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IntroductionThere has pfizer viagra online been considerable interest in elucidating the contribution of genetic factors to the development of common diseases and using this information for better prediction of disease over here risk. The common disease common variant hypothesis pfizer viagra online predicts that variants that are common in the population play a role in disease susceptibility.1 Genome-wide association studies (GWAS) using single nucleotide polymorphism (SNP) arrays were developed as a mechanism by which to investigate these genetic factors and it was hoped this would lead to identification of variants associated with disease risk and subsequent development of predictive tests. Variants identified as associated with particular traits by these studies, for the large part, are SNPs that individually have a minor effect on disease risk and hence, by themselves, cannot be reliably used in disease prediction. Looking at the aggregate impact of these SNPs in the form of a polygenic score (PGS) appeared to be one possible means pfizer viagra online of using this information to predict disease.2 It is thought this will be of benefit as our genetic make-up is largely stable from birth and dictates a ‘baseline risk’ on which external influences act and modulate.

Therefore, PGS are a potential mechanism to act as a risk predictor by capturing information on this genetic liability.The use of PGS as a predictive biomarker is being explored in a number of different disease areas, including cancer,3 4 psychiatric disorders,5–7 metabolic disorders (diabetes,8 obesity9) and coronary artery disease (CAD).10 The proposed applications range from aiding disease diagnosis, informing selection of therapeutic interventions, improvement of risk prediction, informing disease screening and, on a personal level, informing life planning. Therefore, genetic risk information in the form of a PGS is considered to have potential in informing both clinical and individual-level decision-making.Recent advances in statistical techniques, improved computational power and the pfizer viagra online availability of large data sets have led to rapid developments in this area over the past few years. This has resulted in a variety of approaches to construction of models for score calculation and the investigation of these scores for prediction of common diseases.11 Several review articles aimed at researchers with a working knowledge of this field have been produced.6 11–17 In this article, we provide an overview of the key aspects of PGS construction to assist clinicians and researchers in other areas of academia to gain an understanding of the processes involved in score construction. We also consider the implications of evolving methodologies for the development of applications of PGS in healthcare.Evolution in polygenic model construction methodologiesTerminology pfizer viagra online with respect to PGS has evolved over time, reflecting evolving approaches and methodology.

Other terms include PGS, polygenic risk score, polygenic load, genotype score, genetic burden, polygenic hazard score, genetic risk score (GRS), metaGRS and allelic risk score. Throughout this article we use the terms polygenic models to refer to the method used to pfizer viagra online calculate an output in the form of a PGS. Different polygenic models can be used to calculate a PGS and analysis of these scores can be used to examine associations with particular markers or to predict an individuals risk of diseases.12Usual practice in calculating PGS is as a weighted sum of a number of risk alleles carried by an individual, where the risk alleles and their weights are defined by SNPs and their measured effects (figure 1).11 Polygenic models have been constructed using a few, hundreds or thousands of SNPs, and more recently SNPs across the whole genome. Consequently, determining which SNPs to include and the disease-associated weighting to assign to SNPs are important aspects of model construction (figure 2).18 These aspects are influenced by available genotype data and effect size estimates as well as the methodology employed in turning this information into model parameters (ie, pfizer viagra online weighted SNPs).Polygenic score calculation.

This calculation aggregates the SNPs and their weights selected for a polygenic score. Common diseases are thought to be influenced by many genetic variants with small individual effect sizes, such that meaningful risk prediction pfizer viagra online necessitates examining the aggregated impact of these multiple variants including their weightings. PGS, polygenic score." data-icon-position data-hide-link-title="0">Figure 1 Polygenic score calculation. This calculation aggregates the SNPs and their weights selected for a pfizer viagra online polygenic score.

Common diseases are thought to be influenced by many genetic variants with small individual effect sizes, such that meaningful risk pfizer viagra online prediction necessitates examining the aggregated impact of these multiple variants including their weightings. PGS, polygenic score.Construction of a polygenic score. In the process of developing pfizer viagra online a polygenic score, numerous models are tested and then compared. The model that performs best (as determined by one or more measures) is then selected for validation in the external data set.

GWAS, genome-wide association studies." pfizer viagra online data-icon-position data-hide-link-title="0">Figure 2 Construction of a polygenic score. In the process of developing a polygenic score, numerous models are tested and then compared. The model that performs best (as determined by one or more measures) is then selected for validation in the external data set pfizer viagra online. GWAS, genome-wide association studies.Changes in data availability over time have had an impact on the approach taken in SNP selection and weighting.

Early studies pfizer viagra online to identify variants associated with common diseases took the form of candidate gene studies. The small size of candidate gene studies, the limitation of technologies available for genotyping and stringent significance thresholds meant that these studies investigated fewer variants and those that were identified with disease associations had relatively large effect sizes.19 Taken together, this meant that a relatively small number of variants were available for consideration for inclusion in a polygenic model.20 21 Furthermore, weighting parameters for these few variants were often simplistic, such as counts of the number of risk alleles carried, ignoring their individual effect sizes.16The advent of GWAS enabled assessment of SNPs across the genome, leading to the identification of a larger number of disease-associated variants and therefore more variants suitable for inclusion in a polygenic model. In addition, the increasing number of individuals in the pfizer viagra online association studies meant that the power of these studies increased, allowing for more precise estimates of effect sizes.19 Furthermore, some theorised that lowering stringent significance thresholds set for SNP–trait associations could also identify SNPs that might play a part in disease risk.11 16 This resulted in more options with respect to polygenic model parameters of SNPs to include and weights to assign to them. However, the inclusion of more SNPs and direct application of GWAS effect sizes as a weighting parameter does not always equate to better predictive performance.4 16 This is because GWAS do not provide perfect information with respect to the causal SNP, the effect sizes or the number of SNPs that contribute to the trait.

Therefore, different methods have been developed to address these issues and optimise predictive performance pfizer viagra online of the score. Current common practice is to construct models with different iterations of SNPs and weighting, with assessment of the performance of each to identify the optimum configuration of SNPs and their weights (figure 2).Methods used in SNP selection and weighting assignmentSome methods of model development will initially involve selection of SNPs followed by optimisation of weighting, whereas others may involve optimisation of weightings for all SNPs that have been genotyped using their overall GWAS effect sizes, the linkage disequilibrium (LD) and an estimate of the proportion of SNPs that are expected to contribute to the risk.22LD is the phenomenon where some SNPs are coinherited more frequently with other SNPs due to their close proximity on the genome. Segments with strong pfizer viagra online LD between SNPs are referred to as haplotype blocks. This phenomenon means that GWAS often identify multiple SNPs in the same haplotype block associated with disease and the true causal SNP is not known.

As models have started to pfizer viagra online assess more SNPs, careful consideration is required to take into account possible correlation between SNPs as a result of this phenomenon. Correlation between SNPs can lead to double counting of SNPs and association redundancy, where multiple SNPs in a region of LD are identified as being associated with the outcome pfizer viagra online. This can lead to reduction in the predictive performance of the model. Therefore, processes for filtering SNPs and using one SNP (tag SNP) to act pfizer viagra online as a marker in an area of high LD, through LD thinning, were developed.

Through these processes SNPs correlated with other SNPs in a block are removed, by either pruning or clumping. Pruning ignores p value thresholds and ‘eliminates’ pfizer viagra online SNPs by a process of iterative comparison between a pair of SNPs to assess if they are correlated, and subsequently could remove SNPs that are deemed to have evidence of association. Clumping (also known as informed pruning) is guided by GWAS p values and chooses the most significant SNP, therefore keeping the most significant SNP within a block.23 This is all done with the aim of pinpointing relatively small areas of the genome that contribute to risk of the trait. Different significance thresholds may be used to select SNPs from this subgroup for inclusion in models.Poor performance of a model can result from imperfect tagging with pfizer viagra online the underlying causal SNP.16 This is because the causal SNP that is associated with disease might not be in LD with the tag SNP that is in the model but is in LD with another SNP which is not in the model.

This particularly occurs where the LD and variant frequency differs between population groups.24 An alternate approach to filter SNPs is stepwise regression where SNPs are selected based on how much the SNPs improve the model’s performance. This is a statistical approach pfizer viagra online and does not consider the impact of LD or effect size.As described above, early studies used simple weighting approaches or directly applied effect sizes from GWAS as weighting parameters for SNPs. However, application of effect sizes as a weighting parameter directly from a GWAS may not be optimal, due to differences in the population that the GWAS was conducted in and the target population. Also as described above, LD and the fact that not all SNPs may contribute to the trait mean pfizer viagra online that these effect sizes from GWAS are imperfect estimates.

Therefore, methods have been developed that adjust effect size estimates from GWAS using statistical techniques which make assumptions about factors such as the number of causal SNPs, level of LD between SNPs or knowledge of their potential function to better reflect their impact on a trait. Numerous statistical methodologies have been developed to pfizer viagra online improve weighting with a view to enhancing the discriminative power of a PGS.25 26 Examples of some methodological approaches are LDpred,22 winner’s curse correction,23 empirical Bayes estimation,27 shrinkage regression (Lasso),28 linear mixed models,29 with more being developed or tested. An additional improvement on the methods is to embed non-genetic information (eg, age-specific ORs).6 Determination of which methodology or hybrid of methodologies is most appropriate for various settings and conditions is continuously being explored and is evolving with new statistical approaches developing at a rapid pace.In summary, model development has evolved in an attempt to gain the most from available GWAS data and address some of the issues that arise due to working with data sets which cannot be directly translated into parameters for prediction models. The different approaches taken in SNP selection and weighting, and the impact on the predictive performance of a model are important to consider when pfizer viagra online assessing different models.

This is because different approaches to PGS modelling can achieve the same or a similar level of prediction. From a health system implementation perspective, particular approaches may be preferred following practical considerations and trade-offs pfizer viagra online between obtaining genotype data, processes for score construction and model performance. In addition, the degree to which these parameters need to be optimised will also be impacted by the input data and validation data set, and the quality control procedures that need to be applied to these data sets.12Sources of input data for score constructionKey to the development of a polygenic model is the availability of data pfizer viagra online sets that can provide input parameters for model construction. Genotype data used in model construction can either be available as raw GWAS data or provided as GWAS summary statistics.

Data in the raw format are individual-level data from a pfizer viagra online SNP array and may not have undergone basic quality control such as assessment of missingness, sex discrepancy checks, deviation from Hardy-Weinberg equilibrium, heterozygosity rate, relatedness or assessment for outliers.30 31 Availability of raw GWAS data allows for different polygenic models to be developed because of the richness of the data, however computational issues arise because of the size of the data sets. Data based on genome sequencing, as opposed to SNP arrays, could also be used in model construction. There have been limited studies of PGS developed from this form of data due to limitations in data availability, which is mainly due to cost restraints.15 32 Individual-level genomic data are also often not available to researchers due to privacy concerns.Due to these issues, the focus of polygenic model development has therefore been pfizer viagra online on using well-powered GWAS summary statistics.33 These are available from open access repositories and contain summary information such as the allele positions, ORs, CIs and allele frequency, without containing confidential information on individuals. These data sets have usually been through the basic quality control measures mentioned above.

There are, however, no standards for publicly available files, meaning some further processing steps may be required, in particular when various pfizer viagra online data sets are combined for a meta-analysis. Quality control on summary statistics is only possible if information such as missing genotype rate, minor allele frequency, Hardy-Weinberg equilibrium failures and non-Mendelian transmission rates is provided.12Processing of GWAS data may include additional quality control steps, imputation and filtering of the SNP information, which can be done at the level of genotype or summary statistics data. SNP arrays used in GWAS only have common SNPs represented on them as they rely on LD between SNPs to pfizer viagra online cover the entire genome. As described above, one tag SNP on the array can represent many other SNPs.

Imputation of SNPs is common in GWAS and describes the process of predicting genotypes pfizer viagra online that have not been directly genotyped but are statistically inferred (imputed) based on haplotype blocks from a reference sequence.33–35 Often association tests between the imputed SNPs and trait are repeated. As genotype imputation requires individual-level data, researchers have proposed summary statistics imputation as a mechanism to infer the association between untyped SNPs and a trait. The performance of imputation has been evaluated and shown that, with certain limitations, summary pfizer viagra online statistics imputation is an efficient and cost-effective methodology to identify loci associated with traits when compared with imputation done on genotypes.36An alternative source of input data for the selection of SNPs and their weightings is through literature or in existing databases, where already known trait-associated SNPs and their effect sizes are used as the input parameters in model development. A number of studies have taken this approach37 38 and it is possible to use multiple sources when developing various polygenic models and establishing the preferred parameters to use.Currently, there does not appear to be one methodology that works across all contexts and traits, each trait will need to be assessed to determine which method is the most suitable for the trait being evaluated.

