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So remember that time Tori and I posted our first TWTT? Well, we’re back in action! Katherine, Julia and I wanted to share a few quick photos we snapped at our team picnic from yesterday. Some weeks we may have a fun craft, recipe or adventure to share so you can all keep up with us in our personal lives in between the brilliant sessions and weddings we will be posting! I am so excited about these two girls and the stories their hearts have to share. It was so fun meeting at Longs Park, collaborating a fun little meal, talking about photography/the business and just chatting about life and what’s going on for all of us. I’m also so glad the weather is deciding to take a break from the rain and give us some nice sunshine!

Enjoy our little picnic while I head back to editing for the day!

Meagan Nicole

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Protecting the safety and health of essential workers who support America’s food security—including buy kamagra with free samples the meat, poultry, and pork processing industries—is a top priority for the Occupational Safety and Health Administration (OSHA). OSHA and the Centers for Disease Control and Prevention issued additional guidance to reduce the risk of exposure to the erectile dysfunction and keep workers safe and healthy in the meatpacking and meat processing industries —including those involved in beef, pork, and poultry operations. This new guidance provides specific recommendations for employers to meet buy kamagra with free samples their obligations to protect workers in these facilities, where people normally work closely together and share workspaces and equipment.

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OSHA is committed to ensuring that workers and employers in essential industries have clear guidance to keep workers safe and healthy from the erectile dysfunction—including guidance for essential workers in construction, manufacturing, package delivery, and retail. Workers and employers who have questions or concerns about workplace safety can contact OSHA online or by phone at 1-800-321-6742 (OSHA). You can find additional resources and buy kamagra with free samples learn more about OSHA’s response to the erectile dysfunction at www.osha.gov/erectile dysfunction.

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Workers and employers are encouraged to regularly refer to the resources below for updates:Each year on Dec. 6, we celebrate National Miners Day to recognize and applaud the skill, buy kamagra with free samples dedication and hard work miners put into providing many of the products essential to fulfilling America’s most vital needs. I want to take this opportunity to say thank you to every working miner in our nation.

From the coal that provides power for the lights we use to the copper used in our electronics and cookware, miners provide the necessary minerals to make the products integral to our daily lives while sometimes facing hazardous conditions in the workplace. Having worked in the mining industry for the majority of my life, buy kamagra with free samples I fully recognize the hazards that confined spaces, mobile equipment and complex electrical equipment, just to name a few, can present to working miners. This is why my agency, the U.S.

Department of Labor’s Mine Safety and Health Administration (MSHA), exists. MSHA enforces safety and health standards and regulations — at all American coal mines, quarries, copper and other metal mines, and buy kamagra with free samples many other facilities — to protect miners from the hazards they face each day. Our aim is to see every miner go home safe and healthy after every shift.

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NCHS Data how to use kamagra tablets additional info 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 conditions such as how to use kamagra tablets 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 of how to use kamagra tablets 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, how to use kamagra tablets and 22.1% are 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 than 7 hours, on average, in a 24-hour period (35.1%) (Figure 1) how to use kamagra tablets.

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 how to use kamagra tablets. 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 how to use kamagra tablets quadratic 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 how to use kamagra tablets 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 1pdf how to use kamagra tablets icon.SOURCE.

NCHS, National Health Interview Survey, 2015. The percentage of women aged 40–59 who how to use kamagra tablets 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 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 how to use kamagra tablets.

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 trend by how to use kamagra tablets 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 how to use kamagra tablets their last menstrual cycle was 1 year ago or less.

Women were premenopausal if they still had a menstrual cycle. Access data table how to use kamagra tablets 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 how to use kamagra tablets women aged 40–59 had trouble staying asleep four times or 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 how to use kamagra tablets. 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, 2015image icon1Significant linear trend how to use kamagra tablets 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 how to use kamagra tablets 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 how to use kamagra tablets 3pdf 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 wake up feeling well rested 4 days or more in how to use kamagra tablets 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 how to use kamagra tablets. 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?. € http://sjaynephotography.com/seniors7/. 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.

NCHS Data Brief No buy kamagra with free samples http://blog.lumitone.com/?p=146. 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 buy kamagra with free samples for chronic 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 buy kamagra with free samples “the permanent cessation 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, buy kamagra with free samples 74.2% of women are premenopausal, 3.7% are perimenopausal, and 22.1% are 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 than 7 hours, on average, in a 24-hour period buy kamagra with free samples (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 kamagra with free samples. 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 kamagra with free samples <.

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 buy kamagra with free samples 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 1pdf icon.SOURCE buy kamagra with free samples.

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 kamagra with free samples 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 kamagra with free samples.

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 buy kamagra with free samples 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 buy kamagra with free samples 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 2pdf buy kamagra with free samples icon.SOURCE. NCHS, National Health Interview Survey, 2015. The percentage of women aged 40–59 who had buy kamagra with free samples 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 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 kamagra with free samples. 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, 2015image icon1Significant linear trend by menopausal status (p < buy kamagra with free samples. 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 buy kamagra with free samples year ago or less. Women were premenopausal if they still had a menstrual cycle. Access data buy kamagra with free samples table for Figure 3pdf 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 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% buy kamagra with free samples 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 kamagra with free samples. 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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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 his comment is here subsequent severe insulin deficiency and lifelong reliance on exogenous insulin.1 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 best kamagra site 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 best kamagra site 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 extreme example, monogenic/Mendelian disorders such as autoimmune polyendocrinopathy syndrome type I are caused by rare variants with large effect sizes and best kamagra site 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 best kamagra site 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 best kamagra site can lead to the discovery 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 best kamagra site 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 best kamagra site >100x).View 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 best kamagra site detected 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 best kamagra site 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 of the human genome is coding sequence and the functions of protein-coding variants are best kamagra site more easily interpreted, WES is considered a cost-effective technique for discovering rare variants. However, an obvious defect is that best kamagra site WES ignores non-coding regions, which account for 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 best kamagra site 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 best kamagra site 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 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 best kamagra site 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 best kamagra site 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 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 best kamagra site 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 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 best kamagra site 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 expression and biological pathways, best kamagra site 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 best kamagra site 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 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 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 best kamagra site 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 best kamagra site 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 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 chips.66 The presence of gene-gene (epistasis) and gene-environmental interactions may also contribute to the ‘missing heritability’.67In best kamagra site 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 best kamagra site 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 best kamagra site because T1DM is extremely complex and heterogeneous.

The candidate T1DM loci identified by GWAS sometimes contain several distinct genes, and strong LD makes it difficult to pinpoint the precise best kamagra site 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 best kamagra site rare and low-frequency disease-associated variants is helpful for T1DM candidate gene identification. The T1DM-associated region on human chromosome 2q24 harbours interferon (IFN) induced with helicase C domain 1 best kamagra site (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 best kamagra site evidence to indicate which of these 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 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 best kamagra site 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 best kamagra site 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 best kamagra site patients 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 best kamagra site 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, best kamagra site some hypotheses are address still controversial and need further investigation. LD, linkage disequilibrium. MAF.

Minor allele frequency." class="highwire-fragment fragment-images colorbox-load" rel="gallery-fragment-images-815983226" 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 http://controlmyproject.com/?page_id=2 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 diabetes accounts for 5%–19% of diabetes and represents the main form of diabetes in buy kamagra with free samples 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 buy kamagra with free samples 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 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 extreme example, monogenic/Mendelian disorders buy kamagra with free samples 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 if the hypothesis that most rare buy kamagra with free samples variants have only a small effect is true, there is still intrinsic value in this field.

Such studies buy kamagra with free samples can lead to the discovery 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 buy kamagra with free samples 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 buy kamagra with free samples 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 buy kamagra with free samples 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 potential of larger reference panels to impute buy kamagra with free samples 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 of the human genome is coding sequence and the functions buy kamagra with free samples 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 buy kamagra with free samples non-coding regions, which account for 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 targeted sequencing in regions previously associated with inflammatory bowel disease buy kamagra with free samples. 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 buy kamagra with free samples 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 with the goal of decreasing sample sizes buy kamagra with free samples 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 buy kamagra with free samples rare and 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 buy kamagra with free samples 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 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 the pool of buy kamagra with free samples 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 buy kamagra with free samples 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 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 buy kamagra with free samples 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 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 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’ buy kamagra with free samples 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 buy kamagra with free samples 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 buy kamagra with free samples 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 buy kamagra with free samples 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 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 buy kamagra with free samples is extremely complex and heterogeneous.

