Body

Philadelphia, May 4, 2018 - Following the landmark SPRINT trial, there is a growing body of evidence for reducing systolic blood pressure targets, resulting in the development of new US guidelines. However, this has led to many questions about the impact of such fundamental changes in blood pressure management, and whether they should be implemented in other constituencies. Two new studies published in the Canadian Journal of Cardiology assess the benefits and costs of incorporating these more aggressive goals into clinical practice.

The Systolic Blood Pressure Intervention Trial (SPRINT) published in 2015 was a randomized, controlled, open-label trial conducted at 102 clinical sites in the US. It compared an intensive systolic blood pressure target of 120 mmHg to the current standard target of 140 mmHg in individuals at high cardiovascular risk and without diabetes. It was halted early after interim analyses showed patients in the intensive arm showed a significant decrease in fatal and nonfatal cardiovascular events and death from any cause.

Based on these statistically-significant findings, as well as the growing global body of evidence showing a strong association between lower systolic blood pressure targets and a reduction in cardiovascular events, an intensive systolic treatment target of

In Fall 2017, the American College of Cardiology (ACC) and American Heart Association (AHA) issued new guidelines for high blood pressure that redefined hypertension as a blood pressure equal or above 130/80 mmHg, as well as lowered the blood pressure treatment goal for the general American population. However, there has been fierce discussion on both sides of the 49th parallel where to go from here.

In the first of the new studies, Alexander Leung, MD, MPH, from the University of Calgary, Calgary, Alberta, Canada, explained that, "The generalizability of the SPRINT intensive blood pressure treatment strategy to the Canadian population remains unknown. Uptake of these recommendations into clinical practice is expected to have broad implications on healthcare policy, resource utilization, and clinical outcomes and may pose certain challenges such as more frequent clinic visits, increased drug costs, increased rates of adverse events, and other heightened healthcare expenditures."

Dr. Leung and colleagues report on a cross-sectional study, using population-based, nationally representative data, to estimate the prevalence and characteristics of blood pressure in Canadian adults between the ages of 20 and 79 meeting SPRINT eligibility criteria. They found that 1.3 million (5.2 percent) Canadian adults met the criteria. If fully implemented, lowering the systolic blood pressure target to

"Adopting intensive systolic blood pressure targets would result in a large number of individuals with treated hypertension being relabeled as inadequately controlled, as well as a significant proportion of the general population not previously considered to have elevated blood pressure being reclassified as requiring blood pressure lowering therapy," noted Dr. Leung. "Such a change would have far-reaching implications on healthcare resource utilization, public policy, and healthcare delivery."

In the second study, Remi Goupil, MD, MSc, from the Hôpital du Sacré-Coeur de Montréal, Montréal, Quebec, Canada, and colleagues examined the differences between the 2017 Hypertension Canada and 2017 American College of Cardiology and American Heart Association (ACC/AHA) blood pressure guidelines.

"The 2017 ACC/AHA guidelines present a paradigm shift in the definition of high blood pressure, while updating treatment initiation thresholds and blood pressure targets," said Dr. Goupil. "This has led to many questions about the impact of such fundamental changes in blood pressure management, and whether it should be implemented in Canada."

The investigators assessed the number of individuals with a diagnosis of hypertension, blood pressure above thresholds for treatment initiation, and blood pressure below targets using the CARTaGENE population-based cohort. CARTaGENE is a population-based cohort designed to study demographic, clinical, and genetic determinants of chronic diseases. Individuals from the province of Quebec were randomly selected, based on provincial health registries, to be broadly representative of the general population. In total, 20,004 individuals 40-69 years old were selected in four distinct urban areas.

Analysis showed that adopting recommendations from the 2017 ACC/AHA guidelines in Canada would result in a substantial increase in diagnoses of hypertension and of individuals requiring drug treatment in Canadians aged between 40 and 69. It would also result in a change in blood pressure targets in a high proportion of hypertensive patients already receiving treatment. This would represent approximately 1.25 million more individuals with hypertension, and 500,000 more individuals requiring antihypertensive treatment.

"Switching to these new guidelines would result in a higher prevalence of hypertensive individuals in Canada and an increase in the number of people that would need to be treated," remarked Dr. Goupil. "Almost one in five individuals needing treatment would have a different blood pressure target from one guideline to the other. These changes would greatly impact the lives of millions of Canadians and result in a significant increase in the economic burden of this condition, with uncertain effects on cardiovascular complications."

In an accompanying editorial, Ross Feldman, MD, Medical Director of the WRHA Cardiac Sciences Program, Winnipeg, Manitoba, Canada, points out that undertaking these more aggressive goals should be based on frank discussions with patients outlining both benefits and risk, and that management should be based on automatic office blood pressure (AOBP) readings, as used in the SPRINT trial, which may well correspond with higher ambulatory blood pressure (ABP) readings. Dr. Feldman is past President of the Canadian Hypertension Society and Hypertension Canada and has been involved in the Canadian hypertension guidelines since 1991.

"Regardless of the guidelines we use, in the post-SPRINT era there are more patients than ever who can expect clear benefit from applying lower targets for their blood pressure control--but with increased risk of adverse effects. These studies remind us that on a public health basis, getting the guidelines right does matter. For every adjustment in blood pressure targets, there are benefits and there are costs--both for patients and in our publicly-funded healthcare system, for all Canadians," remarked Dr. Feldman.