For example, pfizer viagra online four different polygenic model construction strategies were explored for three skin cancer subtypes4 by using data on SNPs and their effect sizes from different sources, such as the latest GWAS meta-analysis results, the National Human Genome Research Institute (NHGRI) EBI GWAS catalogue, UK Biobank GWAS summary statistics with different thresholds and GWAS summary statistics with LDpred. In this setting for basal cell carcinoma and melanoma, the meta-analysis and catalogue-derived models were found to perform similarly but that the latter was ultimately used as it included more SNPs. For squamous cell carcinoma the meta-analysis-derived model pfizer viagra online performed better than the catalogue-derived model. This demonstrates how each disease subtype, model construction strategy and data set can have their own limitations and advantages.Knowledge of the sources of input pfizer viagra online data and its subsequent use in model development is important in understanding the limitations of available models.

Models that are developed using data sets that reflect the population in which prediction is to be carried out will perform better. For example, data collected from a symptomatic or high-risk population may not be suitable as an input data set for the development of a polygenic model that will be used for disease prediction in pfizer viagra online the general population. Large GWAS studies were previously focused on high-risk individuals, such as patients with breast cancer with a strong family history or known pathogenic variants in BRCA1 or BRCA2. These studies would not be suitable for the pfizer viagra online development of PGS for use in the general population but can inform risk assessment in high-risk individuals.

The source of the data for SNP selection and weighting also has implications for downstream uses and validation. For example, variant frequency and LD patterns can vary between populations and this can translate to poor performance of the polygenic model if the external validation population is different from that of the input data set.39–41 Furthermore, the power and validity of polygenic analyses are influenced pfizer viagra online by the input data sources.12 42From a model to a scorePGS can be calculated using one of the methodologies discussed above. The resulting PGS units of measurement depend on which measurement is used for the weighting.12 For example, the weightings may have been calculated based on logOR for discrete traits or linear regression coefficient (β/beta) in continuous traits from univariate regression tests carried out in the GWAS. The resulting scores are then usually transformed to a standard normal distribution to give scores ranging from −1 pfizer viagra online to 1, or 0 to 100 for ease of interpretation.

This enables further examination of the association between the score and a trait and the predictive ability of different scores generated by different models. Similar to other biomarker analyses, this involves using the PGS as a predictor of pfizer viagra online a trait with other covariates (eg, age, smoking, and so on) added, if appropriate, in a target sample. Examination of differences in the distribution of scores in cases and controls, or by examining differences in traits between different strata of PGS can enable assessment of predictive ability (figure 3). Common practice is for individual-level PGS values to be used to stratify populations pfizer viagra online into distinct groups of risk based on percentile cut-off or threshold values (eg, the top 1%).Example distribution of polygenic scores across a population.

Thresholds can be set to stratify risk as low (some), average (most) and high (some)." data-icon-position data-hide-link-title="0">Figure 3 Example distribution of polygenic scores across a population. Thresholds can be set to stratify risk as low (some), average (most) and high (some).Model validationPolygenic model development is reliant on further data sets for model testing and validation and the composition of these data sets is important in ensuring that the models are pfizer viagra online appropriate for a particular purpose. The development of a model to calculate a PGS involves refinement of the previously discussed input parameters, and selection of the ‘best’ of several models based on pfizer viagra online performance (figure 2). Therefore, a testing/training data set is often required to assess the model’s ability to accurately predict the trait of interest.

This is often a data set that pfizer viagra online is independent of the base/input/discovery data set. It may comprise a subset of the discovery data set that is only used for testing and was not included in the initial development of the model but should ideally be a separate independent data set.Genotype and phenotype data are needed in these data sets. Polygenic models are used to calculate PGS for individuals in the training data set and regression analysis is performed with the PGS pfizer viagra online as a predictor of a trait. Other covariates may also be included, if appropriate.

This testing phase can be considered a process for identifying models with better pfizer viagra online overall performance and/or informing refinements needed. Hence, this phase often involves comparison of different models that are developed using the same input data set to identify those models that have optimal performance.The primary purpose is to determine which model best discriminates between cases and controls. The area under the curve (AUC) or the C-statistic is the most pfizer viagra online commonly used measure in assessing discriminative ability. It has been criticised as being an insensitive measure that is not able to fully capture all aspects of predictive ability.

For instance, in some instances, AUC can remain unchanged between models but the individuals within are categorised into a different risk group.43 Alternative pfizer viagra online metrics that have been used to evaluate model performance include increase in risk difference, integrated discrimination improvement, R2 (estimate of variance explained by the PGS after covariate adjustment), net classification index and the relative risk (highest percentile vs lowest percentile). A clear understanding on how to interpret the performance within various settings is important in determining which model is most suitable.44As per normal practice when developing any prediction model, polygenic models with the optimal performance in a testing/training data set should be further validated in external data sets. External data sets are critical in validation of models and assessment of generalisability, hence must also conform to the desired situations in which a model is to be used pfizer viagra online. The goal is to find a model with suitable parameters of predictive performance in data sets outside of those in which it was developed.

Ideally, external validation requires replication in independent pfizer viagra online data sets. Few existing polygenic models have been validated to this extent, the focus being rather on the development of new models rather than evaluation of existing ones. One example where replication has been carried out is in pfizer viagra online the field of CAD, where the GPSCAD45 and metaGRSCAD10 polygenic models (both developed using UK Biobank data) were evaluated in a Finnish population cohort.46 Predictive ability was found to be lower in the Finnish population. This is likely pfizer viagra online to be due to the differences in genetic structure of this population and the population of the data set used for polygenic model development.

Research is ongoing to evaluate polygenic models in other populations and strategies are being developed to ensure the same performance when used more widely, possibly through reweighting and adjustment of the scores.47Moving towards clinical applicationsPGS are thought to be useful information that could improve risk estimation and provide an avenue for disease prevention and deciding treatment strategies. There are indications from a number of fields that genetic information in the form of PGS can act as independent biomarkers and aid stratification.11 16 48 However, the clinical benefits of stratification using a PGS and the implications for clinical practice are only just beginning to be examined pfizer viagra online. The use of PGS as part of existing risk prediction tools or as a stand-alone predictor has been suggested. This latter option may be true for diseases where knowledge or predictive ability with other risk factors is limited, such as in prostate cancer.49 In either case, polygenic models need to be individually examined to determine suitability and applicability for the specific clinical question.50 Despite some commercial companies developing PGS,51 52 currently PGS are not an established part of clinical practice.Integration into pfizer viagra online clinical practice requires evaluation of a PGS-based test.

An important concept to consider in this regard is the distinction between an assay and a test. This has been previously discussed with respect to genetic test evaluation.53 54 It is worth examining this concept as applied to PGS, as their evaluation is reliant pfizer viagra online on a clear understanding of the test to be offered. As outlined by Zimmern and Kroese,54 the method used to analyse a substance in a sample is considered the assay, whereas a test is the use of an assay within a specific context. With respect to PGS, the process of developing a model to derive a score can be considered the assay, while the use of this model for a pfizer viagra online particular disease, population and purpose can be considered the test.

This distinction is important when assessing if studies are reporting on assay performance as opposed to test performance. It is our view that, with respect to polygenic models, progress has been made with respect to assay development, but PGS-based tests are pfizer viagra online yet to be developed and evaluated. This can enable a clearer understanding of their potential clinical utility and issues that may arise for clinical implementation.11 18 55 It is clear that this is still an evolving field, and going forward different models may be required for different traits due to their underlying genetic architecture,26 different clinical contexts and needs.Clinical contexts where risk stratification is already established practice are most likely where implementation of PGS will occur first. Risk prediction models based on non-genetic factors have been developed for many conditions and are used in clinical care, for example, in cardiovascular disease over 100 such models exist.56 In such contexts, how a PGS and its ability to predict risk compared with, or improves on, pfizer viagra online these existing models is being investigated.3 44 57–61 The extent to which PGS improves prediction, as well as the cost implications of including this, is likely to impact on implementation.Integration of PGS into clinical practice, for any application, requires robust and validated mechanisms to generate these scores.

Therefore, given the numerous models available, an assessment of their suitability as part of a test is required. Parameters or guidelines with respect to aspects of model performance and metrics that could assist in selecting the model pfizer viagra online to take forward as a PGS-based test are limited and need to be addressed. Currently, there are different mechanisms to generate PGS and have arisen in response to the challenges in aggregating large-scale genomic data for prediction. For example, a review reported 29 PGS models for breast cancer from 22 publications.62 Due to there being a number of different pfizer viagra online methodologies to generate a score, numerous models may exist for the same condition and each of the resulting models could perform differently.

Models may perform differently because the population, measured outcome or context of the development data sets used pfizer viagra online to generate the models is diverse, for example, a score for risk of breast cancer versus a breast cancer subtype.44 63 This diversity, alongside the lack of established best practice and standardised reporting in publications, makes comparison and evaluation of polygenic models for use in clinical settings challenging. It is clear that moving the field forward is reliant on transparent reporting and evaluation. Recommendations for best practices on the reporting of polygenic models in literature have been proposed14 64 as well as a database,65 66 which could allow pfizer viagra online for such comparisons. Statements and guidelines for risk prediction model development, such as the Genetic Risk Prediction Studies and Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis (TRIPOD), already exist, but are not consistently used.

TRIPOD explicitly covers the development and validation of prediction models for both diagnosis and prognosis, for all medical domains.One clear issue is generalisability and drop in performance of polygenic models once they are applied in a population group different from the one in which they were developed.22 46 67–70 This is an ongoing challenge in genomics as most GWAS, from which most PGS are being developed, have been conducted in European-Caucasian populations.71 Efforts to improve representation are underway72 and there are attempts to reweight/adjust scores when applied to different population groups which are showing some potential but need further research.47 Others have demonstrated that models developed in more diverse population groups have improved performance when applied to external data sets in different populations.24 73 It is important to consider this issue when moving towards clinical applications as it may pose an ethical challenge if the PGS is not generalisable.A greater understanding of different complex traits and the impact of pleiotropy is only beginning to be investigated.74 There is growing appreciation of the role of pleiotropy as multiple variants have been pfizer viagra online identified to be associated with multiple traits and exert diverse effects, providing insight into overlapping mechanisms.75 76 This, together with the impact of population stratification, genetic relatedness, ascertainment and other sources of heterogeneity leading to spurious signals and reduced power in genetic association studies, all impacting on the predictive ability of PGS in different populations and for different diseases.While many publications report on model development and evaluation, often there is a lack of clarity on intended purpose,50 77 leading to uncertainties as to the clinical pathways in which implementation is envisaged. A clear description of intended use within clinical pathways is a central component in evaluating the use of an application with any form of PGS and in considering practical implications, such as mechanisms of obtaining the score, incorporation into health records, interpretation of scores, relevant cut-offs for intervention initiation, mechanisms for feedback of results and costs, among other issues. These parameters will also be pfizer viagra online impacted by the polygenic model that is taken forward for implementation. Meaning that there are still some important questions that need to be addressed to determine how and where PGS could work within current healthcare systems, particularly at a population level.78It is widely accepted that genotyping using arrays is a lower cost endeavour in comparison to genome sequencing, making the incorporation of PGS into routine healthcare an attractive proposition.

However, we were unable to find any studies pfizer viagra online reporting on the use or associated costs of such technology for population screening. Studies are beginning to examine use case scenarios and model cost-effectiveness, but this has only been in very few, specific investigations.79 80 Costs will also be influenced by the testing technology and by the downstream consequences of testing, which is likely to differ depending on specific applications that are developed and the pathways in which such tests are incorporated. This is particularly the case in screening or primary care pfizer viagra online settings, where such testing is currently not an established part of care pathways and may require additional resources, not least as a result of the volume of testing that could be expected. Moving forward, the clinical role of PGS needs to be developed further, including defining the clinical applications as well as supporting evidence, for example, on the effect of clinical outcomes, the feasibility for use in routine practice and cost-effectiveness.ConclusionThere is a large amount of diversity in the PGS field with respect to model development approaches, and this continues to evolve.

There is rapid progress which pfizer viagra online is being driven by the availability of larger data sets, primarily from GWAS and concomitant developments in statistical methodologies. As understanding and knowledge develops, the usefulness and appropriateness of polygenic models for different diseases and contexts are being explored. Nevertheless, this is still an emerging field, with a variable pfizer viagra online evidence base demonstrating some potential. The validity of PGS needs to be clearly demonstrated, and their applications evaluated prior to clinical implementation..

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To 5 p.m. The hotline can be reached toll-free at (800) 445-7356 or (989) 794-7600. Inquiries can also be sent to MidMichigan Health via Facebook messenger at www.facebook.com/midmichigan.

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Applications and support documentation will only be accepted electronically. The deadline for the 2021-2022 school year is Monday, March 1, 2021.The fund, initiated through a $3.3 million bequest left by Bernard Bailey to MidMichigan, was established to further the goals of students pursuing clinical health care careers from an accredited college or university. Under the stewardship of the MidMichigan Health Foundation, scholarships are awarded to students in health care fields on the basis of merit and established criteria as determined by an overseer committee.