The candidate T1DM loci identified by GWAS sometimes contain several distinct genes, and strong LD makes it difficult to buy kamagra with free samples 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 buy kamagra with free samples variants is helpful for T1DM candidate gene identification. The T1DM-associated region on human chromosome 2q24 harbours interferon (IFN) induced with helicase buy kamagra with free samples 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 kamagra with free samples 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 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 buy kamagra with free samples 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 splicing of PTPN22, was significantly associated with T1DM buy kamagra with free samples independent of T1DM-associated common variant rs2476601. Functional analysis showed this buy kamagra with free samples isoform of LYP can cause hyporesponsiveness of CD4+ T cell to antigen stimulation in patients 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 buy kamagra with free samples 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 buy kamagra with free samples still controversial and need further buy kamagra oral jelly nz investigation. LD, linkage disequilibrium. MAF.

Minor allele frequency." class="highwire-fragment fragment-images colorbox-load" rel="gallery-fragment-images-815983226" 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/..

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Latest Infectious the kamagra store coupon Disease News FRIDAY, Nov go to the website. 19, 2021 (HealthDay News) There was no smallpox kamagra in frozen vials recently discovered at a treatment research facility in Pennsylvania, the U.S. Centers for Disease Control the kamagra store coupon and Prevention said Thursday. Instead of the variola kamagra that causes smallpox, lab tests showed that the vials contained vaccinia, the kamagra used in smallpox treatment, according to the agency. On Nov.

15, federal officials were alerted that the kamagra store coupon the vials were found by a laboratory worker while cleaning out a freezer in the facility. The vials were sent on Nov. 18 to the CDC. Before smallpox was declared eradicated in 1980 by the kamagra store coupon the World Health Organization, the easily transmitted kamagra infected up to 15 million people a year and killed about 30% of them, CNN reported. The last known outbreak in the United States was in 1947.

In 2014, employees of the National Institutes of Health (NIH) found six vials of smallpox in an unused storage room as they packed up a lab at the NIH's Bethesda, Md., campus to move the kamagra store coupon it. Two of the vials contained viable kamagra. The CDC said at the time there was no evidence anyone had been exposed to the contents of any of the vials. There's disagreement the kamagra store coupon among governments about whether to keep samples of smallpox or to destroy all known copies. Routine vaccination for smallpox stopped in 1972, but military personnel and some researchers still get vaccinated, CNN reported.

The CDC recommends that people who need long-term protection get smallpox boosters every 3-5 years, although at least one study found the treatment might protect recipients for life. More information Visit the the kamagra store coupon U.S. Centers for Disease Control and Prevention for more on smallpox. SOURCE. U.S.

Centers for Disease Control and Prevention. CNN Robert Preidt Copyright © 2021 HealthDay. All rights reserved. SLIDESHOW Bacterial s 101. Types, Symptoms, and Treatments See SlideshowLatest Migraine News By Robert Preidt and Ernie Mundell HealthDay ReportersTHURSDAY, Nov.

19, 2021 – People who live with chronic migraines suffer intense throbbing and pulsing, sensitivity to light and sound, nausea and vomiting. Could a plant-based diet, credited with a variety of positive health impacts, also help ease these chronic symptoms?. It might. Researchers in New York have published a case study of one man with severe chronic migraines who had tried everything to curb them, and then switched to a plant-based diet -- loaded with a lot of dark green leafy vegetables. He quickly found significant relief from the headaches, doctors reported online Nov.

18 in the journal BMJ Case Reports. "This report suggests that a whole food plant-based diet may offer a safe, effective and permanent treatment for reversing chronic migraine," wrote a team led by Dr. David Dunaief, who specializes in nutritional medicine and has a private practice in East Setauket, N.Y. One expert in migraine who wasn't connected to the study was cautiously optimistic about the findings. "It is hard to make much from one case report, [but] it does illustrate the importance of all of these non-pharmacological, evidence-based treatments," said Dr.

Noah Rosen. He directs Northwell Health's Headache Center in Great Neck, N.Y. As the researchers noted, more than 1 billion people worldwide have migraines, defined as one-side, pulsating headaches, sometimes with a variety of other symptoms, that last between four and 72 hours. Some migraines are episodic, meaning they happen fewer than 15 days per month. Others are chronic, with 15 or more migraine days per month plus migraine features on eight days per month.

To be considered successful, migraine treatment must cut the frequency and length of the attacks in half or improve symptoms. The 60-year-old man whose experiences are detailed in the report had endured severe migraine headaches without aura for more than 12 years. Six months before his clinic referral, his migraines had become chronic, occurring anywhere from 18 to 24 days each month.He had tried a number of potential fixes, including the prescribed medications zolmitriptan and topiramate. He also cut out potential 'trigger' foods, including chocolate, cheese, nuts, caffeine, and dried fruit. Beyond this, the man also tried yoga and meditation to curb the attacks.

None of those interventions had worked.The man described the pain as throbbing, starting suddenly and intensely in the forehead and temple on the left side of his head. His migraines usually lasted 72 hours and also included sensitivity to light and sound, nausea and vomiting. His pain severity was 10 to 12 out of a scale of 10.He didn't have high levels of systemic inflammation but had a normal level of beta carotene in his blood, possibly because he ate sweet potatoes daily. Sweet potatoes are relatively low in food nutrients known as carotenoids, which carry anti-inflammatory and antioxidant properties, the authors explained. Leafy greens such as spinach, kale and watercress do contain high levels of carotenoids, however.

So, Rosen's team advised the man to adopt the Low Inflammatory Foods Everyday (LIFE) diet. It's a nutrient-dense, whole food, plant-based diet. The regimen advocates eating at least five ounces by weight of raw or cooked dark green leafy vegetables every day, drinking one 32-ounce daily green LIFE smoothie, and limiting intake of whole grains, starchy vegetables, oils, and animal protein, particularly dairy and red meat.After two months on the diet, the man said his migraines had been dramatically reduced -- to just one migraine day per month, and even that headache was less severe. SLIDESHOW 16 Surprising Headache Triggers and Tips for Pain Relief See Slideshow At the same time, his blood tests showed a substantial rise in beta-carotene levels. Soon, the man stopped taking all his migraine meds.

His migraines stopped completely after three months and haven't returned in 7 1/2 years.The man was allergic, and previously published research suggests that better control of allergies may also lead to fewer migraine headaches. In this case, the man's allergy symptoms also improved -- to the point that he no longer needed to use seasonal medication.He was also HIV-positive, and HIV has been linked to a heightened risk of migraines. It is possible that the man's HIV status and antiretroviral drugs had contributed to his symptoms, the authors said, though it wasn't possible to study this further without stopping the antiretroviral treatment."While this report describes one very adherent patient who had a remarkable response, the LIFE diet has reduced migraine frequency within 3 months in several additional patients," Dunaief added. For his part, Rosen said that "the role of proper diet and migraine has had a few studies demonstrating benefit." Being properly hydrated, eating a healthy "low-glycemic" diet and getting lots of omega 3 fatty acids (such as are found in oily fish) have all been shown to have a positive effect on curbing migraines, he said. Beyond food, getting good sleep, regular exercise and psychological interventions such as "cognitive behavioral therapy, mindfulness and progressive muscle relaxation" may also help, Rosen said.

More information Find out more about migraines at the American Migraine Foundation. SOURCE. BMJ Case reports, news release, Nov. 18, 2021 Copyright © 2021 HealthDay. All rights reserved.

From Migraines and Headaches Resources Featured Centers Health Solutions From Our SponsorsLatest Asthma News FRIDAY, Nov. 19, 2021 (HealthDay News) While climate change gets a lot of notice for its numerous negative impacts around the globe, children's allergies may not be among them. Despite climate change, with the longer growing seasons and larger pollen loads that are attributed to it, more than 5,800 children in the Los Angeles area with asthma did not have an increase in allergic sensitization or allergy diagnosis over a 15-year period, a new study showed. The findings were presented earlier this month at an annual meeting of the American College of Allergy, Asthma and Immunology. "We were somewhat surprised at the results as we expected there would be an increase in the number of kids with asthma who were sensitized to pollen and other allergens," said principal investigator Dr.

Kenny Kwong, a Los Angeles-based allergist. "Between 80%-90% of children with asthma have allergy triggers, which is why it's important for children with asthma to be tested for allergies," he said in a meeting news release. "Allergy triggers can cause asthma flares in children." When people's immune systems become sensitized to an allergen, those patients will likely develop symptoms of an allergy each time they are exposed to that same allergen, which for others is harmless. "Although temperatures have been rising and pollen loads increasing, if someone is not genetically predisposed to allergies, they are not likely to be sensitized to more allergens," said allergist and study co-author Dr. Lyne Scott, an associate professor of pediatrics at USC's Keck School of Medicine.

"The growing season is year-round in L.A. And people with allergies who are already sensitized to pollens suffer more intensely when the growing season is longer, or the air quality isn't good," Scott said in the release. "It is important to remember that sensitization does not equate to severity so those with allergies may have worse symptoms." The study followed 5,874 kids with asthma in Los Angeles for 15 years, who underwent more than 123,200 skin prick tests to dust mites, cats, dogs, cockroaches, tree pollen, grass pollen and weed pollen. All the patients had been diagnosed with asthma and allergic rhinitis by an asthma specialist using history, physical examination and spirometry when it was age-appropriate. The researchers found no increase in allergic sensitization or allergy diagnosis among the children.