However, Dr. Feldman also points out that more important than any of the fine details of a guidelines process is the effectiveness in their dissemination and implementation. "It is better to have suboptimal guidelines that are followed than it is to have 'perfectly' crafted and up-to-date guidelines that are ignored."

Women who eat less fruit and more fast food take longer to get pregnant and are less likely to conceive within a year, according to a study by researchers at the University of Adelaide's Robinson Research Institute.

The study published today (Friday 4 May) in Human Reproduction, one of the world's leading reproductive medicine journals, asked 5598 women in Australia, New Zealand, the UK and Ireland about their diet. The women, who had not had a baby before, were interviewed by research midwives during their first antenatal visit.

Professor Claire Roberts, Lloyd Cox Professorial Research Fellow, from the University's Robinson Research Institute, who led the study, said: "The findings show that eating a good quality diet that includes fruit and minimising fast food consumption improves fertility and reduces the time it takes to get pregnant."

Compared to women who ate fruit three or more times a day in the month before conception, women who ate fruit less than one to three times a month took half a month longer to become pregnant. Similarly, compared to women who never or rarely ate fast food, women who consumed fast food four or more times a week took nearly a month longer to become pregnant.

Among all the couples in the study, 468 (8%) couples were classified as infertile (defined as taking longer than a year to conceive) and 2204 (39%) conceived within a month. When the researchers looked at the impact of diet on infertility, they found that in women with the lowest intake of fruit, the risk of infertility increased from 8% to 12%, and in those who ate fast food four or more times a week, the risk of infertility increased from 8% to 16%.

First author Dr Jessica Grieger, post-doctoral research fellow at the University of Adelaide, said: "We recommend that women who want to become pregnant should align their dietary intakes towards national dietary recommendations for pregnancy. Our data shows that frequent consumption of fast foods delays time to pregnancy."

Previous research has tended to focus on the role that diet plays in women diagnosed with or receiving treatment for infertility; the impact of maternal diet before conception in the general population has not been widely studied. This research was carried out in women recruited to the multi-centre Screening for Pregnancy Endpoints (SCOPE) study between 2004 and 2011. Of the 5598 women, the majority (5258, 94%) received no fertility treatments before conception and 340 did.

During the first antenatal visit at around 14-16 weeks' gestation, midwives collected information about the time it took to become pregnant and the women's diet. This included details of their diet in the month before conception, and how frequently they consumed fruit, green leafy vegetables, fish and fast foods. Fast foods included burgers, pizza, fried chicken and chips that were bought from take-away or fast food outlets. Fast foods eaten at home (bought from supermarkets, for example) were not included in the data collected and so consumption of this type of food is likely to be under-reported.

Couples were excluded from the analysis if they were receiving fertility treatment due to the male partner's infertility.

Dr Grieger said: "Most of the women did not have a history of infertility. We adjusted the relationships with pre-pregnancy diet to take account of several factors known to increase the risk of infertility, including elevated body mass index [BMI] and maternal age, smoking and alcohol intake. As diet is a modifiable factor, our findings underscore the importance of considering preconception diet to support timely conception for women planning pregnancy."

The researchers also found that while intake of fruit and fast foods affected time to pregnancy, pre-pregnancy intake of green leafy vegetables or fish did not.

Limitations of the study include the fact that collecting data on pre-pregnancy diet relied on retrospective recall and included a limited range of foods. Information on the fathers' diet was not collected, and it is possible that other, unknown factors might have affected the results. A major strength is the large group of women included in the study.

"For any dietary intake assessment, one needs to use some caution regarding whether participant recall is an accurate reflection of dietary intake. However, given that many women do not change their diet from pre-pregnancy to during pregnancy, we believe that the women's recall of their diet one month prior to pregnancy is likely to be reasonably accurate," said Dr Grieger.

The researchers are continuing their work and plan to identify particular dietary patterns, rather than individual food groups, that may be associated with how long it takes women to become pregnant.

Women who eat less fruit and more fast food take longer to get pregnant and are less likely to conceive within a year, according to a study published today (Friday) in Human Reproduction, one of the world's leading reproductive medicine journals.

During their first antenatal visit, research midwives in Australia, New Zealand, the UK and Ireland asked 5598 women about their diet. The women had not had a baby before. Compared to women who ate fruit three or more times a day in the month before conception, women who ate fruit less than one to three times a month took half a month longer to become pregnant. Similarly, compared to women who never or rarely ate fast food, women who consumed fast food four or more times a week took nearly a month longer to become pregnant.

Among all the couples in the study, 468 (8%) couples were classified as infertile (defined as taking longer than a year to conceive) and 2204 (39%) conceived within a month. When the researchers looked at the impact of diet on infertility, they found that in women with the lowest intake of fruit, the risk of infertility increased from 8% to 12%, and in those who ate fast food four or more times a week, the risk of infertility increased from 8% to 16%.

Professor Claire Roberts, Lloyd Cox Professorial Research Fellow at the University of Adelaide, Australia, who led the study, said: "These findings show that eating a good quality diet that includes fruit and minimising fast food consumption improves fertility and reduces the time it takes to get pregnant."

First author, Dr Jessica Grieger, post-doctoral research fellow at the University of Adelaide, added: "We recommend that women who want to become pregnant should align their dietary intakes towards national dietary recommendations for pregnancy. Our data show that frequent consumption of fast foods delays time to pregnancy."

