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MIPP is for some groups who are either not eligible for -- or who are not yet enrolled in-- the Medicare Savings Program (MSP), which is the main program that pays the Medicare Part B premium buy kamagra tablets online for low-income people. Some people are not eligible for an MSP even though they have full Medicaid with no spend down. This is because they are in a special Medicaid eligibility category -- discussed below -- with Medicaid income limits that are actually HIGHER than the MSP income limits.

MIPP reimburses them for their buy kamagra tablets online Part B premium because they have “full Medicaid” (no spend down) but are ineligible for MSP because their income is above the MSP SLIMB level (120% of the Federal Poverty Level (FPL). Even if their income is under the QI-1 MSP level (135% FPL), someone cannot have both QI-1 and Medicaid). Instead, these consumers can have their Part B premium reimbursed through the MIPP program.

In this article buy kamagra tablets online. The MIPP program was established because the State determined that those who have full Medicaid and Medicare Part B should be reimbursed for their Part B premium, even if they do not qualify for MSP, because Medicare is considered cost effective third party health insurance, and because consumers must enroll in Medicare as a condition of eligibility for Medicaid (See 89 ADM 7). There are generally four groups of dual-eligible consumers that are eligible for MIPP.

Therefore, many MBI WPD consumers have incomes higher than what MSP normally allows, but still have full Medicaid with buy kamagra tablets online no spend down. Those consumers can qualify for MIPP and have their Part B premiums reimbursed. Here is an example.

Sam is age 50 and has buy kamagra tablets online Medicare and MBI-WPD. She gets $1500/mo gross from Social Security Disability and also makes $400/month through work activity. $ 167.50 -- EARNED INCOME - Because she is disabled, the DAB earned income disregard applies.

$400 - $65 = $335 buy kamagra tablets online. Her countable earned income is 1/2 of $335 = $167.50 + $1500.00 -- UNEARNED INCOME from Social Security Disability = $1,667.50 --TOTAL income. This is above the SLIMB limit of $1,288 (2021) but she can still qualify for MIPP.

2 buy kamagra tablets online. Parent/Caretaker Relatives with MAGI-like Budgeting - Including Medicare Beneficiaries. Consumers who fall into the DAB category (Age 65+/Disabled/Blind) and would otherwise be budgeted with non-MAGI rules can opt to use Affordable Care Act MAGI rules if they are the parent/caretaker of a child under age 18 or under age 19 and in school full time.

This is referred to as “MAGI-like budgeting.” Under MAGI rules income can be up to 138% buy kamagra tablets online of the FPL—again, higher than the limit for DAB budgeting, which is equivalent to only 83% FPL. MAGI-like consumers can be enrolled in either MSP or MIPP, depending on if their income is higher or lower than 120% of the FPL. If their income is under 120% FPL, they are eligible for MSP as a SLIMB.

If income is above 120% FPL, then they can enroll in buy kamagra tablets online MIPP. (See GIS 18 MA/001 - 2018 Medicaid Managed Care Transition for Enrollees Gaining Medicare, #4) 3. New Medicare Enrollees who are Not Yet in a Medicare Savings Program When a consumer has Medicaid through the New York State of Health (NYSoH) Marketplace and then enrolls in Medicare when she turns age 65 or because she received Social Security Disability for 24 months, her Medicaid case is normally** transferred to the local department of social services (LDSS)(HRA in NYC) to be rebudgeted under non-MAGI budgeting.

During the transition buy kamagra tablets online process, she should be reimbursed for the Part B premiums via MIPP. However, the transition time can vary based on age. AGE 65+ For those who enroll in Medicare at age 65+, the Medicaid case takes about four months to be rebudgeted and approved by the LDSS.

The consumer is entitled to MIPP payments for at least buy kamagra tablets online three months during the transition. Once the case is with the LDSS she should automatically be re-evaluated for MSP. Consumers UNDER 65 who receive Medicare due to disability status are entitled to keep MAGI Medicaid through NYSoH for up to 12 months (also known as continuous coverage, See NY Social Services Law 366, subd.

4(c). These consumers should receive MIPP payments for as long as their cases remain with NYSoH and throughout the transition to the LDSS. NOTE during erectile dysfunction treatment emergency their case may remain with NYSoH for more than 12 months.

See here. See GIS 18 MA/001 - 2018 Medicaid Managed Care Transition for Enrollees Gaining Medicare, #4 for an explanation of this process. Note.

During the erectile dysfunction treatment emergency, those who have Medicaid through the NYSOH marketplace and enroll in Medicare should NOT have their cases transitioned to the LDSS. They should keep the same MAGI budgeting and automatically receive MIPP payments. See GIS 20 MA/04 or this article on erectile dysfunction treatment eligibility changes 4.

Those with Special Budgeting after Losing SSI (DAC, Pickle, 1619b) Disabled Adult Child (DAC). Special budgeting is available to those who are 18+ and lose SSI because they begin receiving Disabled Adult Child (DAC) benefits (or receive an increase in the amount of their benefit). Consumer must have become disabled or blind before age 22 to receive the benefit.

If the new DAC benefit amount was disregarded and the consumer would otherwise be eligible for SSI, they can keep Medicaid eligibility with NO SPEND DOWN. See this article. Consumers may have income higher than MSP limits, but keep full Medicaid with no spend down.

Therefore, they are eligible for payment of their Part B premiums. See page 96 of the Medicaid Reference Guide (Categorical Factors). If their income is lower than the MSP SLIMB threshold, they can be added to MSP.

If higher than the threshold, they can be reimbursed via MIPP. See also 95-ADM-11. Medical Assistance Eligibility for Disabled Adult Children, Section C (pg 8).

When the Part B Premium Reduces Countable Income to Below the Medicaid Limit Since the Part B premium can be used as a deduction from gross income, it may reduce someone's countable income to below the Medicaid limit. The consumer should be paid the difference to bring her up to the Medicaid level ($904/month in 2021). They will only be reimbursed for the difference between their countable income and $904, not necessarily the full amount of the premium.

See GIS 02-MA-019. Reimbursement of Health Insurance Premiums MIPP and MSP are similar in that they both pay for the Medicare Part B premium, but there are some key differences. MIPP structures the payments as reimbursement -- beneficiaries must continue to pay their premium (via a monthly deduction from their Social Security check or quarterly billing, if they do not receive Social Security) and then are reimbursed via check.

In contrast, MSP enrollees are not charged for their premium. Their Social Security check usually increases because the Part B premium is no longer withheld from their check. MIPP only provides reimbursement for Part B.

It does not have any of the other benefits MSPs can provide, such as. A consumer cannot have MIPP without also having Medicaid, whereas MSP enrollees can have MSP only. Of the above benefits, Medicaid also provides Part D Extra Help automatic eligibility.

There is no application process for MIPP because consumers should be screened and enrolled automatically (00 OMM/ADM-7). Either the state or the LDSS is responsible for screening &. Distributing MIPP payments, depending on where the Medicaid case is held and administered (14 /2014 LCM-02 Section V).

If a consumer is eligible for MIPP and is not receiving it, they should contact whichever agency holds their case and request enrollment. Unfortunately, since there is no formal process for applying, it may require some advocacy. If Medicaid case is at New York State of Health they should call 1-855-355-5777.

Consumers will likely have to ask for a supervisor in order to find someone familiar with MIPP. If Medicaid case is with HRA in New York City, they should email mipp@hra.nyc.gov. If Medicaid case is with other local districts in NYS, call your local county DSS.

Once enrolled, it make take a few months for payments to begin. Payments will be made in the form of checks from the Computer Sciences Corporation (CSC), the fiscal agent for the New York State Medicaid program. The check itself comes attached to a remittance notice from Medicaid Management Information Systems (MMIS).

Unfortunately, the notice is not consumer-friendly and may be confusing. See attached sample for what to look for. Health Insurance Premium Payment Program (HIPP) HIPP is a sister program to MIPP and will reimburse consumers for private third party health insurance when deemed “cost effective.” Directives:Since 2010, the New York State Department of Health Medicaid application form is called the Access NY Application or form DOH-4220.

Download the form at this link (As of January 2021, the form was last updated in March 2015). For those age 65+ or who are disabled or blind, a second form is also required - Supplement A - As of Jan. 2021 the same Supplement A form is used statewide - DOH-5178A (English).

NYC applicants should no longer use DOH-4220. See more information here about Jan. 2021 changes for NYC applicants regarding Supplement A.

This supplement collects information about the applicant's current resources and past resources (for nursing home coverage). All local districts in New York State are required to accept the revised DOH-4220 for non-MAGI Medicaid applicants (Aged 65+, Blind, Disabled) (including for coverage of long-term care services), Medicare Savings Program, the Medicaid Buy-In Program fr Working People with Disabilities. Districts must also continue to accept the LDSS-2921, although it only makes sense to use this when someone is applying for both Medicaid and some other public benefit covered by the Common Application, such as the income benefits such as Safety Net Assistance.

The DOH-4220 - Access NY Health Care application can be used for all Medicaid benefits -- including for those who want to apply for coverage of Medicaid long-term care -- whether through home care or for those in a nursing home.j (with the addition of the Supplement Aform, described below).

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Researchers at Wake Forest School of Medicine have shown that a kamagra phuket targeted therapy using non-thermal http://junksanfrancisco.com/2013/12/post-from-site-test/ radio waves is safe to use in the treatment of hepatocellular carcinoma (HCC), the most common type of liver cancer. The therapy also showed a benefit in overall survival.The study findings appear online in 4Open, kamagra phuket a journal published by EDP Sciences."HCC accounts for nearly 90% of all liver cancers, and current survival rates are between six and 20 months," said Boris Pasche, M.D., Ph.D., chair of cancer biology and director of Wake Forest Baptist's Comprehensive Cancer Center. "Currently, there are limited treatment options for patients with this advanced liver cancer."For the study researchers used a device called TheraBionic P1, invented by Pasche and Alexandre Barbault of TheraBionic GmbH in Ettlingen, Germany, that works by delivering cancer-specific, amplitude-modulated radiofrequency electromagnetic fields (AM RF EMF) programmed specifically for HCC.The frequencies used are specific to the patient's type of cancer as identified through tumor biopsies or blood work, Pasche said.Pasche and Barbault discovered radio frequencies for 15 different types of cancer, as previously reported in a study published in 2009 in the Journal of Experimental &. Clinical Cancer Research kamagra phuket. advertisement TheraBionic P1 is a hand-held device that emits radio frequencies via a spoon-shaped antenna, which is placed on the patient's tongue during treatment and is administered three times a day for one hour to deliver low levels of radiofrequency electromagnetic fields throughout the patient's body.In previous studies, the device, which received breakthrough designation from the FDA in 2019, was shown to block the growth of liver cancer cells in the body without damaging healthy cells.For the current study, 18 patients with advanced HCC participated and received treatment with the device.

Researchers also analyzed previously published data on 41 patients from a kamagra phuket phase II study and historical controls from earlier clinical trials."Our findings show an improvement in overall survival of more than 30% in patients with well-preserved liver function and also in those with more severe disease," Pasche said.Researchers also tracked side effects, and no patients stopped TheraBionic P1 treatment because of adverse reactions. advertisement "We're encouraged by these initial findings," Pasche said. "Our study shows kamagra phuket a benefit in overall survival, and the treatment isn't associated with any significant side effects."Support for this study was provided by TheraBionic Inc. And funds from Wake Forest Baptist's Comprehensive Cancer Center.Pasche noted that the study does have several limitations because of the small sample size and "selection bias inherent in the use of historical control data."However, two additional clinical trials are underway and are being led by William Blackstock, M.D., chair of radiation oncology at Wake Forest Baptist's Comprehensive Cancer Center. One is a single-center study to assess the safety and effectiveness of the TheraBionic device in combination with Regorafenib, kamagra phuket a chemotherapy drug, as a second-line treatment.

Another multicenter, double-blind, randomized study comparing TheraBionic with kamagra phuket placebo will assess the safety and effectiveness of the device as a third-line therapy in the treatment of advanced HCC.Pasche holds stock in TheraBionic Inc. And TheraBionic GmbH. He is chairman of the board and CEO kamagra phuket of TheraBionic Inc. And co-CEO of TheraBionic GmbH. He is also a senior kamagra phuket editorial board member of Life Sciences-Medicine of 4Open by EDP Sciences.

These relationships are being managed per institutional policy by Wake Forest School of Medicine's Conflict of Interest Review Committee.Green manufacturing is becoming an increasingly critical process across industries, propelled by a growing awareness of the negative environmental and health impacts associated with traditional practices. In the biomaterials industry, electrospinning is a universal fabrication method used around the world to produce nano- to microscale fibrous meshes that closely resemble kamagra phuket native tissue architecture. The process, however, has traditionally used solvents that not only are environmentally hazardous but also pose a significant barrier to industrial scale-up, clinical translation, and, ultimately, widespread use.Researchers at Columbia Engineering report that they have developed a "green electrospinning" process that addresses many of the challenges to scaling up this fabrication method, from managing the environmental risks of volatile solvent storage and disposal at large volumes to meeting health and safety standards during both fabrication and implementation. The team's new study, published kamagra phuket June 28, 2021, by Biofabrication, details how they have modernized the nanofiber fabrication of widely utilized biological and synthetic polymers (e.g. Poly-α-hydroxyesters, collagen), kamagra phuket polymer blends, and polymer-ceramic composites.The study also underscores the superiority of green manufacturing.

The group's "green" fibers exhibited exceptional mechanical properties and preserved growth factor bioactivity relative to traditional fiber counterparts, which is essential for drug delivery and tissue engineering applications.Regenerative medicine is a $156 billion global industry, one that is growing exponentially. The team of researchers, led by kamagra phuket Helen H. Lu, Percy K. And Vida L.W kamagra phuket. Hudson Professor of Biomedical Engineering, wanted to address the challenge of establishing scalable green manufacturing practices for biomimetic biomaterials and scaffolds used in regenerative medicine."We think this is a paradigm shift in biofabrication, and will accelerate the translation of scalable biomaterials and biomimetic scaffolds for tissue engineering and regenerative medicine," said Lu, a leader in research on tissue interfaces, particularly the design of biomaterials and therapeutic strategies for recreating the body's natural synchrony between tissues.

"Green electrospinning not only preserves the composition, chemistry, architecture, and biocompatibility of traditionally electrospun fibers, but it also improves their mechanical properties by doubling the ductility of traditional fibers without compromising yield or kamagra phuket ultimate tensile strength. Our work provides both a more biocompatible and sustainable solution for scalable nanomaterial fabrication."The team, which included several BME doctoral students from Lu's group, Christopher Mosher PhD'20 and Philip Brudnicki, as well as Theanne Schiros, an expert in eco-conscious textile synthesis who is also a research scientist at Columbia MRSEC and assistant professor at FIT, applied sustainability principles to biomaterial production, and developed a green electrospinning process by systematically testing what the FDA considers as biologically benign solvents (Q3C Class 3).They identified acetic acid as a green solvent that exhibits low ecological impact (Sustainable Minds® Life Cycle Assessment) and supports a stable electrospinning jet under routine fabrication conditions. By tuning electrospinning parameters, such as needle-plate distance and flow rate, the researchers were able to ameliorate the fabrication of research and industry-standard biomedical polymers, cutting the detrimental manufacturing impacts of the electrospinning process by three to kamagra phuket six times.Green electrospun materials can be used in a broad range of applications. Lu's team is currently working on further innovating these materials for orthopaedic and dental applications, and expanding this eco-conscious fabrication process for scalable production of regenerative materials."Biofabrication has been referred to as the 'fourth industrial revolution' following steam engines, electrical power, and the digital age for automating mass production," noted Mosher, the study's first author. "This work kamagra phuket is an important step towards developing sustainable practices in the next generation of biomaterials manufacturing, which has become paramount amidst the global climate crisis."Symptoms for early erectile dysfunction treatment differ among age groups and between men and women, new research has found.

These differences are most notable between younger age groups (16 to 59 years) compared to older age groups (60 to 80 years and over), and men have different symptoms compared to women in the early stages of erectile dysfunction treatment .The paper, published today in The Lancet Digital kamagra phuket Health, and led by researchers from King's College London analyses data from the ZOE erectile dysfunction treatment Symptom Study app between April 20th to 15th October 2020. App contributors are invited to get tested as soon as they report any new symptoms, thanks to a joint initiative with the Department of Health and Social Care. The researchers modelled the early signs of erectile dysfunction treatment and kamagra phuket successfully detected 80% of cases when using three days of self-reported symptoms.Researchers compared the ability to predict early signs of erectile dysfunction treatment using current National Health Service UK diagnostic criteria and a Hierarchical Gaussian Process model, a type of machine learning.This machine learning model was able to incorporate some characteristics about the person affected, such as age, sex, and health conditions, and showed that symptoms of early erectile dysfunction treatment are different among various groups.18 symptoms were examined, which had different relevance for early detection in different groups. The most important symptoms for earliest detection of erectile dysfunction treatment overall included loss of smell, chest pain, persistent cough, abdominal pain, blisters on the feet, eye soreness and unusual muscle pain. However, loss of kamagra phuket smell lost significance in people over 60 years of age and was not relevant for subjects over 80.

Other early symptoms such as diarrhoea were key in older age groups (60-79 and >80). Fever, while a known symptom of disease, was not an early feature of the disease in any age group.Men were more likely to report shortness of breath, fatigue, chills and shivers, whereas women were more likely to report loss of smell, chest pain and a persistent cough.While these models were generated in the erectile dysfunction treatment Symptom study app, models were replicated across time suggesting they kamagra phuket would also apply to non-app contributors. Although the models were used on the first strain of the kamagra and Alpha variants, the key findings suggest the symptoms of the Delta variant and subsequent variants will also differ across population groups.Lead author, Claire Steves, Reader at King's College London said. "Its important people kamagra phuket know the earliest symptoms are wide-ranging and may look different for each member of a family or household. Testing guidance could be updated to enable cases to be picked up earlier, especially in the face of new variants which kamagra phuket are highly transmissible.

This could include using widely available lateral flow tests for people with any of these non-core symptoms."Dr Liane dos Santos Canas, first author from King's College London, said. "Currently, in the kamagra phuket UK, only a few symptoms are used to recommend self-isolation and further testing. Using a larger number of symptoms and only after a few days of being unwell, using AI, we can better detect erectile dysfunction treatment positive cases. We hope such a method kamagra phuket is used to encourage more people to get tested as early as possible to minimise the risk of spread."Dr Marc Modat, Senior Lecturer at King's College London, said. "As part of our study, we have been able to identify that the profile of symptoms due to erectile dysfunction treatment differs from one group to another.

