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A 43-year-old man admitted to drinking, doing drugs, kamagra for sale online driving, crashing through a Hudson Valley storefront, and pinning a mother and her infant under his vehicle, the District Attorney announced.Yonkers resident David Poncurak pleaded guilty to multiple charges after striking a mother and child with his car after crashing through the front window of an area barbershop earlier this year. Specifically, Poncurak pleaded guilty kamagra for sale online to. Aggravated vehicular assault;Driving while intoxicated;Driving while ability impaired by the combined influence of drugs or alcohol;Aggravated unlicensed operation of a motor vehicle.Westchester County District Attorney Mimi Rocah said that at approximately 8:30 a.m. On Friday, July 23, Poncurak was driving northbound in Yonkers north on Morningside Avenue when he turned West on to kamagra for sale online Lake Avenue, lost control, hopped the curb, and drove through the front of a nearby barbershop.The crash pinned both the mother and infant under the vehicle.

Rocah said that members of the Yonkers Police Department, with the help of bystanders, immediately lifted the car off the victims, who both were injured.Police said that the woman suffered serious injuries to her femur, and the baby suffered a fractured skull and third-degree burns to her back and foot. Both were taken to a nearby hospital for treatment and survived the injuries.The owner of the barbershop also suffered a minor injury.Rocah noted that at kamagra for sale online the time of the crash, Poncurak had a blood alcohol concentration above the legal limit and illegal narcotics in his system.âDavid Poncurakâs decision to drive under the influence of alcohol and drugs put a mother and her infant child at severe risk,â Rocah said. ÂI applaud the extraordinary work of the Yonkers kamagra for sale online Police Department, the bystanders, and the ambulance crew who sprang into action to assist during this harrowing event. These victims are alive today because of the heroic efforts of these brave individuals.âWhen he is sentenced on Jan.

13, 2022, kamagra for sale online Poncurak faces between five and 15 years in state prison. Click here to sign up for Daily Voice's free daily emails and news alerts..

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To date, the federal Can i get renova over the counter government has taken several steps to address the health and economic consequences of the erectile dysfunction treatment kamagra, including sending billions of dollars to hospitals and other providers, providing economic stimulus payments to a majority of Americans, cheap kamagra pills uk and requiring public and private insurers to provide free coverage of erectile dysfunction testing. But the cheap kamagra pills uk kamagra has exposed long-standing gaps in the U.S. Health care system and brought fresh reminders of the health care affordability challenges facing many people, with and without insurance, including people with Medicare.Medicare provides significant health and financial protections to more than 60 million Americans, but there are gaps in coverage and high cost-sharing requirements that can make health care difficult to afford, particularly for beneficiaries with modest incomes who lack supplemental coverage, such as employer-sponsored retiree health coverage, Medigap, or Medicaid. Beneficiaries are responsible for Medicareâs premiums, deductibles and other cost-sharing requirements, unless they have supplemental coverage or have incomes and assets low enough to qualify for the Medicare Savings Programs, which help cover Medicare Part A and Part B out-of-pocket cheap kamagra pills uk costs, or the Medicare Part D low-income subsidy (LIS) program, which helps with Part D premiums and cost sharing only.Beneficiaries in traditional Medicare with no supplemental coverage are vulnerable to high out-of-pocket expenses because Medicare, unlike marketplace and large employer plans, has no cap on out-of-pocket spending for covered services. But even those with supplemental coverage can face affordability challenges.

Although Medicare Advantage plans are required to provide an annual out-of-pocket limit, beneficiaries enrolled in Medicare Advantage plans could still face high out-of-pocket costs, cheap kamagra pills uk depending on the services they use, the drugs they take, and costs charged by their specific plan. And although beneficiaries with Medigap supplemental coverage have help with cost-sharing requirements for Medicare-covered services and protection against catastrophic expenses, premiums for these policies can be costly. With half of all Medicare cheap kamagra pills uk beneficiaries living on an income of less than $30,000 per person, these affordability concerns could be compounded for some by the economic recession caused by the erectile dysfunction treatment kamagra.This report analyzes several policy options that could help make health care more affordable for people covered by Medicare. For each of the options, we discuss implications and tradeoffs, including the added cost to the federal government of providing additional protection for beneficiaries. This report focuses on options to improve affordability of current Medicare benefits, rather than options that would cheap kamagra pills uk expand the benefits Medicare covers, such as adding coverage of dental, vision, or hearing services.

See Methodology for detail on data sources and methods.Key TakeawaysThe policy options examined in this analysis to help make health care more affordable for people covered by Medicare vary in the number of beneficiaries who could be helped and how much help they could receive (Figure 1). Each option would also have cost implications for cheap kamagra pills uk Medicare and/or other payers, as described more fully in the longer discussion of each option following the introduction.Figure 1. Various Policy Options to Make Medicare More Affordable Could Help Between 0.4 Million and 12.3 Million Medicare Beneficiaries in a Given YearAdding an annual out-of-pocket spending limit to traditional Medicare for Medicare Part A and B cost-sharing requirements would limit the risk of incurring high and potentially unaffordable expenses for nearly six million beneficiaries in traditional Medicare who have no supplemental coverage. The number of beneficiaries likely to be helped in any given year, and the average savings per beneficiary reaching the limit, would vary cheap kamagra pills uk based on the amount of the out-of-pocket limit and what counts toward the limit. For example, adding a $6,700 out-of-pocket limit to Medicare Parts A and B would help 0.9 million beneficiaries in 2021, reducing their out-of-pocket costs for Medicare-covered services by approximately $2,700, on average, while adding an income-related limit would help 1.7 million beneficiaries, with average savings of nearly $2,200 in 2021.

Adding an out-of-pocket limit would help people on Medicare with cheap kamagra pills uk complex care needs, such as those who require one or more inpatient stays followed by a lengthy stay in a skilled nursing facility, or those who need high-cost medications that are covered under Medicare Part B. Adding an out-of-pocket limit to traditional Medicare would also lower Medigap premiums and premiums for employer or union-sponsored retiree health benefits for Medicare-eligible retirees, because the new out-of-pocket limit in traditional Medicare would reduce the amount of claims to be paid by these payers, while at the same time increasing Medicare Part B premiums, as Medicare assumes these costs above the limit.Adding a hard cap on out-of-pocket prescription drug spending to the Part D benefit would eliminate potential exposure to high drug costs for nearly 39 million beneficiaries currently enrolled in Part D plans who are not receiving low-income subsidies. Had the cheap kamagra pills uk Part D benefit included a cap in 2017, with no other changes in benefit design, it would have lowered out-of-pocket drug spending for approximately 1 million Part D enrollees with high drug costs, with average savings of approximately $1,400 per enrollee that year.Expanding eligibility under the Medicare Savings Programs would help more low- and modest-income beneficiaries with Medicare premiums and cost-sharing requirements, with the number helped and the amount of assistance varying depending on the option. For example, expanding financial assistance under the Medicare Savings Programs by covering cost sharing for people currently receiving Part B premium assistance only would lower out-of-pocket costs for 1.5 million Medicare beneficiaries, with estimated average savings of $1,500 in 2020. Raising eligibility cheap kamagra pills uk for the Medicare Savings Programs up to 150% or 200% of poverty and eliminating the asset test could help 7 million beneficiaries in total (expanding eligibility up to 150%) or 12.3 million beneficiaries (expanding eligibility up to 200%).

Among these newly-eligible beneficiaries, estimated cheap kamagra pills uk average savings would be $3,235 in 2020 for those who qualified for assistance with both premiums and cost sharing. For beneficiaries with incomes at 150% of poverty in 2020 ($19,140), this total savings represents 17% of their incomes. The group of beneficiaries who are helped under an approach that expanded eligibility up to 200% FPL with no asset test includes an estimated 3.9 cheap kamagra pills uk million beneficiaries in communities of color, including 1.2 million Black beneficiaries, 1.9 million Hispanic beneficiaries, and 0.7 million beneficiaries in other racial and ethnic groups.Expanding eligibility under the Part D Low-Income Subsidy program would help more low and modest income beneficiaries with their Part D prescription drug plan premiums and cost-sharing requirements, with the number helped and the amount of assistance varying depending on the option. For example, providing full Part D low-income subsidies to beneficiaries who would otherwise be eligible for partial subsidies would lower prescription drug-related costs for 0.4 million Medicare beneficiaries, with estimated saving ranging from $270 to $560 in 2020, depending on the level of help they are eligible for under current law. Raising eligibility cheap kamagra pills uk for Part D premium and cost-sharing subsidies from 150% FPL to 200% FPL, and eliminating the asset test would lower prescription drug-related costs for 9.6 million Medicare beneficiaries.

