Friday, January 19, 2018

Should all patients be asked about their sexual orientation?

In late 2017, NHS England released guidelines recommending that health professionals ask all patients about their sexual orientation in order to improve services for non-heterosexual patients, but should they? Experts debate the issue in The BMJ today.

19 jan 2018--After decades of campaigning from lesbian, gay, bisexual and trans (LGBT) charities, sexual orientation is now a protected characteristic that is written into the Equality Act 2010. General practitioner and research fellow Richard Ma, from Imperial College London says all patients should be asked about their sexual orientation.
Ma comments that it would seem like a welcome step for NHS England to include sexual orientation monitoring in health and social care systems.
"Some doctors and patients have expressed concerns about this policy, citing reasons such as intrusion or invasion of privacy, fear of causing offence, doubts about relevance, data security" he says. "Whilst I understand these concerns, they result in inertia; and failure to act undermines hard fought rights of LGBT patients to better healthcare."
Ma states there are flaws in recognising LGBT health needs. A survey of nearly 7000 gay and bisexual men, commissioned by LGBT charity, Stonewall, shows that smoking, alcohol, and drug use were more prevalent in this group compared to men in general.
"Sexual orientation monitoring is necessary to make the health service for LGBT patients fairer. If we don't count our LGBT patients, they don't count." Ma concludes.
But Michael Dixon, a general practitioner, says that it should be up to the individual judgement of GPs as to when it's appropriate or useful to ask such questions about patient sexual orientation.
He says that whilst there are health benefits from knowing a patient's sexuality, the approach of asking 'all' patients is wrong.
"Apparently this is all to stop discrimination under the Equality Act, but surely the best way to avoid discrimination is by not knowing people's sexuality in the first place" he says.
"In good medical practice, the patient's own needs, wishes, choices, beliefs, culture, and perspective should come first - not the rules or diktats of any higher body" he concludes.
In a linked patient commentary, Tamás Bereczky, from the European AIDS Treatment Group, says whilst discussing sexual orientation between doctors and patients can be embarrassing, healthcare professionals should be able to talk about all sensitive topics.
"Visibility and honest discussion can also eventually reduce stigma" he concludes.

More information: Should all patients be asked about their sexual orientation? www.bmj.com/content/360/bmj.k52
Commentary: Let's talk about sex www.bmj.com/content/360/bmj.k76


Provided by British Medical Journal

Thursday, January 18, 2018

Chronic inflammation causes loss of muscle mass during aging

muscle
Skeletal muscle tissue.
People start losing muscle mass at the age of 40—about some 10 percent of the total muscle mass for each 10-year period, which may lead to fall-related injuries, slowing metabolism and reduced quality of life. Today, very little is known as to why muscle mass diminishes with age, but one theory is that it is caused by what has been termed inflammaging. It is characterised by chronic, moderately elevated levels of inflammation markers in the blood.

18 jan 2018--"We wanted more specifically to examine the correlation between CRP, an inflammaging marker, and muscle mass in elderly persons," says Fawzi Kadi, Professor of Sports Physiology and Medicine at Örebro University.
C-reactive protein (CRP) in the blood can be used as a marker for both inflammaging and infection in the body. The results of the study, in which women aged 65 to 70 participated, show a correlation between increased CRP levels in the blood and lower muscle mass.
The research team explored further how CRP affects muscle cell turnover and function by exposing, in a laboratory environment, isolated muscle cells to CRP.
"We were able to see that muscle cells exposed to CRP reduced in size. These are new findings which explain the causal link between elevated CRP values and reduced muscle mass. Researchers have previously only been able to find a correlation between the two, using large population studies," says Fawzi Kadi.
However, the researchers were also able to show exactly how CRP affects the size of muscle cells, which has not been done before. Their findings show that CRP affects muscle cells' protein synthesis, that is, the generation of new proteins taking place in all living cells.
"Muscles are our main protein depots. We saw that CRP interferes with the protein synthesis in the muscle cells, hence contributing to the loss of muscle mass," explains Fawzi Kadi.
With researchers for the first time possessing knowledge of the mechanism that links gradual loss of muscle mass to inflammaging, opens up for new studies with a focus on how to counteract the reduction of muscle mass by controlling levels of inflammation markers.
"A mechanism which explains the connection is of great significance for both preventive measures and drug development. What is interesting is that inflammaging is a process quietly at work. If we can tackle inflammaging in time, are we then able to postpone the development of a number of chronic diseases?"
In their current studies, it is the preventive measures that Fawzi Kadi, together with his colleague Andreas Nilsson, senior lecturer in Sports Physiology, are focusing on. More particularly, lifestyle factors.
"Andreas Nilsson is leading studies where they look at what effects changed behaviour has on health. If you swapped one hour of watching TV for another activity, what effect would that have for the inflammaging in your body? That's just one example from our studies," says Fawzi Kadi.
In another study, the research team is studying the correlation between inflammaging and physical activity, which will involve analysing the levels of a number of inflammatory biomarkers, including CRP.

