Body

COLUMBUS, Ohio - Bans and other policies restricting e-cigarette sales could do more public harm than good, according to a group of public-health, tobacco-policy and ethics experts.

In a piece published online today (Dec. 12, 2019) in the journal Science, the authors, including three public health deans, caution that blanket policies developed in a rush to address two different concerns come with dangerous downsides - most notably the risk of taking away a powerful tool to help smokers quit.

"Illnesses and deaths, which appear to be related to vaping illicit THC oils, have caused justifiable alarm as has the rise of young people who are vaping nicotine. But in our response we must not lump together these troubling developments and fail to consider the powerful evidence supporting the availability of legal nicotine products," said lead author Amy Fairchild, dean of The Ohio State University College of Public Health.

In Science, she and her co-authors write that "Restricting access and appeal among less harmful vaping products out of abundance of caution while leaving deadly combustible products on the market does not protect public health. It threatens to derail a trend that could hasten the demise of cigarettes, poised to take a billion lives this century."

The paper comes after the emergence this year of vaping-related lung injuries and deaths throughout the U.S. The Centers for Disease Control and Prevention has reported 2,291 cases of serious lung injury and 48 deaths as of last week. Authorities have identified vitamin E acetate, a THC-product additive, as a "chemical of concern" and said that many of the products appear to have been acquired through informal sources - not from retail establishments selling products directly from known manufacturers. THC, or Tetrahydrocannabinol, is the primary psychoactive component of marijuana.

Many policymakers and organizations including the American Medical Association have called for an across-the-board ban on vaping, and some municipalities and states have moved to ban either all vaping products or those with flavors other than tobacco flavoring, including menthol.

Fairchild said that vaping policy discussions and debates should include an examination of the immediate crisis in the context of all of the scientific evidence regarding the risks and benefits.

"There are important distinctions to be made between nicotine and THC products, between products manufactured by reputable companies and those sold on the black market, and between the potential risks and benefits to adolescents and to adults," she said.

Drawing comparisons to initial reluctance to offer needle exchange programs that promote safety by preventing life-threatening infections for people who aren't ready to quit heroin, the authors write that evidence about harm reduction should outweigh emotional responses.

"We should be careful to remain aware of the unintended consequences of extreme measures and the important lessons that harm reduction has provided us in areas such a heroin use, HIV prevention and alcohol control," said co-author Cheryl G. Healton, dean of New York University's College of Global Public Health.

The authors point to research showing that not only vaping - but flavored products, in particular - can help adult smokers quit and provide a more effective and appealing option than nicotine replacement therapy.

They urge continued efforts to better understand the risks and benefits of vaping and call for regulatory measures that strike a balance between "making regulated nicotine vaping products available to smokers while adopting forceful measures to limit the risks to and use by youth as much as possible."

Among their suggestions to combat youth use: Implementation and enforcement of laws that restrict purchases to those 21 and older and prohibitions against predatory marketing to children and teens.

They call for the U.S. Food and Drug Administration to implement a product monitoring system and for a surveillance system to detect unanticipated harm early.

Regulatory bans on the menthol front should start with cigarettes and inexpensive little cigars, not with nicotine vape products, they argue.

"Despite two FDA-derived reports that recommended a ban on menthol in combustibles, there has been policy paralysis in the face of appalling evidence," they write, citing statistics showing that more than half of young people and more than 90 percent of African-American youth start smoking with menthol.

Fairchild and her co-authors stress that they take the illnesses and deaths due to vaping seriously but emphasize that each day more than 2,500 U.S. teens start smoking and about 1,300 adults die due to cigarettes. Taking vaping - including flavored products - away as a smoking-cessation and harm-reduction tool now will amount to a public health failure, they argue.

"It is crucial to identify the source of serious lung injuries and closely monitor and regulate the vaping industry - including how it markets its products to young people," said co-author James Curran, dean of the Rollins School of Public Health at Emory University.

"But the evidence so far supports continuing to allow nicotine vaping as a harm-reduction alternative to smoking, which remains the largest preventable cause of death and disability in our country."

The Queen Mary University of London professor leading an international breast cancer study says anastrozole - rather than tamoxifen - should be the preventive drug-of-choice for post-menopausal women at increased risk of developing the disease.

Anastrozole, which inhibits the production of oestrogen in postmenopausal women, has been used to treat breast cancer in that group for more than 20 years. The first phase of this study, which was published in 2013, established its value as a prophylactic therapy. It reported that breast cancer occurrence amongst women taking the drug fell by 53%. It was recommended for preventive use by the National Institute for Health and Care Excellence in the UK in 2017 and by the US Preventive Services Task Force earlier this year.

However, the drug is not currently offered to all the women who could benefit - possibly because some physicians are unsure of the evidence base for long term impact.

A study led by Professor Jack Cuzick of Queen Mary University of London, which is published in The Lancet today, has confirmed that the drug offers significant long term protection for women who take it for five years and stop. His team found that up to seven years after trial participants last took the drug, breast cancer incidence was 49 per cent lower than in women given a placebo.

Professor Cuzick, who is co-chairman of International Breast Cancer Intervention Studies (IBIS), also presented the findings of the IBIS-II trial at the San Antonio Breast Cancer Symposium in Texas today.

He said: "Previous research has confirmed that anastrozole is very effective while women are still taking the drug but this is the only trial looking at whether it offers long term protection for women at high risk of developing breast cancer. After a detailed analysis of the IBIS-II data, we have concluded that it is highly effective in reducing breast cancer occurrence for at least 12 years."

