Notable genes identified here were CDKN2A and WT1, and their antisense counterparts. The former was reported to be nearby of rs1679014 and the latter of rs10835920, as shown in table 1. Moreover, of the 36 candidate target genes, 17 were found to be downregulated while 19 were upregulated in endometrial tumours.The authors also investigated overlap between the 13 endometrial cancer risk loci and top eQTL variants for each target gene.47 In whole blood, of the two particular lead SNPs, rs8822380 at 17q21.32 was a top eQTL for SNX11 and HOXB2, whereas rs937213 at 15q15.1 was a top eQTL for SRP14.

In endometrial tumour, rs7579014 at 2p16.1 was found to be a top eQTL for BCL11A. This is particularly interesting because BCL11A was the only nearby/candidate gene that had a GWAS association reported in both endometrioid and non-endometrioid subtypes. The study looked at protein–protein interactions between endometrial cancer drivers and candidate target gene products. Significant interactions were observed with TP53 (most significant), AKT, PTEN, ESR1 and KRAS, among others. Finally, when 103 target candidate genes and 387 proteins were combined together, 462 pathways were found to be significantly enriched.

Many of these are related to gene regulation, cancer, obesity, insulinaemia and oestrogen exposure. This study clearly showed a potential biological relevance for some of the SNPs reported by ECAC GWAS in 2018.Most of the larger included studies used cohorts primarily composed of women of broad European descent. Hence, there are negligible data available for other ethnicities, particularly African women. This is compounded by the lack of reference genotype data available for comparative analysis, making it harder for research to be conducted in ethnicities other than Europeans. This poses a problem for developing risk prediction models that are equally valuable and predictive across populations.

Thus, our results also are of limited applicability to non-European populations.Furthermore, considering that non-endometrioid cases comprise a small proportion (~20%) of all endometrial cancer cases, much larger cohort sizes are needed to detect any genuine signals for non-endometrioid tumours. Most of the evaluated studies looked at either overall/mixed endometrial cancer subtypes or endometrioid histology, and those that looked at variant associations with non-endometrioid histology were unlikely to have enough power to detect any signal with statistical significance. This is particularly concerning because non-endometrioid subtypes are biologically aggressive tumours with a much poorer prognosis that contribute disproportionately to mortality from endometrial cancer. It is particularly important that attempts to improve early detection and prevention of endometrial cancer focus primarily on improving outcomes from these subtypes. It is also worth noting that, despite the current shift towards a molecular classification of endometrial cancer, most studies used the overarching classical Bokhman’s classification system, type I versus type II, or no histological classification system at all.

Therefore, it is important to create and follow a standardised and comprehensive classification system for reporting tumour subtypes for future studies.This study compiled and presented available information for an extensively studied, yet unproven in large datasets, SNP309 variant in MDM2. Currently, there is no convincing evidence for an association between this variant and endometrial cancer risk. Additionally, of all the studies, only one accounted for the opposing effect of a nearby variant SNP285 in their analyses. Thus, we conclude that until confirmed by a sufficiently large GWAS, this variant should not be considered significant in influencing the risk of endometrial cancer and therefore not included in a PRS. This is also true for the majority of the SNPs reported in candidate-gene studies, as the numbers fall far short of being able to detect genuine signals.This systematic review presents the most up-to-date evidence for endometrial cancer susceptibility variants, emphasising the need for further large-scale studies to identify more variants of importance, and validation of these associations.

Until data from larger and more diverse cohorts are available, the top 24 SNPs presented here are the most robust common genetic variants that affect endometrial cancer risk. The multiplicative effects of these SNPs could be used in a PRS to allow personalised risk prediction models to be developed for targeted screening and prevention interventions for women at greatest risk of endometrial cancer..

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Date published seroquel and propranolol Where can i buy cipro. August 26, 2020On this page Backgroundantidepressant drugs is an infectious disease caused by the antidepressants antidepressants. The World Health Organization declared a global seroquel in March 2020, and the Minister of Health signed the Interim Order Respecting the Importation and Sale of Medical Devices for Use in seroquel and propranolol Relation to antidepressant drugs on March 18, 2020. The Interim Order (IO) allows us to quickly address large-scale public health emergencies.This IO allows for faster authorization of Class I-IV medical devices for antidepressant drugs.This document presents the criteria for safety and effectiveness that apply to test swabs used for antidepressant drugs sampling.

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the swab material inhibits the test reaction or the swab design doesn’t provide enough surface area to obtain a sufficient sample Test swabs that are not safe and effective may cause or lead to harm. For example. A swab that breaks during sample seroquel and propranolol collection can cause physical injury a non-sterile swab that produces an incorrect test result can lead to harmHealth Canada has published a guidance document to support the preparation of applications submitted under the IO. It should be read in conjunction with this document.

