Body

The Institute of Medicine's guidelines currently advise all pregnant women to increase calorie intake by 340-450 calories/day during their second and third trimesters, regardless of their body size at conception. Approximately 2/3 of women with obesity at the time of pregnancy will gain more weight than recommended, highlighting a need for evidence-based guidelines to optimize the health of this population and their offspring.

This week in the JCI, Most et al. describe the results of a clinical trial evaluating weight gain and its two primary determinants -- calorie intake and energy expenditure-- in 54 women with obesity throughout their pregnancies. The study, led by Leanne Redman at Pennington Biomedical Research Center, provides new and important insights into calorie recommendations for pregnant women.

Most et al.'s results contradict the Institute of Medicine's recommendation that women with obesity should increase calorie intake during pregnancy, showing that mobilization of maternal fat stores provided sufficient energy to support fetal development. The researchers also observed that gestational weight gain due to the increased blood volume, expansion of breast tissue and fetal mass, accounted for the 5-9 kg (11-20 pounds) that the Institute of Medicine advises women with obesity to gain during pregnancy. Therefore, even small increases in daily calorie consumption (~200 calories) led to excess weight gain in these women.

This study's findings refute the assumption that pregnant women with obesity require excess calorie intake to support a healthy pregnancy, instead suggesting that they would likely benefit from maintaining pre-pregnancy calorie intake and to focus on improving diet quality. Discussing the results of the trial, Most et al. emphasized that this and other studies of pregnant women with obesity are a crucial step to improving health outcomes associated with gestational weight gain for mothers and babies.

Dr. Sarah Comstock of Michigan State University highlights the study's findings and implications in an accompanying commentary article entitled "Time to change weight gain recommendations for pregnant women with obesity," linked below.

Scientists from the Skoltech Center for Energy Science and Technology and the Institute of Problems of Chemical Physics of RAS in collaboration with researchers from four other Russian and foreign research centers have discovered a new reaction that helps obtain water-soluble fullerene derivatives which effectively combat flu viruses, human immunodeficiency virus (HIV), herpes simplex virus (HSV), and cytomegalovirus (CMV).

Viruses have been affecting social advancement over millennia, often causing vast epidemics wiping out entire cities. Viruses attack every living thing on Earth from higher vertebrates to simple, single-cell life forms, bacteria and even other viruses. Currently, over 90% of human infectious diseases are caused by viruses.

HIV that causes AIDS is one of the most dangerous viruses. According to WHO, the number of HIV-infected patients in Russia has already exceeded 1 million (about 1% of the population) and keeps soaring, making an HIV epidemic an ominous threat to the nation.

Global circulation of seasonal flu viruses that kill 500,000 people worldwide every year is yet another critical public health issue. New varieties of flu viruses often entail high mortality rates (up to 60% for H5N1 and H5N8 avian flu) and are highly resistant to existing drugs.

Modern antiviral drugs extend the lifespan and improve the quality of life, while having quite a few major flaws, such as toxicity, limited bioavailability and development of drug resistance. The circulating sets of flu strains change quickly, reducing the efficiency of the commonly administered anti-flu vaccines. All this makes the search for new classes of antiviral drugs a hot-button issue.

A unique form of carbon, C60 fullerene is shaped like a soccer ball with carbon atoms located at the vertices of its pentagons and hexagons. Although fullerene molecules boast unique biological properties, fullerenes and their classical derivatives are insoluble in water and biological media, making their application in medicine extremely difficult.

Two years ago, a research team led by Skoltech Professor, Pavel Troshin, proposed several effective approaches for the synthesis of water-soluble fullerene derivatives. In their latest study, the researchers discovered a unique new reaction that helped obtain a series of previously unavailable water-soluble fullerene derivatives with high antiviral activity. The mechanism of this unusual transformation of fullerenes was proposed based on the quantum chemical calculations.

"Our latest study focuses on the synthesis of highly effective inhibitors of dangerous viral infections, such as HIV, different varieties of flu, HSV and CMV, using fullerene derivatives as a multifunctional platform. We discovered a unique inversed Arbuzov reaction that allows fine-tuning the antiviral properties of new compounds and establishing fundamental correlations between a compound's structure and antiviral activity," explains the first author of the paper and Skoltech PhD student, Olga Kraevaya.

The results of this study open up vast opportunities for developing effective antiviral drugs capable of suppressing virus resistant lines, which will help combat currently untreatable infections.

The non-viral, bio-inspired gene delivery method developed by researchers at RMIT University has proven effective in laboratory tests and is safer than standard viral approaches.