Previous research has tended to focus on the role that diet plays in women diagnosed with or receiving treatment for infertility; the impact of maternal diet before conception in the general population has not been widely studied. This research was carried out in women recruited to the multi-centre Screening for Pregnancy Endpoints (SCOPE) study between 2004 and 2011. Of the 5598 women, the majority (5258, 94%) received no fertility treatments before conception and 340 did.

During the first antenatal visit at around 14-16 weeks' gestation, midwives collected information about the time it took to become pregnant and the women's diet. This included details of their diet in the month before conception, and how frequently they consumed fruit, green leafy vegetables, fish and fast foods. Fast foods included burgers, pizza, fried chicken and chips that were bought from take-away or fast food outlets. Fast foods eaten at home (bought from supermarkets, for example) were not included in the data collected and so consumption of this type of food is likely to be under-reported.

Couples were excluded from the analysis if they were receiving fertility treatment due to the male partner's infertility.

Dr Grieger said: "Most of the women did not have a history of infertility. We adjusted the relationships with pre-pregnancy diet to take account of several factors known to increase the risk of infertility, including elevated body mass index [BMI] and maternal age, smoking and alcohol intake. As diet is a modifiable factor, our findings underscore the importance of considering preconception diet to support timely conception for women planning pregnancy."

The researchers also found that while intake of fruit and fast foods affected time to pregnancy, pre-pregnancy intake of green leafy vegetables or fish did not.

Limitations of the study include the fact that collecting data on pre-pregnancy diet relied on retrospective recall and included a limited range of foods. Information on the fathers' diet was not collected, and it is possible that other, unknown factors might have affected the results. A major strength is the large group of women included in the study.

"For any dietary intake assessment, one needs to use some caution regarding whether participant recall is an accurate reflection of dietary intake. However, given that many women do not change their diet from pre-pregnancy to during pregnancy, we believe that the women's recall of their diet one month prior to pregnancy is likely to be reasonably accurate," said Dr Grieger.

The researchers are continuing their work and plan to identify particular dietary patterns, rather than individual food groups, that may be associated with how long it takes women to become pregnant.

Scientists at The University of Texas at Austin have successfully tested in animals a drug that, they say, may one day help block the withdrawal symptoms and cravings that incessantly coax people with alcoholism to drink. If eventually brought to market, it could help the more than 15 million Americans, and many more around the world who suffer from alcoholism stay sober.

If what has been shown to work in worms and rats addicted to alcohol can eventually be demonstrated to work in humans with minimal side effects, it would be a true breakthrough. Scientists point out, however, that the drug has more hoops to go through before that happens.

There are already drugs on the market prescribed to help people break their addiction to alcohol, but for many patients, they are not very effective and have negative side effects. The new drug, called JVW-1034, targets a different molecular pathway in the body and so far, in animal models, has no obvious side effects.

"There's clearly a huge need for something different and better," said James Sahn, research scientist in chemistry at UT Austin and co-first author of a new paper. "That's where our approach shines. It's modulating a pathway that doesn't seem to be associated with any of the other drugs that are available."

The researchers reported their findings in the journal Neuropsychopharmacology and have filed a patent on the drug.

The paper's other co-first authors are Luisa Scott, a research associate in neuroscience at UT Austin; and Antonio Ferragud, a postdoctoral associate at Boston University School of Medicine (BUSM). Senior authors are Stephen Martin, professor of chemistry, and Jonathan Pierce, associate professor of neuroscience, both at UT Austin; and Valentina Sabino, associate professor of pharmacology and psychiatry at BUSM.

While the drug is promising, the researchers plan to optimize its chemical properties to have a better chance of being effective in humans. They envision a pill that could one day be taken to block alcohol withdrawal symptoms and cravings, helping people avoid relapsing. But it isn't clear whether such a drug could actually cure alcoholism. That's because there are genetic and regulatory underpinnings to the disorder that researchers don't fully understand yet and that may not be permanently altered by this drug. But even a drug that could be taken chronically or in times of stress could have a huge benefit for people suffering from alcoholism.

"If we could achieve a medication that is effective for more people and doesn't have the negative side effects that some of these drugs have, that would be game-changing," said Martin.

It might also make a dent in the $250 billion annual cost of alcohol misuse in the U.S., as estimated by a 2015 study.

This work was supported by The Robert A. Welch Foundation, the Dell Medical School's Texas Health Catalyst program, donations from individuals including Tom Calhoon and June Waggoner through a crowdfunding program called Hornraiser, and the National Institute on Alcohol Abuse and Alcoholism.

Screening in Worm and Rat Models

The drug JVW-1034 was named in honor of James Virgil Waggoner, a UT Austin alumnus, businessman and philanthropist who donated funds to establish the university's Waggoner Center for Alcohol and Addiction Research.

It was one of many potential compounds developed in the lab by chemists Stephen Martin and James Sahn, which they suspected would interact with a cell receptor found throughout the central nervous systems of animals, called sigma 2. Other researchers had shown that that receptor was involved in cocaine addiction. So Martin and Sahn wondered whether it might also be involved in alcoholism.

To screen their compounds, their colleague Luisa Scott created hungover worms. She exposed C. elegans worms to alcohol for a day and then took it away. She could tell they were hungover because when she placed a tasty-smelling substance on the other side of their petri dish, they sluggishly meandered over.

"It smells like movie theater popcorn," Scott said. "Normal worms are quite speedy, but withdrawal worms go very slowly."

When she administered JVW-1034 to the hungover worms, they once again raced across the dish just like worms that had never been exposed to alcohol.