We are processing applications as quickly as possible. To avoid delays, please ensure you have completed your application properly.Medical Devices Regulations (MDR) classification In the seroquel and propranolol Canadian regulatory framework, Class I devices present the lowest potential risk and Class IV the highest. Swabs are classified according to their labelling and intended use. For example, if a swab is labelled for nasopharyngeal (NP) or oropharyngeal (OP) use only, it will be classified as a Class I medical device according to Classification Rule 2(2) of the MDR.

If a swab is not exclusively for use in oral or nasal cavities, or its use is not explicitly stated, it will be classified as a Class II device by Rule seroquel and propranolol 2(1). These swabs belong to a higher risk class because their use in other body orifices for the collection of tissue samples (for example, to test for chlamydia or ureaplasma) is associated with greater risk. Rule 2 Subject to subrules (2) to (4), all invasive devices that penetrate the body through a body orifice or that come into contact with the seroquel and propranolol surface of the eye are classified as Class II. A device described in subrule (1) that is intended to be placed in the oral or nasal cavities as far as the pharynx or in the ear canal up to the ear drum is classified as Class I.Regulatory pathways for antidepressant drugs devicesManufacturers of Class I swabs may seek authorization to import and sell their products under either.

A Medical Device Establishment Licence (MDEL) MDEL is an establishment oversight framework that is not product-specific and not designed to assess safety and effectiveness an IO authorization information on safety and effectiveness are required as part of the application Health Canada is encouraging a sub-group of swab manufacturers to use the IO authorization pathway for Class I swabs, especially if they are. New to the manufacturing of swabs and manufacturing in Canada (such as a company that has re-tooled to manufacture), or using a new seroquel and propranolol manufacturing process or design for swabs (such as 3D printing or honeycomb design)IO applications for swabs should include the following information.Device description The device description should include. A picture and/or engineering drawing identification of all materials used in the production of the swab the intended use(s) (for example, NP swabs)Quality manufacturingManufacturers must either. demonstrate compliance with Quality Manufacturing Systems (for example, ISO 13485 certificate) applicable to the swab, or provide a clear description of the planned quality manufacturing systems that are consistent with similar existing manufacturing systemsDesign verificationProvide swab design verification (bench testing) data in a summary report.

It should show that seroquel and propranolol the essential minimum design characteristics are met. These data should be based on test samples representative of finished swabs that have undergone sterilization prior to bench testing.Dimensions Swabs should have minimum length specifications and minimum and maximum head diameter specifications in order to be safe and effective. Minimum length specification for example, adult NP swabs require ≥14 cm to reach the posterior nasopharynx minimum and maximum head diameter specification for example, adult NP swabs require 1–4 mm to pass into the mid-inferior portion of the inferior turbinate and maneuver well FlexibilitySwab flexibility is assessed through. Durability for example, seroquel and propranolol tolerate 20 rough repeated insertions into a 4 mm inner diameter clear plastic tube curved back on itself with a curve radius of 3 cm bendability for example, bend tip and neck 90º without breaking ability to maintain initial form for example, restore to initial form following 45º bending Manufacturers may describe the test performed, the number of samples, and a summary of the results.Strength/Breakpoint (failure) To limit the potential for patient harm, the minimum breakpoint distance should be approximately 8 to 9 cm from the nasopharynx.

However, no breaks or fractures should occur following reasonable manipulation. Applicants should submit a rationale for the design of the breakpoint distance from the swab tip. It should seroquel and propranolol demonstrate that the breakpoint length can be accommodated by commercially available swab/media tubes.Surface propertiesThe swab surface should be free of. processing aids (such as disinfectants) foreign materials degreasers mold release agents For injection molded swabs, no burrs, flashing, or sharp edges should be present.

Design validationProvide swab validation (performance) data in a summary report that demonstrates that the swab. can acquire samples comparable to a commercially available swab control, and will not inhibit the PCR reactionThese data should be based on test samples representative of finished swabs that have undergone sterilization prior to testing.Comparable sample acquisition to a control, and PCR compatibilityThe manufacturer should demonstrate test swab cycle seroquel and propranolol threshold (Ct) recovery values (RT-PCR) that are statistically comparable to those obtained from a commercially available swab control using antidepressants (or a scientifically justified surrogate).Pass/Fail criteria. Values ≥ 2Cts indicate significantly less efficient ribonucleic acid collection and/or elution.Clinical feasibility/suitability simulationManufacturers should submit either. A clinical test report or previous clinical data Clinical test reportThe clinical test report should describe the use of the proposed finished seroquel and propranolol swab (sterilized) in a sufficient number of individuals by trained healthcare professionals in a minimum of 30 patients that have tested positive for antidepressants, or a scientifically justified surrogate seroquel.

