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Retinitis pigmentosa is the most prevalent form of congenital blindness. Using a retinitis pigmentosa mouse model, researchers from Ludwig-Maximilians Universitaet (LMU) in Munich have now shown that targeted activation of genes of similar function can compensate for the primary defect. 

As many as 40,000 people in Germany suffer from retinitis pigmentosa. This hereditary disorder is characterized by loss of photoreceptors in the retina, and can be caused by mutations in many different genes. Depending on the nature of the underlying genetic defect, the severity of the condition can vary between night blindness and progressive visual field loss that can ultimately result in total blindness. The first gene therapies for the disease have recently been approved. However, these approaches have certain disadvantages, which limit their range of application. A research team led by PD Dr. Elvir Becirovic at the Department of Pharmacology of Natural Sciences (Head: Prof. Dr. Martin Biel) has developed a new strategy in collaboration with Prof. Dr. Stylianos Michalakis of the Opthalmology Clinic in the LMU Medical Center. This approach is designed to compensate for the causative hereditary defect by activating genes with similar functions that are normally repressed in the affected tissues, and utilizes a variant of the CRISPR/Cas9 technology that was first described in 2015. In the online journal Science Advances, the team describes the first successful application of this method in the context of gene therapy.

Currently, two strategies are being used in the development of gene therapies: In the context of gene supplementation, an attempt is made to replace the defective gene with an intact version. However, this is currently only possible for relatively small genes. The second strategy aims to correct disease-causing mutations, but this usually has to be tailored to each individual mutation. In view of the high effort and the associated development costs, a broad application of this strategy is therefore not possible. "To overcome these limitations, we have developed a new strategy," says Becirovic.

Many genes in the human genome fall into families, whose members fulfill similar functions in different cell types, or are activated at different stages during the differentiation of a particular cell type. "Our idea was to compensate for the mutant gene's loss of function by specifically activating genes that have a similar function but are normally not expressed in retinal cells," says Becirovic. "To do so, we delivered a system called Cas9-VPR into the affected retinal cells." The Cas9-VPR system is a derivative of the CRISPR/Cas9 technology that is widely used for the targeted modification of genes. Akin to the classical CRISPR/Cas9 system, Cas9-VPR utilizes the same targeting principle to guide an activating protein to the particular gene of interest.

Becirovic and colleagues made use of a mouse model for retinitis pigmentosa to test the activation approach. These mice lack the light-sensitive rhodopsin protein that is normally expressed exclusively in the rod cells of the retina, which are required for dim light and night vision. The researchers delivered the Cas9-VPR system into the rod cells with the aid of a harmless virus. By introducing Cas9-VPR into the rods of the mice, the scientists switched on genes closely related to the rhodopsin gene, which are normally active in the cones responsible for color and daylight vision. "In this way, we were able to compensate for the lack of rhodopsin function in the rod cells, to attenuate the rate of retinal degeneration and improve retinal function without detectable side-effects," says Becirovic.

The authors believe that a similar strategy can be applied to a wide range of genes and genetic diseases, and offers a number of significant advantages over existing strategies. "Given the growing importance of gene therapy and its potential benefits for patients, we are convinced that our approach could soon be used in initial clinical feasibility studies," says Becirovic.

Sophia Antipolis, France - 1 Sept 2020: Restricting blood transfusion in anaemic heart attack patients to those with very low haemoglobin levels saves blood with no negative impact on clinical outcomes. That's the finding of the REALITY trial presented in a Hot Line session today at ESC Congress 2020.1

Anaemia affects approximately 5-10% of patients with myocardial infarction and is an independent predictor of cardiac events and increased mortality. The antiplatelet and anticoagulant medications used to treat myocardial infarction raise the risk of bleeding, which in turn elevates the risk of anaemia and mortality.

However, there is uncertainty over the benefits of blood transfusion in these patients. Observational studies have reported that transfusion is associated with a higher rate of mortality in patients with myocardial infarction.2 The optimal transfusion strategy in patients with acute myocardial infarction and anaemia is also unclear. Only two very small randomised trials have been conducted, with conflicting results.3,4

REALITY is the largest randomised trial comparing a restrictive versus a liberal blood transfusion strategy in myocardial infarction patients with anaemia. In the restrictive strategy, transfusion was withheld unless haemoglobin dropped to 8 g/dL. In the liberal strategy, transfusion was given as soon as haemoglobin was 10 g/dL or below. Previous trials have compared these two strategies in other settings such as gastrointestinal bleeding, cardiac surgery or non-cardiac surgery but patients with acute myocardial infarction were excluded.

There were two primary endpoints. The primary clinical endpoint was a composite of major adverse cardiac events (MACE) at 30 days, including all-cause death, myocardial infarction, stroke, and emergency percutaneous coronary intervention (PCI) prompted by myocardial ischaemia. The cost effectiveness endpoint was the incremental cost effectiveness ratio (ICER) at 30 days.

Principal investigator Professor Philippe Gabriel Steg of Hospital Bichat, Paris, France explained the reasons for having both a clinical and cost effectiveness outcome: "Our hypothesis was that in myocardial infarction patients with anaemia, a restrictive strategy would be non-inferior to a liberal strategy with respect to clinical outcomes at 30 days but would be less costly."