Widely considered the next frontier of cancer research, gene therapy involves introducing new genes into a patient's cells to replace missing or malfunctioning ones that cause disease.

As cells are not designed to naturally take up genes or any foreign DNA material, the biggest challenge for gene therapy is getting the therapeutic genes into the cells.

Research has focused on using viral delivery systems to penetrate the cells, however the risks associated with introducing a virus into the body have slowed progress from lab to clinic and only three viral-based therapies have ever been approved by FDA.

Despite being safer and relatively inexpensive, non-viral methods have been the focus of less than 0.25% of gene therapy research due to varying results.

Lead researcher Dr Ravi Shukla said addressing the gap in suitable non-viral methods would be a key step in taking gene therapies out of the lab and into clinics.

"An effective non-viral method would be safer for patients and could significantly reduce the time and expense involved in bringing new treatments to market," he said.

"We have now successfully tested a non-viral alternative that could allow us to sidestep the risks involved in viral methods and help unleash the full potential of gene therapy."

Shukla and his team developed the new non-viral method using Metal Organic Frameworks (MOFs), incredibly versatile and super porous nanomaterials that can be used to store, separate, release or protect almost any biomolecule.

The research is supported by the Commonwealth Scientific and Industrial Research Organisation (CSIRO) who developed a technology to manufacture industrial scale quantities of MOFs.

Predominantly used for industrial or chemical purposes, the biological applications of MOFs are increasingly gaining ground and these latest findings show they have excellent potential in non-viral gene therapy.

Researchers used a MOF subtype known for its biocompatible and biodegradable properties to carry the DNA into a cell.

The MOF-based delivery method was found to be effective in prostate cancer cells and opens the door to treatment of lung and breast cancer as well as other genetic diseases.

PhD researcher Arpita Poddar, who worked with Shukla on the discovery, said the findings were the first step towards opening a line of research that has so far been neglected.

"Now that we have a proof of concept, we can investigate other applications including in transgenomics, implants and even crop improvements," she said.

PITTSBURGH, Sept. 23, 2019 - In March 2016, the Organ Procurement and Transplantation Network revised its criteria for prioritizing children awaiting heart transplantation in the U.S. with the intention of reducing the number of deaths on the waitlist, but a new study suggests unintended consequences.

The study, published today in the American Journal of Transplantation by cardiologists at UPMC Children's Hospital of Pittsburgh, found no overall improvement in waitlist mortality rates after the policy change, and for some types of heart disease, mortality actually increased.

"Changes were made to prioritize sicker children with fewer treatment options -- for instance, kids with congenital heart defects -- but the reality we're showing is that since the criteria change, transplant centers are using more listing status exceptions, essentially short-circuiting the intended benefit," said senior author Brian Feingold, M.D., medical director of pediatric heart failure and heart transplantation at UPMC Children's Hospital of Pittsburgh.

The new policy de-prioritizes some children with cardiomyopathies, a type of heart disease where the heart muscle can't squeeze hard enough to pump effectively.

Since this change, clinicians are getting more exceptions to the policy for their cardiomyopathy patients, especially a subtype called dilated cardiomyopathy, so that patients will retain the highest listing status.

Across the country, exceptions for dilated cardiomyopathy rose by more than 13-fold, yet the study shows high priority status makes no difference in the survival rates of these patients.

On the other hand, children with two other subtypes of cardiomyopathy -- hypertrophic or restrictive -- without an exception, are now dying on the waitlist at a rate 4-6 times higher than before the new criteria went into effect.

"We can't prove causality here, but it would seem that restrictive and hypertrophic cardiomyopathy patients have been disadvantaged by the criteria change," Feingold said. "They're prioritized downward under the umbrella of cardiomyopathy, likely inadvertently, while children with congenital heart defects have not been able to benefit due to increased exception use."

Part of the reason patients with different subtypes of cardiomyopathy are faring so differently under the new guidelines is that children with dilated cardiomyopathy tend to be better candidates for implanted blood pumps called ventricular assist devices (VADs). Considered a type of life support, VADs place patients higher on the waitlist. They also allow patients to rehabilitate, even leave the hospital, while waiting for a transplant.

With this study, the researchers hope to spark discussion about ways to further improve waitlist criteria for pediatric heart transplant candidates.

"The chronic shortage of organ donors means that we must strive to optimize organ allocation as much as possible. It's very difficult to know all of the downstream effects of policy decisions like these, so we should continue to tweak and observe until we get it right," Feingold said.

