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NCHS Data buy levitra online from canada Brief No. 286, September 2017PDF Versionpdf icon (374 KB)Anjel Vahratian, Ph.D.Key findingsData from the National Health Interview Survey, 2015Among those aged 40–59, perimenopausal women (56.0%) were more likely than postmenopausal (40.5%) and premenopausal (32.5%) women to sleep less than 7 hours, on average, in a 24-hour period.Postmenopausal women aged 40–59 were more likely than premenopausal women aged 40–59 to have trouble falling asleep (27.1% compared with 16.8%, respectively), and staying asleep (35.9% compared with 23.7%), four times or more in the past week.Postmenopausal women aged 40–59 (55.1%) were more likely than premenopausal women aged 40–59 (47.0%) to not wake up feeling well rested 4 days or more in the past week.Sleep duration and quality are important contributors to health and wellness. Insufficient sleep is associated with an increased risk for chronic buy levitra online from canada conditions such as cardiovascular disease (1) and diabetes (2).

Women may be particularly vulnerable to sleep problems during times of reproductive hormonal change, such as after the menopausal transition. Menopause is “the permanent cessation buy levitra online from canada of menstruation that occurs after the loss of ovarian activity” (3). This data brief describes sleep duration and sleep quality among nonpregnant women aged 40–59 by menopausal status.

The age range selected for this analysis reflects the focus on midlife sleep health. In this analysis, 74.2% of women are premenopausal, 3.7% are perimenopausal, and 22.1% are buy levitra online from canada postmenopausal. Keywords.

Insufficient sleep, menopause, National Health Interview Survey Perimenopausal women were more likely than premenopausal and postmenopausal women to sleep less than 7 hours, on average, in a 24-hour period.More than one in three nonpregnant women aged 40–59 slept less buy levitra online from canada than 7 hours, on average, in a 24-hour period (35.1%) (Figure 1). Perimenopausal women were most likely to sleep less than 7 hours, on average, in a 24-hour period (56.0%), compared with 32.5% of premenopausal and 40.5% of postmenopausal women. Postmenopausal women were significantly more likely than premenopausal women to sleep less than 7 hours, on average, in a 24-hour period.

Figure 1 buy levitra online from canada. Percentage of nonpregnant women aged 40–59 who slept less than 7 hours, on average, in a 24-hour period, by menopausal status. United States, 2015image icon1Significant quadratic trend by menopausal status (p buy levitra online from canada <.

0.05).NOTES. Women were postmenopausal if they had gone without a menstrual cycle for more than 1 year or were in surgical menopause after the removal of their ovaries. Women were perimenopausal if they no longer had a menstrual cycle buy levitra online from canada and their last menstrual cycle was 1 year ago or less.

Women were premenopausal if they still had a menstrual cycle. Access data buy levitra online from canada table for Figure 1pdf icon.SOURCE. NCHS, National Health Interview Survey, 2015.

The percentage of women aged 40–59 who had trouble falling asleep four times or more in the past week varied by menopausal status.Nearly one in five nonpregnant women aged 40–59 had trouble falling asleep four buy levitra online from canada times or more in the past week (19.4%) (Figure 2). The percentage of women in this age group who had trouble falling asleep four times or more in the past week increased from 16.8% among premenopausal women to 24.7% among perimenopausal and 27.1% among postmenopausal women. Postmenopausal women were significantly more likely than premenopausal women to have trouble falling asleep four times or more in the past week.

Figure 2 buy levitra online from canada. Percentage of nonpregnant women aged 40–59 who had trouble falling asleep four times or more in the past week, by menopausal status. United States, 2015image icon1Significant linear buy levitra online from canada trend by menopausal status (p <.

0.05).NOTES. Women were postmenopausal if they had gone without a menstrual cycle for more than 1 year or were in surgical menopause after the removal of their ovaries. Women were buy levitra online from canada perimenopausal if they no longer had a menstrual cycle and their last menstrual cycle was 1 year ago or less.

Women were premenopausal if they still had a menstrual cycle. Access data table buy levitra online from canada for Figure 2pdf icon.SOURCE. NCHS, National Health Interview Survey, 2015.

The percentage of women aged 40–59 who had trouble staying asleep four times or more in the past week varied by menopausal status.More than one in four nonpregnant women aged 40–59 had trouble staying asleep four times or buy levitra online from canada more in the past week (26.7%) (Figure 3). The percentage of women aged 40–59 who had trouble staying asleep four times or more in the past week increased from 23.7% among premenopausal, to 30.8% among perimenopausal, and to 35.9% among postmenopausal women. Postmenopausal women were significantly more likely than premenopausal women to have trouble staying asleep four times or more in the past week.

Figure 3 buy levitra online from canada. Percentage of nonpregnant women aged 40–59 who had trouble staying asleep four times or more in the past week, by menopausal status. United States, buy levitra online from canada 2015image icon1Significant linear trend by menopausal status (p <.

0.05).NOTES. Women were postmenopausal if they had gone without a menstrual cycle for more than 1 year or were in surgical menopause after the removal of their ovaries. Women were perimenopausal if buy levitra online from canada they no longer had a menstrual cycle and their last menstrual cycle was 1 year ago or less.

Women were premenopausal if they still had a menstrual cycle. Access data table for Figure 3pdf buy levitra online from canada icon.SOURCE. NCHS, National Health Interview Survey, 2015.

The percentage of women aged 40–59 who did not wake up feeling well rested 4 days or more in the past week varied by menopausal status.Nearly one in two nonpregnant women aged 40–59 did not wake up feeling well rested 4 days or more in the past week (48.9%) (Figure 4). The percentage of women in this age group who did not buy levitra online from canada wake up feeling well rested 4 days or more in the past week increased from 47.0% among premenopausal women to 49.9% among perimenopausal and 55.1% among postmenopausal women. Postmenopausal women were significantly more likely than premenopausal women to not wake up feeling well rested 4 days or more in the past week.

Figure 4 buy levitra online from canada. Percentage of nonpregnant women aged 40–59 who did not wake up feeling well rested 4 days or more in the past week, by menopausal status. United States, 2015image icon1Significant linear trend by menopausal status (p <.

0.05).NOTES. Women were postmenopausal if they had gone without a menstrual cycle for more than 1 year or were in surgical menopause after the removal of their ovaries. Women were perimenopausal if they no longer had a menstrual cycle and their last menstrual cycle was 1 year ago or less.

Women were premenopausal if they still had a menstrual cycle. Access data table for Figure 4pdf icon.SOURCE. NCHS, National Health Interview Survey, 2015.

SummaryThis report describes sleep duration and sleep quality among U.S. Nonpregnant women aged 40–59 by menopausal status. Perimenopausal women were most likely to sleep less than 7 hours, on average, in a 24-hour period compared with premenopausal and postmenopausal women.

In contrast, postmenopausal women were most likely to have poor-quality sleep. A greater percentage of postmenopausal women had frequent trouble falling asleep, staying asleep, and not waking well rested compared with premenopausal women. The percentage of perimenopausal women with poor-quality sleep was between the percentages for the other two groups in all three categories.

Sleep duration changes with advancing age (4), but sleep duration and quality are also influenced by concurrent changes in women’s reproductive hormone levels (5). Because sleep is critical for optimal health and well-being (6), the findings in this report highlight areas for further research and targeted health promotion. DefinitionsMenopausal status.

A three-level categorical variable was created from a series of questions that asked women. 1) “How old were you when your periods or menstrual cycles started?. €.

2) “Do you still have periods or menstrual cycles?. €. 3) “When did you have your last period or menstrual cycle?.

€. And 4) “Have you ever had both ovaries removed, either as part of a hysterectomy or as one or more separate surgeries?. € Women were postmenopausal if they a) had gone without a menstrual cycle for more than 1 year or b) were in surgical menopause after the removal of their ovaries.

Women were perimenopausal if they a) no longer had a menstrual cycle and b) their last menstrual cycle was 1 year ago or less. Premenopausal women still had a menstrual cycle.Not waking feeling well rested. Determined by respondents who answered 3 days or less on the questionnaire item asking, “In the past week, on how many days did you wake up feeling well rested?.

€Short sleep duration. Determined by respondents who answered 6 hours or less on the questionnaire item asking, “On average, how many hours of sleep do you get in a 24-hour period?. €Trouble falling asleep.

Determined by respondents who answered four times or more on the questionnaire item asking, “In the past week, how many times did you have trouble falling asleep?. €Trouble staying asleep. Determined by respondents who answered four times or more on the questionnaire item asking, “In the past week, how many times did you have trouble staying asleep?.

€ Data source and methodsData from the 2015 National Health Interview Survey (NHIS) were used for this analysis. NHIS is a multipurpose health survey conducted continuously throughout the year by the National Center for Health Statistics. Interviews are conducted in person in respondents’ homes, but follow-ups to complete interviews may be conducted over the telephone.

Data for this analysis came from the Sample Adult core and cancer supplement sections of the 2015 NHIS. For more information about NHIS, including the questionnaire, visit the NHIS website.All analyses used weights to produce national estimates. Estimates on sleep duration and quality in this report are nationally representative of the civilian, noninstitutionalized nonpregnant female population aged 40–59 living in households across the United States.

The sample design is described in more detail elsewhere (7). Point estimates and their estimated variances were calculated using SUDAAN software (8) to account for the complex sample design of NHIS. Linear and quadratic trend tests of the estimated proportions across menopausal status were tested in SUDAAN via PROC DESCRIPT using the POLY option.

Differences between percentages were evaluated using two-sided significance tests at the 0.05 level. About the authorAnjel Vahratian is with the National Center for Health Statistics, Division of Health Interview Statistics. The author gratefully acknowledges the assistance of Lindsey Black in the preparation of this report.

ReferencesFord ES. Habitual sleep duration and predicted 10-year cardiovascular risk using the pooled cohort risk equations among US adults. J Am Heart Assoc 3(6):e001454.

2014.Ford ES, Wheaton AG, Chapman DP, Li C, Perry GS, Croft JB. Associations between self-reported sleep duration and sleeping disorder with concentrations of fasting and 2-h glucose, insulin, and glycosylated hemoglobin among adults without diagnosed diabetes. J Diabetes 6(4):338–50.

2014.American College of Obstetrics and Gynecology. ACOG Practice Bulletin No. 141.

Management of menopausal symptoms. Obstet Gynecol 123(1):202–16. 2014.Black LI, Nugent CN, Adams PF.

Tables of adult health behaviors, sleep. National Health Interview Survey, 2011–2014pdf icon. 2016.Santoro N.

Perimenopause. From research to practice. J Women’s Health (Larchmt) 25(4):332–9.

2016.Watson NF, Badr MS, Belenky G, Bliwise DL, Buxton OM, Buysse D, et al. Recommended amount of sleep for a healthy adult. A joint consensus statement of the American Academy of Sleep Medicine and Sleep Research Society.

J Clin Sleep Med 11(6):591–2. 2015.Parsons VL, Moriarity C, Jonas K, et al. Design and estimation for the National Health Interview Survey, 2006–2015.

National Center for Health Statistics. Vital Health Stat 2(165). 2014.RTI International.

SUDAAN (Release 11.0.0) [computer software]. 2012. Suggested citationVahratian A.

Sleep duration and quality among women aged 40–59, by menopausal status. NCHS data brief, no 286. Hyattsville, MD.

National Center for Health Statistics. 2017.Copyright informationAll material appearing in this report is in the public domain and may be reproduced or copied without permission. Citation as to source, however, is appreciated.National Center for Health StatisticsCharles J.

Rothwell, M.S., M.B.A., DirectorJennifer H. Madans, Ph.D., Associate Director for ScienceDivision of Health Interview StatisticsMarcie L. Cynamon, DirectorStephen J.

Blumberg, Ph.D., Associate Director for Science.

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Taking this a step further, one spoke in the paediatric (or any medical) pathway is mutual visibility surely difference between viagra and cialis and levitra a predictor of the point at which a family unmanacles themselves of reservations. How long does it take for a mother to disclose (even anonymously) to researchers that every time she enters her home, she risks adding to her bruise count. How many online consultations does it take before a family feel sufficiently at ease to disinter the spectres in their history lurking stage left behind the velvet curtains?. I rest my case… difference between viagra and cialis and levitra or maybe, teasingly, am only just hinting at it.Neglected global diseasesNo one is oblivious to the pernicious effects of intimate partner violence (IPV), but little is known about effect sizes either on the mother or children.

Previous cohort studies that have had the ‘guts’ to examine this pervasive holoendemic disease might have underestimated the prevalence and effects by. Using only physical violence (emotional control is difference between viagra and cialis and levitra more common). Using unidimensional measure (conflict tactics scale, for example) or by missing the opportunity for long term follow-up. Deidre Gartland and colleagues examined close to 700 maternal-child dyads in Melbourne, difference between viagra and cialis and levitra Australia from the Maternal Health Study in children born between 2003 and 2005, recruitment beginning during pregnancy and repeat assessments at 3, 6 and 12 months then at 4 and 10 years.

IPV was assessed with the composite abuse scale and child outcomes by the Strengths and Difficulties Questionnaire (SDQ), Developmental and Well Being Assessment (DAWBA), Spence Children’s anxiety scale, Wechsler intelligence scale NIH picture vocabulary test and the Children’s Communications Shortlist. In short, 13% of mothers of children at 1 year and 16% at 10 years reported some form of IPV. Adjusted ORs for likely psychiatric diagnosis and emotional difficulties difference between viagra and cialis and levitra (DAWBA and SDQ) with respect to IPV at 2.0 and 1.9 respectively were significant. Given the likely under-reporting in such studies the real effect is probably larger, a reflection of the dysfunctional parent -child relationships this sort of abuse inevitably fosters.

So, what do we, difference between viagra and cialis and levitra and paediatricians, do about it?. We ask. We ask difference between viagra and cialis and levitra in the same way that obstetricians do. The line ‘if there’s anything you haven’t already mentioned at home that you’d like to tell me…’ opens doors-literally and metaphorically.

See page 1066The future. Part 1 – distance consultationThe difference between viagra and cialis and levitra levitra reinforced the need to revisit the traditional default of all follow-upvisits needing to be in person both from medical and family need angles. Three papers examine aspects of the evolution of and drawback to this seismic (and I don’t think is an exaggeration) shift towards tele-medicine. Ronny Cheung’s Viewpoint looks at practicalities difference between viagra and cialis and levitra.

What does an outpatient visit entail for a family?. To difference between viagra and cialis and levitra name but a few. Time off work and lost income. Days out of school.

Lost social contact lessons difference between viagra and cialis and levitra and sports. A tedious gridlocked drive through the drizzle with the inherent carbon footprint. The search for difference between viagra and cialis and levitra the elusive car parking spot which is pounced on by another vehicle. Of course, contact is important, but the value of physical proximity surely needs to be weighed up, the default surely being ‘is there a reason for the next visit not to be online—what does the childthink?.

€™The notion that ‘mobile phones are wonderful because they enable parents to instantly send difference between viagra and cialis and levitra images to their children’s paediatricians’ is to some extent justified and predates even that hazy, carefree era before December 2019. It is, though, riddled with potholes. Potholes that are navigable, but potholes, nonetheless. These relate not only to security but difference between viagra and cialis and levitra also on the tacit transfer of responsibility to act on the picture (particularly if unsolicited).

Mahmoud Motawea and colleagues thoughts on their use and implications (even in the face of highly secure NHS mechanisms) lends some context (but not cold water) to the wave of enthusiasm.The issues don’t stop there as, as Robert Wheeler’s Clinical Law series piece articulately demonstrates. The reality is that a video call whether as part of a legal assessment or otherwise simply can’t (or difference between viagra and cialis and levitra can’t at present) replicate the sixth sense one gets (subtleties of movement, parental eye contact, signs of neglect) that being in the same room can. This isn’t always necessary, but the court precedents show there are times that it is. See pages 1041, difference between viagra and cialis and levitra 1044, 1056The future.