The trial was conducted in 35 hospitals in France and Spain. It enrolled 668 patients with acute myocardial infarction and anaemia (haemoglobin 10 g/dL or below, but above 7 g/dL) at any time during admission. Patients were randomly allocated to the restrictive or liberal transfusion strategy and followed-up for 30 days.

The restrictive transfusion strategy was non-inferior to the liberal strategy in preventing 30-day MACE. The primary clinical outcome occurred in 36 patients (11.0%) allocated to the restrictive strategy and 45 patients (14.0%) patients allocated to the liberal strategy (difference -3.0%; 95% confidence interval [CI] -8.4% to 2.4%). The relative risk of 30-day MACE with the restrictive versus liberal strategy was 0.79.

Cost effectiveness analysis indicated that the restrictive strategy had an 84% probability of being cost-saving while improving clinical outcomes, i.e. "dominant" from a medico-economic standpoint.

Regarding safety, compared to patients receiving the liberal strategy, those allocated to the restrictive strategy were significantly less likely to develop an infection (restrictive 0.0% vs. liberal 1.5%; p=0.03) or acute lung injury (restrictive 0.3% vs. liberal 2.2%; p=0.03).

Professor Steg said: "Blood is a precious resource, and transfusion is costly, logistically cumbersome, and has side effects. The REALITY trial supports the use of a restrictive strategy for blood transfusion in myocardial infarction patients with anaemia. The restrictive strategy saves blood, is safe, and is at least as effective in preventing 30-day cardiac events compared to a liberal strategy, while saving money."

The work group around Henriette Uhlenhaut, Professor for Metabolic Programming at TUM School of Life Sciences in Freising-Weihenstephan and researcher in the field of Molecular Endocrinology at Helmholtz Zentrum München is working with so-called glucocorticoids. These are steroidal hormones such as cortisone, which are released by the adrenal glands every day before waking up or whenever a person is subjected to stress. These steroids are bound to their glucocorticoid receptor and control not only our body's immune reaction but also our sugar and fat metabolism.

As glucocorticoid receptors are so efficient at disabling immune reactions, synthetic steroid medication is among the most prescribed drugs overall and it has been for decades.

The goal: Finding molecules with anti-inflammatory effects

"Unfortunately, this useful property leads to severe side effects as one hormone or drug causes different effects in other non-immune cells," explained the professor. Among these effects are the reduction of muscle mass or the deposition of fat.

"We still don't fully understand the effects of steroid compounds," said Uhlenhaut. With her team, she wants to discover the molecular mechanisms that steroids such as cortisone utilize to stop inflammatory reactions.

As soon as researchers know how cortisone works, so how it mutes inflammation genes in immune system cells, they can begin looking for molecules that possess the same anti-inflammatory properties as cortisone, but with fewer side effects.

Common theory refuted

Until recently, scientists believed that the steroids' anti-inflammatory effect was based on protein-to-protein interaction. It was assumed that the glucocorticoid receptor - in other words, the protein that binds these drugs or hormones - would connect to other inflammation inducing proteins without any DNA contact.

Using a new preclinical model, the team of researchers could now demonstrate that DNA binding is required for these drugs to have an effect; for years, scientists had assumed that this was not the case. Without the glucocorticoid receptor (the protein that binds these drugs or hormones) enabling DNA binding to chromosomes, chromatin or genes, there is no biological effect.

A milestone for drug development

"Now we know that DNA binding plays a major role, yet we have not found a way to separate side effects from the desired effects," explained Prof. Uhlenhaut. Regarding COVID-19, researchers do not have a clear answer either as to why these kinds of treatments are successful. Further research in this area is required.

Until now, various approaches focused on protein-to-protein contact, which might explain why these have not been successful. As this basic approach can now be discarded, further research regarding drug development of cortisone alternatives can now focus on the DNA.

When patients are discharged from Hospital those with diabetes are at an increased risk of readmission and mortality, there are guidelines for discharging patients with diabetes to reduce these risks, however researchers from the Institute of Digital Healthcare at WMG, University of Warwick and Warwick Medical School have identified known risk factors for mortality in adult patients discharged from hospital with diabetes.

In the paper, 'A Systematic Review Considering Risk factors for Mortality of Patients Discharged from Hospital with a Diagnosis of Diabetes', published in the Journal of Diabetes and its Complications, researchers identified 35 studies that considered the risk factors relating to mortality for patients discharged from hospital with diabetes, they analysed these studies and identified 48 significant risk factors for mortality.

The 48 risk factors are grouped into the following nine categories:

· Demographic

· Socioeconomic

· Lifestyle

· Patient medical factors

· Inpatient stay factors

· Medication related

· Laboratory results

· Glycaemic status

Professor Theo Arvanitis, from the Institute of Digital Healthcare at WMG, University of Warwick comments:

"The most common risk factor is in the demographic category of age and the second most important factor is co-morbidity burden; this comes under the patient medical factors category, and means patients have more than one condition. We also identified BMI as a significant risk within the patient medical factors category, with those who were at the heavier end of the scales to be more at risk.

