Body

SILVER SPRING, Md.--New research shows that an intensive lifestyle intervention (ILI) aimed at weight loss lowered incidence of obesity-related cancers in adults with overweight or obesity and type 2 diabetes, according to a study published online in Obesity, the flagship journal of The Obesity Society. This study is the only randomized clinical trial that has examined long-term cancer outcomes in an ILI focused on weight loss.

Previous observational studies have shown obesity is associated with increased risk of some cancers, but there was no evidence from clinical trials to date that have evaluated whether ILI for weight loss can reduce the risk of cancer.

"Healthcare providers should be encouraged to provide such counseling or refer patients with obesity to intervention programs that help people manage their weight. Moreover, establishing an environment with easier access to healthy food and physical activities is the foundation of obesity and cancer prevention," said Hsin-Chieh "Jessica" Yeh, PhD, associate professor of medicine, epidemiology, and oncology and associate director, Welch Center for Prevention, Epidemiology, and Clinical Research at Johns Hopkins University in Baltimore, Md. Yeh is the corresponding author of the study.

Data from the Look AHEAD (Action for Health in Diabetes) trial were examined for this study. Researchers investigated whether participants randomized to the ILI designed for weight loss would have reduced overall cancer incidence, obesity-related cancer incidence, and cancer mortality as compared with the Diabetes Support and Education (DSE) comparison group.

For the analysis of cancer outcomes, 4,859 participants who had not reported a cancer diagnosis at baseline (except for nonmelanoma cancer) were included. Participants had to meet the following criteria: 45 to 76 years of age, body mass index greater than 25, glycated hemoglobin less than 11 percent, blood pressure readings less than 160/100 mm Hg, triglyceride levels less than 600 mg/dL and completion of a maximal graded exercise test. Participants were randomly assigned to an ILI or a DSE by a web-based data management system between August 22, 2001 and April 30, 2004 at Wake Forest School of Medicine in Winston-Salem, NC.

The ILI was designed to achieve and maintain weight loss of at least 7 percent by facilitating reduced caloric intake and increased physical activity. Specific intervention strategies included a calorie goal of 1,200 to 1,800 kcal/d, the use of meal replacement products and at least 175 minutes of moderate-intensity physical activity per week. For the DSE comparison group, diabetes support and education was provided through three group sessions per year on diet, exercise and social support during years one through four. In subsequent years, the frequency was reduced to one session annually.

After an average follow-up of 11 years, 684 participants (332 in ILI and 352 in DSE) were diagnosed with cancer. The incidence rates of obesity-related cancers were 6.1 and 7.3 per 1,000 person-years in ILI and DSE, respectively, with a hazard ratio (HR) of 0.84 (95 percent confidence interval (CI), 0.68 to 1.04). No significant difference existed between the two groups in total cancer incidence (HR 0.93, 95 percent CI, 0.80 to 1.08), incidence of non-obesity related cancers (HR 1.02, 95 percent CI 0.83 to 1.27) or total cancer mortality (HR, 0.92, 95 percent CI 0.68 to 1.25).

Researchers found an ILI aimed at weight loss lowered incidence of obesity-related cancers by 16 percent in adults with overweight or obesity and type 2 diabetes. Researchers noted the sample size likely lacked power to determine effect sizes of this magnitude and smaller.

"While underpowered to detect significant differences, this analysis of Look AHEAD data is an important contribution, as it is one of the first studies to provide empirical data to suggest that a weight loss-focused lifestyle intervention can help to lower risk of obesity-related cancers," said Tiffany L. Carson, PhD, MPH, assistant professor, Division of Preventive Medicine, Department of Medicine, University of Alabama at Birmingham. Carson was not associated with the research.

Carson added "in addition to having adequate sample sizes to test for effects which will likely require pooled data, future studies should also explore the magnitude of weight loss that is needed to lower risk for obesity-associated cancers."

DALLAS, Aug. 24, 2020 -- None of the 41 most common high blood pressure medications increased the risk of depression, while nine medications appeared to lower it, according to a study from Denmark, published today in Hypertension, an American Heart Association journal.

Depression is common among patients with high blood pressure (also called hypertension), heart disease and stroke, and this is the first study to systematically investigate whether individual blood pressure medications might influence the risk of developing depression.

"It was highly surprising that none of the 41 most-used anti-hypertensives was associated with increased risk of developing depression and that some within each of the three classes of anti-hypertensives showed protective effects against depression," said Lars Vedel Kessing, M.D., D.M.Sc., lead author of the study and professor of psychiatry at the Psychiatric Center Copenhagen and the University of Copenhagen, Faculty of Health and Medical Sciences in Denmark.

Researchers analyzed real-life data on more than 3.7 million adults who took any of the 41 most-commonly prescribed high blood pressure medications, as reported in health records across several Danish health registries from 2005 to 2015. Thirty-seven of these medications are approved for use in the U.S. by the U.S. Food and Drug Administration. Patients who had been diagnosed with depression or previously prescribed antidepressants were excluded.