Part 2 – robotsMaybe it uncovers the nascent techno-luddite in me, but the mention of robots as the future has generally tended to make me shudder and the notion of robot as anxiolytic a dismissive ‘what’s wrong with a hug/slug of midazolam/nitrous oxide?. €™ I think, though, I’m changing my mind, at least a bit, in no small part the result of Brenda Littler and colleagues’ narrative systematic review on the use of (social) robots in distress alleviation, some, ironically, ‘real’ teddy bears themselves. See page 1095Ethics statementsPatient consent for publicationNot applicable.Wealthy nations must do much more, much faster.The United Nations General Assembly in September 2021 will bring countries together at a critical time for marshalling collective action to tackle difference between viagra and cialis and levitra the global environmental crisis. They will meet again at the biodiversity summit in Kunming, China, and the climate conference (Conference of the Parties (COP)26) in Glasgow, UK.

Ahead of these pivotal meetings, we—the editors of health journals worldwide—call for urgent action to keep average global temperature increases below 1.5°C, halt the destruction of nature and protect health.Health is already being harmed by global temperature increases and the destruction of the natural difference between viagra and cialis and levitra world, a state of affairs health professionals have been bringing attention to for decades.1 The science is unequivocal. A global increase of 1.5°C above the preindustrial average and the continued loss of biodiversity risk catastrophic harm to health that will be impossible to reverse.2 3 Despite the world’s necessary preoccupation with erectile dysfunction treatment, we cannot wait for the levitra to pass to rapidly reduce emissions.Reflecting the severity of the moment, this editorial appears in health journals across the world. We are united in recognising that only fundamental and equitable changes to societies will reverse our difference between viagra and cialis and levitra current trajectory.The risks to health of increases above 1.5°C are now well established.2 Indeed, no temperature rise is ‘safe’. In the past 20 years, heat-related mortality among people aged over 65 has increased by more than 50%.4 Higher temperatures have brought increased dehydration and renal function loss, dermatological malignancies, tropical s, adverse mental health outcomes, pregnancy complications, allergies, and cardiovascular and pulmonary morbidity and mortality.5 6 Harms disproportionately affect the most vulnerable, including children, older populations, ethnic minorities, poorer communities and those with underlying health problems.2 4Global heating is also contributing to the decline in global yield potential for major crops, falling by 1.8%–5.6% since 1981.

This, together with the effects of extreme weather and soil depletion, is hampering efforts to reduce undernutrition.4 Thriving ecosystems are essential to human health, and the widespread destruction of nature, including habitats and species, is eroding water and food security and increasing the chance of levitras.3 7 8The consequences of the environmental crisis fall disproportionately on those countries and communities that have contributed least to the problem and are least able to mitigate the harms. Yet no country, no matter how wealthy, can difference between viagra and cialis and levitra shield itself from these impacts. Allowing the consequences to fall disproportionately on the most vulnerable will breed more conflict, food insecurity, forced displacement and zoonotic disease, with severe implications for all countries and communities. As with the erectile dysfunction treatment levitra, we are globally as difference between viagra and cialis and levitra strong as our weakest member.Rises above 1.5°C increase the chance of reaching tipping points in natural systems that could lock the world into an acutely unstable state.

This would critically impair our ability to mitigate harms and to prevent catastrophic, runaway environmental change.9 10Global targets are not enoughEncouragingly, many governments, financial institutions and businesses are setting targets to reach net-zero emissions, including targets for 2030. The cost of renewable energy is dropping difference between viagra and cialis and levitra rapidly. Many countries are aiming to protect at least 30% of the world’s land and oceans by 2030.11These promises are not enough. Targets are easy to set and hard to achieve.

They are yet to be matched difference between viagra and cialis and levitra with credible short-term and longer-term plans to accelerate cleaner technologies and transform societies. Emissions reduction plans do not adequately incorporate health considerations.12 Concern is growing that temperature rises above 1.5°C are beginning to be seen as inevitable, or even acceptable, to powerful members of the global community.13 Relatedly, current strategies for reducing emissions to net zero by the middle of the century implausibly assume that the world will acquire great capabilities to remove greenhouse gases from the atmosphere.14 15This insufficient action means that temperature increases are likely to be well in excess of 2°C,16 a catastrophic outcome for health and environmental stability. Critically, the destruction of nature does not have parity of esteem with the climate element difference between viagra and cialis and levitra of the crisis, and every single global target to restore biodiversity loss by 2020 was missed.17 This is an overall environmental crisis.18Health professionals are united with environmental scientists, businesses and many others in rejecting that this outcome is inevitable. More can and must be done now—in Glasgow and Kunming—and in the immediate years that follow.

We join health professionals worldwide who have already supported calls for rapid action.1 19Equity must be at difference between viagra and cialis and levitra the centre of the global response. Contributing a fair share to the global effort means that reduction commitments must account for the cumulative, historical contribution each country has made to emissions, as well as its current emissions and capacity to respond. Wealthier countries will have to cut emissions more quickly, making reductions by 2030 beyond those currently proposed20 21 and reaching net-zero emissions before 2050. Similar targets and emergency action are needed for biodiversity loss and the difference between viagra and cialis and levitra wider destruction of the natural world.To achieve these targets, governments must make fundamental changes to how our societies and economies are organised and how we live.

The current strategy of encouraging markets to swap dirty for cleaner technologies is not enough. Governments must intervene to support the redesign of transport systems, cities, production and distribution of food, markets for financial investments, health systems, and difference between viagra and cialis and levitra much more. Global coordination is needed to ensure that the rush for cleaner technologies does not come at the cost of more environmental destruction and human exploitation.Many governments met the threat of the erectile dysfunction treatment levitra with unprecedented funding. The environmental crisis difference between viagra and cialis and levitra demands a similar emergency response.

Huge investment will be needed, beyond what is being considered or delivered anywhere in the world. But such investments will produce huge positive health and economic outcomes. These include high-quality jobs, reduced air difference between viagra and cialis and levitra pollution, increased physical activity, and improved housing and diet. Better air quality alone would realise health benefits that easily offset the global costs of emissions reductions.22These measures will also improve the social and economic determinants of health, the poor state of which may have made populations more vulnerable to the erectile dysfunction treatment levitra.23 But the changes cannot be achieved through a return to damaging austerity policies or the continuation of the large inequalities of wealth and power within and between countries.Cooperation hinges on wealthy nations doing moreIn particular, countries that have disproportionately created the environmental crisis must do more to support low-income and middle-income countries to build cleaner, healthier and more resilient societies.

High-income countries must meet and go beyond their outstanding commitment to provide $100 billion difference between viagra and cialis and levitra a year, making up for any shortfall in 2020 and increasing contributions to and beyond 2025. Funding must be equally split between mitigation and adaptation, including improving the resilience of health systems.Financing should be through grants rather than loans, building local capabilities and truly empowering communities, and should come alongside forgiving large debts, which constrain the agency of so many low-income countries. Additional funding must be marshalled to compensate for inevitable loss and damage caused by the consequences of the environmental crisis.As health professionals, we must do all we can to aid the transition to difference between viagra and cialis and levitra a sustainable, fairer, resilient and healthier world. Alongside acting to reduce the harm from the environmental crisis, we should proactively contribute to global prevention of further damage and action on the root causes of the crisis.

We must hold global leaders to account and continue to educate others about the health risks of the crisis. We must join in difference between viagra and cialis and levitra the work to achieve environmentally sustainable health systems before 2040, recognising that this will mean changing clinical practice. Health institutions have already divested more than $42 billion of assets from fossil fuels. Others should join them.4The greatest threat to global public health is the continued failure of world difference between viagra and cialis and levitra leaders to keep the global temperature rise below 1.5°C and to restore nature.

Urgent, society-wide changes must be made and will lead to a fairer and healthier world. We, as editors of health journals, call for governments and other leaders to act, marking 2021 as the year that the world finally changes course.Ethics statementsPatient consent for publicationNot required..

20/20 visionThere’s no doubt that trust is ‘won’ immediately in some circumstances and in young children is the buy levitra online from canada default position. Usually, though, it has to be earned. And even when deserved buy levitra online from canada it isn’t always granted. I wonder whether this ‘process’ (clumsy word, but possibly the best under the circumstances) has become slower, more attritional and more grudgingly acknowledged, a symbol perhaps of societal changes we might have to accept.

Taking this a step further, one spoke in the paediatric (or any medical) pathway is mutual visibility surely a predictor of the buy levitra online from canada point at which a family unmanacles themselves of reservations. How long does it take for a mother to disclose (even anonymously) to researchers that every time she enters her home, she risks adding to her bruise count. How many online consultations does it take before a family feel sufficiently at ease to disinter the spectres in their history lurking stage left behind the velvet curtains?. I rest my case… or maybe, teasingly, am only just hinting at it.Neglected global diseasesNo one is oblivious to the pernicious effects of intimate partner violence (IPV), but little is known about effect sizes either on the mother or children buy levitra online from canada.

Previous cohort studies that have had the ‘guts’ to examine this pervasive holoendemic disease might have underestimated the prevalence and effects by. Using only buy levitra online from canada physical violence (emotional control is more common). Using unidimensional measure (conflict tactics scale, for example) or by missing the opportunity for long term follow-up. Deidre Gartland and colleagues examined close to 700 maternal-child dyads in Melbourne, Australia from the Maternal Health Study in children born between 2003 and buy levitra online from canada 2005, recruitment beginning during pregnancy and repeat assessments at 3, 6 and 12 months then at 4 and 10 years.

IPV was assessed with the composite abuse scale and child outcomes by the Strengths and Difficulties Questionnaire (SDQ), Developmental and Well Being Assessment (DAWBA), Spence Children’s anxiety scale, Wechsler intelligence scale NIH picture vocabulary test and the Children’s Communications Shortlist. In short, 13% of mothers of children at 1 year and 16% at 10 years reported some form of IPV. Adjusted ORs buy levitra online from canada for likely psychiatric diagnosis and emotional difficulties (DAWBA and SDQ) with respect to IPV at 2.0 and 1.9 respectively were significant. Given the likely under-reporting in such studies the real effect is probably larger, a reflection of the dysfunctional parent -child relationships this sort of abuse inevitably fosters.

So, what do we, and paediatricians, do about it? buy levitra online from canada. We ask. We ask buy levitra online from canada in the same way that obstetricians do. The line ‘if there’s anything you haven’t already mentioned at home that you’d like to tell me…’ opens doors-literally and metaphorically.

See page 1066The future. Part 1 – distance consultationThe levitra reinforced the need to revisit the traditional default of buy levitra online from canada all follow-upvisits needing to be in person both from medical and family need angles. Three papers examine aspects of the evolution of and drawback to this seismic (and I don’t think is an exaggeration) shift towards tele-medicine. Ronny Cheung’s buy levitra online from canada Viewpoint looks at practicalities.

What does an outpatient visit entail for a family?. To name but a buy levitra online from canada few. Time off work and lost income. Days out of school.

Lost social buy levitra online from canada contact lessons and sports. A tedious gridlocked drive through the drizzle with the inherent carbon footprint. The search for the buy levitra online from canada elusive car parking spot which is pounced on by another vehicle. Of course, contact is important, but the value of physical proximity surely needs to be weighed up, the default surely being ‘is there a reason for the next visit not to be online—what does the childthink?.

€™The notion that ‘mobile phones are wonderful because they enable parents to instantly send images to their children’s paediatricians’ is to some extent justified buy levitra online from canada and predates even that hazy, carefree era before December 2019. It is, though, riddled with potholes. Potholes that are navigable, but potholes, nonetheless. These relate buy levitra online from canada not only to security but also on the tacit transfer of responsibility to act on the picture (particularly if unsolicited).

Mahmoud Motawea and colleagues thoughts on their use and implications (even in the face of highly secure NHS mechanisms) lends some context (but not cold water) to the wave of enthusiasm.The issues don’t stop there as, as Robert Wheeler’s Clinical Law series piece articulately demonstrates. The reality is that a video call whether as part of a legal assessment or otherwise simply can’t (or can’t at present) replicate the sixth sense one gets (subtleties of movement, parental eye contact, signs buy levitra online from canada of neglect) that being in the same room can. This isn’t always necessary, but the court precedents show there are times that it is. See pages 1041, 1044, buy levitra online from canada 1056The future.

Part 2 – robotsMaybe it uncovers the nascent techno-luddite in me, but the mention of robots as the future has generally tended to make me shudder and the notion of robot as anxiolytic a dismissive ‘what’s wrong with a hug/slug of midazolam/nitrous oxide?. €™ I think, though, I’m changing my mind, at least a bit, in no small part the result of Brenda Littler and colleagues’ narrative systematic review on the use of (social) robots in distress alleviation, some, ironically, ‘real’ teddy bears themselves. See page 1095Ethics statementsPatient consent for publicationNot applicable.Wealthy nations must do much more, much faster.The United Nations General Assembly in September 2021 will bring countries together at buy levitra online from canada a critical time for marshalling collective action to tackle the global environmental crisis. They will meet again at the biodiversity summit in Kunming, China, and the climate conference (Conference of the Parties (COP)26) in Glasgow, UK.

Ahead of these pivotal meetings, we—the editors of health journals worldwide—call for urgent action to keep average global temperature increases below 1.5°C, halt the destruction of nature and protect health.Health is already being harmed by global temperature increases and the destruction of the natural world, a state of affairs buy levitra online from canada health professionals have been bringing attention to for decades.1 The science is unequivocal. A global increase of 1.5°C above the preindustrial average and the continued loss of biodiversity risk catastrophic harm to health that will be impossible to reverse.2 3 Despite the world’s necessary preoccupation with erectile dysfunction treatment, we cannot wait for the levitra to pass to rapidly reduce emissions.Reflecting the severity of the moment, this editorial appears in health journals across the world. We are united in recognising that only fundamental and equitable changes to societies will reverse our current trajectory.The risks to health of increases above 1.5°C are now well established.2 Indeed, no temperature rise is ‘safe’ buy levitra online from canada. In the past 20 years, heat-related mortality among people aged over 65 has increased by more than 50%.4 Higher temperatures have brought increased dehydration and renal function loss, dermatological malignancies, tropical s, adverse mental health outcomes, pregnancy complications, allergies, and cardiovascular and pulmonary morbidity and mortality.5 6 Harms disproportionately affect the most vulnerable, including children, older populations, ethnic minorities, poorer communities and those with underlying health problems.2 4Global heating is also contributing to the decline in global yield potential for major crops, falling by 1.8%–5.6% since 1981.

This, together with the effects of extreme weather and soil depletion, is hampering efforts to reduce undernutrition.4 Thriving ecosystems are essential to human health, and the widespread destruction of nature, including habitats and species, is eroding water and food security and increasing the chance of levitras.3 7 8The consequences of the environmental crisis fall disproportionately on those countries and communities that have contributed least to the problem and are least able to mitigate the harms. Yet no country, no matter how wealthy, can buy levitra online from canada shield itself from these impacts. Allowing the consequences to fall disproportionately on the most vulnerable will breed more conflict, food insecurity, forced displacement and zoonotic disease, with severe implications for all countries and communities. As with the erectile dysfunction treatment levitra, we are globally as strong as our weakest member.Rises above 1.5°C increase the chance of reaching tipping buy levitra online from canada points in natural systems that could lock the world into an acutely unstable state.

This would critically impair our ability to mitigate harms and to prevent catastrophic, runaway environmental change.9 10Global targets are not enoughEncouragingly, many governments, financial institutions and businesses are setting targets to reach net-zero emissions, including targets for 2030. The cost of renewable energy is buy levitra online from canada dropping rapidly. Many countries are aiming to protect at least 30% of the world’s land and oceans by 2030.11These promises are not enough. Targets are easy to set and hard to achieve.