This suggests that the criteria to encourage people to get tested should kamagra phuket be personalised using individuals' information such as age. Alternatively, a larger set of symptoms could be considered, so the different manifestations of the disease across different groups are taken into account." Story Source. Materials provided by King's College kamagra phuket London. Note. Content may be edited for style and length.The mutations that give rise to melanoma result from a chemical conversion in DNA fueled by sunlight -- not just a DNA copying error as previously believed, reports a study by Van Andel Institute kamagra phuket scientists published today in Science Advances.The findings upend long-held beliefs about the mechanisms underlying the disease, reinforce the importance of prevention efforts and offer a path forward for investigating the origins of other cancer types."Cancers result from DNA mutations that allow defective cells to survive and invade other tissues.

However, in most cases, the source of these mutations is not clear, which complicates development of therapies kamagra phuket and prevention methods," said Gerd Pfeifer, Ph.D., a VAI professor and the study's corresponding author. "In melanoma, we've now shown that damage from sunlight primes the DNA by creating 'premutations' that then give way to full mutations during DNA replication."Melanoma is a serious type of skin cancer that begins in pigment-producing skin cells. Although less common than other types of skin cancer, melanoma is more likely to spread and invade kamagra phuket other tissues, which significantly reduces patient survival. Previous large-scale sequencing studies have shown that melanoma has the most DNA mutations of any cancer. Like other skin cancers, melanoma is kamagra phuket who can buy kamagra linked to sun exposure, specifically a type of radiation called UVB.

Exposure to UVB damages skin cells as well as the DNA within cells.Most cancers are thought to begin when DNA damage directly causes a mutation that is then copied into subsequent generations of cells during normal cellular replication. In the case of melanoma, however, Pfeifer and his team found a different mechanism that produces disease-causing mutations -- the introduction of a chemical base not normally found in DNA that makes it prone to mutation.DNA comprises four chemical bases that kamagra phuket exist in pairs -- adenine (A) and thymine (T), and cytosine (C) and guanine (G). Different sequences of these pairs encode all of the instructions for life. In melanoma, kamagra phuket the problem occurs when UVB radiation from the sun hits certain sequences of bases -- CC, TT, TC and CT -- causing them to chemically link together and become unstable. The resulting instability causes a chemical change to cytosine that transforms it into uracil, kamagra phuket a chemical base found in the messenger molecule RNA but not in DNA.

This change, called a "premutation," primes the DNA to mutate during normal cell replication, thereby causing alterations that underlie melanoma.These mutations may not cause disease right away. Instead, they may lay dormant for kamagra phuket years. They also can accumulate as time goes on and a person's lifetime exposure to sunlight increases, resulting in a tough-to-treat cancer that evades many therapeutic options."Safe sun practices are very important. In our study, 10-15 minutes of exposure to UVB light was equivalent to what a person would experience at high noon, and kamagra phuket was sufficient to cause premutations," Pfeifer said. "While our cells have built-in safeguards to repair DNA damage, this process occasionally lets something slip by.

Protecting the skin is generally kamagra phuket the best bet when it comes to melanoma prevention."The findings were made possible using a method developed by Pfeifer's lab called Circle Damage Sequencing, which allows scientists to "break" DNA at each point where damage occurs. They then coax the DNA into circles, which are replicated thousands of times using a technology called PCR. Once they have enough DNA, they use next-generation sequencing to kamagra phuket identify which DNA bases are present at the breaks. Going forward, Pfeifer and colleagues plan to use this powerful technique to investigate other types of DNA damage in different kinds of cancer.Other authors include Seung-Gi Jin, Ph.D., Dean Pettinga, Jennifer Johnson and Peipei Li, Ph.D., of VAI. Story Source kamagra phuket.

Materials provided by kamagra phuket Van Andel Research Institute. Note. Content may be edited for style and length.UT Southwestern faculty have discovered what appears to be an Achilles' heel in kamagra phuket ovarian cancers, as well as new biomarkers that could point to which patients are the best candidates for possible new treatments.The finding, published in the journal Cell, was made in part using a research tool invented in a UT Southwestern lab in the Cecil H. And Ida Green Center for Reproductive Biology Sciences.The research was led by W. Lee Kraus, Ph.D., Professor of Obstetrics and Gynecology and Pharmacology and a member of kamagra phuket the Harold C.

Simmons Comprehensive Cancer Center."Many researchers are trying to find dependencies in cancers by asking why a cancer cell amplifies a gene, increases the levels of a protein, or upregulates a critical cellular pathway. These changes give that cancer a selective advantage, but at the same time they can become an Achilles' heel -- something that, if the alteration was blocked, would kill the cancer or stop its growth," kamagra phuket he said.Dr. Kraus and his team, including lead author Sridevi Challa, Ph.D., a postdoctoral researcher in the lab, found that ovarian cancers massively amplify an enzyme, NMNAT-2, that makes NAD+. NAD+ is the substrate for a family kamagra phuket of enzymes called PARPs, which chemically modify proteins with ADP-ribose from NAD+. In this study, the team found that one PARP family member, PARP-16, uses NAD+ to modify ribosomes, the protein synthesizing machines of kamagra phuket the cell.A challenge for this work was that a single ADP-ribose group attached to a protein is difficult to detect.

Dr. Kraus and his team overcame this problem by developing a synthetic mono(ADP-ribose) detection reagent made up of natural protein domains fused together, which can be used to detect ADP-ribosylated proteins in kamagra phuket cells and patient samples. advertisement In collaboration with UT Southwestern clinicians, led by Jayanthi Lea, M.D., Professor of Obstetrics and Gynecology and member of the Simmons Cancer Center, Dr. Kraus and his team screened human ovarian cancer patient samples using the mono(ADP-ribose) detection reagent kamagra phuket to identify those with low or high levels of mono(ADP-ribose)."We were able to show that when ribosomes are mono(ADP-ribosyl)ated in ovarian cancer cells, the modification changes the way they translate mRNAs into proteins," Dr. Kraus said.

"The ovarian cancers amplify NMNAT-2 to increase the levels of NAD+ available for PARP-16 to mono(ADP-ribosyl)ate ribosomes, giving them a kamagra phuket selective advantage by allowing them to fine-tune the levels of translation and prevent toxic protein aggregation. But that selective advantage also becomes their Achilles' heel. They're addicted to NMNAT-2, so inhibition or reduction of NMNAT-2 inhibits the growth of the cancer cells."This study identified mono(ADP-ribose) and NMNAT-2 as kamagra phuket potential biomarkers for ovarian cancers, which may allow clinicians to determine which ovarian cancer patients may respond well and which will not. Even more ovarian cancer patients might do well if an inhibitor is developed for PARP-16, which blocks ribosome mono(ADP-ribosyl)ation.Dr. Kraus, an expert in PARPs, said medical science has had great success in developing FDA-approved PARP-1 inhibitors, and an kamagra phuket inhibitor for PARP-16 is likely."No PARP-16 inhibitors are currently in clinical trials, but labs in academia and the pharmaceutical industry are developing specific and potent inhibitors of PARP-16.

Such a drug could be an effective therapeutic for treating kamagra phuket ovarian cancers," he said. advertisement Dr. Kraus is a founder and consultant kamagra phuket for Ribon Therapeutics Inc., and ARase Therapeutics Inc. He is also co-holder of U.S. Patent 9,599,606 covering the mono(ADP-ribose) detection reagent, which has been kamagra phuket licensed to and is sold by EMD Millipore."Dr.

Kraus' research is not just a great advance in basic science. It has real promise for clinician investigators and cancer care practitioners because kamagra phuket it shows a biomarker and a pathway a future drug could target. The fact that technology developed in his laboratory helped make these findings shows how our faculty builds on their findings to break new ground," said Carlos L. Arteaga, M.D., Director of the Simmons Cancer Center.Other researchers who kamagra phuket contributed to this study include Beman R. Khulpateea, Tulip Nandu, Cristel kamagra phuket V.

Camacho, Keun W. Ryu, Hao Chen, kamagra phuket and Yan Peng.The research work was supported by a grant from the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK069710) as well as funds from the Cecil H. And Ida Green Center for Reproductive Biology Sciences Endowment to Kraus, and a postdoctoral fellowship from the Ovarian Cancer Research Alliance (GAA202103-0003) to Challa.Dr. Arteaga holds kamagra phuket the The Lisa K. Simmons Distinguished Chair in Comprehensive Oncology.

Kraus holds kamagra phuket the Cecil H. And Ida Green Distinguished Chair in Reproductive Biology Sciences. Dr. Lea holds the Patricia Duniven Fletcher Distinguished Professorship in Gynecological Oncology..

Researchers at Wake Forest School of buy kamagra tablets online Medicine have shown that a targeted therapy using non-thermal radio waves is safe to use in the treatment of hepatocellular carcinoma (HCC), the most common type of liver cancer. The therapy also showed a benefit in overall survival.The study findings appear online in 4Open, a journal buy kamagra tablets online published by EDP Sciences."HCC accounts for nearly 90% of all liver cancers, and current survival rates are between six and 20 months," said Boris Pasche, M.D., Ph.D., chair of cancer biology and director of Wake Forest Baptist's Comprehensive Cancer Center. "Currently, there are limited treatment options for patients with this advanced liver cancer."For the study researchers used a device called TheraBionic P1, invented by Pasche and Alexandre Barbault of TheraBionic GmbH in Ettlingen, Germany, that works by delivering cancer-specific, amplitude-modulated radiofrequency electromagnetic fields (AM RF EMF) programmed specifically for HCC.The frequencies used are specific to the patient's type of cancer as identified through tumor biopsies or blood work, Pasche said.Pasche and Barbault discovered radio frequencies for 15 different types of cancer, as previously reported in a study published in 2009 in the Journal of Experimental &. Clinical Cancer Research buy kamagra tablets online.

advertisement TheraBionic P1 is a hand-held device that emits radio frequencies via a spoon-shaped antenna, which is placed on the patient's tongue during treatment and is administered three times a day for one hour to deliver low levels of radiofrequency electromagnetic fields throughout the patient's body.In previous studies, the device, which received breakthrough designation from the FDA in 2019, was shown to block the growth of liver cancer cells in the body without damaging healthy cells.For the current study, 18 patients with advanced HCC participated and received treatment with the device. Researchers also analyzed previously published data on 41 patients from a phase II study and historical controls from earlier clinical trials."Our findings show an improvement in overall survival of more than 30% in patients with well-preserved liver function buy kamagra tablets online and also in those with more severe disease," Pasche said.Researchers also tracked side effects, and no patients stopped TheraBionic P1 treatment because of adverse reactions. advertisement "We're encouraged by these initial findings," Pasche said. "Our study shows a benefit in overall survival, and the treatment isn't associated with any significant side effects."Support for buy kamagra tablets online this study was provided by TheraBionic Inc.

And funds from Wake Forest Baptist's Comprehensive Cancer Center.Pasche noted that the study does have several limitations because of the small sample size and "selection bias inherent in the use of historical control data."However, two additional clinical trials are underway and are being led by William Blackstock, M.D., chair of radiation oncology at Wake Forest Baptist's Comprehensive Cancer Center. One is a single-center study to assess the safety and effectiveness of the TheraBionic device in combination with Regorafenib, a chemotherapy drug, as a second-line buy kamagra tablets online treatment. Another multicenter, double-blind, randomized study comparing TheraBionic with placebo will assess the safety and effectiveness of the device as a buy kamagra tablets online third-line therapy in the treatment of advanced HCC.Pasche holds stock in TheraBionic Inc. And TheraBionic GmbH.

He is buy kamagra tablets online chairman of the board and CEO of TheraBionic Inc. And co-CEO of TheraBionic GmbH. He is also a senior editorial board member of buy kamagra tablets online Life Sciences-Medicine of 4Open by EDP Sciences. These relationships are being managed per institutional policy by Wake Forest School of Medicine's Conflict of Interest Review Committee.Green manufacturing is becoming an increasingly critical process across industries, propelled by a growing awareness of the negative environmental and health impacts associated with traditional practices.

In the biomaterials industry, electrospinning is a universal fabrication method used around the world to produce nano- to microscale fibrous meshes buy kamagra tablets online that closely resemble native tissue architecture. The process, however, has traditionally used solvents that not only are environmentally hazardous but also pose a significant barrier to industrial scale-up, clinical translation, and, ultimately, widespread use.Researchers at Columbia Engineering report that they have developed a "green electrospinning" process that addresses many of the challenges to scaling up this fabrication method, from managing the environmental risks of volatile solvent storage and disposal at large volumes to meeting health and safety standards during both fabrication and implementation. The team's new buy kamagra tablets online study, published June 28, 2021, by Biofabrication, details how they have modernized the nanofiber fabrication of widely utilized biological and synthetic polymers (e.g. Poly-α-hydroxyesters, collagen), buy kamagra tablets online polymer blends, and polymer-ceramic composites.The study also underscores the superiority of green manufacturing.

The group's "green" fibers exhibited exceptional mechanical properties and preserved growth factor bioactivity relative to traditional fiber counterparts, which is essential for drug delivery and tissue engineering applications.Regenerative medicine is a $156 billion global industry, one that is growing exponentially. The team of researchers, led buy kamagra tablets online by Helen H. Lu, Percy K. And Vida buy kamagra tablets online L.W.

Hudson Professor of Biomedical Engineering, wanted to address the challenge of establishing scalable green manufacturing practices for biomimetic biomaterials and scaffolds used in regenerative medicine."We think this is a paradigm shift in biofabrication, and will accelerate the translation of scalable biomaterials and biomimetic scaffolds for tissue engineering and regenerative medicine," said Lu, a leader in research on tissue interfaces, particularly the design of biomaterials and therapeutic strategies for recreating the body's natural synchrony between tissues. "Green electrospinning not only preserves the composition, chemistry, architecture, and biocompatibility of traditionally electrospun fibers, but it also improves their mechanical properties by doubling the ductility of traditional fibers without compromising yield or ultimate buy kamagra tablets online tensile strength. Our work provides both a more biocompatible and sustainable solution for scalable nanomaterial fabrication."The team, which included several BME doctoral students from Lu's group, Christopher Mosher PhD'20 and Philip Brudnicki, as well as Theanne Schiros, an expert in eco-conscious textile synthesis who is also a research scientist at Columbia MRSEC and assistant professor at FIT, applied sustainability principles to biomaterial production, and developed a green electrospinning process by systematically testing what the FDA considers as biologically benign solvents (Q3C Class 3).They identified acetic acid as a green solvent that exhibits low ecological impact (Sustainable Minds® Life Cycle Assessment) and supports a stable electrospinning jet under routine fabrication conditions. By tuning electrospinning parameters, such as needle-plate distance and flow rate, the researchers were able to ameliorate the fabrication of research buy kamagra tablets online and industry-standard biomedical polymers, cutting the detrimental manufacturing impacts of the electrospinning process by three to six times.Green electrospun materials can be used in a broad range of applications.

Lu's team is currently working on further innovating these materials for orthopaedic and dental applications, and expanding this eco-conscious fabrication process for scalable production of regenerative materials."Biofabrication has been referred to as the 'fourth industrial revolution' following steam engines, electrical power, and the digital age for automating mass production," noted Mosher, the study's first author. "This work is an important step towards developing sustainable practices in the next generation of biomaterials manufacturing, which has become buy kamagra tablets online paramount amidst the global climate crisis."Symptoms for early erectile dysfunction treatment differ among age groups and between men and women, new research has found. These differences are most notable between younger age groups (16 to 59 years) compared to older age groups (60 to 80 years and over), and men have different symptoms compared to women in the early stages of erectile dysfunction treatment .The paper, published today in The Lancet Digital Health, and led by researchers from buy kamagra tablets online King's College London analyses data from the ZOE erectile dysfunction treatment Symptom Study app between April 20th to 15th October 2020. App contributors are invited to get tested as soon as they report any new symptoms, thanks to a joint initiative with the Department of Health and Social Care.

The researchers modelled the early signs of erectile dysfunction treatment and successfully detected 80% of cases when using three days of self-reported symptoms.Researchers compared the ability to predict early signs of erectile dysfunction treatment using current National Health Service buy kamagra tablets online UK diagnostic criteria and a Hierarchical Gaussian Process model, a type of machine learning.This machine learning model was able to incorporate some characteristics about the person affected, such as age, sex, and health conditions, and showed that symptoms of early erectile dysfunction treatment are different among various groups.18 symptoms were examined, which had different relevance for early detection in different groups. The most important symptoms for earliest detection of erectile dysfunction treatment overall included loss of smell, chest pain, persistent cough, abdominal pain, blisters on the feet, eye soreness and unusual muscle pain. However, loss of buy kamagra tablets online smell lost significance in people over 60 years of age and was not relevant for subjects over 80. Other early symptoms such as diarrhoea were key in older age groups (60-79 and >80).

Fever, while a known symptom of disease, was not an early feature of the disease in any age buy kamagra tablets online group.Men were more likely to report shortness of breath, fatigue, chills and shivers, whereas women were more likely to report loss of smell, chest pain and a persistent cough.While these models were generated in the erectile dysfunction treatment Symptom study app, models were replicated across time suggesting they would also apply to non-app contributors. Although the models were used on the first strain of the kamagra and Alpha variants, the key findings suggest the symptoms of the Delta variant and subsequent variants will also differ across population groups.Lead author, Claire Steves, Reader at King's College London said. "Its important people know the earliest symptoms are wide-ranging and may look different for each member of buy kamagra tablets online a family or household. Testing guidance could be updated to enable cases to be picked up earlier, buy kamagra tablets online especially in the face of new variants which are highly transmissible.

This could include using widely available lateral flow tests for people with any of these non-core symptoms."Dr Liane dos Santos Canas, first author from King's College London, said. "Currently, in buy kamagra tablets online the UK, only a few symptoms are used to recommend self-isolation and further testing. Using a larger number of symptoms and only after a few days of being unwell, using AI, we can better detect erectile dysfunction treatment positive cases. We hope such a method is used to encourage more people to get tested as early as possible to buy kamagra tablets online minimise the risk of spread."Dr Marc Modat, Senior Lecturer at King's College London, said.

"As part of our study, we have been able to identify that the profile of symptoms due to erectile dysfunction treatment differs from one group to another. This suggests that the criteria to encourage people to get tested should be buy kamagra tablets online personalised using individuals' information such as age. Alternatively, a larger set of symptoms could be considered, so the different manifestations of the disease across different groups are taken into account." Story Source. Materials provided by King's buy kamagra tablets online College London.

Note. Content may be edited for style buy kamagra tablets online and length.The mutations that give rise to melanoma result from a chemical conversion in DNA fueled by sunlight -- not just a DNA copying error as previously believed, reports a study by Van Andel Institute scientists published today in Science Advances.The findings upend long-held beliefs about the mechanisms underlying the disease, reinforce the importance of prevention efforts and offer a path forward for investigating the origins of other cancer types."Cancers result from DNA mutations that allow defective cells to survive and invade other tissues. However, in most cases, the source of these mutations is not clear, which complicates development of therapies and prevention methods," said Gerd buy kamagra tablets online Pfeifer, Ph.D., a VAI professor and the study's corresponding author. "In melanoma, we've now shown that damage from sunlight primes the DNA by creating 'premutations' that then give way to full mutations during DNA replication."Melanoma is a serious type of skin cancer that begins in pigment-producing skin cells.