Interested applicants must be a resident or have immediate family living in any of the following mid-Michigan counties. Alcona, Alpena, Bay, Clare, Gladwin, Gratiot, Isabella, Midland, Montcalm, Ogemaw, Presque Isle, Roscommon and Saginaw.More than $207,000 was awarded to 160 students pursuing health care careers for the 2020-2021 school year. More than $2 million in total has been granted by the Bailey Family Fund to assist area students since it began offering health care scholarships in 2005.Those interested in more information may contact Ashley Raetz-Myers at (989) 839-3638 or ashley.raetz-myers@midmichigan.org.

Those interested in additional scholarship opportunities may visit www.midmichigan.org/scholarships..

Early on in the erectile dysfunction treatment viagra, there pfizer viagra online were few options available to health care providers who recommended you read were trying to treat erectile dysfunction treatment-positive patients except to provide supportive care, such as fluids and oxygen when indicated. However, after several months of fighting the viagra, this has changed. Lydia Watson, M.D., senior vice president and chief medical officer at MidMichigan Health, helps to answer some common questions on the different ways to help fight the pfizer viagra online illness and save lives. Q. Are there any treatments available pfizer viagra online for erectile dysfunction treatment?.

A. As we continue to learn more about erectile dysfunction treatment, new treatment options have become available. One of the newest treatment options available pfizer viagra online is produced by Lilly, bamlanivimab, or BAM. In fact, MidMichigan Health is currently offering this treatment to erectile dysfunction treatment positive patients who meet the criteria. If you have been diagnosed with erectile dysfunction treatment, ask your health care provider if you may be a pfizer viagra online candidate to receive this treatment.

Q. What is BAM?. A. BAM is a monoclonal antibody that attaches to the erectile dysfunction and prevents it from entering into cells in our body. BAM was recently approved for emergency use authorization by the FDA.

The medication is intended for erectile dysfunction treatment positive patients who are not hospitalized, but who are at high risk for developing severe symptoms or requiring hospitalization. Patients receive it by IV infusion. Q. Are there other medications that can be used to treat erectile dysfunction treatment?. A.

Another medication that has been used is Remdesivir, which is an FDA-approved antiviral drug. MidMichigan Health has been using Remdesivir since the spring. Remdesivir works by blocking the viagra from replicating in the body, and may help patients who are hospitalized with moderate or severe erectile dysfunction treatment be able to go home quicker. However, the medication doesn’t appear to have an effect on patients who are on high-flow oxygen or a ventilator. Q.

Are erectile dysfunction treatment positive patients receiving oxygen as part of their treatment?. A. Supplemental oxygen use is standard if a patient is suffering from low oxygen levels, which can occur in some severe cases of erectile dysfunction treatment. Q. How do I know if I should be receiving any of these treatments if I am erectile dysfunction treatment positive?.

A. If you’ve received a positive erectile dysfunction treatment test, the most important thing to do is to contact your health care provider for direction regarding any type of treatment. They will be able to work with you to determine what course of treatment, if any, is best suited to you. Q. I’ve had erectile dysfunction treatment, and have now recovered.

Is there anything that I can do to help?. A. Yes. MidMichigan Health is asking individuals who previously tested positive for erectile dysfunction treatment to consider donating their plasma, also known as convalescent plasma, which may help patients currently fighting erectile dysfunction treatment. As a result of your , your plasma now contains erectile dysfunction treatment antibodies, which is one way your immune system fought the viagra when you were sick.

Your plasma is now known as convalescent plasma and this plasma may be beneficial to those infected with erectile dysfunction treatment. The donation could possibly save a life. Those interested in more information or wishing to become a donor may visit www.versiti.org/home/convalescent-plasma-donations. As a service to the community, MidMichigan Health hosts a erectile dysfunction treatment informational hotline with a reminder of CDC guidelines and recommendations. Staff is also available to help answer community questions Monday through Friday from 8 a.m.

To 5 p.m. The hotline can be reached toll-free at (800) 445-7356 or (989) 794-7600. Inquiries can also be sent to MidMichigan Health via Facebook messenger at www.facebook.com/midmichigan. Those interested in a current list of erectile dysfunction treatment testing site locations may visit www.michigan.gov/erectile dysfunctiontest.Applications to the Bernard F. And Melissa Anne Bailey Family Fund Health Care Scholarship program at MidMichigan Health will be available beginning December 1, 2020 for the 2021-2022 school year.

Students may access the application online at www.midmichigan.org/bailey. Applications and support documentation will only be accepted electronically. The deadline for the 2021-2022 school year is Monday, March 1, 2021.The fund, initiated through a $3.3 million bequest left by Bernard Bailey to MidMichigan, was established to further the goals of students pursuing clinical health care careers from an accredited college or university. Under the stewardship of the MidMichigan Health Foundation, scholarships are awarded to students in health care fields on the basis of merit and established criteria as determined by an overseer committee. Interested applicants must be a resident or have immediate family living in any of the following mid-Michigan counties.

Alcona, Alpena, Bay, Clare, Gladwin, Gratiot, Isabella, Midland, Montcalm, Ogemaw, Presque Isle, Roscommon and Saginaw.More than $207,000 was awarded to 160 students pursuing health care careers for the 2020-2021 school year. More than $2 million in total has been granted by the Bailey Family Fund to assist area students since it began offering health care scholarships in 2005.Those interested in more information may contact Ashley Raetz-Myers at (989) 839-3638 or ashley.raetz-myers@midmichigan.org. Those interested in additional scholarship opportunities may visit www.midmichigan.org/scholarships..

What should I tell my health care provider before I take Viagra?

They need to know if you have any of these conditions:

Is sildenafil the same as viagra

Patients Figure http://markolewis.com/generic-propecia-online-for-sale 1 is sildenafil the same as viagra. Figure 1 is sildenafil the same as viagra. Enrollment and Randomization.

Of the 1114 patients who were assessed for eligibility, 1062 is sildenafil the same as viagra underwent randomization. 541 were assigned to the remdesivir group and 521 to the placebo group (intention-to-treat population) (Figure 1). 159 (15.0%) were categorized as having mild-to-moderate disease, and 903 (85.0%) were in is sildenafil the same as viagra the severe disease stratum.

Of those assigned to receive remdesivir, 531 patients (98.2%) received the treatment as assigned. Fifty-two patients had remdesivir treatment discontinued before day 10 because is sildenafil the same as viagra of an adverse event or a serious adverse event other than death and 10 withdrew consent. Of those assigned to receive placebo, 517 patients (99.2%) received placebo as assigned.

Seventy patients discontinued placebo before day 10 because of an adverse event or a serious adverse event other than death and is sildenafil the same as viagra 14 withdrew consent. A total of 517 patients in the remdesivir group and 508 in the placebo group completed the trial through day 29, recovered, or died. Fourteen patients who received remdesivir and 9 who received placebo terminated their participation is sildenafil the same as viagra in the trial before day 29.

A total of 54 of the patients who were in the mild-to-moderate stratum at randomization were subsequently determined to meet the criteria for severe disease, resulting in 105 patients in the mild-to-moderate disease stratum and 957 in the severe stratum. The as-treated population included 1048 patients is sildenafil the same as viagra who received the assigned treatment (532 in the remdesivir group, including one patient who had been randomly assigned to placebo and received remdesivir, and 516 in the placebo group). Table 1.

Table 1 is sildenafil the same as viagra. Demographic and Clinical Characteristics of the Patients at Baseline. The mean age is sildenafil the same as viagra of the patients was 58.9 years, and 64.4% were male (Table 1).

On the basis of the evolving epidemiology of erectile dysfunction treatment during the trial, 79.8% of patients were enrolled at sites in North America, 15.3% in Europe, and 4.9% in Asia (Table S1 in the Supplementary Appendix). Overall, 53.3% of the patients were White, is sildenafil the same as viagra 21.3% were Black, 12.7% were Asian, and 12.7% were designated as other or not reported. 250 (23.5%) is sildenafil the same as viagra were Hispanic or Latino.

Most patients had either one (25.9%) or two or more (54.5%) of the prespecified coexisting conditions at enrollment, most commonly hypertension (50.2%), obesity (44.8%), and type 2 diabetes mellitus (30.3%). The median number of days between symptom onset and randomization was 9 (interquartile range, 6 to 12) (Table S2) is sildenafil the same as viagra. A total of 957 patients (90.1%) had severe disease at enrollment.

285 patients (26.8%) met category 7 criteria on the ordinal scale, 193 (18.2%) category 6, 435 (41.0%) is sildenafil the same as viagra category 5, and 138 (13.0%) category 4. Eleven patients (1.0%) had missing ordinal scale data at enrollment. All these is sildenafil the same as viagra patients discontinued the study before treatment.

During the study, 373 patients (35.6% of the 1048 patients in the as-treated population) received hydroxychloroquine and 241 (23.0%) received a glucocorticoid (Table S3). Primary Outcome Figure is sildenafil the same as viagra 2. Figure 2.

Kaplan–Meier Estimates of is sildenafil the same as viagra Cumulative Recoveries. Cumulative recovery estimates are shown in the overall population (Panel A), in patients with a baseline score of 4 on the ordinal scale (not receiving oxygen. Panel B), in those with is sildenafil the same as viagra a baseline score of 5 (receiving oxygen.

Panel C), in those with a baseline score of 6 (receiving high-flow oxygen or noninvasive mechanical ventilation. Panel D), and in those with a baseline score of 7 (receiving mechanical ventilation or is sildenafil the same as viagra extracorporeal membrane oxygenation [ECMO]. Panel E).Table 2.

Table 2 is sildenafil the same as viagra. Outcomes Overall and According to is sildenafil the same as viagra Score on the Ordinal Scale in the Intention-to-Treat Population. Figure 3.

Figure 3 is sildenafil the same as viagra. Time to Recovery According to Subgroup. The widths of the confidence intervals is sildenafil the same as viagra have not been adjusted for multiplicity and therefore cannot be used to infer treatment effects.

Race and ethnic group were reported by the patients.Patients in the remdesivir group had a shorter time to recovery than patients in the placebo group (median, 10 days, as compared with 15 days. Rate ratio is sildenafil the same as viagra for recovery, 1.29. 95% confidence interval [CI], 1.12 to 1.49.

P<0.001) (Figure 2 is sildenafil the same as viagra and Table 2). In the severe disease stratum (957 patients) the median time to recovery was 11 days, as compared with 18 days (rate ratio for recovery, 1.31. 95% CI, 1.12 is sildenafil the same as viagra to 1.52) (Table S4).

The rate ratio for recovery was largest among patients with a baseline ordinal score of 5 (rate ratio for recovery, 1.45. 95% CI, 1.18 is sildenafil the same as viagra to 1.79). Among patients with a baseline score of 4 and those with a baseline score of 6, the rate ratio estimates for recovery were 1.29 (95% CI, 0.91 to 1.83) and 1.09 (95% CI, 0.76 to 1.57), respectively.

For those receiving mechanical ventilation or ECMO at enrollment (baseline ordinal score of is sildenafil the same as viagra 7), the rate ratio for recovery was 0.98 (95% CI, 0.70 to 1.36). Information on interactions of treatment with baseline ordinal score as a continuous variable is provided in Table S11. An analysis adjusting for is sildenafil the same as viagra baseline ordinal score as a covariate was conducted to evaluate the overall effect (of the percentage of patients in each ordinal score category at baseline) on the primary outcome.

This adjusted analysis produced a similar treatment-effect estimate (rate ratio for recovery, 1.26. 95% CI, 1.09 is sildenafil the same as viagra to 1.46). Patients who underwent randomization during the first 10 days after the onset of symptoms had a rate ratio for recovery of 1.37 (95% CI, 1.14 to 1.64), whereas patients who underwent randomization more than 10 days after the onset is sildenafil the same as viagra of symptoms had a rate ratio for recovery of 1.20 (95% CI, 0.94 to 1.52) (Figure 3).

The benefit of remdesivir was larger when given earlier in the illness, though the benefit persisted in most analyses of duration of symptoms (Table S6). Sensitivity analyses in which data were censored at earliest reported use of glucocorticoids or hydroxychloroquine still showed efficacy of remdesivir (9.0 days to is sildenafil the same as viagra recovery with remdesivir vs. 14.0 days to recovery with placebo.

Rate ratio, is sildenafil the same as viagra 1.28. 95% CI, 1.09 to 1.50, and 10.0 vs. 16.0 days is sildenafil the same as viagra to recovery.

Rate ratio, 1.32. 95% CI, 1.11 to 1.58, respectively) (Table is sildenafil the same as viagra S8). Key Secondary Outcome The odds of improvement in the ordinal scale score were higher in the remdesivir group, as determined by a proportional odds model at the day 15 visit, than in the placebo group (odds ratio for improvement, 1.5.