More information: Britta Wåhlin-Larsson et al. Mechanistic Links Underlying the Impact of C-Reactive Protein on Muscle Mass in Elderly, Cellular Physiology and Biochemistry (2017). DOI: 10.1159/000484679


Provided by Örebro Universitet

Tuesday, January 16, 2018

WHO: All of Sao Paulo state at risk for yellow fever

Sao Paulo

The World Health Organization has added all of Sao Paulo state to its list of areas at risk for yellow fever.
That puts the megacity of Sao Paulo on the list and means that the organization is recommending that all international visitors to the state be vaccinated.

16 jan 2018--Tuesday's announcement comes as an outbreak is gathering steam in Brazil ahead of Carnival, a major draw for foreign tourists. The WHO says 11 human cases have been confirmed through last week and hundreds more found in monkeys.
Much of Brazil is considered at risk for yellow fever, but the coast was largely considered safe. Last year, however, Brazil saw an unusually large outbreak of the disease, including in areas not previously at risk. In response, Brazil rushed to vaccinate millions of people.

Sunday, January 14, 2018

Anxiety: An early indicator of Alzheimer's disease?


Alzheimer's disease
Diagram of the brain of a person with Alzheimer's Disease.
A new study suggests an association between elevated amyloid beta levels and the worsening of anxiety symptoms. The findings support the hypothesis that neuropsychiatric symptoms could represent the early manifestation of Alzheimer's disease in older adults.

14 jan 2018--Alzheimer's disease is a neurodegenerative condition that causes the decline of cognitive function and the inability to carry out daily life activities. Past studies have suggested depression and other neuropsychiatric symptoms may be predictors of AD's progression during its "preclinical" phase, during which time brain deposits of fibrillar amyloid and pathological tau accumulate in a patient's brain. This phase can occur more than a decade before a patient's onset of mild cognitive impairment. Investigators at Brigham and Women's Hospital examined the association of brain amyloid beta and longitudinal measures of depression and depressive symptoms in cognitively normal, older adults. Their findings, published today by The American Journal of Psychiatry, suggest that higher levels of amyloid beta may be associated with increasing symptoms of anxiety in these individuals. These results support the theory that neuropsychiatric symptoms could be an early indicator of AD.
"Rather than just looking at depression as a total score, we looked at specific symptoms such as anxiety. When compared to other symptoms of depression such as sadness or loss of interest, anxiety symptoms increased over time in those with higher amyloid beta levels in the brain," said first author Nancy Donovan, MD, a geriatric psychiatrist at Brigham and Women's Hospital. "This suggests that anxiety symptoms could be a manifestation of Alzheimer's disease prior to the onset of cognitive impairment. If further research substantiates anxiety as an early indicator, it would be important for not only identifying people early on with the disease, but also, treating it and potentially slowing or preventing the disease process early on." As anxiety is common in older people, rising anxiety symptoms may prove to be most useful as a risk marker in older adults with other genetic, biological or clinical indicators of high AD risk.
Researchers derived data from the Harvard Aging Brain Study, an observational study of older adult volunteers aimed at defining neurobiological and clinical changes in early Alzheimer's disease. The participants included 270 community dwelling, cognitively normal men and women, between 62 and 90 years old, with no active psychiatric disorders. Individuals also underwent baseline imaging scans commonly used in studies of Alzheimer's disease, and annual assessments with the 30-item Geriatric Depression Scale (GDS), an assessment used to detect depression in older adults.
The team calculated total GDS scores as well as scores for three clusters symptoms of depression: apathy-anhedonia, dysphoria, and anxiety. These scores were looked at over a span of five years.
From their research, the team found that higher brain amyloid beta burden was associated with increasing anxiety symptoms over time in cognitively normal older adults. The results suggest that worsening anxious-depressive symptoms may be an early predictor of elevated amyloid beta levels - and, in turn AD—and provide support for the hypothesis that emerging neuropsychiatric symptoms represent an early manifestation of preclinical Alzheimer's disease.
Donovan notes further longitudinal follow-up is needed to determine whether these escalating depressive symptoms give rise to clinical depression and dementia stages of Alzheimer's disease over time.