Although less common than other buy kamagra tablets online types of skin cancer, melanoma is more likely to spread and invade other tissues, which significantly reduces patient survival. Previous large-scale sequencing studies have shown that melanoma has the most DNA mutations of any cancer. Like other skin cancers, melanoma is linked to sun exposure, specifically a type buy kamagra tablets online of radiation called UVB. Exposure to UVB damages skin cells as well as the DNA within cells.Most cancers are thought to begin when DNA damage directly causes a mutation that is then copied into subsequent generations of cells during normal cellular replication.

In the case of melanoma, however, Pfeifer and his team found a different buy kamagra tablets online mechanism that produces disease-causing mutations -- the introduction of a chemical base not normally found in DNA that makes it prone to mutation.DNA comprises four chemical bases that exist in pairs -- adenine (A) and thymine (T), and cytosine (C) and guanine (G). Different sequences of these pairs encode all of the instructions for life. In melanoma, the problem occurs when UVB radiation from the sun hits certain sequences buy kamagra tablets online of bases -- CC, TT, TC and CT -- causing them to chemically link together and become unstable. The resulting instability causes buy kamagra tablets online a chemical change to cytosine that transforms it into uracil, a chemical base found in the messenger molecule RNA but not in DNA.

This change, called a "premutation," primes the DNA to mutate during normal cell replication, thereby causing alterations that underlie melanoma.These mutations may not cause disease right away. Instead, they may lay dormant for years buy kamagra tablets online. They also can accumulate as time goes on and a person's lifetime exposure to sunlight increases, resulting in a tough-to-treat cancer that evades many therapeutic options."Safe sun practices are very important. In our study, 10-15 minutes of exposure to UVB light was buy kamagra tablets online equivalent to what a person would experience at high noon, and was sufficient to cause premutations," Pfeifer said.

"While our cells have built-in safeguards to repair DNA damage, this process occasionally lets something slip by. Protecting the skin is generally the best bet when it comes to melanoma prevention."The findings were made possible using a method developed buy kamagra tablets online by Pfeifer's lab called Circle Damage Sequencing, which allows scientists to "break" DNA at each point where damage occurs. They then coax the DNA into circles, which are replicated thousands of times using a technology called PCR. Once they have enough DNA, they use next-generation sequencing to identify which DNA bases are present at the breaks buy kamagra tablets online.

Going forward, Pfeifer and colleagues plan to use this powerful technique to investigate other types of DNA damage in different kinds of cancer.Other authors include Seung-Gi Jin, Ph.D., Dean Pettinga, Jennifer Johnson and Peipei Li, Ph.D., of VAI. Story Source buy kamagra tablets online. Materials provided by Van Andel Research Institute buy kamagra tablets online. Note.

Content may be edited for style and length.UT Southwestern faculty have discovered what appears to be an Achilles' heel in ovarian cancers, as well as new biomarkers that could point to which patients are the best candidates for possible new treatments.The finding, published in buy kamagra tablets online the journal Cell, was made in part using a research tool invented in a UT Southwestern lab in the Cecil H. And Ida Green Center for Reproductive Biology Sciences.The research was led by W. Lee Kraus, Ph.D., Professor of Obstetrics and Gynecology buy kamagra tablets online and Pharmacology and a member of the Harold C. Simmons Comprehensive Cancer Center."Many researchers are trying to find dependencies in cancers by asking why a cancer cell amplifies a gene, increases the levels of a protein, or upregulates a critical cellular pathway.

These changes give that cancer a selective advantage, but at the same time they can become an Achilles' heel -- something buy kamagra tablets online that, if the alteration was blocked, would kill the cancer or stop its growth," he said.Dr. Kraus and his team, including lead author Sridevi Challa, Ph.D., a postdoctoral researcher in the lab, found that ovarian cancers massively amplify an enzyme, NMNAT-2, that makes NAD+. NAD+ is buy kamagra tablets online the substrate for a family of enzymes called PARPs, which chemically modify proteins with ADP-ribose from NAD+. In this study, the team found that one PARP family member, PARP-16, uses NAD+ to modify ribosomes, the protein synthesizing machines of the cell.A challenge for this work was that a single ADP-ribose group attached to a protein is difficult buy kamagra tablets online to detect.

Dr. Kraus and his buy kamagra tablets online team overcame this problem by developing a synthetic mono(ADP-ribose) detection reagent made up of natural protein domains fused together, which can be used to detect ADP-ribosylated proteins in cells and patient samples. advertisement In collaboration with UT Southwestern clinicians, led by Jayanthi Lea, M.D., Professor of Obstetrics and Gynecology and member of the Simmons Cancer Center, Dr. Kraus and his team screened human ovarian cancer buy kamagra tablets online patient samples using the mono(ADP-ribose) detection reagent to identify those with low or high levels of mono(ADP-ribose)."We were able to show that when ribosomes are mono(ADP-ribosyl)ated in ovarian cancer cells, the modification changes the way they translate mRNAs into proteins," Dr.

Kraus said. "The ovarian cancers amplify NMNAT-2 to increase the levels of NAD+ available for PARP-16 to mono(ADP-ribosyl)ate ribosomes, giving them a selective advantage by allowing them to fine-tune the buy kamagra tablets online levels of translation and prevent toxic protein aggregation. But that selective advantage also becomes their Achilles' heel. They're addicted to NMNAT-2, so inhibition or reduction buy kamagra tablets online of NMNAT-2 inhibits the growth of the cancer cells."This study identified mono(ADP-ribose) and NMNAT-2 as potential biomarkers for ovarian cancers, which may allow clinicians to determine which ovarian cancer patients may respond well and which will not.

Even more ovarian cancer patients might do well if an inhibitor is developed for PARP-16, which blocks ribosome mono(ADP-ribosyl)ation.Dr. Kraus, an expert in PARPs, said medical science has had great success in developing FDA-approved PARP-1 inhibitors, and an buy kamagra tablets online inhibitor for PARP-16 is likely."No PARP-16 inhibitors are currently in clinical trials, but labs in academia and the pharmaceutical industry are developing specific and potent inhibitors of PARP-16. Such a drug could be an effective therapeutic for treating ovarian cancers," buy kamagra tablets online he said. advertisement Dr.

Kraus is a founder and buy kamagra tablets online consultant for Ribon Therapeutics Inc., and ARase Therapeutics Inc. He is also co-holder of U.S. Patent 9,599,606 covering the buy kamagra tablets online mono(ADP-ribose) detection reagent, which has been licensed to and is sold by EMD Millipore."Dr. Kraus' research is not just a great advance in basic science.

It has real promise for clinician investigators and cancer buy kamagra tablets online care practitioners because it shows a biomarker and a pathway a future drug could target. The fact that technology developed in his laboratory helped make these findings shows how our faculty builds on their findings to break new ground," said Carlos L. Arteaga, M.D., Director of the Simmons Cancer Center.Other buy kamagra tablets online researchers who contributed to this study include Beman R. Khulpateea, Tulip Nandu, Cristel buy kamagra tablets online V.

Camacho, Keun W. Ryu, Hao Chen, and Yan Peng.The research work was supported by a grant from the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK069710) as well as funds from the Cecil buy kamagra tablets online H. And Ida Green Center for Reproductive Biology Sciences Endowment to Kraus, and a postdoctoral fellowship from the Ovarian Cancer Research Alliance (GAA202103-0003) to Challa.Dr. Arteaga holds buy kamagra tablets online the The Lisa K.

Simmons Distinguished Chair in Comprehensive Oncology. Kraus holds the Cecil buy kamagra tablets online H. And Ida Green Distinguished Chair in Reproductive Biology Sciences. Dr.

Lea holds the Patricia Duniven Fletcher Distinguished Professorship in Gynecological Oncology..

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AbstractIntroduction. We report a very rare case of familial breast cancer and diffuse gastric cancer, with germline pathogenic variants in both BRCA1 and CDH1 genes. To the best of our knowledge, this is the first report of such an association.Family description.

The proband is a woman diagnosed with breast cancer at the age of 52 years. She requested genetic counselling in 2012, at the age of 91 years, because of a history of breast cancer in her daughter, her sister, her niece and her paternal grandmother and was therefore concerned about her relatives. Her sister and maternal aunt also had gastric cancer.

She was tested for several genes associated with hereditary breast cancer.Results. A large deletion of BRCA1 from exons 1 to 7 and two CDH1 pathogenic cis variants were identified.Conclusion. This complex situation is challenging for genetic counselling and management of at-risk individuals.cancer.

Breastcancer. Gastricclinical geneticsgenetic screening/counsellingmolecular geneticsIntroductionGLI-Kruppel family member 3 (GLI3) encodes for a zinc finger transcription factor which plays a key role in the sonic hedgehog (SHH) signalling pathway essential in both limb and craniofacial development.1 2 In hand development, SHH is expressed in the zone of polarising activity (ZPA) on the posterior side of the handplate. The ZPA expresses SHH, creating a gradient of SHH from the posterior to the anterior side of the handplate.

In the presence of SHH, full length GLI3-protein is produced (GLI3A), whereas absence of SHH causes cleavage of GLI3 into its repressor form (GLI3R).3 4 Abnormal expression of this SHH/GLI3R gradient can cause both preaxial and postaxial polydactyly.2Concordantly, pathogenic DNA variants in the GLI3 gene are known to cause multiple syndromes with craniofacial and limb involvement, such as. Acrocallosal syndrome5 (OMIM. 200990), Greig cephalopolysyndactyly syndrome6 (OMIM.

175700) and Pallister-Hall syndrome7 (OMIM. 146510). Also, in non-syndromic polydactyly, such as preaxial polydactyly-type 4 (PPD4, OMIM.

174700),8 pathogenic variants in GLI3 have been described. Out of these diseases, Pallister-Hall syndrome is the most distinct entity, defined by the presence of central polydactyly and hypothalamic hamartoma.9 The other GLI3 syndromes are defined by the presence of preaxial and/or postaxial polydactyly of the hand and feet with or without syndactyly (Greig syndrome, PPD4). Also, various mild craniofacial features such as hypertelorism and macrocephaly can occur.

Pallister-Hall syndrome is caused by truncating variants in the middle third of the GLI3 gene.10–12 The truncation of GLI3 causes an overexpression of GLI3R, which is believed to be the key difference between Pallister-Hall and the GLI3-mediated polydactyly syndromes.9 11 Although multiple attempts have been made, the clinical and genetic distinction between the GLI3-mediated polydactyly syndromes is less evident. This has for example led to the introduction of subGreig and the formulation of an Oro-facial-digital overlap syndrome.10 Other authors, suggested that we should not regard these diseases as separate entities, but as a spectrum of GLI3-mediated polydactyly syndromes.13Although phenotype/genotype correlation of the different syndromes has been cumbersome, clinical and animal studies do provide evidence that distinct regions within the gene, could be related to the individual anomalies contributing to these syndromes. First, case studies show isolated preaxial polydactyly is caused by both truncating and non-truncating variants throughout the GLI3 gene, whereas in isolated postaxial polydactyly cases truncating variants at the C-terminal side of the gene are observed.12 14 These results suggest two different groups of variants for preaxial and postaxial polydactyly.

Second, recent animal studies suggest that posterior malformations in GLI3-mediated polydactyly syndromes are likely related to a dosage effect of GLI3R rather than due to the influence of an altered GLI3A expression.15Past attempts for phenotype/genotype correlation in GLI3-mediated polydactyly syndromes have directly related the diagnosed syndrome to the observed genotype.10–12 16 Focusing on individual hand phenotypes, such as preaxial and postaxial polydactyly and syndactyly might be more reliable because it prevents misclassification due to inconsistent use of syndrome definition. Subsequently, latent class analysis (LCA) provides the possibility to relate a group of observed variables to a set of latent, or unmeasured, parameters and thereby identifying different subgroups in the obtained dataset.17 As a result, LCA allows us to group different phenotypes within the GLI3-mediated polydactyly syndromes and relate the most important predictors of the grouped phenotypes to the observed GLI3 variants.The aim of our study was to further investigate the correlation of the individual phenotypes to the genotypes observed in GLI3-mediated polydactyly syndromes, using LCA. Cases were obtained by both literature review and the inclusion of local clinical cases.

Subsequently, we identified two subclasses of limb anomalies that relate to the underlying GLI3 variant. We provide evidence for two different phenotypic and genotypic groups with predominantly preaxial and postaxial hand and feet anomalies, and we specify those cases with a higher risk for corpus callosum anomalies.MethodsLiterature reviewThe Human Gene Mutation Database (HGMD Professional 2019) was reviewed to identify known pathogenic variants in GLI3 and corresponding phenotypes.18 All references were obtained and cases were included when they were diagnosed with either Greig or subGreig syndrome or PPD4.10–12 Pallister-Hall syndrome and acrocallosal syndrome were excluded because both are regarded distinct syndromes and rather defined by the presence of the non-hand anomalies, than the presence of preaxial or postaxial polydactyly.13 19 Isolated preaxial or postaxial polydactyly were excluded for two reasons. The phenotype/genotype correlations are better understood and both anomalies can occur sporadically which could introduce falsely assumed pathogenic GLI3 variants in the analysis.

Additionally, cases were excluded when case-specific phenotypic or genotypic information was not reported or if these two could not be related to each other. Families with a combined phenotypic description, not reducible to individual family members, were included as one case in the analysis.Clinical casesThe Sophia Children’s Hospital Database was reviewed for cases with a GLI3 variant. Within this population, the same inclusion criteria for the phenotype were valid.

Relatives of the index patients were also contacted for participation in this study, when they showed comparable hand, foot, or craniofacial malformations or when a GLI3 variant was identified. Phenotypes of the hand, foot and craniofacial anomalies of the patients treated in the Sophia Children's Hospital were collected using patient documentation. Family members were identified and if possible, clinically verified.

Alternatively, family members were contacted to verify their phenotypes. If no verification was possible, cases were excluded.PhenotypesThe phenotypes of both literature cases and local cases were extracted in a similar fashion. The most frequently reported limb and craniofacial phenotypes were dichotomised.

The dichotomised hand and foot phenotypes were preaxial polydactyly, postaxial polydactyly and syndactyly. Broad halluces or thumbs were commonly reported by authors and were dichotomised as a presentation of preaxial polydactyly. The extracted dichotomised craniofacial phenotypes were hypertelorism, macrocephaly and corpus callosum agenesis.

All other phenotypes were registered, but not dichotomised.Pathogenic GLI3 variantsAll GLI3 variants were extracted and checked using Alamut Visual V.2.14. If indicated, variants were renamed according to standard Human Genome Variation Society nomenclature.20 Variants were grouped in either missense, frameshift, nonsense or splice site variants. In the group of frameshift variants, a subgroup with possible splice site effect were identified for subgroup analysis when indicated.

Similarly, nonsense variants prone for nonsense mediated decay (NMD) and nonsense variants with experimentally confirmed NMD were identified.21 Deletions of multiple exons, CNVs and translocations were excluded for analysis. A full list of included mutations is available in the online supplementary materials.Supplemental materialThe location of the variant was compared with five known structural domains of the GLI3 gene. (1) repressor domain, (2) zinc finger domain, (3) cleavage site, (4) activator domain, which we defined as a concatenation of the separately identified transactivation zones, the CBP binding domain and the mediator binding domain (MBD) and (5) the MID1 interaction region domain.1 6 22–24 The boundaries of each of the domains were based on available literature (figure 1, exact locations available in the online supplementary materials).

The boundaries used by different authors did vary, therefore a consensus was made.In this figure the posterior probability of an anterior phenotype is plotted against the location of the variant, stratified for the type of mutation that was observed. For better overview, only variants with a location effect were displayed. The full figure, including all variant types, can be found in the online supplementary figure 1.

Each mutation is depicted as a dot, the size of the dot represents the number of observations for that variant. If multiple observations were made, the mean posterior odds and IQR are plotted. For the nonsense variants, variants that were predicted to produce nonsense mediated decay, are depicted using a triangle.

Again, the size indicates the number of observations." data-icon-position data-hide-link-title="0">Figure 1 In this figure the posterior probability of an anterior phenotype is plotted against the location of the variant, stratified for the type of mutation that was observed. For better overview, only variants with a location effect were displayed. The full figure, including all variant types, can be found in the online supplementary figure 1.

Each mutation is depicted as a dot, the size of the dot represents the number of observations for that variant. If multiple observations were made, the mean posterior odds and IQR are plotted. For the nonsense variants, variants that were predicted to produce nonsense mediated decay, are depicted using a triangle.

Again, the size indicates the number of observations.Supplemental materialLatent class analysisTo cluster phenotypes and relate those to the genotypes of the patients, an explorative analysis was done using LCA in R (R V.3.6.1 for Mac. Polytomous variable LCA, poLCA V.1.4.1.). We used our LCA to detect the number of phenotypic subgroups in the dataset and subsequently predict a class membership for each case in the dataset based on the posterior probabilities.In order to make a reliable prediction, only phenotypes that were sufficiently reported and/or ruled out were feasible for LCA, limiting the analysis to preaxial polydactyly, postaxial polydactyly and syndactyly of the hands and feet.

Only full cases were included. To determine the optimal number of classes, we fitted a series of models ranging from a one-class to a six-class model. The optimal number of classes was based on the conditional Akaike information criterion (cAIC), the non adjusted and the sample-size adjusted Bayesian information criterion (BIC and aBIC) and the obtained entropy.25 The explorative LCA produces both posterior probabilities per case for both classes and predicted class membership.

Using the predicted class membership, the phenotypic features per class were determined in a univariate analysis (χ2, SPSS V.25). Using the posterior probabilities on latent class (LC) membership, a scatter plot was created using the location of the variant on the x-axis and the probability of class membership on the y-axis for each of the types of variants (Tibco Spotfire V.7.14). Using these scatter plots, variants that give similar phenotypes were clustered.Genotype/phenotype correlationBecause an LC has no clinical value, the correlation between genotypes and phenotypes was investigated using the predictor phenotypes and the clustered phenotypes.

First, those phenotypes that contribute most to LC membership were identified. Second those phenotypes were directly related to the different types of variants (missense, nonsense, frameshift, splice site) and their clustered locations. Quantification of the relation was performed using a univariate analysis using a χ2 test.

Because of our selection criteria, meaning patients at least have two phenotypes, a multivariate using a logistic regression analysis was used to detect the most significant predictors in the overall phenotype (SPSS V.25). Finally, we explored the relation of the clustered genotypes to the presence of corpus callosum agenesis, a rare malformation in GLI3-mediated polydactyly syndromes which cannot be readily diagnosed without additional imaging.ResultsWe included 251 patients from the literature and 46 local patients,10–12 16 21 26–43 in total 297 patients from 155 different families with 127 different GLI3 variants, 32 of which were large deletions, CNVs or translocations. In six local cases, the exact variant could not be retrieved by status research.The distribution of the most frequently observed phenotypes and variants are presented in table 1.