They are yet to be matched with credible short-term and longer-term plans to accelerate cleaner buy levitra online from canada technologies and transform societies. Emissions reduction plans do not adequately incorporate health considerations.12 Concern is growing that temperature rises above 1.5°C are beginning to be seen as inevitable, or even acceptable, to powerful members of the global community.13 Relatedly, current strategies for reducing emissions to net zero by the middle of the century implausibly assume that the world will acquire great capabilities to remove greenhouse gases from the atmosphere.14 15This insufficient action means that temperature increases are likely to be well in excess of 2°C,16 a catastrophic outcome for health and environmental stability. Critically, the destruction of nature does not have parity buy levitra online from canada of esteem with the climate element of the crisis, and every single global target to restore biodiversity loss by 2020 was missed.17 This is an overall environmental crisis.18Health professionals are united with environmental scientists, businesses and many others in rejecting that this outcome is inevitable. More can and must be done now—in Glasgow and Kunming—and in the immediate years that follow.

We join health professionals worldwide who have already supported calls for rapid action.1 19Equity must be buy levitra online from canada at the centre of the global response. Contributing a fair share to the global effort means that reduction commitments must account for the cumulative, historical contribution each country has made to emissions, as well as its current emissions and capacity to respond. Wealthier countries will have to cut emissions more quickly, making reductions by 2030 beyond those currently proposed20 21 and reaching net-zero emissions before 2050. Similar targets and emergency action are needed for biodiversity loss and the wider destruction of the natural world.To achieve these targets, governments must make fundamental changes to how our societies and economies are buy levitra online from canada organised and how we live.

The current strategy of encouraging markets to swap dirty for cleaner technologies is not enough. Governments must intervene to support the redesign of transport systems, cities, production and distribution of food, markets for financial investments, health systems, and much more buy levitra online from canada. Global coordination is needed to ensure that the rush for cleaner technologies does not come at the cost of more environmental destruction and human exploitation.Many governments met the threat of the erectile dysfunction treatment levitra with unprecedented funding. The environmental buy levitra online from canada crisis demands a similar emergency response.

Huge investment will be needed, beyond what is being considered or delivered anywhere in the world. But such investments will produce huge positive health and economic outcomes. These include high-quality jobs, reduced air buy levitra online from canada pollution, increased physical activity, and improved housing and diet. Better air quality alone would realise health benefits that easily offset the global costs of emissions reductions.22These measures will also improve the social and economic determinants of health, the poor state of which may have made populations more vulnerable to the erectile dysfunction treatment levitra.23 But the changes cannot be achieved through a return to damaging austerity policies or the continuation of the large inequalities of wealth and power within and between countries.Cooperation hinges on wealthy nations doing moreIn particular, countries that have disproportionately created the environmental crisis must do more to support low-income and middle-income countries to build cleaner, healthier and more resilient societies.

High-income countries must meet and go beyond their outstanding commitment to provide $100 billion a year, making up for buy levitra online from canada any shortfall in 2020 and increasing contributions to and beyond 2025. Funding must be equally split between mitigation and adaptation, including improving the resilience of health systems.Financing should be through grants rather than loans, building local capabilities and truly empowering communities, and should come alongside forgiving large debts, which constrain the agency of so many low-income countries. Additional funding must be marshalled to compensate for inevitable loss and damage caused by the consequences of the environmental crisis.As health professionals, we must buy levitra online from canada do all we can to aid the transition to a sustainable, fairer, resilient and healthier world. Alongside acting to reduce the harm from the environmental crisis, we should proactively contribute to global prevention of further damage and action on the root causes of the crisis.

We must hold global leaders to account and continue to educate others about the health risks of the crisis. We must join in the work to achieve environmentally sustainable buy levitra online from canada health systems before 2040, recognising that this will mean changing clinical practice. Health institutions have already divested more than $42 billion of assets from fossil fuels. Others should join them.4The greatest threat to global public health buy levitra online from canada is the continued failure of world leaders to keep the global temperature rise below 1.5°C and to restore nature.

Urgent, society-wide changes must be made and will lead to a fairer and healthier world. We, as editors of health journals, call for governments and other leaders to act, marking 2021 as the year that the world finally changes course.Ethics statementsPatient consent for publicationNot required..

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Lilly Cheng Immergluck of Morehouse School of Medicine answers some common questions about variants and what you can do to best protect yourself.1. What Are Variants and How where can i buy levitra over the counter Do They Emerge?. levitraes mutate over time to adapt to their environment and improve their survival.

Over the course of the levitra, erectile dysfunction, the novel erectile dysfunction that causes erectile dysfunction treatment, has mutated enough to change both its ability to spread through the population and its where can i buy levitra over the counter ability to infect people.These new strains are called variants. The U.S. Centers for Disease Control and Prevention where can i buy levitra over the counter currently classifies variants into three categories, listed in order of least to most concerning:Variant of Interest (VOI).

Have features that may reduce your immune system’s ability to prevent . For example, you might have heard of VOI eta, iota or where can i buy levitra over the counter kappa.Variant of Concern (VOC). Are less responsive to treatments or treatments and more likely to evade diagnostic detection.

They tend where can i buy levitra over the counter to be more transmissible, or contagious, and result in more severe s. Alpha and delta are VOCs, for instance.Variant of High Consequence (VOHC). Are significantly where can i buy levitra over the counter less responsive to existing diagnostic, prevention and treatment options.

They also result in more severe s and hospitalizations. There have not been any VOHCs identified so far.The World Health Organization uses similar classifications, but their definitions where can i buy levitra over the counter may differ from the CDC’s U.S.-based ones, as variant features and effects may differ by geographic location.2. Are Variants Always More Harmful?.

A variant may be more or less dangerous than other strains depending on the mutations in its genetic code. Mutations can affect attributes like how contagious a viral variant is, how it where can i buy levitra over the counter interacts with the immune system or the severity of the symptoms it triggers.For example, the alpha variant is more transmissible than the original form of erectile dysfunction. Studies show it’s somewhere between 43% to 90% more contagious than the levitra that was most common at the start of the levitra.

Alpha also is more likely to cause severe disease, as indicated by increased rates of hospitalization and death after .Even more extreme, the delta variant is reported to be nearly twice as contagious as previous strains and may cause even more severe disease among where can i buy levitra over the counter those who are unvaccinated. The viral load of those infected with delta – meaning the amount of levitra detected from the nasal passages of an infected person – is also reported to be over 1,000 times higher than in those infected with the original form of erectile dysfunction. Recent evidence also where can i buy levitra over the counter suggests that both unvaccinated and vaccinated people carry similar viral loads, further contributing to the especially contagious nature of this variant.3.

Which Variants Are Most Common in the US?. Over the course of a few months, the delta variant has become the predominant where can i buy levitra over the counter strain in the U.S., accounting for the vast majority of erectile dysfunction treatment cases at the end of July 2021.(Credit. The Conversation/CDC erectile dysfunction treatment Data Tracker)But there are regional variations across the country.

As of July 31, the CDC estimated that the alpha variant represented over 3% of cases identified in a region of eight states that includes where can i buy levitra over the counter Georgia, Florida and Tennessee, compared with less than 1% in the region that includes Iowa, Kansas, Missouri and Nebraska. The CDC tracks variants in cooperation with state health departments and other public health agencies. erectile dysfunction treatment samples from where can i buy levitra over the counter across the country are genetically sequenced each week to identify existing and new variants.And new variants will likely continue to appear as the levitra evolves.

Delta plus, for instance, is a sub-lineage of delta. The effects of this where can i buy levitra over the counter subvariant are yet to be determined.4. How Are treatments Holding Up Against Variants?.

Researchers are working to figure out how effective the three where can i buy levitra over the counter erectile dysfunction treatments currently authorized for emergency use in the U.S. Are at preventing from variants in “real-world” conditions where variant distribution and frequency constantly change. Several preliminary studies that have not yet been peer-reviewed suggest that these treatments are still effective in preventing erectile dysfunction treatment-related serious s and death.No treatment is perfect, however, and breakthrough erectile dysfunction treatment s are possible in those who where can i buy levitra over the counter are vaccinated.

Older adults and those with immunocompromising conditions may be at increased risk to have these breakthrough s.treatments are not foolproof, but they significantly reduce the risk of severe . (Credit. Xinhua News Agency/Getty Images)Thankfully, fully vaccinated individuals generally where can i buy levitra over the counter experience milder erectile dysfunction treatment s.

For example, a study analyzing erectile dysfunction treatment cases in England estimated that two doses of the Pfizer BioNTech treatment are 93.7% effective in preventing symptomatic disease from the alpha variant and 88% effective from delta. A different study in Ontario, Canada, that is not yet peer-reviewed reported that the Moderna treatment is 92% effective in preventing symptomatic where can i buy levitra over the counter disease from alpha.5. How Can I Stay Safe?.

How cautious where can i buy levitra over the counter you should be depends on a number of individual and external factors.One factor is whether you’re fully vaccinated. Nearly all - 99.5% - of erectile dysfunction treatment deaths in the U.S. Over the past few months were among unvaccinated people.The most recent CDC guidelines recommend that everyone wear a mask in areas of where can i buy levitra over the counter substantial or high transmission, regardless of whether or not they’re vaccinated.

More caution should especially be taken if you aren’t fully vaccinated or have a weakened immune system.Another factor to consider is the level of community transmission and the proportion of unvaccinated people in your local community. For example, someone who lives in an area that is below the national average for erectile dysfunction treatment vaccinations may have a higher chance of where can i buy levitra over the counter encountering someone who is unvaccinated – and so more likely to spread the erectile dysfunction – than someone in an area with higher vaccination rates.[embedded content]Finally, there are still a significant number of people who are at high risk of erectile dysfunction treatment, including children. As of Aug.

3, 2021, only 29.1% where can i buy levitra over the counter of children ages 12 to 15, and 40.4% of those ages 16 and 17, had been fully vaccinated. The American Academy of Pediatrics and the Children’s Hospital Association note that 4,292,120 total child erectile dysfunction treatment cases had been reported as of Aug. 5.

Children make up 14.3% of reported erectile dysfunction treatment cases. If your child is unvaccinated, the best way you can protect them and other unvaccinated members of your household is to get yourself vaccinated and have everyone wear a mask in indoor public spaces.Guidelines provided by public health agencies are simply that – general guidelines. They are not tailored to be prescriptive for each individual and their personal risk assessments.treatments remain the best protection against every strain of the novel erectile dysfunction.

But masking, social distancing and avoiding crowds and poorly ventilated indoor spaces add extra layers of protection against breakthrough s and lower your risk of inadvertently spreading the levitra.Lilly Cheng Immergluck is a professor at Morehouse School of Medicine. This article is republished from The Conversation under a Creative Commons license. Read the original article..

With the delta variant making buy levitra online from canada up over 93% of erectile dysfunction treatment cases where is better to buy levitra in the U.S. At the end of July 2021, questions arise about how to stay protected against evolving forms of the erectile dysfunction levitra. Here, pediatrician and infectious disease specialist Dr buy levitra online from canada. Lilly Cheng Immergluck of Morehouse School of Medicine answers some common questions about variants and what you can do to best protect yourself.1.

What Are buy levitra online from canada Variants and How Do They Emerge?. levitraes mutate over time to adapt to their environment and improve their survival. Over the course of the levitra, erectile dysfunction, the novel erectile dysfunction that causes erectile dysfunction treatment, has mutated enough to change both its ability to spread through the population and its ability to infect people.These new strains are called variants buy levitra online from canada. The U.S.

Centers for Disease Control and Prevention currently classifies variants into buy levitra online from canada three categories, listed in order of least to most concerning:Variant of Interest (VOI). Have features that may reduce your immune system’s ability to prevent . For example, you might have heard of VOI eta, buy levitra online from canada iota or kappa.Variant of Concern (VOC). Are less responsive to treatments or treatments and more likely to evade diagnostic detection.

They tend to be more transmissible, buy levitra online from canada or contagious, and result in more severe s. Alpha and delta are VOCs, for instance.Variant of High Consequence (VOHC). Are significantly less responsive to existing diagnostic, prevention and treatment options buy levitra online from canada. They also result in more severe s and hospitalizations.

There have not been any VOHCs identified so far.The World Health Organization uses similar classifications, but their definitions may differ from buy levitra online from canada the CDC’s U.S.-based ones, as variant features and effects may differ by geographic location.2. Are Variants Always More Harmful?. A variant may be more or less dangerous than other strains depending on the mutations in its genetic code. Mutations can buy levitra online from canada affect attributes like how contagious a viral variant is, how it interacts with the immune system or the severity of the symptoms it triggers.For example, the alpha variant is more transmissible than the original form of erectile dysfunction.

Studies show it’s somewhere between 43% to 90% more contagious than the levitra that was most common at the start of the levitra. Alpha also is more likely to cause severe buy levitra online from canada disease, as indicated by increased rates of hospitalization and death after .Even more extreme, the delta variant is reported to be nearly twice as contagious as previous strains and may cause even more severe disease among those who are unvaccinated. The viral load of those infected with delta – meaning the amount of levitra detected from the nasal passages of an infected person – is also reported to be over 1,000 times higher than in those infected with the original form of erectile dysfunction. Recent evidence also suggests that both unvaccinated and vaccinated people carry similar viral loads, further contributing to the especially buy levitra online from canada contagious nature of this variant.3.

Which Variants Are Most Common in the US?. Over the course of a few months, the delta variant has become the predominant strain in the U.S., accounting for the vast majority of erectile dysfunction treatment cases at buy levitra online from canada the end of July 2021.(Credit. The Conversation/CDC erectile dysfunction treatment Data Tracker)But there are regional variations across the country. As of July 31, buy levitra online from canada the CDC estimated that the alpha variant represented over 3% of cases identified in a region of eight states that includes Georgia, Florida and Tennessee, compared with less than 1% in the region that includes Iowa, Kansas, Missouri and Nebraska.

The CDC tracks variants in cooperation with state health departments and other public health agencies. erectile dysfunction treatment buy levitra online from canada samples from across the country are genetically sequenced each week to identify existing and new variants.And new variants will likely continue to appear as the levitra evolves. Delta plus, for instance, is a sub-lineage of delta. The effects of this subvariant are yet to be buy levitra online from canada determined.4.

How Are treatments Holding Up Against Variants?. Researchers are buy levitra online from canada working to figure out how effective the three erectile dysfunction treatments currently authorized for emergency use in the U.S. Are at preventing from variants in “real-world” conditions where variant distribution and frequency constantly change. Several preliminary studies that have not yet buy levitra online from canada been peer-reviewed suggest that these treatments are still effective in preventing erectile dysfunction treatment-related serious s and death.No treatment is perfect, however, and breakthrough erectile dysfunction treatment s are possible in those who are vaccinated.

Older adults and those with immunocompromising conditions may be at increased risk to have these breakthrough s.treatments are not foolproof, but they significantly reduce the risk of severe . (Credit. Xinhua News Agency/Getty Images)Thankfully, fully vaccinated individuals generally experience milder erectile dysfunction treatment buy levitra online from canada s. For example, a study analyzing erectile dysfunction treatment cases in England estimated that two doses of the Pfizer BioNTech treatment are 93.7% effective in preventing symptomatic disease from the alpha variant and 88% effective from delta.

A different study in Ontario, Canada, that is not yet peer-reviewed buy levitra online from canada reported that the Moderna treatment is 92% effective in preventing symptomatic disease from alpha.5. How Can I Stay Safe?. How cautious you buy levitra online from canada should be depends on a number of individual and external factors.One factor is whether you’re fully vaccinated. Nearly all - 99.5% - of erectile dysfunction treatment deaths in the U.S.