"Thirty-Seven of the risk factors we identified from one research paper. This tell us that this research in general is still very early, and more studies are needed to identify the importance and possibly any other risk factors. This could decrease the mortality rate of diabetics discharged from hospitals in the future."

Drugs used to treat initial signs of rheumatoid arthritis also improve the early stages of heart disease, according to new research.

Having rheumatoid arthritis (RA) is known to at least double the chances of developing cardiovascular disease (CVD) - one of the main causes of death and disability in the UK - because of links to atherosclerosis (a build-up of plaque inside the arteries), heart failure and strokes.

A two-year study by the University of Leeds has for the first time linked treatment of RA with improvements in vascular stiffness - an indicator of CVD.

The findings could influence treatment of the UK's 400,000 RA sufferers - particularly those who have just developed the condition - and highlights the need to consider the increased risk factor of CVD for those patients.

The study, published in Annals of the Rheumatic Diseases, was jointly led by Sven Plein, Professor of Cardiology at Leeds' School of Medicine, and Maya Buch, Professor of Rheumatology, formerly at Leeds and now at the University of Manchester.

The team had set out to explore possible connections between the very earliest signs of RA and indicators of CVD.

At the start of the study, detailed MRI heart scans were given to 82 patients with no known heart issues.

The scans revealed the presence of increased vascular stiffness in the aorta, which is a gradual loss of elasticity in the large arteries, compared to healthy people.

There was also evidence of cardiac scarring and changes in the wall of the left ventricle (the heart's main pumping chamber), suggesting heart abnormalities had started before the RA diagnosis.

Professor Plein said: "Our research shows that even at the earliest stages of rheumatoid arthritis, there is increased vascular stiffness in people with no or minimal traditional CVD risk factors such as hypertension, high cholesterol or smoking."

After their initial scans, the 82 patients were given one of two RA drug courses. After a year of treatment, further scans were then carried out on 71 of the patients.

The scans revealed that the vascular stiffness of the aorta (the main artery) had improved during the RA therapy.

Professor Plein added: "The rheumatoid arthritis treatment improved vascular stiffness, regardless of how the patient responded to the RA medication.

"These improvements in vascular stiffness independently of response to RA treatment were unexpected.

"They imply that, in addition to suppressing inflammation, RA treatments may influence CVD risk through other means, possibly through changes to metabolic profile and direct effect on the processes of heart and vascular disease.

"Our research highlights the importance of commencing treatment of RA early in order to also lessen the risk of developing CVD."

Rheumatoid arthritis itself typically affects the hands, wrists and feet, causing swelling, stiffness and pain in joints.

Although incurable, early diagnosis and treatment with DMARDs (disease-modifying antirheumatic drugs) can effectively control the condition, which is more likely to occur in women, smokers and those with a family history of the illness.

The inflammation of RA is also considered to contribute to increased CVD risk, although disturbances in lipid and glucose metabolism may also play a role.

The new research, funded by NIHR EME (National Institute for Health Research Efficacy Mechanism Evaluation) was carried out with the rheumatology and cardiology departments of Leeds Teaching Hospitals NHS Trust.

Research joint lead Professor Maya Buch, said: "Identifying patients at the earliest stage of RA with most risk of CVD is important to inform management strategy.

"The benefits of RA treatment on CVD extend beyond traditional suppression of inflammation. Until further data are acquired, these data also suggest we should be cautious if considering a reduction in RA therapy (due to good joint control) for concern of risk of CVD progression.

"We now need to ensure the link between early RA and CVD morbidity remains a central area of research, and work towards tailoring therapies to address both RA joint disease and associated CVD."

Why so many COVID-19 patients get blood clots (thrombosis) remains uncertain. But scientists at Uppsala University and the University Hospital have now identified a mechanism they believe to be implicated. A particular protein triggers a part of our immune system that can boost the blood's tendency to coagulate and form clots. The study is now published in Thrombosis and Haemostasis.

Since thrombosis has proved to be a common complication in severe COVID-19, most people receiving hospital care for the disease get them.

In a new study, researchers at Uppsala University have found that a key mechanism of clot formation in COVID-19 may be activation of what is known as the complement system, which is part of the immune system we are born with. This can be initiated by certain proteins, one example being mannose-binding lectin (MBL).

Sixty-five patients receiving intensive care at Uppsala University Hospital had their MBL levels and activity measured. In all those who developed thrombosis during their hospital stay, MBL activity and levels were found to be elevated.

The scientists believe that when the complement system is activated by means of MBL, it contributes to a massive activation of the blood coagulation system as well. This change, seen in many COVID-19 patients, results in thrombosis. The study indicates that the complement system not only is included in our immune defences, but can also serve to boost the blood's clotting propensity.

"Our results are especially interesting since we think MBL activates blood coagulation in a way that blood-thinning drugs can't prevent. This might explain why so many patients suffer from clots in spite of treatment," says the study's lead author Oskar Eriksson, a doctor at the University Hospital and researcher at the Department of Immunology, Genetics and Pathology, Uppsala University.