Other recurring phenotypes included developmental delay (n=22), broad nasal root (n=23), frontal bossing or prominent forehead (n=16) and craniosynostosis (n=13), camptodactyly (n=8) and a broad first interdigital webspace of the foot (n=6).View this table:Table 1 Baseline phenotypes and genotypes of selected populationThe LCA model was fitted using the six defined hand/foot phenotypes. Model fit indices for the LCA are displayed in table 2. Based on the BIC, a two-class model has the best fit for our data.

The four-class model does show a gain in entropy, however with a higher BIC and loss of df. Therefore, based on the majority of performance statistics and the interpretability of the model, a two-class model was chosen. Table 3 displays the distribution of phenotypes and genotypes over the two classes.View this table:Table 2 Model fit indices for the one-class through six-class model evaluated in our LCAView this table:Table 3 Distribution of phenotypes and genotypes in the two latent classes (LC)Table 1 depicts the baseline phenotypes and genotypes in the obtained population.

Note incomplete data especially in the cranium phenotypes. In total 259 valid genotypes were present. In total, 289 cases had complete data for all hand and foot phenotypes (preaxial polydactyly, postaxial polydactyly and syndactyly) and thus were available for LCA.

Combined, for phenotype/genotype correlation 258 cases were available with complete genotypes and complete hand and foot phenotypes.Table 2 depicts the model fit indices for all models that have been fitted to our data.Table 3 depicts the distribution of phenotypes and genotypes over the two assigned LCs. Hand and foot phenotypes were used as input for the LCA, thus are all complete cases. Malformation of the cranium and genotypes do have missing cases.

Note that for the LCA, full case description was required, resulting in eight cases due to incomplete phenotypes. Out of these eight, one also had a genotype that thus needed to be excluded. Missingness of genotypic data was higher in LC2, mostly due to CNVs (table 1).In 54/60 cases, a missense variant produced a posterior phenotype.

Likewise, splice site variants show the same phenotype in 23/24 cases (table 3). For both frameshift and nonsense variants, this relation is not significant (52 anterior vs 54 posterior and 26 anterior vs 42 posterior, respectively). Therefore, only for nonsense and frameshift variants the location of the variant was plotted against the probability for LC2 membership in figure 1.

A full scatterplot of all variants is available in online supplementary figure 1.Figure 1 reveals a pattern for these nonsense and frameshift variants that reveals that variants at the C-terminal of the gene predict anterior phenotypes. When relating the domains of the GLI3 protein to the observed phenotype, we observe that the majority of patients with a nonsense or frameshift variant in the repressor domain, the zinc finger domain or the cleavage site had a high probability of an LC2/anterior phenotype. This group contains all variants that are either experimentally determined to be subject to NMD (triangle marker in figure 1) or predicted to be subject to NMD (diamond marker in figure 1).

Frameshift and nonsense variants in the activator domain result in high probability for an LC1/posterior phenotype. These variants will be further referred to as truncating variants in the activator domain.The univariate relation of the individual phenotypes to these two groups of variants are estimated and presented in table 4. In our multivariate analysis, postaxial polydactyly of the foot and hand are the strongest predictors (Beta.

2.548, p<0001 and Beta. 1.47, p=0.013, respectively) for patients to have a truncating variant in the activator domain. Moreover, the effect sizes of preaxial polydactyly of the hand and feet (Beta.

ˆ’0.797, p=0123 and −1.772, p=0.001) reveals that especially postaxial polydactyly of the foot is the dominant predictor for the genetic substrate of the observed anomalies.View this table:Table 4 Univariate and multivariate analysis of the phenotype/genotype correlationTable 4 shows exploration of the individual phenotypes on the genotype, both univariate and multivariate. The multivariate analysis corrects for the presence of multiple phenotypes in the underlying population.Although the craniofacial anomalies could not be included in the LCA, the relation between the observed anomalies and the identified genetic substrates can be studied. The prevalence of hypertelorism was equally distributed over the two groups of variants (47/135 vs 21/47 respectively, p<0.229).

However for corpus callosum agenesis and macrocephaly, there was a higher prevalence in patients with a truncating variant in the activator domain (3/75 vs 11/41, p<0.001. OR. 8.8, p<0.001) and 42/123 vs 24/48, p<0.05).

Noteworthy is the fact that 11/14 cases with corpus callosum agenesis in the dataset had a truncating variant in the activator domain.DiscussionIn this report, we present new insights into the correlation between the phenotype and the genotype in patients with GLI3-mediated polydactyly syndromes. We illustrate that there are two LCs of patients, best predicted by postaxial polydactyly of the hand and foot for LC1, and the preaxial polydactyly of the hand and foot and syndactyly of the foot for LC2. Patients with postaxial phenotypes have a higher risk of having a truncating variant in the activator domain of the GLI3 gene which is also related to a higher risk of corpus callosum agenesis.

These results suggest a functional difference between truncating variants on the N-terminal and the C-terminal side of the GLI3 cleavage site.Previous attempts of phenotype to genotype correlation have not yet provided the clinical confirmation of these assumed mechanisms in the pathophysiology of GLI3-mediated polydactyly syndromes. Johnston et al have successfully determined the Pallister-Hall region in which truncating variants produce a Pallister-Hall phenotype rather than Greig syndrome.11 However, in their latest population study, subtypes of both syndromes were included to explain the full spectrum of observed malformations. In 2015, Demurger et al reported the higher incidence of corpus callosum agenesis in the Greig syndrome population with truncating mutations in the activator domain.12 Al-Qattan in his review summarises the concept of a spectrum of anomalies dependent on haplo-insufficiency (through different mechanisms) and repressor overexpression.13 However, he bases this theory mainly on reviewed experimental data.

Our report is the first to provide an extensive clinical review of cases that substantiate the phenotypic difference between the two groups that could fit the suggested mechanisms. We agree with Al-Qattan et al that a variation of anomalies can be observed given any pathogenic variant in the GLI3 gene, but overall two dominant phenotypes are present. A population with predominantly preaxial anomalies and one with postaxial anomalies.

The presence of preaxial or postaxial polydactyly and syndactyly is not mutually exclusive for one of these two subclasses. Meaning that preaxial polydactyly can co-occur with postaxial polydactyly. However, truncating mutations in the activator domain produce a postaxial phenotype, as can be derived from the risk in table 4.

The higher risk of corpus callosum agenesis in this population shows that differentiating between a preaxial phenotype and a postaxial phenotype, instead of between the different GLI3-mediated polydactyly syndromes, might be more relevant regarding diagnostics for corpus callosum agenesis.We chose to use LCA as an exploratory tool only in our population for two reasons. First of all, LCA can be useful to identify subgroups, but there is no ‘true’ model or number of subgroups you can detect. The best fitting model can only be estimated based on the available measures and approximates the true subgroups that might be present.

Second, LC membership assignment is a statistical procedure based on the posterior probability, with concordant errors of the estimation, rather than a clinical value that can be measured or evaluated. Therefore, we decided to use our LCA only in an exploratory tool, and perform our statistics using the actual phenotypes that predict LC membership and the associated genotypes. Overall, this method worked well to differentiate the two subgroups present in our dataset.

However, outliers were observed. A qualitative analysis of these outliers is available in the online supplementary data.The genetic substrate for the two phenotypic clusters can be discussed based on multiple experiments. Overall, we hypothesise two genetic clusters.

One that is due to haploinsufficiency and one that is due to abnormal truncation of the activator. The hypothesised cluster of variants that produce haploinsufficiency is mainly based on the experimental data that confirms NMD in two variants and the NMD prediction of other nonsense variants in Alamut. For the frameshift variants, it is also likely that the cleavage of the zinc finger domain results in functional haploinsufficiency either because of a lack of signalling domains or similarly due to NMD.

Missense variants could cause haploinsufficiency through the suggested mechanism by Krauss et al who have illustrated that missense variants in the MID1 domain hamper the functional interaction with the MID1-α4-PP2A complex, leading to a subcellular location of GLI3.24 The observed missense variants in our study exceed the region to which Krauss et al have limited the MID-1 interaction domain. An alternative theory is suggested by Zhou et al who have shown that missense variants in the MBD can cause deficiency in the signalling of GLI3A, functionally implicating a relative overexpression of GLI3R.22 However, GLI3R overexpression would likely produce a posterior phenotype, as determined by Hill et al in their fixed homo and hemizygous GLI3R models.15 Therefore, our hypothesis is that all included missense variants have a similar pathogenesis which is more likely in concordance with the mechanism introduced by Krauss et al. To our knowledge, no splice site variants have been functionally described in literature.

However, it is noted that the 15 and last exon encompasses the entire activator domain, thus any splice site mutation is by definition located on the 5′ side of the activator. Based on the phenotype, we would suggest that these variants fail to produce a functional protein. We hypothesise that the truncating variants of the activator domain lead to overexpression of GLI3R in SHH rich areas.

In normal development, the presence of SHH prevents the processing of full length GLI34 into GLI3R, thus producing the full length activator. In patients with a truncating variant of the activator domain of GLI3, thus these variants likely have the largest effect in SHH rich areas, such as the ZPA located at the posterior side of the hand/footplate. Moreover, the lack of posterior anomalies in the GLI3∆699/- mouse model (hemizygous fixed repressor model) compared with the GLI3∆699/∆699 mouse model (homozygous fixed repressor model), suggesting a dosage effect of GLI3R to be responsible for posterior hand anomalies.15 These findings are supported by Lewandowski et al, who show that the majority of the target genes in GLI signalling are regulated by GLI3R rather than GLI3A.44 Together, these findings suggest a role for the location and type of variant in GLI3-mediated syndromes.Interestingly, the difference between Pallister-Hall syndrome and GLI3-mediated polydactyly syndromes has also been attributed to the GLI3R overexpression.

However, the difference in phenotype observed in the cases with a truncating variant in the activator domain and Pallister-Hall syndrome suggest different functional consequences. When studying figure 1, it is noted that the included truncating variants on the 3′ side of the cleavage site seldomly affect the CBP binding region, which could provide an explanation for the observed differences. This binding region is included in the Pallister-Hall region as defined by Johnston et al and is necessary for the downstream signalling with GLI1.10 11 23 45 Interestingly, recent reports show that pathogenic variants in GLI1 can produce phenotypes concordant with Ellis von Krefeld syndrome, which includes overlapping features with Pallister-Hall syndrome.46 The four truncating variants observed in this study that do affect the CBP but did not result in a Pallister-Hall phenotype are conflicting with this theory.

Krauss et al postulate an alternative hypothesis, they state that the MID1-α4-PP2A complex, which is essential for GLI3A signalling, could also be the reason for overlapping features of Opitz syndrome, caused by variants in MID1, and Pallister-Hall syndrome. Further analysis is required to fully appreciate the functional differences between truncating mutations that cause Pallister-Hall syndrome and those that result in GLI3-mediated polydactyly syndromes.For the clinical evaluation of patients with GLI3-mediated polydactyly syndromes, intracranial anomalies are likely the most important to predict based on the variant. Unfortunately, the presence of corpus callosum agenesis was not routinely investigated or reported thus this feature could not be used as an indicator phenotype for LC membership.

Interestingly when using only hand and foot phenotypes, we did notice a higher prevalence of corpus callosum agenesis in patients with posterior phenotypes. The suggested relation between truncating mutations in the activator domain causing these posterior phenotypes and corpus callosum agenesis was statistically confirmed (OR. 8.8, p<0.001).

Functionally this relation could be caused by the GLI3-MED12 interaction at the MBD. Pathogenic DNA variants in MED12 can cause Opitz-Kaveggia syndrome, a syndrome in which presentation includes corpus callosum agenesis, broad halluces and thumbs.47In conclusion, there are two distinct phenotypes within the GLI3-mediated polydactyly population. Patients with more posteriorly and more anteriorly oriented hand anomalies.

Furthermore, this difference is related to the observed variant in GLI3. We hypothesise that variants that cause haploinsufficiency produce anterior anomalies of the hand, whereas variants with abnormal truncation of the activator domain have more posterior anomalies. Furthermore, patients that have a variant that produces abnormal truncation of the activator domain, have a greater risk for corpus callosum agenesis.

Thus, we advocate to differentiate preaxial or postaxial oriented GLI3 phenotypes to explain the pathophysiology as well as to get a risk assessment for corpus callosum agenesis.Data availability statementData are available upon reasonable request.Ethics statementsPatient consent for publicationNot required.Ethics approvalThe research protocol was approved by the local ethics board of the Erasmus MC University Medical Center (MEC 2015-679)..

AbstractIntroduction Cheap zithromax canada buy kamagra tablets online. We report a very rare case of familial breast cancer and diffuse gastric cancer, with germline pathogenic variants in both BRCA1 and CDH1 genes. To the best of our knowledge, this is buy kamagra tablets online the first report of such an association.Family description. The proband is a woman diagnosed with breast cancer at the age of 52 years.

She requested genetic counselling in 2012, at the age of 91 years, because of a history of breast cancer in her daughter, her sister, her niece buy kamagra tablets online and her paternal grandmother and was therefore concerned about her relatives. Her sister and maternal aunt also had gastric cancer. She was tested for several genes associated with hereditary buy kamagra tablets online breast cancer.Results. A large deletion of BRCA1 from exons 1 to 7 and two CDH1 pathogenic cis variants were identified.Conclusion.

This complex situation is challenging for genetic counselling and buy kamagra tablets online management of at-risk individuals.cancer. Breastcancer. Gastricclinical geneticsgenetic screening/counsellingmolecular geneticsIntroductionGLI-Kruppel family member 3 (GLI3) encodes for a zinc finger transcription factor which plays a key role in the buy kamagra tablets online sonic hedgehog (SHH) signalling pathway essential in both limb and craniofacial development.1 2 In hand development, SHH is expressed in the zone of polarising activity (ZPA) on the posterior side of the handplate. The ZPA expresses SHH, creating a gradient of SHH from the posterior to the anterior side of the handplate.

In the presence of SHH, full length GLI3-protein is produced (GLI3A), whereas absence of SHH causes cleavage of GLI3 into its repressor form (GLI3R).3 4 Abnormal expression of this buy kamagra tablets online SHH/GLI3R gradient can cause both preaxial and postaxial polydactyly.2Concordantly, pathogenic DNA variants in the GLI3 gene are known to cause multiple syndromes with craniofacial and limb involvement, such as. Acrocallosal syndrome5 (OMIM. 200990), Greig cephalopolysyndactyly buy kamagra tablets online syndrome6 (OMIM. 175700) and Pallister-Hall syndrome7 (OMIM.

146510). Also, in non-syndromic polydactyly, such as preaxial polydactyly-type 4 (PPD4, OMIM. 174700),8 pathogenic variants in GLI3 have been described. Out of these diseases, Pallister-Hall syndrome is the most distinct entity, defined by the presence of central polydactyly and hypothalamic hamartoma.9 The other GLI3 syndromes are defined by the presence of preaxial and/or postaxial polydactyly of the hand and feet with or without syndactyly (Greig syndrome, PPD4).

Also, various mild craniofacial features such as hypertelorism and macrocephaly can occur. Pallister-Hall syndrome is caused by truncating variants in the middle third of the GLI3 gene.10–12 The truncation of GLI3 causes an overexpression of GLI3R, which is believed to be the key difference between Pallister-Hall and the GLI3-mediated polydactyly syndromes.9 11 Although multiple attempts have been made, the clinical and genetic distinction between the GLI3-mediated polydactyly syndromes is less evident. This has for example led to the introduction of subGreig and the formulation of an Oro-facial-digital overlap syndrome.10 Other authors, suggested that we should not regard these diseases as separate entities, but as a spectrum of GLI3-mediated polydactyly syndromes.13Although phenotype/genotype correlation of the different syndromes has been cumbersome, clinical and animal studies do provide evidence that distinct regions within the gene, could be related to the individual anomalies contributing to these syndromes. First, case studies show isolated preaxial polydactyly is caused by both truncating and non-truncating variants throughout the GLI3 gene, whereas in isolated postaxial polydactyly cases truncating variants at the C-terminal side of the gene are observed.12 14 These results suggest two different groups of variants for preaxial and postaxial polydactyly.

Second, recent animal studies suggest that posterior malformations in GLI3-mediated polydactyly syndromes are likely related to a dosage effect of GLI3R rather than due to the influence of an altered GLI3A expression.15Past attempts for phenotype/genotype correlation in GLI3-mediated polydactyly syndromes have directly related the diagnosed syndrome to the observed genotype.10–12 16 Focusing on individual hand phenotypes, such as preaxial and postaxial polydactyly and syndactyly might be more reliable because it prevents misclassification due to inconsistent use of syndrome definition. Subsequently, latent class analysis (LCA) provides the possibility to relate a group of observed variables to a set of latent, or unmeasured, parameters and thereby identifying different subgroups in the obtained dataset.17 As a result, LCA allows us to group different phenotypes within the GLI3-mediated polydactyly syndromes and relate the most important predictors of the grouped phenotypes to the observed GLI3 variants.The aim of our study was to further investigate the correlation of the individual phenotypes to the genotypes observed in GLI3-mediated polydactyly syndromes, using LCA. Cases were obtained by both literature review and the inclusion of local clinical cases. Subsequently, we identified two subclasses of limb anomalies that relate to the underlying GLI3 variant.

We provide evidence for two different phenotypic and genotypic groups with predominantly preaxial and postaxial hand and feet anomalies, and we specify those cases with a higher risk for corpus callosum anomalies.MethodsLiterature reviewThe Human Gene Mutation Database (HGMD Professional 2019) was reviewed to identify known pathogenic variants in GLI3 and corresponding phenotypes.18 All references were obtained and cases were included when they were diagnosed with either Greig or subGreig syndrome or PPD4.10–12 Pallister-Hall syndrome and acrocallosal syndrome were excluded because both are regarded distinct syndromes and rather defined by the presence of the non-hand anomalies, than the presence of preaxial or postaxial polydactyly.13 19 Isolated preaxial or postaxial polydactyly were excluded for two reasons. The phenotype/genotype correlations are better understood and both anomalies can occur sporadically which could introduce falsely assumed pathogenic GLI3 variants in the analysis. Additionally, cases were excluded when case-specific phenotypic or genotypic information was not reported or if these two could not be related to each other. Families with a combined phenotypic description, not reducible to individual family members, were included as one case in the analysis.Clinical casesThe Sophia Children’s Hospital Database was reviewed for cases with a GLI3 variant.

Within this population, the same inclusion criteria for the phenotype were valid. Relatives of the index patients were also contacted for participation in this study, when they showed comparable hand, foot, or craniofacial malformations or when a GLI3 variant was identified. Phenotypes of the hand, foot and craniofacial anomalies of the patients treated in the Sophia Children's Hospital were collected using patient documentation. Family members were identified and if possible, clinically verified.