A new Canadian guideline lays out the optimal strategies for providing injectable opioid agonist treatment with prescription heroin and hydromorphone for people with severe opioid use disorder. The clinical guideline was created for a wide range of health care providers to address an urgent need for evidence-based treatment of opioid use causing overdose and death, and is published in CMAJ (Canadian Medical Association Journal).

In 2018, of the 4,460 Canadians who died from opioid overdoses, 94% were accidental
deaths, a 9% increase from 2017 and a 48% increase from 2016. This guideline will support health care providers to deliver life-saving prescription treatments for opioid addiction, which may prevent overdoses.

"Opioid use disorder is a public health emergency nationwide; unfortunately, resources for the treatment of opioid addiction have been scarce and guidelines outlining best practices for innovative treatments have been lacking. This guideline is a blueprint for health practitioners to step up and provide evidence-based care," says Dr. Nadia Fairbairn, British Columbia Centre on Substance Use and the University of British Columbia, Vancouver, BC.

Oral opioid agonist treatments are the most effective approach to reducing death in people using opioids, although many do not benefit from this therapy because of opioid cravings, inability to achieve an effective dose, adverse reactions or contraindications, and ongoing injection drug use.

Evidence included in the guideline demonstrates that injectable opioid agonist treatment with prescription heroin (known as diacetylmorphine) and hydromorphone is an evidence-based, cost-effective treatment for individuals with severe opioid use disorder who have not benefitted from these other treatments and continue to face high risk of harms related to injection opioid use. The writing committee, led by the Canadian Institutes of Health Research's Canadian Research Initiative in Substance Misuse (CRISM), included health care practitioners from across the country with broad experience, and people with opioid use disorder experience. The three key clinical recommendations were determined using the GRADE approach.

Key recommendations:

Injectable opioid agonist treatment should be considered for people with severe opioid addiction who do not respond to oral treatments, as well as for people who actively use illicit injectable opioids.

Diacetylmorphine and hydromorphone, two injectable opioid agonist therapies, are recommended as options for patients likely to benefit from injectable opioid agonist treatment, with the decision of which treatment to use made based on availability, patient choice and the judgment of the prescriber.

As assigning an end date to treatment is associated with a return to illicit opioid use, injectable opioid agonist treatments should be prescribed on an open-ended basis, and the decision to transition to another treatment should be made in collaboratively with the patient.

The guideline also includes expert opinion on clinical care approaches, including who is eligible for this treatment, doses and missed doses. Patient values and preferences were considered in the development of the recommendations.

"Offering injectable opioid treatments is an effective way for clinicians to address the toxicity of the fentanyl-adulterated drug supply and help people achieve stability so they can focus on other aspects of their lives to get well, such as housing, employment, and connecting with family," says Dr. Christy Sutherland, Medical Director of PHS Community Services Society in Vancouver, BC.

In addition to the clinical guideline published in CMAJ, CRISM also released operational guidance for delivering injectable opioid agonist therapy.

In people with diabetes, fat mass index, not body mass index (BMI), is associated with a higher risk of cardiovascular events, according to new research in CMAJ (Canadian Medical Association Journal).

Heart disease is a major cause of death worldwide, and obesity is a major risk factor. Body mass index, a common measure of obesity, has been recently shown to be an imperfect metric because it does not distinguish between lean muscle mass and fat mass. When issues related to obesity are studied, suitable metrics that describe obesity accurately are extremely important.

Researchers analyzed data on 10 251 adults from the ACCORD study, a randomized controlled trial in the United States looking at diabetes and cardiovascular disease (CVD). The mean age was almost 63 years, and 62% of participants were men. The researchers found that people with type 2 diabetes and higher fat mass were at increased risk of major cardiovascular events compared to people with lower fat mass. In contrast to previous research, the protective role of lean body mass was not observed in the research population with type 2 diabetes as a whole.

"We found that the protective effect of lean body mass was observed in participants with a lean BMI of less than 16.7 kg/m2," writes Dr. Xinqun Hu, Departments of Cardiovascular Medicine and Emergency Medicine, The Second Xiangya Hospital, Changsha, Hunan, China, with coauthors. "The increased risk of CVD in [type 2 diabetes mellitis] patients with lower BMI may be attributed to the adverse effect of lower lean body mass that overrides the positive effect of lower fat mass."

Opioid use is increasing in pregnancy as well as the general population. A "Five things to know about ..." practice article on opioid disuse in pregnancy in CMAJ (Canadian Medical Association Journal) provides information on how to manage this vulnerable population.