In follow-up experiments, Scott demonstrated that the receptor sigma 2 was in fact the target of JVW-1034. This also demonstrated for the first time that sigma 2 is involved in alcohol addiction. She noted that it can be difficult to identify which parts of an animal's cells a drug interacts with. In fact, scientists still don't know the targets of many drugs that have been in use for many years.

"So for me, being able to show that this really is the target it binds to, that's a big deal," she said.

Finally, a group of collaborators led by Valentina Sabino tested JVW-1034 in alcoholic rats. Alcoholic rats that could freely access alcohol and were then given JVW-1034 dramatically reduced their alcohol consumption.

The researchers are developing several other promising drugs that target the sigma 2 receptor to treat other neurological disorders, including traumatic brain injury, neuropathic pain and Alzheimer's disease.

Inflammation, and in particular chronic inflammation, are major contributors to a large number of diseases, such as cancer, acute pancreatic inflammation, fatty liver disease, diabetes, ulcerative colitis, Crohn's disease, rheumatoid arthritis, chronic liver disease, atherosclerosis, multiple sclerosis, and many others. These pathological conditions are associated with the release of substances, known as pro-inflammatory cytokines, by the immune system. These substances participate in the neutralization of invading pathogens, repair injured tissues, and promote wound healing. However, during chronic or excessive activation of the immune system, when these cytokines are released in an uncontrolled manner, they can lead to unnecessary inflammation that frequently causes tissue damage.

In addition, a family of substances, designated as reactive oxygen species (ROS) is also among the major contributors to many chronic diseases. ROS are involved in oxidation processes. Although oxidative reactions catalyzed by ROS are of great importance in metabolic processes and removal of toxic substances from the body, they are also involved in major damage to cells and tissues leading to cell death, possible DNA mutations and aging. Though the presence of oxygen is necessary for maintaining life, oxygen and its derived products (ROS) are involved in a variety of toxic effects. It has been said that "without oxygen we die but oxygen kills us".

Prof. Abraham Nudelman and his graduate student Shani Zeeli, from the Department of Chemistry at Bar-Ilan University, in collaboration with Prof. Marta Weinstock and her students and assistants from the School of Pharmacy at the Hebrew University, have discovered a new family of substances which has been found to display highly potent activity against the release of pro-inflammatory cytokines and the toxicity induced by ROS. Their findings were recently published in the Journal of Medicinal Chemistry, and in other early papers.

The novel compounds synthesized and evaluated belong to a family of low molecular weight substances named indolines. In early experiments, these compounds have shown promising activity in the treatment of acute pancreatic inflammation, acute fatty liver damage, and diabetes.

"It is expected that further studies in humans will reveal the potential usefulness of these substances in the treatment of a variety of diseases where inflammation is a major contributor to the disease," says Prof. Nudelman, a lead author of the paper. Further studies on the influence of these compounds on these diseases, and other pathological conditions, are being conducted.

Bottom Line: An algorithm could detect signs of a serious eye disease in images from premature infants with accuracy comparable to or better than human experts.

Why The Research Is Interesting: Retinopathy of prematurity (ROP) is a leading cause of childhood blindness worldwide. The decision to treat is primarily based on the presence of plus disease, which is when retinal vessels are dilated and twisted. However, clinical diagnosis of plus disease can be highly subjective and variable.

What and When: A machine learning algorithm was trained to diagnose plus disease using 5,511 retinal photographs. Data were collected from July 2011 to December 2016 and analyzed from December 2016 to September 2017.

Study Measures: The algorithm to detect plus disease was tested on an independent set of 100 images against eight ROP experts.

Authors: Michael F. Chiang, M.D., Oregon Health and Science University, Portland, Jayashree Kalpathy-Cramer, Ph.D., Massachusetts General Hospital, Boston, and coauthors

Results: The algorithm diagnosed plus disease with comparable or better accuracy than human ROP experts.

Study Limitations: Algorithms in artificial neural networks are only as good as the data on which they are trained. It is unknown how factors such as image quality, resolution, different camera systems and field of view may affect the output of these deep learning systems.

DES PLAINES, IL--Endotracheal intubation (ETI) is the most common advanced airway technique used in the resuscitation of out-of-hospital cardiac arrest (OHCA), but Supraglottic airway devices such as the King Laryngeal Tube (LT) offer simpler airway management alternatives. Which is associated with better clinical outcomes? During a Plenary Session to be held May 16, on opening day of SAEM18 in Indianapolis, Dr. Henry E. Wang, professor and vice chair for research at the University of Texas Health Science Center at Houston, will present the findings of his multicenter, pragmatic clinical trial comparing the effectiveness of initial LT insertion versus initial ETI upon outcomes in adult OHCA. EMS educator and consultant, William F. Toon, EdD, NRP, formerly the EMS training manager for the Loudoun County (Va.) Fire, Rescue, and Emergency Management, had this to say about the presentation:

"It is very exciting to know that one of the plenary presentations at SAEM18 will be 'Laryngeal Tube vs. Endotracheal Intubation in Adult Out-of-Hospital Cardiac Arrest: The Resuscitation Outcomes Consortium Pragmatic Airway Resuscitation Trial.' The results of this study will help answer an important question regarding EMS airway management for out-of-hospital cardiac arrest patients. This study is a game changer and will have national and international impact."