Include comparisons of the proposed swab against a flocked swab commercially available in Canada with respect to. flexibility fit ability to navigate to the nasopharynx (or other areas specified in the indications) ability to collect a specimen/respiratory epithelial cells for example, using the RNase P housekeeping gene test results agreement for example, ≥ 90% positive % agreement using a composite control (positive % agreement calculation that includes all positive findings from control and test swabs) Clinical testing considerations A scientifically justified surrogate seroquel may be used if antidepressant drugs-positive patients are not available. Positive % seroquel and propranolol agreement should not be determined using high Ct samples. One-half (1/2) to two-thirds (2/3) of antidepressant drugs-positive samples should have a high viral loads (Cts <.

30). Report agreement between control and test swabs in seroquel and propranolol terms of quantitative (Ct) and qualitative (+/- test) values with appropriate descriptive statistics. Include patient symptomatology for samples. For example, days from symptom onset, known vs.

Suspected antidepressant drugs status seroquel and propranolol. Use of different VTM/universal transport media (V/UTM) across antidepressant drugs-positive samples may contribute to Ct variability. Ensure consistency by using the same media/tubes for each specimen within a clinical evaluation. Validate the chosen V/UTM media/tubes to show they will not interfere with the PCR test seroquel and propranolol results.

For example, allowing 7 days of swab positive specimen incubation with the chosen media/vial is considered a worst-case transportation scenario to evaluate maximal leaching/interaction potential). Use a single PCR test platform throughout each clinical evaluation. The platform seroquel and propranolol should have been previously authorized by HC or another jurisdiction. Location (for example, left vs right nostril) and order of sampling (for example, control vs.

Test swab) can affect specimen quality and results variability. Location and swab sampling order should be randomized.For additional information on collecting, handling, and testing antidepressant drugs specimens, please refer to the Centers for Disease Control and Prevention (CDC) Interim Guidelines seroquel and propranolol for Collecting, Handling, and Testing Clinical Specimens for antidepressant drugs.Previous clinical dataPreviously obtained clinical data may be submitted in lieu of clinical testing. Those data should demonstrate the safe and effective use of a swab of identical design and materials in human subjects. The proposed swab should be compared against a flocked swab commercially available in Canada with respect to seroquel and propranolol.

flexibility fit ability to navigate to the nasopharynx (or other areas specified in the indications) ability to collect a specimen/respiratory epithelial cells for example, using the RNase P housekeeping gene test results agreement for example, ≥ 90% positive % agreement) using a composite control (positive % agreement calculation that includes all positive findings from control and test swabs) Sterility Provide sterilization validation data in a summary report. It should demonstrate that the chosen sterilization method will achieve a minimum Sterility Assurance Level (SAL) of 10-6 for the proposed swab, using an appropriate biological indicator (BI) organism (see below). If the seroquel and propranolol swab will be sterilized using an ethylene oxide (EtO) method, you should demonstrate that EtO and ethylene chlorohydrin (ECH) residuals meet the tolerable contact limits (TCL) specified in ISO 10993-7. Commonly used swab materials, compatible sterilization methods, and appropriate biological indicators are described below.

Sterilization Method Swab Materials EtO(for example, ISO 11135) Gamma Irradiation(ISO 11137) Polystyrene handle, polyester bicomponent fiber tipFootnote * X(for example, Puritan 25-3316-H/U) Not applicable Polystyrene handle, nylon flocked fiber tipFootnote * X(for example, Copan 503CS01) X(for example, BD 220252) Footnote * The CDC provides guidance on the types of swabs that should be used for optimal specimen collection for PCR testing. They include swabs that are made of polyester (for example, seroquel and propranolol Dacron), rayon, or nylon-flocked. Cotton-tipped or calcium alginate swabs are not acceptable because residues present in those materials inhibit the PCR reaction. Return to footnote * referrer Appropriate BIIf ionizing radiation will be used to sterilize the swab.

Bacillus pumilus seroquel and propranolol spores are recommended for doses of 25 kGy Bacillus cereus or Bacillus sphaericus spores are recommended for doses of >. 25 kGy (World Health Organization, The International Pharmacopoeia, 9th Ed., 2019) Sterilization Process Spore (Indicator Organism) Steam Geobacillus stearothermophilus(formerly Bacillus stearothermophilus) Dry Heat Bacillus atrophaeus (formerly Bacillus subtilis var. Niger) Ethlylene Oxide Bacillus atrophaeus (formerly Bacillus subtilis var. Niger) Hydrogen Peroxide Geobacillus stearothermophilus(formerly Bacillus stearothermophilus) seroquel and propranolol Source.

US Food and Drug Administration, "Biological Indicator (BI) Premarket Notification [510(k)] Submissions," October 2007. [Online].Packaging validation Provide packaging validation data in a summary report. It should demonstrate that the swab packaging system seroquel and propranolol will maintain a sterile environment across the labelled shelf life (for example, ASTM F1980). without leakage (for example, ASTM D3078-02) with adequate seal strength (for example, ASTM F88/EN 868-5)Test packaging samples should be representative of finished swab packages that have undergone sterilization prior to testing.Biocompatibility Provide biocompatibility data in a summary report.