The four main categories of blood pressure-lowering medications were reviewed: angiotensin agents (angiotensin converting enzyme inhibitors, ACE inhibitors and angiotensin II receptor blockers, or ARBs); calcium antagonists; beta-blockers; and diuretics.

The analysis found:

None of the 41 most common high blood pressure medications increased the risk of depression.

Nine medications - a few within each category - significantly lowered depression risk: 2 of 16 angiotensin agents, 3 of 10 calcium antagonists and 4 of 15 beta-blockers.

Diuretic medications showed no impact on depression risk.

The nine individual high blood pressure medications found to significantly lower depression risk are enalapril and ramipril (angiotensin agents); amlodipine, verapamil and verapamil combinations (calcium antagonists); and propranolol, atenolol, bisoprolol and carvedilol (beta-blockers). All nine are approved for prescribing in the U.S.

"It is possible that the mechanism involved in decreasing the risk of depression is the anti-inflammatory effect among these nine medications," Kessing continued. "In the future, it will be important to compare the inflammatory properties of these nine hypertensives that lowered depression risk." (Low-grade inflammation is common in high blood pressure and heart disease, as well as in depression.)

"Our study's findings could help guide prescriptions for patients with high blood pressure who are at risk of developing depression, those with prior depression or anxiety, and patients with a family history of depression," said Kessing. "However, if a patient is doing well with their current blood pressure prescription, there is no reason to switch. If depression develops, a medication switch may be considered to one of the nine anti-hypertensive medications that lowered depression risk."

The findings of this study are likely generalizable to other populations. However, limitations of the study include it relied on a clinical diagnosis of depression, that it was not a controlled clinical trial that randomly selected which medication patients receive, and that the impact on depression risk was analyzed for each high blood pressure medication individually; they were not tested side by side or as combinations of one or more other antihypertensive medications.

Sophia Antipolis, France - 24 Aug 2020: Deep chest compressions can crack ribs, but they reduce brain damage during cardiac arrest, reports a study presented today at ESC Congress 2020.1

Study author Dr. Irene Marco Clement of University Hospital La Paz, Madrid, Spain said: "Deep chest compressions improve blood flow to the brain, improving survival and brain function."

CPR guidelines are updated every five years and are used to train health professionals and members of the public. The 2010 recommendation for deeper chest compressions generated concerns over the possibility of increasing CPR-related injuries.

This study examined the impact of this advice on neurological outcomes in survivors of cardiac arrest. It also assessed the rate of CPR-related injuries and their association with prognosis.

The study limited participation to comatose survivors of cardiac arrest, since they would have received prolonged resuscitation. In contrast, survivors who regain consciousness have generally received an immediate electric shock and brief chest compressions to restore circulation. "We wanted to analyse the effect of deep chest compressions during prolonged resuscitation, when they could make a real difference to outcomes," said Dr. Marco Clement.

In 2006 to 2020, the study enrolled consecutive patients admitted to an acute cardiac care unit after a cardiac arrest in hospital or in the community. Patients were divided into three groups corresponding to updates of the CPR guidelines: 2006-2010, 2011-2015, and 2016-2020.

The study included 510 patients who survived cardiac arrest and were admitted to hospital while unconscious. The average age was 63 years and 81% were men. CPR by lay bystanders and the use of automated external defibrillators (AEDs) progressively increased over the study period.

After 2010, there was a higher proportion of CPR-related injuries: 12.7% in 2006-2010, 23.5% in 2011-2015, 22.7% in 2016-2020 (p=0.02). Just over half of patients survived and were discharged from the hospital (51.6%). Brain performance at three months significantly increased over the course of the study (i.e. it was highest in the 2016-2020 group).2

Patients with CPR-related injuries were more likely to have better brain performance. Nearly two-thirds (65.1%) of patients with injuries had high brain function compared to 43.2% without injuries (p

"Survival and neurological outcome improved significantly during the 14-year study," said Dr. Marco Clement. "Members of the public increasingly came to the rescue with CPR and there was greater use of AEDs. Injuries from CPR rose, but these patients were less likely to have brain damage."

She noted that lay people have been reluctant to do CPR during the COVID-19 pandemic due to fear of infection. She said: "Personal safety always comes first, and resuscitators should only do what they feel comfortable with. If you are concerned about possible contagion, you could omit mouth-to-mouth breaths: chest compressions alone may be as effective as conventional CPR."

How to improve survival and prevent brain damage from cardiac arrest

* Ask a bystander to call emergency services and find an AED.

* Start deep chest compressions immediately.

* Do not delay CPR by trying to find a pulse.

Philadelphia, August 24, 2020--Despite intensive treatment, high-risk solid tumors like neuroblastoma, Ewing sarcoma, and rhabdomyosarcoma are challenging to cure because the disease in those high-risk patients does not respond to therapy. Conventional chemotherapy given by vein or by mouth delivers only a small amount of the drugs to the tumor, which not only renders the treatment ineffective but also leads to drug resistance and severe side effects, including diarrhea, bone marrow suppression and secondary malignancies.