95% CI, 1.2 to 1.9, adjusted for disease severity) (Table is sildenafil the same as viagra 2 and Fig. S7). Mortality Kaplan–Meier estimates of mortality by day 15 were 6.7% in the remdesivir group and 11.9% is sildenafil the same as viagra in the placebo group (hazard ratio, 0.55.

95% CI, 0.36 to 0.83). The estimates by day 29 were 11.4% and 15.2% is sildenafil the same as viagra in two groups, respectively (hazard ratio, 0.73. 95% CI, 0.52 to 1.03).

The between-group differences in mortality varied considerably according to baseline severity (Table 2), with the largest difference seen among patients with is sildenafil the same as viagra a baseline ordinal score of 5 (hazard ratio, 0.30. 95% CI, 0.14 to 0.64). Information on interactions of treatment with baseline ordinal is sildenafil the same as viagra score with respect to mortality is provided in Table S11.

Additional Secondary Outcomes Table 3. Table 3 is sildenafil the same as viagra. Additional Secondary is sildenafil the same as viagra Outcomes.

Patients in the remdesivir group had a shorter time to improvement of one or of two categories on the ordinal scale from baseline than patients in the placebo group (one-category improvement. Median, 7 is sildenafil the same as viagra vs. 9 days.

Rate ratio for recovery, 1.23 is sildenafil the same as viagra. 95% CI, 1.08 to 1.41. Two-category improvement is sildenafil the same as viagra.

Median, 11 vs. 14 days is sildenafil the same as viagra. Rate ratio, 1.29.

95% CI, 1.12 to is sildenafil the same as viagra 1.48) (Table 3). Patients in the remdesivir group had a shorter time to discharge or to a National Early Warning Score of 2 or lower than those in the placebo group (median, 8 days vs. 12 days is sildenafil the same as viagra.

Hazard ratio, 1.27. 95% CI, is sildenafil the same as viagra 1.10 to 1.46). The initial length of hospital stay was shorter in the remdesivir group than in the placebo group (median, 12 days vs.

17 days) is sildenafil the same as viagra. 5% of patients in the remdesivir group were readmitted to the hospital, as compared with 3% in the placebo group. Among the 913 patients receiving oxygen at enrollment, those in the remdesivir group continued to receive oxygen is sildenafil the same as viagra for fewer days than patients in the placebo group (median, 13 days vs.

21 days), and the incidence of new oxygen use among patients who were not receiving oxygen at enrollment was lower in the remdesivir group than in the placebo group (incidence, 36% [95% CI, 26 is sildenafil the same as viagra to 47] vs. 44% [95% CI, 33 to 57]). For the 193 patients receiving noninvasive ventilation or high-flow oxygen at enrollment, the median is sildenafil the same as viagra duration of use of these interventions was 6 days in both the remdesivir and placebo groups.

Among the 573 patients who were not receiving noninvasive ventilation, high-flow oxygen, invasive ventilation, or ECMO at baseline, the incidence of new noninvasive ventilation or high-flow oxygen use was lower in the remdesivir group than in the placebo group (17% [95% CI, 13 to 22] vs. 24% [95% CI, 19 to 30]) is sildenafil the same as viagra. Among the 285 patients who were receiving mechanical ventilation or ECMO at enrollment, patients in the remdesivir group received these interventions for fewer subsequent days than those in the placebo group (median, 17 days vs.

20 days), and the incidence of new mechanical ventilation or ECMO use among the 766 patients who were not receiving these interventions at enrollment was lower in the is sildenafil the same as viagra remdesivir group than in the placebo group (13% [95% CI, 10 to 17] vs. 23% [95% CI, 19 to 27]) (Table 3). Safety Outcomes In the as-treated population, serious adverse events occurred in 131 of is sildenafil the same as viagra 532 patients (24.6%) in the remdesivir group and in 163 of 516 patients (31.6%) in the placebo group (Table S17).

There were 47 serious respiratory failure adverse events in the remdesivir group (8.8% of patients), including acute respiratory failure and the need for endotracheal intubation, and 80 in the placebo group (15.5% of patients) (Table S19). No deaths were is sildenafil the same as viagra considered by the investigators to be related to treatment assignment. Grade 3 or 4 adverse events occurred on or before day 29 in 273 patients (51.3%) in the remdesivir group and in 295 (57.2%) in the placebo group (Table S18).

41 events is sildenafil the same as viagra were judged by the investigators to be related to remdesivir and 47 events to placebo (Table S17). The most common nonserious adverse events occurring in at least 5% of all patients included decreased glomerular filtration rate, decreased hemoglobin level, decreased lymphocyte count, respiratory failure, anemia, pyrexia, hyperglycemia, increased blood creatinine level, and increased blood glucose level (Table S20). The incidence of these adverse events was generally similar in the remdesivir and is sildenafil the same as viagra placebo groups.

Crossover After the data and safety monitoring board recommended that the preliminary primary analysis report be provided to the sponsor, data on a total of 51 patients (4.8% of the total study enrollment) — 16 (3.0%) in the remdesivir group and 35 (6.7%) in the placebo group — were unblinded. 26 (74.3%) of those in the is sildenafil the same as viagra placebo group whose data were unblinded were given remdesivir. Sensitivity analyses evaluating the unblinding (patients whose treatment assignments were unblinded had their data censored at the time of unblinding) and crossover (patients in the placebo group treated with remdesivir had their data censored at the initiation of remdesivir treatment) produced results similar to those of the primary analysis (Table S9)..

Patients Figure go to my site 1 pfizer viagra online. Figure 1 pfizer viagra online. Enrollment and Randomization. Of the 1114 patients who were assessed pfizer viagra online for eligibility, 1062 underwent randomization.

541 were assigned to the remdesivir group and 521 to the placebo group (intention-to-treat population) (Figure 1). 159 (15.0%) pfizer viagra online were categorized as having mild-to-moderate disease, and 903 (85.0%) were in the severe disease stratum. Of those assigned to receive remdesivir, 531 patients (98.2%) received the treatment as assigned. Fifty-two patients had remdesivir treatment discontinued before day 10 because of an adverse event pfizer viagra online or a serious adverse event other than death and 10 withdrew consent.

Of those assigned to receive placebo, 517 patients (99.2%) received placebo as assigned. Seventy patients discontinued placebo before day 10 because pfizer viagra online of an adverse event or a serious adverse event other than death and 14 withdrew consent. A total of 517 patients in the remdesivir group and 508 in the placebo group completed the trial through day 29, recovered, or died. Fourteen patients who received remdesivir and 9 who received placebo pfizer viagra online terminated their participation in the trial before day 29.

A total of 54 of the patients who were in the mild-to-moderate stratum at randomization were subsequently determined to meet the criteria for severe disease, resulting in 105 patients in the mild-to-moderate disease stratum and 957 in the severe stratum. The as-treated population included 1048 patients who received the assigned treatment (532 in the remdesivir group, including one patient who had been randomly assigned to placebo and received pfizer viagra online remdesivir, and 516 in the placebo group). Table 1. Table 1 pfizer viagra online.

Demographic and Clinical Characteristics of the Patients at Baseline. The mean age of the patients was 58.9 pfizer viagra online years, and 64.4% were male (Table 1). On the basis of the evolving epidemiology of erectile dysfunction treatment during the trial, 79.8% of patients were enrolled at sites in North America, 15.3% in Europe, and 4.9% in Asia (Table S1 in the Supplementary Appendix). Overall, 53.3% of the patients were White, 21.3% were Black, 12.7% were Asian, pfizer viagra online and 12.7% were designated as other or not reported.

250 (23.5%) were Hispanic or pfizer viagra online Latino. Most patients had either one (25.9%) or two or more (54.5%) of the prespecified coexisting conditions at enrollment, most commonly hypertension (50.2%), obesity (44.8%), and type 2 diabetes mellitus (30.3%). The median number of days between symptom pfizer viagra online onset and randomization was 9 (interquartile range, 6 to 12) (Table S2). A total of 957 patients (90.1%) had severe disease at enrollment.

285 patients (26.8%) met category 7 criteria on the ordinal scale, 193 (18.2%) category 6, 435 (41.0%) category 5, and 138 (13.0%) category pfizer viagra online 4. Eleven patients (1.0%) had missing ordinal scale data at enrollment. All these patients discontinued the study before pfizer viagra online treatment. During the study, 373 patients (35.6% of the 1048 patients in the as-treated population) received hydroxychloroquine and 241 (23.0%) received a glucocorticoid (Table S3).

Primary Outcome pfizer viagra online Figure 2. Figure 2. Kaplan–Meier Estimates pfizer viagra online of Cumulative Recoveries. Cumulative recovery estimates are shown in the overall population (Panel A), in patients with a baseline score of 4 on the ordinal scale (not receiving oxygen.

Panel B), in those with a baseline score of pfizer viagra online 5 (receiving oxygen. Panel C), in those with a baseline score of 6 (receiving high-flow oxygen or noninvasive mechanical ventilation. Panel D), and in those with a baseline score of 7 pfizer viagra online (receiving mechanical ventilation or extracorporeal membrane oxygenation [ECMO]. Panel E).Table 2.

Table 2 pfizer viagra online. Outcomes Overall and According to Score on the Ordinal Scale in the Intention-to-Treat pfizer viagra online Population. Figure 3. Figure 3 pfizer viagra online.

Time to Recovery According to Subgroup. The widths of the confidence intervals have not been adjusted for multiplicity and therefore cannot be used to infer treatment effects pfizer viagra online. Race and ethnic group were reported by the patients.Patients in the remdesivir group had a shorter time to recovery than patients in the placebo group (median, 10 days, as compared with 15 days. Rate ratio for pfizer viagra online recovery, 1.29.

95% confidence interval [CI], 1.12 to 1.49. P<0.001) (Figure 2 and Table pfizer viagra online 2). In the severe disease stratum (957 patients) the median time to recovery was 11 days, as compared with 18 days (rate ratio for recovery, 1.31. 95% CI, 1.12 to 1.52) (Table pfizer viagra online S4).

The rate ratio for recovery was largest among patients with a baseline ordinal score of 5 (rate ratio for recovery, 1.45. 95% CI, 1.18 to pfizer viagra online 1.79). Among patients with a baseline score of 4 and those with a baseline score of 6, the rate ratio estimates for recovery were 1.29 (95% CI, 0.91 to 1.83) and 1.09 (95% CI, 0.76 to 1.57), respectively. For those pfizer viagra online receiving mechanical ventilation or ECMO at enrollment (baseline ordinal score of 7), the rate ratio for recovery was 0.98 (95% CI, 0.70 to 1.36).

Information on interactions of treatment with baseline ordinal score as a continuous variable is provided in Table S11. An analysis adjusting for baseline ordinal score as a pfizer viagra online covariate was conducted to evaluate the overall effect (of the percentage of patients in each ordinal score category at baseline) on the primary outcome. This adjusted analysis produced a similar treatment-effect estimate (rate ratio for recovery, 1.26. 95% CI, 1.09 pfizer viagra online to 1.46).

Patients who underwent randomization during the first 10 days after the onset of symptoms had pfizer viagra online a rate ratio for recovery of 1.37 (95% CI, 1.14 to 1.64), whereas patients who underwent randomization more than 10 days after the onset of symptoms had a rate ratio for recovery of 1.20 (95% CI, 0.94 to 1.52) (Figure 3). The benefit of remdesivir was larger when given earlier in the illness, though the benefit persisted in most analyses of duration of symptoms (Table S6). Sensitivity analyses in which data pfizer viagra online were censored at earliest reported use of glucocorticoids or hydroxychloroquine still showed efficacy of remdesivir (9.0 days to recovery with remdesivir vs. 14.0 days to recovery with placebo.

Rate ratio, 1.28 pfizer viagra online. 95% CI, 1.09 to 1.50, and 10.0 vs. 16.0 days pfizer viagra online to recovery. Rate ratio, 1.32.

95% CI, 1.11 to pfizer viagra online 1.58, respectively) (Table S8). Key Secondary Outcome The odds of improvement in the ordinal scale score were higher in the remdesivir group, as determined by a proportional odds model at the day 15 visit, than in the placebo group (odds ratio for improvement, 1.5. 95% CI, 1.2 to 1.9, adjusted for disease severity) pfizer viagra online (Table 2 and Fig. S7).

Mortality Kaplan–Meier estimates of mortality by pfizer viagra online day 15 were 6.7% in the remdesivir group and 11.9% in the placebo group (hazard ratio, 0.55. 95% CI, 0.36 to 0.83). The estimates by day 29 were 11.4% and 15.2% in two groups, respectively (hazard ratio, 0.73 pfizer viagra online. 95% CI, 0.52 to 1.03).