The research team recorded data on the women's health over a 12-year period, with a median follow-up of 10.9 years. Professor Cuzick said that the 49% reduction achieved 12 years after women started taking anastrozole (seven years after stopping) is significantly higher than the 28% decrease in breast cancer recorded for women who take tamoxifen.

Dr Ivana Sestak, Reader in Medical Statistics at Queen Mary, said: "The findings mean that for every 29 women taking anastrozole for five years, one case of breast cancer will be prevented during a 12 year period. Around 49 women would need to take tamoxifen for five years to prevent one breast cancer case during the same period."

Professor Cuzick said: "This is an exciting finding which makes a strong case for anastrozole being the drug of choice for post-menopausal women at high risk of developing breast cancer. Tamoxifen could be offered to the relatively few women who experience serious side-effects from anastrozole."

However, Professor Cuzick said that with few deaths from breast cancer among trial participants, longer follow-up studies will be needed to evaluate whether anastrozole can reduce deaths from the disease.

The latest report also confirms that anastrozole does not have the same type of long term side-effects associated with tamoxifen - including endometrial cancer.

Clinical lead Professor Tony Howell from the University of Manchester said: "Importantly, this study shows that there are no significant long term side-effects in the five years after completion of anastrozole, particularly no increase in fractures or heart disease."

Adherence during the five years of taking the pills was 77.0% in the placebo arm and 74.6% in the anastrozole group. This indicates that even during treatment side-effects were not severe enough to significantly deter women from taking the drug.

Cancer Research UK, the Breast Cancer Research Foundation, Sano? Aventis, Astra Zeneca and the National Health and Medical Research Council Australia funded the research.

Professor Charles Swanton, Cancer Research UK's chief clinician, said: "Both tamoxifen and anastrozole can be given to women who are at higher risk of breast cancer. Up until now we only knew that tamoxifen has long lasting benefits, so it's reassuring that this study looking specifically at anastrozole, which has fewer long term side-effects, gives better protection to women years after they stopped taking the drug.

"Doctors may still decide that tamoxifen is more appropriate for some women, but it's great that there are options. Anyone with questions about these findings, or about their family history and risk of breast cancer, should speak to their doctor, who can help work out which medication is best for them."

Breast cancer is the most common cancer in women and affects over 55,000 UK women each year, killing more than 11,000. It is estimated that more than 2 million women across the world developed the disease last year, with more than 600,000 deaths.

Four unsolved mysteries around schizophrenia have long plagued the medical community, but a new hypothesis identifying a common link between them and an almost forgotten epidemic of a disease called pellagra could have profound implications for our understanding of psychosis in poorer nations. The new hypothesis has implications for how a subgroup of people with active psychosis could be potentially screened, treated, and cured.

The idea behind the hypothesis occurred to Esme Fuller-Thomson, professor at the University of Toronto's Factor-Inwentash Faculty of Social Work (FIFSW) after learning about recent research conducted in South India. This study newly identified a link between schizophrenia and a variant of the gene NAPRT1, which lowers the body's ability to use niacin, or Vitamin B3, which naturally occurs in meat, poultry, fish, and eggs.

"When I read this study a light bulb went on in my head," says Fuller-Thomson, who published the hypothesis in the journal Schizophrenia Research this month with doctoral student, Rukshan Mehta. "This seems to be the missing link that explains all these medical mysteries."

The researchers speculate that there is a critical interaction between an expectant mother's prenatal niacin deficiency due to malnourishment and the NAPRT1 variant that impedes the fetus' ability to use niacin. This interaction between the gene and the prenatal environment may predispose the offspring to develop a psychotic disorder.

Several studies indicate that the offspring of mothers who experience famine in their first trimester of pregnancy have double the chance of developing schizophrenia. Most researchers assume nutrient deficiency must be playing a role, but the particular nutrient has yet to be identified. Fuller Thomson now speculates that niacin may be the key nutrient involved.

The identification of the NAPRT1 risk variant also provides some insights into a second medical mystery: Normally when people are given high doses of niacin, their skin reddens and can tingle, burn, or itch; however, many individuals with schizophrenia experience limited or no flushing to the same high dose amount. The presence of a gene inhibiting the uptake of niacin may explain why people with schizophrenia do not show the same reddening of the skin in response to large doses: they simply have a lower ability to absorb the vitamin.

Pellagra could be an important part of the puzzle as well. Between 1906 to 1940, almost 3 million Americans developed pellagra due to a niacin deficient diet. The symptoms include dermatitis, dementia, and death. In four to ten percent of cases, active psychosis develops, which mimics schizophrenia. Pellagra became the leading cause of death in psychiatric hospitals in the Southern United States in that era.

"Treatment with niacin quickly and permanently cures the disease including the psychosis and the dermatitis," reported co-author Rukshan Mehta, an MSW graduate of the FIFSW who is currently a doctoral candidate in Nutrition & Health Sciences at Emory University. "By 1941, flour was fortified with niacin in the USA and the disease was soon after largely eradicated."

Today, diagnosis of pellagra is rare, but Fuller-Thomson and Mehta wonder if it might be going undetected in the developing world.

In most cases of pellagra, a bad rash is the first symptom, and this is usually how the disorder is diagnosed. The researchers hypothesize that individuals with psychosis and the risky gene variant may not present with dermatitis. This would result in the patients being misclassified as having schizophrenia instead of the easily treatable psychosis associated with niacin deficiency.