Now, in a breakthrough study, researchers at Children's Hospital of Philadelphia (CHOP) have shown that an enhanced treatment developed in their lab leads to long-term remissions in 80% to 100% of mice with drug-resistant or high-risk solid tumors. The research, which could soon lead to clinical trials, was described today in Cancer Research, a journal of the American Association for Cancer Research.

"The results of our studies show that the cancer therapeutic we developed is highly effective in treating at least three different types of high-risk pediatric solid tumors with intrinsic or acquired drug resistance," said Garrett M. Brodeur, MD, Director of the Cancer Predisposition Program at CHOP and co-senior author of the study, along with Michael Chorny, PhD, and Ivan Alferiev, PhD. "Given that this treatment is also likely to be much less toxic than most cancer therapies for these types of tumors, in addition to showing remarkable therapeutic effects against aggressive disease, we think these results warrant further exploration of the agent in clinical trials."

Building a Better (Pro)Drug

The agent developed by the researchers is a prodrug, a medication that is inert until it is converted by the body into a pharmacologically active drug. The active drug in this study belongs to a family of camptothecins, compounds known to promote cell death and destroy tumors. Other camptothecins, in particular irinotecan and topotecan, have been used to treat solid tumors, but they are often ineffective against high-risk disease because the tumors are either initially resistant to the drug or develop resistance over time. Irinotecan itself is also a prodrug whose active agent, SN38, shows limited efficacy because it rapidly gets inactivated and removed from the body, so only a small fraction of it reaches the tumor. At the same time, irinotecan still manages to cause serious side effects, including bone marrow suppression and intractable diarrhea.

To overcome the issues of poor efficacy and high toxicity, the researchers engineered a prodrug that links four residues of a pharmacologically enhanced drug, SN22, through a breakable bond to a four-arm polyethylene glycol scaffold. By attaching the SN22 components in this way, the research team was able to extend the drug's circulation time, which in turn allowed 50 to 100 times as much drug to be taken up by the tumor.

Due to its modified structure, SN22 is also protected from enzymes that could inactivate it, as they do other camptothecins, and from cell transporters that could pump the drug out of tumor cells. Together, all of these modifications helped more drug accumulate in the tumor, where it stayed in the cells without being exported, so the high drug levels in the tumor tissue were sustained for hours and days.

The researchers tested their prodrug in several mouse models of disease, including neuroblastoma with both intrinsic and acquired drug resistance, a chemo-resistant Ewing sarcoma, and a fusion-positive rhabdomyosarcoma. Prodrug delivery of SN22 resulted in complete tumor disappearance in all models, and these complete remissions lasted for more than 6 months in 80 to 100% of cases, whereas treatment with irinotecan had little or no effect.

Better Safety Profile

In addition to being highly effective against drug-resistant tumors, the engineered prodrug also had less toxicity than irinotecan. Whereas irinotecan led to elevated liver enzymes and altered blood counts, the SN22 prodrug did not, nor did it lead to any other adverse effects. SN22 delivery in the prodrug form also reduced the exposure of healthy organs to the active drug, and the increased potency of SN22 in comparison to irinotecan meant that the researchers could use less total drug to shrink the tumors - a low and slow approach that exposes tissues to a low level of drug over long period of time.

"Taken together, the superior efficacy and improved biocompatibility of our prodrug, which we demonstrated in several clinically relevant models of high-risk cancer, make it a highly promising new therapeutic capable of addressing the considerable limitations of current treatments," said Chorny. "Our strategy is readily scalable, and we look forward to assessing its effectiveness and safety in patients."

Nonprescribed fentanyl and stimulants were the primary contributors to overdose mortality, while few people had prescribed opioids in their systems, according to new toxicology research in CMAJ (Canadian Medical Association Journal).

"With health professional organizations introducing guidelines to reduce prescribing of opioids and other controlled substances, understanding the relative contribution of prescribed substances and illicitly obtained substances to overdose deaths is key to developing effective programs to reduce overdose mortality," writes Dr. Alexis Crabtree, BC Centre for Disease Control and the University of British Columbia, with coauthors.

The postmortem study looked at deaths from drug overdoses identified by the BC Coroners Service between 2015 and 2017 with 1 or more illicit drugs. The deaths were linked to the person's prescription medication history in British Columbia's PharmaNet database. Of the total 2872 deaths, toxicology results were available for 1789 deaths, in which the majority (85.5%) had 1 or more opioids present. However, only 8.7% of individuals had taken prescribed opioids, and methadone and buprenorphine, used in opioid agonist therapy, were rarely detected in postmortem toxicology.

Of the deaths linked to nonprescribed opioids, fentanyl or fentanyl analogues were found in 79% of cases. Stimulants were found in 71% of deaths, almost all nonprescribed. Of the deaths in which benzodiazepines were detected, 63% had not been prescribed.

Death rates from illicit drugs increased more than fourfold between 2014 and 2018, which has been attributed to the contamination of the illicit drug supply. Over the past 5 years, British Columbia has had the highest rates of deaths from illicit drug use in Canada.

"[P]rescribing policies are insufficient to address the current overdose crisis in Canada and additional strategies are needed," write the authors. "Physicians should be encouraged to practise patient-centred opioid prescribing."