The between-group differences in mortality varied considerably according to baseline severity (Table 2), with pfizer viagra online the largest difference seen among patients with a baseline ordinal score of 5 (hazard ratio, 0.30. 95% CI, 0.14 to 0.64). Information on interactions of treatment with baseline ordinal score with respect to mortality pfizer viagra online is provided in Table S11. Additional Secondary Outcomes Table 3.

Table 3 pfizer viagra online. Additional Secondary Outcomes pfizer viagra online. Patients in the remdesivir group had a shorter time to improvement of one or of two categories on the ordinal scale from baseline than patients in the placebo group (one-category improvement. Median, 7 pfizer viagra online vs.

9 days. Rate ratio for recovery, 1.23 pfizer viagra online. 95% CI, 1.08 to 1.41. Two-category improvement pfizer viagra online.

Median, 11 vs. 14 days pfizer viagra online. Rate ratio, 1.29. 95% CI, 1.12 to 1.48) pfizer viagra online (Table 3).

Patients in the remdesivir group had a shorter time to discharge or to a National Early Warning Score of 2 or lower than those in the placebo group (median, 8 days vs. 12 days pfizer viagra online. Hazard ratio, 1.27. 95% CI, 1.10 pfizer viagra online to 1.46).

The initial length of hospital stay was shorter in the remdesivir group than in the placebo group (median, 12 days vs. 17 days) pfizer viagra online. 5% of patients in the remdesivir group were readmitted to the hospital, as compared with 3% in the placebo group. Among the 913 patients receiving oxygen at enrollment, those in the remdesivir group continued to receive oxygen for fewer days than patients in the pfizer viagra online placebo group (median, 13 days vs.

21 days), pfizer viagra online and the incidence of new oxygen use among patients who were not receiving oxygen at enrollment was lower in the remdesivir group than in the placebo group (incidence, 36% [95% CI, 26 to 47] vs. 44% [95% CI, 33 to 57]). For the 193 patients receiving noninvasive ventilation or high-flow oxygen at enrollment, the median duration of use of pfizer viagra online these interventions was 6 days in both the remdesivir and placebo groups. Among the 573 patients who were not receiving noninvasive ventilation, high-flow oxygen, invasive ventilation, or ECMO at baseline, the incidence of new noninvasive ventilation or high-flow oxygen use was lower in the remdesivir group than in the placebo group (17% [95% CI, 13 to 22] vs.

24% [95% CI, 19 pfizer viagra online to 30]). Among the 285 patients who were receiving mechanical ventilation or ECMO at enrollment, patients in the remdesivir group received these interventions for fewer subsequent days than those in the placebo group (median, 17 days vs. 20 days), and the incidence of new mechanical ventilation or ECMO use among the 766 patients who were not receiving these interventions at enrollment was lower in the remdesivir group than in the placebo group pfizer viagra online (13% [95% CI, 10 to 17] vs. 23% [95% CI, 19 to 27]) (Table 3).

Safety Outcomes In the as-treated population, serious adverse events occurred in 131 of 532 patients (24.6%) in the remdesivir group and in 163 of 516 patients (31.6%) in the pfizer viagra online placebo group (Table S17). There were 47 serious respiratory failure adverse events in the remdesivir group (8.8% of patients), including acute respiratory failure and the need for endotracheal intubation, and 80 in the placebo group (15.5% of patients) (Table S19). No deaths were considered by the investigators to be related to pfizer viagra online treatment assignment. Grade 3 or 4 adverse events occurred on or before day 29 in 273 patients (51.3%) in the remdesivir group and in 295 (57.2%) in the placebo group (Table S18).

41 events were judged by the investigators to be related to pfizer viagra online remdesivir and 47 events to placebo (Table S17). The most common nonserious adverse events occurring in at least 5% of all patients included decreased glomerular filtration rate, decreased hemoglobin level, decreased lymphocyte count, respiratory failure, anemia, pyrexia, hyperglycemia, increased blood creatinine level, and increased blood glucose level (Table S20). The incidence of these adverse events was generally similar in the remdesivir and placebo groups pfizer viagra online. Crossover After the data and safety monitoring board recommended that the preliminary primary analysis report be provided to the sponsor, data on a total of 51 patients (4.8% of the total study enrollment) — 16 (3.0%) in the remdesivir group and 35 (6.7%) in the placebo group — were unblinded.

26 (74.3%) pfizer viagra online of those in the placebo group whose data were unblinded were given remdesivir. Sensitivity analyses evaluating the unblinding (patients whose treatment assignments were unblinded had their data censored at the time of unblinding) and crossover (patients in the placebo group treated with remdesivir had their data censored at the initiation of remdesivir treatment) produced results similar to those of the primary analysis (Table S9)..

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On 22nd September 2020 the site link UK Government announced new lockdown restrictions to supress the erectile dysfunction treatment viagra, with some areas of England viagra ad having more restrictive lockdown guidance. Students in a number of cities have been confined to their halls of residences after outbreaks of erectile dysfunction treatment and in Manchester security guards were preventing students leaving the buildings. The scientific community are, unsurprisingly, divided over the question of how far viagra ad lockdowns should extend.1 Monday 21st September 2020 saw the publication of two open letter to the UK government and Chief Medical Officers. One group, Sunetra Gupta et al,2 argued for a selective lockdown targeting the most vulnerable. The other, headed by Trisha Greenhalgh, arguing that attempts to suppress the viagra should operate across the whole community.3 As we enter what appears to be a second wave of erectile dysfunction treatment s and accompanying lockdown measures, ethical debates over the appropriateness and extent of such measures are critical.Julian Savulescu and James Cameron4 in their article on lockdown of the elderly and why this is not ageist, put forward the case that, ‘an appropriate approach may be to lift the general lockdown but implement selective isolation of the elderly.’ Their central viagra ad claim is that selective isolation of the elderly is to be preferred to imposing lockdown on all members of society.

The aim of lockdown, restricting movement and key activities, is designed to reduce the number of deaths from erectile dysfunction treatment and also to prevent the healthcare system from becoming overwhelmed. As the elderly are at significantly more risk of having severe cases of erectile dysfunction treatment and therefore more likely viagra ad to place demands on healthcare services, they are clearly prime candidates for lockdown measures, measures that will not only benefit them but the whole of society. This is not ageist as they point out that differential treatment is not always discrimination if there is a morally relevant reason for the differential treatment. The morally relevant reason in this case is that the elderly, and other groups who may be vulnerable to erectile dysfunction treatment, are viagra ad at greater risk of adverse effects from erectile dysfunction treatment and consequently more likely to burden the heath service if they get erectile dysfunction treatment. Even if this is discrimination they claim that it would be proportionate, as it benefits both the elderly and the wider population.

Savulescu and Cameron argue that to require viagra ad everyone to be lockdown is the levelling down of equality – that is. €˜In order for there to be equality, people who could be better off are made worse off in order to achieve equality.’ And in their view such levelling down is ‘morally repugnant’ and unethical.In his response to Savulescu and Cameron, Jonathan Hughes5 takes issue with their claim that general lockdown measures that affect all members of society equally are a form of levelling down of equality. Hughes argues that the claim that the levelling down of equality is always unethical can be challenged, but his main argument is that ‘the choice to maintain a general lockdown, rather than easing it for the young while maintaining it for the elderly, is not an instance of levelling down.’ For selective lockdown of the elderly to be an instance of levelling down of equality, it would have to make everyone else worse off with no additional benefit to the elderly. However, Hughes argues that a general lockdown does produce benefits or reduce burdens for the elderly and hence is not the viagra ad levelling down of equality. General lockdown will result in lower levels in the wider population and thus the elderly are less likely to contract erectile dysfunction treatment.

Even during lockdown many elderly people have carers or service viagra ad providers visiting them to perform caring responsibilities and with lower general rates these visits are less likely to result in the spread of . Hence, the elderly are less likely to become a burden on the health service and lower levels of will mean an easing of lockdown for everyone sooner. €˜These considerations demonstrate that maintaining a general lockdown in preference to selective lockdown of the elderly and vulnerable need not only equalise the burdens by making the young and healthy worse off, but can benefit the elderly in absolute as well as relative terms.’5As both Savulescu and Cameron, and Hughes note there is an issue of proportionality that needs to be viagra ad considered. Savulescu and Cameron give three reasons why the selective lockdown of the elderly, the restriction of their liberty, is proportionate. The benefits viagra ad to others are significant.

The restriction will produce benefit for the elderly. And finally, this is the option that results viagra ad in the least amount of liberty restriction. Hughes also points out, as do Savulescu and Cameron, that the harms to the elderly due to lockdown might be greater than for other groups, and therefore a general lockdown could be justified on the grounds of Parfit’s Priority View, that benefiting the worse off is more important.This raises the problem of how we determine who is worse off in this scenario, as both sets of authors point out that the elderly may have fewer social networks and hence be more socially isolated and find lockdown particularly hard. Further, if they only have a limited time to live, lockdown may present a relatively greater loss. However, the young, who are facing huge disruption to their social development, their education and a curbing of their freedoms and life choices at critical junctures (ie, going to University and being away from home for the first time), may viagra ad want to argue that they are much more greatly harmed than the elderly.

These potential inter-generational trade-offs need to be debated, and Stephen John argues we need to think about lockdown in terms of intergenerational justice. He argues age is a relevant categorization for discussing lockdown policies in relation to erectile dysfunction treatment, as it is generally ‘an epistemically robust category, which can be operationalized.’3 and viagra ad has particular significance for the aetiology of erectile dysfunction treatment. As John observes, ‘However we approach the ethics of lockdown, we need to do ethical work in deciding how to describe the effects of lockdown in the first place. In turn, I want to suggest that this process is an important, although easily overlooked site of ethical and political contestation.’6 The effects of the erectile dysfunction treatment response on those who are likely to suffer less viagra ad from the disease, the younger generation, and on those whose non-erectile dysfunction treatment healthcare has been suspended, according to some, are likely to outweigh the harms caused by erectile dysfunction treatment itself.7 Hence, describing the effects of erectile dysfunction treatment and lockdown policies is no simple task.Elsewhere in this issue the Editor’s Choice article, Protecting health privacy even when privacy8 is lost by T.J. Kasperbauer considers the ethical and regulatory issues raised by the flow and sharing of data in modern healthcare.

He points out that the predominant model of safeguarding the privacy of healthcare data is one of information control, that is an attempt to limit access to personal viagra ad health data. However, limiting access has important implications for developments in healthcare such as leaning health systems and precision medicine, initiatives that require a large amount of health data. Limiting access could make many data-linkage viagra ad schemes unfeasible in practice. Such uses of data have the potential to make significant contributions to improving healthcare, both in terms of developing new treatments and at an organisational level, re-designing patient pathways and utilising healthcare resources more effectively.9 As an alternative to a control view of privacy, he suggests three measures that could be instituted to enable greater sharing of data, ‘such that pervasive data sharing would not automatically entail a loss of privacy.’ These are. Data obfuscation, this is making the data obscure so it is not possible to make inferences about individuals.

Penalisation of data viagra ad misuse. And transparency, making any access to our data transparent so that it discourages inappropriate data use and we can see who has accessed our data. There are trade-offs and difficulties with all these suggestions as Kasperbauer notes and although changing laws around privacy is possibly the most important and most effective of these measures it is also the most difficult.The value of big data sets rests on their size viagra ad and comprehensiveness, my desire to keep my health data private and opt out of big data initiatives can comprise their success. Therefore, we need to explore ways of balancing individual concerns over privacy, with using data for the greater good, and how to address possible tensions between the two.10 How policy makers and healthcare systems will manage information privacy will be a growing issue and is another example, along with the erectile dysfunction treatment viagra,11 of how we are increasingly thinking about ethical issues at a community, rather than an individual, level and in wider global contexts. In a viagra ad more connected bioethics, concepts such as justice and more community-based values such as stewardship, solidarity and reciprocity are likely to become key tools to frame these debates.12erectile dysfunction treatment continues to dominate 2020 and is likely to be a feature of our lives for some time to come.

Given this, how should health systems respond ethically to the persistent challenges of responding to the ongoing impact of the viagra?. Relatedly, what viagra ad ethical values should underpin the resetting of health services after the initial wave, knowing that local spikes and further waves now seem inevitable?. In this editorial, we outline some of the ethical challenges confronting those running health services as they try to resume non-erectile dysfunction treatment-related services, and the downstream ethical implications these have for healthcare professionals’ day-to-day decision making. This is a phase viagra ad of recovery, resumption and renewal. A form of reset for health services.1 This reset phase will define the ‘new normal' for healthcare delivery, and it offers an opportunity to reimagine and change services for the better.