Over the past few months were among unvaccinated people.The most recent CDC guidelines recommend that everyone wear a mask in areas of substantial or high transmission, regardless buy levitra online from canada of whether or not they’re vaccinated. More caution should especially be taken if you aren’t fully vaccinated or have a weakened immune system.Another factor to consider is the level of community transmission and the proportion of unvaccinated people in your local community. For example, someone who lives in an area that is below the buy levitra online from canada national average for erectile dysfunction treatment vaccinations may have a higher chance of encountering someone who is unvaccinated – and so more likely to spread the erectile dysfunction – than someone in an area with higher vaccination rates.[embedded content]Finally, there are still a significant number of people who are at high risk of erectile dysfunction treatment, including children. As of Aug.

3, 2021, only buy levitra online from canada 29.1% of children ages 12 to 15, and 40.4% of those ages 16 and 17, had been fully vaccinated. The American Academy of Pediatrics and the Children’s Hospital Association note that 4,292,120 total child erectile dysfunction treatment cases had been reported as of Aug. 5. Children make up 14.3% of reported erectile dysfunction treatment cases.

If your child is unvaccinated, the best way you can protect them and other unvaccinated members of your household is to get yourself vaccinated and have everyone wear a mask in indoor public spaces.Guidelines provided by public health agencies are simply that – general guidelines. They are not tailored to be prescriptive for each individual and their personal risk assessments.treatments remain the best protection against every strain of the novel erectile dysfunction. But masking, social distancing and avoiding crowds and poorly ventilated indoor spaces add extra layers of protection against breakthrough s and lower your risk of inadvertently spreading the levitra.Lilly Cheng Immergluck is a professor at Morehouse School of Medicine. This article is republished from The Conversation under a Creative Commons license.

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Over the past 20 years, a large body of research has documented a relationship between higher nurse-to-patient staffing ratios and better patient outcomes, including shorter hospital stays, lower rates of failure to prevent mortality after an in-hospital complication, inpatient mortality for multiple types of patients, hospital-acquired pneumonia, unplanned extubation, respiratory failure and cardiac arrest.1–5 In addition, patients report higher satisfaction when they are cared for in hospitals with higher staffing levels.6 7To date, most studies have not identified an ‘optimal’ nurse staffing ratio,8 which creates levitra over the counter a challenge for determining appropriate staffing levels. If increasing nurse staffing always produces at least some improvement in the quality of care, how does one determine what staffing level is best?. This decision is ultimately an economic one, balancing the benefits of nurse staffing with the other options for which those resources could be levitra over the counter used. It is in this context that hospitals develop staffing plans, generally based on historical patterns of patient acuity.Practical challenges of nurse staffingHospital staffing plans provide the structure necessary for determining hiring and scheduling, but fall short for a number of reasons.

First, there are multiple ways in which patient acuity can be measured, which can have measurable effects on the staffing levels resulting from acuity models.9 Second, patient volume and acuity can shift rapidly levitra over the counter with changes in the volume of admissions, discharges and transfers between units. Third, staffing plans provide little guidance regarding the optimal mix of permanent staff, variable staff and externally contracted staff.The paper by Saville and colleagues10 in this issue of BMJ Quality &. Safety addresses the latter two issues by applying a simulation model to identify the optimal target for baseline nurse staffing in order to minimise periods of understaffing levitra over the counter. Included in this model is consideration of the extent to which hospitals should leverage temporary personnel (typically obtained through an external agency) to fill gaps.

The model acknowledges the likelihood that a hospital cannot realistically prevent all shifts from having a shortfall of nurses at all times, as well as the reality levitra over the counter that hospital managers lack information about the best balance between permanent and temporary staff. In addition, the analysis includes a calculation of the costs of each staffing approach, drawing from the records of 81 inpatient wards in four hospital organisations.The application of sophisticated simulation models and other advanced analyticl approaches to analysis of nurse staffing has been limited to date, and this paper is an exemplar of the value of such research. Recent studies have used machine learning methods to forecast hospital discharge volume,11 a discrete event simulation model to determine nursing staff needs in a neonatal intensive care unit,12 and a prediction model using machine learning and hierarchical linear regression to link variation in nurse staffing with patient outcomes.13 This new levitra over the counter study applied a unique Monte Carlo simulation model to estimate demand for nursing care and test different strategies to meet demand.The results of the analysis are not surprising in that hospitals are much less likely to experience understaffed patient shifts if they aim to have higher baseline staffing. The data demonstrate a notable leftward skew, indicating that hospitals are more likely to have large unanticipated increases in patient volume and acuity than to have unanticipated decreases.

This results in hospitals being more likely to have shifts that are understaffed than shifts that are overstaffed, which levitra over the counter inevitably places pressure on hospitals to staff at a higher level and/or have access to a larger pool of temporary nurses. It also is not surprising that hospitals will need to spend more money per patient day if they aim to reduce the percent of shifts that are understaffed. What is surprising about the results is that hospitals do not necessarily achieve cost savings by relying on temporary personnel versus setting regular staffing at a higher level.Trade-offs between permanent and temporary staffThe temporary nursing workforce enables healthcare facilities to maintain flexible yet full care teams based on patient care needs. Hospitals can use temporary nurses to address staffing gaps during leaves of absence, turnover or gaps between recruitment of permanent nurses, as levitra over the counter well as during high-census periods.

Temporary personnel are typically more expensive on an hourly basis than permanent staff. In addition, over-reliance on temporary levitra over the counter staff can have detrimental effects on permanent nurses’ morale and motivation. Orientations prior to shifts are often limited, which leads to a twofold concern as temporary nurses feel ill-prepared for shifts and permanent staff feel flustered when required to bring the temporary nurse up to speed while being expected to continue normal operations.14 Agency nurses may be assigned to patients and units that are incongruent with their experience and skills—either to unfamiliar units, which affects their ability to confidently deliver care, or to less complex patients where they feel as if their skills are not used adequately.14 15 These issues can create tension between temporary and permanent nursing staff, which can be compounded by the wage disparity. Permanent staff might feel demoralised and expendable levitra over the counter when working alongside temporary staff who are not integrated into the social fabric of the staff.16Hospital managers also must be cognisant of the potential quality impact of relying heavily on temporary nursing staff.

Research on the impact of contingent nursing employment on costs and quality have often found negative effects on quality, including mortality, and higher costs.17 18 However, other studies have found that the association between temporary nursing staff and low quality result from general shortages of nursing staff, which make a hospital more likely to employ temporary staff, and not directly from the contingent staff.19–21 Thus, temporary nurses play an important role in alleviating staffing shortages that would otherwise lead to lower quality of care.22Charting a path forward in hospital management and healthcare researchThe maturation of electronic health records and expansion of computerised healthcare management systems provide opportunities both for improved decision making about workforce deployment and for advanced workforce research. In the area of workforce management, nursing and other leaders have a levitra over the counter growing array of workforce planning tools available to them. Such tools are most effective when they display clear information about predicted patient needs and staff availability, but managers still must rely on their on-the-ground understanding of their staff and their context of patient care.23 Integration of human resources data with patient outcomes data has revealed that individual nurses and their characteristics have important discrete effects on the quality of care.24 25 Future development of workforce planning tools should translate this evidence to practice. In addition, new technology platforms are emerging to facilitate direct matching between temporary healthcare personnel and healthcare levitra over the counter organisations.

One recent study tested a smartphone-based application that allowed for direct matching of locum tenens physicians with a hospital in the English National Health Service, finding that the platform generated benefits including greater transparency and lower cost.26 Similar technologies for registered nurses could facilitate better matching between hospital needs and temporary nurses’ preparedness to meet those needs.Analytical methods that fully leverage the large datasets compiled through electronic health records, human resources systems and other sources can be applied to advance research on the composition of nursing teams to improve quality of care. As noted above, prior research has applied machine learning and discrete event simulation levitra over the counter to analyses of healthcare staffing. Other recent studies have leveraged natural language processing of nursing notes to identify fall risk factors27 and applied data mining of human resources records to understand the job titles held by nurses.28 Linking these rapidly advancing analytical approaches that assess the outcomes and costs of nurse staffing strategies, such as the work by Saville and colleagues published in this issue, to data on the impact of nurse staffing on the long-term costs of patient care will further advance the capacity of hospital leaders to design cost-effective policies for workforce deployment.Guidelines aim to align clinical care with best practice. However, simply publishing a guideline rarely triggers behavioural changes to match guideline recommendations.1–3 We thus transform guideline recommendations into actionable tasks by introducing interventions that promote behavioural changes meant to produce guideline-concordant care.

Unfortunately, not much has changed in the 25 years since levitra over the counter Oxman and colleagues concluded that we have no ‘magic bullets’ when it comes to changing clinician behaviour.4 In fact, far from magic bullets, interventions aimed at increasing the degree to which patients receive care recommended in guidelines (eg, educational interventions, reminders, audit and feedback, financial incentives, computerised decision support) typically produce disappointingly small improvements in care.5–10Much improvement work aims to ‘make the right thing to do the easy thing to do.’ Yet, design solutions which hardwire the desired actions remain few and far between. Further, improvement interventions which ‘softwire’ such actions—not guaranteeing that they occur, but at least increasing the likelihood that clinicians will deliver the care recommended in guidelines—mostly produce small improvements.5–9 Until this situation changes, we need to acknowledge the persistent reality that guidelines themselves represent a main strategy for promoting care consistent with current evidence, which means their design should promote the desired actions.11 12In this respect, guidelines constitute a type of clinical decision support. And, like levitra over the counter all decision support interventions, guidelines require. (1) user testing to assess if the content is understood as intended and (2) empirical testing to assess if the decision support provided by the guideline does in fact promote the desired behaviours.

While the levitra over the counter processes for developing guidelines have received substantial attention over the years,13–18 surprisingly little attention has been paid to empirically answering basic questions about the finished product. Do users understand guidelines as intended?. And, what version of a levitra over the counter given guideline engenders the desired behaviours by clinicians?. In this issue of BMJ Quality and Safety, Jones et al19 address this gap by using simulation to compare the frequency of medication errors when clinicians administer an intravenous medication using an existing guideline in the UK’s National Health Service (NHS) versus a revised and user-tested version of the guideline that more clearly promotes the desired actions.

Their findings demonstrate that levitra over the counter changes to guideline design (through addition of actionable decision supports) based on user feedback does in fact trigger changes in behaviour that can improve safety. This is an exciting use of simulation, which we believe should encourage further studies in this vein.Ensuring end users understand and use guidelines as intendedJones and colleagues’ approach affords an opportunity to reflect on the benefits of user testing and simulation of guidelines. The design and evaluation of their revised guidelines provides an excellent example of a careful stepwise progression in the development and levitra over the counter evaluation of a guideline as a type of decision support for clinicians. First, in a prior study,20 they user tested the original NHS guidelines to improve retrieval and comprehension of information.

The authors produced a revised guideline, which included reformatted sections as well as increased support for key calculations, such as for infusion rates. The authors again user tested the revised levitra over the counter guideline, successfully showing higher rates of comprehension. Note that user testing refers to a specific approach focused on comprehension rather than behaviour21 and is distinct from usability testing. Second, in the levitra over the counter current study, Jones et al evaluated whether nurse and midwife end users exhibited the desired behavioural changes when given the revised guidelines (with addition of actionable decision supports), compared with a control group working with the current version of the guidelines used in practice.

As a result, Jones and colleagues verify that end users (1) understand the content in the guideline and (2) actually change their behaviour in response to using it.Simulation can play a particularly useful role in this context, as it can help identify problems with users’ comprehension of the guideline and also empirically assess what behavioural changes occur in response to design changes in the guidelines. The level of methodological control and qualitative detail that simulation provides is difficult to feasibly replicate with real-world pilot studies, and therefore simulation fills a critical gap.Jones et al report successful changes in behaviour due to the levitra over the counter revised guidelines in which they added actionable decision supports. For example, their earlier user testing found that participants using the initial guidelines did not account for displacement volume when reconstituting the powdered drug, leading to dosing errors. A second error with the initial guidelines involved participants using the shortest infusion rate provided (eg, guidelines state ‘1 to 3 hours’), without levitra over the counter realising that the shortest rate is not appropriate for certain doses (eg, 1 hour is appropriate for smaller doses, but larger doses should not be infused over 1 hour because the drug would then be administered faster than the maximum allowable infusion rate of 3 mg/kg/hour).

These two issues were addressed in the revised guidelines by providing key determinants for ‘action’ such as calculation formulas that account for displacement volume and infusion duration, thereby more carefully guiding end users to avoid these dose and rate errors. These changes to the guideline triggered specific behaviours (eg, calculations that account for all variables) that did not occur with the initial guidelines levitra over the counter. Therefore, the simulation testing demonstrated the value of providing determinants for action, such as specific calculation formulas to support end users, by showing a clear reduction in dose and rate errors when using the revised guidelines compared with the initial guidelines.The authors also report that other types of medication-specific errors remained unaffected by the revised guidelines (eg, incorrect technique and flush errors)—the changes made did not facilitate the desired actions. The initial guidelines indicate ‘DO NOT SHAKE’ in capital letters, and there is levitra over the counter a section specific to ‘Flushing’.

In contrast, the revised guidelines do not capitalise the warning about shaking the vial, but embed the warning with a numbered sequence in the medication preparation section, aiming to increase the likelihood of reading it at the appropriate time. The revised guidelines do not have a section specific to flushing, but embed the flushing instructions as an unnumbered step in the administration section. Thus, the value of embedding technique and flushing information within the context of use was not validated in the simulation testing (ie, no significant differences in the rates levitra over the counter of these errors), highlighting precisely the pivotal role that simulation can play in assessing whether attempts to improve usability result in actual behavioural changes.Finally, simulation can identify potential unintended consequences of a guideline. For instance, Jones and colleagues observed an increase in errors (although not statistically significant) that were not medication specific (eg, non-aseptic technique such as hand washing, swabbing vials with an alcohol wipe).

Given that the revised guidelines were specific to the medication tested, it is unusual that we see a tendency toward a worsening effect on generic medication levitra over the counter preparation skills. Again, this finding was not significant, but we highlight this to remind ourselves of the very real possibility that some interventions might introduce new and unexpected errors in response to changing workflow and practice6. Simulations offer an opportunity to spot these risks in advance.Now that Jones et levitra over the counter al have seen how the revised guidelines change behaviour, they are optimally positioned to move forward. On one hand, they have the option of revising the guidelines further in attempts to address these resistant errors, and on the other, they can consider designing other interventions to be implemented in parallel with their user-tested guidance.

At first glance, the errors that were resistant to change appear to be mechanical tasks levitra over the counter that end users might think of as applying uniformly to multiple medications (eg, flush errors, non-aseptic technique). Therefore, a second intervention that has a more general scope (rather than drug specific) might be pursued. Regardless of what they decide to pursue, we applaud their measured approach and highlight that the key takeaway is that their next steps are supported with clearer evidence of what to expect when the guidelines are released—certainly a helpful piece of information to guide decisions as to whether broad levitra over the counter implementation of guidelines is justified.Caveats and conclusionSimulation is not a panacea—it is not able to assess longitudinal adherence, and there are limitations to how realistically clinicians behave when observed for a few sample procedures when under the scrutiny of observers. Further, studies where interventions are implemented to assess whether they move the needle on the outcomes we care about (eg, adverse events, length of stay, patient mortality) are needed and should continue.

However, having end users physically perform clinical tasks with the intervention in representative environments represents an important strategy levitra over the counter to assess the degree to which guidelines and other decision support interventions in fact promote the desired behaviours and to spot problems in advance of implementation. Such simulation testing is not currently a routine step in intervention design. We hope it becomes a more common phenomenon, with more improvement work following the example of the approach so effectively demonstrated by Jones and colleagues..