It should demonstrate compliance with biocompatibility tests recommended for devices in limited contact (≤24 hrs) with mucosal membranes, as per ISO 10993-1. These include seroquel and propranolol. cytotoxicity sensitization irritation/intracutaneous reactivityThese data should be based on test samples representative of finished swabs that have undergone sterilization prior to testing.LabellingSwabs should be individually packaged and labelled. The application must include the swab label, which seroquel and propranolol must include.

The name and model number of the device the term ‘sterile’, along with the sterilization method (EtO = ethylene oxide. R = gamma irradiation), if the swab is intended to be sold in a sterile condition the name and address of the manufacturer manufacturing and expiry datesIf swabs are not sterile but must be sterilized at the user facility, then the sterilization parameters and method should be clearly described in accompanying instructions for use documentation.Post-market requirementsAs stated in Section 12 of the IO, within 10 days of becoming aware of an incident in Canada, all IO authorization holders must. report the incident specify the nature of the incident specify the circumstances surrounding the incidentOn this page About face shields Personal protective equipment seroquel and propranolol (PPE) can help prevent potential exposure to infectious disease. They are considered medical devices in Canada and therefore must follow the requirements outlined in the Medical Devices Regulations.

Medical devices are classified into 4 groups (Class I, II, III and IV) based on their risk to health and safety. Class I devices, such as gauze bandages, pose the lowest potential risk, while Class seroquel and propranolol IV devices, such as pacemakers, pose the greatest potential risk. In Canada, face shields are Class I medical devices. A face shield has a transparent window or visor that shields the face and associated mucous membranes (eyes, nose and mouth).

It protects the wearer against exposure from splashes and sprays of body seroquel and propranolol fluids. Face shields are made of shatterproof plastic, fit over the face and are held in place by head straps or caps. They may be made of polycarbonate, propionate, acetate, polyvinyl chloride, or polyethylene terephthalate. They are usually worn with other PPE, such as a seroquel and propranolol medical mask, respirator or eyewear.

Health Canada strongly advises against the use of plastic bags as an alternative to face shields. Standards and requirements for face shields Organizations that are manufacturing face shields are advised to consult some or all of the following standards throughout the design and testing stages. ANSI/ISEA Z.87.1 (2015), American National Standard for Occupational and Educational Personal Eye and Face seroquel and propranolol Protection Devices CSA Z94.3 (2020), Eye and Face Protectors CSA Z94.3.1 (2016), Guideline for Selection, Use, and Care of Eye and Face Protectors BS EN 166 (2002), Personal Eye Protection. Specifications.

Minimum specifications must be incorporated into the design and verification stages to ensure safe and effective face shields. Provide adequate coverage seroquel and propranolol (CSA Z94.3 Sections 0.2.1/10.2.2/10.3/10.4). The size of the face shield is important because it must protect the face and front part of the head. This includes the eyes, forehead, cheeks, nose, mouth, and chin.

Protection may also need seroquel and propranolol to extend to the front of the neck in situations with flying particles and sprays of hazardous liquids. Fit snugly to afford a good seal to the forehead area and to prevent slippage of the device Footnote 1. Be made of optically clear, distortion-free, lightweight materials (CSA Z94.3.1-16 and seroquel and propranolol Footnote 1). Be free of visible defects or flaws that would impede vision (ANSI Z87.1 Section 9.4).

Be comfortable and easy to assemble, use and remove by health care professionals. Provide adequate space between the wearer’s face and the inner surface of the visor to allow for the use of seroquel and propranolol ancillary equipment (for example, medical mask, respirator, eyewear) Footnote 1. The characteristics and performance requirements of face shields must not be altered when attaching shields to other protective equipment, such as hats or caps. Display anti-fog characteristics on inside and outside of shield (CSA Z94.3.1-16).

For face shields that are not seroquel and propranolol fog resistant, anti-fog spray must be provided. Provide user-contacting materials that have adequate material biocompatibility (skin sensitivity and cytotoxic testing) (ISO 10993-5, 10). Other items to take note of include. Face shields used for seroquel and propranolol protection in hospital settings do not have to be impact- or flame- resistant.

If the device is specifically designed to withstand impact from sharp or fast projectiles, it must comply with set-out standards (ANSI Z87.1, sections 9.2 and 9.3, CSA Z94.3, section 10.1). For reuse, manufacturers must provide validated cleaning instructions. Sterilization procedures must not compromise the shield in any way, such seroquel and propranolol as deformation or cracking. Regulatory authorization Most PPE, including face shields, are Class I medical devices if they are manufactured, sold or represented for use for reducing the risk of or preventing the user from .

This includes antidepressant drugs. Face shields may be authorized for sale seroquel and propranolol or import into Canada through the following regulatory pathways. Pathway 1. Interim order authorization to import and sell medical devices related to antidepressant drugs.