1. Opioid use and opioid use disorders in pregnancy are rising.

2. Guidelines support universal screening for drug use, including opioids, by prenatal care providers.

3. Opioid agonist therapy is the standard of care for opioid use disorders in pregnancy, along with counselling and mental health supports. Pregnant women with an opioid use disorder should be offered timely access to opioid agonist therapy.

4. Neonatal opioid withdrawal syndrome is best managed by keeping mothers and infants together after delivery. Breastfeeding should be encouraged in women who are stable on opioid agonist therapy, for whom there are no concerns about ongoing drug use.

5. Ongoing support in the postpartum period is essential, as women with opioid use disorders are at increased risk of fatal overdose in the first year postpartum.

This release was amended on 26/09/19 to clarify the impact of the research.

Researchers at Chalmers University of Technology, Sweden, have discovered a new aspect to the way that DNA binds itself, and the role played by hydrophobic effects. They show how small changes in water properties can delicately control the binding process. The discovery opens doors for new understanding in research in medicine and life sciences. The researchers’ findings are presented in the journal PNAS.

DNA is constructed of two strands, consisting of sugar molecules and phosphate groups. Between these two strands are nitrogen bases, the compounds which make up organisms' genes, with hydrogen bonds between them. Those hydrogen bonds have sometimes been seen as crucial to holding the two strands together.

But now, researchers from Chalmers University of Technology show that the secret to DNA's helical structure may be that the molecules have a hydrophobic interior, in an environment consisting mainly of water. The environment is therefore hydrophilic, while the DNA molecules' nitrogen bases are hydrophobic, pushing away the surrounding water. When hydrophobic units are in a hydrophilic environment, they group together, to minimise their exposure to the water.

The role of the hydrogen bonds, which have sometimes been seen as crucial to holding DNA helixes together, appears to be more to do with sorting the base pairs, so that they link together in the correct sequence.

The discovery is crucial for understanding DNA's relationship with its environment.

"Cells want to protect their DNA, and not expose it to hydrophobic environments, which can sometimes contain harmful molecules," says Bobo Feng, one of the researchers behind the study. "But at the same time, the cells' DNA needs to open up in order to be used."

"We believe that the cell keeps its DNA in a water solution most of the time, but as soon as a cell wants to do something with its DNA, like read, copy or repair it, it exposes the DNA to a hydrophobic environment."

Reproduction, for example, involves the base pairs dissolving from one another and opening up. Enzymes then copy both sides of the helix to create new DNA. When it comes to repairing damaged DNA, the damaged areas are subjected to a hydrophobic environment, to be replaced. A catalytic protein creates the hydrophobic environment. This type of protein is central to all DNA repairs, meaning it could be the key to fighting many serious sicknesses.

Understanding these proteins could yield many new insights into how we could, for example, fight resistant bacteria, or potentially even cure cancer. Bacteria use a protein called RecA to repair their DNA, and the researchers believe their results could provide new insight into how this process works - potentially offering methods for stopping it and thereby killing the bacteria.

In human cells, the protein Rad51 repairs DNA and fixes mutated DNA sequences, which otherwise could lead to cancer.

"To understand cancer, we need to understand how DNA repairs. To understand that, we first need to understand DNA itself," says Bobo Feng. "So far, we have not, because we believed that hydrogen bonds were what held it together. Now, we have shown that instead it is the hydrophobic forces which lie behind it. We have also shown that DNA behaves totally differently in a hydrophobic environment. This could help us to understand DNA, and how it repairs. Nobody has previously placed DNA in a hydrophobic environment like this and studied how it behaves, so it's not surprising that nobody has discovered this until now."

More information on the methods the researchers used to show how DNA binds together:

The researchers studied how DNA behaves in an environment which is more hydrophobic than normal, a method they were the first to experiment with.

They used the hydrophobic solution polyethylene glycol, and step-by-step changed the DNA's surroundings from the naturally hydrophilic environment to a hydrophobic one. They aimed to discover if there is a limit where DNA starts to lose its structure, when the DNA does not have a reason to bind, because the environment is no longer hydrophilic. The researchers observed that when the solution reached the borderline between hydrophilic and hydrophobic, the DNA molecules' characteristic spiral form started to unravel.

Upon closer inspection, they observed that when the base pairs split from one another (due to external influence, or simply from random movements), holes are formed in the structure, allowing water to leak in. Because DNA wants to keep its interior dry, it presses together, with the base pairs coming together again to squeeze out the water. In a hydrophobic environment, this water is missing, so the holes stay in place.