They suggest removing barriers to medically supervised opioid agonist therapy to provide a safer alternative to illegal drugs and supporting harm reduction organizations to provide care to people using nonprescribed medications.

In a related commentary, Dr. Mark Tyndall, School of Population and Public Health, University of British Columbia, Vancouver, BC, writes, "In the last 5 years, the major responses to the overdose crisis have been to reverse overdoses through harm reduction programs, build a better addiction care system, and create better housing and social services. Although these may be important actions and aspirations in the long term, they will not address the current emergency. Unless there is a radical change in our approach to the epidemic, overdose deaths will continue unabated. It is time to scale up safe supply and decriminalize drug use."

"Toxicology and prescribed medication histories among people experiencing fatal illicit drug overdose in British Columbia, Canada" is published August 24, 2020.

Philadelphia, August 24, 2020 - Autism is a neurodevelopmental condition that researchers are now tracing back to prenatal development, even though the disorder is not diagnosed until at least 18 months of age. A new study now shows in human brain cells that the atypical development starts at the very earliest stages of brain organization, at the level of individual brain cells.

The study from scientists at King's College London and Cambridge University, UK appears in Biological Psychiatry, published by Elsevier.

Deepak Srivastava, PhD, from the MRC Centre for Neurodevelopmental Disorders and Department of Basic and Clinical Neuroscience at King's College London, who supervised the study, said: "In this study we used induced pluripotent stem cells, or iPSCs, to model early brain development. Our findings indicate that brain cells from autistic people develop differently to those from typical individuals."

The researchers isolated hair samples from nine autistic people and six typical people. By treating the cells with an array of growth factors, the scientists were able to drive the hair cells to become nerve cells, or neurons--much like those found in either the cortex or the midbrain region. iPSCs retain the genetic identity of the person from which they came and the cells re-start their development as it would have happened in the womb, providing a window into that person's brain development.

Dwaipayan Adhya, PhD, a molecular biologist at the Autism Research Centre in Cambridge and Department of Basic and Clinical Neuroscience at King's College London, said: "Using iPSCs from hair samples is the most ethical way to study early brain development in autistic people. It bypasses the need for animal research, it is non-invasive and it simply requires a single hair or skin sample from a person."

At various stages, the authors examined the developing cells' appearance and sequenced their RNA, to see which genes the cells were expressing.

At day 9, developing neurons from typical people formed "neural rosettes," an intricate, dandelion-like shape indicative of typically developing neurons. Cells from autistic people formed smaller rosettes or did not form rosettes at all. And key developmental genes were expressed at lower levels in cells from autistic people.

At days 21 and 35, the cells from typical and autistic people differed significantly in a number of ways, suggesting that the makeup of neurons in the cortex differs in the autistic and typically developing brain.

John Krystal, PhD, Editor-in-Chief of Biological Psychiatry, said of the findings: "The emergence of differences associated with autism in these nerve cells shows that these differences arise very early in life."

In contrast to the differences seen in cortical neurons, cells directed to develop as midbrain neurons - a brain region not implicated in autism dysfunction - showed only negligible differences between typical and autistic people.

"The use of iPSCs allows us to examine more precisely the differences in cell fates and gene pathways that occur in neural cells from autistic and typical individuals. These findings will hopefully contribute to our understanding of why there is such diversity in brain development," said Dr. Srivastava.

Simon Baron-Cohen, PhD, Director of the Autism Research Centre at Cambridge, who co-led the study, added, "Some people may be worried that basic research into differences in the autistic and typical brain prenatally may be intended to 'prevent,' 'eradicate,' or 'cure' autism. This is not our motivation, and we are outspoken in our values in standing up against eugenics and in valuing neurodiversity. Such studies will lead to a better understanding of brain development in both autistic and typical individuals."

"The brain has been the ultimate black box. Here, the authors have used nerve cells derived from peripheral stem cells to peek inside this box. This important study suggests that this is possible and is deepening our understanding of autism," Dr. Krystal added.

The mass media's coverage of the pandemic health crisis carries an important responsibility to offer balanced messaging about COVID-19 and public behaviour, Flinders University public health researchers says.

While freely available, trustworthy news is vital - in particular when conveying personal risk and government mandated guidelines - the Flinders University research warns of less favourable issues such as inciting panic or causing stigmatisation in the community by laying blame on certain groups or organisations.

"How the media portray health crises is an important influence not only on public behaviour but also on the long-term repercussions for health," according to the new paper in Frontiers in Public Health.

The study, which focuses on national Australian newspaper coverage from early 2020 and after the WHO declaration of 'pandemic' on 11 March 2020, notes a range of themes such as moral evaluations of pandemic-related issues and behaviours - ranging from its origins in Wuhan province in China, disruption to business and community to opportunistic price gouging and cruise ship evacuations.

The initial coverage in these leading news sources was objective and generally authoritative, says lead author Trevor Thomas.

"Our study found the frequency and tone of COVID-19 articles published in The Australian and Sydney Morning Herald escalated in line with the rise in health, societal and economic disruptions," says postgraduate Mr Thomas.