Alternatively, family members were contacted to verify their phenotypes. If no verification was possible, cases were excluded.PhenotypesThe phenotypes of both literature cases and local cases were extracted in a similar fashion. The most frequently reported limb and craniofacial phenotypes were dichotomised. The dichotomised hand and foot phenotypes were preaxial polydactyly, postaxial polydactyly and syndactyly.

Broad halluces or thumbs were commonly reported by authors and were dichotomised as a presentation of preaxial polydactyly. The extracted dichotomised craniofacial phenotypes were hypertelorism, macrocephaly and corpus callosum agenesis. All other phenotypes were registered, but not dichotomised.Pathogenic GLI3 variantsAll GLI3 variants were extracted and checked using Alamut Visual V.2.14. If indicated, variants were renamed according to standard Human Genome Variation Society nomenclature.20 Variants were grouped in either missense, frameshift, nonsense or splice site variants.

In the group of frameshift variants, a subgroup with possible splice site effect were identified for subgroup analysis when indicated. Similarly, nonsense variants prone for nonsense mediated decay (NMD) and nonsense variants with experimentally confirmed NMD were identified.21 Deletions of multiple exons, CNVs and translocations were excluded for analysis. A full list of included mutations is available in the online supplementary materials.Supplemental materialThe location of the variant was compared with five known structural domains of the GLI3 gene. (1) repressor domain, (2) zinc finger domain, (3) cleavage site, (4) activator domain, which we defined as a concatenation of the separately identified transactivation zones, the CBP binding domain and the mediator binding domain (MBD) and (5) the MID1 interaction region domain.1 6 22–24 The boundaries of each of the domains were based on available literature (figure 1, exact locations available in the online supplementary materials).

The boundaries used by different authors did vary, therefore a consensus was made.In this figure the posterior probability of an anterior phenotype is plotted against the location of the variant, stratified for the type of mutation that was observed. For better overview, only variants with a location effect were displayed. The full figure, including all variant types, can be found in the online supplementary figure 1. Each mutation is depicted as a dot, the size of the dot represents the number of observations for that variant.

If multiple observations were made, the mean posterior odds and IQR are plotted. For the nonsense variants, variants that were predicted to produce nonsense mediated decay, are depicted using a triangle. Again, the size indicates the number of observations." data-icon-position data-hide-link-title="0">Figure 1 In this figure the posterior probability of an anterior phenotype is plotted against the location of the variant, stratified for the type of mutation that was observed. For better overview, only variants with a location effect were displayed.

The full figure, including all variant types, can be found in the online supplementary figure 1. Each mutation is depicted as a dot, the size of the dot represents the number of observations for that variant. If multiple observations were made, the mean posterior odds and IQR are plotted. For the nonsense variants, variants that were predicted to produce nonsense mediated decay, are depicted using a triangle.

Again, the size indicates the number of observations.Supplemental materialLatent class analysisTo cluster phenotypes and relate those to the genotypes of the patients, an explorative analysis was done using LCA in R (R V.3.6.1 for Mac. Polytomous variable LCA, poLCA V.1.4.1.). We used our LCA to detect the number of phenotypic subgroups in the dataset and subsequently predict a class membership for each case in the dataset based on the posterior probabilities.In order to make a reliable prediction, only phenotypes that were sufficiently reported and/or ruled out were feasible for LCA, limiting the analysis to preaxial polydactyly, postaxial polydactyly and syndactyly of the hands and feet. Only full cases were included.

To determine the optimal number of classes, we fitted a series of models ranging from a one-class to a six-class model. The optimal number of classes was based on the conditional Akaike information criterion (cAIC), the non adjusted and the sample-size adjusted Bayesian information criterion (BIC and aBIC) and the obtained entropy.25 The explorative LCA produces both posterior probabilities per case for both classes and predicted class membership. Using the predicted class membership, the phenotypic features per class were determined in a univariate analysis (χ2, SPSS V.25). Using the posterior probabilities on latent class (LC) membership, a scatter plot was created using the location of the variant on the x-axis and the probability of class membership on the y-axis for each of the types of variants (Tibco Spotfire V.7.14).

Using these scatter plots, variants that give similar phenotypes were clustered.Genotype/phenotype correlationBecause an LC has no clinical value, the correlation between genotypes and phenotypes was investigated using the predictor phenotypes and the clustered phenotypes. First, those phenotypes that contribute most to LC membership were identified. Second those phenotypes were directly related to the different types of variants (missense, nonsense, frameshift, splice site) and their clustered locations. Quantification of the relation was performed using a univariate analysis using a χ2 test.

Because of our selection criteria, meaning patients at least have two phenotypes, a multivariate using a logistic regression analysis was used to detect the most significant predictors in the overall phenotype (SPSS V.25). Finally, we explored the relation of the clustered genotypes to the presence of corpus callosum agenesis, a rare malformation in GLI3-mediated polydactyly syndromes which cannot be readily diagnosed without additional imaging.ResultsWe included 251 patients from the literature and 46 local patients,10–12 16 21 26–43 in total 297 patients from 155 different families with 127 different GLI3 variants, 32 of which were large deletions, CNVs or translocations. In six local cases, the exact variant could not be retrieved by status research.The distribution of the most frequently observed phenotypes and variants are presented in table 1. Other recurring phenotypes included developmental delay (n=22), broad nasal root (n=23), frontal bossing or prominent forehead (n=16) and craniosynostosis (n=13), camptodactyly (n=8) and a broad first interdigital webspace of the foot (n=6).View this table:Table 1 Baseline phenotypes and genotypes of selected populationThe LCA model was fitted using the six defined hand/foot phenotypes.

Model fit indices for the LCA are displayed in table 2. Based on the BIC, a two-class model has the best fit for our data. The four-class model does show a gain in entropy, however with a higher BIC and loss of df. Therefore, based on the majority of performance statistics and the interpretability of the model, a two-class model was chosen.

Table 3 displays the distribution of phenotypes and genotypes over the two classes.View this table:Table 2 Model fit indices for the one-class through six-class model evaluated in our LCAView this table:Table 3 Distribution of phenotypes and genotypes in the two latent classes (LC)Table 1 depicts the baseline phenotypes and genotypes in the obtained population. Note incomplete data especially in the cranium phenotypes. In total 259 valid genotypes were present. In total, 289 cases had complete data for all hand and foot phenotypes (preaxial polydactyly, postaxial polydactyly and syndactyly) and thus were available for LCA.

Combined, for phenotype/genotype correlation 258 cases were available with complete genotypes and complete hand and foot phenotypes.Table 2 depicts the model fit indices for all models that have been fitted to our data.Table 3 depicts the distribution of phenotypes and genotypes over the two assigned LCs. Hand and foot phenotypes were used as input for the LCA, thus are all complete cases. Malformation of the cranium and genotypes do have missing cases. Note that for the LCA, full case description was required, resulting in eight cases due to incomplete phenotypes.

Out of these eight, one also had a genotype that thus needed to be excluded. Missingness of genotypic data was higher in LC2, mostly due to CNVs (table 1).In 54/60 cases, a missense variant produced a posterior phenotype. Likewise, splice site variants show the same phenotype in 23/24 cases (table 3). For both frameshift and nonsense variants, this relation is not significant (52 anterior vs 54 posterior and 26 anterior vs 42 posterior, respectively).

Therefore, only for nonsense and frameshift variants the location of the variant was plotted against the probability for LC2 membership in figure 1. A full scatterplot of all variants is available in online supplementary figure 1.Figure 1 reveals a pattern for these nonsense and frameshift variants that reveals that variants at the C-terminal of the gene predict anterior phenotypes. When relating the domains of the GLI3 protein to the observed phenotype, we observe that the majority of patients with a nonsense or frameshift variant in the repressor domain, the zinc finger domain or the cleavage site had a high probability of an LC2/anterior phenotype. This group contains all variants that are either experimentally determined to be subject to NMD (triangle marker in figure 1) or predicted to be subject to NMD (diamond marker in figure 1).

Frameshift and nonsense variants in the activator domain result in high probability for an LC1/posterior phenotype. These variants will be further referred to as truncating variants in the activator domain.The univariate relation of the individual phenotypes to these two groups of variants are estimated and presented in table 4. In our multivariate analysis, postaxial polydactyly of the foot and hand are the strongest predictors (Beta. 2.548, p<0001 and Beta.

1.47, p=0.013, respectively) for patients to have a truncating variant in the activator domain. Moreover, the effect sizes of preaxial polydactyly of the hand and feet (Beta. ˆ’0.797, p=0123 and −1.772, p=0.001) reveals that especially postaxial polydactyly of the foot is the dominant predictor for the genetic substrate of the observed anomalies.View this table:Table 4 Univariate and multivariate analysis of the phenotype/genotype correlationTable 4 shows exploration of the individual phenotypes on the genotype, both univariate and multivariate. The multivariate analysis corrects for the presence of multiple phenotypes in the underlying population.Although the craniofacial anomalies could not be included in the LCA, the relation between the observed anomalies and the identified genetic substrates can be studied.

The prevalence of hypertelorism was equally distributed over the two groups of variants (47/135 vs 21/47 respectively, p<0.229). However for corpus callosum agenesis and macrocephaly, there was a higher prevalence in patients with a truncating variant in the activator domain (3/75 vs 11/41, p<0.001. OR. 8.8, p<0.001) and 42/123 vs 24/48, p<0.05).

Noteworthy is the fact that 11/14 cases with corpus callosum agenesis in the dataset had a truncating variant in the activator domain.DiscussionIn this report, we present new insights into the correlation between the phenotype and the genotype in patients with GLI3-mediated polydactyly syndromes. We illustrate that there are two LCs of patients, best predicted by postaxial polydactyly of the hand and foot for LC1, and the preaxial polydactyly of the hand and foot and syndactyly of the foot for LC2. Patients with postaxial phenotypes have a higher risk of having a truncating variant in the activator domain of the GLI3 gene which is also related to a higher risk of corpus callosum agenesis. These results suggest a functional difference between truncating variants on the N-terminal and the C-terminal side of the GLI3 cleavage site.Previous attempts of phenotype to genotype correlation have not yet provided the clinical confirmation of these assumed mechanisms in the pathophysiology of GLI3-mediated polydactyly syndromes.

Johnston et al have successfully determined the Pallister-Hall region in which truncating variants produce a Pallister-Hall phenotype rather than Greig syndrome.11 However, in their latest population study, subtypes of both syndromes were included to explain the full spectrum of observed malformations. In 2015, Demurger et al reported the higher incidence of corpus callosum agenesis in the Greig syndrome population with truncating mutations in the activator domain.12 Al-Qattan in his review summarises the concept of a spectrum of anomalies dependent on haplo-insufficiency (through different mechanisms) and repressor overexpression.13 However, he bases this theory mainly on reviewed experimental data. Our report is the first to provide an extensive clinical review of cases that substantiate the phenotypic difference between the two groups that could fit the suggested mechanisms. We agree with Al-Qattan et al that a variation of anomalies can be observed given any pathogenic variant in the GLI3 gene, but overall two dominant phenotypes are present.

A population with predominantly preaxial anomalies and one with postaxial anomalies. The presence of preaxial or postaxial polydactyly and syndactyly is not mutually exclusive for one of these two subclasses. Meaning that preaxial polydactyly can co-occur with postaxial polydactyly. However, truncating mutations in the activator domain produce a postaxial phenotype, as can be derived from the risk in table 4.

The higher risk of corpus callosum agenesis in this population shows that differentiating between a preaxial phenotype and a postaxial phenotype, instead of between the different GLI3-mediated polydactyly syndromes, might be more relevant regarding diagnostics for corpus callosum agenesis.We chose to use LCA as an exploratory tool only in our population for two reasons. First of all, LCA can be useful to identify subgroups, but there is no ‘true’ model or number of subgroups you can detect. The best fitting model can only be estimated based on the available measures and approximates the true subgroups that might be present. Second, LC membership assignment is a statistical procedure based on the posterior probability, with concordant errors of the estimation, rather than a clinical value that can be measured or evaluated.

Therefore, we decided to use our LCA only in an exploratory tool, and perform our statistics using the actual phenotypes that predict LC membership and the associated genotypes. Overall, this method worked well to differentiate the two subgroups present in our dataset. However, outliers were observed. A qualitative analysis of these outliers is available in the online supplementary data.The genetic substrate for the two phenotypic clusters can be discussed based on multiple experiments.

Overall, we hypothesise two genetic clusters. One that is due to haploinsufficiency and one that is due to abnormal truncation of the activator. The hypothesised cluster of variants that produce haploinsufficiency is mainly based on the experimental data that confirms NMD in two variants and the NMD prediction of other nonsense variants in Alamut. For the frameshift variants, it is also likely that the cleavage of the zinc finger domain results in functional haploinsufficiency either because of a lack of signalling domains or similarly due to NMD.

Missense variants could cause haploinsufficiency through the suggested mechanism by Krauss et al who have illustrated that missense variants in the MID1 domain hamper the functional interaction with the MID1-α4-PP2A complex, leading to a subcellular location of GLI3.24 The observed missense variants in our study exceed the region to which Krauss et al have limited the MID-1 interaction domain. An alternative theory is suggested by Zhou et al who have shown that missense variants in the MBD can cause deficiency in the signalling of GLI3A, functionally implicating a relative overexpression of GLI3R.22 However, GLI3R overexpression would likely produce a posterior phenotype, as determined by Hill et al in their fixed homo and hemizygous GLI3R models.15 Therefore, our hypothesis is that all included missense variants have a similar pathogenesis which is more likely in concordance with the mechanism introduced by Krauss et al. To our knowledge, no splice site variants have been functionally described in literature. However, it is noted that the 15 and last exon encompasses the entire activator domain, thus any splice site mutation is by definition located on the 5′ side of the activator.

Based on the phenotype, we would suggest that these variants fail to produce a functional protein. We hypothesise that the truncating variants of the activator domain lead to overexpression of GLI3R in SHH rich areas. In normal development, the presence of SHH prevents the processing of full length GLI34 into GLI3R, thus producing the full length activator. In patients with a truncating variant of the activator domain of GLI3, thus these variants likely have the largest effect in SHH rich areas, such as the ZPA located at the posterior side of the hand/footplate.

Moreover, the lack of posterior anomalies in the GLI3∆699/- mouse model (hemizygous fixed repressor model) compared with the GLI3∆699/∆699 mouse model (homozygous fixed repressor model), suggesting a dosage effect of GLI3R to be responsible for posterior hand anomalies.15 These findings are supported by Lewandowski et al, who show that the majority of the target genes in GLI signalling are regulated by GLI3R rather than GLI3A.44 Together, these findings suggest a role for the location and type of variant in GLI3-mediated syndromes.Interestingly, the difference between Pallister-Hall syndrome and GLI3-mediated polydactyly syndromes has also been attributed to the GLI3R overexpression. However, the difference in phenotype observed in the cases with a truncating variant in the activator domain and Pallister-Hall syndrome suggest different functional consequences. When studying figure 1, it is noted that the included truncating variants on the 3′ side of the cleavage site seldomly affect the CBP binding region, which could provide an explanation for the observed differences. This binding region is included in the Pallister-Hall region as defined by Johnston et al and is necessary for the downstream signalling with GLI1.10 11 23 45 Interestingly, recent reports show that pathogenic variants in GLI1 can produce phenotypes concordant with Ellis von Krefeld syndrome, which includes overlapping features with Pallister-Hall syndrome.46 The four truncating variants observed in this study that do affect the CBP but did not result in a Pallister-Hall phenotype are conflicting with this theory.

Krauss et al postulate an alternative hypothesis, they state that the MID1-α4-PP2A complex, which is essential for GLI3A signalling, could also be the reason for overlapping features of Opitz syndrome, caused by variants in MID1, and Pallister-Hall syndrome. Further analysis is required to fully appreciate the functional differences between truncating mutations that cause Pallister-Hall syndrome and those that result in GLI3-mediated polydactyly syndromes.For the clinical evaluation of patients with GLI3-mediated polydactyly syndromes, intracranial anomalies are likely the most important to predict based on the variant. Unfortunately, the presence of corpus callosum agenesis was not routinely investigated or reported thus this feature could not be used as an indicator phenotype for LC membership. Interestingly when using only hand and foot phenotypes, we did notice a higher prevalence of corpus callosum agenesis in patients with posterior phenotypes.

The suggested relation between truncating mutations in the activator domain causing these posterior phenotypes and corpus callosum agenesis was statistically confirmed (OR. 8.8, p<0.001). Functionally this relation could be caused by the GLI3-MED12 interaction at the MBD. Pathogenic DNA variants in MED12 can cause Opitz-Kaveggia syndrome, a syndrome in which presentation includes corpus callosum agenesis, broad halluces and thumbs.47In conclusion, there are two distinct phenotypes within the GLI3-mediated polydactyly population.

Patients with more posteriorly and more anteriorly oriented hand anomalies. Furthermore, this difference is related to the observed variant in GLI3. We hypothesise that variants that cause haploinsufficiency produce anterior anomalies of the hand, whereas variants with abnormal truncation of the activator domain have more posterior anomalies. Furthermore, patients that have a variant that produces abnormal truncation of the activator domain, have a greater risk for corpus callosum agenesis.

Thus, we advocate to differentiate preaxial or postaxial oriented GLI3 phenotypes to explain the pathophysiology as well as to get a risk assessment for corpus callosum agenesis.Data availability statementData are available upon reasonable request.Ethics statementsPatient consent for publicationNot required.Ethics approvalThe research protocol was approved by the local ethics board of the Erasmus MC University Medical Center (MEC 2015-679)..

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N/A 2017-12-22 2023-12-22 N/A 2025-12-22 linaclotide 161056 Constella Forest Laboratories Canada Inc kamagra online pharmacy uk. N/A 2013-12-02 2019-12-02 N/A 2021-12-02 lixisenatide 193862 Adlyxine Sanofi-aventis Canada Inc. Soliqua 2017-05-25 2023-05-25 N/A 2025-05-25 lomitapide mesylate 160385 kamagra online pharmacy uk Juxtapid Aegerion Pharmaceuticals Canada Ltd. N/A 2014-02-04 2020-02-04 N/A 2022-02-04 lorlatinib 215733 Lorbrena Pfizer Canada ULC N/A 2019-02-22 2025-02-22 N/A 2027-02-22 lubiprostone 179333 Amitiza Sucampo Pharma Americas LLC N/A 2015-10-14 2021-10-14 N/A 2023-10-14 lumacaftor 181715 Orkambi Vertex Pharmaceuticals (Canada) Incorporated N/A 2016-01-26 2022-01-26 Yes 2024-07-26 luspatercept 236441 Reblozyl Celgene Inc. N/A 2020-09-25 2026-09-25 N/A 2028-09-25 lutetium177 Lu oxodotreotide 217184 Lutathera Advanced Accelerator Applications USA, Inc.