The findings were also published recently in the journal Annals of Allergy, Asthma and Immunology. More information The U.S. National Library of Medicine has more on seasonal allergies. SOURCE. American College of Allergy, Asthma and Immunology, news release, Nov.

5, 2021 Cara Murez Copyright © 2021 HealthDay. All rights reserved. SLIDESHOW What is Asthma?. Asthma Myths Debunked See Slideshow.

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15, federal officials were alerted that the vials were found by a laboratory worker while cleaning out a freezer in the buy kamagra with free samples facility. The vials were sent on Nov. 18 to the CDC. Before smallpox was declared eradicated in buy kamagra with free samples 1980 by the World Health Organization, the easily transmitted kamagra infected up to 15 million people a year and killed about 30% of them, CNN reported. The last known outbreak in the United States was in 1947.

In 2014, employees of the National Institutes of Health (NIH) found six vials of smallpox in an unused storage room buy kamagra with free samples as they packed up a lab at the NIH's Bethesda, Md., campus to move it. Two of the vials contained viable kamagra. The CDC said at the time there was no evidence anyone had been exposed to the contents of any of the vials. There's disagreement among governments about whether to keep samples buy kamagra with free samples of smallpox or to destroy all known copies. Routine vaccination for smallpox stopped in 1972, but military personnel and some researchers still get vaccinated, CNN reported.

The CDC recommends that people who need long-term protection get smallpox boosters every 3-5 years, although at least one study found the treatment might protect recipients for life. More information Visit buy kamagra with free samples the U.S. Centers for Disease Control and Prevention for more on smallpox. SOURCE. U.S.

Centers for Disease Control and Prevention. CNN Robert Preidt Copyright © 2021 HealthDay. All rights reserved. SLIDESHOW Bacterial s 101. Types, Symptoms, and Treatments See SlideshowLatest Migraine News By Robert Preidt and Ernie Mundell HealthDay ReportersTHURSDAY, Nov.

19, 2021 – People who live with chronic migraines suffer intense throbbing and pulsing, sensitivity to light and sound, nausea and vomiting. Could a plant-based diet, credited with a variety of positive health impacts, also help ease these chronic symptoms?. It might. Researchers in New York have published a case study of one man with severe chronic migraines who had tried everything to curb them, and then switched to a plant-based diet -- loaded with a lot of dark green leafy vegetables. He quickly found significant relief from the headaches, doctors reported online Nov.

18 in the journal BMJ Case Reports. "This report suggests that a whole food plant-based diet may offer a safe, effective and permanent treatment for reversing chronic migraine," wrote a team led by Dr. David Dunaief, who specializes in nutritional medicine and has a private practice in East Setauket, N.Y. One expert in migraine who wasn't connected to the study was cautiously optimistic about the findings. "It is hard to make much from one case report, [but] it does illustrate the importance of all of these non-pharmacological, evidence-based treatments," said Dr.

Noah Rosen. He directs Northwell Health's Headache Center in Great Neck, N.Y. As the researchers noted, more than 1 billion people worldwide have migraines, defined as one-side, pulsating headaches, sometimes with a variety of other symptoms, that last between four and 72 hours. Some migraines are episodic, meaning they happen fewer than 15 days per month. Others are chronic, with 15 or more migraine days per month plus migraine features on eight days per month.

To be considered successful, migraine treatment must cut the frequency and length of the attacks in half or improve symptoms. The 60-year-old man whose experiences are detailed in the report had endured severe migraine headaches without aura for more than 12 years. Six months before his clinic referral, his migraines had become chronic, occurring anywhere from 18 to 24 days each month.He had tried a number of potential fixes, including the prescribed medications zolmitriptan and topiramate. He also cut out potential 'trigger' foods, including chocolate, cheese, nuts, caffeine, and dried fruit. Beyond this, the man also tried yoga and meditation to curb the attacks.

None of those interventions had worked.The man described the pain as throbbing, starting suddenly and intensely in the forehead and temple on the left side of his head. His migraines usually lasted 72 hours and also included sensitivity to light and sound, nausea and vomiting. His pain severity was 10 to 12 out of a scale of 10.He didn't have high levels of systemic inflammation but had a normal level of beta carotene in his blood, possibly because he ate sweet potatoes daily. Sweet potatoes are relatively low in food nutrients known as carotenoids, which carry anti-inflammatory and antioxidant properties, the authors explained. Leafy greens such as spinach, kale and watercress do contain high levels of carotenoids, however.

So, Rosen's team advised the man to adopt the Low Inflammatory Foods Everyday (LIFE) diet. It's a nutrient-dense, whole food, plant-based diet. The regimen advocates eating at least five ounces by weight of raw or cooked dark green leafy vegetables every day, drinking one 32-ounce daily green LIFE smoothie, and limiting intake of whole grains, starchy vegetables, oils, and animal protein, particularly dairy and red meat.After two months on the diet, the man said his migraines had been dramatically reduced -- to just one migraine day per month, and even that headache was less severe. SLIDESHOW 16 Surprising Headache Triggers and Tips for Pain Relief See Slideshow At the same time, his blood tests showed a substantial rise in beta-carotene levels. Soon, the man stopped taking all his migraine meds.

His migraines stopped completely after three months and haven't returned in 7 1/2 years.The man was allergic, and previously published research suggests that better control of allergies may also lead to fewer migraine headaches. In this case, the man's allergy symptoms also improved -- to the point that he no longer needed to use seasonal medication.He was also HIV-positive, and HIV has been linked to a heightened risk of migraines. It is possible that the man's HIV status and antiretroviral drugs had contributed to his symptoms, the authors said, though it wasn't possible to study this further without stopping the antiretroviral treatment."While this report describes one very adherent patient who had a remarkable response, the LIFE diet has reduced migraine frequency within 3 months in several additional patients," Dunaief added. For his part, Rosen said that "the role of proper diet and migraine has had a few studies demonstrating benefit." Being properly hydrated, eating a healthy "low-glycemic" diet and getting lots of omega 3 fatty acids (such as are found in oily fish) have all been shown to have a positive effect on curbing migraines, he said. Beyond food, getting good sleep, regular exercise and psychological interventions such as "cognitive behavioral therapy, mindfulness and progressive muscle relaxation" may also help, Rosen said.

More information Find out more about migraines at the American Migraine Foundation. SOURCE. BMJ Case reports, news release, Nov. 18, 2021 Copyright © 2021 HealthDay. All rights reserved.

From Migraines and Headaches Resources Featured Centers Health Solutions From Our SponsorsLatest Asthma News FRIDAY, Nov. 19, 2021 (HealthDay News) While climate change gets a lot of notice for its numerous negative impacts around the globe, children's allergies may not be among them. Despite climate change, with the longer growing seasons and larger pollen loads that are attributed to it, more than 5,800 children in the Los Angeles area with asthma did not have an increase in allergic sensitization or allergy diagnosis over a 15-year period, a new study showed. The findings were presented earlier this month at an annual meeting of the American College of Allergy, Asthma and Immunology. "We were somewhat surprised at the results as we expected there would be an increase in the number of kids with asthma who were sensitized to pollen and other allergens," said principal investigator Dr.

Kenny Kwong, a Los Angeles-based allergist. "Between 80%-90% of children with asthma have allergy triggers, which is why it's important for children with asthma to be tested for allergies," he said in a meeting news release. "Allergy triggers can cause asthma flares in children." When people's immune systems become sensitized to an allergen, those patients will likely develop symptoms of an allergy each time they are exposed to that same allergen, which for others is harmless. "Although temperatures have been rising and pollen loads increasing, if someone is not genetically predisposed to allergies, they are not likely to be sensitized to more allergens," said allergist and study co-author Dr. Lyne Scott, an associate professor of pediatrics at USC's Keck School of Medicine.

"The growing season is year-round in L.A. And people with allergies who are already sensitized to pollens suffer more intensely when the growing season is longer, or the air quality isn't good," Scott said in the release. "It is important to remember that sensitization does not equate to severity so those with allergies may have worse symptoms." The study followed 5,874 kids with asthma in Los Angeles for 15 years, who underwent more than 123,200 skin prick tests to dust mites, cats, dogs, cockroaches, tree pollen, grass pollen and weed pollen. All the patients had been diagnosed with asthma and allergic rhinitis by an asthma specialist using history, physical examination and spirometry when it was age-appropriate. The researchers found no increase in allergic sensitization or allergy diagnosis among the children.

The findings were also published recently in the journal Annals of Allergy, Asthma and Immunology. More information The U.S. National Library of Medicine has more on seasonal allergies. SOURCE. American College of Allergy, Asthma and Immunology, news release, Nov.