"By and large, the broadsheets were fairly objective during the early stages and didn't seem to explicitly apportion blame to any one group or politician, although this was before handling of the Ruby Princess cruise ship in NSW, the 'second wave' in Victoria, criticism of Premier Daniel Andrews, and Morrison Government's inquiry into the WHO and China's pandemic approach."

With epidemics such as COVID-19 likely to become more frequent and possibly more harmful due to globalisation and increase in human-animal contact, he says the media's role should be scrutinised in the latest pandemic conditions.

Flinders University Professor Paul Ward says the press coverage studied had generally taken seriously the public's need to know, and as gatekeepers of public information had sought out experts including government, scientists and public health experts.

"They're widely seen and trusted by the community and media gets to decide what is and isn't highlighted," says Professor Ward.

"In their arsenal of public health measures they can mediate behaviour to point fingers and create a sense that it's a foreign thing, or a politician or government's fault, and this can be motivated from a need to keep the story going.

"But this can be harmful to rational, sensible debate which keeps a sound perspective on the situation and the need for a united front to overcome this pandemic."

What The Study Did: COVID-19 among incarcerated individuals and staff in Massachusetts jails and prisons is described in this observational study, which assesses the association of COVID-19 case rates with decarceration and testing rates.

Authors: Monik C. Jiménez, Sc.D., S.M., F.A.H.A., of Brigham and Women's Hospital and Harvard Medical School in Boston, is the corresponding author.

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

(doi:10.1001/jamanetworkopen.2020.18851)

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

#  #  #

Media advisory: The full study is linked to this news release.

Embed this link to provide your readers free access to the full-text article This link will be live at the embargo time http://jamanetwork.com/journals/jamanetworkopen/fullarticle/10.1001/jamanetworkopen.2020.18851?utm_source=For_The_Media&utm_medium=referral&utm_campaign=ftm_links&utm_term=082120

About JAMA Network Open: JAMA Network Open is the new online-only open access general medical journal from the JAMA Network. On weekdays, the journal publishes peer-reviewed clinical research and commentary in more than 40 medical and health subject areas. Every article is free online from the day of publication.

What The Study Did: This open-label randomized trial compares the effect of remdesivir (5 or 10 days) compared with standard care on clinical status 11 days after treatment initiation among patients with confirmed SARS-CoV-2 infection hospitalized with moderate pneumonia.

Authors: Diana M. Brainard, M.D., of Gilead Sciences in Foster City, California, is the corresponding author.

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

(doi:10.1001/jama.2020.16349)

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

Physicists at the University of Göttingen, together with pathologists and lung specialists at the Medical University of Hannover, have developed a three-dimensional imaging technique that enables high resolution and three-dimensional representation of damaged lung tissue following severe Covid-19. Using a special X-ray microscopy technique, they were able to image changes caused by the coronavirus in the structure of alveoli (the tiny air sacs in the lung) and the vasculature. The results of the study were published in the research journal eLife.

In severe Covid-19 disease, the researchers observed significant changes in the vasculature, inflammation, blood clots and "hyaline membranes", which are composed of proteins and dead cells deposited on the alveolar walls, which make gas exchange difficult or impossible. With their new imaging approach, these changes can be visualized for the first time in larger tissue volumes, without cutting and staining or damaging the tissue as in conventional histology. It is particularly well suited for tracing small blood vessels and their branches in three dimensions, localizing cells of the immune systems which are recruited to the inflammation sites, and measuring the thickness of the alveolar walls. Due to the three-dimensional reconstruction, the data could also be used to simulate gas exchange.

"Using zoom tomography, large areas of lung tissue embedded in wax can be scanned enabling detailed examination to locate particularly interesting areas around inflammation, blood vessels or bronchial tubes," says lead author Professor Tim Salditt from the Institute of X-ray Physics at the University of Göttingen. Since X-rays penetrate deep into tissue, this enables scientists to understand the relation between the microscopic tissue structure and the larger functional architecture of an organ. This is important, for example, to visualize the tree of blood vessels down to the smallest capillaries.

The authors foresee that this new X-ray technique will be an extension to traditional histology and histopathology, areas of study which go back to the 19th century when optical microscopes had just become available and pathologists could thereby unravel the microscopic origins of many diseases. Even today, pathologists still follow the same basic steps to prepare and investigate tissue: chemical fixation, slicing, staining and microscopy. This traditional approach, however, is not sufficient if three-dimensional images are required or if large volumes have to be screened, digitalized or analysed with computer programmes.

Three-dimensional imaging is well known from medical computerized tomography (CT). However, the resolution and contrast of this conventional technique are not sufficient to detect the tissue structure with cellular or sub-cellular resolution. Therefore, the authors used "phase contrast", which exploits the different propagation velocities of X-rays in tissue to generate an intensity pattern on the detector. Salditt and his research group at the Institute for X-ray Physics developed special illumination optics and algorithms to reconstruct sharp images from these patterns, an approach which they have now adapted for the study of lung tissue affected by severe progression of Covid-19. The Göttingen team could record lung tissue at scalable size and resolution, yielding both larger overviews and close-up reconstructions. Depending on the setting, their method can even yield structural details below the resolution of conventional light microscopy. To achieve this, the researchers used highly powerful X-ray radiation generated at the PETRAIII storage ring of the German Electron Synchrotron (DESY) in Hamburg.