Pathway 2 seroquel and propranolol. Expedited review and issuance of Medical Device Establishment Licences (MDEL) related to antidepressant drugs. MDEL holders that import and sell face shields should take seroquel and propranolol measures to ensure they are safe and effective. Pathway 3.

Exceptional importation and sale of certain non-compliant medical devices related to antidepressant drugs. Note that a seroquel and propranolol sale generally requires the transfer of ownership of a device from one party to another and does not necessitate any transfer of money. Applicants should carefully review the pathways and select the most appropriate authorization route for their product. For more information, see Personal protective equipment (antidepressant drugs).

How to seroquel and propranolol get authorization. If you intend to manufacture 3D print face shields in response to the antidepressant drugs crisis, see. 3D printing and other manufacturing of personal protective equipment in response to antidepressant drugs Feedback If you have any questions or comments about this notice, contact the Medical Devices Directorate at hc.meddevices-instrumentsmed.sc@canada.ca R. J.

Roberge, "Face shields for control. A review," Journal of Occupational and Environmental Hygiene, pp. 235-242, 2016. Related links FootnotesFootnote 1 R.

J. Roberge, "Face shields for control. A review," Journal of Occupational and Environmental Hygiene, pp. 235-242, 2016.Return to footnote 1 referrer.

Date published what do you need to buy seroquel advice. August 26, 2020On this page Backgroundantidepressant drugs is an infectious disease caused by the antidepressants antidepressants. The World Health Organization declared a global seroquel in March 2020, what do you need to buy seroquel and the Minister of Health signed the Interim Order Respecting the Importation and Sale of Medical Devices for Use in Relation to antidepressant drugs on March 18, 2020. The Interim Order (IO) allows us to quickly address large-scale public health emergencies.This IO allows for faster authorization of Class I-IV medical devices for antidepressant drugs.This document presents the criteria for safety and effectiveness that apply to test swabs used for antidepressant drugs sampling.

It also provides guidance on how to meet these criteria in an application under the IO pathway. Diagnostic testing what do you need to buy seroquel is a key element in both. identifying cases of preventing the spread of the antidepressants A test swab may be used to collect a sample for either Polymerase Chain Reaction (PCR) laboratory testing or point-of-care testing. Point-of-care testing can be done directly in a hospital or doctor’s office.

Once the sample has been taken, the swab is either placed in a preserving liquid and sent to a laboratory for testing, or placed directly in a testing device (point-of-care).Swabs may be packaged in a variety of seroquel what do you need to buy seroquel transport media (VTM). Specifications for individual VTMs are beyond the scope of this document. Swabs play a role in the accuracy of antidepressant drugs diagnostic testing. For example, false negatives can occur in PCR tests what do you need to buy seroquel if.

the swab material inhibits the test reaction or the swab design doesn’t provide enough surface area to obtain a sufficient sample Test swabs that are not safe and effective may cause or lead to harm. For example. A swab that breaks during sample collection can cause physical injury a non-sterile swab that produces an incorrect test result can lead to harmHealth Canada has published a guidance document to support the preparation what do you need to buy seroquel of applications submitted under the IO. It should be read in conjunction with this document.

We are processing applications as quickly as possible. To avoid delays, please ensure you have completed your application properly.Medical Devices Regulations (MDR) classification In the Canadian regulatory framework, Class I what do you need to buy seroquel devices present the lowest potential risk and Class IV the highest. Swabs are classified according to their labelling and intended use. For example, if a swab is labelled for nasopharyngeal (NP) or oropharyngeal (OP) use only, it will be classified as a Class I medical device according to Classification Rule 2(2) of the MDR.

If a swab is not exclusively for use in oral or nasal what do you need to buy seroquel cavities, or its use is not explicitly stated, it will be classified as a Class II device by Rule 2(1). These swabs belong to a higher risk class because their use in other body orifices for the collection of tissue samples (for example, to test for chlamydia or ureaplasma) is associated with greater risk. Rule 2 Subject to subrules (2) to (4), all invasive devices that penetrate the body through a body orifice or that come into contact what do you need to buy seroquel with the surface of the eye are classified as Class II. A device described in subrule (1) that is intended to be placed in the oral or nasal cavities as far as the pharynx or in the ear canal up to the ear drum is classified as Class I.Regulatory pathways for antidepressant drugs devicesManufacturers of Class I swabs may seek authorization to import and sell their products under either.