OAKLAND, Calif. -- Patients with type 2 diabetes who were in poor health were more likely to continue taking insulin after age 75 than their counterparts in better health, according to Kaiser Permanente research published today in JAMA Internal Medicine. As people with type 2 diabetes age, the risks of insulin use can outweigh its benefits, creating the need for increased provider and patient education.

"Leading medical specialty organizations recommend reducing diabetes treatment intensity for older patients, particularly when they have multiple, life-limiting health conditions. But in current practice we found that these sicker patients were less likely to stop taking insulin," said senior author Richard W. Grant, MD, MPH, research scientist with the Kaiser Permanente Division of Research in Oakland, California.

Insulin is a hormone that helps the body regulate sugar in the blood and is a key component of treatment for many patients with type 2 diabetes. Older adults who continue to use insulin are at greater risk of dangerously low blood sugar, or hypoglycemia; this can happen when people take too large a dose of insulin, Grant explained.

In the study "The Use and Discontinuation of Insulin Among Adults Aged 75-79 with Type 2 Diabetes: A Longitudinal Cohort Study," researchers followed 21,531 Kaiser Permanente members age 75 and older in Northern California who had type 2 diabetes. Nearly one-fifth of the patients used insulin at the beginning of the study, and among them, about one-third discontinued its use over the next 4 years.

The researchers grouped patients into three categories of health (poor, intermediate, and good) using information in the medical record about the number of chronic conditions, functional status, and indicators of end-stage disease. Insulin use was highest among older adults in poor health (29% of them used insulin) with a serious end-stage disease, or intermediate health (28% used insulin) with at least two other health conditions. In contrast, just 11% of those in good health used insulin. The findings were similar even when researchers took into account how well patients were controlling their blood sugar.

"Revisiting the need for potentially harmful medications such as insulin when the risks outweigh the benefits can help to reduce adverse events like hypoglycemia and improve the quality of care in older patients," Dr. Grant said.

Pharmacists, primary care physicians, geriatric specialists and others are working together to address "polypharmacy" -- when older patients take 5 or more medications for multiple conditions -- and to "de-prescribe" medications by reducing doses or taking people off them, he added.

A recent Kaiser Permanente study showed that discontinuing diabetes medications reduced the risk of hypoglycemia in elderly patients with well-controlled type 2 diabetes.

"We're raising awareness about the need for physicians and patients to have conversations and reconsider medications that may lose benefit or add more risk as patients age," said Maisha S. Draves, MD, medical director of pharmacy for The Permanente Medical Group at Kaiser Permanente in Northern California.

Researchers at University of California San Diego School of Medicine say they are getting closer to identifying the mechanisms of autism spectrum disorder (ASD) and biomarkers that can aid in early diagnosis and predictions of symptom severity.

A team of scientists analyzed blood gene expression data from 302 one- to four-year-old boys with and without the diagnosis of ASD. They uncovered a critical gene network that is disrupted in ASD, noting that the perturbed gene network is related to fetal brain development and also dysregulated in ASD cellular models.

The findings, published online September 23, 2019 in Nature Neuroscience, suggest genetic factors influencing brain development during pregnancy are a primary cause of ASD.

"The genetics of ASD are extremely heterogeneous," said co-senior author Nathan E. Lewis, PhD, associate professor of pediatrics and bioengineering. "Hundreds of genes have been implicated, but the underlying mechanisms remain murky. These findings identify how ASD genetics dysregulate a core network that influences brain development at fetal and in the very early years of life and, consequently, the severity of later ASD symptoms."

The findings could form the basis for early diagnosis and prediction of symptom severity of ASD, wrote the authors. Early intervention is known to enhance the quality of life of individuals with ASD by improving symptoms, such as cognitive and learning impairments.

However, current diagnosis methodologies rely heavily upon clinical identification of tell-tale behavioral symptoms, such as abnormal facial expressions, limited communications skills and inappropriate social interactions -- all of which can be unstable at early ages, making diagnosis and predicted outcomes very difficult. No reliable, practical and objective markers of prognosis currently exist.

"There is an urgent need for robust tests that can identify the disorder and its expected severity at very early ages so that treatment can start early, enabling a better outcome for each child," said co-senior author Eric Courchesne, PhD, professor of neuroscience and co-director of the UC San Diego Autism Center of Excellence.