The scientists think their results might eventually lead to testing of MBL activity in COVID-19 patients to identify those who are at high risk of getting thrombosis. MBL could also be a possible target in future development of drugs to prevent the condition.

SINGAPORE / DURHAM, NC, USA, 3 September 2020 - A new study published in The Lancet Public Health found that a series of public health interventions in Singapore cumulatively increased the likelihood of cardiopulmonary resuscitation (CPR) by bystanders during out-of-hospital cardiac arrests (OHCA) nearly eightfold and survival over threefold, underscoring the importance of such interventions to improve OHCA outcomes.

Sudden cardiac arrest is a serious healthcare concern all over the world. In the United States, over 350,000 cardiac arrests occur outside of a hospital annually, and about 90 per cent of the victims die, according to 2015 statistics cited by the American Heart Association. In Singapore, a 2015 study found that about 70 per cent of OHCA occurred at home and just over three per cent of casualties survived to hospital discharge.

For a victim of sudden cardiac arrest in an out-of-hospital setting, CPR (performed by pushing hard and fast on the centre of the chest) by a bystander could save their life. But in many communities around the world, the rate of bystander CPR is low, prompting some health authorities to initiate bystander-focused public health interventions at the community-level to improve this.

The study by researchers at Duke-NUS Medical School (Singapore), Duke University (Durham, NC, USA), Singapore Health Services (SingHealth), the Singapore Civil Defence Force (SCDF) and the Singapore Ministry of Health's Unit for Prehospital Emergency Care (UPEC) found that three national public health interventions in the city-state increased the rate of bystander CPR more than twofold. These measures included 1) dispatch-assisted CPR, 2) CPR and automated external defibrillator (AED) training, and 3) a first responder mobile application, known as myResponder, which alerts volunteer first responders trained in CPR to give life-saving assistance when they are in close proximity to someone experiencing cardiac arrest, before paramedics arrive on the scene.

"Our findings clearly showed that a bundled, national, bystander-focused public health intervention increased the chances of laypeople performing bystander CPR," said Assistant Professor Audrey L. Blewer, an epidemiologist and resuscitation scientist in the Department of Family Medicine and Community Health at Duke University School of Medicine - the study's lead and corresponding author. "While we were unable to examine the individual effect of the interventions, the study suggests the importance of bundling interventions, especially for the public, to improve outcomes for OHCA."

While previous studies have shown the independent impact of such interventions on bystander CPR, no study has examined the cumulative impact of each added bystander intervention on bystander CPR. In this research, which focused on a population cohort from Singapore, data were analysed from national bystander intervention programmes from 2011-2016. Analysis was done on 6,788 patients with a mean age of 67, among whom 68 per cent were male and 65 per cent were of Chinese ethnicity.

When the likelihood of bystander CPR was modelled, it was seen that, with each added intervention, the predicted probability of receiving bystander CPR increased. Moreover, when all three measures were adopted and bundled in a national bystander-focused public health intervention strategy, it increased the likelihood of layperson CPR over twofold.

In the nationally gathered datasets that were analysed in this research, it was seen that, in general, bystander CPR was administered in nearly half (48 per cent) of OHCA events. With the implementation of dispatch-assisted CPR, the likelihood of bystander CPR increased. Additional implementation of CPR and AED training further increased the likelihood of bystander CPR. Finally, the addition of the myResponder mobile application to the intervention strategies resulted in nearly eight times increased likelihood of bystander CPR compared to no intervention.

In this population, when all three measures were adopted, the likelihood of survival increased more than threefold, compared to no intervention. Variations were seen in the predicted bystander CPR probability and survival rate after adopting each of these measures for residential versus non-residential settings.

"Understanding the impact of public health interventions helps inform strategies to increase bystander CPR and targeted initiatives to improve survival from OHCA," said Prof Marcus Ong, senior author of the study, who is Director of the Health Services and Systems Research Programme at Duke-NUS Medical School, and Senior Consultant at the Department of Emergency Medicine in Singapore General Hospital. "Importantly, our findings show that the increased likelihood of bystander CPR resulting from the bundled interventions was associated with increased survival."

As next steps, the team will continue to work with the relevant partners to build on robust quality and assurance measures, and ensure adherence to the protocol and resuscitation process metrics. Additionally, Singapore's health authorities continue to optimise the dispatch-assisted CPR protocol to improve outcomes and survival from OHCA. Future work may consider taking aspects of the Singapore protocol and implementing it in other locations, such as across Asia and urban cities in the USA.

The Ministry of Education in Singapore requires that school-aged children are taught CPR in physical education classes. In addition to this requirement, Singapore offers free CPR and AED training to schools, community-based groups, and workplaces, which removes one of the known barriers to CPR training - specifically, cost and access to the course.

Prof Ong, who is also Director of SingHealth's Health Services Research Centre, and Medical Director of UPEC and Senior Consultant at the Ministry of Health, Hospital Services Division, added, "Over the last 10 years, we have been advocating for the immediate application of chest compressions and the use of an AED during an OHCA. Patients stand a much better chance - up to 50 per cent - of survival if those interventions are performed. Studies like this allow us to enhance our public health systems and save more lives in the process."