Part D enrollees who are not currently eligible for premium or cost-sharing assistance would see estimated savings of $850 in 2020 on their Part D prescription drug cost sharing and premiums, on average, if they qualified for full LIS benefits.As noted above, each of these options would also have cost implications for Medicare that would vary depending upon specific policy features. In addition, some of these options would cheap kamagra pills uk have spillover effects for other payers (Medicaid, employers and unions). These effects are discussed more fully below.President-elect Joe Biden campaigned on supporting and building upon the Affordable Care Act (ACA), better managing the erectile dysfunction kamagra and lowering prescription drug costs. However, with the political balance of the Senate uncertain, some Biden proposals, like creating a new cheap kamagra pills uk public option and lowering the Medicare age to 60, are less likely to be enacted. Even so, as president, Biden could exercise executive branch authority to move forward on a variety of policy changes he has advocated through administrative action without Congress.The table below includes potential administrative actions under the incoming Biden Administration, based on campaign pledges, and actions that would reverse or modify controversial regulations or guidance issued by the Trump Administration.

The table also describes actions Biden could take as president that have cheap kamagra pills uk received a great deal of attention from other prominent Democrats or are generally consistent with his campaign proposals, and that may therefore be priorities in Bidenâs Administration. This table is not an exhaustive list of possible Biden Administration actions and does not include potential administrative actions pertaining to all health policy areas, including Medicare and prescription drug costs, where there is no clear indication of whether or how the Biden Administration would modify Trump Administration policies. If Bidenâs health proposals are stymied by a divided Congress, he may look to use administrative actions beyond whatâs detailed here to cheap kamagra pills uk advance his health care agenda.In this table, we note whether executive actions require regulatory change, as an indication of how much time it may take the Biden Administration to implement these changes. For some regulatory changes, the Biden Administration will need to issue a new Notice of Proposed Rule Making (NPRM) and allow a public comment period before revising the regulation. Rules made through annual payment notices, such as the Notice of Benefit and Payment Parameters (NBPP) may be revised annually.By contrast, the Biden Administration may more quickly be able to cheap kamagra pills uk reverse Trump Administration regulations that are proposed but not yet final as well as policies made through sub-regulatory agency guidance or executive order.

Some sub-regulatory actions, such as renewing the erectile dysfunction treatment Public Health Emergency Declaration that is currently set to expire on Inauguration Day, will require attention on Bidenâs first day in office. Biden would also likely rescind pending rules that would sunset HHS regulations if not reviewed every 10 years (which could increase administrative cheap kamagra pills uk burden for the agency and result in regulations with beneficiary protections expiring). Issue Brief.

To date, the federal government has taken several steps to address the health Can i get renova over the counter and economic consequences of the erectile dysfunction treatment kamagra, including sending billions of dollars to hospitals and other providers, providing economic stimulus payments to a majority of Americans, and requiring public and private insurers kamagra for sale online to provide free coverage of erectile dysfunction testing. But the kamagra has kamagra for sale online exposed long-standing gaps in the U.S. Health care system and brought fresh reminders of the health care affordability challenges facing many people, with and without insurance, including people with Medicare.Medicare provides significant health and financial protections to more than 60 million Americans, but there are gaps in coverage and high cost-sharing requirements that can make health care difficult to afford, particularly for beneficiaries with modest incomes who lack supplemental coverage, such as employer-sponsored retiree health coverage, Medigap, or Medicaid. Beneficiaries are responsible for Medicareâs premiums, deductibles and other cost-sharing requirements, unless they have supplemental coverage or have incomes and assets low enough to qualify for the Medicare Savings Programs, which help cover Medicare Part A and Part B out-of-pocket costs, or the Medicare Part D low-income subsidy (LIS) program, which helps kamagra for sale online with Part D premiums and cost sharing only.Beneficiaries in traditional Medicare with no supplemental coverage are vulnerable to high out-of-pocket expenses because Medicare, unlike marketplace and large employer plans, has no cap on out-of-pocket spending for covered services.

But even those with supplemental coverage can face affordability challenges. Although Medicare Advantage plans are required to provide an annual out-of-pocket limit, beneficiaries enrolled in Medicare Advantage plans could still face kamagra for sale online high out-of-pocket costs, depending on the services they use, the drugs they take, and costs charged by their specific plan. And although beneficiaries with Medigap supplemental coverage have help with cost-sharing requirements for Medicare-covered services and protection against catastrophic expenses, premiums for these policies can be costly. With half of all Medicare beneficiaries living on an income of less than $30,000 per person, these affordability concerns could be kamagra for sale online compounded for some by the economic recession caused by the erectile dysfunction treatment kamagra.This report analyzes several policy options that could help make health care more affordable for people covered by Medicare.

For each of the options, we discuss implications and tradeoffs, including the added cost to the federal government of providing additional protection for beneficiaries. This report focuses on options to improve kamagra for sale online affordability of current Medicare benefits, rather than options that would expand the benefits Medicare covers, such as adding coverage of dental, vision, or hearing services. See Methodology for detail on data sources and methods.Key TakeawaysThe policy options examined in this analysis to help make health care more affordable for people covered by Medicare vary in the number of beneficiaries who could be helped and how much help they could receive (Figure 1). Each option would also have cost implications for Medicare and/or other payers, as described more fully in the kamagra for sale online longer discussion of each option following the introduction.Figure 1.

Various Policy Options to Make Medicare More Affordable Could Help Between 0.4 Million and 12.3 Million Medicare Beneficiaries in a Given YearAdding an annual out-of-pocket spending limit to traditional Medicare for Medicare Part A and B cost-sharing requirements would limit the risk of incurring high and potentially unaffordable expenses for nearly six million beneficiaries in traditional Medicare who have no supplemental coverage. The number of beneficiaries likely to be helped in any given year, and the average savings per beneficiary reaching the limit, would vary based on the amount of the out-of-pocket kamagra for sale online limit and what counts toward the limit. For example, adding a $6,700 out-of-pocket limit to Medicare Parts A and B would help 0.9 million beneficiaries in 2021, reducing their out-of-pocket costs for Medicare-covered services by approximately $2,700, on average, while adding an income-related limit would help 1.7 million beneficiaries, with average savings of nearly $2,200 in 2021. Adding an out-of-pocket limit would help people on Medicare with complex care needs, such as those who require one kamagra for sale online or more inpatient stays followed by a lengthy stay in a skilled nursing facility, or those who need high-cost medications that are covered under Medicare Part B.

Adding an out-of-pocket limit to traditional Medicare would also lower Medigap premiums and premiums for employer or union-sponsored retiree health benefits for Medicare-eligible retirees, because the new out-of-pocket limit in traditional Medicare would reduce the amount of claims to be paid by these payers, while at the same time increasing Medicare Part B premiums, as Medicare assumes these costs above the limit.Adding a hard cap on out-of-pocket prescription drug spending to the Part D benefit would eliminate potential exposure to high drug costs for nearly 39 million beneficiaries currently enrolled in Part D plans who are not receiving low-income subsidies. Had the Part D benefit included a cap in 2017, with no other changes in benefit design, it would kamagra for sale online have lowered out-of-pocket drug spending for approximately 1 million Part D enrollees with high drug costs, with average savings of approximately $1,400 per enrollee that year.Expanding eligibility under the Medicare Savings Programs would help more low- and modest-income beneficiaries with Medicare premiums and cost-sharing requirements, with the number helped and the amount of assistance varying depending on the option. For example, expanding financial assistance under the Medicare Savings Programs by covering cost sharing for people currently receiving Part B premium assistance only would lower out-of-pocket costs for 1.5 million Medicare beneficiaries, with estimated average savings of $1,500 in 2020. Raising eligibility for the Medicare Savings Programs up to 150% or 200% of poverty and eliminating the asset test could help 7 million beneficiaries in total (expanding eligibility kamagra for sale online up to 150%) or 12.3 million beneficiaries (expanding eligibility up to 200%).

Among these newly-eligible beneficiaries, estimated average savings kamagra for sale online would be $3,235 in 2020 for those who qualified for assistance with both premiums and cost sharing. For beneficiaries with incomes at 150% of poverty in 2020 ($19,140), this total savings represents 17% of their incomes. The group of beneficiaries who are helped under an approach that expanded eligibility up to 200% FPL with no asset test includes an estimated 3.9 million beneficiaries in communities of color, including 1.2 million Black beneficiaries, 1.9 million Hispanic kamagra for sale online beneficiaries, and 0.7 million beneficiaries in other racial and ethnic groups.Expanding eligibility under the Part D Low-Income Subsidy program would help more low and modest income beneficiaries with their Part D prescription drug plan premiums and cost-sharing requirements, with the number helped and the amount of assistance varying depending on the option. For example, providing full Part D low-income subsidies to beneficiaries who would otherwise be eligible for partial subsidies would lower prescription drug-related costs for 0.4 million Medicare beneficiaries, with estimated saving ranging from $270 to $560 in 2020, depending on the level of help they are eligible for under current law.