A letter from three University of Chicago researchers in this week's New England Journal of Medicine updates a 47-year-old series of reports on the risks of exposure during pregnancy to a supplement, diethylstilbestrol (DES), that was once widely used but since 1971 has been linked to a rare cancer: clear-cell adenocarcinoma of the vagina and cervix.

In the May 3, 2018, issue of the NEJM, the authors show that DES-exposed patients with clear-cell adenocarcinoma had "increased mortality across their life span."

"The risk of death for women aged 10 to 34 who had been exposed to DES in utero and had clear-cell adenocarcinoma was 27 times higher than the risk for women in the general U.S. population," said study author Dezheng Huo, MD, PhD, associate professor of public health sciences at the University of Chicago Medicine. That fell to five times higher for women ages 35 to 49, mainly due to late recurrences. The risk of death for women between 50 and 65 fell to just two times higher.

This series of reports on DES began on April 22, 1971, when the NEJM published a classic study, titled "Adenocarcinoma of the Vagina -- Association of Maternal Stilbestrol Therapy with Tumor Appearance in Young Women." It described a few unusual cancer cases at a Boston hospital: eight women, age 15 to 22, who suffered from this extraordinarily rare tumor.

Although clear-cell adenocarcinoma had been described in older women, "none of us had heard of it in young people," recalled the study's lead author Arthur Herbst, MD, the Joseph Bolivar DeLee distinguished service professor emeritus and former chairman of obstetrics and gynecology at the UChicago.

Herbst and his Boston colleagues connected the onset of this rare cancer to DES exposure. Seven of the eight women with clear-cell adenocarcinoma in the original study had taken DES.

This finding raised many concerns. In the previous 25 years, an estimated 4.8 million women in the United States and as many as 10 million worldwide had taken DES during pregnancy. These eight cases were the first evidence of a delayed but potentially devastating side effect.

DES, created in 1938, the same year as the Food and Drug Administration (FDA), was the first synthetic estrogen. It was cheap, potent and unpatented. It was initially developed and tested for use in livestock, but in 1941 the FDA approved human use of DES for a wide range of indications, primarily relief from "estrogen-deficient states." In 1947, the agency added miscarriage prevention.

Advertisements in medical journals claimed DES combined with certain vitamins could prevent abortion, miscarriage and premature labor 96 percent of the time and was "recommended for routine prophylaxis in ALL pregnancies."

Four years after the FDA approved DES for pregnant women, William Dieckmann, MD, chairman of obstetrics at the UChicago at the time, launched a randomized, controlled clinical trial of the hormone. The results, published in 1953, showed DES had "no beneficial effect whatsoever on the prevention of miscarriage." Nevertheless, the drug remained in use for that purpose. Ten years later, the National Academy of Sciences still rated it as "possibly effective."

In 1966, a few odd cases of young women with tumors previously seen only in post-menopausal women began turning up. Herbst and pathologist Robert Scully, MD, at the Massachusetts General Hospital, collected cases of clear-cell adenocarcinoma. They interviewed the mothers. One mother mentioned that she took a drug during pregnancy, something called DES, and wondered if that had anything to do with it.

Soon, the researchers had eight cases. Seven of the eight mothers with daughters with clear-cell adenocarcinoma took DES during the first trimester for either bleeding or prior miscarriage, and one of the 32 controls did. The odds of that happening by chance were less than one in 100,000.

"These women were given the drug in good faith by people who believed it would help them," Herbst said. "They took it because they wanted to have a baby. And then they find out -- 15, 20, 25 years later -- that this terrible thing happened. The feeling of guilt was awful."

As soon as the 1971 paper was published "it was all over the news," Herbst said. An accompanying editorial called it a work of "great scientific importance and serious social implications." The FDA warned against the use of DES in pregnant women. It was withdrawn from the market a few months after publication.

From eight cases in 1971, the numbers quickly multiplied. A follow-up study, published in 1972, included 91 cancer cases in patients age 8 to 25. By 1981, 10 years after the initial study, the Registry included nearly 500 adenocarcinomas of the vagina or cervix in women age 7 to 30 at diagnosis. By 2014, the study had registered about 700 adenocarcinoma patients and collected their long-term follow-up data. They had a 20-year survival rate of 69 percent, thanks to early diagnoses and aggressive surgery.

Other problems were detected. Mothers who ingested DES appear to have an increased risk of breast cancer. Daughters exposed in utero have an increased risk of breast cancer after age 40.

The excess risk of death after age 50, reported in the current study, emphasizes the importance of other life-threatening health conditions in later life of the DES population. Many of these women have structural changes in the vagina, cervix, uterus or fallopian tubes. These can make it more difficult to conceive a child or carry a pregnancy to term. DES sons have some genital-tract abnormalities, such as cysts and, perhaps, undescended testicles. The grandchildren, although still being assessed, do not appear to have any third-generation effects.

The DES story highlighted the extreme vulnerability of the developing fetus. A perspective piece in the NEJM, emphasized how the discovery "changed medical thinking" about embryologic development and the mechanism of carcinogenesis. A follow-up commentary in the NEJM, published in 2011, concluded that the DES saga "humbles us. It serves as a reminder that though the narrow lens of today might reassure us that an intervention is safe, it is only with the wisdom of time that the full consequences of our actions are revealed."

Eight U.S. jurisdictions (seven states plus the District of Columbia) now allow physicians to prescribe a lethal dose of medication to a mentally competent, terminally ill patient, provided that certain conditions are met.

Hawaii passed a medical aid-in-dying law in April, and similar proposed laws are currently under consideration in North Carolina, New York and other states.