As was the case when the modern microscope was invented 150 years ago, significant progress has resulted from collaboration between physicists and medical researchers. The interdisciplinary research team hopes that the new method will support the development of treatment methods, medicines to prevent or alleviate severe lung damage in Covid-19, or to promote regeneration and recovery. "It is only when we can clearly see and understand what is really going on, that we can develop targeted interventions and drugs," adds Danny Jonigk (Medical University Hannover), who led the medical part of the interdisciplinary study.

After the first fragility fracture, there is a high risk of subsequent fractures, with the risk highest in the following two years. Despite the enormous human and cost burden of secondary fractures, bone health experts warn that too little is being done to systematically identify and treat high risk patients who are in danger of sustaining such fractures, including highly debilitating and life-threatening hip fractures.

As in previous years, secondary fracture prevention, and specifically topics related to Post-fracture Care Coordination Program (such as Fracture Liaison Service - FLS) development, are a focus of several live and pre-recorded presentations at the virtual World Congress on Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (WCO-IOF-ESCEO 2020 from August 20-22, 2020. The Congress is the largest event in the field, organized annually by the International Osteoporosis Foundation (IOF) and the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO).

IOF President and Congress Co-Chair, Professor Cyrus Cooper, noted:

"Implementation of effective post-fracture care coordination programmes worldwide is a key focus of the global healthcare community's efforts to reduce secondary osteoporosis-related fractures, frailty and mortality in older patients. It is therefore heartening to see that this is a key topic addressed at the World Congress."

Among the research presented is an abstract (OCS8) and oral presentation by R. Pineda-Villanueva (University of Oxford, NDORMS) which introduces a novel FLS benefits and budget impact calculator [1]. The interactive tool models the expected clinical and healthcare resource use and cost savings impact of Post-Fracture Care services such as FLS and is expected to support decision-making at national and local levels. The model is currently undergoing input parameter population and calibration for Spain and Japan, and is expected to be operational for 16 countries by 2022.

A Canadian study (OC36) presented by J. Delisle (CIUSSS Nord de L'Ile de Montreal, Montreal, Canada) assesses the success of the Lucky BoneTM FLS in the management of hip fractures based on initiation/continuation of anti-osteoporosis treatment (Osteoporosis Canada Guidelines). The study finds that the combined treatment initiation or continuation rate of the hip fracture patients in the studied FLS was 71.4%. In contrast, most FLS identifying hip fractures report an approximate 46% treatment initiation rate. It also finds that the ca. 30% of patients that were not initiated on treatment were the most at-risk for a subsequent fracture.

The drive to implement systems of secondary fracture prevention is addressed from a policy perspective in a non-sponsored symposium 'Winning the political case for change - launch of a policy toolkit for osteoporosis and fragility fractures' [3]. A further symposium 'Nationwide identification of vertebral fragility fractures: Collaborating with Radiology' pointed to the need for collaboration to improve patient outcomes, and the benefits of and future directions in the identification of vertebral fractures within post-fracture care coordination programs such as FLS [4].

In June 2020 the IOF launched its Capture the Fracture (CTF) Partnership which aims to support wider implementation of post-fracture care coordination services with the goal of reducing the incidence of hip and vertebral fractures by 25% by the year 2025. Mentorship to develop new, and improve existing, services is a key pillar of the CTF Partnership. The new 'Train the Trainer' programme of the CTF Partnership Mentorship pillar is presented in the session 'CTF Getting to Gold Framework' chaired by Prof. Kassim Javaid (CTF Steering Committee Co-chair, University of Oxford).[5]

As well, Dr Radmila Matijevic (Faculty of Medicine, University of Novi Sad, Serbia) is hosting a Meet-the-Expert Session on the efficacy and cost/benefit of FLS, services which ensure that all patients aged 50 years or over, who present to urgent care services with a fragility fracture, undergo fracture risk assessment and receive treatment in accordance with prevailing national clinical guidelines for osteoporosis.[6]

"Approximately 80% of individuals who have sustained a fracture related to osteoporosis do not receive the follow-up post-fracture care they need to decrease the risk of subsequent fractures," added Professor Cooper.

"As reflected in the WCO-IOF-ESCEO 2020 scientific programme, evidence shows that post-fracture care coordination programmes can dramatically improve osteoporosis treatment rates for fragility fracture patients and reduce secondary fractures and associated costs. It is essential that bone health experts continue to shine a spotlight on this critical topic, working in collaboration to advance policy change and encourage widespread implementation worldwide. "

Download abstracts here:
https://virtual.wco-iof-esceo.org/sites/wco20/pdf/WCO20-AbstractBook.pdf

References:

[1] Abstract OCs8: An interactive benefits and budget impact calculator to estimate potential effects of fracture liaison services. R. Pinedo-Villanueva, A. Sami, S. Kolovos, E. Burn, M. Fujita, P. Halbout, C. Cooper, M. K. Javaid