Over the past 20 years, a large body of research has documented a relationship between higher nurse-to-patient staffing ratios and better patient outcomes, including shorter hospital stays, lower rates of failure to prevent mortality after an in-hospital complication, inpatient mortality for multiple types of patients, hospital-acquired pneumonia, unplanned extubation, respiratory failure and cardiac arrest.1–5 In addition, patients report higher satisfaction when they Kamagra oral jelly wholesalers are cared for in buy levitra online from canada hospitals with higher staffing levels.6 7To date, most studies have not identified an ‘optimal’ nurse staffing ratio,8 which creates a challenge for determining appropriate staffing levels. If increasing nurse staffing always produces at least some improvement in the quality of care, how does one determine what staffing level is best?. This decision is buy levitra online from canada ultimately an economic one, balancing the benefits of nurse staffing with the other options for which those resources could be used.

It is in this context that hospitals develop staffing plans, generally based on historical patterns of patient acuity.Practical challenges of nurse staffingHospital staffing plans provide the structure necessary for determining hiring and scheduling, but fall short for a number of reasons. First, there are multiple ways in which patient acuity can be measured, which can have measurable effects on the staffing levels resulting from acuity models.9 Second, patient volume and acuity can shift rapidly with changes buy levitra online from canada in the volume of admissions, discharges and transfers between units. Third, staffing plans provide little guidance regarding the optimal mix of permanent staff, variable staff and externally contracted staff.The paper by Saville and colleagues10 in this issue of BMJ Quality &.

Safety addresses buy levitra online from canada the latter two issues by applying a simulation model to identify the optimal target for baseline nurse staffing in order to minimise periods of understaffing. Included in this model is consideration of the extent to which hospitals should leverage temporary personnel (typically obtained through an external agency) to fill gaps. The model acknowledges the likelihood that a hospital cannot realistically prevent all shifts from having a shortfall of nurses at buy levitra online from canada all times, as well as the reality that hospital managers lack information about the best balance between permanent and temporary staff.

In addition, the analysis includes a calculation of the costs of each staffing approach, drawing from the records of 81 inpatient wards in four hospital organisations.The application of sophisticated simulation models and other advanced analyticl approaches to analysis of nurse staffing has been limited to date, and this paper is an exemplar of the value of such research. Recent studies have used machine learning methods to forecast hospital discharge volume,11 a discrete event simulation model to determine nursing staff needs in a neonatal intensive care unit,12 and a prediction model using machine learning and hierarchical linear regression to link variation in nurse staffing with patient outcomes.13 This new study applied a unique Monte Carlo simulation model to estimate demand for nursing care and test different strategies to meet demand.The results of the analysis are not surprising in buy levitra online from canada that hospitals are much less likely to experience understaffed patient shifts if they aim to have higher baseline staffing. The data demonstrate a notable leftward skew, indicating that hospitals are more likely to have large unanticipated increases in patient volume and acuity than to have unanticipated decreases.

This results in hospitals being more likely to have shifts that are understaffed than shifts that are overstaffed, which inevitably places pressure on hospitals to staff buy levitra online from canada at a higher level and/or have access to a larger pool of temporary nurses. It also is not surprising that hospitals will need to spend more money per patient day if they aim to reduce the percent of shifts that are understaffed. What is surprising about the results is that hospitals do not necessarily achieve cost savings by relying on temporary personnel versus setting regular staffing at a higher level.Trade-offs between permanent and temporary staffThe temporary nursing workforce enables healthcare facilities to maintain flexible yet full care teams based on patient care needs.

Hospitals can use temporary nurses to address staffing gaps during leaves of absence, turnover or gaps between recruitment of buy levitra online from canada permanent nurses, as well as during high-census periods. Temporary personnel are typically more expensive on an hourly basis than permanent staff. In addition, over-reliance on buy levitra online from canada temporary staff can have detrimental effects on permanent nurses’ morale and motivation.

Orientations prior to shifts are often limited, which leads to a twofold concern as temporary nurses feel ill-prepared for shifts and permanent staff feel flustered when required to bring the temporary nurse up to speed while being expected to continue normal operations.14 Agency nurses may be assigned to patients and units that are incongruent with their experience and skills—either to unfamiliar units, which affects their ability to confidently deliver care, or to less complex patients where they feel as if their skills are not used adequately.14 15 These issues can create tension between temporary and permanent nursing staff, which can be compounded by the wage disparity. Permanent staff might feel demoralised and expendable when working alongside temporary staff who are not integrated into the buy levitra online from canada social fabric of the staff.16Hospital managers also must be cognisant of the potential quality impact of relying heavily on temporary nursing staff. Research on the impact of contingent nursing employment on costs and quality have often found negative effects on quality, including mortality, and higher costs.17 18 However, other studies have found that the association between temporary nursing staff and low quality result from general shortages of nursing staff, which make a hospital more likely to employ temporary staff, and not directly from the contingent staff.19–21 Thus, temporary nurses play an important role in alleviating staffing shortages that would otherwise lead to lower quality of care.22Charting a path forward in hospital management and healthcare researchThe maturation of electronic health records and expansion of computerised healthcare management systems provide opportunities both for improved decision making about workforce deployment and for advanced workforce research.

In the area of workforce management, nursing and other leaders have a growing array of workforce planning tools available buy levitra online from canada to them. Such tools are most effective when they display clear information about predicted patient needs and staff availability, but managers still must rely on their on-the-ground understanding of their staff and their context of patient care.23 Integration of human resources data with patient outcomes data has revealed that individual nurses and their characteristics have important discrete effects on the quality of care.24 25 Future development of workforce planning tools should translate this evidence to practice. In addition, new technology buy levitra online from canada platforms are emerging to facilitate direct matching between temporary healthcare personnel and healthcare organisations.

One recent study tested a smartphone-based application that allowed for direct matching of locum tenens physicians with a hospital in the English National Health Service, finding that the platform generated benefits including greater transparency and lower cost.26 Similar technologies for registered nurses could facilitate better matching between hospital needs and temporary nurses’ preparedness to meet those needs.Analytical methods that fully leverage the large datasets compiled through electronic health records, human resources systems and other sources can be applied to advance research on the composition of nursing teams to improve quality of care. As noted above, buy levitra online from canada prior research has applied machine learning and discrete event simulation to analyses of healthcare staffing. Other recent studies have leveraged natural language processing of nursing notes to identify fall risk factors27 and applied data mining of human resources records to understand the job titles held by nurses.28 Linking these rapidly advancing analytical approaches that assess the outcomes and costs of nurse staffing strategies, such as the work by Saville and colleagues published in this issue, to data on the impact of nurse staffing on the long-term costs of patient care will further advance the capacity of hospital leaders to design cost-effective policies for workforce deployment.Guidelines aim to align clinical care with best practice.

However, simply publishing a guideline rarely triggers behavioural changes to match guideline recommendations.1–3 We thus transform guideline recommendations into actionable tasks by introducing interventions that promote behavioural changes meant to produce guideline-concordant care. Unfortunately, not much has changed in the 25 years buy levitra online from canada since Oxman and colleagues concluded that we have no ‘magic bullets’ when it comes to changing clinician behaviour.4 In fact, far from magic bullets, interventions aimed at increasing the degree to which patients receive care recommended in guidelines (eg, educational interventions, reminders, audit and feedback, financial incentives, computerised decision support) typically produce disappointingly small improvements in care.5–10Much improvement work aims to ‘make the right thing to do the easy thing to do.’ Yet, design solutions which hardwire the desired actions remain few and far between. Further, improvement interventions which ‘softwire’ such actions—not guaranteeing that they occur, but at least increasing the likelihood that clinicians will deliver the care recommended in guidelines—mostly produce small improvements.5–9 Until this situation changes, we need to acknowledge the persistent reality that guidelines themselves represent a main strategy for promoting care consistent with current evidence, which means their design should promote the desired actions.11 12In this respect, guidelines constitute a type of clinical decision support.

And, like all buy levitra online from canada decision support interventions, guidelines require. (1) user testing to assess if the content is understood as intended and (2) empirical testing to assess if the decision support provided by the guideline does in fact promote the desired behaviours. While the processes for developing guidelines have received substantial attention buy levitra online from canada over the years,13–18 surprisingly little attention has been paid to empirically answering basic questions about the finished product.

Do users understand guidelines as intended?. And, what version of a given guideline engenders the desired behaviours buy levitra online from canada by clinicians?. In this issue of BMJ Quality and Safety, Jones et al19 address this gap by using simulation to compare the frequency of medication errors when clinicians administer an intravenous medication using an existing guideline in the UK’s National Health Service (NHS) versus a revised and user-tested version of the guideline that more clearly promotes the desired actions.

Their findings demonstrate that changes to guideline design (through addition of actionable decision supports) based on user feedback does in fact trigger changes in behaviour buy levitra online from canada that can improve safety. This is an exciting use of simulation, which we believe should encourage further studies in this vein.Ensuring end users understand and use guidelines as intendedJones and colleagues’ approach affords an opportunity to reflect on the benefits of user testing and simulation of guidelines. The design and evaluation of their revised guidelines provides an excellent example of buy levitra online from canada a careful stepwise progression in the development and evaluation of a guideline as a type of decision support for clinicians.

First, in a prior study,20 they user tested the original NHS guidelines to improve retrieval and comprehension of information. The authors produced a revised guideline, which included reformatted sections as well as increased support for key calculations, such as for infusion rates. The authors again user tested the revised guideline, buy levitra online from canada successfully showing higher rates of comprehension.

Note that user testing refers to a specific approach focused on comprehension rather than behaviour21 and is distinct from usability testing. Second, in the current study, Jones et al evaluated whether nurse and midwife end users exhibited the desired behavioural changes when given the revised guidelines (with addition of actionable decision supports), compared with buy levitra online from canada a control group working with the current version of the guidelines used in practice. As a result, Jones and colleagues verify that end users (1) understand the content in the guideline and (2) actually change their behaviour in response to using it.Simulation can play a particularly useful role in this context, as it can help identify problems with users’ comprehension of the guideline and also empirically assess what behavioural changes occur in response to design changes in the guidelines.

The level of methodological control and qualitative detail that simulation provides is difficult to feasibly replicate with real-world pilot studies, and therefore simulation fills a critical gap.Jones et al report successful changes in behaviour due to the revised guidelines in which they added actionable buy levitra online from canada decision supports. For example, their earlier user testing found that participants using the initial guidelines did not account for displacement volume when reconstituting the powdered drug, leading to dosing errors. A second error with the initial guidelines involved participants using the shortest infusion rate provided (eg, guidelines state ‘1 to 3 hours’), without realising that the shortest rate is not appropriate for certain doses (eg, 1 hour is appropriate for smaller doses, but larger doses should not be infused buy levitra online from canada over 1 hour because the drug would then be administered faster than the maximum allowable infusion rate of 3 mg/kg/hour).

These two issues were addressed in the revised guidelines by providing key determinants for ‘action’ such as calculation formulas that account for displacement volume and infusion duration, thereby more carefully guiding end users to avoid these dose and rate errors. These changes to the guideline triggered specific behaviours (eg, calculations that account for all variables) that did not occur with buy levitra online from canada the initial guidelines. Therefore, the simulation testing demonstrated the value of providing determinants for action, such as specific calculation formulas to support end users, by showing a clear reduction in dose and rate errors when using the revised guidelines compared with the initial guidelines.The authors also report that other types of medication-specific errors remained unaffected by the revised guidelines (eg, incorrect technique and flush errors)—the changes made did not facilitate the desired actions.

The initial guidelines indicate ‘DO NOT SHAKE’ in capital letters, buy levitra online from canada and there is a section specific to ‘Flushing’. In contrast, the revised guidelines do not capitalise the warning about shaking the vial, but embed the warning with a numbered sequence in the medication preparation section, aiming to increase the likelihood of reading it at the appropriate time. The revised guidelines do not have a section specific to flushing, but embed the flushing instructions as an unnumbered step in the administration section.

Thus, the value of embedding technique and flushing information within the context of use was not validated in the simulation testing (ie, no significant differences in the rates of these buy levitra online from canada errors), highlighting precisely the pivotal role that simulation can play in assessing whether attempts to improve usability result in actual behavioural changes.Finally, simulation can identify potential unintended consequences of a guideline. For instance, Jones and colleagues observed an increase in errors (although not statistically significant) that were not medication specific (eg, non-aseptic technique such as hand washing, swabbing vials with an alcohol wipe). Given that the revised guidelines were specific to the medication tested, it is unusual that we see a tendency toward a worsening effect on generic medication buy levitra online from canada preparation skills.

Again, this finding was not significant, but we highlight this to remind ourselves of the very real possibility that some interventions might introduce new and unexpected errors in response to changing workflow and practice6. Simulations offer an opportunity to spot these risks in advance.Now that Jones et al have seen how the revised guidelines change behaviour, they are optimally positioned to move forward buy levitra online from canada. On one hand, they have the option of revising the guidelines further in attempts to address these resistant errors, and on the other, they can consider designing other interventions to be implemented in parallel with their user-tested guidance.

At first glance, the errors that were resistant to change appear to be mechanical buy levitra online from canada tasks that end users might think of as applying uniformly to multiple medications (eg, flush errors, non-aseptic technique). Therefore, a second intervention that has a more general scope (rather than drug specific) might be pursued. Regardless of what they decide to pursue, we applaud their measured approach and highlight that the key takeaway is that their next steps are supported with clearer evidence of what to expect when the guidelines buy levitra online from canada are released—certainly a helpful piece of information to guide decisions as to whether broad implementation of guidelines is justified.Caveats and conclusionSimulation is not a panacea—it is not able to assess longitudinal adherence, and there are limitations to how realistically clinicians behave when observed for a few sample procedures when under the scrutiny of observers.

Further, studies where interventions are implemented to assess whether they move the needle on the outcomes we care about (eg, adverse events, length of stay, patient mortality) are needed and should continue. However, having end users physically perform clinical tasks with the intervention in representative environments represents an important strategy to assess the degree to which guidelines and other decision support interventions in fact promote the desired buy levitra online from canada behaviours and to spot problems in advance of implementation. Such simulation testing is not currently a routine step in intervention design.

We hope it becomes a more common phenomenon, with more improvement work following the example of the approach so effectively demonstrated by Jones and colleagues..

Dangers of levitra

IntroductionCurrently, type 1 diabetes mellitus (T1DM) is defined as an autoimmune disorder classically characterised by pancreatic islet beta-cell destruction triggered by autoreactive T cells, resulting in subsequent severe insulin deficiency and lifelong reliance on exogenous insulin.1 2 This autoimmune dangers of levitra diabetes accounts for 5%–19% of diabetes and represents the main form of diabetes in children and adolescents.3 Its incidence is increasing worldwide at a rate of 2%–5% per year.4 This rising incidence and multiple severe diabetic complications lead to increased mortality and morbidity and aggravate the economic burden of the disease. It is accepted that the interplay between genetic factors and environmental precipitators, including ancestry and geographic location, viral and bacterial s, vitamin D, hygiene and microbiota, leads to specific tissue inflammation, namely, insulitis, insulin-producing cell death and consequent clinical disease.5–9The genetic component of T1DM can be demonstrated by the fact that siblings and offspring of patients with T1DM have a higher risk than the general population, and disease concordance in identical twins is higher than that in dizygotic twins.10 11 Over the past few years, genome-wide association study (GWAS), which measures and analyses a million or more DNA sequence variations in known linkage regions in unrelated individuals, have identified at least 58 susceptible loci combined with linkage analysis and candidate gene studies (figure 1).12–14 Most of the identified variants are common (minor allele frequency (MAF) >5%) and have modest effects (OR <1.5), although the effects of susceptibility genes such as human leucocyte antigen (HLA), insulin (INS) and protein tyrosine phosphatase, non-receptor type 22 (PTPN22) are stronger (figure 1).13 The HLA region (OR >6), located on human chromosome 6p21 and identified by linkage analysis, accounts for the largest proportion of T1DM heritability and explains dangers of levitra approximately 50% of genetic T1DM risk.15 In addition to HLA, variants within the INS and PTPN22 loci, which were first identified by candidate gene studies, have larger effect sizes (OR >2) than other variants.13 The INS gene on human chromosome 11p15.5 offers the next strongest genetic risk association with T1DM after HLA and accounts for approximately 10% of genetic susceptibility to T1DM.16 It is believed that ‘missing heritability’ can be at least partially elucidated by rare and low-frequency variants (rare variants defined as variants with MAF ≤1% and low-frequency variants defined as variants with MAF=1%–5%), and some findings have indicated that rare variants have larger effect sizes than common variants.17–19 From an evolutionary standpoint, risk variants with higher penetrance are more likely to be rare due to negative selection. Taking an dangers of levitra extreme example, monogenic/Mendelian disorders such as autoimmune polyendocrinopathy syndrome type I are caused by rare variants with large effect sizes and high penetrance. Intriguingly, recent and previous studies focusing on the identification of rare and low-frequency variants involved in T1DM have found a handful of such variants, and some of them do have large effect sizes.13 20–23Candidate genes or loci of type 1 diabetes mellitus (T1DM) and their ORs (the yellow bars represent the rare and low-frequency genetic variants of T1DM).76–79 " data-icon-position data-hide-link-title="0">Figure 1 Candidate genes or loci of type 1 diabetes mellitus (T1DM) and their ORs (the yellow bars represent the rare and low-frequency genetic variants of T1DM).76–79However, some studies suggest that most rare variants have only small or modest effects.24 Therefore, it remains to be seen whether the tendency of rare and low-frequency variants to have large effects is a universal phenomenon. Even though dangers of levitra its practical value in clinical medicine may be restricted if the hypothesis that most rare variants have only a small effect is true, there is still intrinsic value in this field.