5, 2021 Cara Murez Copyright © 2021 HealthDay. All rights reserved. SLIDESHOW What is Asthma?. Asthma Myths Debunked See Slideshow.

Buy super kamagra online uk

Medicare Part D is a buy super kamagra online uk voluntary outpatient prescription drug benefit for people with Medicare, provided through private plans approved by the federal government. Beneficiaries can choose to enroll in either a stand-alone prescription drug plan (PDP) to supplement traditional Medicare or a Medicare Advantage prescription drug plan (MA-PD), mainly HMOs and PPOs, that cover all Medicare benefits including drugs. In 2020, 46 million of the more than 60 million people covered by Medicare are enrolled buy super kamagra online uk in Part D plans. This fact sheet provides an overview of the Medicare Part D program, plan availability, enrollment, and spending and financing, based on data from the Centers for Medicare &. Medicaid Services (CMS), the Congressional Budget Office (CBO), and other sources.Medicare Prescription Drug Plan Availability in 2021In 2021, 996 PDPs will be offered across the 34 PDP regions nationwide (excluding the buy super kamagra online uk territories).

This represents an increase of 48 PDPs from 2020 (a 5% increase) and an increase of 250 plans (a 34% increase) since 2017 (Figure 1).Figure 1. A Total of 996 Medicare Part D Stand-Alone Prescription Drug Plans Will Be Offered in 2021, a buy super kamagra online uk 5% Increase From 2020 and a 33% Increase Since 2017The relatively large increase in the number of PDPs in recent years is likely due to the elimination by CMS of the “meaningful difference” requirement for enhanced benefit PDPs offered by the same organization in the same region. Plans with enhanced benefits can offer a lower deductible, reduced cost sharing, or a higher initial coverage limit. Previously, PDP sponsors were required to demonstrate that their enhanced PDPs were meaningfully different in terms of buy super kamagra online uk enrollee out-of-pocket costs in order to ensure that plan offerings were more distinct. Between 2018 and 2021, the number of enhanced PDPs has increased by nearly 50%, from 421 to 618, largely due to this policy change.Beneficiaries in each state will have a choice of multiple stand-alone PDPs in 2021, ranging from 25 PDPs in Alaska to 35 PDPs in Texas (see map).

In addition, beneficiaries will be able to choose from buy super kamagra online uk among multiple MA-PDs offered at the local level for coverage of their Medicare benefits. New for 2021, beneficiaries in each state will have the option to enroll in a Part D plan participating in the Trump Administration’s new Innovation Center model in which enhanced drug plans cover insulin products at a monthly copayment of $35 in the deductible, initial coverage, and coverage gap phases of the Part D benefit. Participating plans do not have to cover all insulin products at the $35 monthly copayment amount, just one of each dosage form (vial, pen) and insulin type (rapid-acting, short-acting, intermediate-acting, and long-acting) buy super kamagra online uk. In 2021, a total of 1,635 Part D plans will participate in this model, which represents just over 30% of both PDPs (310 plans) and MA-PDs (1,325 plans) available in 2021, including plans in the territories. Between 8 and 10 PDPs in each region are participating buy super kamagra online uk in the model, in addition to multiple MA-PDs (see map).

Low-Income Subsidy Plan Availability in 2021Beneficiaries with low incomes and modest assets are eligible for assistance with Part D plan premiums and cost sharing. Through the Part D Low-Income Subsidy (LIS) program, additional premium and cost-sharing assistance is available for Part D enrollees with low incomes (less than 150% of poverty, or $19,140 for individuals/$25,860 for married couples in 2020) and modest assets (less than $14,610 for individuals/$29,160 for couples buy super kamagra online uk in 2020).In 2021, 259 plans will be available for enrollment of LIS beneficiaries for no premium, 15 more than in 2020 (a 6% increase), and the second year with an increase in the number of benchmark plans since 2018 (Figure 2). Just over one-fourth of PDPs in 2021 (26%) are benchmark plans. Some enrollees have fewer benchmark plan options than others, since benchmark plan availability varies at the Part D buy super kamagra online uk region level. The number of premium-free PDPs in 2021 ranges across states from 5 to 10 plans (see map).

LIS enrollees can select any plan offered in their area, but if they are enrolled in a buy super kamagra online uk non-benchmark plan, they may be required to pay some portion of their plan’s monthly premium Figure 2. In 2021, 259 Part D Stand-Alone Drug Plans Will Be Available Without a Premium to Enrollees Receiving the Low-Income Subsidy (“Benchmark” Plans)Part D Plan Premiums and Benefits in 2021PremiumsThe 2021 Part D base beneficiary premium – which is based on bids submitted by both PDPs and MA-PDs and is not weighted by enrollment – is $33.06, a modest (1%) increase from 2020. But actual premiums paid buy super kamagra online uk by Part D enrollees vary considerably. For 2021, PDP monthly premiums range from a low of $5.70 for a PDP in Hawaii to a high of $205.30 for a PDP in South Carolina (unweighted by plan enrollment). Even within a state, PDP premiums can vary.

For example, in Florida, monthly premiums range from $7.30 to buy super kamagra online uk $172. In addition to the monthly premium, Part D enrollees with higher incomes ($87,000/individual. $174,000/couple) pay an income-related premium surcharge, ranging from $12.32 to $77.14 per month in 2021 (depending on income).BenefitsThe Part D defined standard benefit buy super kamagra online uk has several phases, including a deductible, an initial coverage phase, a coverage gap phase, and catastrophic coverage. Between 2020 and 2021, the parameters of the standard benefit are rising, which means Part D enrollees will face higher out-of-pocket costs for the deductible and in the initial coverage phase, as they have in prior years, and will have to pay more out-of-pocket before qualifying for catastrophic coverage (Figure 3).The standard deductible is increasing from $435 in 2020 to $445 in 2021The initial coverage limit is increasing from $4,020 to $4,130, andThe out-of-pocket spending threshold is increasing from $6,350 to $6,550 (equivalent to $10,048 in total drug spending in 2021, up from $9,719 in 2020).The standard benefit amounts are indexed to change annually based on the rate of Part D per capita spending growth, and, with the exception of 2014, have increased each year since 2006.Figure 3. Medicare Part D Standard Benefit Parameters Will Increase in 2021For costs in the coverage gap phase, beneficiaries pay 25% for both brand-name and generic drugs, with manufacturers providing a 70% discount on brands and buy super kamagra online uk plans paying the remaining 5% of brand drug costs, and plans paying the remaining 75% of generic drug costs.

For total drug costs above the catastrophic threshold, Medicare pays 80%, plans pay 15%, and enrollees pay either 5% of total drug costs or $3.70/$9.20 for each generic and brand-name drug, respectively.Part D plans must offer either the defined standard benefit or an alternative equal in value (“actuarially equivalent”) and can also provide enhanced benefits. Both basic and enhanced benefit plans buy super kamagra online uk vary in terms of their specific benefit design, coverage, and costs, including deductibles, cost-sharing amounts, utilization management tools (i.e., prior authorization, quantity limits, and step therapy), and formularies (i.e., covered drugs). Plan formularies must include drug classes covering all disease states, and a minimum of two chemically distinct drugs in each class. Part D plans are required to cover all drugs in buy super kamagra online uk six so-called “protected” classes. Immunosuppressants, antidepressants, antipsychotics, anticonvulsants, antiretrovirals, and antineoplastics.Part D and Low-Income Subsidy EnrollmentEnrollment in Medicare Part D plans is voluntary, with the exception of beneficiaries who are eligible for both Medicare and Medicaid and certain other low-income beneficiaries who are automatically enrolled in a PDP if they do not choose a plan on their own.

Unless beneficiaries have drug coverage from another source that is at least as good as standard Part D coverage (“creditable coverage”), they face a penalty equal to 1% of the buy super kamagra online uk national average premium for each month they delay enrollment.In 2020, 46.5 million Medicare beneficiaries are enrolled in Medicare Part D plans, including employer-only group plans. Of the total, just over half (53%) are enrolled in stand-alone PDPs and nearly half (47%) are enrolled in Medicare Advantage drug plans (Figure 4). Another 1.3 million beneficiaries are estimated to have drug coverage through employer-sponsored retiree plans where the employer receives a subsidy from the federal government equal to 28% of drug expenses between $445 and $9,200 per retiree (in buy super kamagra online uk 2021). Several million beneficiaries are estimated to have other sources of drug coverage, including employer plans for active workers, FEHBP, TRICARE, and Veterans Affairs (VA). Another 12% of people with Medicare are buy super kamagra online uk estimated to lack creditable drug coverage.Figure 4.