More information: Donovan et al. "Longitudinal Association of Amyloid Beta and Anxious-Depressive Symptoms in Cognitively Normal Older Adults" The American Journal of Psychiatry DOI: 10.1176/appi.ajp.2017.17040442


Provided by Brigham and Women's Hospital

Saturday, January 13, 2018

Longevity insights from demographic, phenotypic and genetic studies



Longevity insights from demographic, phenotypic and genetic studies
Centenarians in Japan between 1963 and 2015
Understanding the demographic, phenotypic and genetic features associated with ageing has been the subject of many studies worldwide. Japan offers a unique opportunity for such studies since it has a large population with a very high longevity rate. Recent studies have shown that the number of centenarians in Japan increased from 154 in 1963 to 61,568 in 2015, and has increased 4.2-fold between 1996 and 2006, compared to an increase of 2- and 1.6-fold in France and Denmark, respectively.

13 jan2018--Researchers in Japan have previously shown that Sirt1 overexpression can alleviate acute kidney injury in a Sirt1-overexpressing mouse model. The same group has now established the mechanism that links, at least in part, Sirt1 with the pathogenesis of renal damage in diabetes.
In a recent review, Yasumichi Arai and colleagues at the Keio University School of Medicine give an overview of previous and current findings relating to the health status of centenarians in Japan. Interdisciplinary studies revealed that approximately 20 percent of centenarians had reasonably high functional capacity and enjoy physical and cognitive independence. Furthermore, those who were independent at the age of 100 were more likely to reach 105 (semi-supercentenarians) and even 110 (supercentenarians). These findings prompted the group to shift their research to focus on semi-supercentenarians as a model of healthy longevity.
Despite cardiovascular disease being the leading cause of death in old age, centenarians have a low risk of cardiovascular disease, with low prevalence of atherosclerosis. Prevalence of diabetes is only 6 percent in centenarians compared to 14.7 percent in the general population aged in their 70s. The prevalence of hypertension was about 60 percent, however, this was paradoxically found to be associated with high levels of physical and cognitive function. The authors used data from several longevity studies in order to investigate several factors, including haematopoiesis, inflammation, liver function and cellular senescence, and their association with capability and cognition during ageing. Low-level of inflammation was found to be correlated with survival, capability and cognition. Telomere length, which is a marker of cellular senescence, was more efficiently maintained by centenarians and their off-spring compare to the general population. The authors have now started a whole genome sequencing analysis of supercentenarians, semi-supercentenarians, and young centenarians.
The authors conclude that "centenarians and particularly supercentenarians can live active lives, or they have at least done so for the majority of their very long lives." Regarding the DNA sequencing study and they are confident that the whole genome sequencing and analysis of these distinct centenarian cohorts will provide clues for identifying genetic factors that could contribute to healthy longevity.


Longevity insights from demographic, phenotypic and genetic studies





More information: Yasumichi Arai et al. Demographic, phenotypic, and genetic characteristics of centenarians in Okinawa and Honshu, Japan: Part 2 Honshu, Japan, Mechanisms of Ageing and Development (2017). DOI: 10.1016/j.mad.2017.02.005


Provided by Keio University

Friday, January 12, 2018

Study shows link between regular attendance at religious services and health and longevity

religious

Researchers from the Emory Rollins School of Public Health have published a paper in PLOS ONE that links regular attendance at religious services with improved health and lowered mortality.
The researchers conducted an empirical study on data collected 2004-2014 through the University of Michigan's Health and Retirement Study (HRS), which surveyed social and economic determinants of mortality in middle-aged and older adults, including religious factors.