Such studies can lead to the discovery dangers of levitra of new candidate genes implicated in disorders or human phenotypes25 and determine causal genes in candidate regions identified by GWAS. Other than understanding better its pathophysiology, new loci could lead to the identification of new biomarkers or represent drug targets for T1DM.Identifying rare and low-frequency variantsRecently, advances in next-generation DNA sequencing technologies as well as bioinformatic tools and methods to process and analyse the resulting data have enhanced the ability of researchers to find rare variants, and the decreasing cost of these technologies has made it feasible to apply them to related studies (table 1).26 The most comprehensive approach is high-depth whole-genome sequencing (WGS) due to its excellent coverage. However, high costs and multiple computational challenges have restricted its application.21 In addition to WGS with high or low depth, SNP-array genome-wide dangers of levitra genotyping and imputation has been used to identify rare variants. Notably, current sequencing depth (especially 30x) of WGS is likely to miss at least some coding variants as compared with whole-exome sequencing (WES, especially >100x).View dangers of levitra this table:Table 1 Technologies and study designs for detecting rare variantsThere are some lower-cost alternatives as well. First, a combination of low-depth WGS and imputation is another choice.

Imputation is a statistical method that can determine genotypes that are not directly detected by taking advantage of various previously dangers of levitra sequenced reference panels. For instance, Martínez-Bueno and Alarcón-Riquelme identified rare variants that were jointly associated with systemic lupus erythematosus (SLE) within 98 SLE candidate genes by applying genome-wide imputation and other techniques.27 Notably, some studies have indicated that the newer imputation panels, such as the recent dangers of levitra Haplotype Reference Consortium panel and the combined UK10K and 1000 Genomes projects phase III, provide better quality of imputation for rare variants compared with early panel, such as the UK10K, which underlines the significance and potential of larger reference panels to impute rare variants.28 29 Nevertheless, the power of imputation for identifying rare variants is attenuated because its accuracy decreases with decreasing MAF. Additionally, studies have indicated that the utility of population-specific panels leads to improved imputation accuracy of rare variants.30 Therefore, the utilisation of imputation is relatively limited in non-European populations because of the lack of ethnicity-specific reference cohorts.Second, using WES finds rare variants within protein-coding regions. Given the reality that only an exceedingly small portion dangers of levitra of the human genome is coding sequence and the functions of protein-coding variants are more easily interpreted, WES is considered a cost-effective technique for discovering rare variants. However, an obvious defect is that WES ignores non-coding regions, which account for dangers of levitra 98% of the human genome.

Moreover, most loci identified by GWAS are located in non-coding regions, and evidence indicates that these regions play critical roles in complex disorders and have significant biological functions.31 32Third, targeted sequencing investigates a specific part of the genome, including candidate genes identified by previous studies and clinically significant genes. For instance, Rivas et al identified a protein-truncating variant of the gene dangers of levitra RNF186 that can exert a protective effect against ulcerative colitis via changed localisation and decreased expression by conducting targeted sequencing in regions previously associated with inflammatory bowel disease. They found that this loss-of-function variant was a promising therapeutic target.33 However, dangers of levitra some targeted sequencing studies have failed to detect rare risk variants, indicating the deficiency of this method in discovering rare and low-frequency variants.24 34In addition, burden tests, which collapse information for multiple variants into a single genetic score and analyse the association between the score and disease characteristic, are a common approach in genomics to potentialise identification of rare variants, because aggregating analysis of variants within a gene can improve the power to detect statistical signals between case and control subjects. For example, a study analysed WES data from 393 patients with idiopathic hypogonadotropic hypogonadism (IHH) against 123 136 control subjects from public sequencing database, and identified a significant burden in TYRO3, a candidate gene implicated in IHH in mouse models.35 However, this gene-based burden testing approach will lose power when effects of variants are not in the same direction or the causal variants only account for a small fraction.36Traditional genetic studies have focused mostly on DNA sequences collected from unrelated individuals. However, a variety of new study designs have been applied to finding rare variants dangers of levitra with the goal of decreasing sample sizes and costs.

The common feature of these designs, including extreme phenotype sampling, population isolates and family studies (table 1), is that they improve the power of rare variant testing by selecting a specific population.37–39Challenges for identifying rare and low-frequency variantsThe detection and analysis of rare and low-frequency variants constitute a rising research field, but this field has encountered dangers of levitra substantial obstacles and challenges. First, the statistical analysis of rare and low-frequency variants is far more complicated and difficult than the analysis of common variants. For example, because the number of rare variants is greater than the number of common variants, the significance threshold or p value established for GWAS is not appropriate for rare variant association studies.40 The linkage disequilibrium (LD) r2 between two rare variants or a common variant and a rare variant cannot be accurately calculated, and as such it is difficult to define if novel rare variants are independent from known rare or common variants.41 42 A variety of traditional methods used to reduce or eliminate confounding factors and population stratification, such as linear mixed effect models and principal components analysis, are not applicable dangers of levitra to the analysis of rare and low-frequency variants because rare variants and the distribution of disease risk are strictly localised. A study indicates that the dangers of levitra estimated ancestry scores can be used to control the population stratification if the pool of control is large. Also, off-targeted read might be applied for controlling population stratification in targeted sequencing.43 Moreover, because these variants are rare, the strategy used to analyse common variants, which is based on analysing a single variant at a time, is underpowered to detect rare variants and can do so only if the effect size or sample size is exceedingly large.44 Thus, alternative methods have been developed to analyse the aggregate effect of rare variants.45–47 These methods, such as burden tests, variance component test and exponential combination tests, evaluate association for multiple variants in a gene or a biologically region.

Combined analysis of genetic association data with other biological information, such as methylation, gene dangers of levitra expression and biological pathways, can also leads to substantial gain In the statistical power of rare variants studies.48–50Second, it still remains challenging to apply genetic information obtained by rare variants association studies to diagnostic and prognostic medicine because some healthy individuals carry deleterious variants. For example, Flannick et al found that a large portion of the general population carries low-frequency non-synonymous mutations that can change the length or sequence of coding proteins in maturity-onset diabetes of young genes, and these carriers remain normoglycaemic through middle age.51 In addition, Bick et al discovered that rare variants in sarcomere protein genes could boost the risk of adverse cardiovascular events in Framingham Heart Study participants, and more surprisingly, a large number of non-synonymous variants, including nonsense, dangers of levitra missense and splice variants, are present in healthy populations.52 Therefore, the functional validation of rare and low-frequency genetic variants is necessary to determine the causality in genotype-phenotype analysis.Third, many rare and low-frequency variants are geographically localised and population specific, so it is difficult to find suitable replication panels and generate a common population. Nelson et al sequenced 202 drug target genes in coding regions in 14 002 people and found that 95% of observed variants are rare and at least 74% are detected in only one or two individuals.53 Similarly, a study conducted in 2440 individuals of African and European ancestry found that 86% of over 500 000 variants identified are rare, and most are previously unknown.54 Notably, these studies indicate that the vast majority of rare variant allelic spectra are unique to their sample sets and need to be identified by direct resequencing.Finally, although some detection studies of rare and low-frequency variants, such as WES and data processing software, are relatively standardised, many aspects of this emerging field, including WES capture technologies and even the definition of rare variants, still do not have uniform standards. Therefore, combining data generated from different groups is problematic.Benefits of identifying rare and low-frequency variantsIt has been suggested that rare and low-frequency variants account for a large proportion dangers of levitra of the genetic variation in the human genome represented by the 1000 Genomes Project.55 56 Although a substantial number of SNPs have been identified by GWAS, there is still a so-called ‘missing heritability’ phenomenon in complex disorders.57 For instance, GWAS have identified >80 common variants with small effect sizes for T2DM, which can explain only 10% of the total heritability.58 To address this issue, several hypotheses have been proposed, and great technological advances have provided a better understanding of the genetic architecture of common diseases over the past several years. Rare and low-frequency variants can influence both susceptibility to common complex diseases and their phenotypes (table 2).59–62 For example, researchers performed WGS in 1038 pulmonary arterial hypertension (PAH, a rare disorder characterised by occlusion dangers of levitra of arterioles in the lung) cases and 6385 control subjects and make the total proportion of cases explained by mutations increased to 23.5% from previously established 19.9% by incorporating novel rare variants and genes identified.63 Also, a study indicated that rare variants of SLC22A12 gene influence urate reabsorption and the heritability explained by these SLC22A12 variants exceeds 10%, indicating that rare functional variants make substantial contribution to the ‘missing heritability’ of serum urate level.64 In fact, a ‘common disease-rare variant model’ that assumes rare variants with high penetrance may be involved in increased complex disease risk has been proposed.59 65 It is obvious that great genetic heterogeneity exists under this model.

Intriguingly, in line with this model, some autoimmune diseases, such as T1DM, are extremely heterogeneous.View this table:Table 2 Rare and low-frequency variants associated with T1DM, T2DM and other autoimmune diseasesBesides rare and low-frequency genetic variants, there are some other hypotheses to explain the ‘missing heritability’.59 For example, empirical and theoretical analyses have indicated that multiple genetic variants with small effects are missed because GWAS are underpowered to capture these variants, therefore, taking into account genetic variants with smaller effects that do not reach significance will contribute to disease susceptibility and phenotype variability. Additionally, structural variants, such as CNV, are poorly studied owing to insufficient coverage on SNP dangers of levitra chips.66 The presence of gene-gene (epistasis) and gene-environmental interactions may also contribute to the ‘missing heritability’.67In addition, the candidate regions identified by GWAS sometimes harbour several different genes. Identifying rare genetic variants is helpful to pinpoint causal genes within the loci identified by GWAS.68 Moreover, the identification of rare and low-frequency variants may result in the identification of new candidate genes.40 For instance, researchers identified a heterozygote truncating mutation within CLCN1 gene by performing WES in patients with statin-associated myopathy and therefore, determined a novel candidate gene of this disease.69 Additionally, it has been suggested that rare variants are likely to have appeared more recently than common variants, leading to reduced LD and making them more easily interpretable than common variants.21Moreover, early studies have indicated that rare and low-frequency genetic variants may have larger effects on complex disease phenotypes and susceptibility than common variants.70 Therefore, it is helpful to reveal the genetic pathways underlying diseases and to dangers of levitra provide clinically actionable targets for personalised medicine. As an example, Roth et al found that rare and low-frequency genetic variants with large phenotypic effects within the proprotein convertase subtilisin/kexin 9 (PCSK9) gene, which encodes products that bind to the low-density lipoprotein (LDL) receptor and increase its degradation, can lower the risk of coronary heart disease (CHD) by reducing the circulating level of LDL cholesterol.71 Based on this research, a fully human monoclonal antibody targeting PCSK9 has been proven to increase LDL receptor recycling and decrease LDL cholesterol level.72 These findings provide a new treatment and prevention strategy for hypercholesterolaemia and CHD and offer inspiration for the transformation of genetic discoveries into clinical practice.Rare and low-frequency variants and T1DMFocusing on autoimmune diabetes, fully understanding the genetic factors underlying T1DM is beneficial for revealing its pathophysiology, discovering new drug targets and developing predictive and personalised medicine (figure 2). It is especially vital and valuable because dangers of levitra T1DM is extremely complex and heterogeneous.

The candidate T1DM loci identified by GWAS sometimes contain several dangers of levitra distinct genes, and strong LD makes it difficult to pinpoint the precise causative genes in genomic regions. In addition, the fact that many SNPs reside in non-coding regions or do not have obvious functional effects offers few clues to ascertain the causative genes. However, the discovery of rare and low-frequency disease-associated variants is helpful for T1DM candidate gene dangers of levitra identification. The T1DM-associated region on dangers of levitra human chromosome 2q24 harbours interferon (IFN) induced with helicase C domain 1 (IFIH1), GCA, FAP and part of KCNH7. The interaction between IFIH1 and double-stranded RNA, a byproduct of viral replication, leads to the secretion of IFNs.

While IFIH1 is a plausible susceptibility gene on the basis of its biological function, there is no direct evidence to indicate which of these genes in this locus is responsible for increased T1DM dangers of levitra risk. Nejentsev et al resequenced the exons and splice sites of 10 candidate genes in pools of DNA dangers of levitra from 480 patients and 480 controls and discovered 4 rare or low-frequency variants (OR=0.51–0.74, MAF <3%) with low LD within IFIH1 that could change the structure or expression of its product, melanoma differentiation-associated protein 5 and protect against T1DM.23 This finding suggests that IFIH1 is the disease-causing gene. Moreover, Ge et al found several rare deleterious variants, including two novel frameshift mutations (ss538819444 and ss37186329) and two missense mutations (rs74163663 and rs56048322) within PTPN22 by deeply sequencing the protein-coding regions of 301 genes in 49 loci previously identified by GWAS in 70 T1DM cases of European ancestry.22 This finding further confirmed that PTPN22 is a T1DM candidate gene on chromosome 1p13.2. Subsequent genotyping in dangers of levitra 3609 families with T1DM indicated rs56048322 (MAF=0.87%), which leads to the production of two alternative PTPN22 transcripts and a novel isoform of its encoding protein, LYP, through affecting splicing of PTPN22, was significantly associated with T1DM independent of T1DM-associated common variant rs2476601. Functional analysis showed this isoform of LYP can cause hyporesponsiveness of CD4+ T cell to antigen stimulation in patients with T1DM.50 candidate loci have dangers of levitra been identified by genome-wide association study.

The genetic variants within these risk regions can be divided into common variants, low-frequency variants and rare variants according to their different minor allele frequencies. The rare and low-frequency variants are likely to have more practical value in the treatment of T1DM because dangers of levitra their ORs are larger than those of common variants. However, as the study of rare and low-frequency variants is an dangers of levitra emerging research field, some hypotheses are still controversial and need further investigation. LD, linkage disequilibrium. MAF.

Minor allele frequency." class="highwire-fragment fragment-images colorbox-load" rel="gallery-fragment-images-48462583" data-figure-caption="The development of type 1 diabetes mellitus (T1DM). T1DM is caused by interplay between genetic and environmental factors, and epigenetics serves as a bridge between the two. To date, >50 candidate loci have been identified by genome-wide association study. The genetic variants within these risk regions can be divided into common variants, low-frequency variants and rare variants according to their different minor allele frequencies. The rare and low-frequency variants are likely to have more practical value in the treatment of T1DM because their ORs are larger than those of common variants.