Fuller-Thomson and Mehta's hypothesis also provides new insights into the most perplexing of the medical mysteries associated with schizophrenia: studies by the World Health Organization show that patients with schizophrenia in the developing world recover at a markedly higher rate than those in western nations, despite the fact that those in the west receive more extensive medical interventions.?If some of the schizophrenia patients in the developing world were, in fact, undiagnosed pellagra cases, their psychosis may have been cured inadvertently by simply spending time in a hospital where nutritious niacin-rich food such as meat and eggs are provided.

The final medical mystery has been generating debate for half a century. Six randomized controlled trials conducted in Saskatchewan, Canada in the 1950s found excellent results treating patients with schizophrenia with high doses of niacin, but multiple efforts to replicate the study in the 1970s found the intervention ineffective.

The 1950s Canadian studies were conducted among patients born in the Great Depression before niacin fortification of flour was adopted. "It is highly probable that those with schizophrenia in Saskatchewan had malnourished, niacin-deficient mothers," says Fuller-Thomson. "If the patients' psychosis was due to undiagnosed pellagra, of course the niacin treatment would be effective. The pregnant mothers of the participants in the later study benefited from universal niacin fortification and therefore the patients were unlikely to have pellagra."

The researchers emphasize that both a correct diagnosis and medical supervision of niacin treatment for pellagra are essential. "Taking high dose niacin can cause life-threatening problems if not properly monitored," cautions Fuller-Thomson.

"We acknowledge that this hypothesis is highly speculative, but feel further exploration of these ideas are warranted," says Fuller-Thomson.?"In cases where the psychosis is due to pellagra, these patients could be inexpensively, quickly, and permanently cured with high dose niacin, allowing them to live a healthy normal life."

WASHINGTON--The Endocrine Society and Avalere Health introduced the first-ever quality measures to help healthcare providers assess how well they identify and care for older adults at greater risk of hypoglycemia--low blood sugar that can be a dangerous complication of diabetes treatment.

A panel of diabetes experts published the quality measures, which focus on outpatient treatment for adults who are 65 and older and have type 2 diabetes, in the Society's Journal of Clinical Endocrinology & Metabolism. The panelists relied on their clinical background, measure development expertise, and insight into patient perspectives to develop the measure set.

"We convened an expert panel of endocrinologists, primary care physicians, diabetes educators, pharmacists, measurement experts and patient advocates to ensure that the quality measures reflect a variety of perspectives and a wide breadth of knowledge on hypoglycemia prevention," said James L. Rosenzweig, MD, of Hebrew SeniorLife in Boston, Mass., who led the expert panel.

An estimated 33 percent of adults aged 65 or older have diabetes, and this age group faces increased risk of developing hypoglycemia. Hypoglycemia can lead to seizures, coma and even death. The U.S. Department of Health and Human Services identified hypoglycemia as one of the top three preventable and measurable adverse drug events.

"Hypoglycemia is an area where we can make meaningful strides in improving diabetes care," said Rosenzweig. "Our research has shown a lack of widespread initiatives to address this issue. These first-of-their-kind quality measures will help clinicians better identify patients who are at risk and combat hypoglycemia."

"Avalere is excited to have been involved in the development of measures focused on older adults who are at risk of having hypoglycemia," said Kristi Mitchell, Practice Director at Avalere Health. "To date, there has been a gap in outpatient measures that screens patients for risk of hypoglycemia and setting tailored targets for this population. We look forward to continuing our work with the Hypoglycemia Prevention Initiative to address this need."

The quality measures outline key risk factors that raise an individual's chances of developing hypoglycemia and emphasize the importance of people who meet these criteria receiving education to help prevent future episodes.

Key risk factors include:

Experiencing a hypoglycemic event where blood glucose levels dropped below 54 mg/dL and required immediate attention within the past year

Experiencing altered mental or physical status requiring assistance during a severe hypoglycemic event in the past year

Among individuals who manage their blood sugar with insulin or medicines like sulfonylureas that increase the risk of hypoglycemia:

o A documented A1c of less than 7 percent in the past six months, or

o At least one other relevant chronic medical problem.

The expert panel also recommends healthcare providers capture information about hypoglycemic episodes where individuals experienced altered mental or physical status requiring assistance within the past year. This information can help clinicians better determine if an individual is experiencing growing unawareness of hypoglycemia over time and identify what kinds of interventions stand the best chance of helping the patient avoid future episodes.

Once medical centers and practices begin using the quality measures, the Society and Avalere hope to use information and data from users to refine the quality measures in the future.

Other authors of the report and recommendations include: Paul R. Conlin, MD, of VA Boston Healthcare System in Boston, Mass.; Jasmine D. Gozalvo, PharmD, BCPS, BC-ADM, CDE, LDE, FAADE, of Purdue University in West Lafayette, Ind.; Stephanie B. Kutler, Endocrine Society; Nisa Maruthur, MD, MHS, of Johns Hopkins University in Baltimore, Md.; Penelope Soli, JD, Avalere Health in Washington, D.C.; Sandeep Vijan, MD, of the University of Michigan in Ann Arbor, Mich.; Amish Wallia, MD, of Northwestern University in Chicago, Ill.; and Robin Fein Wright, LCSW, of Diabetes Sisters in Bolingbrook, Ill.

The work on measures was part of a broader quality improvement effort, the Hypoglycemia Prevention Initiative, which was launched by the Endocrine Society and Avalere Health to study how hypoglycemia could be prevented in older individuals with type 2 diabetes and whether primary care physicians could incorporate diagnostic and preventive services into their workflow. The Hypoglycemia Prevention Initiative is supported by Merck & Co., Inc.; Lilly USA, LLC; Novo Nordisk Inc.; Sanofi; and Abbott Diabetes Care Inc.