Raising eligibility for Part D premium and cost-sharing subsidies from 150% FPL to 200% FPL, and eliminating the asset test would lower prescription drug-related costs for kamagra for sale online 9.6 million Medicare beneficiaries. Part D enrollees who are not currently eligible for premium or cost-sharing assistance would see estimated savings of $850 in 2020 on their Part D prescription drug cost sharing and premiums, on average, if they qualified for full LIS benefits.As noted above, each of these options would also have cost implications for Medicare that would vary depending upon specific policy features. In addition, some of these options would have spillover kamagra for sale online effects for other payers (Medicaid, employers and unions). These effects are discussed more fully below.President-elect Joe Biden campaigned on supporting and building upon the Affordable Care Act (ACA), better managing the erectile dysfunction kamagra and lowering prescription drug costs.

However, with the political balance of the Senate uncertain, some Biden proposals, like creating a new public option kamagra for sale online and lowering the Medicare age to 60, are less likely to be enacted. Even so, as president, Biden could exercise executive branch authority to move forward on a variety of policy changes he has advocated through administrative action without Congress.The table below includes potential administrative actions under the incoming Biden Administration, based on campaign pledges, and actions that would reverse or modify controversial regulations or guidance issued by the Trump Administration. The table also describes actions Biden could take as president that have received a great deal of attention from other prominent Democrats or are generally consistent with his kamagra for sale online campaign proposals, and that may therefore be priorities in Bidenâs Administration. This table is not an exhaustive list of possible Biden Administration actions and does not include potential administrative actions pertaining to all health policy areas, including Medicare and prescription drug costs, where there is no clear indication of whether or how the Biden Administration would modify Trump Administration policies.

If Bidenâs health proposals are stymied by a divided Congress, he may look to use administrative actions beyond whatâs detailed here kamagra for sale online to advance his health care agenda.In this table, we note whether executive actions require regulatory change, as an indication of how much time it may take the Biden Administration to implement these changes. For some regulatory changes, the Biden Administration will need to issue a new Notice of Proposed Rule Making (NPRM) and allow a public comment period before revising the regulation. Rules made through annual payment notices, such as the Notice of Benefit and Payment Parameters (NBPP) may be revised annually.By contrast, the Biden Administration may more quickly be able to reverse Trump Administration kamagra for sale online regulations that are proposed but not yet final as well as policies made through sub-regulatory agency guidance or executive order. Some sub-regulatory actions, such as renewing the erectile dysfunction treatment Public Health Emergency Declaration that is currently set to expire on Inauguration Day, will require attention on Bidenâs first day in office.

Biden would also likely rescind pending rules that would sunset HHS regulations if not reviewed every 10 years (which could increase administrative burden for the agency and result in regulations with kamagra for sale online beneficiary protections expiring). Issue Brief.

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AbstractIntroduction Full Article how to buy kamagra in usa. 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 how to buy kamagra in usa 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 how to buy kamagra in usa relatives.

Her sister and maternal aunt also had gastric cancer. She was tested for several how to buy kamagra in usa 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 how to buy kamagra in usa for genetic counselling and management of at-risk individuals.cancer. Breastcancer.

Gastricclinical geneticsgenetic screening/counsellingmolecular geneticsIntroductionGLI-Kruppel family how to buy kamagra in usa 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 how to buy kamagra in usa syndromes with craniofacial and limb involvement, such as. Acrocallosal syndrome5 (OMIM. 200990), Greig cephalopolysyndactyly how to buy kamagra in usa 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.10â12 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.10â12 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 PPD4.10â12 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 Childrenâs 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 22â24 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 (Ï2, 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 Ï2 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,10â12 16 21 26â43 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 http://alohafromoahu.com/39/ 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<0001âand 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. Â0.797, p=0123âand â1.772, 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 âtrueâ 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-Î±4-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 5â² 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 GLI3â699/- mouse model (hemizygous fixed repressor model) compared with the GLI3â699/â699 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 3â² 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-Î±4-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 http://www.re-lock.com/testimonials/ kamagra for sale online. We report a very rare case of familial breast cancer and diffuse gastric cancer, with germline pathogenic variants in both BRCA1 and CDH1 genes. To the best of kamagra for sale online 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 kamagra for sale online 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 kamagra for sale online 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 kamagra for sale online and management of at-risk individuals.cancer. Breastcancer. Gastricclinical geneticsgenetic kamagra for sale online 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 kamagra for sale online 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 kamagra for sale online (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).

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.10â12 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 PPD4.10â12 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 Childrenâs 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.

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 22â24 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.

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 (Ï2, 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 Ï2 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,10â12 16 21 26â43 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.

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<0001âand Beta.

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.

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-Î±4-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 5â² 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.

Krauss et al postulate an alternative hypothesis, they state that the MID1-Î±4-PP2A complex, which is essential for GLI3A signalling, could also be the reason for overlapping features of Opitz syndrome, caused by variants in MID1, and Pallister-Hall syndrome. Further analysis is required to fully appreciate the functional differences between truncating mutations that cause Pallister-Hall syndrome and those that result in GLI3-mediated polydactyly syndromes.For the clinical evaluation of patients with GLI3-mediated polydactyly syndromes, intracranial anomalies are likely the most important to predict based on the variant. Unfortunately, the presence of corpus callosum agenesis was not routinely investigated or reported thus this feature could not be used as an indicator phenotype for LC membership. Interestingly when using only hand and foot phenotypes, we did notice a higher prevalence of corpus callosum agenesis in patients with posterior phenotypes.

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

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

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

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End Further Info End Preamble Start Supplemental Information The Public Readiness and Emergency Preparedness Act (PREP Act) authorizes Start Printed Page 51161the Secretary of Health and Human Services (the Secretary) to issue a Declaration to provide liability immunity to certain individuals and entities (Covered Persons) against what is kamagra tablets any claim of loss caused by, arising out of, relating to, or resulting from the manufacture, distribution, administration, or use of medical countermeasures (Covered Countermeasures), except for claims involving âwillful misconductâ as defined in the PREP Act. Under the PREP Act, a Declaration may be amended as circumstances warrant. The PREP Act was enacted on December 30, 2005, as Public Law 109-148, Division C, Â§â2. It amended the Public Health Service (PHS) Act, adding section 319F-3, which addresses liability immunity, and section 319F-4, what is kamagra tablets which creates a compensation program. These sections are codified at 42 U.S.C.

247d-6d and 42 U.S.C. 247d-6e, respectively what is kamagra tablets. Section 319F-3 of the PHS Act has been amended by the kamagra and All-Hazards Preparedness Reauthorization Act (PAHPRA), Public Law 113-5, enacted on March 13, 2013, and the erectile dysfunction Aid, Relief, and Economic Security (CARES) Act, Public Law 116-136, enacted on March 27, 2020, to expand Covered Countermeasures under the PREP Act. On January 31, 2020, the former Secretary, Alex M. Azar II, what is kamagra tablets declared a public health emergency pursuant to section 319 of the PHS Act, 42 U.S.C.

247d, effective January 27, 2020, for the entire United States to aid in the response of the nation's health care community to the erectile dysfunction treatment outbreak. Pursuant to section 319 of the PHS Act, the Secretary renewed that declaration effective on April 26, 2020, July 25, 2020, October 23, 2020, January 21, 2021, April 21, 2021 and July 20, 2021. On March 10, 2020, former Secretary Azar issued a Declaration under the PREP Act for what is kamagra tablets medical countermeasures against erectile dysfunction treatment (85 FR 15198, Mar. 17, 2020) (the Declaration). On April 10, the former Secretary amended the Declaration under the PREP Act to extend liability immunity to covered countermeasures authorized under the CARES Act (85 FR 21012, Apr.

15, 2020) what is kamagra tablets. On June 4, the former Secretary amended the Declaration to clarify that covered countermeasures under the Declaration include qualified countermeasures that limit the harm erectile dysfunction treatment might otherwise cause. (85 FR 35100, June 8, 2020). On August 19, the former Secretary amended the what is kamagra tablets declaration to add additional categories of Qualified Persons and amend the category of disease, health condition, or threat for which he recommended the administration or use of the Covered Countermeasures. (85 FR 52136, Aug.

24, 2020). On December 3, 2020, the former Secretary amended the declaration to incorporate Advisory Opinions of the General Counsel interpreting the PREP Act and the Secretary's Declaration and authorizations what is kamagra tablets issued by the Department's Office of the Assistant Secretary for Health as an Authority Having Jurisdiction to respond. Added an additional category of qualified persons under Section V of the Declaration. Made explicit that the Declaration covers all qualified kamagra and epidemic products as defined under the PREP Act. Added a third method of distribution to provide liability protections what is kamagra tablets for, among other things, private distribution channels.