There are difficulties, however, healthcare systems are already weakened by austerity and the first wave of erectile dysfunction treatment and remain under stress as the viagra continues. The reset period is operating alongside, rather than at the end, of the viagra and this creates difficult ethical choices.Ethical challenges of resetBalancing the greater good with individual careviagras—and public health emergencies more generally—reinforce approaches to ethics viagra ad that emphasise or derive from the interests of communities, rather than those grounded in the claims of the autonomous individual. The response has been to draw on more public health focused ethics, ‘if demand outstrips the ability to deliver to existing standards, more strictly utilitarian considerations will have to be applied, and decisions about how to meet the individual's need will give way to decisions about how to maximise overall benefit’.2 Alongside this, effective control of viagras requires that we all adopt strategies to reduce disease transmission such as the lockdown measures instituted by governments worldwide. Individual liberties are curtailed for the greater viagra ad good.Together, these factors shift the weighting of ethical concepts to emphasise the individual within a community.3 4 For many years, public health ethicists and practitioners have drawn attention to the importance of the health of the whole community5 and the broader determinants of health, including the built environment and the way that society is structured.6 7 Public health emergencies, such as erectile dysfunction treatment, demonstrate our mutual dependencies and highlight the need to prioritise the interests of the community. The difficulty of balancing these tensions between the interests of the ‘wider community’ and the patient as the ‘first concern’ has been well rehearsed.

In the viagra ad reset period, how to further the public good is contested. Should health services prioritise the response to erectile dysfunction treatment. Or should we now be viagra ad trying to give equal or greater priority to providing non-erectile dysfunction treatment services?. It has been argued that the response to erectile dysfunction treatment will produce much greater detrimental effects on population health than the disease itself, including the impact of those who need healthcare for non-erectile dysfunction treatment conditions not receiving treatment.8 9 Thus, in the current viagra, how to promote the public good is by no means clear and which wider community’s interests should be prioritised needs careful ethical consideration.Attention also needs to be paid to relationships between healthcare professionals and patients, as elements of non-verbal communication are inhibited by wearing masks. The calming and reassuring gesture of touch is prohibited or distorted viagra ad by the use of personal protective equipment (PPE).

And patients have to attend appointments on their own without any support, no matter how difficult or traumatic the consultation is expected to be.10 This raises important ethical questions about how the demands of control should be balanced against the need for personalised, dignified and supportive care. Responding to these competing demands can result in moral distress for healthcare professionals who feel ill-prepared or unable to pursue ethically appropriate actions.11 erectile dysfunction treatment has created new and uncertain circumstances that continue to disrupt our understandings of what ‘good care’ looks like and, in so doing, shifts the underpinning values or assumptions on which care is based, raising new ethical considerations for day-to-day decision making.Resource allocationResource allocation is a perennial problem in health systems and the persistence of erectile dysfunction treatment will magnify concerns about National Health Service (NHS) resources long after the first wave. With the suspension of many non-erectile dysfunction treatment services from March 2020 in the UK, the backlog viagra ad of demand for non-erectile dysfunction treatment services has grown, and the pressures on healthcare services are even greater. At the same time, healthcare is necessarily less efficient because of erectile dysfunction treatment control precautions. Each healthcare interaction takes longer because of the time it takes to clean equipment and the treatment area, don and doff PPE, and patients cannot be left waiting in shared rooms viagra ad but must be tightly scheduled.In the first wave of the viagra, the analysis focused on resource allocation between patients with erectile dysfunction treatment.12 In this reset period, attention must now turn to how to allocate resources between those with erectile dysfunction treatment and all other patients, including those whose conditions are not life-threatening and these kinds of decisions need focused ethical scrutiny.What should be done?.

Guidance on ethical responses for the acute phase of a viagra is readily available.13 This is not the case when considering how health systems ought to reset in the immediate aftermath of a viagra or other public health emergency. We are at a juncture where the challenges brought on by the response to erectile dysfunction treatment are forcing the re-evaluation viagra ad of traditional clinical ethical approaches. The theoretical basis is shifting to give greater weight to the interests of the community as a whole. For example, the principle of justice may need to be given greater prominence, as well as a more self-conscious and widespread inclusion of values such as solidarity and reciprocity in decision viagra ad making at both individual and organisational levels.14The viagra has also highlighted how longstanding health, housing, financial and racial inequalities interact with the erectile dysfunction treatment viagra, exacting a disproportionate impact on those already facing disadvantage and discrimination.15 In the healthcare context, an additional dimension to this is the disproportionate impact of erectile dysfunction treatment on healthcare workers from Black, Asian and minority ethnic communities.16 As Richard Horton has argued, erectile dysfunction treatment is not a viagra it is a syndemic. Seeing erectile dysfunction treatment as a syndemic directs the focus towards the social and biological interactions that increase someone’s susceptibility to worse health outcomes.17 Consequently, in the reset phase, ethical decision making must pay more attention to the interaction between erectile dysfunction treatment and longstanding health and socioeconomic inequalities.The speed of response necessary for the first wave of the erectile dysfunction treatment viagra meant that decisions were made with little public scrutiny or consultation.18 But this approach cannot be justified in the reset period.

The statutory, and ethical, obligation to maintain public involvement in decisions relating to service provision was reiterated by NHS England in March 2020.19 And this obligation extends to the scrutiny of the ethical values and arguments that underpin—implicitly or explicitly—the ways that services are reconfigured and the decisions about which patients and staff will bear the costs of reconfiguration.The transition through repeated waves of erectile dysfunction treatment, while not just viagra ad re-establishing but also resetting NHS services, will require new ways of thinking about how to integrate public health, organisational and systems-based approaches with clinical ethics. All health systems need to think about which ethical considerations are important in the reset period, which values and interests should take precedence, and how competing interests can and should be managed. These matters deserve more explicit consideration in ethical and practitioner literature and much wider public consultation..

On 22nd September 2020 the UK cvs viagra price Government announced new lockdown restrictions to supress the erectile dysfunction treatment viagra, with some pfizer viagra online areas of England having more restrictive lockdown guidance. Students in a number of cities have been confined to their halls of residences after outbreaks of erectile dysfunction treatment and in Manchester security guards were preventing students leaving the buildings. The scientific community are, unsurprisingly, pfizer viagra online divided over the question of how far lockdowns should extend.1 Monday 21st September 2020 saw the publication of two open letter to the UK government and Chief Medical Officers. One group, Sunetra Gupta et al,2 argued for a selective lockdown targeting the most vulnerable. The other, headed by Trisha Greenhalgh, arguing that attempts to suppress the viagra should operate across the whole community.3 As we enter what appears to be a second wave of erectile dysfunction treatment s and accompanying lockdown measures, ethical debates over the appropriateness and extent of such measures are critical.Julian pfizer viagra online Savulescu and James Cameron4 in their article on lockdown of the elderly and why this is not ageist, put forward the case that, ‘an appropriate approach may be to lift the general lockdown but implement selective isolation of the elderly.’ Their central claim is that selective isolation of the elderly is to be preferred to imposing lockdown on all members of society.

The aim of lockdown, restricting movement and key activities, is designed to reduce the number of deaths from erectile dysfunction treatment and also to prevent the healthcare system from becoming overwhelmed. As the elderly are pfizer viagra online at significantly more risk of having severe cases of erectile dysfunction treatment and therefore more likely to place demands on healthcare services, they are clearly prime candidates for lockdown measures, measures that will not only benefit them but the whole of society. This is not ageist as they point out that differential treatment is not always discrimination if there is a morally relevant reason for the differential treatment. The morally relevant reason in this case is that the elderly, and other groups who may be vulnerable to pfizer viagra online erectile dysfunction treatment, are at greater risk of adverse effects from erectile dysfunction treatment and consequently more likely to burden the heath service if they get erectile dysfunction treatment. Even if this is discrimination they claim that it would be proportionate, as it benefits both the elderly and the wider population.

Savulescu and Cameron argue that to require everyone to be lockdown is pfizer viagra online the levelling down of equality – that is. €˜In order for there to be equality, people who could be better off are made worse off in order to achieve equality.’ And in their view such levelling down is ‘morally repugnant’ and unethical.In his response to Savulescu and Cameron, Jonathan Hughes5 takes issue with their claim that general lockdown measures that affect all members of society equally are a form of levelling down of equality. Hughes argues that the claim that the levelling down of equality is always unethical can be challenged, but his main argument is that ‘the choice to maintain a general lockdown, rather than easing it for the young while maintaining it for the elderly, is not an instance of levelling down.’ For selective lockdown of the elderly to be an instance of levelling down of equality, it would have to make everyone else worse off with no additional benefit to the elderly. However, Hughes argues that a general lockdown does produce benefits or reduce burdens for pfizer viagra online the elderly and hence is not the levelling down of equality. General lockdown will result in lower levels in the wider population and thus the elderly are less likely to contract erectile dysfunction treatment.

Even during lockdown many elderly people have carers pfizer viagra online or service providers visiting them to perform caring responsibilities and with lower general rates these visits are less likely to result in the spread of . Hence, the elderly are less likely to become a burden on the health service and lower levels of will mean an easing of lockdown for everyone sooner. €˜These considerations demonstrate that maintaining a general lockdown in preference to selective lockdown of the elderly and vulnerable need not only equalise the burdens by making the young and healthy worse off, but can benefit the elderly in absolute as well as pfizer viagra online relative terms.’5As both Savulescu and Cameron, and Hughes note there is an issue of proportionality that needs to be considered. Savulescu and Cameron give three reasons why the selective lockdown of the elderly, the restriction of their liberty, is proportionate. The benefits to others are pfizer viagra online significant.

The restriction will produce benefit for the elderly. And finally, this is the option that results in the least amount pfizer viagra online of liberty restriction. Hughes also points out, as do Savulescu and Cameron, that the harms to the elderly due to lockdown might be greater than for other groups, and therefore a general lockdown could be justified on the grounds of Parfit’s Priority View, that benefiting the worse off is more important.This raises the problem of how we determine who is worse off in this scenario, as both sets of authors point out that the elderly may have fewer social networks and hence be more socially isolated and find lockdown particularly hard. Further, if they only have a limited time to live, lockdown may present a relatively greater loss. However, the young, who are facing huge disruption to their social development, their education and a curbing of their freedoms and life choices at critical junctures (ie, going to University and being away from home for the pfizer viagra online first time), may want to argue that they are much more greatly harmed than the elderly.

These potential inter-generational trade-offs need to be debated, and Stephen John argues we need to think about lockdown in terms of intergenerational justice. He argues age is a relevant categorization for discussing lockdown policies in relation to erectile dysfunction treatment, as it is generally ‘an epistemically robust category, which can be operationalized.’3 and has particular pfizer viagra online significance for the aetiology of erectile dysfunction treatment. As John observes, ‘However we approach the ethics of lockdown, we need to do ethical work in deciding how to describe the effects of lockdown in the first place. In turn, I want to suggest that this process is an important, although easily overlooked site of ethical and political contestation.’6 The effects of the erectile dysfunction treatment response on those who are likely to suffer less from pfizer viagra online the disease, the younger generation, and on those whose non-erectile dysfunction treatment healthcare has been suspended, according to some, are likely to outweigh the harms caused by erectile dysfunction treatment itself.7 Hence, describing the effects of erectile dysfunction treatment and lockdown policies is no simple task.Elsewhere in this issue the Editor’s Choice article, Protecting health privacy even when privacy8 is lost by T.J. Kasperbauer considers the ethical and regulatory issues raised by the flow and sharing of data in modern healthcare.

He points out that the predominant model of safeguarding the privacy of healthcare data is one of information pfizer viagra online control, that is an attempt to limit access to personal health data. However, limiting access has important implications for developments in healthcare such as leaning health systems and precision medicine, initiatives that require a large amount of health data. Limiting access could make pfizer viagra online many data-linkage schemes unfeasible in practice. Such uses of data have the potential to make significant contributions to improving healthcare, both in terms of developing new treatments and at an organisational level, re-designing patient pathways and utilising healthcare resources more effectively.9 As an alternative to a control view of privacy, he suggests three measures that could be instituted to enable greater sharing of data, ‘such that pervasive data sharing would not automatically entail a loss of privacy.’ These are. Data obfuscation, this is making the data obscure so it is not possible to make inferences about individuals.

Penalisation of pfizer viagra online data misuse. And transparency, making any access to our data transparent so that it discourages inappropriate data use and we can see who has accessed our data. There are trade-offs and difficulties with all these suggestions as Kasperbauer notes and although changing laws pfizer viagra online around privacy is possibly the most important and most effective of these measures it is also the most difficult.The value of big data sets rests on their size and comprehensiveness, my desire to keep my health data private and opt out of big data initiatives can comprise their success. Therefore, we need to explore ways of balancing individual concerns over privacy, with using data for the greater good, and how to address possible tensions between the two.10 How policy makers and healthcare systems will manage information privacy will be a growing issue and is another example, along with the erectile dysfunction treatment viagra,11 of how we are increasingly thinking about ethical issues at a community, rather than an individual, level and in wider global contexts. In a more connected bioethics, concepts such as justice and more community-based values such as stewardship, solidarity and reciprocity are likely to become key tools to frame these debates.12erectile dysfunction treatment continues to dominate 2020 pfizer viagra online and is likely to be a feature of our lives for some time to come.