Data presented in a special COVID-19 session at the European and International Congress on Obesity (ECOICO 2020) suggests that there are overlaps between the immunological disturbances found in both COVID-19 disease and patients with obesity, which could explain the increased disease severity and mortality risk faced by patients with obesity and COVID-19. Since fat mass generally increases with ageing, this might also partly explain the increased death risk in older patients.

The presentation is by Associate Professor Gijs Goossens, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre, Netherlands. Further details are provided in a Position Paper by Goossens and colleagues published in the journal Obesity Facts, the official journal of the European Association for the Study of Obesity (EASO) that organises the congress.

Adipose tissue is an active metabolic organ with a role in many processes, including immunity and inflammation. In people with a healthy weight, adipose (fat) tissue functions normally. However, fat cells accumulate fat and become larger during weight gain, resulting in chronic low-grade inflammation in obesity that is associated with various complications, including type 2 diabetes, cardiovascular disease, respiratory diseases and some cancers. This inflammation causes a release of molecules called cytokines that trigger a response from the body's immune system.

The metabolic changes and sustained low-grade inflammation in people with obesity leave them with an impaired immune response to infections and increased viral loads when infected by viruses, resulting in poorer outcomes and recovery from infections. Studies have also shown people with obesity respond less well to antiviral medication and vaccinations.

In COVID-19, the attempts of the immune system to eliminate the virus produce a constant stream of these cytokines, which can lead to an effect known as the 'cytokine storm', which can cause organ damage (e.g. lung injury), leading to poor outcomes and death.

Various research around COVID-19 is focusing on the renin-angiotensin-aldosterone system (RAAS) in the body, since SARS-CoV-2 enters the host cells through the angiotensin-converting enzyme-2 (ACE-2), which is part of the RAAS system. The RAAS, among other things, increases blood pressure and inflammation. In obesity, the RAAS system is overactivated and may play a critical role in the increased susceptibility and worse clinical outcomes of COVID-19 in people with obesity.

In this presentation (and the linked Position Paper), Dr Goossens says: "We suggest that the increased fat mass may contribute to increased RAAS activity and inflammation in obesity, thereby providing a critical link between obesity and the increased COVID-19 susceptibility and poorer disease outcomes."

Furthermore, it is also well documented that increased age is a major determinant of severe disease and COVID-19-related mortality. Dr Goossens says: "Since ageing is accompanied by changes in body composition, namely reduced muscle mass and increased fat mass, it is tempting to postulate that this may at least partly contribute to the poorer outcomes in older individuals infected by SARS-CoV-2."

Along with the authors of the Position Paper, Dr Goossens says: "The collision of the obesity and COVID-19 pandemics highlights the importance of understanding shared disease pathophysiology, which may steer therapeutic choices to prevent or dampen the complications of COVID-19, especially in vulnerable populations such as people living with obesity and related chronic diseases."

He concludes: "Detailed analysis of patients with COVID-19 is essential to identify individuals or subgroups at increased risk of developing this disease, and better predict disease progression and outcomes. In particular, the potential role of (abdominal) adipose tissue in the development of COVID-19 warrants further investigation. Clearly, obesity prevention and continuous obesity management are crucial during the COVID-19 pandemic."

BOSTON - An experimental medication slows the progression of the neurodegenerative disease called Amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease, according to recently released results from a clinical trial run by investigators at the Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital (MGH) and Amylyx Pharmaceuticals, Inc., the company that manufactures the medication. The findings, reported in the New England Journal of Medicine, offer hope that a treatment may one day be available for patients with ALS, a fatal condition with no cure that attacks the nerve cells in the brain and the spinal cord to progressively hinder individuals' ability to move, speak, eat, and even breathe.

Called AMX0035, the oral medication is a combination of two drugs, sodium phenylbutyrate and taurursodiol, that each target a different cell component important for protecting against nerve cell death.

In the CENTAUR trial, 137 participants with ALS were randomized in a two-toone ratio to receive AMX0035 or placebo. Over six months, participants who were treated with AMX0035 had better functional outcomes than those treated with placebo as measured by the ALS Functional Rating Scale (ALSFRS-R), a questionnaire that evaluates several activities of daily living such as a patient's ability to walk, hold a pen or swallow food.

"The participants treated with AMX0035 demonstrated a significant slowing of ALS disease progression as measured by the ALSFRS-R. This is a milestone in our fight against ALS," said Sabrina Paganoni, MD, PhD, principal investigator of the CENTAUR study, investigator at the Healey & AMG Center for ALS at MGH, and assistant professor of PM&R at Harvard Medical School (HMS) and Spaulding Rehabilitation Hospital. Paganoni noted that the trial involved a partnership between industry, foundations such as the ALS Association and ALS Finding a Cure and academia, with input from world-renowned leaders in neurology and drug development.

Senior author Merit Cudkowicz, MD, director of the Healey & AMG Center for ALS at MGH, chief of Neurology at MGH, and the Julieanne Dorn Professor of Neurology at HMS, commented, "Amylyx took a novel approach to the problem of motor nerve cell dysfunction. With guidance from our team and in collaboration with our colleagues in the Northeast ALS Consortium (NEALS), Mass General Biostats and the Barrows Neurological Institute, the clinical trial moved forward quickly and carefully. We are proud of this important study. We are also very thankful to the participants and their families for their key role in advancing research."