The manuscript, "2019 Endocrine Society Measure Set for Older Adults with Type 2 Diabetes at Risk for Hypoglycemia," was published online, ahead of print.

Fewer than 10% of dermatologists practice in rural areas, according to the Journal of the American Academy of Dermatology. That means primary care physicians (PCPs) are often relied upon to diagnose skin cancers in areas where access to dermatologists is lacking, even though multiple studies have shown most PCPs do not feel adequately prepared to diagnose and treat many skin conditions. Researchers from the University of Missouri School of Medicine conducted a two-year study of the Extension for Community Healthcare Outcomes (ECHO) telehealth program in Missouri and found the program provided participating PCPs with expert recommendations that benefited nearly 84% of adult cases and 72% of pediatric cases.

"When it comes to skin cancer--which is the most common type of cancer in the United States--a timely diagnosis saves lives," said Mirna Becevic, PhD, assistant research professor at the MU School of Medicine. "Given the shortage of dermatologists in rural parts of the country, it is essential that we increase the PCPs skill in identifying patients with a high risk for skin cancer."

The retrospective study examined 137 adult and 44 pediatric dermatology cases presented between 2016 and 2017 through the University of Missouri Show-Me ECHO Project where 60 PCPs from rural areas across Missouri were linked via videoconferencing with dermatologists at University of Missouri Health Care in Columbia, who provided presentations and expert recommendations on de-identified cases during weekly, hour-long sessions. During those videoconferences, the research team discovered 44% of adult dermatology cases and nearly 28% of pediatric cases were incorrectly diagnosed by the PCP.

"A lot of literature was pointing to the fact that residents and PCPs do not get enough training in dermatology, but a big part of their clinic is skin conditions," Becevic said. "We wanted to find out how much do the participating PCPs know about skin issues, how accurate are their diagnoses, and how accurate is their treatment? Our study results matched what we knew from the literature--that a majority of PCPs do not feel adequately prepared to diagnose and treat common skin conditions."

"This program breaks the mold," said study co-author Jonathan Dyer, MD, professor and interim chair of the Department of Dermatology at the MU School of Medicine. "These are real cases and real-life discussions. We believe this project will help doctors take the cases presented and apply them to others in their clinic. The patient will benefit from this program because they are provided the correct diagnosis at the correct time, right at the point of care, which will improve their outcome and reduce their cost and the expense incurred by the health system."

COLUMBUS, Ohio - The out-of-pocket financial burden for insured working Americans is substantial and growing - especially when it comes to out-of-network, non-emergency hospital care, a new study has found.

Researchers at The Ohio State University analyzed claims from more than 22 million enrollees in private insurance plans and found that out-of-pocket costs for non-emergency out-of-network hospital care nearly doubled in five years.

The study included enrollees 18 to 64 years old who were part of an employer-sponsored plan for at least one year from 2012 to 2017 and looked at claims related to emergency department and non-emergency care.

Though the prevalence of use of out-of-network care dropped during the study period, cost-sharing for that care rose rapidly from 2012 through 2016 before slowing down in 2017. About 16 percent of individuals encountered out-of-network care, at an average out-of-pocket cost of $621.

The fastest cost-sharing increases for enrollees arose from non-emergency hospitalizations. The average out-of-pocket cost for this type of out-of-network hospital care increased from $671 to $1,286 during the study period. Consumer costs for out-of-network emergency hospitalizations also rose, but less dramatically - from $452 to $565.

"These out-of-network costs are concerning because many insured Americans cannot afford to pay a higher percentage of their health care bills, and in some cases they may not even be aware that their providers are out of network," said lead author Wendy Yi Xu, a health economist and assistant professor of health services management and policy at Ohio State.

The study appears online today (Dec. 12, 2019) in the American Journal of Managed Care.

In the paper, the authors call on policymakers and others to consider the burdens on working Americans and to seek solutions.

They acknowledge that networks are important strategies for health plans to lower prices. However, they also note that state and federal consumer protection efforts have not focused on the costs of out-of-network care.

Among the policy recommendations from Xu and her co-authors:

Patients should be told if providers and facilities are out of network, regardless of the urgency of their care.

Disclosure requirements should further protect consumers by holding them harmless should providers fail to inform the patient of network status.

States may need to re-examine criteria for network adequacy in an effort to ensure that patients can get the care they need without going out of network.

In recent years, the increase in out-of-pocket payments - including deductibles, copayments and coinsurance - has outpaced wage growth in the United States, the study authors point out. And as of 2018, almost a fifth of large employers have used narrow networks of medical providers in their plans.

"Health care costs are putting pressure on many American families, and we believe that they shouldn't be held responsible for these bills if these higher-cost services are provided without their knowledge or consent," Xu said. "Even when a hospital is in-network, care is often provided by out-of-network physicians."

Caution is advised in interpreting the findings of the recent JAMA Internal Medicine publication1 on radioactive iodine treatment for hyperthyroid patients and cancer mortality. The paper's conclusion that "in RAI-treated patients with hyperthyroidism, greater organabsorbed doses appeared to be modestly positively associated with risk of death from solid cancer, including breast cancer", has raised concerns among patients and clinicians.

To help address the concerns of patients and clinicians, the Society for Endocrinology and British Thyroid Association have issued a statement2 indicating that caution is needed in interpreting these findings. Although this retrospective analysis of data from the large multicentre Cooperative Thyrotoxicosis Therapy Follow?up study does suggest a modest increase in potential risk of death from cancer in people who receive radioiodine therapy for hyperthyroidism, there are some limitations to take into account. Our statement highlights these caveats and advises that more research is needed.