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N/A 2015-06-02 2021-06-02 N/A 2023-06-02 necitumumab 193689 Portrazza Eli Lilly Canada Inc kamagra online pharmacy uk. N/A 2017-03-16 2023-03-16 N/A 2025-03-16 neisseria meningitidis serogroup A polysaccharide, neisseria meningitidis serogroup C polysaccharide, neisseria meningitidis serogroup W-135 polysaccharide, neisseria meningitidis serogroup Y polysaccharide, conjugated to tetanus toxoid carrier protein 154290 Nimenrix Pfizer Canada Inc. N/A 2013-03-05 2019-03-05 Yes 2021-09-05 neisseria meningitidis serogroup B recombinant lipoprotein 2086 (rLP2086) subfamily A and Neisseria meningitidis serogroup B recombinant lipoprotein 2086 (rLP2086) subfamily B 195550 Trumenba Pfizer Canada Inc. N/A 2017-10-05 2023-10-05 Yes 2026-04-05 neratinib kamagra online pharmacy uk maleate 218224 Nerlynx Knight Therapeutics Inc. N/A 2019-07-16 2025-07-16 N/A 2027-07-16 netupitant 196495 Akynzeo Elvium Life Sciences N/A 2017-09-28 2023-09-28 N/A 2025-09-28 nintedanib (supplied as nintedanib esilate) 176043 Ofev Boehringer Ingelheim (Canada) Ltd N/A 2015-06-25 2021-06-25 N/A 2023-06-25 niraparib 216792 Zejula GlaxoSmithKline Inc.

N/A 2019-06-27 2025-06-27 N/A 2027-06-27 nivolumab 180828 Opdivo Bristol-Myers-Squibb Canada N/A 2015-09-25 2021-09-25 Yes 2024-03-25 kamagra online pharmacy uk nusinersen 200070 Spinraza Biogen Canada Inc. N/A 2017-06-29 2023-06-29 Yes 2025-12-29 obeticholic acid 198418 Ocaliva Intercept Pharmaceuticals Inc. N/A 2017-05-24 2023-05-24 N/A 2025-05-24 obiltoxaximab 230825 Anthim Elusys Therapeutics, Inc. N/A 2020-07-30 2026-07-30 N/A 2028-07-30 obinutuzumab 168227 Gazyva kamagra online pharmacy uk Hoffmann-La Roche Limited N/A 2014-11-25 2020-11-25 N/A 2022-11-25 ocrelizumab 198094 Ocrevus Hoffmann-La Roche Limited N/A 2017-08-14 2023-08-14 N/A 2025-08-14 ocriplasmin 161356 Jetrea ThromboGenics N.V. N/A 2013-08-13 2019-08-13 N/A 2021-08-13 olaparib 182823 Lynparza AstraZeneca Canada Inc.

N/A 2016-04-29 2022-04-29 N/A 2024-04-29 olaratumab 203478 Lartruvo Eli Lilly Canada Inc kamagra online pharmacy uk. N/A 2017-11-23 2023-11-23 N/A 2025-11-23 ombitasvir, paritaprevir, dasabuvir sodium 174739 Holkira Pak Abbvie Corporation Technivie 2014-12-22 2020-12-22 N/A 2022-12-22 onasemnogene abeparvovec 239719 Zolgensma Novartis Pharmaceuticals Canada Inc. N/A 2020-12-15 2026-12-15 Yes 2029-06-15 osimertinib mesylate 188171 Tagrisso AstraZeneca Canada Inc. N/A 2016-07-05 kamagra online pharmacy uk 2022-07-05 N/A 2024-07-05 ospemifene 222001 Osphena Duchesnay Inc. N/A 2021-07-16 2027-07-16 N/A 2029-07-16 ozanimod (supplied as ozanimod hydrochloride) 232761 Zeposia Celgene Inc.

N/A 2020-10-02 2026-10-02 N/A 2028-10-02 ozenoxacin 192925 Ozanex Ferrer kamagra online pharmacy uk Internacional, S.A. N/A 2017-05-01 2023-05-01 Yes 2025-11-01 palbociclib 182048 Ibrance Pfizer Canada Inc. N/A 2016-03-16 2022-03-16 Yes 2024-09-16 pasireotide diaspartate 145005 Signifor Novartis Pharmaceuticals Canada Inc. Signifor Lar 2013-09-23 2019-09-23 kamagra online pharmacy uk N/A 2021-09-23 patiromer sorbitex calcium 210368 Veltassa Vifor Fresenius Medical Care Renal Pharma Ltd. N/A 2018-10-03 2024-10-03 N/A 2026-10-03 patisiran (as patisiran sodium) 221896 Onpattro Alnylam Netherlands B.V.

N/A 2019-06-07 2025-06-07 N/A 2027-06-07 peginterferon beta-1a 166974 Plegridy Biogen Idec Canada Inc. N/A 2015-08-10 2021-08-10 N/A 2023-08-10 pembrolizumab 175884 Keytruda Merck Canada Inc kamagra online pharmacy uk. N/A 2015-05-19 2021-05-19 Yes 2023-11-19 peramivir 191280 Rapivab BioCryst Pharmaceuticals Inc. N/A 2017-01-05 2023-01-05 N/A 2025-01-05 perampanel 153747 Fycompa Eisai Limited N/A 2013-04-04 2019-04-04 Yes 2021-10-04 pitolisant hydrochloride 238175 Wakik Endo Ventures kamagra online pharmacy uk Ltd. N/A 2021-05-25 2027-05-25 N/A 2029-05-25 plecanatide 215288 Trulance Bausch Health, Canada Inc.

N/A 2019-10-10 2025-10-10 N/A 2027-10-10 polatuzumab vedotin 232303 Polivy Hoffmann-La Roche Limited N/A 2020-07-09 2026-07-09 N/A 2028-07-09 polidocanol 177359 Varithena Provensis Ltd. N/A 2015-08-04 2021-08-04 N/A 2023-08-04 pomalidomide 165891 Pomalyst Celgene kamagra online pharmacy uk Inc. N/A 2014-01-20 2020-01-20 Yes 2022-07-20 pralatrexate 207545 Folotyn Servier Canada Inc. N/A 2018-10-26 2024-10-26 N/A 2026-10-26 pralsetinib 243731 Gavreto Hoffmann-La Roche Limited N/A 2021-06-30 2027-06-30 N/A 2029-06-30 kamagra online pharmacy uk prasterone 198822 Intrarosa Endoceutics Inc. N/A 2019-11-01 2025-11-01 N/A 2027-11-01 ponatinib hydrochloride 165121 Iclusig Ariad Pharmaceuticals Inc.

N/A 2015-04-02 2021-04-02 N/A 2023-04-02 ponesimod 239537 Ponvory Janssen Inc. N/A 2021-04-28 kamagra online pharmacy uk 2027-04-28 N/A 2029-04-28 propiverine hydrochloride 188323 Mictoryl / Mictoryl Pediatric Duchesnay Inc. N/A 2017-01-05 2023-01-05 Yes 2025-07-05 radium - 223 dichloride 161312 Xofigo Bayer Inc. N/A 2013-12-12 2019-12-12 N/A 2021-12-12 ramucirumab 176810 Cyramza Eli kamagra online pharmacy uk Lilly Canada Inc. N/A 2015-07-16 2021-07-16 N/A 2023-07-16 ravulizumab 217955 Ultomiris Alexion Pharma GmbH N/A 2019-08-28 2025-08-28 N/A 2027-08-28 recombinant haemagglutinin protein-strain A (H1N1) recombinant haemagglutinin protein-strain A (H3N2) recombinant haemagglutinin protein-strain B (Victoria) recombinant haemagglutinin protein-strain B (Yamagata) 235672 Supemtek Sanofi Pasteur Limited N/A 2021-01-14 2027-01-14 N/A 2029-01-14 recombinant human papillomakamagra types 31, 33, 45, 52 and 58 170006 Gardasil 9 Merck Canada Inc.

N/A 2015-02-05 2021-02-05 Yes 2023-08-05 recombinant neisseria meningitidis group B NHBA fusion protein, recombinant neisseria meningitidis group B NadA protein, recombinant neisseria meningitidis group B FHBP fusion protein, outer membrane vesicle (neisseria meningitidis group B NZ98/254 strain) 147275 Bexsero GlaxoSmithKline Inc. N/A 2013-12-06 2019-12-06 Yes 2022-06-06 recombinant porcine factor VIII (antihemophilic factor (recombinant), porcine sequence) 177290 Obizur Takeda Canada Inc kamagra online pharmacy uk. N/A 2015-10-14 2021-10-14 N/A 2023-10-14 regorafenib monohydrate 157970 Stivarga Bayer Inc. N/A 2013-03-11 2019-03-11 Yes 2021-09-11 remdesivir 240551 kamagra online pharmacy uk Veklury Gilead Sciences Canada, Inc. N/A 2020-07-27 2026-07-27 N/A 2028-07-27 reslizumab 185873 Cinqair Teva Canada Limited N/A 2016-07-20 2022-07-20 Yes 2025-01-20 ribociclib (supplied as ribociclib succinate) 203884 Kisqali Novartis Pharmaceuticals Canada Inc.

N/A 2018-03-02 2024-03-02 N/A 2026-03-02 rifaximin 161256 Zaxine Salix Pharmaceuticals Inc. N/A 2013-08-13 2019-08-13 N/A 2021-08-13 riociguat 162761 kamagra online pharmacy uk Adempas Bayer Inc. N/A 2013-09-19 2019-09-19 N/A 2021-09-19 ripretinib 234688 Qinlock Deciphera Pharmaceuticals, LLC N/A 2020-06-19 2026-06-19 N/A 2028-06-19 risankizumab 215753 Skyrizi AbbVie Corporation N/A 2019-04-17 2025-04-17 N/A 2027-04-17 risdiplam 242373 Evrysdi Hoffman-La Roche Limited N/A 2021-04-14 2027-04-14 Yes 2029-10-14 romidepsin 152293 Istodax Celgene Inc. N/A 2013-10-16 2019-10-16 N/A 2021-10-16 romosozumab 197713 Evenity Amgen Canada Inc. N/A 2019-06-17 kamagra online pharmacy uk 2025-06-17 N/A 2027-06-17 rupatadine (supplied as rupatadine fumarate) 186488 Rupall Medexus Pharmaceuticals Inc.

N/A 2016-07-20 2022-07-20 Yes 2025-01-20 sacubitril 182734 Entresto Novartis Pharmaceuticals Canada Inc. N/A 2015-10-02 2021-10-02 N/A 2023-10-02 safinamide (as safinamide mesylate) 207115 Onstryv Valeo kamagra online pharmacy uk Pharma Inc. N/A 2019-01-10 2025-01-10 N/A 2027-01-10 sarilumab 191745 Kevzara Sanofi-aventis Canada Inc. N/A 2017-01-12 2023-01-12 N/A 2025-01-12 satralizumab 233642 Enspryng Hoffmann-La Roche Limited N/A 2020-06-01 2026-06-01 Yes 2028-12-01 sebelipase alfa 204085 Kanuma Alexion Pharma GmbH N/A 2017-12-15 2023-12-15 Yes 2026-06-15 secukinumab 170732 Cosentyx Novartis Pharmaceuticals Canada Inc. N/A 2015-02-27 kamagra online pharmacy uk 2021-02-27 Yes 2023-08-27 selexipag 182114 Uptravi Janssen Inc.

N/A 2016-01-20 2022-01-20 N/A 2024-01-20 selpercatinib 243748 Retevmo Loxo Oncology Inc. N/A 2021-06-15 2027-06-15 Yes 2029-12-15 semaglutide 202059 Ozempic Novo Nordisk kamagra online pharmacy uk Canada Inc. Rybelsus 2018-01-04 2024-01-04 N/A 2026-01-04 siltuximab 174291 Sylvant EUSA Pharma (UK) Limited N/A 2014-12-03 2020-12-03 N/A 2022-12-03 simeprevir 164021 Galexos Janssen Inc. N/A 2013-11-18 2019-11-18 N/A 2021-11-18 siponimod 223225 Mayzent Novartis Pharmaceuticals Canada Inc. N/A 2020-02-20 2026-02-20 N/A 2028-02-20 sodium zirconium cyclosilicate 218799 Lokelma AstraZeneca Canada kamagra online pharmacy uk Inc.

N/A 2019-07-25 2025-07-25 N/A 2027-07-25 sofosbuvir 165043 Sovaldi Gilead Sciences Canada Inc. HarvoniEpclusaVosevi 2013-12-13 2019-12-13 N/A 2021-12-13 solriamfetol hydrochloride 237511 Sunosi Jazz kamagra online pharmacy uk Pharmaceuticals Ireland Ltd. N/A 2021-05-13 2027-05-13 N/A 2029-11-13 sonidegib phosphate 229407 Odomzo Sun Pharma Global FZE N/A 2020-06-12 2026-06-12 N/A 2028-06-12 sucroferric oxyhydroxide 201492 Velphoro Vifor Fresenius Medical Care Renal Pharma Ltd. N/A 2018-01-05 2024-01-05 N/A 2026-01-05 sugammadex sodium 180385 Bridion Merck Canada Inc. N/A 2016-02-05 2022-02-05 N/A kamagra online pharmacy uk 2024-02-05 suvorexant 196367 Belsomra Merck Canada Inc.

N/A 2018-11-29 2024-11-29 N/A 2026-11-29 tafamidis meglumine 228368 Vyndaqel Pfizer Canada ULC Vyndamax 2020-01-20 2026-01-20 N/A 2028-01-20 tafluprost 165596 Saflutan Purdue Pharma N/A 2014-05-26 2020-05-26 N/A 2022-05-26 talazoparib (supplied as talazoparib tosylate) 220584 Talzenna Pfizer Canada ULC N/A 2019-09-06 2025-09-06 N/A 2027-09-06 taliglucerase alfa 140854 Elelyso Pfizer Canada Inc. N/A 2014-05-29 2020-05-29 Yes 2022-11-29 tedizolid phosphate 173603 Sivextro Merck Canada Inc. N/A 2015-03-17 2021-03-17 N/A 2023-03-17 kamagra online pharmacy uk teduglutide 180223 Revestive Takeda Canada Inc. N/A 2015-09-04 2021-09-04 Yes 2024-03-04 telotristat ethyl (as telotristat etiprate) 208730 Xermelo Ipsen Biopharmaceuticals Canada Inc. N/A 2018-10-10 2024-10-10 N/A kamagra online pharmacy uk 2026-10-10 tenapanor hydrochloride 224850 Ibsrela Knight Therapeutics Inc.

N/A 2020-04-15 2026-04-15 N/A 2028-04-15 tenofovir alafenamide hemifumarate 181399 Genvoya Gilead Sciences Canada Inc. DescovyOdefseyVemlidySymtuzaBiktarvy 2015-11-27 2021-11-27 Yes 2024-05-27 tepotinib (supplied as tepotinib hydrochloride) 242300 Tepmetko EMD Serono, a Division of EMD Inc., Canada N/A 2021-05-27 2027-05-27 N/A 2029-05-27 teriflunomide 160646 Aubagio Genzyme Canada a division of Sanofi-aventis Canada Inc. N/A 2013-11-14 2019-11-14 Yes 2022-05-14 tesamorelin 131836 kamagra online pharmacy uk Egrifta Theratechnologies Inc. N/A 2014-04-29 2020-04-29 N/A 2022-04-29 tezacaftor 211292 Symdeko Vertex Pharmaceuticals (Canada) Incorporated N/A 2018-06-27 2024-06-27 Yes 2026-12-27 tildrakizumab 224036 Ilumya Sun Pharma Global FZE N/A 2021-05-19 2027-05-19 N/A 2029-05-19 tisagenlecleucel 213547 / 213698 Kymriah Novartis Pharmaceuticals Canada Inc. N/A 2018-09-05 2024-09-05 Yes 2027-03-05 tofacitinib 154642 Xeljanz Pfizer kamagra online pharmacy uk Canada Inc.

N/A 2014-04-17 2020-04-17 Yes 2022-10-17 trastuzumab deruxtecan 242104 Enhertu AstraZeneca Canada Inc. N/A 2021-04-15 2027-04-15 N/A 2029-04-15 trastuzumab emtansine 162414 Kadcyla Hoffmann-La Roche Limited N/A 2013-09-11 2019-09-11 N/A 2021-09-11 trifarotene 221945 Aklief Galderma Canada Inc. N/A 2019-11-25 2025-11-25 kamagra online pharmacy uk Yes 2028-05-25 tipiracil hydrochloride 205852 Lonsurf Taiho Pharma Canada Inc. N/A 2018-01-25 2024-01-25 N/A 2026-01-25 triheptanoin 242196 Dojolvi Uagenyx Pharmaceutical Inc. N/A 2021-02-15 2027-02-15 Yes 2029-08-15 tucatinib 235295 kamagra online pharmacy uk Tukysa Seagen Inc.

N/A 2020-06-05 2026-06-05 N/A 2028-06-05 turoctocog alfa 170796 Zonovate Novo Nordisk Canada Inc. N/A 2014-12-08 2020-12-08 Yes 2023-06-08 umeclidinium bromide 161585 Anoro Ellipta GlaxoSmithKline Inc. Incruse Ellipta 2013-12-23 2019-12-23 N/A 2021-12-23 upadacitinib 223734 kamagra online pharmacy uk Rinvoq AbbVie Corporation N/A 2019-12-23 2025-12-23 N/A 2027-12-23 varicella-zoster kamagra glycoprotein E (gE) 200244 Shingrix GlaxoSmithKline Inc. N/A 2017-10-13 2023-10-13 N/A 2025-10-13 vedolizumab 169414 Entyvio Takeda Canada Inc. N/A 2015-01-29 2021-01-29 Yes 2023-07-29 velpatasvir 190521 Epclusa Gilead Sciences Canada Inc.

Vosevi 2016-07-11 2022-07-11 Yes 2025-01-11 venetoclax 190761 Venclexta AbbVie Corporation N/A 2016-09-30 2022-09-30 N/A 2024-09-30 vernakalant hydrochloride kamagra online pharmacy uk 190817 Brinavess Cipher Pharmaceuticals Inc. N/A 2017-03-13 2023-03-13 N/A 2025-03-13 vilanterol trifenatate 157301 Breo Ellipta GlaxoSmithKline Inc. Anoro ElliptaTrelegy Ellipta 2013-07-03 2019-07-03 Yes 2022-01-03 vilazodone hydrochloride 176820 Viibryd Allergan kamagra online pharmacy uk Inc. N/A 2015-07-16 2021-07-16 Yes 2024-01-16 von willebrand factor (recombinant) (vonicog alfa) 213188 Vonvendi Takeda Canada Inc. N/A 2019-01-10 2025-01-10 N/A 2027-01-10 vorapaxar sulfate 179320 Zontivity Toprol Acquisition LLC N/A 2016-05-13 2022-05-13 N/A 2024-05-13 voretigene neparvovec 233097 Luxturna Novartis Pharmaceuticals Canada Inc.