Medicare Part D Enrollment in Stand-Alone Drug Plans Has Declined Recently But Has Increased Steadily in Medicare Advantage Drug PlansAn estimated 13 million Part D enrollees receive the Low-Income Subsidy in 2020. Beneficiaries who are dually eligible, QMBs, SLMBs, QIs, and SSI-onlys automatically qualify for the additional assistance, and Medicare automatically buy super kamagra online uk enrolls them into PDPs with premiums at or below the regional average (the Low-Income Subsidy benchmark) if they do not choose a plan on their own. Other beneficiaries are subject to both an income and asset test and need to apply for the Low-Income Subsidy through either the Social Security Administration or Medicaid.Part D Spending and FinancingPart D SpendingThe Congressional Budget Office (CBO) estimates that spending on Part D benefits will total $96 billion in 2021, representing 13% of net Medicare outlays (net of offsetting receipts from premiums and state transfers). Part D spending depends on several factors, including the total number of Part D enrollees, their health status and drug use, the number of high-cost enrollees (those with drug spending above the catastrophic threshold), the number of enrollees receiving the Low-Income Subsidy, and plans’ ability to negotiate discounts (rebates) with drug companies and preferred pricing arrangements with pharmacies, and manage use (e.g., promoting use of generic drugs, prior authorization, step therapy, quantity limits, and mail order) buy super kamagra online uk. Federal law currently prohibits the Secretary of Health and Human Services from interfering in drug price negotiations between Part D plan sponsors and drug manufacturers.Part D FinancingFinancing for Part D comes from general revenues (71%), beneficiary premiums (16%), and state contributions (12%).

The monthly premium paid by enrollees is set to cover buy super kamagra online uk 25.5% of the cost of standard drug coverage. Medicare subsidizes the remaining 74.5%, based on bids submitted by plans for their expected benefit payments. Higher-income Part D enrollees pay a larger share of standard Part D costs, ranging from 35% to 85%, depending on income.Payments to PlansFor 2021, Medicare’s actuaries estimate that Part D plans will receive direct subsidy payments averaging $216 per enrollee overall, $2,639 for enrollees receiving the LIS, and $1,026 in reinsurance payments for very high-cost enrollees. Employers are expected to receive, on average, $575 buy super kamagra online uk for retirees in employer-subsidy plans. Part D plans also receive additional risk-adjusted payments based on the health status of their enrollees, and plans’ potential total losses or gains are limited by risk-sharing arrangements with the federal government (“risk corridors”).Under reinsurance, Medicare subsidizes 80% of total drug spending incurred by Part D enrollees with relatively high drug spending above the catastrophic coverage threshold.

In the aggregate, Medicare’s reinsurance payments to Part D plans now account for close to half of total Part D spending (45%), up from 14% in 2006 (increasing from $6 billion buy super kamagra online uk in 2006 to $46 billion in 2019) (Figure 5). Higher benefit spending above the catastrophic threshold is a result of several factors, including an increase in the number of high-cost drugs, prescription drug price increases, and a change made by the ACA to count the manufacturer discount on the price of brand-name drugs in the coverage gap towards the out-of-pocket threshold for catastrophic coverage. This change has led to more buy super kamagra online uk Part D enrollees with spending above the catastrophic threshold over time.Figure 5. Spending for Catastrophic Coverage (“Reinsurance”) Now Accounts for Close to Half (45%) of Total Medicare Part D Spending, up from 14% in 2006Issues for the FutureThe Medicare drug benefit has helped to reduce out-of-pocket drug spending for enrollees, which is especially important to those with modest incomes or very high drug costs. But with drug costs on the rise, more plans charging coinsurance rather than flat copayments for covered brand-name drugs, and annual increases in the out-of-pocket spending threshold, many Part D enrollees are likely to face higher out-of-pocket costs for their medications.In light of ongoing attention to prescription drug spending and rising drug costs, policymakers have issued several buy super kamagra online uk proposals to control drug spending by Medicare and beneficiaries.

Several of these proposals address concerns about the lack of a hard cap on out-of-pocket spending for Part D enrollees, the significant increase in Medicare spending for enrollees with high drug costs, and the relatively weak financial incentives faced by Part D plan sponsors to control high drug costs. Such proposals include allowing Medicare to negotiate the price of drugs, restructuring the Part D benefit to add a hard cap on out-of-pocket drug spending, requiring manufacturers to pay a rebate to the federal government if their drug prices increase faster than inflation, using drug prices in other countries in determining pricing for drugs in the U.S., allowing for drug importation, and shifting more of the responsibility for catastrophic coverage costs to Part D plans and drug manufacturers.Understanding how well Part D continues to meet the needs of people on Medicare will be informed by ongoing monitoring of the Part D plan marketplace, examining buy super kamagra online uk formulary coverage and costs for new and existing medications, assessing the impact of the new insulin model, and keeping tabs on Medicare beneficiaries’ out-of-pocket drug spending.The erectile dysfunction kamagra, social distancing, and resulting economic downturn have had considerable implications for the U.S. Health system, including health insurers. The kamagra caused a sizable decrease in the use of health care services during the first half of 2020, job losses appear to have led to coverage loss in the buy super kamagra online uk employer market and increases in Medicaid enrollment, and insurers projecting costs for next year must assess the relative effects of pent-up demand for delayed care, the continuing kamagra, and a potential treatment.In this brief, we analyze data from 2013 to 2020 to examine how insurance markets performed through the first half of this year as the kamagra developed and worsened in the U.S. We use financial data reported by insurance companies to the National Association of Insurance Commissioners and compiled by Mark Farrah Associates to look at average medical loss ratios and gross margins in the individual (also known as non-group), fully-insured group (employer), and Medicare Advantage health insurance markets.

A more detailed description of each market is included in buy super kamagra online uk the Appendix.We find that, as of the end of June 2020, average margins have increased and loss ratios have dropped across the fully-insured group and Medicare Advantage markets, relative to the same time period in 2019. If administrative costs were roughly the same in 2020 as in 2019, these findings suggest higher profits for many insurers during the kamagra. Individual market loss ratios were already quite low and remained flat into 2020, suggesting continued profitability buy super kamagra online uk. The results for the individual and group markets indicate that commercial insurers are on track to owe substantial rebates to consumers again next year under the Affordable Care Act (ACA) Medical Loss Ratio provision.Gross MarginsOne way to assess insurer financial performance is to examine average gross margins per member per month, or the average amount by which premium income exceeds claims costs per enrollee in a given month. Gross margins are an indicator of performance, but positive margins do not necessarily translate into profitability since they do not buy super kamagra online uk account for administrative expenses.

However, a sharp increase in margins from one year to the next, without a commensurate increase in administrative costs, would indicate that these health insurance markets have become more profitable during the kamagra.Despite many insurers covering the full cost of erectile dysfunction testing and treatment for their enrollees, insurers across most markets have seen their claims costs fall, and margins increase since the start of the kamagra, and relative to 2019. This is consistent with the sharp drop in utilization buy super kamagra online uk documented in other analyses.Gross margins among group market plans increased 22% (or $20 pmpm) through the second quarter of 2020 relative to the same period in 2019. Gross margins among Medicare Advantage plans also increased, rising 41% (or $64 pmpm) through the first six months of 2020 compared to gross margins at the same point last year. (Gross margins per member per month tend to be higher for Medicare Advantage than for the other health buy super kamagra online uk insurance markets mainly because Medicare covers an older, sicker population with higher average costs). Prior to the kamagra, margins in the group and Medicare Advantage markets had grown gradually over recent years.Figure 1.

Average Gross Margins Per Member Per Month buy super kamagra online uk Through June, 2013 – 2020​Individual market margins have been more volatile than the other private markets since the early years of the Affordable Care Act (ACA), as described in more depth in our earlier analyses of individual market financial performance. Individual market margins remained relatively stable through the first six months of 2020, decreasing just $4 per member per month, and remaining much higher than in the earlier years of the ACA. These data suggest that insurers in the individual market remain financially healthy after a year and a half with no individual mandate penalty, even while the erectile dysfunction outbreak worsened.Medical Loss RatiosAnother way to assess insurer financial performance is to look at medical loss ratios, which are the percent of premium income that insurers pay out in the form of medical claims. Generally, lower medical loss ratios mean that insurers have more income remaining, after buy super kamagra online uk paying medical costs, to use for administrative costs or keep as profits. Each health insurance market has different administrative needs and costs, so low loss ratios in one market do not necessarily mean that market is more profitable than another market.

However, in a given market, if administrative costs hold mostly constant from one year to the next, a drop in loss ratios would imply that plans are becoming more profitable.Medical loss ratios are used in state and federal insurance regulation buy super kamagra online uk in a variety of ways. In the commercial insurance (individual and group) markets, insurers must issue rebates to individuals and businesses if their loss ratios fail to reach minimum standards set by the ACA. Medicare Advantage buy super kamagra online uk insurers are required to report loss ratios at the contract level. They are also required to issue rebates to the federal government if they fall short of 85%, and are subject to additional penalties if they fail to meet loss ratio requirements for multiple consecutive years in a row.The loss ratios shown in this issue brief differ from the definition of MLR in the ACA, which makes some adjustments for quality improvement and taxes, and do not account for reinsurance, risk corridors, or risk adjustment payments. The chart below shows simple medical loss ratios, or the share of premium income that insurers pay out in claims, without any modifications (Figure buy super kamagra online uk 2).