However, in the states were medical aid-in-dying laws are already in effect, patients who wish to use them still face substantial barriers to access, according to a new analytic essay by Mara Buchbinder, PhD, an associate professor in the department of social medicine at the University of North Carolina School of Medicine.

"People think the main barrier is their state's legal status and that legalization will resolve access issues. My research suggests otherwise," Buchbinder said.

Her analysis was recently published online by the American Journal of Public Health.

Buchbinder's article argues that although medical aid-in-dying laws are on the rise in the U.S., legalization does not guarantee access. Patients can and do encounter substantial barriers to access in jurisdictions where medical aid-in-dying is legal, and access is hindered by the same socioeconomic inequalities that are common in U.S. health care.

For example, patients with higher incomes have easier access to physicians who are willing to prescribe the lethal medication. They are also more likely to have insurance that will cover it, or to be able to afford to pay for these services themselves.

If you tilt a plant, it will alter its growth to bend back upwards. But how does it detect the inclination? With cellular clinometers: cells filled with microscopic grains of starch called statoliths. In each of these cells, the pile of statoliths settles to the bottom. This provides a point of reference to guide growth--by modifying the distribution of a growth hormone--so that the plant may return to an upright position.

The mystery of plants is what makes them so extremely responsive to gravity, at even the tiniest deviation from the vertical. But a heap of grains would seem to be a lousy clinometer. Normally, friction and interparticle locking would limit the flow of the grains, making the granular system ineffective below a threshold angle of inclination. However, plant statoliths are astonishingly precise.

Researchers from the Institut Universitaire des Systèmes Thermiques Industriels (CNRS/Aix-Marseille University) and the Physique et Physiologie Intégratives de l'Arbre en Environnement Fluctuant laboratory (INRA/Université Clermont Auvergne) teamed up to solve this puzzle. First, they directly observed the movement of statoliths in response to tilting, discovering they did not behave like a standard granular system. Statoliths move and flow no matter how the cell is angled. The surface of the statolith piles always settles into a horizontal plane, just like a liquid. But how do cells make these piles so fluid?

To elucidate the origin of this property, the team continued their study by developing a model of plant statoliths: microbeads in artificial cells sized like real ones. Comparison of the two systems allowed them to conclude that the collective fluidity of statoliths emerges from the independent movement of each. The molecular "motors" of the cell are constantly stirring them about. As a result, they don't jam together, and over a sufficiently long timescale, the pile of statoliths as a whole exhibits properties similar to those of liquids. This behavior is essential to the plant. It means that there is no threshold inclination, so the slightest deviation is detected, and that growth is not disturbed when the plant is shaken by the wind.

The team's discovery helps us understand what makes plants so sensitive to gravity, by providing a partial explanation of statolith motion. Though more study is needed to understand how the plant detects the position of statoliths, these findings already pave the way for bioinspired industrial applications--like robust, miniature clinometers offering an alternative to today's gyroscopes and accelerometers.

Every day, people all over the world unwittingly release a flood of data on what drugs they are taking and what illnesses they are battling, simply by going to the bathroom and flushing. And according to an article in Chemical & Engineering News (C&EN), the weekly newsmagazine of the American Chemical Society, researchers aren't letting all of that information go to waste.

Senior Correspondent Celia Henry Arnaud explains that wastes entering treatment plants are a rich source of information about a population. In the 1990s, researchers started realizing the potential of this overlooked treasure trove and began analyzing wastes for illicit drugs. These wastewater-based epidemiologists found that these analyses could back up or even improve estimates of drug use obtained by conventional methods. That's at least partially because unlike people filling out a questionnaire, wastewater samples don't lie.

Now, researchers are going beyond illegal drugs, monitoring many other substances. Some are looking for evidence of consumption of legal lifestyle compounds, such as nicotine and caffeine. Others are searching for compounds that could indicate human exposure to pesticides or plasticizers. But the future of wastewater-based epidemiology might lie in health studies that attempt to describe the health of a population and thereby serve as an early warning system to alert officials of burgeoning epidemics.

PITTSBURGH, May 2, 2018 - Due to the opioid epidemic, hepatitis C virus (HCV) is increasing
among pregnant women, resulting in a greater risk of perinatal transmission and HCV infection among children. Despite this increased prevalence, HCV-exposed infants are not adequately screened and many pediatric HCV infections remain undetected, according to a new study from researchers at Magee-Womens Research Institute (MWRI).

The results are reported in today's issue of the journal Pediatrics.

In the United States, perinatal transmission is the primary cause of HCV infection in children. According to the National Center for Biotechnology Information, at least 40,000 children are exposed to HCV during pregnancy annually, resulting in an estimated 2,700 to 4,000 new cases of pediatric HCV infections each year. Like hepatitis B infection, approximately 80 percent of children who acquired HCV infection through perinatal transmission develop chronic infection.

"Without appropriate screening, children at risk for perinatal transmission may remain undiagnosed until the child becomes symptomatic or has abnormal liver enzyme testing found incidentally," said senior author Catherine Chappell, M.D., Ms.C., OB/GYN, and assistant professor in the department of obstetrics, gynecology and reproductive sciences at UPMC Magee-Womens Hospital. "Delays in diagnosis could lead to delays in appropriate referrals and curative treatment, or even irreversible liver disease, such as cirrhosis or hepatocellular carcinoma."