"Radioiodine is a very effective treatment for hyperthyroidism and has been used successfully for more than 70 years. The recent JAMA Internal Medicine article has raised concerns for health care practitioners and patients. We felt that the findings of this paper need to be interpreted in the right context and that continued surveillance of patients who have been treated with radioiodine is required." The Society for Endocrinology Clinical Committee & the British Thyroid Association Executive Committee

A new, objective way of measuring flavanol intake has been developed, which could help nutritional experts assess the link between these compounds and their health benefits at scale.

In the first study of its kind published in Nature Scientific Reports, researchers at the University of Reading, the University of California Davis and Mars, Incorporated have identified and validated the first biomarkers for flavanol- and procyanidin intake at scale.

This research, recently presented at the International Conference on Polyphenols and Health 2019, validates the use of specific biomarkers to objectively and accurately estimate the intake of flavanols and procyanidins. These studies have been published amid a growing consensus that many nutritional epidemiological studies have considerable limitations due to their dependence on subjective self-reporting, uncertainty around food content data and the impact of food preparation on nutrient content.

To address these limitations, there is an urgent need for new methods that objectively measure the intake of specific nutrients in large populations. Using these newly developed biomarkers, researchers can now investigate the links between dietary intake of flavanols and procyanidins and associated health benefits at scale, without constraints inherent to past research approaches.

KEY FINDINGS

With this new method researchers can, for the first time, accurately assess dietary flavanol and procyanidin intake in humans

Researchers can now measure how much epicatechin - the flavanol monomer responsible for improvements in vascular function - a person has consumed, enabling further investigation into associations between intake and disease risk

This research has also demonstrated that new biomarkers can be developed to improve the reliability and rigor of nutritional epidemiological research

With reliable biomarkers, researchers can now investigate the links between flavanol and procyanidins intake and health benefits in large-scale studies, free from limitations inherent to past research approaches

Flavanols and procyanidins are bioactive compounds naturally present in various foods including apples, blueberries, grapes, pears and cocoa. These compounds are being widely investigated for their health benefits. Researchers have now established the first method to assess actual bioactive intake, without relying on a surrogate. This will enable more accurate studies into links between dietary intake of flavanols and procyanidins and health benefits. Beyond investigating these compounds, this research has wide-reaching consequences for the field of nutritional epidemiologic studies more broadly.

Professor Gunter Kuhnle, Lead Investigator at the University of Reading, said: "If we can't objectively measure what people eat, we can't give evidence-based recommendations. We now know that previous approaches to measure dietary flavanols intake are simply not accurate. This new methodology has the potential to improve the study of how diet impacts human health by providing researchers with an accurate method for assessing the intake of bioactives and creating a way forward for more robust nutritional epidemiology standards."

Supporting Improvement in Cardiovascular Disease Prevention & Health

A strong body of evidence now suggests that flavanols can be beneficial for cardiovascular disease prevention and health maintenance, and recent data have shown that the monomer (?)-epicatechin is responsible for improvements in vascular function. This research, which has identified a new biomarker for (?)-epicatechin, opens up the possibility to investigate associations between (?)-epicatechin intake and health outcomes in large-scale observational studies. In the future this method could hold the potential to objectively assess dietary epicatechin adequacy as part of approaches for personalized nutrition goals.

Dr Javier Ottaviani, Research Associate at Mars, Incorporated added: "Mars has a long-term commitment to investigating a group of flavanols naturally present in cocoa. A series of comprehensive and collaborative studies now indicate that consuming flavanols, including (?)-epicatechin, could help maintain heart health. By using these new biomarkers, we can now more accurately assess how much of these beneficial compounds someone has actually consumed and more definitively investigate their impact on human health."

This research is a collaborative project between the University of Reading, the University of California Davis and Mars, Incorporated. This research sought to establish a validated methodology to objectively measure dietary intake of bioactive compounds. Research was conducted between 2014 and 2018. The study considered how bioactive compounds were metabolized and used these metabolites to develop the biomarkers to objectively measure flavanol intake.

SAN ANTONIO, TX - In the updated results from NRG Oncology/NSABP B-42 trial through 10 years of observation, extending letrozole therapy for additional five years after five years of adjuvant endocrine therapy resulted in a statistically significant improvement in the 10-year disease-free survival (DFS) of postmenopausal women with hormone-receptor-positive breast cancer. The study continues to show no difference in overall survival with letrozole compared to placebo. The findings were presented at the 2019 San Antonio Breast Cancer Symposium, held December 10-14.

The NRG Oncology/NSABP B-42 trial enrolled 3,966 patients between September 2006 and January 2010. Patients were randomized to receive 2.5mg letrozole or placebo daily for 5 years after having undergone 5 previous years of hormonal therapy, (with either an aromatase inhibitor or tamoxifen followed by an aromatase inhibitor). In the original results of this phase III trial, presented at the San Antonio Breast Cancer Symposium in 2016, the beneficial effect of extended letrozole therapy on DFS did not reach statistical significance. The updated results, with median follow-up of 9.3 years, demonstrate a similar but statistically significant benefit for letrozole vs placebo (HR=0.84; 95% CI 0.74, 0.96; p=0.011). In addition, letrozole continues to provide a statistically significant improvement in breast-cancer-free interval (26% decrease in the risk of BCFI events) and distant recurrence (29% reduction in the risk of DR events). Overall survival rates, as in the earlier analysis, continued to show no significant improvement with letrozole. There were no significant differences in the risk of osteoporotic fractures and arterial thrombotic events between the letrozole and the placebo groups.