However, as the study of rare and low-frequency variants is an emerging research field, some hypotheses are still controversial and need further investigation. LD, linkage disequilibrium. MAF. Minor allele frequency." data-icon-position data-hide-link-title="0">Figure 2 The development of type 1 diabetes mellitus (T1DM). T1DM is caused by interplay between genetic and environmental factors, and epigenetics serves as a bridge between the two.

To date, >50 candidate loci have been identified by genome-wide association study. The genetic variants within these risk regions can be divided into common variants, low-frequency variants and rare variants according to their different minor allele frequencies. The rare and low-frequency variants are likely to have more practical value in the treatment of T1DM because their ORs are larger than those of common variants. However, as the study of rare and low-frequency variants is an emerging research field, some hypotheses are still controversial and need further investigation. LD, linkage disequilibrium.

MAF. Minor allele frequency.Additionally, as mentioned above, most variants that confer T1DM risk are common and have modest effects, limiting the clinical application of their discovery. However, some research has suggested that rare and low-frequency variants might have larger effect sizes than common variants. Theoretically, if a disorder affects reproduction, such as an autoimmune disease with early onset, genetic variants with strong effects will be maintained at a relatively low frequency through negative selection.21 Forgetta et al applied deep imputation of genotyped data in 9358 patients with T1DM and 15 705 controls from European cohorts to identify novel rare and low-frequency variants with large effect sizes on T1DM risk.13 Three novel rare and low-frequency variants, including rs192324744 in LDL receptor-related protein 1B (LRP1B, MAF=1.3%, OR=1.63), rs60587303 in serine threonine kinase 39 (STK39, MAF=0.5%, OR=1.97) and the intergenic variant rs2128344 (MAF=0.55%, OR=2.12), were found and validated by subsequent de novo genotyping.13 Notably, the effects of these SNPs (ORs ≥1.5) are comparable to those of the lead variants in INS and PTPN22. In vitro experiments indicated that STK39 is involved in T cell activation and effector functions and that inhibition of Stk39 can augment the inflammatory response by enhancing interleukin (IL)-2 signalling.

Therefore, STK39 may be a promising clinical intervention target.13Besides, previous study through fine mapping of known T1DM susceptible loci has identified a low-frequency variant rs34536443 (MAF=4%, OR=0.67) within tyrosine kinase 2 (TYK2) and a rare variant rs41295121 (MAF=1%, OR=0.49) within RNA binding motif protein 17 (RBM17, in the same locus as IL2RA).20 TYK2, belonging to Janus kinase (JAK) family, is associated with regulation of type I IFN signalling pathway. Some studies have demonstrated that rs34530443 plays protective roles in multiple autoimmune disorders and the underlying mechanisms might lie in the diminishment of IL-12, IL-23 and type I IFN signalling.73 The specific function of rs41295121 in context of autoimmunity and T1DM needs further investigation.As for some practical issues such as sample sizes and high costs, a study indicated that a well-powered rare variant association study should include discovery sets with at least 25 000 cases and a substantial replication set.44 There are some alternative methods to decrease the sample sizes or costs in the context of T1DM. For example, combined analysis of rare variants within a T1DM-associated gene or region can lead to substantial reduction of required sample sizes. In addition, preferential selection of individuals with extreme phenotype on the basis of known risk factors, including age of disease onset, family history of diabetes and diabetic auto-antibodies, can also improve the association power because rare variants might be enriched among them.74Overall, among the identified T1DM loci, the candidate genes with rare or low-frequency variants include TYK2, IFIH1, RBM17, PTPN22, STK39 and LRP1B.13 20 22 23 Many unidentified variants may remain to be dissected, because studies focused on other diseases suggest that rare and low-frequency variants account for the majority of all variants.27 75ConclusionDriven by advancements in sequencing technologies, there has been great improvement in the identification of rare and low-frequency variants that cause complex human diseases, such as T1DM. The benefits of this field can be stated as follows.

(1) characterisation of rare and low-frequency variants may lead to a full understanding of the genetic component of this disorder. (2) detection of rare and low-frequency variants can pinpoint the genes that are actually responsible for increased T1DM risk within the loci identified by GWAS. (3) some new candidate genes for T1DM can be found due to enhanced power to discover rare variants. (4) rare and low-frequency variants are expected to make a significant contribution to human phenotypes and disease susceptibility because some studies indicate the majority of protein-coding variants tend to be evolutionarily recent and rare54. (5) accumulated evidence indicates that rare and low-frequency variants have larger phenotypic effects than common variants, suggesting that they will offer more actionable clinical targets and hold tremendous promise in predictive and personalised medicine.However, some issues remain to be addressed.

First, controversy persists about the importance of rare and low-frequency variants in common diseases. Encouragingly, recent studies have found that some such variants, such as rs60587303 in STK39, indeed have larger effect sizes than common variants in the pathogenesis of T1DM. Second, the candidate genes for T1DM that have rare or low-frequency variants included only TYK2, RBM17, IFIH1, PTPN22, STK39 and LRP1B, which means there may still be many unidentified variants. Moreover, most studies in this field have examined European populations. However, rare and low-frequency variants are geographically localised and population specific.

In particular, the heritable background of T1DM varies among different ethnic groups. These facts will limit the practical application of rare and low-frequency variants.In conclusion, the identification of rare and low-frequency genetic variants will provide new insights into the pathophysiology of T1DM and offer new potential drug targets in the post-GWAS era, despite the many challenges and uncertainties remaining in this field.AbstractAccurate classification of variants in cancer susceptibility genes (CSGs) is key for correct estimation of cancer risk and management of patients. Consistency in the weighting assigned to individual elements of evidence has been much improved by the American College of Medical Genetics (ACMG) 2015 framework for variant classification, UK Association for Clinical Genomic Science (UK-ACGS) Best Practice Guidelines and subsequent Cancer Variant Interpretation Group UK (CanVIG-UK) consensus specification for CSGs. However, considerable inconsistency persists regarding practice in the combination of evidence elements. CanVIG-UK is a national subspecialist multidisciplinary network for cancer susceptibility genomic variant interpretation, comprising clinical scientist and clinical geneticist representation from each of the 25 diagnostic laboratories/clinical genetic units across the UK and Republic of Ireland.

Here, we summarise the aggregated evidence elements and combinations possible within different variant classification schemata currently employed for CSGs (ACMG, UK-ACGS, CanVIG-UK and ClinGen gene-specific guidance for PTEN, TP53 and CDH1). We present consensus recommendations from CanVIG-UK regarding (1) consistent scoring for combinations of evidence elements using a validated numerical ‘exponent score’ (2) new combinations of evidence elements constituting likely pathogenic’ and ‘pathogenic’ classification categories, (3) which evidence elements can and cannot be used in combination for specific variant types and (4) classification of variants for which there are evidence elements for both pathogenicity and benignity.geneticsgenomicsgenetic testinggeneticsmedicalgenetic variationhttps://creativecommons.org/licenses/by/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See. Https://creativecommons.org/licenses/by/4.0/..

IntroductionCurrently, type 1 diabetes mellitus (T1DM) is defined as an autoimmune disorder classically characterised by pancreatic islet beta-cell destruction triggered by autoreactive T cells, resulting in subsequent severe insulin deficiency and lifelong reliance on exogenous insulin.1 discount levitra prices 2 This autoimmune diabetes accounts for 5%–19% of diabetes and represents the main form of diabetes in children and adolescents.3 Its incidence is increasing worldwide at a rate of 2%–5% per year.4 This rising incidence and buy levitra online from canada multiple severe diabetic complications lead to increased mortality and morbidity and aggravate the economic burden of the disease. It is accepted that the interplay between genetic factors and environmental precipitators, including ancestry and geographic location, viral and bacterial s, vitamin D, hygiene and microbiota, leads to specific tissue inflammation, namely, insulitis, insulin-producing cell death and consequent clinical disease.5–9The genetic component of T1DM can be demonstrated by the fact that siblings and offspring of patients with T1DM have a higher risk than the general population, and disease concordance in identical twins is higher than that buy levitra online from canada in dizygotic twins.10 11 Over the past few years, genome-wide association study (GWAS), which measures and analyses a million or more DNA sequence variations in known linkage regions in unrelated individuals, have identified at least 58 susceptible loci combined with linkage analysis and candidate gene studies (figure 1).12–14 Most of the identified variants are common (minor allele frequency (MAF) >5%) and have modest effects (OR <1.5), although the effects of susceptibility genes such as human leucocyte antigen (HLA), insulin (INS) and protein tyrosine phosphatase, non-receptor type 22 (PTPN22) are stronger (figure 1).13 The HLA region (OR >6), located on human chromosome 6p21 and identified by linkage analysis, accounts for the largest proportion of T1DM heritability and explains approximately 50% of genetic T1DM risk.15 In addition to HLA, variants within the INS and PTPN22 loci, which were first identified by candidate gene studies, have larger effect sizes (OR >2) than other variants.13 The INS gene on human chromosome 11p15.5 offers the next strongest genetic risk association with T1DM after HLA and accounts for approximately 10% of genetic susceptibility to T1DM.16 It is believed that ‘missing heritability’ can be at least partially elucidated by rare and low-frequency variants (rare variants defined as variants with MAF ≤1% and low-frequency variants defined as variants with MAF=1%–5%), and some findings have indicated that rare variants have larger effect sizes than common variants.17–19 From an evolutionary standpoint, risk variants with higher penetrance are more likely to be rare due to negative selection. Taking an buy levitra online from canada extreme example, monogenic/Mendelian disorders such as autoimmune polyendocrinopathy syndrome type I are caused by rare variants with large effect sizes and high penetrance. Intriguingly, recent and previous studies focusing on the identification of rare and low-frequency variants involved in T1DM have found a handful of such variants, and some of them do have large effect sizes.13 20–23Candidate genes or loci of type 1 diabetes mellitus (T1DM) and their ORs (the yellow bars represent the rare and low-frequency genetic variants of T1DM).76–79 " data-icon-position data-hide-link-title="0">Figure 1 Candidate genes or loci of type 1 diabetes mellitus (T1DM) and their ORs (the yellow bars represent the rare and low-frequency genetic variants of T1DM).76–79However, some studies suggest that most rare variants have only small or modest effects.24 Therefore, it remains to be seen whether the tendency of rare and low-frequency variants to have large effects is a universal phenomenon.

Even though its practical value in clinical medicine may be restricted buy levitra online from canada if the hypothesis that most rare variants have only a small effect is true, there is still intrinsic value in this field. Such studies can lead to the discovery of new candidate genes buy levitra online from canada implicated in disorders or human phenotypes25 and determine causal genes in candidate regions identified by GWAS. Other than understanding better its pathophysiology, new loci could lead to the identification of new biomarkers or represent drug targets for T1DM.Identifying rare and low-frequency variantsRecently, advances in next-generation DNA sequencing technologies as well as bioinformatic tools and methods to process and analyse the resulting data have enhanced the ability of researchers to find rare variants, and the decreasing cost of these technologies has made it feasible to apply them to related studies (table 1).26 The most comprehensive approach is high-depth whole-genome sequencing (WGS) due to its excellent coverage. However, high costs and buy levitra online from canada multiple computational challenges have restricted its application.21 In addition to WGS with high or low depth, SNP-array genome-wide genotyping and imputation has been used to identify rare variants.

Notably, current sequencing depth (especially 30x) of WGS is likely to miss at least some coding variants as compared with whole-exome sequencing (WES, especially >100x).View this table:Table 1 buy levitra online from canada Technologies and study designs for detecting rare variantsThere are some lower-cost alternatives as well. First, a combination of low-depth WGS and imputation is another choice. Imputation is a statistical method that can determine genotypes that are not directly detected buy levitra online from canada by taking advantage of various previously sequenced reference panels. For instance, Martínez-Bueno and Alarcón-Riquelme identified rare variants that were jointly associated with systemic lupus erythematosus (SLE) within 98 SLE candidate genes by applying genome-wide imputation and other techniques.27 Notably, some studies have indicated that the newer imputation panels, such as the recent Haplotype Reference Consortium panel and the combined UK10K and 1000 Genomes projects phase III, provide better quality of imputation for rare variants compared with early panel, such as the UK10K, which underlines the significance and buy levitra online from canada potential of larger reference panels to impute rare variants.28 29 Nevertheless, the power of imputation for identifying rare variants is attenuated because its accuracy decreases with decreasing MAF.

Additionally, studies have indicated that the utility of population-specific panels leads to improved imputation accuracy of rare variants.30 Therefore, the utilisation of imputation is relatively limited in non-European populations because of the lack of ethnicity-specific reference cohorts.Second, using WES finds rare variants within protein-coding regions. Given the buy levitra online from canada reality that only an exceedingly small portion of the human genome is coding sequence and the functions of protein-coding variants are more easily interpreted, WES is considered a cost-effective technique for discovering rare variants. However, an obvious defect is that WES ignores non-coding regions, which account for buy levitra online from canada 98% of the human genome. Moreover, most loci identified by GWAS are located in non-coding regions, and evidence indicates that these regions play critical roles in complex disorders and have significant biological functions.31 32Third, targeted sequencing investigates a specific part of the genome, including candidate genes identified by previous studies and clinically significant genes.

For instance, Rivas et al identified a protein-truncating variant of the gene RNF186 that can exert a protective effect against ulcerative colitis via changed localisation and decreased expression by conducting buy levitra online from canada targeted sequencing in regions previously associated with inflammatory bowel disease. They found that this loss-of-function variant was a promising therapeutic target.33 However, some targeted sequencing studies have failed to detect rare risk variants, indicating the deficiency of this method in discovering rare and low-frequency variants.24 34In addition, burden tests, which collapse information for multiple variants into a single genetic score and analyse the association between the score and disease characteristic, are a common approach in genomics to potentialise identification of rare variants, because aggregating analysis of variants within a gene can improve the power buy levitra online from canada to detect statistical signals between case and control subjects. For example, a study analysed WES data from 393 patients with idiopathic hypogonadotropic hypogonadism (IHH) against 123 136 control subjects from public sequencing database, and identified a significant burden in TYRO3, a candidate gene implicated in IHH in mouse models.35 However, this gene-based burden testing approach will lose power when effects of variants are not in the same direction or the causal variants only account for a small fraction.36Traditional genetic studies have focused mostly on DNA sequences collected from unrelated individuals. However, a variety of buy levitra online from canada new study designs have been applied to finding rare variants with the goal of decreasing sample sizes and costs.

The common feature of these designs, including extreme phenotype sampling, population isolates and family studies (table 1), is that they improve the power of rare variant testing by selecting a specific population.37–39Challenges for identifying rare and buy levitra online from canada low-frequency variantsThe detection and analysis of rare and low-frequency variants constitute a rising research field, but this field has encountered substantial obstacles and challenges. First, the statistical analysis of rare and low-frequency variants is far more complicated and difficult than the analysis of common variants. For example, because the number of rare variants is greater than the number of common variants, the significance threshold or p value established for GWAS is not appropriate for rare variant association studies.40 The linkage disequilibrium (LD) r2 between two rare variants or a common variant and a rare variant cannot be accurately calculated, and as such it is difficult to define if novel rare variants are independent from known rare or common variants.41 42 A variety of traditional methods used to reduce or eliminate confounding factors and population stratification, such as linear buy levitra online from canada mixed effect models and principal components analysis, are not applicable to the analysis of rare and low-frequency variants because rare variants and the distribution of disease risk are strictly localised. A study indicates that the estimated ancestry scores can be used to control the population stratification if buy levitra online from canada the pool of control is large.