In 2015, Amylyx co-founders and co-CEOs Joshua Cohen and Justin Klee were introduced to Cudkowicz through a colleague and shared their vision for AMX0035. The teams decided that MGH's expertise in designing and leading clinical trials and Amylyx's potential treatment would make for a great collaboration. Cudkowicz introduced them to Paganoni and to the science advisory committee for NEALS, a trial network Cudkowicz co-founded. Soon after, the CENTAUR Trial came to fruition and sites throughout the NEALS consortium began enrolling patients.

"Today's news builds upon the progress we have made in ALS research," said Cohen. "This experimental medicine has demonstrated that it can help patients retain their physical function, which is an incredible feat given the debilitating nature of this disease. It is our hope that AMX0035 will one day be available for patients and we are committed to making that a reality."

"Patients and their families do not have time to wait," said Klee. "People with ALS progressively lose their ability to function and care for themselves, so we want to do everything we can to help them slow down this devastating disease. We will be working with the FDA to determine next steps and the path for patients to gain access to AMX0035. We'll continue to share our plans with the community as they develop."

An Open Label Extension trial, in which all patients in the study have been offered AMX0035, is ongoing to assess the medication's long-term impact.

CLEVELAND, Ohio (August 31, 2020)--The North American Menopause Society (NAMS) announces publication of its 2020 Genitourinary Syndrome of Menopause (GSM) Position Statement. The new recommendations reflect the healthcare community's most recent and proven safe and effective therapies for treating women with GSM, including intravaginal dehydroepiandrosterone (DHEA), oral ospemifene, and a low-dose estradiol vaginal insert. The position statement is available online and will be published in the September issue of Menopause, the journal of NAMS.

Genitourinary syndrome of menopause affects approximately 27% to 84% of postmenopausal women and can significantly impair health, sexual function, and quality of life. Unfortunately, it remains underdiagnosed and undertreated, leaving many women to suffer silently. The most commonly reported symptoms include irritation of the vulva, inadequate vaginal lubrication, burning, dysuria, dyspareunia, and vaginal discharge.

In developing the new position statement, NAMS reviewed current data on a wide variety of proposed treatments to determine their efficacy and safety before making recommendations. According to the 2020 position statement, first-line therapies for less-severe symptoms include nonhormone vulvar and vaginal lubricants with sexual activity and long-acting vaginal moisturizers used regularly. Prescription therapies include low-dose vaginal estrogens, vaginal DHEA inserts, and oral ospemifene. For women with moderate to severe dyspareunia associated with GSM and with concurrent vasomotor symptoms, transdermal and oral hormone therapy are effective options.

The position statement additionally points out that long-term studies on the endometrial safety of vaginal estrogen, vaginal DHEA, and ospemifene are lacking. In addition, NAMS believes there are insufficient placebo-controlled trials of energy-based therapies, including laser, to draw conclusions on their efficacy and safety or to make treatment recommendations for those devices.

The new position statement can be found online at https://www.menopause.org/docs/default-source/default-document-library/2020-gsm-ps.pdf.

"Since our last position statement on this topic published in 2013, there have been important additions in terms of safe and effective therapeutic options for women with GSM," says Dr. Stephanie S. Faubion, NAMS Medical Director and member of the Editorial Panel of the Position Statement. "NAMS has reviewed existing data on these therapies as well as on emerging treatment modalities such as energy devices. What hasn't changed is that GSM remains underdiagnosed and undertreated and continues to be a significant quality-of-life issue for women. NAMS endorses educating about and screening for GSM in all perimenopausal and postmenopausal women."

For more information about menopause and healthy aging, visit http://www.menopause.org.

Founded in 1989, The North American Menopause Society (NAMS) is North America's leading nonprofit organization dedicated to promoting the health and quality of life of all women during midlife and beyond through an understanding of menopause and healthy aging. Its multidisciplinary membership of 2,000 leaders in the field--including clinical and basic science experts from medicine, nursing, sociology, psychology, nutrition, anthropology, epidemiology, pharmacy, and education--makes NAMS uniquely qualified to serve as the definitive resource for health professionals and the public for accurate, unbiased information about menopause and healthy aging. To learn more about NAMS, visit http://www.menopause.org.

Approximately 500 000 Norwegians suffer from chronic sleep disorders, also called insomnia. Researchers have long known that cognitive behavioural therapy for insomnia is the best documented treatment, but few people have access to such therapy.

A fully automated digital version of this treatment has proven effective for many patients and can reduce the use of sleeping pills.

"Our results show that it's possible to provide very effective and drug-free sleep treatment on a large scale. This can be done without meeting with health personnel," says clinical psychologist Håvard Kallestad.

Kallestad is a researcher at St. Olav's Hospital and at the Norwegian University of Science and Technology's (NTNU) Department of Mental Health. He is also one of the first authors of a newly published article in The Lancet Digital Health.