"Our findings continue to suggest that careful assessment of potential risks and benefits is necessary for selecting appropriate candidates for extended letrozole therapy among patients with early-stage breast cancer," according to Terry Mamounas, MD, of the Orlando Health UF Health Cancer Center, and lead investigator of the study.

NEW YORK - Nearly one-quarter of people living with HIV were willing to risk near-certain death in a clinical trial, if volunteering for the trial would help find a cure for the disease, according to the new study "HIV Cure Research." "I am not going to live forever," said one interviewee, "it is about the next man, the next woman, and you have to have the mindset to care about people, which I do." Another interviewee said, "I'm willing to go the course for the cure and for the HIV community. I can't imagine how many people's lives would change if there was a cure." The authors of the study write that if people living with HIV are permitted to enroll in risky HIV cure trials, there need to be additional ethical safeguards. They concluded that this does not mean that people should be allowed to participate in research that is "sure to kill them," but that patient preferences should play a strong role in research that involves risk of harm.

In "Safeguarding Participants in Psychiatric Genetic Research," the authors write that genetic and psychiatric research may elicit "exceptionalism," the belief that these types of research deserve special protections. They find that patients and family members view safeguards as more important than other stakeholders do, creating implications for research participation and informed consent.

And in "Including Pregnant Women in Clinical Research," Pamela Payne proposes guidance for including pregnant women in research. Scanty evidence exists for the safe and effective use of medications for women that they may need to treat health issues during their pregnancies. Payne writes that researchers should justify, not presume, exclusion of pregnant women from research trials.

Looking to gain a deeper understanding of cancer, a team led by researchers at Baylor College of Medicine conducted an extensive computational analysis of the similarities and differences in the entire set of proteins, called the proteome, of more than 500 cancers from five different tissue sites. Published in the journal Nature Communications, the work led to the classification of the cancers into 10 subtypes, each including cancers that shared common proteins that seemed to be involved in the disease.

The proteomic analysis confirmed molecular players that had been involved in cancer before, but, importantly, revealed others that had not appeared in previous analyses based on different molecular components. The findings suggest novel molecular pathways to be considered for further study regarding their potential involvement in cancer.

"Cancer is currently understood not as a single disease, but as a collection of diseases. Cancer can develop through alterations in different molecular pathways, and in this study we applied data from molecular profiling technologies to sort out protein alterations that could be linked to cancer," said corresponding author Dr. Chad Creighton, associate professor of medicine and co-director of Cancer Bioinformatics of the Dan L Duncan Comprehensive Cancer Center at Baylor College of Medicine.

Creighton and his colleagues and other groups have traditionally approached molecular profiling by analyzing mRNA rather than protein data. Messenger RNA (mRNA) is the genetic material that is actually translated into proteins.

"When looking at mRNA data, it's assumed that they represent what happens at the actual protein level, but this is not always the case," Creighton said. "Proteins can be modified after they are synthesized, for example, and this is something mRNA data would not show. Nevertheless, most studies do not acquire protein data. In the current study we analyzed protein data, looking to identify molecular pathways that previous mRNA data analyses might have missed."

Creighton and colleagues worked with data from the Clinical Proteomic Tumor Analysis Consortium (CPTAC), which conducted proteomic profiling of more than 10,000 proteins in hundreds of cancers. They also examined cancer protein and mRNA datasets outside of CPTAC. In total, the researchers analyzed data from more than 500 cancers representing five types of cancer: breast, colon, ovarian, renal and uterine.

Protein profiling reveals potential new players in cancer

Analysis of the protein data led to the classification of the cancers into 10 subtypes, each with a distinct set of protein alterations. The subtypes included multiple organ tissue sites sharing common altered molecular pathways. Knowing the pathways suggests potential therapeutic opportunities.

"We found that many of the subtypes that we had found based on mRNA observations that we made before held up when we looked at the protein level," Creighton said. "Interestingly, four of these 10 subtypes actually do not involve the cancer cells themselves. They represent differences in the tumor microenvironment, the cells and tissues that surround the tumor, and these subtypes are very distinct from each other."

Two of the four subtypes involved immune components associated with the tumor microenvironment. The first immune subtype was characterized by the presence of immune T cells. The second immune subtype, on the other hand, highlighted the complement activation pathway, which is an important component of tumor-promoting inflammation thought to play a role in cancer initiation and progression. Previous studies appear to have missed the complement pathway as being associated with cancer subtypes.

Another novel finding was the discovery of three subtypes that had not been identified in previous mRNA-based analyses.

"Some of the pathways we found associated with these three subtypes may not be commonly associated with human cancers, but links to them have been found," Creighton said. "One subtype involved the Golgi apparatus of the cell. Reports have linked the Golgi to malignant transformation, for instance. Another subtype, which was specific to renal carcinoma, was associated with hemoglobin increases. Finally, the third subtype involved the endoplasmic reticulum, an intracellular component."

The researchers hope that studies like this will shed some light on some of these pathways that are not well studied in relation to cancer and stimulate further research that may lead to improved therapies or to novel treatments that could benefit patients that do not respond to therapy.

WASHINGTON -- Brain imaging of veterans with Gulf War illness show varying abnormalities after moderate exercise that can be categorized into two distinct groups -- an outcome that suggests a more complex illness that previously thought.