Given this, how should health systems respond ethically to the persistent challenges of responding to the ongoing impact of the viagra?. Relatedly, what ethical values should underpin the resetting of health services after the initial wave, knowing that local spikes and pfizer viagra online further waves now seem inevitable?. In this editorial, we outline some of the ethical challenges confronting those running health services as they try to resume non-erectile dysfunction treatment-related services, and the downstream ethical implications these have for healthcare professionals’ day-to-day decision making. This is a phase pfizer viagra online of recovery, resumption and renewal. A form of reset for health services.1 This reset phase will define the ‘new normal' for healthcare delivery, and it offers an opportunity to reimagine and change services for the better.

There are difficulties, however, healthcare systems are already weakened by austerity and the first wave of erectile dysfunction treatment and remain under stress as the viagra continues. The reset period is operating alongside, rather pfizer viagra online than at the end, of the viagra and this creates difficult ethical choices.Ethical challenges of resetBalancing the greater good with individual careviagras—and public health emergencies more generally—reinforce approaches to ethics that emphasise or derive from the interests of communities, rather than those grounded in the claims of the autonomous individual. The response has been to draw on more public health focused ethics, ‘if demand outstrips the ability to deliver to existing standards, more strictly utilitarian considerations will have to be applied, and decisions about how to meet the individual's need will give way to decisions about how to maximise overall benefit’.2 Alongside this, effective control of viagras requires that we all adopt strategies to reduce disease transmission such as the lockdown measures instituted by governments worldwide. Individual liberties are curtailed for the greater good.Together, these factors shift the weighting of ethical concepts to emphasise the individual within a community.3 4 For many years, public health ethicists and practitioners have drawn attention to the importance of the health of the whole pfizer viagra online community5 and the broader determinants of health, including the built environment and the way that society is structured.6 7 Public health emergencies, such as erectile dysfunction treatment, demonstrate our mutual dependencies and highlight the need to prioritise the interests of the community. The difficulty of balancing these tensions between the interests of the ‘wider community’ and the patient as the ‘first concern’ has been well rehearsed.

In the pfizer viagra online reset period, how to further the public good is contested. Should health services prioritise the response to erectile dysfunction treatment. Or should we now pfizer viagra online be trying to give equal or greater priority to providing non-erectile dysfunction treatment services?. It has been argued that the response to erectile dysfunction treatment will produce much greater detrimental effects on population health than the disease itself, including the impact of those who need healthcare for non-erectile dysfunction treatment conditions not receiving treatment.8 9 Thus, in the current viagra, how to promote the public good is by no means clear and which wider community’s interests should be prioritised needs careful ethical consideration.Attention also needs to be paid to relationships between healthcare professionals and patients, as elements of non-verbal communication are inhibited by wearing masks. The calming and reassuring gesture of touch is prohibited or distorted by the use of pfizer viagra online personal protective equipment (PPE).

And patients have to attend appointments on their own without any support, no matter how difficult or traumatic the consultation is expected to be.10 This raises important ethical questions about how the demands of control should be balanced against the need for personalised, dignified and supportive care. Responding to these competing demands can result in moral distress for healthcare professionals who feel ill-prepared or unable to pursue ethically appropriate actions.11 erectile dysfunction treatment has created new and uncertain circumstances that continue to disrupt our understandings of what ‘good care’ looks like and, in so doing, shifts the underpinning values or assumptions on which care is based, raising new ethical considerations for day-to-day decision making.Resource allocationResource allocation is a perennial problem in health systems and the persistence of erectile dysfunction treatment will magnify concerns about National Health Service (NHS) resources long after the first wave. With the suspension of many non-erectile dysfunction treatment services from March 2020 in the UK, the backlog of demand for non-erectile dysfunction treatment services has grown, and the pressures on healthcare services are even pfizer viagra online greater. At the same time, healthcare is necessarily less efficient because of erectile dysfunction treatment control precautions. Each healthcare interaction takes longer because of the time it takes to clean equipment and the treatment area, don and doff PPE, and patients cannot be left waiting in shared rooms but must be tightly scheduled.In the first wave of the viagra, the analysis focused on resource allocation between patients with erectile dysfunction treatment.12 In this reset period, attention must now pfizer viagra online turn to how to allocate resources between those with erectile dysfunction treatment and all other patients, including those whose conditions are not life-threatening and these kinds of decisions need focused ethical scrutiny.What should be done?.

Guidance on ethical responses for the acute phase of a viagra is readily available.13 This is not the case when considering how health systems ought to reset in the immediate aftermath of a viagra or other public health emergency. We are at a juncture where the challenges brought pfizer viagra online on by the response to erectile dysfunction treatment are forcing the re-evaluation of traditional clinical ethical approaches. The theoretical basis is shifting to give greater weight to the interests of the community as a whole. For example, the principle of justice may need to be given greater prominence, as well as a more self-conscious and widespread inclusion of values such as solidarity and reciprocity in decision making at both individual and organisational levels.14The viagra has also highlighted how longstanding health, housing, financial and racial inequalities interact with the erectile dysfunction treatment viagra, exacting a disproportionate impact on those already facing disadvantage and discrimination.15 In the healthcare context, an additional dimension to this is the disproportionate impact of erectile dysfunction treatment on healthcare workers from pfizer viagra online Black, Asian and minority ethnic communities.16 As Richard Horton has argued, erectile dysfunction treatment is not a viagra it is a syndemic. Seeing erectile dysfunction treatment as a syndemic directs the focus towards the social and biological interactions that increase someone’s susceptibility to worse health outcomes.17 Consequently, in the reset phase, ethical decision making must pay more attention to the interaction between erectile dysfunction treatment and longstanding health and socioeconomic inequalities.The speed of response necessary for the first wave of the erectile dysfunction treatment viagra meant that decisions were made with little public scrutiny or consultation.18 But this approach cannot be justified in the reset period.

The statutory, and ethical, obligation to maintain public involvement pfizer viagra online in decisions relating to service provision was reiterated by NHS England in March 2020.19 And this obligation extends to the scrutiny of the ethical values and arguments that underpin—implicitly or explicitly—the ways that services are reconfigured and the decisions about which patients and staff will bear the costs of reconfiguration.The transition through repeated waves of erectile dysfunction treatment, while not just re-establishing but also resetting NHS services, will require new ways of thinking about how to integrate public health, organisational and systems-based approaches with clinical ethics. All health systems need to think about which ethical considerations are important in the reset period, which values and interests should take precedence, and how competing interests can and should be managed. These matters deserve more explicit consideration in ethical and practitioner literature and much wider public consultation..

Que es viagra

Latest Sleep que es viagra News By Learn More Dennis ThompsonHealthDay ReporterTHURSDAY, Aug. 27, 2020A frequent need to nap could be que es viagra a red flag for future heart problems and a higher risk of early death, a new analysis concludes.Long naps lasting more than an hour are associated with a 34% elevated risk of heart disease and a 30% greater risk of death, according to the combined results of 20 previous studies.Overall, naps of any length were associated with a 19% increased risk of premature death, a Chinese research team found. The study results were released Wednesday for presentation at the virtual annual meeting of the European Society of Cardiology."If you want to take a siesta, our study indicates it's safest to keep it under an hour," lead researcher Zhe Pan of Guangzhou Medical University said in a society news release. "For those of us not in the habit of a daytime slumber, there is no convincing evidence to start."For their study, the researchers analyzed que es viagra data from 20 studies involving more than 313,000 participants.

About two in five people in the studies said they nap.The investigators found that the connection was more pronounced in people aged 65 and older que es viagra. These older folks had a 27% higher risk of death associated with napping and a 36% greater risk of heart disease. Women also had a stronger association que es viagra between napping and poor health, with a 22% greater risk of death and a 31% greater risk of heart problems.Interestingly, long naps were linked with an increased risk of death in people who sleep more than six hours a night. That would seem to rule out poor sleep as an explanation for the increased risk of death and heart health issues.Adults who get less than seven hours of sleep each night are more likely to say they've had a heart attack, according to the U.S.

Centers for Disease Control and Prevention que es viagra. Poor sleep also has been linked to high blood pressure, type 2 diabetes and obesity, all of which increase the risk of heart disease, heart attack and stroke.Pan speculated that long naps might affect the body because they are associated with higher levels of inflammation.But heart health experts said that just que es viagra because you're sleeping through the night doesn't mean you've gotten a good night's sleep -- something for which this study doesn't account.Regarding how well you're resting at night, napping "might be a sign that there's something else going on," said Dr. Nieca Goldberg, a cardiologist and director of the NYU Langone Center for Women's Health, in New York City."What kind of sleep were these individuals getting?. " Goldberg said of the study que es viagra participants.

"Were they waking up at night?. Did que es viagra they have sleep apnea?. "Dr. Matthew Tomey, a cardiologist with Mount Sinai Morningside in New York City, agreed that these folks might be suffering from poor sleep."Some people take naps as a matter of habit, or they take a power nap," Tomey said.

"For others, they're taking potentially longer naps during the daytime because of too little or too poor quality sleep at night."People should take a nap when they feel like it, but if they regularly need naps that could be a sign of trouble, Tomey said."If they notice that they feel excessively sleepy during the daytime, needing multiple or long naps, that's a wake-up call to pay attention to the quality and quantity of their nighttime sleep," he added.People who frequently nap should talk with their doctor about their sleep issues, since they might be suffering from sleep apnea or some other issue that disrupts quality sleep, Tomey and Goldberg said.Good sleep habits, according to the CDC, include:Sticking to a regular sleep schedule.Getting enough natural light during the day, to positively influence brain chemicals related to sleep.Exercising regularly, but not within a few hours of bedtime.Avoiding artificial light near bedtime.Keeping your bedroom cool, dark and quiet.Copyright © 2020 HealthDay. All rights reserved. SLIDESHOW Sleep Disorders. Foods That Help Sleep or Keep You Awake See Slideshow References SOURCES.

Nieca Goldberg, MD, cardiologist and director, NYU Langone Center for Women's Health, New York City. Matthew Tomey, MD, cardiologist, Mount Sinai Morningside, New York City. European Society of Cardiology, annual meeting.Latest Heart News By Serena McNiffHealthDay ReporterWEDNESDAY, Aug. 26, 2020 (HealthDay News)Most strokes strike when an artery in the brain suddenly becomes blocked, but new research shows a rarer cause of strokes is becoming more common.It's called cerebral venous thrombosis (CVT), and it happens when a vein in the brain is clogged.

While CVT is estimated to cause less than 1% of all strokes, scientists discovered it is now more prevalent and affecting a different demographic than previously thought.Study author Dr. Fadar Otite and his colleagues pored over years of hospital records from New York and Florida to find out how many cases of CVT occurred in these states between 2006 and 2016. Otite is an assistant professor of neurology at SUNY Upstate Medical University in Syracuse, N.Y.Based on the data they analyzed, the researchers estimated that the number of CVT cases in the United States rose from around 14 cases per million in 2006 to 20 cases per million in 2014."We still find that the incidence of CVT is less than 1% of all strokes, even across our study period, but the incidence increased by 70% over time," Otite said. "In 2006, the proportion of all strokes that were CVT was 0.47%.

At the end of our study, which was in 2016, that proportion increased to 0.80%."CVT causes blood clots to form in the veins of the brain. These veins drain blood that has already been used by brain cells, sending it back to the heart to be replenished with oxygen. If a clot forms in one of these veins, it may leak into the surrounding brain tissue and could cause a stroke, the researchers explained.While CVT is still most common in young women -- about two-thirds of all CVT hospitalizations included in the study were in females -- the researchers found that the number of cases among this demographic did not increase over the 10-year study period. Instead, they saw increases in CVT among men and older women."Part of the message is that we agree that CVT is still more common in women, but because of the diverse clinical presentation of CVT, when other symptoms that may be attributable to CVT are present in other demographics, we should take them with more seriousness," Otite said.Another major finding was that CVT incidence in Black people was significantly higher than in other races.

But why that is the case remains unknown. "We have no clear explanation, because this is truly the first study to ever relate the incidence of CVT between races," he added.Several factors may put one at a higher risk of developing CVT, including pregnancy and taking hormonal birth control pills, which may be why it is more common in younger women, the researchers noted.And many of the risk factors for CVT -- like blood clotting disorders or medications that cause clotting, severe dehydration, s of the ear, face or neck, head trauma, obesity and cancer -- are somewhat different from the triggers typically associated with stroke.It is important for clinicians to be aware of this rise in CVT incidence because the condition can easily be confused as something else, Otite said. Patients with CVT may have unspecific complaints such as headaches, blurry vision or seizures.Around 3% of patients in a prior study who had CVT and went to the hospital were diagnosed with something else and sent home, according to Otite. "So, it's important to recognize this from the start, because by the next time the clinical condition may be worse," he said.CVT can be treated with medication to thin the blood and help prevent further clotting, which may not be prescribed if the condition isn't properly diagnosed, he added.Dr.