Digital sleep support can help people identify the underlying causes of their sleep issues. The treatment addresses problematic sleep patterns, various stressors and other factors that interfere with sleep. Patients keep a journal that can provide insight into their own situation.

The new study in The Lancet Digital Health is encouraging.

The treatment study included 1721 participants, who received either digital sleep therapy or good sleep advice and digital information about sleep problems. All were Norwegian adults over the age of 18 who had difficulty sleeping. The findings are quite clear.

Approximately six of ten participants (58 per cent) experienced substantial improvement from the digital sleep therapy. In the control group, which received good sleep advice and digital information, only around 20 per cent experienced a similar effect. The digital sleep treatment was thus about three times as effective.

Thirty-eight per cent of participants achieved normal sleep quality after undergoing the digital sleep therapy. Only eight per cent of the control group had similar results.

"We also found that the participants who received digital sleep treatment were able to reduce their use of sleeping pills more than participants who only received sleep advice," says Kallestad.

This form of psychological therapy for a significant public health problem could prove to be more accessible than sleep medication treatment.

Digital sleep therapy is fully automated, meaning that no appointment with a health care provider is needed for the treatment. The study interventions were also automated.

The sleep treatment takes about 6 to 8 weeks to complete.

Sophia Antipolis, France - 1 Sept 2020: An educational mailing for atrial fibrillation patients and their clinicians did not increase uptake of stroke prevention drugs, according to results of the IMPACT-AFib trial presented in a Hot Line session today at ESC Congress 2020.1

Patients with atrial fibrillation are at increased risk of stroke. Studies have shown that most of these strokes can be prevented with oral anticoagulation.2,3 However, oral anticoagulant medication is underused by patients with atrial fibrillation.

The IMPACT-AFib trial investigated whether education on stroke prevention in atrial fibrillation for patients and their healthcare providers could increase the use of oral anticoagulants.

The primary endpoint was the proportion of patients started on oral anticoagulation over the course of the 12-month trial.

The trial enrolled atrial fibrillation patients aged 30 years and older with a guideline-based indication for oral anticoagulation (defined as a CHA?DS?-VASc score of 2 or greater).4 Participants had not been prescribed an anticoagulant in the prior 12 months, and had not been admitted to hospital for bleeding in the prior six months.

Patients were randomly allocated to the educational intervention or usual care (control group). In the intervention group, patients and their healthcare providers received one mailing at the start of the trial.

A total of 47,333 patients were included in the analysis. The average age of participants was 78 years. At one year, the primary endpoint occurred in 2,328 patients (9.89%) in the intervention group and 2,330 patients (9.80%) in the control group. The adjusted odds ratio was 1.01 (95% confidence interval 0.95-1.07).

Study author Dr. Sean Pokorney of Duke University, Durham, US said: "Among a population with a guideline indication for oral anticoagulant[s] for stroke prevention with atrial fibrillation, there was no statistically significant difference in rates of oral anticoagulant initiation at one year with a single education intervention."

Dr. Pokorney said: "Numerically more patients initiated oral anticoagulants early after [the] mailing, raising the question of whether multiple mailings or further contact may have been beneficial."

Modafinil is used to treat conditions such as narcolepsy. Reports have associated the drug with an increased risk of malformation in babies born to mothers who had taken it while pregnant. Now, a large registry study involving over two million pregnant women in Sweden and Norway shows that there is no such association. The study, which is published in JAMA, was conducted by researchers at Sweden's Karolinska Institutet and the Norwegian Institute of Public Health.

"This study is based on twice as many pregnancies as earlier studies, and we find no increase in the risk of malformation in infants exposed to modafinil during pregnancy," says the study's lead author Carolyn Cesta, researcher at the Centre for Pharmacoepidemiology at Karolinska Institutet's Department of Medicine in Solna.

Modafinil is used to improve wakefulness in adults with narcolepsy, MS-related fatigue and, sometimes, ADHD.

Larger than earlier studies

Earlier studies from countries such as Denmark have reported an increased risk of malformation in infants that were possibly exposed to modafinil while at the fetal stage of development. However, these studies were conducted on smaller populations and modafinil use is uncommon during pregnancy.

To discover more about the potential risks of modafinil use during pregnancy, researchers at Karolinska Institutet in Sweden and the Norwegian Institute of Public Health have now conducted a much larger study using data from each country's health registries.

Two million women in Sweden and Norway

The study is based on almost two million pregnancies between 2005 and 2017 in Sweden and Norway, and compared women who took modafinil from 30 days before conception to the end of the first trimester with women who did not take the drug at all.

A total of 133 (0.007 per cent) of the infants had had in-utero exposure to modafinil, and of them three (2.6 per cent) were born with a major malformation, as compared with 2.1 per cent of the non-exposed infants. This represents a relative risk of 1.06, a difference that is not statistically significant.

The researchers therefore draw the conclusion that there is no increase in the risk of malformation for infants exposed to modafinil during early pregnancy compared with non-exposed infants.

"Our results show how important it is to combine data sources, ideally from several countries, when examining the impact on a fetus of a drug that relatively few people use," says Kari Furu, senior researcher at the Norwegian Institute of Public Health and the study's last author.