Made explicit that there can be situations where not administering a covered countermeasure to a particular individual can fall within the PREP Act and the Declaration's liability protections. Made explicit that there are substantive federal legal and policy issues and interests in having a unified whole-of-nation response to the erectile dysfunction treatment kamagra among federal, state, local, and private-sector entities. Revised the effective what is kamagra tablets time period of the Declaration. And republished the declaration in full. (85 FR 79190, Dec.

9, 2020) what is kamagra tablets. On February 2, 2021, the Acting Secretary Norris Cochran amended the Declaration to add additional categories of Qualified Persons authorized to prescribe, dispense, and administer erectile dysfunction treatments that are covered countermeasures under the Declaration (86 FR 7872, Feb. 2, 2021). On February 16, 2021, the Acting Secretary amended the Declaration to add additional categories of Qualified Persons authorized to prescribe, dispense, and administer erectile dysfunction treatments that what is kamagra tablets are covered countermeasures under the Declaration (86 FR 9516, Feb. 16, 2021) and on February 22, 2021, the Department filed a notice of correction to the February 2 and February 16 notices correcting effective dates stated in the Declaration, and correcting the description of qualified persons added by the February 16, 2021 amendment.

(86 FR 10588, Feb. 22, 2021) what is kamagra tablets. On March 11, 2021, the Acting Secretary amended the Declaration to add additional Qualified Persons authorized to prescribe, dispense, and administer covered countermeasures under the Declaration. (86 FR 14462, Mar. 16, 2021) what is kamagra tablets.

On August 4, 2021, Secretary Xavier Becerra amended the Declaration to clarify categories of Qualified Persons and to expand the scope of authority for certain Qualified Persons to administer seasonal influenza treatments to adults. (86 FR 41977, Aug. 4, 2021) what is kamagra tablets. Secretary Xavier Becerra now amends section V of the Declaration to add subsection (i) to expand the scope of authority for licensed pharmacists to order and administer and qualified pharmacy technicians and pharmacy interns to administer erectile dysfunction treatment therapeutics subcutaneously, intramuscularly, or orally as authorized, approved, or licensed by the U.S. Food and Drug Administration (FDA).

Accordingly, subsection V(i) authorizes what is kamagra tablets. (i) A State-licensed pharmacist who orders and administers, and pharmacy interns and qualified pharmacy technicians who administer (if the pharmacy intern or technician acts under the supervision of such pharmacist and the pharmacy intern or technician is licensed or registered by his or her State board of pharmacy)â[] FDA authorized, approved, or licensed erectile dysfunction treatment therapeutics. Such State-licensed pharmacists and the State-licensed or registered interns or technicians under their supervision are qualified persons only if the following requirements are met. I. The erectile dysfunction treatment therapeutic must be authorized, approved, or licensed by the FDA.

Ii. In the case of a licensed pharmacist ordering a erectile dysfunction treatment therapeutic, the therapeutic must be ordered for subcutaneous, intramuscular, or oral administration and in accordance with the FDA approval, authorization, or licensing;Start Printed Page 51162 iii. In the case of licensed pharmacists, qualified pharmacy technicians, and licensed or registered pharmacy interns administering the erectile dysfunction treatment therapeutic, the therapeutic must be administered subcutaneously, intramuscularly, or orally in accordance with the FDA approval, authorization, or licensing. Iv. In the case of qualified pharmacy technicians, the supervising pharmacist must be readily and immediately available to the qualified pharmacy technician.

V. In the case of erectile dysfunction treatment therapeutics administered through intramuscular or subcutaneous injections, the licensed pharmacist, licensed or registered pharmacy intern and qualified pharmacy technician must complete a practical training program that is approved by the Accreditation Council for Pharmacy Education (ACPE). This training program must include hands-on injection technique, clinical evaluation of indications and contraindications of erectile dysfunction treatment therapeutics, the recognition and treatment of emergency reactions to erectile dysfunction treatment therapeutics, and any additional training required in the FDA approval, authorization, or licensing. Vi. The licensed pharmacist, licensed or registered pharmacy intern and qualified pharmacy technician must have a current certificate in basic cardiopulmonary resuscitation;â[] vii.

The licensed pharmacist must comply with recordkeeping and reporting requirements of the jurisdiction in which he or she administers erectile dysfunction treatment therapeutics, including informing the patient's primary-care provider when available and complying with requirements with respect to reporting adverse events. Viii. The licensed pharmacist, the licensed or registered pharmacy intern and the qualified pharmacy technician must comply with any applicable requirements (or conditions of use) that apply to the administration of erectile dysfunction treatment therapeutics. Description of This Amendment by Section Section V. Covered Persons Under the PREP Act and the Declaration, a âqualified personâ is a âcovered person.â Subject to certain limitations, a covered person is immune from suit and liability under Federal and State law with respect to all claims for loss caused by, arising out of, relating to, or resulting from the administration or use of a covered countermeasure if a declaration under the PREP Act has been issued with respect to such countermeasure.

ÂQualified personâ includes (A) a licensed health professional or other individual who is authorized to prescribe, administer, or dispense such countermeasures under the law of the State in which the countermeasure was prescribed, administered, or dispensed. Or (B) âa person within a category of persons so identified in a declaration by the Secretaryâ under subsection (b) of the PREP Act. 42 U.S.C. 247d-6d(i)(8). By this amendment to the Declaration, the Secretary clarifies and expands the authorization for a category of persons who are qualified persons under section 247d-6d(i)(8)(B).

First, the amendment clarifies that licensed pharmacists are authorized to order and administer and licensed or registered pharmacy interns and qualified pharmacy technicians are authorized to administer erectile dysfunction treatment therapeutics that are Covered Countermeasures under section VI of this Declaration. The Secretary anticipates that there will be a need to increase the available pool of providers able to order and administer erectile dysfunction treatment therapeutics to address rising erectile dysfunction treatment cases, to expand patient access to these critical therapies, and to keep as many patients out of the hospital as possible. Rising erectile dysfunction treatment cases, largely attributable to the Delta variant, is a public health threat caused by erectile dysfunction treatment, placing additional strains on our healthcare system. Pharmacists, pharmacy technicians, and pharmacy interns are well positioned to increase access to therapeutics and have played a critical role in this kamagra in overseeing erectile dysfunction treatment testing and treatment administration. Given their skill set and training, as well as looming provider shortages, pharmacists, pharmacy technicians, and pharmacy interns will quickly expand access to erectile dysfunction treatment therapeutics.

erectile dysfunction treatment therapeutics may be administered as intramuscular injections, subcutaneous injections, or orally and would require minimal, if any, additional training to administer beyond training pharmacists, pharmacy technicians, and pharmacy interns have already received for treatment administration, and would not place any undue training burden on providers. As qualified persons, these licensed pharmacists, qualified pharmacy technicians and interns will be afforded liability protections in accordance with the PREP Act and the terms of this amended Declaration. Second, to the extent that any State law that would otherwise prohibit these healthcare professionals who are a âqualified personâ from prescribing, dispensing, or administering erectile dysfunction treatment therapeutics or other Covered Countermeasures, such law is preempted. On May 19, 2020, the Office of the General Counsel issued an advisory opinion concluding that, because licensed pharmacists are âqualified personsâ under this declaration, the PREP Act preempts state law that would otherwise prohibit such pharmacists from ordering and administering authorized erectile dysfunction treatment diagnostic tests.[] The opinion relied in part on the fact that the Congressional delegation of authority to the Secretary under the PREP Act to specify a class of persons, beyond those who are authorized to administer a covered countermeasure under State law, as âqualified personsâ would be rendered a nullity in the absence of such preemption. This opinion is incorporated by reference into this declaration.

Based on the reasoning set forth in the May 19, 2020 advisory opinion, any State law that would otherwise prohibit a member of any of the classes of âqualified personsâ specified in this declaration from administering a covered countermeasure is likewise preempted. In accordance with section 319F-3(i)(8)(A) of the Public Health Service Act, a State remains free to expand the universe of individuals authorized to administer Start Printed Page 51163covered countermeasures within its jurisdiction under State law. The plain language of the PREP Act makes clear that there is preemption of state law as described above. Furthermore, preemption of State law is justified to respond to the nation-wide public health emergency caused by erectile dysfunction treatment as it will enable States to quickly expand the vaccination, treatment and prevention workforces with additional qualified healthcare professionals where State or local requirements might otherwise inhibit or delay allowing these healthcare professionals to participate in the erectile dysfunction treatment countermeasure program. Amendments to Declaration Amended Declaration for Public Readiness and Emergency Preparedness Act Coverage for medical countermeasures against erectile dysfunction treatment.