12 jan 2018--"We wanted to link the research on religion—especially religious attendance—into the social determinants of health framework," says Idler.
This was an idea the paper's authors also examined in their book, Religion as a Social Determinant of Public Health (Oxford University Press, 2014), edited by Idler and featuring chapters by Blevins, Kiser, and Hogue, in addition to numerous additional Emory faculty.
"With this paper, we were able to take a theory and a conceptual framework to real data and came back with some dramatic findings. "
They found that there is a substantial amount of protection against mortality from all causes for people who attend religious services once a week or more often. Even those who attended less frequently had a greater protection against mortality than those who didn't attend at all. There were no differences by religious affiliation.
Part of this may be due to the positive health behaviors shown among those who attend religious services more often. For instance, those who attended services more often were less likely to smoke or drink alcohol than those who never attended, and they were more likely to exercise and get health screenings. Those frequenting religious services also experienced social benefits linked to health, like being part of a socially supportive community or volunteering to help others.
The findings showed that the protective effect of frequent attendance at services was very comparable to the effects of higher levels of income and wealth, economic factors that were especially well measured in the HRS.

More information: Ellen Idler et al. Religion, a social determinant of mortality? A 10-year follow-up of the Health and Retirement Study, PLOS ONE (2017). DOI: 10.1371/journal.pone.0189134


Provided by Emory University

Tuesday, January 09, 2018

Structured exercise program provides mobility benefits to all older patients, regardless of frailty status

exercise

Physicians should prescribe physical activity to all older patients, regardless of frailty status. A structured, moderate-intensity physical activity program was not associated with a reduced risk for frailty over 2 years among sedentary older adults; however, it did reduce major mobility disability in both frail and nonfrail patients. Findings from a secondary analysis of the LIFE (Lifestyle Interventions and Independence for Elders) trial are published in Annals of Internal Medicine.

09 jan 2017--Researchers from the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University and Geneva University Hospitals analyzed data for 1,635 community-dwelling adults, aged 70 to 89 years, with functional limitations to determine whether a long-term, structured, moderate-intensity physical activity program is associated with a lower risk for frailty and whether frailty status alters the effect of physical activity on the reduction in major mobility disability risk.
Participants were randomly assigned to a program consisting of aerobic, resistance, and flexibility activities or a health education program consisting of workshops and stretching exercise. Over 2 years follow-up, the risk for frailty was not statistically significantly different in the physical activity versus the health education group. Using a defined measure of frailty, the physical activity intervention was associated with improvement in the inability to rise from a chair.
These findings suggest that physical activity can benefit all older patients
.
More information: Study: http://annals.org/aim/article/doi/10.7326/M16-2011
Editorial: http://annals.org/aim/article/doi/10.7326/M17-3048
Summary for Patients: http://annals.org/aim/article/doi/10.7326/P17-9052


Provided by American College of Physicians

Monday, January 08, 2018

APA releases new practice guideline on treatment of alcohol use disorder

Today, the American Psychiatric Association (APA) released a new practice guideline on the treatment of alcohol use disorder. This practice guideline provides evidence-based statements designed to increase knowledge of the disorder and ensure the appropriate use of medications. An executive summary of the guideline is published in the American Journal of Psychiatry, available online today. The full guideline, executive summary and related materials are available at psychiatry.org/psychiatrists/practice/clinical-practice-guidelines.

08 jan 2018--"This new guideline is an important step in bringing effective, evidence-based treatments for alcohol use disorder to many more people and in helping address the public health burden of alcohol use," said APA President Anita Everett, M.D.
The estimated lifetime prevalence rate for alcohol use disorder in the U.S. is 29 percent, and it places a significant strain on individuals, their families and on public health. Effective, evidence-based interventions are available, yet alcohol use disorder remains undertreated. Fewer than one in 10 individuals in the U.S. with a 12-month diagnosis of alcohol use disorder receive any treatment.
The Practice Guideline for the Pharmacological Treatment of Patients with Alcohol Use Disorder focuses specifically on evidence-based pharmacological treatments for alcohol use disorder.