Researchers at Georgetown University Medical Center, using functional magnetic resonance imaging (fMRI), have shown the Gulf War Illness patients have one of two different of kinds of changes after exercise when compared with healthy patients. The results clarify that Gulf War illness (GWI) leads to measurable physiological changes in the brain, suggesting multiple strategies for future treatments of Gulf War illness patients.

GWI affects about 25% to 30% of veterans from the 1990-1991 Persian Gulf War. Cognitive and memory problems (often described as "brain fog"), pain, and fatigue following mild to moderate exertion are similar to myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS).

In a study published December 12 in the journal Brain Communications (10.1093/braincomms/fcz039), researchers in the laboratory of James Baraniuk, MD, professor of medicine at Georgetown University Medical Center, imaged the brains of veterans with Gulf War illness before and after moderate exercise. The following day, the groups had a second stress test and a memory test during brain imaging.

There were no differences in fMRI scans between veterans before exercise. The veterans were then divided into those who had previously shown racing heart rates after standing up and those who did not. According to Stuart Washington, PhD, a post-doctoral fellow and lead author on the study, both groups of Gulf War illness veterans had differences in brain activity compared to healthy patients, but the type of abnormal brain activity was different between the groups. After exercise, the veterans prone to racing heart rates had a significant decrease in brain activity in the cerebellum, the part of the brain responsible for fine motor control, cognition, pain, and emotion. In contrast, the group not prone to racing heart rates had a significant increase in brain activity in a different part of the brain that is responsible for planning of body movements and is also associated with chronic pain. The healthy patients had no changes at all.

"While these findings present new challenges to treating people with Gulf War illness, they also present new opportunities," says Washington.

"Gulf War illness remains a debilitating disease, but we are getting a better handle on the cognitive dysfunction," explains Baraniuk. "Now that different regions of the brain have been associated with two subtypes of GWI, we can study these regions through imaging and other techniques to improve diagnosis and, perhaps, to study future treatments."

He concludes, "We are grateful to the veterans who participated in this research because they are providing the answers to medical questions and leading the charge to new therapies for GWI."

Researchers from the University of Adelaide have made significant advances in developing a novel vaccine against Zika virus, which could potentially lead to global elimination of the disease.

The virology team, led by Professor Eric Gowans and Dr Branka Grubor-Bauk - based at the Basil Hetzel Institute for Translational Health Research and supported by The Hospital Research Foundation - has developed a vaccine that prevents Zika infection in pre-clinical models of the disease.

Their findings have been published today in the leading international journal Science Advances.

Zika is a mosquito-transmitted 'flavivirus' which can cause microcephaly (a birth defect where a baby's head is significantly smaller than expected) and severe birth defects in infants born to infected mothers.

The introduction of an effective vaccine for Zika will prevent infection of pregnant women and the resultant congenital effects in the unborn child.

Dr Grubor-Bauk, senior research officer with the Adelaide Medical School, said the team had developed a novel vaccine against Zika that proved effective in mouse models.

"This is the first vaccine study that shows that a T cell-based vaccine can confer protection against a systemic Zika infection,'' she said.

"Our vaccine offers an advantage over other vaccines in development by eliminating the ongoing concerns in the field about enhancement of infection following exposure to dengue virus. This finding demonstrates for the first time that protective T cell vaccines against Zika are achievable.

"Zika virus is extremely detrimental if you're pregnant and there has been no therapy or vaccine available to date. If we can progress this work and immunise women who are of reproductive age and most at risk, we can stop the devastating effects of Zika infection in pregnancy and make a huge difference to the health of the global community."

This research, which has been years in the making, has progressed to this significant stage thanks to funding from National Foundation for Medical Research and Innovation (NFMRI) and ongoing funding from The Hospital Research Foundation.

The work was done in collaboration with eminent global vaccine researcher Prof Dan Barouch, Director of Harvard Medical School's Centre for Virology and Vaccine Research (CVVR) at Beth Israel Deaconess Medical Centre; as well as Adelaide's Prof Sarah Robertson, Director of the Robinson Research Institute, University of Adelaide; and other scientists from the universities of Adelaide, South Australia and Flinders.

"The next steps are to advance the vaccine to being ready for Phase I human clinical trials. This involves further pre-clinical studies which are vitally important to identify the most effective dosing and demonstrate protection against Zika infection in different pre-clinical models of the disease," Dr Grubor-Bauk said.

"The goal is to de-risk and create an attractive technology with a strong IP position, for licensing or co-development with a commercial partner.

"We are grateful to The Hospital Research Foundation which has been instrumental in their support of our research over this time. We could not have reached this point without them."

The findings of this study will also greatly inform other research in the development of flavivirus vaccines by shifting the focus of vaccine development from viral envelope and antibody-based vaccines to T-cell based vaccines.

Baby boys who are born small for their gestational age are at increased risk of having fertility problems in adulthood, according to research published today (Friday) in Human Reproduction [1], one of the world's leading reproductive medicine journals.

Researchers in Denmark looked at 5594 men and 5342 women born between 1984 and 1987 and followed them through to adulthood until the end of 2017. They found that men who had been born small for gestational age had a 55% increased risk of infertility as adults compared to men born within the appropriate weight range for gestational age. They found no link between gestational age and infertility in women.

Ms Anne Thorsted, who carried out the study when she was part of a research group from the Department of Public Health at Aarhus University, Denmark, said: "Among the men who were born small for gestational age, we found that 8.3% had been diagnosed or were being treated for infertility by the end of 2017 compared to 5.7% of men born with the appropriate weight."