First author Vahid H. Gazestani, PhD, said data from the boys' blood gene expression, combined with neuron models, revealed dysregulation of a common gene network containing key signaling pathways with roles in fetal brain development. "We found that many of the known ASD risk genes regulate this core network and hence their mutations can disrupt this developmentally critical network."

The worse the network dysregulation, the scientists found, the more severe the symptoms experienced later on by affected boys. Although the authors cautioned that the findings need to be replicated in larger studies, they said the data are consistent with previous studies by the Courchesne and Lewis labs and other groups, which have shown the diagnostic and prognostic power of blood gene expression for ASD.

"Increasingly, evidence indicates that ASD is a progressive disorder that, at prenatal and early postnatal stages, involves a cascade of molecular and cellular changes, such as those resulting from dysregulation of signaling pathways and networks," said Courchesne.

"Our evidence suggests that abnormal signals from known ASD risk genes may be channeled through this important gene network," added Gazestani, "and that, in turn, sends signals that alter fetal and postnatal brain formation and wiring patterns."

The researchers hope to create a framework in which physicians and others can systematically diagnose, classify and prognostically stratify patients with ASD at much earlier ages, based upon genetic or molecular markers, expediting treatment.

"The study shows that through analyses of gene expression from ordinary blood samples, it is possible to study aspects of ASD's fetal molecular origins, uncover the functional impact of hundreds of ASD risk genes that have been discovered over the years, and develop clinical tests of ASD diagnosis and severity prognosis," said Lewis.

What The Study Did: This study used enrollment data to examine changes in the internal medicine subspecialty choices of women and men from 1991 to 2016. Data were examined for nine internal medicine subspecialties: cardiovascular disease, endocrinology, gastroenterology, geriatric medicine, hematology and oncology, infectious disease, nephrology, pulmonary disease and critical care, and rheumatology.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

Authors: Mary Norine Walsh, M.D., M.A.C.C., of the St. Vincent Hospital and Heart Center in Indianapolis, is the corresponding author.

(doi:10.1001/jamainternmed.2019.3833)

Editor's Note: The article contains conflict of interest and funding/support disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

A new study of men and women with hypersexual disorder has revealed a possible role of the hormone oxytocin, according to results published in the journal Epigenetics. The finding could potentially open the door to treating the disorder by engineering a way to suppress its activity.

Hypersexual disorder, or an overactive sex drive, is recognized as a compulsive sexual behaviour disorder, listed as an impulse-control disorder by the World Health Organisation. It can be characterised by obsessive thoughts of sex, a compulsion to perform sexual acts, a loss of control, or sexual habits that carry potential problems or risks. While prevalence estimates vary, literature indicates that hypersexual disorder affects 3-6% of population.

Controversy surrounds diagnosis because it often occurs alongside other mental health issues, suggesting it could be an extension or manifestation of an existing mental disorder. Little is known about the neurobiology behind it.

"We set out to investigate the epigenetic regulatory mechanisms behind hypersexual disorder so we could determine whether it has any hallmarks that make it distinct from other health issues," says lead author Adrian Boström from the Department of Neuroscience at Uppsala University, Sweden who conducted the study with researchers from the Andrology/Sexual Medicine Group (ANOVA) at Karolinska Institutet, Stockholm, Sweden.

"To our knowledge, our study is the first to implicate dysregulated epigenetic mechanisms of both DNA methylation and microRNA activity and the involvement of oxytocin in the brain among patients seeking treatment for hypersexuality."

The scientists measured DNA methylation patterns in the blood from 60 patients with hypersexual disorder and compared them to samples from 33 healthy volunteers.

They investigated 8,852 regions of DNA methylation associated to nearby microRNAs to identify any variations between samples. DNA methylation can affect gene expression and the function of genes, typically acting to reduce their activity. Where changes in DNA methylation were detected, the researchers investigated levels of gene expression of the associated microRNA. MicroRNAs are particularly interesting as they can pass the blood-brain-barrier and modulate or degrade the expression of up to several hundred different genes in brain and other tissues.

They also compared their findings to samples from 107 subjects, 24 of whom were alcohol-dependent, to explore an association with addictive behaviour.

Results identified two regions of DNA that were altered in hypersexual disorder patients. Normal function of DNA methylation was disrupted and an associated microRNA, involved in gene silencing, was found to be under-expressed. Analysis revealed that the microRNA identified, microRNA-4456, targets genes that are normally expressed at particularly high levels in the brain and that are involved in the regulation of the hormone oxytocin. With gene silencing reduced, oxytocin may be expected to be at elevated levels, although the current study does not confirm this.