A Medical Device Establishment Licence (MDEL) MDEL is an establishment oversight framework that is not product-specific and not designed to assess safety and effectiveness an IO authorization information on safety and effectiveness are required as part of the application Health Canada is encouraging a sub-group of swab manufacturers to use the IO authorization pathway for Class I swabs, especially if they are. New to the manufacturing of swabs and manufacturing in Canada (such as a company that has re-tooled to manufacture), or using a new manufacturing process or design for swabs (such as 3D printing or honeycomb design)IO applications for swabs should include the following information.Device description The device description should include what do you need to buy seroquel. A picture and/or engineering drawing identification of all materials used in the production of the swab the intended use(s) (for example, NP swabs)Quality manufacturingManufacturers must either. demonstrate compliance with Quality Manufacturing Systems (for example, ISO 13485 certificate) applicable to the swab, or provide a clear description of the planned quality manufacturing systems that are consistent with similar existing manufacturing systemsDesign verificationProvide swab design verification (bench testing) data in a summary report.

It should show that what do you need to buy seroquel the essential minimum design characteristics are met. These data should be based on test samples representative of finished swabs that have undergone sterilization prior to bench testing.Dimensions Swabs should have minimum length specifications and minimum and maximum head diameter specifications in order to be safe and effective. Minimum length specification for example, adult NP swabs require ≥14 cm to reach the posterior nasopharynx minimum and maximum head diameter specification for example, adult NP swabs require 1–4 mm to pass into the mid-inferior portion of the inferior turbinate and maneuver well FlexibilitySwab flexibility is assessed through. Durability for example, tolerate 20 rough repeated insertions into a 4 mm inner diameter clear plastic tube curved back on itself with a curve radius of 3 cm bendability for example, bend tip and neck 90º without breaking ability to maintain initial form for example, restore to initial form following 45º bending Manufacturers may describe the test performed, the number of samples, and a summary of the results.Strength/Breakpoint (failure) To limit the potential what do you need to buy seroquel for patient harm, the minimum breakpoint distance should be approximately 8 to 9 cm from the nasopharynx.

However, no breaks or fractures should occur following reasonable manipulation. Applicants should submit a rationale for the design of the breakpoint distance from the swab tip. It should demonstrate that the breakpoint length what do you need to buy seroquel can be accommodated by commercially available swab/media tubes.Surface propertiesThe swab surface should be free of. processing aids (such as disinfectants) foreign materials degreasers mold release agents For injection molded swabs, no burrs, flashing, or sharp edges should be present.

Design validationProvide swab validation (performance) data in a summary report that demonstrates that the swab. can acquire samples comparable to a commercially available swab control, and will not inhibit the PCR reactionThese data should be based on test samples representative of finished swabs that have undergone sterilization prior to testing.Comparable sample acquisition to a control, and PCR compatibilityThe manufacturer should demonstrate test swab cycle threshold (Ct) recovery values (RT-PCR) what do you need to buy seroquel that are statistically comparable to those obtained from a commercially available swab control using antidepressants (or a scientifically justified surrogate).Pass/Fail criteria. Values ≥ 2Cts indicate significantly less efficient ribonucleic acid collection and/or elution.Clinical feasibility/suitability simulationManufacturers should submit either. A clinical what do you need to buy seroquel test report or previous clinical data Clinical test reportThe clinical test report should describe the use of the proposed finished swab (sterilized) in a sufficient number of individuals by trained healthcare professionals in a minimum of 30 patients that have tested positive for antidepressants, or a scientifically justified surrogate seroquel.

Include comparisons of the proposed swab against a flocked swab commercially available in Canada with respect to. flexibility fit ability to navigate to the nasopharynx (or other areas specified in the indications) ability to collect a specimen/respiratory epithelial cells for example, using the RNase P housekeeping gene test results agreement for example, ≥ 90% positive % agreement using a composite control (positive % agreement calculation that includes all positive findings from control and test swabs) Clinical testing considerations A scientifically justified surrogate seroquel may be used if antidepressant drugs-positive patients are not available. Positive % agreement should not be determined what do you need to buy seroquel using high Ct samples. One-half (1/2) to two-thirds (2/3) of antidepressant drugs-positive samples should have a high viral loads (Cts <.

30). Report agreement between control and test swabs in terms of quantitative (Ct) and what do you need to buy seroquel qualitative (+/- test) values with appropriate descriptive statistics. Include patient symptomatology for samples. For example, days from symptom onset, known vs.

Suspected antidepressant drugs what do you need to buy seroquel status. Use of different VTM/universal transport media (V/UTM) across antidepressant drugs-positive samples may contribute to Ct variability. Ensure consistency by using the same media/tubes for each specimen within a clinical evaluation. Validate the chosen V/UTM media/tubes to show they will not interfere with the what do you need to buy seroquel PCR test results.

For example, allowing 7 days of swab positive specimen incubation with the chosen media/vial is considered a worst-case transportation scenario to evaluate maximal leaching/interaction potential). Use a single PCR test platform throughout each clinical evaluation. The platform should what do you need to buy seroquel have been previously authorized by HC or another jurisdiction. Location (for example, left vs right nostril) and order of sampling (for example, control vs.