Section V of the March 10, 2020 Declaration under the PREP Act for medical countermeasures against erectile dysfunction treatment, as amended April 10, 2020, June 4, 2020, August 19, 2020, as amended and republished on December 3, 2020, as amended on February 2, 2021, as amended March 11, 2021, and as amended on August 4, 2021, is further amended pursuant to section 319F-3(b)(4) of the PHS Act as described below. All other sections of the Declaration remain in effect as republished at 85 FR 79190 (Dec. 9, 2020). 1. Covered Persons, section V, delete in full and replace with.

V. Covered Persons 42 U.S.C. 247d-6d(i)(2), (3), (4), (6), (8)(A) and (B) Covered Persons who are afforded liability immunity under this Declaration are âmanufacturers,â âdistributors,â âprogram planners,â âqualified persons,â and their officials, agents, and employees, as those terms are defined in the PREP Act, and the United States. ÂOrderâ as used herein and in guidance issued by the Office of the Assistant Secretary for Healthâ[] means a provider medication order, which includes prescribing of treatments, or a laboratory order, which includes prescribing laboratory orders, if required. In addition, I have determined that the following additional persons are qualified persons.

(a) Any person authorized in accordance with the public health and medical emergency response of the Authority Having Jurisdiction, as described in Section VII below, to prescribe, administer, deliver, distribute or dispense the Covered Countermeasures, and their officials, agents, employees, contractors and volunteers, following a Declaration of an Emergency, as that term is defined in Section VII of this Declaration;[] (b) Any person authorized to prescribe, administer, or dispense the Covered Countermeasures or who is otherwise authorized to perform an activity under an Emergency Use Authorization in accordance with Section 564 of the FD&C Act. (c) Any person authorized to prescribe, administer, or dispense Covered Countermeasures in accordance with Section 564A of the FD&C Act. (d) A State-licensed pharmacist who orders and administers, and pharmacy interns and qualified pharmacy technicians who administer (if the pharmacy intern or technician acts under the supervision of such pharmacist and the pharmacy intern or technician is licensed or registered by his or her State board of pharmacy),[] (1) treatments that the Advisory Committee on Immunization Practices (ACIP) recommends to persons ages three through 18 according to ACIP's standard immunization schedule or (2) seasonal influenza treatment administered by qualified pharmacy technicians and interns that the ACIP recommends to persons aged 19 and older according to ACIP's standard immunization schedule. Or (3) FDA authorized or FDA licensed erectile dysfunction treatments to persons ages three or older. Such State-licensed pharmacists and the State-licensed or registered interns or technicians under their supervision are qualified persons only if the following requirements are met.

I. The treatment must be authorized, approved, or licensed by the FDA. Ii. In the case of a erectile dysfunction treatment, the vaccination must be ordered and administered according to ACIP's erectile dysfunction treatment recommendation(s). Iii.

In the case of a childhood treatment, the vaccination must be ordered and administered according to ACIP's standard immunization schedule. Iv. In the case of seasonal influenza treatment administered by qualified pharmacy technicians and interns, the vaccination must be ordered and administered according to ACIP's standard immunization schedule. V. In the case of pharmacy technicians, the supervising pharmacist must be readily and immediately available to the immunizing qualified pharmacy technician.

Vi. The licensed pharmacist must have completed the immunization Start Printed Page 51164training that the licensing State requires for pharmacists to order and administer treatments. If the State does not specify training requirements for the licensed pharmacist to order and administer treatments, the licensed pharmacist must complete a vaccination training program of at least 20 hours that is approved by the ACPE to order and administer treatments. Such a training program must include hands on injection technique, clinical evaluation of indications and contraindications of treatments, and the recognition and treatment of emergency reactions to treatments. Vii.

The licensed or registered pharmacy intern and qualified pharmacy technician must complete a practical training program that is approved by the ACPE. This training program must include hands-on injection technique, clinical evaluation of indications and contraindications of treatments, and the recognition and treatment of emergency reactions to treatments. Viii. The licensed pharmacist, licensed or registered pharmacy intern and qualified pharmacy technician must have a current certificate in basic cardiopulmonary resuscitation;â[] ix. The licensed pharmacist must complete a minimum of two hours of ACPE-approved, immunization-related continuing pharmacy education during each State licensing period.

X. The licensed pharmacist must comply with recordkeeping and reporting requirements of the jurisdiction in which he or she administers treatments, including informing the patient's primary-care provider when available, submitting the required immunization information to the State or local immunization information system (treatment registry), complying with requirements with respect to reporting adverse events, and complying with requirements whereby the person administering a treatment must review the treatment registry or other vaccination records prior to administering a treatment. Xi. The licensed pharmacist must inform his or her childhood-vaccination patients and the adult caregiver accompanying the child of the importance of a well-child visit with a pediatrician or other licensed primary care provider and refer patients as appropriate. And xii.

The licensed pharmacist, the licensed or registered pharmacy intern and the qualified pharmacy technician must comply with any applicable requirements (or conditions of use) as set forth in the Centers for Disease Control and Prevention (CDC) erectile dysfunction treatment vaccination provider agreement and any other federal requirements that apply to the administration of erectile dysfunction treatment- 19 treatment(s). (e) Healthcare personnel using telehealth to order or administer Covered Countermeasures for patients in a state other than the state where the healthcare personnel are licensed or otherwise permitted to practice. When ordering and administering Covered Countermeasures by means of telehealth to patients in a state where the healthcare personnel are not already permitted to practice, the healthcare personnel must comply with all requirements for ordering and administering Covered Countermeasures to patients by means of telehealth in the state where the healthcare personnel are permitted to practice. Any state law that prohibits or effectively prohibits such a qualified person from ordering and administering Covered Countermeasures by means of telehealth is preempted.[] Nothing in this Declaration shall preempt state laws that permit additional persons to deliver telehealth services. (f) Any healthcare professional or other individual who holds an active license or certification permitting the person to prescribe, dispense, or administer treatments under the law of any State as of the effective date of this amendment, or a pharmacist or pharmacy intern as authorized under the section V(d) of this Declaration, who prescribes, dispenses, or administers erectile dysfunction treatments that are Covered Countermeasures under section VI of this Declaration in any jurisdiction where the PREP Act applies, other than the State in which the license or certification is held, in association with a erectile dysfunction treatment vaccination effort by a federal, State, local Tribal or territorial authority or by an institution in the State in which the erectile dysfunction treatment covered countermeasure is administered, so long as the license or certification of the healthcare professional has not been suspended or restricted by any licensing authority, surrendered while under suspension, discipline or investigation by a licensing authority or surrendered following an arrest, and the individual is not on the List of Excluded Individuals/Entities maintained by the Office of Inspector General, subject to.

(i) Documentation of completion of the Centers for Disease Control and Prevention erectile dysfunction treatment (CDC) treatment Training Modulesâ[] and, for healthcare providers who are not currently practicing, documentation of an observation period by a currently practicing healthcare professional experienced in administering intramuscular injections, and for whom administering intramuscular injections is in their ordinary scope of practice, who confirms competency of the healthcare provider in preparation and administration of the erectile dysfunction treatment(s) to be administered. (g) Any member of a uniformed service (including members of the National Guard in a Title 32 duty status) (hereafter in this paragraph âservice memberâ) or Federal government, employee, contractor, or volunteer who prescribes, administers, delivers, distributes or dispenses a Covered Countermeasure. Such Federal government service members, employees, contractors, or volunteers are qualified persons if the following requirement is met. The executive department or agency by or for which the Federal service member, employee, contractor, or volunteer is employed, contracts, or volunteers has authorized or could authorize that service member, employee, contractor, or volunteer to prescribe, administer, deliver, distribute, or dispense the Covered Countermeasure as any part of the duties or responsibilities of that service member, employee, contractor, or volunteer, even if those authorized duties or responsibilities ordinarily would not extend to members of the public or otherwise would be more limited in scope than the activities such service member, employees, contractors, Start Printed Page 51165or volunteers are authorized to carry out under this declaration. And (h) The following healthcare professionals and students in a healthcare profession training program subject to the requirements of this paragraph.