It has been seen in specific vole and primate species the neuropeptide oxytocin plays a central role in the regulation of pair-bonding behaviour. Previous studies have demonstrated that oxytocin is associated with the regulation of social and pair-bonding, sexual reproduction and aggressive behaviour in both men and women. The comparison with alcohol-dependent subjects revealed the same DNA region to be significantly under-methylated, suggesting that it may be primarily associated with the addictive components of hypersexual disorder, such as sex addiction, dysregulated sexual desire, compulsivity and impulsivity.

"Further research will be needed to investigate the role of microRNA-4456 and oxytocin in hypersexual disorder, but our results suggest it could be worthwhile to examine the benefits of drug and psychotherapy to reduce the activity of oxytocin," says Professor Jussi Jokinen from Umeå University, Sweden.

The authors note that a limitation of the study is that the mean difference in DNA methylation between hypersexual disorder patients and healthy volunteers was only around 2.6%, so the impact on physiological changes might be called into question. However, a growing body of evidence suggestions that just subtle methylation changes can have wide-ranging consequences for complex conditions such as depression or schizophrenia.

A new family of drugs which inhibit the activity of a protein associated with prostate and other cancers has been reported by scientists from the University of Bath.

They provide a promising avenue for research to potentially develop new therapies to treat a range of cancers thanks to the design of the study, which rationally investigates how the drugs work. The research team from the Departments of Pharmacy & Pharmacology and Chemistry study a protein called α-methylacyl-CoA racemase (AMACR). Levels of the AMACR protein and its activity are increased by ~10-fold in all prostate cancers, and a number of other cancers as well.

Reducing levels of AMACR in prostate cancer cells using genetic techniques makes them less aggressive, and their behaviour becomes more like normal cells.

Until recently it was difficult to accurately measure AMACR activity and therefore hard to determine the effectiveness of drugs designed to reduce AMACR activity. This means that few studies on developing AMACR-targeted drugs had been carried out, and those that had been did not systematically investigate the structural features which contribute to high effectiveness. In this study a new family of drugs which inhibit AMACR is reported. The structure of a feature called a side-chain was systematically varied in order to identify important structural features which are required for highly effective inhibition of AMACR activity. This work resulted in a 20-fold increase in effectiveness in the drugs compared to those already known, such as ibuprofenoyl-CoA. The reported new drugs proved to work in a different way to ibuprofenoyl-CoA and similar drugs.

The study is published in the journal Bioorganic Chemistry.

Lead author Dr Matthew Lloyd, from the Department of Pharmacy & Pharmacology, said "This study is really significant because it gives detailed information about the structure of these drugs and provides a rational basis for understanding their behaviour. That means that we have some really promising avenues to explore as we work towards developing new treatments against prostate cancer, and other cancers where AMACR is involved.

"It is also particularly nice that this study provided important training to the next generation of researchers at Bath."

Synthesis of the new drugs was performed by post-doc, Dr Maksims Yevglevskis, Bath Pharmacy undergraduate Suzanne Al-Rawi (who undertook this is a part of a Biochemical Society Summer Vacation Studentship), and Shandong Pharmacy undergraduate Tingying Jiao (as part of a Bath-Shandong Visiting Student Exchange Programme). Biological testing of the drugs was undertaken by post-doc Dr Amit Nathubhai, and Masters in Drug Discovery with Chemistry student Katty Wadda.

Prostate Cancer UK funded part of this research with support from Movember.

Simon Grieveson, Head of Research Funding at Prostate Cancer UK said: "With one man dying from prostate cancer every 45 minutes in the UK there is a desperate need to develop new and effective treatments for the disease, and that's why it's so important that we continue to fund explorative studies like this. The protein AMACR has been shown to be present in larger quantities in aggressive prostate cancer cells, and this research group have successfully developed a technique to find the protein and monitor its activity. Further to this, they have now found certain compounds that can target this protein's activity in the lab, and stop the cancer cells in their tracks. The research is still in its infancy and is some way off from clinical investigation, however this is certainly promising and we look forward to seeing how this research progresses over the coming years."

In the United Kingdom, prostate cancer is the most common male-specific cancer with 47,151 new diagnoses reported in 2015 and 11,287 deaths in 2014. It accounts for 26% of all cancers diagnosed in men, with one in eight men being diagnosed with prostate cancer in their lifetime. Although 84% of men will survive for at least 10 years with the disease, new treatments are urgently needed especially for those men diagnosed with more advanced disease.