[2] Abstract OC36: Treatment initiation rate post hip fracture as a key indicator in an orthopaedic fracture liaison service. J. Delisle, B. Benoit, G. Y. Laflamme, S. Leduc, H. Ngyuen, P. Ranger, J. Fernandes

[3] Abstracts NSS21-NSS23: Non-sponsored symposium 'Winning the political case for change - launch of a policy toolkit for osteoporosis and fragility fractures'

[4] Abstracts NSS17-NSS20: Non-Sponsored Symposium 'Nationwide identification of vertebral fragility fractures: Collaborating with Radiology'

[5] Abstracts NSS38-41: Non-sponsored Symposium 'CTF Getting to Gold Framework'

[6] Abstract MTE12: Efficacy and cost/benefit of FLS. R. Matijevic, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia

Publication: Journal of General Internal Medicine

Authors: Girish Nadkarni, MD, Co-Chair; Anuradha Lala, MD, Member; Benjamin Glicksberg, PhD, Member; and other coauthors of the Mount Sinai COVID Informatics Center at the Icahn School of Medicine at Mount Sinai.

Bottom Line: This study describes characteristics of patients with COVID-19 who returned to the ER or required readmission to the hospital within 14 days of being discharged. Understanding what conditions impact these patient outcomes can help improve care during the hospital stay and after discharge.

Researchers found the most common cause for a patient's early hospital readmission after discharge was for respiratory distress. These patients were also more likely to have other ailments including chronic obstructive pulmonary disease and hypertension.

Results: Of the nearly 2,900 discharged patients, more than 100 (3.6%) returned for emergency care after about 4.5 days; 56 of those returning patients required readmittance into the hospital. Half the patients returned for respiratory complications. Compared to patients who did not return, those returning had higher rates of chronic obstructive pulmonary disease and hypertension.

Patients who returned also had a shorter length hospital stay during treatment, lower rates of anticoagulation treatment, and were less likely to require intensive care. Age, sex, and race/ethnicity were no different among readmitted patients compared to those who did not return.

Why the Research Is Interesting: The findings provide insight that can potentially lead to improved care for patients hospitalized with COVID-19 to reduce both complications after discharge and hospital readmissions.

Who: 2,864 patients with COVID who were treated and discharged from five hospitals in the Mount Sinai Health System, and later readmitted.

When: COVID patients hospitalized between February 27 to April 12, 2020.

What: The study describes clinical characteristics of patients with COVID-19 who were most likely to return to the ER or require hospital readmission within two weeks of being discharged.

How: Researchers examined data collected from electronic health records including time spent in the emergency department and within an outpatient lab visit. They also considered more than 100 variables including demographics, key vitals, disease diagnoses, comorbid conditions, procedures during hospitalization, ICU-level care, and outcomes.

Study Conclusions: A return to the hospital after admission for COVID-19 within 14 days of discharge was relatively low for the majority of patients. However, the most common cause for a patient's return to the hospital was for respiratory distress. Patients who returned were more likely to have chronic obstructive pulmonary disease and hypertension.

Said Mount Sinai's Girish Nadkarni of the research:

"This study shows that many patients have lingering effects from hospitalization for COVID-19 and thus, there is opportunity for longitudinal studies that could further assess the long-term effects of COVID on patient outcomes when they are discharged."

Said Mount Sinai's Dr. Anuradha Lala of the research:

"COVID-19 has diminished and then resurged in many places, and as such, it is crucial for us to understand the post-hospitalization course and risk factors for coming back into the hospital. While caring for patients during the peak of the pandemic in NYC, our focus was on safe and efficient discharge to make room for new patients and prevent additional exposure. As we move into a phase where COVID-19 is no longer a novel disease, we must transition our attention to the post-acute phase to understand how to keep patients well and out of the hospital."

Said Mount Sinai's Dr. Benjamin Glicksberg of the research:

"We found that individuals with certain comorbid conditions, specifically COPD and hypertension, were more likely to return to the hospital. These findings may help clinical practitioners optimize discharge strategies in the short-term and suggest the need for future studies on tailored monitoring to decrease the risk of hospital returns."

View the full paper here. To schedule an interview with an expert from the Mount Sinai COVID Informatics Center, please contact Stacy A. Anderson at stacy.anderson@mountsinai.org or 347-346-3390.

Scientists have developed an injectable drug that blocks HIV from entering cells. They say the new drug potentially offers long-lasting protection from the infection with fewer side effects. The drug, which was tested in non-human primates, could eventually replace or supplement components of combination drug "cocktail" therapies currently used to prevent or treat the virus.

University of Utah Health scientists led the study in collaboration with researchers from the National Institute of Allergy and Infectious Diseases (NIAID), Beth Israel Deaconess Medical Center in Boston, and Navigen, Inc.

"This is an exciting new HIV therapeutic option for both prevention and treatment, with a unique mechanism of action compared to other approved drugs," says Michael S. Kay, M.D. Ph.D., a senior author of the study and a U of U Health professor of biochemistry. "It has great potential to help patients who suffer from drug resistance as well as those who would benefit from a longer-acting, injectable anti-HIV drug cocktail."