N/A 2020-10-13 2026-10-13 Yes 2029-04-13 kamagra online pharmacy uk vortioxetine hydrobromide 159019 Trintellix Lundbeck Canada Inc. N/A 2014-10-22 2020-10-22 Yes 2023-04-22 voxilaprevir 202324 Vosevi Gilead Sciences Canada Inc. N/A 2017-08-16 2023-08-16 N/A 2025-08-16 zanubrutinib 242748 Brukinsa BeiGene Switzerland GmbH N/A 2021-03-01 kamagra online pharmacy uk 2027-03-01 N/A 2029-03-01Date. July 23, 2021Our file number. 21-113500-270Key messages Health Canada has proposed regulatory amendments that would restore potential access to restricted drugsFootnote 1, which include psychedelic drugs, through the Special Access Program (SAP).

Until such time as the regulations are amended, access to these substances via kamagra online pharmacy uk the SAP remains prohibited. Should the regulations be amended, practitionersFootnote 2 would be able to request access to restricted drugs for their patients with a serious or life-threatening condition on a case-by-case basis when other therapies have failed and where there is sufficient evidence of safety and efficacy for the treatment of the patient's condition. The SAP does not have a wait kamagra online pharmacy uk list, as it is meant for emergency access. The proposed regulatory amendments do not signal any intent towards the decriminalization or legalization of restricted drugs, and they are not intended to create large-scale access to restricted drugs. Advertising of unauthorized drugs accessed through the SAP is prohibitedFootnote 3.

Health care professionals wishing to access psychedelic drugs for professional training purposes are not eligible kamagra online pharmacy uk for the SAP. Clinical trials remain the best option to request access to restricted drugs (or any other unapproved drugs) and to generate scientific evidence. Sponsors who are considering undertaking a clinical trial to investigate restricted drugs are encouraged to request a pre-application meeting with the Office of Clinical Trials to discuss their proposed trial and applicable regulatory requirements.Drugs are authorized for sale in Canada once they kamagra online pharmacy uk have successfully gone through the drug review process, which includes the assessment of the safety, efficacy and quality of the drug. However, Health Canada's SAP allows practitioners to request access to drugs that are not available in Canada for the emergency treatment of patients with serious or life-threatening conditions who have exhausted other treatment options. Due to regulatory changes made in 2013, restricted drugs cannot currently be accessed through the SAP.

Although restricted drugs do not generally have authorized medical kamagra online pharmacy uk uses, the science regarding the efficacy and safety of certain restricted drugs has continued to advance. In December 2020, Health Canada published a Notice of Intent that proposed to reverse the regulatory changes made in 2013, and thereby restore potential access to restricted drugs through the SAP. In practice, this would mean that practitioners could request access to restricted drugs through the SAP on a patient-by-patient basis on behalf of patients with serious or life-threatening conditions, in instances where other therapies have failed, are unsuitable or are not available in Canada. However, it is important to note that the proposed amendments would not kamagra online pharmacy uk guarantee that restricted drugs would be approved through the SAP. The proposed amendments would simply treat restricted drugs like all other drugs for the purposes of the SAP.

The SAP is a science-based program that only grants access to an unapproved drug where scientific evidence is available to support the potential effective and safe kamagra online pharmacy uk use of the drug for the treatment of the underlying medical condition. All requests will continue to be assessed on a case-by-case basis taking into consideration the level of evidence regarding the safety and efficacy for the proposed use, the quality of the drug, as well as the patient's condition and their clinical status.Next stepsShould Health Canada proceed with these proposed changes, the regulatory amendments will be published in the Canada Gazette.Contact usFor questions about SAP, please contact us at. Special Access ProgramHealth Canada Telephone. 613-941-2108Fax. 613-941-3194E-mail.

Hc.sapd-pasm.sc@canada.caRelated links Footnote 1 Restricted drugs are controlled substances listed in the Schedule to Part J of the Food and Drug Regulations (FDR) (https://laws-lois.justice.gc.ca/eng/regulations/c.r.c.,_c._870/page-189.html#docCont). Return to footnote 1 referrer Footnote 2 Section C.01.001. Of the FDR (https://laws-lois.justice.gc.ca/eng/regulations/c.r.c.,_c._870/page-94.html#h-574670) defines a practitioner as "a person who (a) is entitled under the laws of a province to treat patients with a prescription drug, and (b) is practising their profession in that province". Return to footnote 2 referrer Footnote 3 In accordance with Section C.08.002 of the FDR (https://laws-lois.justice.gc.ca/eng/regulations/c.r.c.,_c._870/page-142.html#docCont) Return to footnote 3 referrerOne billion children experience violence and abuse every year. That shocking figure has risen even higherduring the erectile dysfunction treatment kamagra.

Violence prevention and response services have been disrupted for 1.8billion children living in more than 100 countries. 1.5 billion young people affected by school closures lost the protection and support that schools often provide.Measures to contain the kamagra, along with economic hardship and family stress, have combined to create‘perfect storm’ conditions for children vulnerable to observing or experiencing physical, emotional andsexual abuse. Despite the benefits of digital connectivity, a life lived more online for learning, socialising andgaming has significantly increased children’s exposure to those who wish to harm them.Today, we stand at a critical moment for the world’s children. Unless we act now and with urgency, we risklosing a generation of children to the long-term impacts of violence and abuse that will undermine childsafety, health, learning and development long after the kamagra subsides. We cannot let that happen.As the world starts to emerge from the kamagra, we have an opportunity to reimagine and create morepeaceful, just and inclusive societies.

Now is the time to redouble our collective efforts and translate what weknow works into accelerated progress towards the goal of a world where every child grows-up safe, secureand in a nurturing environment.We must create a world. Where every child can grow up and thrive with dignity. Where violence and abuse ofchildren is legally outlawed and socially unacceptable. Where the relationship between parents and childrenprevents the intergenerational transmission of violence. Where children in every community can safely takeadvantage of the digital world for learning, playing and socialising.

Where girls and boys experience strongerdevelopmental and educational outcomes because schools and other learning environments are safe,gender-sensitive, inclusive and supportive. Where sport is safe for children. Where every effort is made toprotect the most vulnerable children from all forms of violence, exploitation and abuse, including those livingin situations of conflict and fragility (including climate-related fragility). And where all children can access safeand child-friendly help when they need it.The moral imperative and economic case for action to end violence against children are compelling. Actiontoday will not only prevent the devastating intergenerational social and economic impacts of violence onchildren, families and societies.

It will also help to address the wider impacts of erectile dysfunction treatment and supportprogress towards multiple Sustainable Development Goals.Together, as leaders of organisations committed to ending violence against children, we urge leaders ingovernment, the private sector, faith communities, multilateral organisations, civil society and sportsbodies to seize the moment and be champions of this agenda in their countries, organisations, networksand communities. We call on these leaders to prioritise protecting children in their policies, planning,budgets and communications, and to work together to deliver six game-changing actions to end violenceagainst children. Ban all forms of violence against children by 2030Equip parents and caregivers to keep children safeMake the internet safe for childrenMake schools safe, non-violent and inclusiveProtect children from violence in humanitarian settingsMore investment, better spentAs global organisations working to end violence against children, we will continue to advocate for andinvest in effective child protection, promoting solutions that recognise the different ways in which girlsand boys experience violence and abuse. We will collectively develop and share technical resources andguidance for policymakers, practitioners, parents, caregivers and children themselves. And we will supportthe courageous health, education, child protection and humanitarian professionals working alongsidefaith leaders, community volunteers, parents and young people to keep children safe during theseunprecedented times.In recent years, we have made significant gains in protecting children from violence.

We must do all we canto keep children safe during the current turmoil, and work together to build back better — to end all forms ofviolence, abuse and exploitation of children.SignatoriesAlice Albright, CEO, Global Partnership for EducationNiklas Andréen, President and Chief Operating Officer, Carlson Wagonlit TravelInger Ashing, CEO, Save the Children InternationalAudrey Azoulay, Director-General, UNESCOIrakli Beridze, Head of the Centre for Artificial Intelligence and Robotics, UNICRIScott Berkowitz, President and Founder, RAINNAnna Borgstrom, CEO, NetCleanProfessor Lucle Cluver, Universities of Oxford and Cape TownJulie Cordua, CEO, ThornBob Cunningham, CEO, International Centre for Missing and Exploited ChildrenProfessor Jennifer Davidson, Executive Director, Inspiring Children’s Futures, Uni. Of StrathclydeMichelle DeLaune, Chief Operating Officer, National Center for Missing &. Exploited ChildrenIain Drennan, Executive Director, WeProtect Global AllianceSuzanne Ehlers, CEO, Malala FundHelga Fogstad,, Executive-Director, PMNCHHenrietta H. Fore, Executive Director, UNICEFDr. Debi Fry, Co-Director, End Violence Lab, University of EdinburghVirginia Gamba, UN Special Representative of the Secretary-General for Children and Armed ConflictMeg Gardinier, Secretary General, ChildFund AllianceDr.

Tedros Adhanom Ghebreyesus, Director-General, WHOFilippo Grandi, UN High Commissioner for RefugeesPaula Guillet de Monthoux, Secretary General, World Childhood FoundationSusie Hargreaves, CEO, Internet Watch FoundationMary Harvey, CEO, Centre for Sport and Human RightsDenton Howard, Executive Director, INHOPEIngrid Johansen, CEO, SOS Children’s Villages InternationalEylah Kadjar, Secretary General ad Interim, Terre des Hommes International FederationBaroness Beeban Kidron OBE, Founder and Chair, 5Rights FoundationPatrick Krens, Executive Director, Child Helpline InternationalDr. A.K. Shiva Kumar, Global Co-Chair, Know Violence in ChildhoodDr. Daniela Ligiero, Executive Director and CEO, Together for GirlsElizabeth Lule, Executive Director, Early Childhood Development Action NetworkDr. Najat Maalla M’jid, UN Special Representative of the Secretary-General on Violence Against ChildrenRev.

Keishi Miyamoto, President, Arigatou InternationalPhumzile Mlambo-Ngcuka, Executive Director, UN WomenAndrew Morley, President and CEO, World Vision InternationalThomas Muller, Acting Executive Director, ECPAT InternationalRaj Nooyi, Interim CEO, Plan InternationalDr. Joan Nyanyuki, Executive Director, African Child Policy ForumMabel van Oranje, Founder and Board Chair, Girls Not BridesPramila Patten, UN Special Representative of the Secretary-General on Sexual Violence in ConflictJoy Phumaphi, Board Co-Chair, Global Partnership to End Violence Against ChildrenRev. Prof. Dr. Ioan Sauca, Acting General Secretary, World Council of ChurchesDr.

Rajeev Seth, Chair of the Board, IPSCANYasmine Sherif, Director, Education Cannot WaitDr. Howard Taylor, Executive Director, Global Partnership to End Violence Against ChildrenHelle Thorning-Schmidt, Board Co-Chair, Global Partnership to End Violence Against ChildrenLiv Tørres, Director, Pathfinders for Peaceful, Just and Inclusive Societies, New York UniversityDr. Jennifer Wortham, Chair, World Day Global CollaborativeAlmost half (46%) of the world’s 1.7 million children living with HIV were not on treatment in 2020 and 150 000 children were newly infected with HIV, four times more than the 2020 target of 40 000In the final report from the Start Free, Stay Free, AIDS Free initiative, UNAIDS and partners* warn that progress towards ending AIDS among children, adolescents and young women has stalled and none of the targets for 2020 were met. The report shows that the total number of children on treatment declined for the first time, despite the fact that nearly 800 000 children living with HIV are not currently on treatment. It also shows that opportunities to identify infants and young children living with HIV early are being missed—more than one third of children born to mothers living with HIV were not tested.

If untreated, around 50% of children living with HIV die before they reach their second birthday. “Over 20 years ago, initiatives for families and children to prevent vertical transmission and to eliminate children dying of AIDS truly kick-started what has now become our global AIDS response. This stemmed from an unprecedented activation of all partners, yet, despite early and dramatic progress, despite more tools and knowledge than ever before, children are falling way behind adults and way behind our goals,” said Shannon Hader, UNAIDS Deputy Executive Director, Programme. €œThe inequalities are striking—children are nearly 40% less likely than adults to be on life-saving treatment (54% of children versus 74% of adults), and account for a disproportionate number of deaths (just 5% of all people living with HIV are children, but children account for 15% of all AIDS-related deaths). This is about children’s right to health and healthy lives, their value in our societies.

It’s time to reactivate on all fronts—we need the leadership, activism, and investments to do what’s right for kids.”Start Free, Stay Free, AIDS Free is a five-year framework that began in 2015, following on from the hugely successful Global Plan towards the elimination of new HIV s among children by 2015 and keeping their mothers alive. It called for a super Fast-Track approach to ensure that every child has an HIV-free beginning, that they stay HIV-free through adolescence and that every child and adolescent living with HIV has access to antiretroviral therapy. The approach intensified focus on 23 countries, 21 of which were in Africa, that accounted for 83% of the global number of pregnant women living with HIV, 80% of children living with HIV and 78% of young women aged 15–24 years newly infected with HIV.“The HIV community has a long history of tackling unprecedented challenges, today we need that same energy and perseverance to address the needs of the most vulnerable—our children. African leaders have the power to help us change the pace of care and should act and lead until no child living with HIV is left behind,” said Ren Minghui, Assistant Director-General of the Universal Health Coverage/Communicable and Noncommunicable Diseases Division of the World Health Organization.Although the 2020 targets were missed, the 21 focus countries in Africa made better progress than the non-focus countries. However, there were major disparities between countries, and these countries still bear the highest burden of disease.

11 countries account for nearly 70% of the “missing children”—those living with HIV but not on treatment. There was a 24% decline in new HIV s among children from 2015 to 2020 in focus countries versus a 20% decline globally. Focus countries also achieved 89% treatment coverage for pregnant women living with HIV, compared to 85% globally, but still short of the target of 95%, and there were huge differences between countries. For example, Botswana achieved 100% treatment coverage, yet the Democratic Republic of the Congo only reached 39%.“While we are deeply distressed by the global paediatric HIV shortfalls, we are also encouraged by the fact that we largely have the tools we need to change this,” said Angeli Achrekar, Acting United States Global AIDS Coordinator. €œSo, let this report be a call to action to challenge complacency and to work tirelessly to close the gap.” The report outlines three actions necessary to end new HIV s among children in the focus countries.

First, reach pregnant women with testing and treatment as early as possible—66 000 new HIV s occurred among children because their mothers did not receive treatment at all during pregnancy or breastfeeding. Second, ensure the continuity of treatment and viral suppression during pregnancy, breastfeeding and for life—38 000 children became newly infected with HIV because their mothers were not continued in care during pregnancy and breastfeeding. Third, prevent new HIV s among women who are pregnant and breastfeeding—35 000 new s among children occurred because a woman became newly infected with HIV during pregnancy or breastfeeding. There has been some progress in preventing adolescent girls and young women from acquiring HIV. In the focus countries, the number of adolescent girls and young women acquiring HIV declined by 27% from 2015 to 2020.

However, the number of adolescent girls and young women acquiring HIV in the 21 focus countries was 200 000, twice the global target for 2020 (100 000). In addition, erectile dysfunction treatment and school closures are now disrupting many educational and sexual and reproductive health services for adolescent girls and young women, highlighting the urgent need to redouble HIV prevention efforts to reach young women and adolescent girls.“The lives of the most vulnerable girls and young women hang in the balance, locked into deeply entrenched cycles of vulnerability and neglect that must urgently be interrupted. With the endorsement of United Nations Member States, the new global AIDS strategy recommits us all to address these intersecting vulnerabilities to halt and reverse the effects of HIV by 2030. We know that rapid gains can be achieved for girls and young women. What is needed is the courage to apply the solutions, and the discipline to implement these with rigor and scale,” said Chewe Luo, United Nations Children’s Fund Chief of HIV and Associate Director of Health Programmes.UNAIDS and partners will continue to work together to develop new frameworks to address the unfinished agenda.

New targets for 2025 were officially adopted by United Nations Member States in the 2021 Political Declaration on HIV and AIDS. Ending Inequalities and Getting on Track to End AIDS by 2030 in June this year, providing a road map for the next five years. €œIt is clear that ending mother-to-child transmission requires innovative approaches that support the whole woman throughout the life course, including intensified primary prevention efforts, such as pre-exposure prophylaxis (PrEP), access to comprehensive reproductive care, and focused attention on adolescent girls and young women. The Start Free, Stay Free, AIDS Free report includes new the new targets for 2025 that, if met, will propel a new era of HIV prevention and treatment for women, children and families. This is not the time for complacency, but rather an opportunity to redouble investments to reduce and eliminate mother-to-child transmission,” said Chip Lyons, President and Chief Executive Officer of the Elizabeth Glaser Pediatric AIDS Foundation.*The United States President’s Emergency Plan for AIDS Relief, UNAIDS, the United Nations Children’s Fund and the World Health Organization, with support from the Elizabeth Glaser Pediatric AIDS Foundation.

UNAIDS The Joint United Nations Programme on HIV/AIDS (UNAIDS) leads and inspires the world to achieve its shared vision of zero new HIV s, zero discrimination and zero AIDS-related deaths. UNAIDS unites the efforts of 11 UN organizations—UNHCR, UNICEF, WFP, UNDP, UNFPA, UNODC, UN Women, ILO, UNESCO, WHO and the World Bank—and works closely with global and national partners towards ending the AIDS epidemic by 2030 as part of the Sustainable Development Goals. Learn more at unaids.org and connect with us on Facebook, Twitter, Instagram and YouTube.PEPFARPEPFAR is the largest commitment by any nation to address a single disease in history. Managed and overseen by the U.S. Department of State, and supported through the compassion and generosity of the American people, PEPFAR has saved 20 million lives, prevented millions of s, and helped transform the global AIDS response.UNICEFUNICEF works in some of the world’s toughest places, to reach the world’s most disadvantaged children.

Across more than 190 countries and territories, we work for every child, everywhere, to build a better world for everyone. Follow UNICEF on Twitter, Facebook, Instagram and YouTubeWHODedicated to the well-being of all people and guided by science, the World Health Organization (WHO) leads and champions global efforts to give everyone, everywhere an equal chance at a safe and healthy life. We are the UN agency for heath that connects nations, partners and people on the front lines in 150+ locations – leading the world’s response to health emergencies, preventing disease, addressing the root causes of health issues and expanding access to medicines and health care. Our mission is to promote health, keep the world safe and serve the vulnerable. Www.who.int Elizabeth Glaser Pediatric AIDS FoundationEGPAF is a proven leader in the fight for an AIDS-free generation and has reached over 31 million pregnant women with services to prevent transmission of HIV to their babies.

Founded in 1988, EGPAF has supported over 15,000 sites and currently works in 17 countries to offer HIV counseling, prevention, diagnosis, and treatment services alongside high-quality family health care. Each stage of life—from infancy to adulthood—brings new and different challenges, and EGPAF is driven to see a world where no other mother, child, or family is devastated by this disease. For more information, visit www.pedaids.org..