Dengue virus (DENV) infects about 400 million people annually around the world, with a high prevalence in tropical and sub-tropical regions. The virus causes diseases ranging from mild dengue fever to severe dengue haemorrhagic fever and dengue shock syndrome.

DENV2 exists as smooth spherical surface particles while growing at the mosquito's physiological temperature (29 degrees Celsius). It then changes to bumpy surfaced particles at human physiological temperature (37 degrees Celsius). This ability to morph helps the virus to evade the immune system of the human host. Hence, understanding the mechanism behind this is important for therapeutics and vaccine development.

"Together with Professor Pei-Yong Shi from UTMB, we found that in laboratory developed DENV2 strains, mutations in the virus' E protein causes its transformation into bumpy particles. These structural changes can cause vaccines and therapeutics to be ineffective against the virus," said Ms Xin-Ni Lim, the study's lead author who is from Duke-NUS' Emerging Infectious Diseases (EID) Programme.

The team also tested four DENV2 strains obtained from patients. They observed that in contrast to the laboratory adapted viruses, the majority of these clinical strains maintained smooth surface structure at 37 degrees Celsius. However, at 40 degrees Celsius, the temperature of a fever, all virus strains took on a bumpy surface.

"Our study gives a new direction to vaccine development and treatment for dengue disease. For prevention of disease through vaccines that are administered to the patient before dengue infection, we should use those that are effective against the smooth surface virus. When it comes to patients displaying fever symptoms, treatment strategies effective against the bumpy surface particles should be implemented," said Dr Sheemei Lok, Professor, Duke-NUS' EID and corresponding author of this study.

"This study is a first step towards gaining more insight into how DENV2 reacts and adapts to the host's immunological defenses. We were also able to use computational modelling approaches to predict why particles from different DENV2 strains are more or less adept at morphing from the smooth to bumpy structures. By better understanding the interactions between the virus and the host, we will be able to develop better therapies and vaccines to treat or prevent infections, and contribute to public health outcomes," said Dr Peter Bond, Principal Investigator from A*STAR's BII.

The study's findings also show that the lab adapted DENV2 may not be a good model for research, as its structure is different from the clinical strains isolated from patients. The team is planning to study the other DENV serotypes to find out if there are any other possible structural changes.

In early July, the German Institute for Quality and Efficiency in Health Care (IQWiG) conducted two early benefit assessments to investigate whether certain drug combinations with pembrolizumab have advantages in comparison with the respective appropriate comparator therapy for patients with metastatic squamous or non-squamous non-small cell lung cancer (NSCLC). Due to a contradictory presentation of the operationalization of the key outcome "overall survival" in the drug manufacturer's dossiers, the presented data were not interpretable, however.

The manufacturer resolved the contradictions in the subsequent commenting procedure: It had conducted correct analyses on overall survival, but had provided a wrong presentation in the dossiers. IQWiG was now able to include these analyses in two addenda to the original assessments: An added benefit was shown for specific subpopulations.

Gene expression influences the results

In both commissions, the Federal Joint Committee (G-BA) had distinguished between two groups of patients, i.e. those whose tumours express the T-cell receptor ligand PD-L1 with over 50 per cent, and those with a PD-L1 expression of under 50 per cent. In one of the commissions, the data additionally suggested a modification of the results by sex.

Overall, there is now proof of major added benefit for women and an indication of minor added benefit for men in the first-line treatment of non-squamous NSCLC without EGFR or ALK-positive tumour mutations with PD-L1 expression below 50 per cent. If PD-L1 expression is above 50 per cent, there is a hint of a major added benefit for women, whereas for men, there is a hint of lesser benefit in comparison with the appropriate comparator therapy.

In first-line treatment of squamous NSCLC, however, sex does not influence the results of treatment with pembrolizumab. There is an indication of major added benefit in PD-L1 expression below 50 per cent. An added benefit is not proven for men or women with PD-L1 expression above 50 per cent.

G-BA decides on the extent of added benefit

The dossier assessments are part of the early benefit assessment according to the Act on the Reform of the Market for Medicinal Products (AMNOG) supervised by the G-BA. After publication of the manufacturer dossiers and the IQWiG dossier assessments, the manufacturer submitted additional information in the commenting procedure. The G-BA subsequently commissioned IQWiG to assess this information. IQWiG now presents this assessment in the form of two addenda. The G-BA makes final decisions on the extent of added benefit.

The English translation of the addenda will be published soon. If you would like to be informed when these documents are available, please send an e-mail to info@iqwig.de.