Test swab) can affect specimen quality and results variability. Location and swab sampling order should be randomized.For additional information on collecting, handling, and testing what do you need to buy seroquel antidepressant drugs specimens, please refer to the Centers for Disease Control and Prevention (CDC) Interim Guidelines for Collecting, Handling, and Testing Clinical Specimens for antidepressant drugs.Previous clinical dataPreviously obtained clinical data may be submitted in lieu of clinical testing. Those data should demonstrate the safe and effective use of a swab of identical design and materials in human subjects. The proposed swab should be compared against a flocked swab commercially available in Canada with respect to what do you need to buy seroquel.

flexibility fit ability to navigate to the nasopharynx (or other areas specified in the indications) ability to collect a specimen/respiratory epithelial cells for example, using the RNase P housekeeping gene test results agreement for example, ≥ 90% positive % agreement) using a composite control (positive % agreement calculation that includes all positive findings from control and test swabs) Sterility Provide sterilization validation data in a summary report. It should demonstrate that the chosen sterilization method will achieve a minimum Sterility Assurance Level (SAL) of 10-6 for the proposed swab, using an appropriate biological indicator (BI) organism (see below). If the swab will be sterilized using an ethylene oxide what do you need to buy seroquel (EtO) method, you should demonstrate that EtO and ethylene chlorohydrin (ECH) residuals meet the tolerable contact limits (TCL) specified in ISO 10993-7. Commonly used swab materials, compatible sterilization methods, and appropriate biological indicators are described below.

Sterilization Method Swab Materials EtO(for example, ISO 11135) Gamma Irradiation(ISO 11137) Polystyrene handle, polyester bicomponent fiber tipFootnote * X(for example, Puritan 25-3316-H/U) Not applicable Polystyrene handle, nylon flocked fiber tipFootnote * X(for example, Copan 503CS01) X(for example, BD 220252) Footnote * The CDC provides guidance on the types of swabs that should be used for optimal specimen collection for PCR testing. They include swabs that are made of polyester what do you need to buy seroquel (for example, Dacron), rayon, or nylon-flocked. Cotton-tipped or calcium alginate swabs are not acceptable because residues present in those materials inhibit the PCR reaction. Return to footnote * referrer Appropriate BIIf ionizing radiation will be used to sterilize the swab.

Bacillus pumilus spores are recommended for what do you need to buy seroquel doses of 25 kGy Bacillus cereus or Bacillus sphaericus spores are recommended for doses of >. 25 kGy (World Health Organization, The International Pharmacopoeia, 9th Ed., 2019) Sterilization Process Spore (Indicator Organism) Steam Geobacillus stearothermophilus(formerly Bacillus stearothermophilus) Dry Heat Bacillus atrophaeus (formerly Bacillus subtilis var. Niger) Ethlylene Oxide Bacillus atrophaeus (formerly Bacillus subtilis var. Niger) Hydrogen Peroxide Geobacillus stearothermophilus(formerly Bacillus stearothermophilus) Source what do you need to buy seroquel.

US Food and Drug Administration, "Biological Indicator (BI) Premarket Notification [510(k)] Submissions," October 2007. [Online].Packaging validation Provide packaging validation data in a summary report. It should demonstrate that the swab packaging system will maintain a sterile what do you need to buy seroquel environment across the labelled shelf life (for example, ASTM F1980). without leakage (for example, ASTM D3078-02) with adequate seal strength (for example, ASTM F88/EN 868-5)Test packaging samples should be representative of finished swab packages that have undergone sterilization prior to testing.Biocompatibility Provide biocompatibility data in a summary report.

It should demonstrate compliance with biocompatibility tests recommended for devices in limited contact (≤24 hrs) with mucosal membranes, as per ISO 10993-1. These include what do you need to buy seroquel. cytotoxicity sensitization irritation/intracutaneous reactivityThese data should be based on test samples representative of finished swabs that have undergone sterilization prior to testing.LabellingSwabs should be individually packaged and labelled. The application must include the swab what do you need to buy seroquel label, which must include.

The name and model number of the device the term ‘sterile’, along with the sterilization method (EtO = ethylene oxide. R = gamma irradiation), if the swab is intended to be sold in a sterile condition the name and address of the manufacturer manufacturing and expiry datesIf swabs are not sterile but must be sterilized at the user facility, then the sterilization parameters and method should be clearly described in accompanying instructions for use documentation.Post-market requirementsAs stated in Section 12 of the IO, within 10 days of becoming aware of an incident in Canada, all IO authorization holders must. report the incident specify the nature of the incident specify the circumstances surrounding the incidentOn this page About face shields Personal protective equipment (PPE) can help prevent what do you need to buy seroquel potential exposure to infectious disease. They are considered medical devices in Canada and therefore must follow the requirements outlined in the Medical Devices Regulations.