Jose Biller, chair of the neurology department at Loyola University Medical Center in Hines, Ill., said the takeaway from this study is that more attention should be paid to CVT."I think that there should be an increased awareness of cerebral venous thrombosis because, by and large, when people think about stroke, they don't think about it," Biller said. "There should be an increasing level of awareness because this is a condition that has a specific treatment."The study was published online Aug. 26 in the journal Neurology.Copyright © 2020 HealthDay. All rights reserved.

SLIDESHOW Stroke Causes, Symptoms, and Recovery See Slideshow References SOURCES. Fadar Oliver Otite, MD, assistant professor, neurology, State University of New York (SUNY) Upstate Medical University, Syracuse, N.Y.. Jose Biller, MD, chair, department of neurology, Loyola University Medical Center, Hines, Ill.. Neurology, Aug.

26, 2020, onlineLatest Hearing News WEDNESDAY, Aug. 26, 2020 (HealthDay News)Even if they appear unresponsive, dying people may still be able to hear.That's the takeaway from a Canadian analysis of hospice patients in Vancouver.Researchers compared electroencephalography (EEG) data -- a measure of electrical activity in the brain -- collected when patients were conscious and when they became unresponsive at the end of life. Those patients were compared to a healthy control group.The study looked at brain response to various patterns of common and rare sounds that changed frequency, and found that responses of some of the dying patients were similar to those of healthy people -- even hours before death."In the last hours before an expected natural death, many people enter a period of unresponsiveness," said lead author Elizabeth Blundon, a doctoral student in psychology at the University of British Columbia at the time of the study."Our data shows that a dying brain can respond to sound, even in an unconscious state, up to the last hours of life," she said in a university news release.Co-author Lawrence Ward, a professor of psychology, said researchers were able to identify specific mental processes in both groups of participants."We had to look very carefully at the individual control participants' data, to see if each one of them showed a particular type of brain response before we felt confident that the unresponsive patient's brain reacted similarly," he said in the release.The findings were recently published in the journal Scientific Reports."This research gives credence to the fact that hospice nurses and physicians noticed that the sounds of loved ones helped comfort people when they were dying," said study co-author Dr. Romayne Gallagher, a now-retired palliative care physician at St.

John Hospice in Vancouver."And to me, it adds significant meaning to the last days and hours of life and shows that being present, in person or by phone, is meaningful," she said. "It is a comfort to be able to say goodbye and express love."While the evidence of brain activity supports the idea that dying people might hear, it's not known if they're aware of what they're hearing, Blundon noted."Their brains responded to the auditory stimuli, but we can't possibly know if they're remembering, identifying voices, or understanding language," she said. "There are all these other questions that have yet to be answered. This first glimpse supports the idea that we have to keep talking to people when they are dying because something is happening in their brain."-- Robert PreidtCopyright © 2020 HealthDay.

All rights reserved. QUESTION What is hearing loss?. See Answer References SOURCE. University of British Columbia, news release, July 8, 2020.

Latest Sleep pfizer viagra online News By Dennis ThompsonHealthDay ReporterTHURSDAY, Aug. 27, 2020A frequent need to nap could be a red flag for future heart problems and a higher risk of pfizer viagra online early death, a new analysis concludes.Long naps lasting more than an hour are associated with a 34% elevated risk of heart disease and a 30% greater risk of death, according to the combined results of 20 previous studies.Overall, naps of any length were associated with a 19% increased risk of premature death, a Chinese research team found. The study results were released Wednesday for presentation at the virtual annual meeting of the European Society of Cardiology."If you want to take a siesta, our study indicates it's safest to keep it under an hour," lead researcher Zhe Pan of Guangzhou Medical University said in a society news release. "For those of us not in the habit of a daytime slumber, there is no convincing evidence to pfizer viagra online start."For their study, the researchers analyzed data from 20 studies involving more than 313,000 participants. About two in five people in the studies said they nap.The investigators found that the connection was more pronounced in people aged 65 and pfizer viagra online older.

These older folks had a 27% higher risk of death associated with napping and a 36% greater risk of heart disease. Women also had a stronger association between napping and poor health, with a 22% greater risk of death and a 31% greater risk of heart problems.Interestingly, long naps were linked with an increased risk of death in people who sleep more than six hours a pfizer viagra online night. That would seem to rule out poor sleep as an explanation for the increased risk of death and heart health issues.Adults who get less than seven hours of sleep each night are more likely to say they've had a heart attack, according to the U.S. Centers for Disease pfizer viagra online Control and Prevention. Poor sleep also has been linked to high blood pressure, type 2 diabetes and obesity, all of which increase the risk of heart disease, heart attack and stroke.Pan speculated that long naps might affect the body because they are associated with higher levels of inflammation.But heart health experts said that just because you're sleeping through the night doesn't mean you've gotten a good night's sleep -- pfizer viagra online something for which this study doesn't account.Regarding how well you're resting at night, napping "might be a sign that there's something else going on," said Dr.

Nieca Goldberg, a cardiologist and director of the NYU Langone Center for Women's Health, in New York City."What kind of sleep were these individuals getting?. " Goldberg said of the pfizer viagra online study participants. "Were they waking up at night?. Did they pfizer viagra online have sleep apnea?. "Dr.

Matthew Tomey, a cardiologist with Mount Sinai Morningside in New York City, agreed that these folks might be suffering from poor sleep."Some people take naps as a matter of habit, or they take a power nap," Tomey said. "For others, they're taking potentially longer naps during the daytime because of too little or too poor quality sleep at night."People should take a nap when they feel like it, but if they regularly need naps that could be a sign of trouble, Tomey said."If they notice that they feel excessively sleepy during the daytime, needing multiple or long naps, that's a wake-up call to pay attention to the quality and quantity of their nighttime sleep," he added.People who frequently nap should talk with their doctor about their sleep issues, since they might be suffering from sleep apnea or some other issue that disrupts quality sleep, Tomey and Goldberg said.Good sleep habits, according to the CDC, include:Sticking to a regular sleep schedule.Getting enough natural light during the day, to positively influence brain chemicals related to sleep.Exercising regularly, but not within a few hours of bedtime.Avoiding artificial light near bedtime.Keeping your bedroom cool, dark and quiet.Copyright © 2020 HealthDay. All rights reserved. SLIDESHOW Sleep Disorders. Foods That Help Sleep or Keep You Awake See Slideshow References SOURCES.

Nieca Goldberg, MD, cardiologist and director, NYU Langone Center for Women's Health, New York City. Matthew Tomey, MD, cardiologist, Mount Sinai Morningside, New York City. European Society of Cardiology, annual meeting.Latest Heart News By Serena McNiffHealthDay ReporterWEDNESDAY, Aug. 26, 2020 (HealthDay News)Most strokes strike when an artery in the brain suddenly becomes blocked, but new research shows a rarer cause of strokes is becoming more common.It's called cerebral venous thrombosis (CVT), and it happens when a vein in the brain is clogged. While CVT is estimated to cause less than 1% of all strokes, scientists discovered it is now more prevalent and affecting a different demographic than previously thought.Study author Dr.

Fadar Otite and his colleagues pored over years of hospital records from New York and Florida to find out how many cases of CVT occurred in these states between 2006 and 2016. Otite is an assistant professor of neurology at SUNY Upstate Medical University in Syracuse, N.Y.Based on the data they analyzed, the researchers estimated that the number of CVT cases in the United States rose from around 14 cases per million in 2006 to 20 cases per million in 2014."We still find that the incidence of CVT is less than 1% of all strokes, even across our study period, but the incidence increased by 70% over time," Otite said. "In 2006, the proportion of all strokes that were CVT was 0.47%. At the end of our study, which was in 2016, that proportion increased to 0.80%."CVT causes blood clots to form in the veins of the brain. These veins drain blood that has already been used by brain cells, sending it back to the heart to be replenished with oxygen.

If a clot forms in one of these veins, it may leak into the surrounding brain tissue and could cause a stroke, the researchers explained.While CVT is still most common in young women -- about two-thirds of all CVT hospitalizations included in the study were in females -- the researchers found that the number of cases among this demographic did not increase over the 10-year study period. Instead, they saw increases in CVT among men and older women."Part of the message is that we agree that CVT is still more common in women, but because of the diverse clinical presentation of CVT, when other symptoms that may be attributable to CVT are present in other demographics, we should take them with more seriousness," Otite said.Another major finding was that CVT incidence in Black people was significantly higher than in other races. But why that is the case remains unknown. "We have no clear explanation, because this is truly the first study to ever relate the incidence of CVT between races," he added.Several factors may put one at a higher risk of developing CVT, including pregnancy and taking hormonal birth control pills, which may be why it is more common in younger women, the researchers noted.And many of the risk factors for CVT -- like blood clotting disorders or medications that cause clotting, severe dehydration, s of the ear, face or neck, head trauma, obesity and cancer -- are somewhat different from the triggers typically associated with stroke.It is important for clinicians to be aware of this rise in CVT incidence because the condition can easily be confused as something else, Otite said. Patients with CVT may have unspecific complaints such as headaches, blurry vision or seizures.Around 3% of patients in a prior study who had CVT and went to the hospital were diagnosed with something else and sent home, according to Otite.

"So, it's important to recognize this from the start, because by the next time the clinical condition may be worse," he said.CVT can be treated with medication to thin the blood and help prevent further clotting, which may not be prescribed if the condition isn't properly diagnosed, he added.Dr. Jose Biller, chair of the neurology department at Loyola University Medical Center in Hines, Ill., said the takeaway from this study is that more attention should be paid to CVT."I think that there should be an increased awareness of cerebral venous thrombosis because, by and large, when people think about stroke, they don't think about it," Biller said. "There should be an increasing level of awareness because this is a condition that has a specific treatment."The study was published online Aug. 26 in the journal Neurology.Copyright © 2020 HealthDay. All rights reserved.

SLIDESHOW Stroke Causes, Symptoms, and Recovery See Slideshow References SOURCES. Fadar Oliver Otite, MD, assistant professor, neurology, State University of New York (SUNY) Upstate Medical University, Syracuse, N.Y.. Jose Biller, MD, chair, department of neurology, Loyola University Medical Center, Hines, Ill.. Neurology, Aug. 26, 2020, onlineLatest Hearing News WEDNESDAY, Aug.

26, 2020 (HealthDay News)Even if they appear unresponsive, dying people may still be able to hear.That's the takeaway from a Canadian analysis of hospice patients in Vancouver.Researchers compared electroencephalography (EEG) data -- a measure of electrical activity in the brain -- collected when patients were conscious and when they became unresponsive at the end of life. Those patients were compared to a healthy control group.The study looked at brain response to various patterns of common and rare sounds that changed frequency, and found that responses of some of the dying patients were similar to those of healthy people -- even hours before death."In the last hours before an expected natural death, many people enter a period of unresponsiveness," said lead author Elizabeth Blundon, a doctoral student in psychology at the University of British Columbia at the time of the study."Our data shows that a dying brain can respond to sound, even in an unconscious state, up to the last hours of life," she said in a university news release.Co-author Lawrence Ward, a professor of psychology, said researchers were able to identify specific mental processes in both groups of participants."We had to look very carefully at the individual control participants' data, to see if each one of them showed a particular type of brain response before we felt confident that the unresponsive patient's brain reacted similarly," he said in the release.The findings were recently published in the journal Scientific Reports."This research gives credence to the fact that hospice nurses and physicians noticed that the sounds of loved ones helped comfort people when they were dying," said study co-author Dr. Romayne Gallagher, a now-retired palliative care physician at St. John Hospice in Vancouver."And to me, it adds significant meaning to the last days and hours of life and shows that being present, in person or by phone, is meaningful," she said. "It is a comfort to be able to say goodbye and express love."While the evidence of brain activity supports the idea that dying people might hear, it's not known if they're aware of what they're hearing, Blundon noted."Their brains responded to the auditory stimuli, but we can't possibly know if they're remembering, identifying voices, or understanding language," she said.

"There are all these other questions that have yet to be answered. This first glimpse supports the idea that we have to keep talking to people when they are dying because something is happening in their brain."-- Robert PreidtCopyright © 2020 HealthDay. All rights reserved. QUESTION What is hearing loss?. See Answer References SOURCE.

University of British Columbia, news release, July 8, 2020.

Over the counter viagra substitute walgreens

AbstractIntroduction viagra prices costco over the counter viagra substitute walgreens. 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 over the counter viagra substitute walgreens 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 over the counter viagra substitute walgreens 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 over the counter viagra substitute walgreens 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 over the counter viagra substitute walgreens 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 over the counter viagra substitute walgreens 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 over the counter viagra substitute walgreens craniofacial and limb involvement, such as. Acrocallosal syndrome5 (OMIM. 200990), Greig over the counter viagra substitute walgreens 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. 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)..