Guideline recommendations
  • Naltrexone and acamprosate are recommended to treat patients with moderate to severe alcohol use disorder in specific circumstances (e.g., when nonpharmacological approaches have not produced an effect or when patients prefer to use one of these medications).
  • Disulfiram produces physical reactions (e.g., flushing) if alcohol is taken within 12-24 hours of the medication use and is not generally used as a first-line treatment.
  • Topiramate and gabapentin are also suggested as medications for patients with moderate to severe alcohol use disorder, but typically after trying naltrexone and acamprosate first.
The guideline also includes statements related to assessment and treatment planning. Evidence-based psychotherapeutic treatments for alcohol use disorder, including cognitive-behavioral therapy, 12-step facilitation, and motivational enhancement therapy, also play a major role in treatment. In addition, community-based peer support groups such as Alcoholics Anonymous (AA) and other programs are helpful for many patients. However, specific recommendations related to these treatments are outside the scope of this guideline.
The guideline was approved by the APA Board of Trustees in July 2017. It was developed using a systematic process that is intended to be consistent with the recommendations of the Institute of Medicine and the Council of Medical Specialty Societies and to meet requirements for inclusion in the National Guidelines Clearinghouse.


Provided by American Psychiatric Association

Sunday, January 07, 2018

How Alzheimer's disease spreads throughout the brain – new study

How Alzheimer's disease spreads throughout the brain – new study
Harmful tau protein spreads through networks.
Alzheimer's disease is a devastating brain illness that affects an estimated 47m people worldwide. It is the most common cause of dementia in the Western world. Despite this, there are currently no treatments that are effective in curing Alzheimer's disease or preventing its relentless progression.

Alzheimer's disease is caused by the build-up of two abnormal proteins, beta-amyloid and tau. Tau is particularly important because it causes neurons and their connections to die, preventing brain regions from communicating with each other normally. In the majority of cases, tau pathology first appears in the memory centres of the brain, known as the entorhinal cortex and hippocampal formation. This has been shown to occur many years before patients have any symptoms of disease.
Over time, tau begins to appear in increasing quantities throughout the brain. This causes the characteristic progression of symptoms in Alzheimer's diseases, where initial memory loss is followed by more widespread changes in thinking and behaviour that lead to a loss of independence. How this occurs has been controversial.
Transneuronal spread
In our study, published in Brain, we provide the first evidence from humans that tau spreads between connected neurons. This is an important step, because stopping this spread at an early stage might prevent or freeze the symptoms of Alzheimer's disease.
This idea, called "transneuronal spread", has been proposed before and is supported by studies in mice. If abnormal tau is injected into a healthy mouse brain, it quickly spreads and causes the mice to manifest dementia symptoms. However, it had not previously been shown that this same process occurs in humans. The evidence from mouse studies was controversial, as the amount of tau injected was relatively high, and disease progression occurred much more rapidly than it does in humans.
In our study, we combined two advanced brain imaging techniques. The first, positron emission tomography (PET), allows us to scan the brain for the presence of specific molecules. With this, we were able to directly observe the abnormal tau in living patients, to see exactly how much of it was present in each part of the brain.
The second, functional magnetic resonance imaging (fMRI), measures blood flow in the brain in real time. This allowed us to observe the activity produced by brain regions communicating with each other. For the first time, by scanning the same people with both methods, we were able to directly relate the connections of the brain to the distribution of abnormal tau in living humans with Alzheimer's disease.
How Alzheimer's disease spreads throughout the brain – new study
Artist’s impression of tau spreading between connected neurons.
We used a mathematical technique called "graph analysis" to analyse brain connectivity. This technique involved splitting the brain up into 598 regions of equal size. We then treated the connectivity between regions like a social network, assessing factors such as the number of contacts a brain region had, how many "friendship" groups it took part in, and how many of a brain region's contacts were also contacts of each other.
In a flu epidemic, people with a large number of social contacts are most likely to become infected and then to pass the infection on to others. Similarly, the transneuronal spread hypothesis predicts that strongly connected brain regions will accrue most tau. This is what we observed. This relationship was present within each brain network individually, as well as across the whole brain.
We were also able to exclude potential alternative explanations for the appearance of tau throughout the brain. It had previously been suggested that tau might appear at brain regions that were vulnerable because of high metabolic demand or a lack of support from their neighbours. While it is possible that these factors are important in neuronal death, our observations were not consistent with them being the primary drivers of the initial accumulation of abnormal tau.
In addition, by looking at patients with a range of disease severity, from mild cognitive impairment through to established Alzheimer's disease, we were able to disentangle the causes of tau accumulation from its consequences. We showed that increasing amounts of tau in Alzheimer's disease caused the brain to become less connected overall, and the connections that remained became increasingly random.
Long-range connections
Finally, we contrasted the findings in Alzheimer's disease to a rarer condition called progressive supranuclear palsy (PSP), which affects approximately three in every 100,000 people. This condition is also caused by tau, but it remains confined to the base of the brain. We demonstrated that in PSP the evidence did not support transneuronal spread. This might be because of the different structure of abnormal tau pathology in the two diseases. In Alzheimer's disease, tau is present in "paired helical filaments", while in PSP it is in "straight filaments".
We showed that as PSP progresses, direct long-range connections are preferentially damaged, meaning that information had to take a more indirect route across the brain. This might explain why, when asked a question, patients with PSP usually respond slowly but correctly.
Overall, evidence of transneuronal spread in humans with Alzheimer's disease provides proof of concept for exciting new treatment strategies to lock up tau pathology before it can cause significant damage.