1. Any midwife, paramedic, advanced or intermediate emergency medical technician (EMT), physician assistant, respiratory therapist, dentist, podiatrist, optometrist or veterinarian licensed or certified to practice under the law of any state who prescribes, dispenses, or administers erectile dysfunction treatments that are Covered Countermeasures under section VI of this Declaration in any jurisdiction where the PREP Act applies in association with a erectile dysfunction treatment vaccination effort by a State, local, Tribal or territorial authority or by an institution in which the erectile dysfunction treatment covered countermeasure is administered. 2. Any physician, advanced practice registered nurse, registered nurse, practical nurse, pharmacist, pharmacy intern, midwife, paramedic, advanced or intermediate EMT, respiratory therapist, dentist, physician assistant, podiatrist, optometrist, or veterinarian who has held an active license or certification under the law of any State within the last five years, which is inactive, expired or lapsed, who prescribes, dispenses, or administers erectile dysfunction treatments that are Covered Countermeasures under section VI of this Declaration in any jurisdiction where the PREP Act applies in association with a erectile dysfunction treatment vaccination effort by a State, local, Tribal or territorial authority or by an institution in which the erectile dysfunction treatment covered countermeasure is administered, so long as the license or certification was active and in good standing prior to the date it went inactive, expired or lapsed and was not revoked by the licensing authority, surrendered while under suspension, discipline or investigation by a licensing authority or surrendered following an arrest, and the individual is not on the List of Excluded Individuals/Entities maintained by the Office of Inspector General. 3.

Any medical, nursing, pharmacy, pharmacy intern, midwife, paramedic, advanced or intermediate EMT, physician assistant, respiratory therapy, dental, podiatry, optometry or veterinary student with appropriate training in administering treatments as determined by his or her school or training program and supervision by a currently practicing healthcare professional experienced in administering intramuscular injections who administers erectile dysfunction treatments that are Covered Countermeasures under section VI of this Declaration in any jurisdiction where the PREP Act applies in association with a erectile dysfunction treatment vaccination effort by a State, local, Tribal or territorial authority or by an institution in which the erectile dysfunction treatment covered countermeasure is administered. Subject to the following requirements. I. The treatment must be authorized, approved, or licensed by the FDA. Ii.

Vaccination must be ordered and administered according to ACIP's erectile dysfunction treatment recommendation(s). Iii. The healthcare professionals and students must have documentation of completion of the Centers for Disease Control and Prevention erectile dysfunction treatment Training Modules and, if applicable, such additional training as may be required by the State, territory, locality, or Tribal area in which they are prescribing, dispensing, or administering erectile dysfunction treatments. Iv. The healthcare professionals and students must have documentation of an observation period by a currently practicing healthcare professional experienced in administering intramuscular injections, and for whom administering vaccinations is in their ordinary scope of practice, who confirms competency of the healthcare provider or student in preparation and administration of the erectile dysfunction treatment(s) to be administered and, if applicable, such additional training as may be required by the State, territory, locality, or Tribal area in which they are prescribing, dispensing, or administering erectile dysfunction treatments.

V. The healthcare professionals and students must have a current certificate in basic cardiopulmonary resuscitation;â[] vi. The healthcare professionals and students must comply with recordkeeping and reporting requirements of the jurisdiction in which he or she administers treatments, including informing the patient's primary-care provider when available, submitting the required immunization information to the State or local immunization information system (treatment registry), complying with requirements with respect to reporting adverse events, and complying with requirements whereby the person administering a treatment must review the treatment registry or other vaccination records prior to administering a treatment. And vii. The healthcare professionals and students comply with any applicable requirements (or conditions of use) as set forth in the Centers for Disease Control and Prevention (CDC) erectile dysfunction treatment vaccination provider agreement and any other federal requirements that apply to the administration of erectile dysfunction treatment(s).

(i) A State-licensed pharmacist who orders and administers, and pharmacy interns and qualified pharmacy technicians who administer (if the pharmacy intern or technician acts under the supervision of such pharmacist and the pharmacy intern or technician is licensed or registered by his or her State board of pharmacy)â[] FDA authorized, approved, or licensed erectile dysfunction treatment therapeutics. Such State-licensed pharmacists and the State-licensed or registered interns or technicians under their supervision are Start Printed Page 51166qualified persons only if the following requirements are met. Ix. The erectile dysfunction treatment therapeutic must be authorized, approved, or licensed by the FDA. X.

In the case of a licensed pharmacist ordering a erectile dysfunction treatment therapeutic, the therapeutic must be ordered for subcutaneous, intramuscular, or oral administration and in accordance with the FDA approval, authorization, or licensing. Xi. In the case of licensed pharmacists, qualified pharmacy technicians, and licensed or registered pharmacy interns administering the erectile dysfunction treatment therapeutic, the therapeutic must be administered subcutaneously, intramuscularly, or orally in accordance with the FDA approval, authorization, or licensing. Xii. In the case of qualified pharmacy technicians, the supervising pharmacist must be readily and immediately available to the qualified pharmacy technician.

Xiii. In the case of erectile dysfunction treatment therapeutics administered through intramuscular or subcutaneous injections, the licensed pharmacist, licensed or registered pharmacy intern and qualified pharmacy technician must complete a practical training program that is approved by the ACPE. This training program must include hands-on injection technique, clinical evaluation of indications and contraindications of erectile dysfunction treatment therapeutics, the recognition and treatment of emergency reactions to erectile dysfunction treatment therapeutics, and any additional training required in the FDA approval, authorization, or licensing.

Azar II, declared a kamagra for sale online public health emergency pursuant to section 319 of the PHS Act, 42 U.S.C. 247d, effective January 27, 2020, for the entire United States to aid in the response of the nation's health care community to the erectile dysfunction treatment outbreak. Pursuant to section 319 of the PHS Act, the Secretary renewed that declaration effective on April 26, 2020, July 25, 2020, October 23, 2020, January 21, 2021, April 21, 2021 and July 20, 2021.

On March 10, 2020, former Secretary Azar issued a Declaration under the PREP Act for medical kamagra for sale online countermeasures against erectile dysfunction treatment (85 FR 15198, Mar. 17, 2020) (the Declaration). On April 10, the former Secretary amended the Declaration under the PREP Act to extend liability immunity to covered countermeasures authorized under the CARES Act (85 FR 21012, Apr.

15, 2020) kamagra for sale online. On June 4, the former Secretary amended the Declaration to clarify that covered countermeasures under the Declaration include qualified countermeasures that limit the harm erectile dysfunction treatment might otherwise cause. (85 FR 35100, June 8, 2020).

On August 19, the former Secretary amended the declaration to add additional kamagra for sale online categories of Qualified Persons and amend the category of disease, health condition, or threat for which he recommended the administration or use of the Covered Countermeasures. (85 FR 52136, Aug. 24, 2020).

On December 3, 2020, the former Secretary amended the declaration to incorporate Advisory Opinions of the General Counsel interpreting the PREP Act and the Secretary's Declaration and authorizations issued by the Department's Office of the Assistant Secretary kamagra for sale online for Health as an Authority Having Jurisdiction to respond. Added an additional category of qualified persons under Section V of the Declaration. Made explicit that the Declaration covers all qualified kamagra and epidemic products as defined under the PREP Act.

Added a third method of distribution kamagra for sale online to provide liability protections for, among other things, private distribution channels. Made explicit that there can be situations where not administering a covered countermeasure to a particular individual can fall within the PREP Act and the Declaration's liability protections. Made explicit that there are substantive federal legal and policy issues and interests in having a unified whole-of-nation response to the erectile dysfunction treatment kamagra among federal, state, local, and private-sector entities.

Revised the kamagra for sale online effective time period of the Declaration. And republished the declaration in full. (85 FR 79190, Dec.

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On February 16, 2021, the Acting Secretary amended the Declaration to add additional categories of Qualified Persons authorized to prescribe, dispense, and administer erectile dysfunction treatments that are covered countermeasures under the Declaration kamagra for sale online (86 FR 9516, Feb. 16, 2021) and on February 22, 2021, the Department filed a notice of correction to the February 2 and February 16 notices correcting effective dates stated in the Declaration, and correcting the description of qualified persons added by the February 16, 2021 amendment. (86 FR 10588, Feb.

22, 2021) kamagra for sale online. On March 11, 2021, the Acting Secretary amended the Declaration to add additional Qualified Persons authorized to prescribe, dispense, and administer covered countermeasures under the Declaration. (86 FR 14462, Mar.

16, 2021) kamagra for sale online. On August 4, 2021, Secretary Xavier Becerra amended the Declaration to clarify categories of Qualified Persons and to expand the scope of authority for certain Qualified Persons to administer seasonal influenza treatments to adults. (86 FR 41977, Aug.

4, 2021) kamagra for sale online. Secretary Xavier Becerra now amends section V of the Declaration to add subsection (i) to expand the scope of authority for licensed pharmacists to order and administer and qualified pharmacy technicians and pharmacy interns to administer erectile dysfunction treatment therapeutics subcutaneously, intramuscularly, or orally as authorized, approved, or licensed by the U.S. Food and Drug Administration (FDA).