Yale researchers are completing a first-of-its-kind clinical trial to test the efficacy of an automated bilingual alcohol screening and intervention tool for use in emergency departments (EDs). The computerized tool, administered to English- and Spanish-speaking Latino patient volunteers, is designed to address health disparities in the treatment of alcohol use disorders.

Previous studies show that the Latino population is particularly at risk for dangerous drinking behaviors, including heavy daily drinking, binge drinking, alcohol dependency, impaired driving, and alcohol-related arrests. Emergency departments are uniquely positioned to address these concerns, said Dr. Federico Vaca, professor of emergency medicine and at the Yale Child Study Center.
"

It is our sincere hope that the findings of this large study will advance our understanding of how best to address the health disparities in alcohol use disorders, and the ED is an ideal setting as we know that some of the most vulnerable groups, when it comes to alcohol use, seek emergency care as a result of alcohol-related medical conditions."

The clinical trial, led by Vaca, recently concluded enrollment at a large, urban emergency department where Latinos make up 38% of city residents. Patients volunteering to be in the study were given a health quiz to identify those with high-risk drinking behaviors for inclusion in the trial. Using a bilingual online health tool called AB-CASI (automated bilingual computerized alcohol screening and brief intervention), participants were prompted to share information about their drinking, including quantity and frequency, reasons that would make them consider reducing their drinking or seeking specialized treatment services, any motor vehicle, legal, or employment-related events, and any treatment they may be receiving. Via interview, patients were assisted in finding healthier coping strategies and advised on treatment options. Follow up assessments were made by telephone at one, six, and twelve months.

To date, there have been almost no studies of this kind that have enrolled Spanish-speaking participants, and none that have used an automated bilingual computerized approach, which is more likely to compel participants to share sensitive information, the researchers said. This study is particularly unique not only because it uses bilingual health information technology in the ED, they noted, but because the brief intervention that is delivered is automated and tailored specifically for individual patients based on their responses to reflective questioning by AB-CASI.

In addition, noted Vaca: "We will have the opportunity to explore the unique differences within Latino subgroups, as we know that the U.S. Latino population is not homogenous and this has implications for treatment services."

Scientists have taken a significant step forward in the search to find effective new drug candidates for the treatment of motor neurone disease.

Researchers from the Universities of Liverpool (UK) and Nagoya (Japan) have shown that a Selenium-based drug-molecule called ebselen and a number of other novel compounds developed at Liverpool can change many of the toxic characteristics of a protein, superoxide dismutase (SOD1), which causes some cases of Amyotrophic lateral sclerosis (ALS), also known as motor neurone disease.

The study is published in the journal EBioMedicine.

ALS is a neurodegenerative disease which affects motor neurons and the neuronal links between our brain and our muscles. Over the course of the disease these nerve links die, and the patient becomes paralysed, with the majority dying within 2 to 5 years of diagnosis. Around 20% of the familial ALS cases arise from dominant mutations in the sod1 gene. Aggregation of mutant SOD1 protein in familial cases and of wild-type SOD1 in at least some sporadic ALS cases is one of the known causes of the disease. Riluzole, approved in 1995 and edaravone in 2017 remain the only drugs with limited therapeutic benefits.

Stabilisation of the original SOD structure is seen as a key strategy to avoid aggregation. The team have developed a number of ebselen-based compounds with improvements in SOD1 stabilisation and in vitro therapeutic effects with significantly better potency than edaravone. Structure-activity relationship of hits has been guided by high resolution structures of ligand-bound A4V SOD1, a mutant which causes the most severe disease. They were also able to show clear disease onset delay of ebselen in a transgenic ALS model mouse, holding encouraging promise for potential therapeutic compounds.

Professor Samar Hasnain, who led the international team of interdisciplinary experts said: "The fact that this new generation of organo-selenium compounds have better in vitro neuroprotective activity than edaravone holds a significance promise for the potential of this class of compounds as an alternative therapeutic agent for ALS treatment.

"The ability of these compounds to target cysteine 111 in SOD may have wider therapeutic applications targeting cysteines of enzymes involved in pathogenic and viral diseases including the main protease of SARS-Cov-2 (COVID-19)."

Professor Paul O'Neill, who lead the medicinal chemistry programme said: "Our medicinal chemistry approach, guided by protein-ligand crystallography studies, focused on the design of ebselen based analogues that have improved in vitro potency coupled with excellent predicted CNS exposure and improved solubility and metabolic stability characteristics. By employing this multi-parameter optimisation approach to drug design, the next key stage will be to screen our next generation compounds in appropriate disease models."

Professor Koji Yamanaka, a physician-neuroscientist at Nagoya University, said: "It is very encouraging that a number of these novel Selenium compounds exhibited better in vitro neuroprotection in mouse neuronal cells than edaravone. In vivo disease onset delay by ebselen has been demonstrated for the first time in ALS mouse model and further improvement can be expected from the new novel compounds in view of their improved in vitro protection. Choices are very limited for a current ALS therapy, therefore, we are excited to take a significant step forward for developing a new class of drug candidate for ALS."