Chappell and her colleagues at MWRI analyzed data on pregnancies and deliveries at Magee between 2006 and 2014, using data from the Magee Maternal and Infant (MOMI) database, a dataset which contains information on all births at the hospital from 1995 to the present. The women were identified and classified as HCV-infected or HCV-uninfected. Infant records linked to the HCV-infected pregnant women were identified and queried for the receipt of well-child services.

HCV-infected women were more likely than HCV-uninfected women to be younger than 30 years of age, white, insured by Medicaid and have opiate use disorder. Infants born to HCV-infected women were more likely to be preterm and low birth weight. Among the 1,025 HCV-exposed infants with available pediatric records, 31 percent received well-child services and among these, only 30 percent were screened for HCV.

There are several possible reasons for the failure to adequately screen infants perinatally exposed to HCV. Information regarding the maternal HCV diagnosis might not be accurately transferred to the pediatric record. If not transferred electronically, pediatric providers may fail to obtain accurate historical information regarding HCV risk exposures, as parents may selectively disclose stigmatizing behaviors such as past illegal drug use.

"Between 2006 and 2014, HCV prevalence increased by 60 percent. This is a wakeup call for providers to be aware of the increased risk of HCV in pregnant women and the affects it could have on their babies," Chappell said. "While more research needs to be done on why screening rates are so low, it is important providers are properly testing for HCV, especially in high prevalence areas, and that we have programs focused on identifying pregnant women with HCV during prenatal care."

Academic institutions have been slow to adhere to new, stricter requirements by the Department of Health and Human Services (HHS) and National Institutes of Health (NIH) for clinical trial registration and reporting, according to a study led by researchers at Johns Hopkins Bloomberg School of Public Health.

For the study, published May 2 in the journal BMC Medicine, the researchers obtained survey data from more than 350 U.S. academic institutions that conduct clinical trials, and found that relatively few had the staff or policies needed to comply with the new requirements.

"Some organizations have good leadership on this issue and are complying with the law, but for many organizations, it seems that their leaders have not taken the necessary steps towards compliance," says study lead author Evan Mayo-Wilson, DPhil, assistant scientist in the Department of Epidemiology at the Bloomberg School. "If we want scientists to share their research, then academic institutions need to create systems in which it is expected and easy for individual scientists to do the right thing."

Traditionally, many clinical trial results have been published without adequate details or have not been published at all, especially if they found no evidence of effectiveness for the candidate treatment tested. However, failing to disclose trial results can lead to unnecessary further trials of the treatment and otherwise allow a false picture of its clinical value.

Inadequate reporting also violates the promise made to trial participants: that the study will help other patients and advance medical knowledge. "If we don't share results, then we're essentially lying to the people who volunteer for clinical research," Mayo-Wilson says.

Many scientists therefore have been calling for more complete clinical trial registration and reporting, and HHS and NIH policies have been tightening up accordingly. The landmark Food and Drug Administration (FDA) Amendments Act of 2007 requires that sponsors register and report results for many clinical trials. A subsequent "Final Rule" expanded these requirements and took effect in April 2017. A complementary NIH policy took effect in January 2018.

Over a period of several months before the Final Rule came into effect, Mayo-Wilson and colleagues conducted an online survey of academic institutions that have accounts at ClinicalTrials.gov, to determine how ready they were to comply with the new requirements. They contacted the 783 eligible account holders, and received responses from 366.

Among these 366 organizations willing to respond, the responses indicated a low level of preparedness. Only 43 percent had a policy on clinical trial registration, for example, and just 35 percent had a policy on the reporting of trial results. Few policies allowed organizations to punish investigators who failed to register trials or report results--and only one responding organization had ever punished a researcher for non-compliance.

Consistent with these observations, the researchers found that responders typically reported allocating almost no staff time to ClinicalTrials.gov registration and reporting requirements: The median full-time staff equivalent was just 0.08, implying a single employee was assigned to devote just eight percent of his or her time--a few hours per week--to regulatory compliance.

These results, as worrying as they may be, represent a "best-case scenario," because the hundreds of institutions that did not respond are less likely to be in compliance than those that did respond. Daniel Ford, MD, MPH, vice dean for clinical investigation at the Johns Hopkins School of Medicine, said "The National Library of Medicine and the National Institutes of Health could make it easier to comply with the new policies. It is the government's responsibility to minimize burden and to ensure that the system is suitable for all the trials that are now required to register and report their results."

"A lot of discussion about research transparency has focused on individual scientists," Mayo-Wilson says. "But institutions that accept research grants and employ scientists are responsible for compliance. We found that non-compliance is explained by things that are happening, or not happening, at the organizational level--at institutions where the provosts and deans have developed good procedures and hired staff, they're doing a great job."

Organizations that are compliant with the new rules tend to conduct large numbers of clinical trials, the researchers found. The researchers suspect it could be difficult for institutions that conduct only a few clinical trials to support staff with expertise in regulatory compliance.

The FDA, under the 2007 legislation and the Final Rule, has the power to assess civil money penalties on trial sponsors of more than $11,000 per day per trial for non-compliance. The cumulative amounts--designed to sway even major pharmaceutical companies--could run into the millions of dollars for a single trial. Although scientists and journalists have documented numerous cases of non-compliance, FDA has not assessed any penalties. "The institutions that are compliant today want to lead the field scientifically and ethically," Mayo-Wilson says. "The prospect of fines provides another reason to do the right thing."