Loss ratios in the Medicare Advantage market decreased 5 percentage points through the first six months of 2020 relative to the same period in 2019, and group market loss ratios decreased by an average of 3 percentage points relative to last year.Figure 2. Average Medical Loss Ratios Through June, 2013 – 2020​The individual buy super kamagra online uk market was the only market in which average loss ratios held steady from last year. Even so, loss ratios in the individual market were already quite low and insurers in that market are issuing record-large rebates to consumers based in part on their 2019 experience.DiscussionAlthough we cannot measure profits directly, all signs suggest that health insurers in most markets have become more profitable so far during the kamagra. Medicare Advantage buy super kamagra online uk and group health plans saw rising margins and falling loss ratios through June 2020, relative to the same time last year. In contrast, margins and loss ratios among individual market insurers have generally remained flat through the second quarter compared to the same time last year, though insurers in this market already had high margins and low loss ratios last year.That insurers appear to be becoming more profitable during a kamagra may be counter-intuitive.

Insurers were generally required to cover erectile dysfunction treatment testing costs, and many also voluntarily covered the buy super kamagra online uk full cost of erectile dysfunction treatment for a period of time (see for example, announcements from UnitedHealthcare, CVSHealth (Aetna), and Cigna). Even with these increased kamagra-related expenses, though, many insurers saw claims costs fall as enrollees delayed or went without other types of health care due to social distancing restrictions, cancelation of elective procedures, or out of fear of contracting the kamagra. Job losses and economic instability may also affect health care utilization.The drop in utilization that has contributed to higher gross margins and lower medical loss ratios presents uncertainty and challenges buy super kamagra online uk for insurers, particularly given the unknown trajectory of the kamagra. For Medicare Advantage insurers, these trends may result in plans offering more benefits than they currently do, which are popular and attract enrollees. But if insurers fall short in meeting required loss ratio requirements for multiple years, they face additional penalties, including the possibility buy super kamagra online uk of being terminated.

In the individual and group markets, insurers are reporting kamagra-related uncertainty as they set premiums for next year, and insurers are making different assumptions about the extent to which utilization will rebound or health costs will change due to factors like the potential for widespread vaccination.Unless these patterns change substantially in late 2020, ACA medical loss ratio rebates in 2021 likely will be exceptionally large across commercial markets. Rebates to consumers are calculated using a three-year average of medical loss ratios, meaning that 2021 rebates will be based on insurer performance in 2018, 2019, and 2020 buy super kamagra online uk. In the individual market in particular, insurers were quite profitable in 2018 and 2019, so even if 2020 turns out to be a more average year, these insurers will likely owe large rebates to consumers. Group market insurers may also owe larger rebates to employers buy super kamagra online uk and employees than plans have in typical years, as loss ratios have dropped substantially. This may, in part, explain why many commercial insurers have volunteered to cover erectile dysfunction treatment costs, waived telemedicine cost-sharing, or expanded mental health services during the kamagra.

By increasing their claims costs, insurers can proactively increase loss ratios and owe smaller rebates next year..

Medicare Part D is a voluntary outpatient prescription drug benefit for people with Medicare, provided through private plans approved by the federal government buy kamagra with free samples. Beneficiaries can choose to enroll in either a stand-alone prescription drug plan (PDP) to supplement traditional Medicare or a Medicare Advantage prescription drug plan (MA-PD), mainly HMOs and PPOs, that cover all Medicare benefits including drugs. In 2020, 46 million of the more than 60 buy kamagra with free samples million people covered by Medicare are enrolled in Part D plans. This fact sheet provides an overview of the Medicare Part D program, plan availability, enrollment, and spending and financing, based on data from the Centers for Medicare &.

Medicaid Services (CMS), the Congressional Budget Office (CBO), and other sources.Medicare Prescription Drug Plan Availability in 2021In 2021, 996 PDPs will be offered across the 34 PDP regions nationwide (excluding the buy kamagra with free samples territories). This represents an increase of 48 PDPs from 2020 (a 5% increase) and an increase of 250 plans (a 34% increase) since 2017 (Figure 1).Figure 1. A Total of 996 Medicare Part D Stand-Alone Prescription Drug Plans Will Be Offered buy kamagra with free samples in 2021, a 5% Increase From 2020 and a 33% Increase Since 2017The relatively large increase in the number of PDPs in recent years is likely due to the elimination by CMS of the “meaningful difference” requirement for enhanced benefit PDPs offered by the same organization in the same region. Plans with enhanced benefits can offer a lower deductible, reduced cost sharing, or a higher initial coverage limit.

Previously, PDP sponsors were required to demonstrate that their enhanced PDPs buy kamagra with free samples were meaningfully different in terms of enrollee out-of-pocket costs in order to ensure that plan offerings were more distinct. Between 2018 and 2021, the number of enhanced PDPs has increased by nearly 50%, from 421 to 618, largely due to this policy change.Beneficiaries in each state will have a choice of multiple stand-alone PDPs in 2021, ranging from 25 PDPs in Alaska to 35 PDPs in Texas (see map). In addition, beneficiaries will be able to choose from buy kamagra with free samples among multiple MA-PDs offered at the local level for coverage of their Medicare benefits. New for 2021, beneficiaries in each state will have the option to enroll in a Part D plan participating in the Trump Administration’s new Innovation Center model in which enhanced drug plans cover insulin products at a monthly copayment of $35 in the deductible, initial coverage, and coverage gap phases of the Part D benefit.

Participating plans do not have to cover all buy kamagra with free samples insulin products at the $35 monthly copayment amount, just one of each dosage form (vial, pen) and insulin type (rapid-acting, short-acting, intermediate-acting, and long-acting). In 2021, a total of 1,635 Part D plans will participate in this model, which represents just over 30% of both PDPs (310 plans) and MA-PDs (1,325 plans) available in 2021, including plans in the territories. Between 8 buy kamagra with free samples and 10 PDPs in each region are participating in the model, in addition to multiple MA-PDs (see map). Low-Income Subsidy Plan Availability in 2021Beneficiaries with low incomes and modest assets are eligible for assistance with Part D plan premiums and cost sharing.

Through the Part D Low-Income Subsidy (LIS) program, additional premium and cost-sharing assistance is available for Part D enrollees with low incomes (less than 150% of poverty, or $19,140 for individuals/$25,860 for married couples in 2020) and modest assets (less than $14,610 for individuals/$29,160 for couples in 2020).In 2021, 259 plans will be available for enrollment of LIS beneficiaries for no premium, buy kamagra with free samples 15 more than in 2020 (a 6% increase), and the second year with an increase in the number of benchmark plans since 2018 (Figure 2). Just over one-fourth of PDPs in 2021 (26%) are benchmark plans. Some enrollees have fewer benchmark plan buy kamagra with free samples options than others, since benchmark plan availability varies at the Part D region level. The number of premium-free PDPs in 2021 ranges across states from 5 to 10 plans (see map).

LIS enrollees can select any plan offered in their area, but if they are enrolled in a non-benchmark plan, they may buy kamagra with free samples be required to pay some portion of their plan’s monthly premium Figure 2. In 2021, 259 Part D Stand-Alone Drug Plans Will Be Available Without a Premium to Enrollees Receiving the Low-Income Subsidy (“Benchmark” Plans)Part D Plan Premiums and Benefits in 2021PremiumsThe 2021 Part D base beneficiary premium – which is based on bids submitted by both PDPs and MA-PDs and is not weighted by enrollment – is $33.06, a modest (1%) increase from 2020. But actual buy kamagra with free samples premiums paid by Part D enrollees vary considerably. For 2021, PDP monthly premiums range from a low of $5.70 for a PDP in Hawaii to a high of $205.30 for a PDP in South Carolina (unweighted by plan enrollment).

Even within a state, PDP premiums can vary. For example, in Florida, monthly premiums range from $7.30 to buy kamagra with free samples $172. In addition to the monthly premium, Part D enrollees with higher incomes ($87,000/individual. $174,000/couple) pay an income-related premium surcharge, ranging from $12.32 to $77.14 per month in 2021 (depending on buy kamagra with free samples income).BenefitsThe Part D defined standard benefit has several phases, including a deductible, an initial coverage phase, a coverage gap phase, and catastrophic coverage.