Accordingly, subsection V(i) kamagra for sale online authorizes. (i) A State-licensed pharmacist who orders and administers, and pharmacy interns and qualified pharmacy technicians who administer (if the pharmacy intern or technician acts under the supervision of such pharmacist and the pharmacy intern or technician is licensed or registered by his or her State board of pharmacy)â[] FDA authorized, approved, or licensed erectile dysfunction treatment therapeutics. Such State-licensed pharmacists and the State-licensed or registered interns or technicians under their supervision are qualified persons only if the following requirements are met.

I. The erectile dysfunction treatment therapeutic must be authorized, approved, or licensed by the FDA. Ii.

In the case of a licensed pharmacist ordering a erectile dysfunction treatment therapeutic, the therapeutic must be ordered for subcutaneous, intramuscular, or oral administration and in accordance with the FDA approval, authorization, or licensing;Start Printed Page 51162 iii. In the case of licensed pharmacists, qualified pharmacy technicians, and licensed or registered pharmacy interns administering the erectile dysfunction treatment therapeutic, the therapeutic must be administered subcutaneously, intramuscularly, or orally in accordance with the FDA approval, authorization, or licensing. Iv.

In the case of qualified pharmacy technicians, the supervising pharmacist must be readily and immediately available to the qualified pharmacy technician. V. In the case of erectile dysfunction treatment therapeutics administered through intramuscular or subcutaneous injections, the licensed pharmacist, licensed or registered pharmacy intern and qualified pharmacy technician must complete a practical training program that is approved by the Accreditation Council for Pharmacy Education (ACPE).

This training program must include hands-on injection technique, clinical evaluation of indications and contraindications of erectile dysfunction treatment therapeutics, the recognition and treatment of emergency reactions to erectile dysfunction treatment therapeutics, and any additional training required in the FDA approval, authorization, or licensing. Vi. The licensed pharmacist, licensed or registered pharmacy intern and qualified pharmacy technician must have a current certificate in basic cardiopulmonary resuscitation;â[] vii.

Description of This Amendment by Section Section V. Covered Persons Under the PREP Act and the Declaration, a âqualified personâ is a âcovered person.â Subject to certain limitations, a covered person is immune from suit and liability under Federal and State law with respect to all claims for loss caused by, arising out of, relating to, or resulting from the administration or use of a covered countermeasure if a declaration under the PREP Act has been issued with respect to such countermeasure. ÂQualified personâ includes (A) a licensed health professional or other individual who is authorized to prescribe, administer, or dispense such countermeasures under the law of the State in which the countermeasure was prescribed, administered, or dispensed.

Or (B) âa person within a category of persons so identified in a declaration by the Secretaryâ under subsection (b) of the PREP Act. 42 U.S.C. 247d-6d(i)(8).

By this amendment to the Declaration, the Secretary clarifies and expands the authorization for a category of persons who are qualified persons under section 247d-6d(i)(8)(B). First, the amendment clarifies that licensed pharmacists are authorized to order and administer and licensed or registered pharmacy interns and qualified pharmacy technicians are authorized to administer erectile dysfunction treatment therapeutics that are Covered Countermeasures under section VI of this Declaration. The Secretary anticipates that there will be a need to increase the available pool of providers able to order and administer erectile dysfunction treatment therapeutics to address rising erectile dysfunction treatment cases, to expand patient access to these critical therapies, and to keep as many patients out of the hospital as possible.

Rising erectile dysfunction treatment cases, largely attributable to the Delta variant, is a public health threat caused by erectile dysfunction treatment, placing additional strains on our healthcare system. Pharmacists, pharmacy technicians, and pharmacy interns are well positioned to increase access to therapeutics and have played a critical role in this kamagra in overseeing erectile dysfunction treatment testing and treatment administration. Given their skill set and training, as well as looming provider shortages, pharmacists, pharmacy technicians, and pharmacy interns will quickly expand access to erectile dysfunction treatment therapeutics.

On May 19, 2020, the Office of the General Counsel issued an advisory opinion concluding that, because licensed pharmacists are âqualified personsâ under this declaration, the PREP Act preempts state law that would otherwise prohibit such pharmacists from ordering and administering authorized erectile dysfunction treatment diagnostic tests.[] The opinion relied in part on the fact that the Congressional delegation of authority to the Secretary under the PREP Act to specify a class of persons, beyond those who are authorized to administer a covered countermeasure under State law, as âqualified personsâ would be rendered a nullity in the absence of such preemption. This opinion is incorporated by reference into this declaration. Based on the reasoning set forth in the May 19, 2020 advisory opinion, any State law that would otherwise prohibit a member of any of the classes of âqualified personsâ specified in this declaration from administering a covered countermeasure is likewise preempted.

In accordance with section 319F-3(i)(8)(A) of the Public Health Service Act, a State remains free to expand the universe of individuals authorized to administer Start Printed Page 51163covered countermeasures within its jurisdiction under State law. The plain language of the PREP Act makes clear that there is preemption of state law as described above. Furthermore, preemption of State law is justified to respond to the nation-wide public health emergency caused by erectile dysfunction treatment as it will enable States to quickly expand the vaccination, treatment and prevention workforces with additional qualified healthcare professionals where State or local requirements might otherwise inhibit or delay allowing these healthcare professionals to participate in the erectile dysfunction treatment countermeasure program.

Amendments to Declaration Amended Declaration for Public Readiness and Emergency Preparedness Act Coverage for medical countermeasures against erectile dysfunction treatment. Section V of the March 10, 2020 Declaration under the PREP Act for medical countermeasures against erectile dysfunction treatment, as amended April 10, 2020, June 4, 2020, August 19, 2020, as amended and republished on December 3, 2020, as amended on February 2, 2021, as amended March 11, 2021, and as amended on August 4, 2021, is further amended pursuant to section 319F-3(b)(4) of the PHS Act as described below. All other sections of the Declaration remain in effect as republished at 85 FR 79190 (Dec.

9, 2020). 1. Covered Persons, section V, delete in full and replace with.

ÂOrderâ as used herein and in guidance issued by the Office of the Assistant Secretary for Healthâ[] means a provider medication order, which includes prescribing of treatments, or a laboratory order, which includes prescribing laboratory orders, if required. In addition, I have determined that the following additional persons are qualified persons. (a) Any person authorized in accordance with the public health and medical emergency response of the Authority Having Jurisdiction, as described in Section VII below, to prescribe, administer, deliver, distribute or dispense the Covered Countermeasures, and their officials, agents, employees, contractors and volunteers, following a Declaration of an Emergency, as that term is defined in Section VII of this Declaration;[] (b) Any person authorized to prescribe, administer, or dispense the Covered Countermeasures or who is otherwise authorized to perform an activity under an Emergency Use Authorization in accordance with Section 564 of the FD&C Act.

(c) Any person authorized to prescribe, administer, or dispense Covered Countermeasures in accordance with Section 564A of the FD&C Act. (d) A State-licensed pharmacist who orders and administers, and pharmacy interns and qualified pharmacy technicians who administer (if the pharmacy intern or technician acts under the supervision of such pharmacist and the pharmacy intern or technician is licensed or registered by his or her State board of pharmacy),[] (1) treatments that the Advisory Committee on Immunization Practices (ACIP) recommends to persons ages three through 18 according to ACIP's standard immunization schedule or (2) seasonal influenza treatment administered by qualified pharmacy technicians and interns that the ACIP recommends to persons aged 19 and older according to ACIP's standard immunization schedule. Or (3) FDA authorized or FDA licensed erectile dysfunction treatments to persons ages three or older.

Such State-licensed pharmacists and the State-licensed or registered interns or technicians under their supervision are qualified persons only if the following requirements are met. I. The treatment must be authorized, approved, or licensed by the FDA.

Ii. In the case of a erectile dysfunction treatment, the vaccination must be ordered and administered according to ACIP's erectile dysfunction treatment recommendation(s). Iii.

V. In the case of pharmacy technicians, the supervising pharmacist must be readily and immediately available to the immunizing qualified pharmacy technician. Vi.

The licensed pharmacist must have completed the immunization Start Printed Page 51164training that the licensing State requires for pharmacists to order and administer treatments. If the State does not specify training requirements for the licensed pharmacist to order and administer treatments, the licensed pharmacist must complete a vaccination training program of at least 20 hours that is approved by the ACPE to order and administer treatments. Such a training program must include hands on injection technique, clinical evaluation of indications and contraindications of treatments, and the recognition and treatment of emergency reactions to treatments.

Vii. The licensed or registered pharmacy intern and qualified pharmacy technician must complete a practical training program that is approved by the ACPE. This training program must include hands-on injection technique, clinical evaluation of indications and contraindications of treatments, and the recognition and treatment of emergency reactions to treatments.