The All of Us Research Program opens for national enrollment Sunday, May 6. Led by the National Institutes of Health (NIH), All of Us is an unprecedented effort to gather genetic, biological, environmental, health and lifestyle data from 1 million or more volunteer participants living in the United States. A major component of the federal Precision Medicine Initiative, the program's ultimate goal is to accelerate research and improve health.

"The diversity expected among California's participants in the All of Us Research Program will be an important part of the scientific journey to discover how people's personal characteristics, including genetics, behaviors and their physical environment, affect individual health," said Hoda Anton-Culver, PhD, co-leader of the California Precision Medicine Consortium, principal investigator of the All of Us Research Program at UCI School of Medicine and director of the UCI Genetic Epidemiology Research Institute. "We look forward to advancing the future of health with our many participants."

Unlike research studies that are focused on a specific disease or population, All of Us will serve as a national research resource to inform thousands of studies, covering a wide variety of health conditions. Researchers will be able to access data from the program to learn more about how individual differences in lifestyle, environment and biological makeup can influence health and disease. Participants will be able to access their own health information, summary data about the entire participant community and information about studies and findings that come from All of Us.

In California, the All of Us Research Program is being implemented by the California Precision Medicine Consortium, which is co-led by Anton-Culver and Lucila Ohno-Machado, MD, PhD, at UC San Diego Health and also includes UC Davis, UC San Francisco, Keck School of Medicine of the University of Southern California, Cedars-Sinai Medical Center and the San Diego Blood Bank. In San Diego, San Ysidro Health is also enrolling participants, and the Scripps Translational Science Institute at The Scripps Research Institute is working with corporate partners to enroll participants nationwide.

Congress has authorized $1.5 billion over 10 years for All of Us. More than 25,000 people nationwide have already joined the program as part of a yearlong beta testing phase that helped shape the participant experience.

"The time is now to transform how we conduct research -- with participants as partners -- to shed new light on how to stay healthy and manage disease in more personalized ways. This is what we can accomplish through All of Us," said NIH Director Francis S. Collins, MD, PhD.

SAN DIEGO - May 1, 2018 - According to a new study, the status of lymph nodes rather than the status of the primary tumor following preoperative neoadjuvant chemotherapy or chemoradiation therapy is the most important factor that determines whether patients with locally advanced esophageal cancer will survive. The study presented at the American Association for Thoracic Surgery's 98th Annual Meeting indicates that while preoperative chemotherapy and radiation therapy improve the survival of patients with esophageal cancer, patients with malignant lymph nodes following therapy were less likely to survive than patients with no cancer in the lymph nodes.

Nearly half a million patients worldwide are diagnosed with esophageal cancer each year, and its incidence has doubled in the US in the last 20 years. The combination of chemotherapy with or without radiation therapy followed by surgery with negative margins offers the best chance for long-term survival for patients with locally advanced esophageal adenocarcinoma. Preoperative neoadjuvant therapy - chemotherapy and/or radiation therapy before surgery - is frequently administered. Importantly, the tumor's response to this initial treatment has the potential to help guide further therapy.

"There is a clear benefit associated with esophagectomy as part of a multimodal treatment strategy, along with chemotherapy with or without radiation therapy. for patients with locally advanced esophageal adenocarcinoma," explains Shawn S. Groth, MD, MS, FACS, Assistant Professor, Baylor College of Medicine, Division of Thoracic Surgery, Michael E. DeBakey Department of Surgery, Houston, who led the study and presented the findings at the AATS meeting. "However, there has been little clinical evidence to predict which patients might benefit."

Therefore, investigators set out to describe disease response rates (no, partial, or complete response) associated with the use of neoadjuvant chemotherapy or chemoradiation therapy to evaluate the association between the degree of pathologic response and overall survival, and to characterize the relative impact on survival by evaluating the response of the primary tumor versus the response of the lymph nodes to initial therapy.

Investigators reviewed records in the National Cancer Database of nearly 3,000 patients aged 18-80 who were diagnosed between 2006 and 2012 with clinically staged, locally advanced esophageal adenocarcinoma, and who had received neoadjuvant chemotherapy or chemoradiation therapy followed by an esophagectomy with negative margins.

Of the patients in the study, 17.3 percent had a complete response and 34.5 percent had a partial response to neoadjuvant therapy. Compared with neoadjuvant chemoradiation, neoadjuvant chemotherapy was associated with lower primary tumor (21.3 percent vs. 33.9 percent) and nodal response rates (32.7 percent vs. 55.9 percent) and was less likely to achieve a partial or complete response.

Significantly, the study found that as the completeness of response increased, survival rates improved. It also determined that patients who still had cancer in lymph nodes after preoperative chemotherapy and radiation therapy, independent of how well the tumor responded to treatment, had worse survival rates than patients who had no cancer in their lymph nodes.

Pathologic nodal, rather than primary tumor, response to neoadjuvant therapy is associated with improved survival. These data suggest a need to optimize neoadjuvant strategies associated with more complete nodal response rates and to consider more aggressive adjuvant treatment for patients with residual nodal disease after esophagectomy.

According to Dr. Groth, "Given the aggressive nature of esophageal cancer, our inability to predict which patients will respond to neoadjuvant therapy, and the morbidity associated with surgical resection which currently limits the number of patients who are able to receive adjuvant treatment, certain patients with locally advanced esophageal adenocarcinoma may also benefit from this 'total upfront" approach prior to esophagectomy."

These findings could be used to help physicians counsel patients about their prognosis and determine which patients may benefit from additional chemotherapy before or after surgery.