Medical devices are classified into 4 groups (Class I, II, III and IV) based on their risk to health and safety. Class I devices, such as gauze bandages, pose the lowest potential risk, what do you need to buy seroquel while Class IV devices, such as pacemakers, pose the greatest potential risk. In Canada, face shields are Class I medical devices. A face shield has a transparent window or visor that shields the face and associated mucous membranes (eyes, nose and mouth).

It protects the wearer against exposure from splashes and sprays of what do you need to buy seroquel body fluids. Face shields are made of shatterproof plastic, fit over the face and are held in place by head straps or caps. They may be made of polycarbonate, propionate, acetate, polyvinyl chloride, or polyethylene terephthalate. They are usually worn with other PPE, such as a medical mask, respirator or what do you need to buy seroquel eyewear.

Health Canada strongly advises against the use of plastic bags as an alternative to face shields. Standards and requirements for face shields Organizations that are manufacturing face shields are advised to consult some or all of the following standards throughout the design and testing stages. ANSI/ISEA Z.87.1 (2015), American National Standard for Occupational and Educational Personal Eye and Face Protection Devices CSA Z94.3 (2020), Eye and Face Protectors CSA Z94.3.1 (2016), Guideline for Selection, Use, and Care of Eye what do you need to buy seroquel and Face Protectors BS EN 166 (2002), Personal Eye Protection. Specifications.

Minimum specifications must be incorporated into the design and verification stages to ensure safe and effective face shields. Provide adequate coverage (CSA what do you need to buy seroquel Z94.3 Sections 0.2.1/10.2.2/10.3/10.4). The size of the face shield is important because it must protect the face and front part of the head. This includes the eyes, forehead, cheeks, nose, mouth, and chin.

Protection may also what do you need to buy seroquel need to extend to the front of the neck in situations with flying particles and sprays of hazardous liquids. Fit snugly to afford a good seal to the forehead area and to prevent slippage of the device Footnote 1. Be made of optically clear, distortion-free, lightweight materials (CSA Z94.3.1-16 and Footnote what do you need to buy seroquel 1). Be free of visible defects or flaws that would impede vision (ANSI Z87.1 Section 9.4).

Be comfortable and easy to assemble, use and remove by health care professionals. Provide adequate space between the wearer’s face and the inner surface of the visor to allow for the what do you need to buy seroquel use of ancillary equipment (for example, medical mask, respirator, eyewear) Footnote 1. The characteristics and performance requirements of face shields must not be altered when attaching shields to other protective equipment, such as hats or caps. Display anti-fog characteristics on inside and outside of shield (CSA Z94.3.1-16).

For face shields that are not fog resistant, anti-fog what do you need to buy seroquel spray must be provided. Provide user-contacting materials that have adequate material biocompatibility (skin sensitivity and cytotoxic testing) (ISO 10993-5, 10). Other items to take note of include. Face shields used for what do you need to buy seroquel protection in hospital settings do not have to be impact- or flame- resistant.

If the device is specifically designed to withstand impact from sharp or fast projectiles, it must comply with set-out standards (ANSI Z87.1, sections 9.2 and 9.3, CSA Z94.3, section 10.1). For reuse, manufacturers must provide validated cleaning instructions. Sterilization procedures must not compromise the shield in any way, such as deformation what do you need to buy seroquel or cracking. Regulatory authorization Most PPE, including face shields, are Class I medical devices if they are manufactured, sold or represented for use for reducing the risk of or preventing the user from .

This includes antidepressant drugs. Face shields may be authorized what do you need to buy seroquel for sale or import into Canada through the following regulatory pathways. Pathway 1. Interim order authorization to import and sell medical devices related to antidepressant drugs.

Pathway 2 what do you need to buy seroquel. Expedited review and issuance of Medical Device Establishment Licences (MDEL) related to antidepressant drugs. MDEL holders what do you need to buy seroquel that import and sell face shields should take measures to ensure they are safe and effective. Pathway 3.

Exceptional importation and sale of certain non-compliant medical devices related to antidepressant drugs. Note that a sale generally requires the transfer of ownership of a device from one party to another and what do you need to buy seroquel does not necessitate any transfer of money. Applicants should carefully review the pathways and select the most appropriate authorization route for their product. For more information, see Personal protective equipment (antidepressant drugs).

How to what do you need to buy seroquel get authorization. If you intend to manufacture 3D print face shields in response to the antidepressant drugs crisis, see. 3D printing and other manufacturing of personal protective equipment in response to antidepressant drugs Feedback If you have any questions or comments about this notice, contact the Medical Devices Directorate at hc.meddevices-instrumentsmed.sc@canada.ca R. J.

Roberge, "Face shields for control. A review," Journal of Occupational and Environmental Hygiene, pp. 235-242, 2016. Related links FootnotesFootnote 1 R.

J. Roberge, "Face shields for control. A review," Journal of Occupational and Environmental Hygiene, pp. 235-242, 2016.Return to footnote 1 referrer.