This article was originally published on The Conversation. Read the original article.The Conversation

Provided by The Conversation

Thursday, January 04, 2018

Do you take calcium and vitamin D to protect your bones? A new study says it doesn't help

vitamin D

If taking more vitamin and mineral supplements is part of your plan for a healthier new year, a new study may prompt you to reconsider.
Researchers who scoured the medical literature for evidence that calcium and vitamin D pills could help prevent bone fractures came up empty.

04 JAN 2018--Their analysis focused on adults older than age 50 who lived on their own (that is, not in a nursing home or other type of residential care facility). Fractures are a serious health concern for this population—previous studies have found that about 40 percent of women in this age group will wind up with at least one "major osteoporotic fracture" at some point in their lives, and that among adults who break a hip, 20 percent died within a year of their injury.
The researchers, led by Dr. Jia-Guo Zhao of Tianjin Hospital in northeastern China, combed through clinical trials, systematic reviews and other reports published in the last decade, since late 2006. They identified 51,145 people who were included in studies assessing the role of calcium and/or vitamin D in preventing bone fractures.
Their findings appear in Tuesday's edition of the Journal of the American Medical Association.
Among the 14 trials that pitted calcium supplements against either a placebo or no treatment, there was no statistically significant relationship between use of the mineral (in pill form) and the risk of suffering a hip fracture. Nor was there any clear link between calcium supplements and fractures involving the spine or other bones.
Even when the researchers accounted for each study participant's gender, past history of bone fractures, the amount of calcium they consumed in their diets and the dose of the calcium pills they took (if they did), there was still no sign that supplements were helpful.
An additional 17 trials examined the role of vitamin D, which helps the body absorb calcium. Once again, they found no statistically significant link between supplement use and hip fracture risk. Ditto for fractures in the spine and elsewhere.
Upon drilling down to certain subgroups, they found that for people who started out with at least 20 nanograms of vitamin D per milliliter of blood, adding more vitamin D through supplements was associated with a greater risk of hip fractures. The same was true for people who took high doses of vitamin D supplements just once a year.
Finally, there were 13 trials involving people who took a combined calcium-vitamin D supplement. As before, there was no statistically significant link between supplement use and the risk for any kind of fracture or combination of fractures. That held up even when accounting for gender, past fractures, supplement dose, dietary calcium or baseline blood levels of vitamin D.
The researchers noted that thousands of people in this final group were participants in the Women's Health Initiative, a long-term study sponsored by the National Heart, Lung and Blood Institute in the U.S. Earlier reports based on data gathered by the Women's Health Initiative found that calcium and vitamin D supplements were associated with a lower risk of fractures, but only for women who took hormone therapy after menopause. To get a clearer picture of the direct link (if any) between supplements and fracture risk, Zhao and his colleagues opted not to include data from women on hormone therapy.
It's still possible that calcium and vitamin D supplements are useful for people who live in nursing homes or other residential facilities, the study authors wrote. Such people are more likely to have osteoporosis, due to a combination of poor diet, less sun exposure (which the body needs to synthesize vitamin D) and other factors.
But for older adults who live on their own, they wrote, the results are clear: "These findings do not support the routine use of these supplements."

More information: Jia-Guo Zhao et al. Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults, JAMA (2017). DOI: 10.1001/jama.2017.19344