Also, off-targeted read might be applied for controlling population stratification in targeted sequencing.43 Moreover, because these variants are rare, the strategy used to analyse common variants, which is based on analysing a single variant at a time, is underpowered to detect rare variants and can do so only if the effect size or sample size is exceedingly large.44 Thus, alternative methods have been developed to analyse the aggregate effect of rare variants.45–47 These methods, such as burden tests, variance component test and exponential combination tests, evaluate association for multiple variants in a gene or a biologically region. Combined analysis of genetic association data with other biological information, such as methylation, gene expression and biological pathways, can also leads to substantial gain In the statistical power of rare variants studies.48–50Second, it still remains challenging to apply genetic buy levitra online from canada information obtained by rare variants association studies to diagnostic and prognostic medicine because some healthy individuals carry deleterious variants. For example, Flannick et al found that a large portion of the general population carries low-frequency non-synonymous mutations that can change the length or sequence of coding proteins in maturity-onset diabetes of young genes, and these carriers remain normoglycaemic through middle age.51 In addition, Bick et al discovered that rare variants in sarcomere protein genes could boost the risk of adverse cardiovascular events in Framingham Heart Study participants, and more surprisingly, a large number of non-synonymous variants, including nonsense, missense and splice variants, are present in healthy populations.52 Therefore, the functional validation of rare and low-frequency genetic variants is necessary buy levitra online from canada to determine the causality in genotype-phenotype analysis.Third, many rare and low-frequency variants are geographically localised and population specific, so it is difficult to find suitable replication panels and generate a common population. Nelson et al sequenced 202 drug target genes in coding regions in 14 002 people and found that 95% of observed variants are rare and at least 74% are detected in only one or two individuals.53 Similarly, a study conducted in 2440 individuals of African and European ancestry found that 86% of over 500 000 variants identified are rare, and most are previously unknown.54 Notably, these studies indicate that the vast majority of rare variant allelic spectra are unique to their sample sets and need to be identified by direct resequencing.Finally, although some detection studies of rare and low-frequency variants, such as WES and data processing software, are relatively standardised, many aspects of this emerging field, including WES capture technologies and even the definition of rare variants, still do not have uniform standards.

Therefore, combining data generated from different groups is buy levitra online from canada problematic.Benefits of identifying rare and low-frequency variantsIt has been suggested that rare and low-frequency variants account for a large proportion of the genetic variation in the human genome represented by the 1000 Genomes Project.55 56 Although a substantial number of SNPs have been identified by GWAS, there is still a so-called ‘missing heritability’ phenomenon in complex disorders.57 For instance, GWAS have identified >80 common variants with small effect sizes for T2DM, which can explain only 10% of the total heritability.58 To address this issue, several hypotheses have been proposed, and great technological advances have provided a better understanding of the genetic architecture of common diseases over the past several years. Rare and low-frequency variants can influence both susceptibility to common complex diseases and their phenotypes (table 2).59–62 For example, researchers performed WGS in 1038 pulmonary arterial hypertension (PAH, a rare disorder characterised by occlusion of arterioles in the lung) cases and 6385 control subjects and make the total proportion of cases explained by mutations increased to 23.5% from previously buy levitra online from canada established 19.9% by incorporating novel rare variants and genes identified.63 Also, a study indicated that rare variants of SLC22A12 gene influence urate reabsorption and the heritability explained by these SLC22A12 variants exceeds 10%, indicating that rare functional variants make substantial contribution to the ‘missing heritability’ of serum urate level.64 In fact, a ‘common disease-rare variant model’ that assumes rare variants with high penetrance may be involved in increased complex disease risk has been proposed.59 65 It is obvious that great genetic heterogeneity exists under this model. Intriguingly, in line with this model, some autoimmune diseases, such as T1DM, are extremely heterogeneous.View this table:Table 2 Rare and low-frequency variants associated with T1DM, T2DM and other autoimmune diseasesBesides rare and low-frequency genetic variants, there are some other hypotheses to explain the ‘missing heritability’.59 For example, empirical and theoretical analyses have indicated that multiple genetic variants with small effects are missed because GWAS are underpowered to capture these variants, therefore, taking into account genetic variants with smaller effects that do not reach significance will contribute to disease susceptibility and phenotype variability. Additionally, structural variants, such as CNV, buy levitra online from canada are poorly studied owing to insufficient coverage on SNP chips.66 The presence of gene-gene (epistasis) and gene-environmental interactions may also contribute to the ‘missing heritability’.67In addition, the candidate regions identified by GWAS sometimes harbour several different genes.

Identifying rare genetic variants is helpful to pinpoint causal genes within the loci identified by GWAS.68 Moreover, the identification buy levitra online from canada of rare and low-frequency variants may result in the identification of new candidate genes.40 For instance, researchers identified a heterozygote truncating mutation within CLCN1 gene by performing WES in patients with statin-associated myopathy and therefore, determined a novel candidate gene of this disease.69 Additionally, it has been suggested that rare variants are likely to have appeared more recently than common variants, leading to reduced LD and making them more easily interpretable than common variants.21Moreover, early studies have indicated that rare and low-frequency genetic variants may have larger effects on complex disease phenotypes and susceptibility than common variants.70 Therefore, it is helpful to reveal the genetic pathways underlying diseases and to provide clinically actionable targets for personalised medicine. As an example, Roth et al found that rare and low-frequency genetic variants with large phenotypic effects within the proprotein convertase subtilisin/kexin 9 (PCSK9) gene, which encodes products that bind to the low-density lipoprotein (LDL) receptor and increase its degradation, can lower the risk of coronary heart disease (CHD) by reducing the circulating level of LDL cholesterol.71 Based on this research, a fully human monoclonal antibody targeting PCSK9 has been proven to increase LDL receptor recycling and decrease LDL cholesterol level.72 These findings provide a new treatment and prevention strategy for hypercholesterolaemia and CHD and offer inspiration for the transformation of genetic discoveries into clinical practice.Rare and low-frequency variants and T1DMFocusing on autoimmune diabetes, fully understanding the genetic factors underlying T1DM is beneficial for revealing its pathophysiology, discovering new drug targets and developing predictive and personalised medicine (figure 2). It is especially vital and valuable because T1DM is extremely complex and buy levitra online from canada heterogeneous. The candidate T1DM loci identified by GWAS sometimes buy levitra online from canada contain several distinct genes, and strong LD makes it difficult to pinpoint the precise causative genes in genomic regions.

In addition, the fact that many SNPs reside in non-coding regions or do not have obvious functional effects offers few clues to ascertain the causative genes. However, the discovery buy levitra online from canada of rare and low-frequency disease-associated variants is helpful for T1DM candidate gene identification. The T1DM-associated region buy levitra online from canada on human chromosome 2q24 harbours interferon (IFN) induced with helicase C domain 1 (IFIH1), GCA, FAP and part of KCNH7. The interaction between IFIH1 and double-stranded RNA, a byproduct of viral replication, leads to the secretion of IFNs.

While IFIH1 is a plausible susceptibility gene on the basis of its biological function, there is no direct evidence to indicate which of these buy levitra online from canada genes in this locus is responsible for increased T1DM risk. Nejentsev et al resequenced the exons and splice sites of 10 candidate genes in pools of DNA from 480 patients and 480 buy levitra online from canada controls and discovered 4 rare or low-frequency variants (OR=0.51–0.74, MAF <3%) with low LD within IFIH1 that could change the structure or expression of its product, melanoma differentiation-associated protein 5 and protect against T1DM.23 This finding suggests that IFIH1 is the disease-causing gene. Moreover, Ge et al found several rare deleterious variants, including two novel frameshift mutations (ss538819444 and ss37186329) and two missense mutations (rs74163663 and rs56048322) within PTPN22 by deeply sequencing the protein-coding regions of 301 genes in 49 loci previously identified by GWAS in 70 T1DM cases of European ancestry.22 This finding further confirmed that PTPN22 is a T1DM candidate gene on chromosome 1p13.2. Subsequent genotyping in 3609 families with T1DM indicated rs56048322 (MAF=0.87%), which leads to the production of two alternative PTPN22 transcripts and a novel isoform of its encoding protein, LYP, through affecting buy levitra online from canada splicing of PTPN22, was significantly associated with T1DM independent of T1DM-associated common variant rs2476601.

Functional analysis showed this isoform of LYP can cause hyporesponsiveness of CD4+ T cell to antigen stimulation in patients buy levitra online from canada with T1DM.50 candidate loci have been identified by genome-wide association study. The genetic variants within these risk regions can be divided into common variants, low-frequency variants and rare variants according to their different minor allele frequencies. The rare and low-frequency variants are likely to have more practical value in the treatment of T1DM because their ORs are larger than those of common buy levitra online from canada variants. However, as the study of rare and low-frequency variants is an buy levitra online from canada emerging research field, some hypotheses are still controversial and need further investigation.

LD, linkage disequilibrium. MAF. Minor allele frequency." class="highwire-fragment fragment-images colorbox-load" rel="gallery-fragment-images-48462583" data-figure-caption="The development of type 1 diabetes mellitus (T1DM). T1DM is caused by interplay between genetic and environmental factors, and epigenetics serves as a bridge between the two.

To date, >50 candidate loci have been identified by genome-wide association study. The genetic variants within these risk regions can be divided into common variants, low-frequency variants and rare variants according to their different minor allele frequencies. The rare and low-frequency variants are likely to have more practical value in the treatment of T1DM because their ORs are larger than those of common variants. However, as the study of rare and low-frequency variants is an emerging research field, some hypotheses are still controversial and need further investigation.

LD, linkage disequilibrium. MAF. Minor allele frequency." data-icon-position data-hide-link-title="0">Figure 2 The development of type 1 diabetes mellitus (T1DM). T1DM is caused by interplay between genetic and environmental factors, and epigenetics serves as a bridge between the two.

To date, >50 candidate loci have been identified by genome-wide association study. The genetic variants within these risk regions can be divided into common variants, low-frequency variants and rare variants according to their different minor allele frequencies. The rare and low-frequency variants are likely to have more practical value in the treatment of T1DM because their ORs are larger than those of common variants. However, as the study of rare and low-frequency variants is an emerging research field, some hypotheses are still controversial and need further investigation.

LD, linkage disequilibrium. MAF. Minor allele frequency.Additionally, as mentioned above, most variants that confer T1DM risk are common and have modest effects, limiting the clinical application of their discovery. However, some research has suggested that rare and low-frequency variants might have larger effect sizes than common variants.

Theoretically, if a disorder affects reproduction, such as an autoimmune disease with early onset, genetic variants with strong effects will be maintained at a relatively low frequency through negative selection.21 Forgetta et al applied deep imputation of genotyped data in 9358 patients with T1DM and 15 705 controls from European cohorts to identify novel rare and low-frequency variants with large effect sizes on T1DM risk.13 Three novel rare and low-frequency variants, including rs192324744 in LDL receptor-related protein 1B (LRP1B, MAF=1.3%, OR=1.63), rs60587303 in serine threonine kinase 39 (STK39, MAF=0.5%, OR=1.97) and the intergenic variant rs2128344 (MAF=0.55%, OR=2.12), were found and validated by subsequent de novo genotyping.13 Notably, the effects of these SNPs (ORs ≥1.5) are comparable to those of the lead variants in INS and PTPN22. In vitro experiments indicated that STK39 is involved in T cell activation and effector functions and that inhibition of Stk39 can augment the inflammatory response by enhancing interleukin (IL)-2 signalling. Therefore, STK39 may be a promising clinical intervention target.13Besides, previous study through fine mapping of known T1DM susceptible loci has identified a low-frequency variant rs34536443 (MAF=4%, OR=0.67) within tyrosine kinase 2 (TYK2) and a rare variant rs41295121 (MAF=1%, OR=0.49) within RNA binding motif protein 17 (RBM17, in the same locus as IL2RA).20 TYK2, belonging to Janus kinase (JAK) family, is associated with regulation of type I IFN signalling pathway. Some studies have demonstrated that rs34530443 plays protective roles in multiple autoimmune disorders and the underlying mechanisms might lie in the diminishment of IL-12, IL-23 and type I IFN signalling.73 The specific function of rs41295121 in context of autoimmunity and T1DM needs further investigation.As for some practical issues such as sample sizes and high costs, a study indicated that a well-powered rare variant association study should include discovery sets with at least 25 000 cases and a substantial replication set.44 There are some alternative methods to decrease the sample sizes or costs in the context of T1DM.

For example, combined analysis of rare variants within a T1DM-associated gene or region can lead to substantial reduction of required sample sizes. In addition, preferential selection of individuals with extreme phenotype on the basis of known risk factors, including age of disease onset, family history of diabetes and diabetic auto-antibodies, can also improve the association power because rare variants might be enriched among them.74Overall, among the identified T1DM loci, the candidate genes with rare or low-frequency variants include TYK2, IFIH1, RBM17, PTPN22, STK39 and LRP1B.13 20 22 23 Many unidentified variants may remain to be dissected, because studies focused on other diseases suggest that rare and low-frequency variants account for the majority of all variants.27 75ConclusionDriven by advancements in sequencing technologies, there has been great improvement in the identification of rare and low-frequency variants that cause complex human diseases, such as T1DM. The benefits of this field can be stated as follows. (1) characterisation of rare and low-frequency variants may lead to a full understanding of the genetic component of this disorder.

(2) detection of rare and low-frequency variants can pinpoint the genes that are actually responsible for increased T1DM risk within the loci identified by GWAS. (3) some new candidate genes for T1DM can be found due to enhanced power to discover rare variants. (4) rare and low-frequency variants are expected to make a significant contribution to human phenotypes and disease susceptibility because some studies indicate the majority of protein-coding variants tend to be evolutionarily recent and rare54. (5) accumulated evidence indicates that rare and low-frequency variants have larger phenotypic effects than common variants, suggesting that they will offer more actionable clinical targets and hold tremendous promise in predictive and personalised medicine.However, some issues remain to be addressed.

First, controversy persists about the importance of rare and low-frequency variants in common diseases. Encouragingly, recent studies have found that some such variants, such as rs60587303 in STK39, indeed have larger effect sizes than common variants in the pathogenesis of T1DM. Second, the candidate genes for T1DM that have rare or low-frequency variants included only TYK2, RBM17, IFIH1, PTPN22, STK39 and LRP1B, which means there may still be many unidentified variants. Moreover, most studies in this field have examined European populations.

However, rare and low-frequency variants are geographically localised and population specific. In particular, the heritable background of T1DM varies among different ethnic groups. These facts will limit the practical application of rare and low-frequency variants.In conclusion, the identification of rare and low-frequency genetic variants will provide new insights into the pathophysiology of T1DM and offer new potential drug targets in the post-GWAS era, despite the many challenges and uncertainties remaining in this field.AbstractAccurate classification of variants in cancer susceptibility genes (CSGs) is key for correct estimation of cancer risk and management of patients. Consistency in the weighting assigned to individual elements of evidence has been much improved by the American College of Medical Genetics (ACMG) 2015 framework for variant classification, UK Association for Clinical Genomic Science (UK-ACGS) Best Practice Guidelines and subsequent Cancer Variant Interpretation Group UK (CanVIG-UK) consensus specification for CSGs.

However, considerable inconsistency persists regarding practice in the combination of evidence elements. CanVIG-UK is a national subspecialist multidisciplinary network for cancer susceptibility genomic variant interpretation, comprising clinical scientist and clinical geneticist representation from each of the 25 diagnostic laboratories/clinical genetic units across the UK and Republic of Ireland. Here, we summarise the aggregated evidence elements and combinations possible within different variant classification schemata currently employed for CSGs (ACMG, UK-ACGS, CanVIG-UK and ClinGen gene-specific guidance for PTEN, TP53 and CDH1). We present consensus recommendations from CanVIG-UK regarding (1) consistent scoring for combinations of evidence elements using a validated numerical ‘exponent score’ (2) new combinations of evidence elements constituting likely pathogenic’ and ‘pathogenic’ classification categories, (3) which evidence elements can and cannot be used in combination for specific variant types and (4) classification of variants for which there are evidence elements for both pathogenicity and benignity.geneticsgenomicsgenetic testinggeneticsmedicalgenetic variationhttps://creativecommons.org/licenses/by/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made.

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