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N/A 2020-10-13 2026-10-13 Yes 2029-04-13 buy kamagra tablets online vortioxetine hydrobromide 159019 Trintellix Lundbeck Canada Inc. N/A 2014-10-22 2020-10-22 Yes 2023-04-22 voxilaprevir 202324 Vosevi Gilead Sciences Canada Inc. N/A 2017-08-16 2023-08-16 N/A 2025-08-16 zanubrutinib 242748 Brukinsa BeiGene Switzerland buy kamagra tablets online GmbH N/A 2021-03-01 2027-03-01 N/A 2029-03-01Date. July 23, 2021Our file number. 21-113500-270Key messages Health Canada has proposed regulatory amendments that would restore potential access to restricted drugsFootnote 1, which include psychedelic drugs, through the Special Access Program (SAP).

Until such time as the regulations are amended, access to these substances via the SAP remains prohibited buy kamagra tablets online. Should the regulations be amended, practitionersFootnote 2 would be able to request access to restricted drugs for their patients with a serious or life-threatening condition on a case-by-case basis when other therapies have failed and where there is sufficient evidence of safety and efficacy for the treatment of the patient's condition. The SAP does not buy kamagra tablets online have a wait list, as it is meant for emergency access. The proposed regulatory amendments do not signal any intent towards the decriminalization or legalization of restricted drugs, and they are not intended to create large-scale access to restricted drugs. Advertising of unauthorized drugs accessed through the SAP is prohibitedFootnote 3.

Health care professionals wishing to access psychedelic drugs for professional training purposes are not eligible for buy kamagra tablets online the SAP. Clinical trials remain the best option to request access to restricted drugs (or any other unapproved drugs) and to generate scientific evidence. Sponsors who buy kamagra tablets online are considering undertaking a clinical trial to investigate restricted drugs are encouraged to request a pre-application meeting with the Office of Clinical Trials to discuss their proposed trial and applicable regulatory requirements.Drugs are authorized for sale in Canada once they have successfully gone through the drug review process, which includes the assessment of the safety, efficacy and quality of the drug. However, Health Canada's SAP allows practitioners to request access to drugs that are not available in Canada for the emergency treatment of patients with serious or life-threatening conditions who have exhausted other treatment options. Due to regulatory changes made in 2013, restricted drugs cannot currently be accessed through the SAP.

Although restricted drugs do not generally have authorized medical uses, the science regarding the efficacy and safety of buy kamagra tablets online certain restricted drugs has continued to advance. In December 2020, Health Canada published a Notice of Intent that proposed to reverse the regulatory changes made in 2013, and thereby restore potential access to restricted drugs through the SAP. In practice, this would mean that practitioners could request access to restricted drugs through the SAP on a patient-by-patient basis on behalf of patients with serious or life-threatening conditions, in instances where other therapies have failed, are unsuitable or are not available in Canada. However, it is important to note that the proposed buy kamagra tablets online amendments would not guarantee that restricted drugs would be approved through the SAP. The proposed amendments would simply treat restricted drugs like all other drugs for the purposes of the SAP.

The SAP is a science-based program that only grants access buy kamagra tablets online to an unapproved drug where scientific evidence is available to support the potential effective and safe use of the drug for the treatment of the underlying medical condition. All requests will continue to be assessed on a case-by-case basis taking into consideration the level of evidence regarding the safety and efficacy for the proposed use, the quality of the drug, as well as the patient's condition and their clinical status.Next stepsShould Health Canada proceed with these proposed changes, the regulatory amendments will be published in the Canada Gazette.Contact usFor questions about SAP, please contact us at. Special Access ProgramHealth Canada Telephone. 613-941-2108Fax. 613-941-3194E-mail.

Hc.sapd-pasm.sc@canada.caRelated links Footnote 1 Restricted drugs are controlled substances listed in the Schedule to Part J of the Food and Drug Regulations (FDR) (https://laws-lois.justice.gc.ca/eng/regulations/c.r.c.,_c._870/page-189.html#docCont). Return to footnote 1 referrer Footnote 2 Section C.01.001. Of the FDR (https://laws-lois.justice.gc.ca/eng/regulations/c.r.c.,_c._870/page-94.html#h-574670) defines a practitioner as "a person who (a) is entitled under the laws of a province to treat patients with a prescription drug, and (b) is practising their profession in that province". Return to footnote 2 referrer Footnote 3 In accordance with Section C.08.002 of the FDR (https://laws-lois.justice.gc.ca/eng/regulations/c.r.c.,_c._870/page-142.html#docCont) Return to footnote 3 referrerOne billion children experience violence and abuse every year. That shocking figure has risen even higherduring the erectile dysfunction treatment kamagra.

Violence prevention and response services have been disrupted for 1.8billion children living in more than 100 countries. 1.5 billion young people affected by school closures lost the protection and support that schools often provide.Measures to contain the kamagra, along with economic hardship and family stress, have combined to create‘perfect storm’ conditions for children vulnerable to observing or experiencing physical, emotional andsexual abuse. Despite the benefits of digital connectivity, a life lived more online for learning, socialising andgaming has significantly increased children’s exposure to those who wish to harm them.Today, we stand at a critical moment for the world’s children. Unless we act now and with urgency, we risklosing a generation of children to the long-term impacts of violence and abuse that will undermine childsafety, health, learning and development long after the kamagra subsides. We cannot let that happen.As the world starts to emerge from the kamagra, we have an opportunity to reimagine and create morepeaceful, just and inclusive societies.

Now is the time to redouble our collective efforts and translate what weknow works into accelerated progress towards the goal of a world where every child grows-up safe, secureand in a nurturing environment.We must create a world. Where every child can grow up and thrive with dignity. Where violence and abuse ofchildren is legally outlawed and socially unacceptable. Where the relationship between parents and childrenprevents the intergenerational transmission of violence. Where children in every community can safely takeadvantage of the digital world for learning, playing and socialising.

Where girls and boys experience strongerdevelopmental and educational outcomes because schools and other learning environments are safe,gender-sensitive, inclusive and supportive. Where sport is safe for children. Where every effort is made toprotect the most vulnerable children from all forms of violence, exploitation and abuse, including those livingin situations of conflict and fragility (including climate-related fragility). And where all children can access safeand child-friendly help when they need it.The moral imperative and economic case for action to end violence against children are compelling. Actiontoday will not only prevent the devastating intergenerational social and economic impacts of violence onchildren, families and societies.

It will also help to address the wider impacts of erectile dysfunction treatment and supportprogress towards multiple Sustainable Development Goals.Together, as leaders of organisations committed to ending violence against children, we urge leaders ingovernment, the private sector, faith communities, multilateral organisations, civil society and sportsbodies to seize the moment and be champions of this agenda in their countries, organisations, networksand communities. We call on these leaders to prioritise protecting children in their policies, planning,budgets and communications, and to work together to deliver six game-changing actions to end violenceagainst children. Ban all forms of violence against children by 2030Equip parents and caregivers to keep children safeMake the internet safe for childrenMake schools safe, non-violent and inclusiveProtect children from violence in humanitarian settingsMore investment, better spentAs global organisations working to end violence against children, we will continue to advocate for andinvest in effective child protection, promoting solutions that recognise the different ways in which girlsand boys experience violence and abuse. We will collectively develop and share technical resources andguidance for policymakers, practitioners, parents, caregivers and children themselves. And we will supportthe courageous health, education, child protection and humanitarian professionals working alongsidefaith leaders, community volunteers, parents and young people to keep children safe during theseunprecedented times.In recent years, we have made significant gains in protecting children from violence.

We must do all we canto keep children safe during the current turmoil, and work together to build back better — to end all forms ofviolence, abuse and exploitation of children.SignatoriesAlice Albright, CEO, Global Partnership for EducationNiklas Andréen, President and Chief Operating Officer, Carlson Wagonlit TravelInger Ashing, CEO, Save the Children InternationalAudrey Azoulay, Director-General, UNESCOIrakli Beridze, Head of the Centre for Artificial Intelligence and Robotics, UNICRIScott Berkowitz, President and Founder, RAINNAnna Borgstrom, CEO, NetCleanProfessor Lucle Cluver, Universities of Oxford and Cape TownJulie Cordua, CEO, ThornBob Cunningham, CEO, International Centre for Missing and Exploited ChildrenProfessor Jennifer Davidson, Executive Director, Inspiring Children’s Futures, Uni. Of StrathclydeMichelle DeLaune, Chief Operating Officer, National Center for Missing &. Exploited ChildrenIain Drennan, Executive Director, WeProtect Global AllianceSuzanne Ehlers, CEO, Malala FundHelga Fogstad,, Executive-Director, PMNCHHenrietta H. Fore, Executive Director, UNICEFDr. Debi Fry, Co-Director, End Violence Lab, University of EdinburghVirginia Gamba, UN Special Representative of the Secretary-General for Children and Armed ConflictMeg Gardinier, Secretary General, ChildFund AllianceDr.

Tedros Adhanom Ghebreyesus, Director-General, WHOFilippo Grandi, UN High Commissioner for RefugeesPaula Guillet de Monthoux, Secretary General, World Childhood FoundationSusie Hargreaves, CEO, Internet Watch FoundationMary Harvey, CEO, Centre for Sport and Human RightsDenton Howard, Executive Director, INHOPEIngrid Johansen, CEO, SOS Children’s Villages InternationalEylah Kadjar, Secretary General ad Interim, Terre des Hommes International FederationBaroness Beeban Kidron OBE, Founder and Chair, 5Rights FoundationPatrick Krens, Executive Director, Child Helpline InternationalDr. A.K. Shiva Kumar, Global Co-Chair, Know Violence in ChildhoodDr. Daniela Ligiero, Executive Director and CEO, Together for GirlsElizabeth Lule, Executive Director, Early Childhood Development Action NetworkDr. Najat Maalla M’jid, UN Special Representative of the Secretary-General on Violence Against ChildrenRev.

Keishi Miyamoto, President, Arigatou InternationalPhumzile Mlambo-Ngcuka, Executive Director, UN WomenAndrew Morley, President and CEO, World Vision InternationalThomas Muller, Acting Executive Director, ECPAT InternationalRaj Nooyi, Interim CEO, Plan InternationalDr. Joan Nyanyuki, Executive Director, African Child Policy ForumMabel van Oranje, Founder and Board Chair, Girls Not BridesPramila Patten, UN Special Representative of the Secretary-General on Sexual Violence in ConflictJoy Phumaphi, Board Co-Chair, Global Partnership to End Violence Against ChildrenRev. Prof. Dr. Ioan Sauca, Acting General Secretary, World Council of ChurchesDr.

Rajeev Seth, Chair of the Board, IPSCANYasmine Sherif, Director, Education Cannot WaitDr. Howard Taylor, Executive Director, Global Partnership to End Violence Against ChildrenHelle Thorning-Schmidt, Board Co-Chair, Global Partnership to End Violence Against ChildrenLiv Tørres, Director, Pathfinders for Peaceful, Just and Inclusive Societies, New York UniversityDr. Jennifer Wortham, Chair, World Day Global CollaborativeAlmost half (46%) of the world’s 1.7 million children living with HIV were not on treatment in 2020 and 150 000 children were newly infected with HIV, four times more than the 2020 target of 40 000In the final report from the Start Free, Stay Free, AIDS Free initiative, UNAIDS and partners* warn that progress towards ending AIDS among children, adolescents and young women has stalled and none of the targets for 2020 were met. The report shows that the total number of children on treatment declined for the first time, despite the fact that nearly 800 000 children living with HIV are not currently on treatment. It also shows that opportunities to identify infants and young children living with HIV early are being missed—more than one third of children born to mothers living with HIV were not tested.

If untreated, around 50% of children living with HIV die before they reach their second birthday. “Over 20 years ago, initiatives for families and children to prevent vertical transmission and to eliminate children dying of AIDS truly kick-started what has now become our global AIDS response. This stemmed from an unprecedented activation of all partners, yet, despite early and dramatic progress, despite more tools and knowledge than ever before, children are falling way behind adults and way behind our goals,” said Shannon Hader, UNAIDS Deputy Executive Director, Programme. €œThe inequalities are striking—children are nearly 40% less likely than adults to be on life-saving treatment (54% of children versus 74% of adults), and account for a disproportionate number of deaths (just 5% of all people living with HIV are children, but children account for 15% of all AIDS-related deaths). This is about children’s right to health and healthy lives, their value in our societies.

It’s time to reactivate on all fronts—we need the leadership, activism, and investments to do what’s right for kids.”Start Free, Stay Free, AIDS Free is a five-year framework that began in 2015, following on from the hugely successful Global Plan towards the elimination of new HIV s among children by 2015 and keeping their mothers alive. It called for a super Fast-Track approach to ensure that every child has an HIV-free beginning, that they stay HIV-free through adolescence and that every child and adolescent living with HIV has access to antiretroviral therapy. The approach intensified focus on 23 countries, 21 of which were in Africa, that accounted for 83% of the global number of pregnant women living with HIV, 80% of children living with HIV and 78% of young women aged 15–24 years newly infected with HIV.“The HIV community has a long history of tackling unprecedented challenges, today we need that same energy and perseverance to address the needs of the most vulnerable—our children. African leaders have the power to help us change the pace of care and should act and lead until no child living with HIV is left behind,” said Ren Minghui, Assistant Director-General of the Universal Health Coverage/Communicable and Noncommunicable Diseases Division of the World Health Organization.Although the 2020 targets were missed, the 21 focus countries in Africa made better progress than the non-focus countries. However, there were major disparities between countries, and these countries still bear the highest burden of disease.

11 countries account for nearly 70% of the “missing children”—those living with HIV but not on treatment. There was a 24% decline in new HIV s among children from 2015 to 2020 in focus countries versus a 20% decline globally. Focus countries also achieved 89% treatment coverage for pregnant women living with HIV, compared to 85% globally, but still short of the target of 95%, and there were huge differences between countries. For example, Botswana achieved 100% treatment coverage, yet the Democratic Republic of the Congo only reached 39%.“While we are deeply distressed by the global paediatric HIV shortfalls, we are also encouraged by the fact that we largely have the tools we need to change this,” said Angeli Achrekar, Acting United States Global AIDS Coordinator. €œSo, let this report be a call to action to challenge complacency and to work tirelessly to close the gap.” The report outlines three actions necessary to end new HIV s among children in the focus countries.

First, reach pregnant women with testing and treatment as early as possible—66 000 new HIV s occurred among children because their mothers did not receive treatment at all during pregnancy or breastfeeding. Second, ensure the continuity of treatment and viral suppression during pregnancy, breastfeeding and for life—38 000 children became newly infected with HIV because their mothers were not continued in care during pregnancy and breastfeeding. Third, prevent new HIV s among women who are pregnant and breastfeeding—35 000 new s among children occurred because a woman became newly infected with HIV during pregnancy or breastfeeding. There has been some progress in preventing adolescent girls and young women from acquiring HIV. In the focus countries, the number of adolescent girls and young women acquiring HIV declined by 27% from 2015 to 2020.

However, the number of adolescent girls and young women acquiring HIV in the 21 focus countries was 200 000, twice the global target for 2020 (100 000). In addition, erectile dysfunction treatment and school closures are now disrupting many educational and sexual and reproductive health services for adolescent girls and young women, highlighting the urgent need to redouble HIV prevention efforts to reach young women and adolescent girls.“The lives of the most vulnerable girls and young women hang in the balance, locked into deeply entrenched cycles of vulnerability and neglect that must urgently be interrupted. With the endorsement of United Nations Member States, the new global AIDS strategy recommits us all to address these intersecting vulnerabilities to halt and reverse the effects of HIV by 2030. We know that rapid gains can be achieved for girls and young women. What is needed is the courage to apply the solutions, and the discipline to implement these with rigor and scale,” said Chewe Luo, United Nations Children’s Fund Chief of HIV and Associate Director of Health Programmes.UNAIDS and partners will continue to work together to develop new frameworks to address the unfinished agenda.

New targets for 2025 were officially adopted by United Nations Member States in the 2021 Political Declaration on HIV and AIDS. Ending Inequalities and Getting on Track to End AIDS by 2030 in June this year, providing a road map for the next five years. €œIt is clear that ending mother-to-child transmission requires innovative approaches that support the whole woman throughout the life course, including intensified primary prevention efforts, such as pre-exposure prophylaxis (PrEP), access to comprehensive reproductive care, and focused attention on adolescent girls and young women. The Start Free, Stay Free, AIDS Free report includes new the new targets for 2025 that, if met, will propel a new era of HIV prevention and treatment for women, children and families. This is not the time for complacency, but rather an opportunity to redouble investments to reduce and eliminate mother-to-child transmission,” said Chip Lyons, President and Chief Executive Officer of the Elizabeth Glaser Pediatric AIDS Foundation.*The United States President’s Emergency Plan for AIDS Relief, UNAIDS, the United Nations Children’s Fund and the World Health Organization, with support from the Elizabeth Glaser Pediatric AIDS Foundation.

UNAIDS The Joint United Nations Programme on HIV/AIDS (UNAIDS) leads and inspires the world to achieve its shared vision of zero new HIV s, zero discrimination and zero AIDS-related deaths. UNAIDS unites the efforts of 11 UN organizations—UNHCR, UNICEF, WFP, UNDP, UNFPA, UNODC, UN Women, ILO, UNESCO, WHO and the World Bank—and works closely with global and national partners towards ending the AIDS epidemic by 2030 as part of the Sustainable Development Goals. Learn more at unaids.org and connect with us on Facebook, Twitter, Instagram and YouTube.PEPFARPEPFAR is the largest commitment by any nation to address a single disease in history. Managed and overseen by the U.S. Department of State, and supported through the compassion and generosity of the American people, PEPFAR has saved 20 million lives, prevented millions of s, and helped transform the global AIDS response.UNICEFUNICEF works in some of the world’s toughest places, to reach the world’s most disadvantaged children.

Across more than 190 countries and territories, we work for every child, everywhere, to build a better world for everyone. Follow UNICEF on Twitter, Facebook, Instagram and YouTubeWHODedicated to the well-being of all people and guided by science, the World Health Organization (WHO) leads and champions global efforts to give everyone, everywhere an equal chance at a safe and healthy life. We are the UN agency for heath that connects nations, partners and people on the front lines in 150+ locations – leading the world’s response to health emergencies, preventing disease, addressing the root causes of health issues and expanding access to medicines and health care. Our mission is to promote health, keep the world safe and serve the vulnerable. Www.who.int Elizabeth Glaser Pediatric AIDS FoundationEGPAF is a proven leader in the fight for an AIDS-free generation and has reached over 31 million pregnant women with services to prevent transmission of HIV to their babies.

Founded in 1988, EGPAF has supported over 15,000 sites and currently works in 17 countries to offer HIV counseling, prevention, diagnosis, and treatment services alongside high-quality family health care. Each stage of life—from infancy to adulthood—brings new and different challenges, and EGPAF is driven to see a world where no other mother, child, or family is devastated by this disease. For more information, visit www.pedaids.org..