Between 2020 and 2021, the parameters of the standard benefit are rising, which means Part D enrollees will face higher out-of-pocket costs for the deductible and in the initial coverage phase, as they have in prior years, and will have to pay more out-of-pocket before qualifying for catastrophic coverage (Figure 3).The standard deductible is increasing from $435 in 2020 to $445 in 2021The initial coverage limit is increasing from $4,020 to $4,130, andThe out-of-pocket spending threshold is increasing from $6,350 to $6,550 (equivalent to $10,048 in total drug spending in 2021, up from $9,719 in 2020).The standard benefit amounts are indexed to change annually based on the rate of Part D per capita spending growth, and, with the exception of 2014, have increased each year since 2006.Figure 3. Medicare Part D Standard Benefit Parameters Will Increase in 2021For costs in the coverage gap phase, beneficiaries pay 25% for both brand-name and generic drugs, with manufacturers providing a 70% discount on brands and plans paying the buy kamagra with free samples remaining 5% of brand drug costs, and plans paying the remaining 75% of generic drug costs. For total drug costs above the catastrophic threshold, Medicare pays 80%, plans pay 15%, and enrollees pay either 5% of total drug costs or $3.70/$9.20 for each generic and brand-name drug, respectively.Part D plans must offer either the defined standard benefit or an alternative equal in value (“actuarially equivalent”) and can also provide enhanced benefits. Both basic and enhanced benefit plans vary in terms of their specific buy kamagra with free samples benefit design, coverage, and costs, including deductibles, cost-sharing amounts, utilization management tools (i.e., prior authorization, quantity limits, and step therapy), and formularies (i.e., covered drugs).

Plan formularies must include drug classes covering all disease states, and a minimum of two chemically distinct drugs in each class. Part D plans are required to cover all buy kamagra with free samples drugs in six so-called “protected” classes. Immunosuppressants, antidepressants, antipsychotics, anticonvulsants, antiretrovirals, and antineoplastics.Part D and Low-Income Subsidy EnrollmentEnrollment in Medicare Part D plans is voluntary, with the exception of beneficiaries who are eligible for both Medicare and Medicaid and certain other low-income beneficiaries who are automatically enrolled in a PDP if they do not choose a plan on their own. Unless beneficiaries have drug coverage from another source that is at least as good as buy kamagra with free samples standard Part D coverage (“creditable coverage”), they face a penalty equal to 1% of the national average premium for each month they delay enrollment.In 2020, 46.5 million Medicare beneficiaries are enrolled in Medicare Part D plans, including employer-only group plans.

Of the total, just over half (53%) are enrolled in stand-alone PDPs and nearly half (47%) are enrolled in Medicare Advantage drug plans (Figure 4). Another 1.3 million beneficiaries are estimated to have drug coverage through employer-sponsored retiree plans where the employer receives a subsidy buy kamagra with free samples from the federal government equal to 28% of drug expenses between $445 and $9,200 per retiree (in 2021). Several million beneficiaries are estimated to have other sources of drug coverage, including employer plans for active workers, FEHBP, TRICARE, and Veterans Affairs (VA). Another 12% of people with buy kamagra with free samples Medicare are estimated to lack creditable drug coverage.Figure 4.

Medicare Part D Enrollment in Stand-Alone Drug Plans Has Declined Recently But Has Increased Steadily in Medicare Advantage Drug PlansAn estimated 13 million Part D enrollees receive the Low-Income Subsidy in 2020. Beneficiaries who are dually eligible, QMBs, SLMBs, QIs, and SSI-onlys automatically qualify for the additional assistance, and Medicare automatically enrolls them into PDPs with premiums at or below the regional average (the Low-Income Subsidy benchmark) if they do not choose a plan buy kamagra with free samples on their own. Other beneficiaries are subject to both an income and asset test and need to apply for the Low-Income Subsidy through either the Social Security Administration or Medicaid.Part D Spending and FinancingPart D SpendingThe Congressional Budget Office (CBO) estimates that spending on Part D benefits will total $96 billion in 2021, representing 13% of net Medicare outlays (net of offsetting receipts from premiums and state transfers). Part D spending depends on several factors, including the total number of Part D enrollees, their health status and drug use, the number of high-cost enrollees (those with drug spending above the catastrophic threshold), the number of enrollees receiving the Low-Income Subsidy, and plans’ ability to negotiate discounts (rebates) with drug companies and preferred pricing arrangements with buy kamagra with free samples pharmacies, and manage use (e.g., promoting use of generic drugs, prior authorization, step therapy, quantity limits, and mail order).

Federal law currently prohibits the Secretary of Health and Human Services from interfering in drug price negotiations between Part D plan sponsors and drug manufacturers.Part D FinancingFinancing for Part D comes from general revenues (71%), beneficiary premiums (16%), and state contributions (12%). The monthly premium paid by enrollees is set to cover 25.5% of the buy kamagra with free samples cost of standard drug coverage. Medicare subsidizes the remaining 74.5%, based on bids submitted by plans for their expected benefit payments. Higher-income Part D enrollees pay a larger share of standard Part D costs, ranging from 35% to 85%, depending on income.Payments to PlansFor 2021, Medicare’s actuaries estimate that Part D plans will receive direct subsidy payments averaging $216 per enrollee overall, $2,639 for enrollees receiving the LIS, and $1,026 in reinsurance payments for very high-cost enrollees.

Employers are expected to receive, on average, $575 for retirees in employer-subsidy plans buy kamagra with free samples. Part D plans also receive additional risk-adjusted payments based on the health status of their enrollees, and plans’ potential total losses or gains are limited by risk-sharing arrangements with the federal government (“risk corridors”).Under reinsurance, Medicare subsidizes 80% of total drug spending incurred by Part D enrollees with relatively high drug spending above the catastrophic coverage threshold. In the aggregate, Medicare’s reinsurance payments to Part D plans now account for close to half of total Part D spending (45%), up from 14% in 2006 (increasing from buy kamagra with free samples $6 billion in 2006 to $46 billion in 2019) (Figure 5). Higher benefit spending above the catastrophic threshold is a result of several factors, including an increase in the number of high-cost drugs, prescription drug price increases, and a change made by the ACA to count the manufacturer discount on the price of brand-name drugs in the coverage gap towards the out-of-pocket threshold for catastrophic coverage.

This change has led to more Part D enrollees with spending above the catastrophic threshold over time.Figure buy kamagra with free samples 5. Spending for Catastrophic Coverage (“Reinsurance”) Now Accounts for Close to Half (45%) of Total Medicare Part D Spending, up from 14% in 2006Issues for the FutureThe Medicare drug benefit has helped to reduce out-of-pocket drug spending for enrollees, which is especially important to those with modest incomes or very high drug costs. But with drug buy kamagra with free samples costs on the rise, more plans charging coinsurance rather than flat copayments for covered brand-name drugs, and annual increases in the out-of-pocket spending threshold, many Part D enrollees are likely to face higher out-of-pocket costs for their medications.In light of ongoing attention to prescription drug spending and rising drug costs, policymakers have issued several proposals to control drug spending by Medicare and beneficiaries. Several of these proposals address concerns about the lack of a hard cap on out-of-pocket spending for Part D enrollees, the significant increase in Medicare spending for enrollees with high drug costs, and the relatively weak financial incentives faced by Part D plan sponsors to control high drug costs.

Such proposals include allowing Medicare to negotiate the price of buy kamagra with free samples drugs, restructuring the Part D benefit to add a hard cap on out-of-pocket drug spending, requiring manufacturers to pay a rebate to the federal government if their drug prices increase faster than inflation, using drug prices in other countries in determining pricing for drugs in the U.S., allowing for drug importation, and shifting more of the responsibility for catastrophic coverage costs to Part D plans and drug manufacturers.Understanding how well Part D continues to meet the needs of people on Medicare will be informed by ongoing monitoring of the Part D plan marketplace, examining formulary coverage and costs for new and existing medications, assessing the impact of the new insulin model, and keeping tabs on Medicare beneficiaries’ out-of-pocket drug spending.The erectile dysfunction kamagra, social distancing, and resulting economic downturn have had considerable implications for the U.S. Health system, including health insurers. The kamagra caused a sizable decrease in the use of health care services during the first buy kamagra with free samples half of 2020, job losses appear to have led to coverage loss in the employer market and increases in Medicaid enrollment, and insurers projecting costs for next year must assess the relative effects of pent-up demand for delayed care, the continuing kamagra, and a potential treatment.In this brief, we analyze data from 2013 to 2020 to examine how insurance markets performed through the first half of this year as the kamagra developed and worsened in the U.S. We use financial data reported by insurance companies to the National Association of Insurance Commissioners and compiled by Mark Farrah Associates to look at average medical loss ratios and gross margins in the individual (also known as non-group), fully-insured group (employer), and Medicare Advantage health insurance markets.

A more detailed description of each market is included in the Appendix.We find that, as of the end of June 2020, average margins have increased and loss ratios have dropped across the fully-insured group and buy kamagra with free samples Medicare Advantage markets, relative to the same time period in 2019. If administrative costs were roughly the same in 2020 as in 2019, these findings suggest higher profits for many insurers during the kamagra. Individual market loss ratios were already buy kamagra with free samples quite low and remained flat into 2020, suggesting continued profitability. The results for the individual and group markets indicate that commercial insurers are on track to owe substantial rebates to consumers again next year under the Affordable Care Act (ACA) Medical Loss Ratio provision.Gross MarginsOne way to assess insurer financial performance is to examine average gross margins per member per month, or the average amount by which premium income exceeds claims costs per enrollee in a given month.