Viii. The licensed pharmacist, licensed or registered pharmacy intern and qualified pharmacy technician must have a current certificate in basic cardiopulmonary resuscitation;â[] ix. The licensed pharmacist must complete a minimum of two hours of ACPE-approved, immunization-related continuing pharmacy education during each State licensing period.

The licensed pharmacist must inform his or her childhood-vaccination patients and the adult caregiver accompanying the child of the importance of a well-child visit with a pediatrician or other licensed primary care provider and refer patients as appropriate. And xii. The licensed pharmacist, the licensed or registered pharmacy intern and the qualified pharmacy technician must comply with any applicable requirements (or conditions of use) as set forth in the Centers for Disease Control and Prevention (CDC) erectile dysfunction treatment vaccination provider agreement and any other federal requirements that apply to the administration of erectile dysfunction treatment- 19 treatment(s).

(e) Healthcare personnel using telehealth to order or administer Covered Countermeasures for patients in a state other than the state where the healthcare personnel are licensed or otherwise permitted to practice. When ordering and administering Covered Countermeasures by means of telehealth to patients in a state where the healthcare personnel are not already permitted to practice, the healthcare personnel must comply with all requirements for ordering and administering Covered Countermeasures to patients by means of telehealth in the state where the healthcare personnel are permitted to practice. Any state law that prohibits or effectively prohibits such a qualified person from ordering and administering Covered Countermeasures by means of telehealth is preempted.[] Nothing in this Declaration shall preempt state laws that permit additional persons to deliver telehealth services.

(f) Any healthcare professional or other individual who holds an active license or certification permitting the person to prescribe, dispense, or administer treatments under the law of any State as of the effective date of this amendment, or a pharmacist or pharmacy intern as authorized under the section V(d) of this Declaration, who prescribes, dispenses, or administers erectile dysfunction treatments that are Covered Countermeasures under section VI of this Declaration in any jurisdiction where the PREP Act applies, other than the State in which the license or certification is held, in association with a erectile dysfunction treatment vaccination effort by a federal, State, local Tribal or territorial authority or by an institution in the State in which the erectile dysfunction treatment covered countermeasure is administered, so long as the license or certification of the healthcare professional has not been suspended or restricted by any licensing authority, surrendered while under suspension, discipline or investigation by a licensing authority or surrendered following an arrest, and the individual is not on the List of Excluded Individuals/Entities maintained by the Office of Inspector General, subject to. (i) Documentation of completion of the Centers for Disease Control and Prevention erectile dysfunction treatment (CDC) treatment Training Modulesâ[] and, for healthcare providers who are not currently practicing, documentation of an observation period by a currently practicing healthcare professional experienced in administering intramuscular injections, and for whom administering intramuscular injections is in their ordinary scope of practice, who confirms competency of the healthcare provider in preparation and administration of the erectile dysfunction treatment(s) to be administered. (g) Any member of a uniformed service (including members of the National Guard in a Title 32 duty status) (hereafter in this paragraph âservice memberâ) or Federal government, employee, contractor, or volunteer who prescribes, administers, delivers, distributes or dispenses a Covered Countermeasure.

Such Federal government service members, employees, contractors, or volunteers are qualified persons if the following requirement is met. The executive department or agency by or for which the Federal service member, employee, contractor, or volunteer is employed, contracts, or volunteers has authorized or could authorize that service member, employee, contractor, or volunteer to prescribe, administer, deliver, distribute, or dispense the Covered Countermeasure as any part of the duties or responsibilities of that service member, employee, contractor, or volunteer, even if those authorized duties or responsibilities ordinarily would not extend to members of the public or otherwise would be more limited in scope than the activities such service member, employees, contractors, Start Printed Page 51165or volunteers are authorized to carry out under this declaration. And (h) The following healthcare professionals and students in a healthcare profession training program subject to the requirements of this paragraph.

Any physician, advanced practice registered nurse, registered nurse, practical nurse, pharmacist, pharmacy intern, midwife, paramedic, advanced or intermediate EMT, respiratory therapist, dentist, physician assistant, podiatrist, optometrist, or veterinarian who has held an active license or certification under the law of any State within the last five years, which is inactive, expired or lapsed, who prescribes, dispenses, or administers erectile dysfunction treatments that are Covered Countermeasures under section VI of this Declaration in any jurisdiction where the PREP Act applies in association with a erectile dysfunction treatment vaccination effort by a State, local, Tribal or territorial authority or by an institution in which the erectile dysfunction treatment covered countermeasure is administered, so long as the license or certification was active and in good standing prior to the date it went inactive, expired or lapsed and was not revoked by the licensing authority, surrendered while under suspension, discipline or investigation by a licensing authority or surrendered following an arrest, and the individual is not on the List of Excluded Individuals/Entities maintained by the Office of Inspector General. 3. Any medical, nursing, pharmacy, pharmacy intern, midwife, paramedic, advanced or intermediate EMT, physician assistant, respiratory therapy, dental, podiatry, optometry or veterinary student with appropriate training in administering treatments as determined by his or her school or training program and supervision by a currently practicing healthcare professional experienced in administering intramuscular injections who administers erectile dysfunction treatments that are Covered Countermeasures under section VI of this Declaration in any jurisdiction where the PREP Act applies in association with a erectile dysfunction treatment vaccination effort by a State, local, Tribal or territorial authority or by an institution in which the erectile dysfunction treatment covered countermeasure is administered.

Subject to the following requirements. I. The treatment must be authorized, approved, or licensed by the FDA.

Ii. Vaccination must be ordered and administered according to ACIP's erectile dysfunction treatment recommendation(s). Iii.

The healthcare professionals and students must have documentation of completion of the Centers for Disease Control and Prevention erectile dysfunction treatment Training Modules and, if applicable, such additional training as may be required by the State, territory, locality, or Tribal area in which they are prescribing, dispensing, or administering erectile dysfunction treatments. Iv. The healthcare professionals and students must have documentation of an observation period by a currently practicing healthcare professional experienced in administering intramuscular injections, and for whom administering vaccinations is in their ordinary scope of practice, who confirms competency of the healthcare provider or student in preparation and administration of the erectile dysfunction treatment(s) to be administered and, if applicable, such additional training as may be required by the State, territory, locality, or Tribal area in which they are prescribing, dispensing, or administering erectile dysfunction treatments.

And vii. The healthcare professionals and students comply with any applicable requirements (or conditions of use) as set forth in the Centers for Disease Control and Prevention (CDC) erectile dysfunction treatment vaccination provider agreement and any other federal requirements that apply to the administration of erectile dysfunction treatment(s). (i) A State-licensed pharmacist who orders and administers, and pharmacy interns and qualified pharmacy technicians who administer (if the pharmacy intern or technician acts under the supervision of such pharmacist and the pharmacy intern or technician is licensed or registered by his or her State board of pharmacy)â[] FDA authorized, approved, or licensed erectile dysfunction treatment therapeutics.

Such State-licensed pharmacists and the State-licensed or registered interns or technicians under their supervision are Start Printed Page 51166qualified persons only if the following requirements are met. Ix. The erectile dysfunction treatment therapeutic must be authorized, approved, or licensed by the FDA.

X. In the case of a licensed pharmacist ordering a erectile dysfunction treatment therapeutic, the therapeutic must be ordered for subcutaneous, intramuscular, or oral administration and in accordance with the FDA approval, authorization, or licensing. Xi.

In the case of licensed pharmacists, qualified pharmacy technicians, and licensed or registered pharmacy interns administering the erectile dysfunction treatment therapeutic, the therapeutic must be administered subcutaneously, intramuscularly, or orally in accordance with the FDA approval, authorization, or licensing. Xii. In the case of qualified pharmacy technicians, the supervising pharmacist must be readily and immediately available to the qualified pharmacy technician.

Xiv. The licensed pharmacist, licensed or registered pharmacy intern and qualified pharmacy technician must have a current certificate in basic cardiopulmonary resuscitation;â[] xv. The licensed pharmacist must comply with recordkeeping and reporting requirements of the jurisdiction in which he or she administers erectile dysfunction treatment therapeutics, including informing the patient's primary-care provider when available and complying with requirements with respect to reporting adverse events.

Xvi. The licensed pharmacist, the licensed or registered pharmacy intern and the qualified pharmacy technician must comply with any applicable requirements (or conditions of use) that apply to the administration of erectile dysfunction treatment therapeutics. Nothing in this Declaration shall be construed to affect the National treatment Injury Compensation Program, including an injured party's ability to obtain compensation under that program.

Covered countermeasures that are subject to the National treatment Injury Compensation Program authorized under 42 U.S.C. 300aa-10 et seq. Are covered under this Declaration for the purposes of liability immunity and injury compensation only to the extent that injury compensation is not provided under that Program.

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