Small for gestational age is defined as babies having birth weights in the bottom 10% according to each week of gestation compared to other children of the same gestational age. For instance, the weight range for babies born at full term (40 weeks) was between approximately 2500-4500 grams (5.5-9.9 Ibs) in this study, so full-term babies born weighing less than 3000 grams were defined as being small for gestational age and weighed less than 90% of other children of the same gestational age.

Previous research has suggested a link between restricted growth of the foetus in the womb and a two to three times increased risk of penis and testicular problems in boys; in particular, hypospadias (a malformation where the opening of the urethra is not at the tip of the penis), cryptorchidism (undescended testis) and testicular cancer. These conditions are linked to fertility problems. However, there have been few and conflicting studies on the link between birth weight for gestational age and infertility.

In the current study, when the researchers excluded men born with hypospadias or cryptorchidism, the link between being born small for gestational age and infertility weakened. They found a statistically non-significant 37% increased risk of infertility among the remaining men, with 7.3% of men born small for gestational age being infertile compared to 5.6% of men born with the appropriate weight.

Ms Thorsted said: "This may indicate that part of the association between gestational weight and infertility is mediated by the effects of hypospadias and cryptorchidism, which is known to be related to later risk of infertility."

She said it was not yet clear what the potential mechanisms could be for the link between birth weight and infertility.

"A suboptimal growth environment for the foetus, for whatever reason, could itself be detrimental to the development of sperm production and reproductive organs," she said. "It could also be speculated that the mother's health and lifestyle during pregnancy could affect both foetal growth and the development of reproductive functions; for instance, we know already that if the mother smokes, this can have an impact on the foetus. It may well be that cryptorchidism, hypospadias and infertility have common origins in foetal life.

"Our results show that sometimes we must look at the very early life to find explanations of health problems that occur later in life," she concluded.

The men and women in the study were all singleton births, born in two Danish regions, Aalborg and Odense, between 1984 and 1987. The researchers obtained information on birth weight and gestational age from birth records, and retrieved information on infertility diagnoses and fertility treatments from the Danish National Patient Registry and the Danish In Vitro Fertilisation registry. The mothers of all the participants had completed a questionnaire during pregnancy that asked about factors that could affect the results, such as age, lifestyle (smoking and alcohol consumption), health (including body mass index) and sociodemographic status (employment and whether or not the parents lived together). At the end of the follow-up period in 2017, the average age of the participants was 32.

Strengths of the study include the large numbers and the high participation rate (87%) among the pregnant women involved in the "Health Habits for Two" study. In addition, the availability of data from the Danish registers resulted in a 98% follow-up rate for the participants, reducing the risk of bias and making it a representative sample.

The researchers acknowledge that the participants had not reached the end of their reproductive life by 2017 and it would be interesting to see what the situation was in another ten years' time. Limitations of the study include that different methods were used for estimating gestational age, and that participants were classified as infertile if they either had a diagnosis of infertility or were part of a couple seeking fertility treatment, thus including lesbian and single mothers. However, when the researchers excluded all participants with missing information on the cause of infertility, the risk of infertility among men born small for gestational age increased from 55% to 88%, suggesting this might reflect the true risk of infertility in this group more accurately.

About 12.5% of couples are affected by infertility, which is defined as unsuccessfully attempting to conceive for a year or longer. Male infertility is responsible for about a third of cases, female infertility is responsible for another third and the remaining third is due either to problems in both the man and the woman or to an unidentified cause.

Is it safe to give ivermectin to pregnant women? In order to answer this question, researchers from the Barcelona Institute for Global Health (ISGlobal), an institution supported by "la Caixa", conducted a systematic review and meta-analysis of studies that reported cases of accidental exposure to the drug among pregnant women. The conclusion of the analysis, published in The Lancet Global Health, is that there is not sufficient evidence to support the safety of ivermectin administration during pregnancy.

Ivermectin was shown in the 1980s to be highly effective against onchocerciasis, or river blindness, a devastating disease caused by a parasitic worm and transmitted by flies. Since then, about 3.7 billion doses of ivermectin have been distributed in mass drug administration campaigns aimed at eliminating the disease. Given its efficacy in treating other parasitic diseases such as lymphatic filariasis, strongyloidiasis, scabies, and soil-transmitted helminthiasis, and its potential use against malaria-transmitting mosquitoes, its use is expected to increase in the future.

Despite the drug's multiple health benefits, pregnant women are typically excluded from ivermectin administration due to its potential effect on the foetus. However, no formal evaluation of the drug's safety during pregnancy has been performed to date. "Weighing the risks and benefits of giving ivermectin to pregnant women is key for informing public health policies," explains Patricia Nicolás, ISGlobal researcher and first auhor of the meta-analysis. "In this study, we evaluated existing evidence for serious adverse events after inadvertent exposure in pregnant women," she adds.

From over 140 reports identified, six studies, including one clinical trial, were included for analysis. These studies, published between 1990 and 2004 and performed in six African countries, included a total of 893 pregnant women who received ivermectin during pregnancy. No evidence was found for increased risk of neonatal deaths, preterm births or low birthweight. Some evidence was found for spontaneous abortions, stillbirths, and congenital anomalies, but the number of cases was too low to be conclusive - fewer than 100 women were exposed during the first trimester, when the foetus is expected to be more vulnerable to the drug's effect.

In order to obtain better safety data, the authors argue for the need of establishing an open data repository of inadvertent drug exposures during pregnancy, and of conducting toxicological studies in animal models. "Meanwhile, treatment campaigns should make further efforts to prevent inadvertent treatment of pregnant women," concludes Nicolás.