Gross margins are an indicator of performance, but positive buy kamagra with free samples margins do not necessarily translate into profitability since they do not account for administrative expenses. However, a sharp increase in margins from one year to the next, without a commensurate increase in administrative costs, would indicate that these health insurance markets have become more profitable during the kamagra.Despite many insurers covering the full cost of erectile dysfunction testing and treatment for their enrollees, insurers across most markets have seen their claims costs fall, and margins increase since the start of the kamagra, and relative to 2019. This is consistent with the sharp drop in utilization documented in other analyses.Gross margins among group market plans increased 22% (or buy kamagra with free samples $20 pmpm) through the second quarter of 2020 relative to the same period in 2019. Gross margins among Medicare Advantage plans also increased, rising 41% (or $64 pmpm) through the first six months of 2020 compared to gross margins at the same point last year.

(Gross margins per member per month tend to be higher for Medicare Advantage than for the other health insurance markets mainly because Medicare covers an older, sicker population with higher buy kamagra with free samples average costs). Prior to the kamagra, margins in the group and Medicare Advantage markets had grown gradually over recent years.Figure 1. Average Gross Margins Per Member Per Month Through June, 2013 – 2020​Individual market margins have been more volatile than the other private markets since the buy kamagra with free samples early years of the Affordable Care Act (ACA), as described in more depth in our earlier analyses of individual market financial performance. Individual market margins remained relatively stable through the first six months of 2020, decreasing just $4 per member per month, and remaining much higher than in the earlier years of the ACA.

These data suggest that insurers in the individual market remain financially healthy after a year and a half with no individual mandate penalty, even while the erectile dysfunction outbreak worsened.Medical Loss RatiosAnother way to assess insurer financial performance is to look at medical loss ratios, which are the percent of premium income that insurers pay out in the form of medical claims. Generally, lower buy kamagra with free samples medical loss ratios mean that insurers have more income remaining, after paying medical costs, to use for administrative costs or keep as profits. Each health insurance market has different administrative needs and costs, so low loss ratios in one market do not necessarily mean that market is more profitable than another market. However, in a given market, if administrative costs hold mostly constant from one year to the next, a drop in loss ratios buy kamagra with free samples would imply that plans are becoming more profitable.Medical loss ratios are used in state and federal insurance regulation in a variety of ways.

In the commercial insurance (individual and group) markets, insurers must issue rebates to individuals and businesses if their loss ratios fail to reach minimum standards set by the ACA. Medicare Advantage insurers are required to buy kamagra with free samples report loss ratios at the contract level. They are also required to issue rebates to the federal government if they fall short of 85%, and are subject to additional penalties if they fail to meet loss ratio requirements for multiple consecutive years in a row.The loss ratios shown in this issue brief differ from the definition of MLR in the ACA, which makes some adjustments for quality improvement and taxes, and do not account for reinsurance, risk corridors, or risk adjustment payments. The chart below shows simple medical loss ratios, or the share buy kamagra with free samples of premium income that insurers pay out in claims, without any modifications (Figure 2).

Loss ratios in the Medicare Advantage market decreased 5 percentage points through the first six months of 2020 relative to the same period in 2019, and group market loss ratios decreased by an average of 3 percentage points relative to last year.Figure 2. Average Medical Loss Ratios Through June, 2013 – 2020​The individual market was the only market in which average loss ratios buy kamagra with free samples held steady from last year. Even so, loss ratios in the individual market were already quite low and insurers in that market are issuing record-large rebates to consumers based in part on their 2019 experience.DiscussionAlthough we cannot measure profits directly, all signs suggest that health insurers in most markets have become more profitable so far during the kamagra. Medicare Advantage and group health plans saw rising margins and falling loss ratios through June 2020, relative buy kamagra with free samples to the same time last year.

In contrast, margins and loss ratios among individual market insurers have generally remained flat through the second quarter compared to the same time last year, though insurers in this market already had high margins and low loss ratios last year.That insurers appear to be becoming more profitable during a kamagra may be counter-intuitive. Insurers were generally required to buy kamagra with free samples cover erectile dysfunction treatment testing costs, and many also voluntarily covered the full cost of erectile dysfunction treatment for a period of time (see for example, announcements from UnitedHealthcare, CVSHealth (Aetna), and Cigna). Even with these increased kamagra-related expenses, though, many insurers saw claims costs fall as enrollees delayed or went without other types of health care due to social distancing restrictions, cancelation of elective procedures, or out of fear of contracting the kamagra. Job losses and economic instability buy kamagra with free samples may also affect health care utilization.The drop in utilization that has contributed to higher gross margins and lower medical loss ratios presents uncertainty and challenges for insurers, particularly given the unknown trajectory of the kamagra.

For Medicare Advantage insurers, these trends may result in plans offering more benefits than they currently do, which are popular and attract enrollees. But if insurers fall short in meeting required loss ratio requirements buy kamagra with free samples for multiple years, they face additional penalties, including the possibility of being terminated. In the individual and group markets, insurers are reporting kamagra-related uncertainty as they set premiums for next year, and insurers are making different assumptions about the extent to which utilization will rebound or health costs will change due to factors like the potential for widespread vaccination.Unless these patterns change substantially in late 2020, ACA medical loss ratio rebates in 2021 likely will be exceptionally large across commercial markets. Rebates to consumers are calculated using a three-year average of medical loss ratios, meaning that 2021 rebates will be based on insurer performance in 2018, buy kamagra with free samples 2019, and 2020.

In the individual market in particular, insurers were quite profitable in 2018 and 2019, so even if 2020 turns out to be a more average year, these insurers will likely owe large rebates to consumers. Group market insurers may also owe larger rebates to employers and employees than plans have in buy kamagra with free samples typical years, as loss ratios have dropped substantially. This may, in part, explain why many commercial insurers have volunteered to cover erectile dysfunction treatment costs, waived telemedicine cost-sharing, or expanded mental health services during the kamagra. By increasing their claims costs, insurers can proactively increase loss ratios and owe smaller rebates next year..

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A few weeks ago my fiance Caleb and I ordered a custom table for our new, rustic home that sits in the woods. I came across Ben Shea through some mutual friends and immediately fell in love with his work! After I saw the finished product of our table, I was definitely NOT disappointed. Ben is an awesome guy, so easy to work with and he totally made our vision become a reality! It’s exactly what I wanted. Raw, rustic, knots and grain. I’m.. obsessed. Ben is constantly creating lots of amazing wood pieces for homes, offices and gifts! Check out his Facebook fan-page HERE, his Etsy shop HERE, and his website HERE.

Meagan Nicole

 


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This Sunday my mom and sister threw me a surprise bridal shower! I knew I was having the bridal shower, but I had absolutely nothing to do with the planning so I had no clue what to expect or who would be coming (although seeing random pieces of thrifted china and table clothes hidden around the house was getting me very excited!). It was more beautiful than I could’ve imaged and exactly what I hoped for. So many lovely faces came that I wasn’t expecting which made it all the sweeter. The theme was an outdoor garden party! My mom made her famous chicken salad recipe, a blueberry-raspberry-strawberry fruit medley, and greens with an olive oil lemon dressing (the one they use at Tomato Pie) YUM! The vintage dresser held two baskets- everyone brought their favorite kitchen spice or  cleaning item (which went in the awesome, wooden hamper my nana gifted us to the right of the dresser)! I loved the date night jar. Everyone wrote down date ideas on popcycle sticks for Caleb and I. We’ve been enjoying reading everyones recommendations.. especially the hilarious X-rated ones. haha!

If you’re wondering why my face looks so crazy in the opening-gifts photos it’s because we were playing the bubble gum game! Previously my sister had asked Caleb a bunch of random questions that he gave his answers to. While opening gifts, I was asked these questions as well and had to try and answer the same as Caleb did. For every question I got wrong I gad to put a piece of gum in my mouth. I actually did pretty good but still wound up with a few wads of gum, whoops. I never thought I could get tired of bubble gum until Sunday. HA! This was such a fun and exciting day! Huge thank you’s to my mom and sister for pulling it all together and getting so creative.. I know how much work and thought you put into everything to make it perfect for me and it means so much! To each and every lady that came to the party- you all made me feel so loved and blessed! Thank you for celebrating this time in my life; Caleb and I are beyond thankful for all of the amazing gifts and well wishes you showered us with. 🙂

*Beautiful cake by Wendy Hess at Oregon Dairy Bakery!

**All photographs taken by my amazing friend Rebekah of Rebekah Viola Photography! Thank you so much for capturing these memories for me.

Meagan Nicole


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