The study appears in Proceedings of the National Academy of Sciences (PNAS).

In 2019, about 1.7 million people worldwide were newly infected with HIV, according to the World Health Organization. More than 38 million people are currently living with the infection. Combination antiretroviral therapy (cART), the so-called "drug cocktail," has dramatically improved survival and quality of life for such patients, but it is also costly, often has serious side effects, and requires patients to take pills daily. In addition, because HIV frequently mutates, drug resistance is a constant challenge, Kay says, so researchers are always seeking new drugs with novel mechanisms of action to produce more robust combination therapies.

In this new study, the researchers tested a unique drug called CPT31, based on a D-peptide that targets a critical pocket on HIV's fusion machinery that rarely mutates. D-peptides are mirror images of naturally occurring peptides. To imagine it, think of right and left hands. The building blocks and overall structure of natural peptides are analogous to our left hand versus our right hand for D-peptides.

Because of that, CPT31 and other D-peptides are not degraded in the body. Therefore, they last much longer than natural peptides, making them especially suitable for a long-acting injectable formulation.

"In addition to their durability in the body, D-peptides are largely ignored by the immune system, preventing immune reactions that are a side effect often seen with traditional peptide and protein drugs," says Brett Welch, a co-author of the study and senior director of technology and strategy at Navigen, Inc., the Salt Lake City company that co-developed CPT31 and is managing clinical trials. "As a D-peptide, our hope is that CPT31 will provide extended viral suppression with a lower dose and reduced side effects."

To see if CPT31 could prevent HIV infection, Kay and colleagues first injected the drug into healthy macaque monkeys starting several days prior to exposure to a hybrid simian-human form of HIV called SHIV. The monkeys were completely protected from this very high SHIV exposure, much higher than what humans typically encounter, and never developed signs of infection. Subsequently, the scientists identified the minimum dose of CPT31 needed to confer complete protection, information that will help inform clinical trials.

"We think this drug could be used by itself to prevent HIV infection because initial HIV exposure typically involves a relatively small amount of virus," Kay says. "This study showed that the vast majority of circulating HIV strains from around the world are potently blocked by CPT31."

But what about later stages of the disease when there are billions of copies of the virus circulating in the body?

To find out, the researchers gave CPT31 to monkeys with untreated SHIV infections and high viral loads. Over the course of 30 days, the drug significantly lowered the presence of SHIV in their bloodstreams. However, virus levels rebound in two to three weeks due to drug resistance, as typically observed when treating established infections with a single drug.

Finally, the researchers tested the drug's ability to maintain viral suppression after a cART drug cocktail is discontinued in macaques. cART reduces SHIV to an undetectable level, but the virus rapidly rebounds after discontinuing therapy (as also seen in humans). In this study, CPT31 by itself effectively kept the virus at an undetectable level for months (until drug administration was discontinued).

"Such a simplified 'maintenance therapy' could present patients with a new option for viral control that is more cost-effective, convenient to take, and has fewer side effects," Kay says.

In parallel with clinical trials, Navigen is developing a long-acting injectable formulation of CPT31 with the goal of only requiring injection of the drug once every three months.

"Long-acting injectable formulations appear to be greatly preferred by both patients and physicians compared to current daily drug regimens that can be challenging to maintain," Welch says. "Additionally, the steady therapeutic drug levels provided by such a formulation would reduce the risk of drug resistance caused by missed daily pills, as well as reduce side effects."

Upcoming human trials, scheduled for later this year, will help determine whether CPT31 is safe and effective in humans. Kay says that the full course of human clinical trials and subsequent FDA approval could take several years.

The word 'synbiotic' appears on a growing number of food and supplement products, with synbiotic ingredients showing promise for modulating the community of microbes living in the human gut, while providing a health benefit. Synbiotics are generally understood to be a combination of a probiotic and a prebiotic--but experts have deemed this description too limiting for innovation in this field and too ambiguous to allow for a clear understanding of synbiotic health benefits.

To address the scientific ambiguity around synbiotics, a group of 11 leading international scientists formed a panel to create a consensus definition and to clarify the evidence required to show synbiotics are safe and effective.

In a paper published in Nature Reviews Gastroenterology & Hepatology, the authors advance a new definition of synbiotics, which is informed by the latest scientific developments in the field: "a mixture comprising live microorganisms and substrate(s) selectively utilized by host microorganisms that confers a health benefit on the host".

The experts on the panel emphasize that the definition is designed to be inclusive--many different combinations of live microorganisms and selectively utilized substrates could qualify as synbiotics, as long as a human study demonstrates the health benefits of any particular combination. Furthermore, synbiotics need not be limited to the gut; they could potentially target any part of the human body that harbours a community of microorganisms.

"We hope the publication of this definition will mark a shift in people's understanding of synbiotics," says first author Kelly Swanson, Professor in the Department of Animal Sciences and Division of Nutritional Sciences, University of Illinois at Urbana-Champaign. "We can begin discussing synbiotics in a more scientifically accurate way, giving everyone a shared vocabulary for understanding what they do, how they work, and what evidence is needed to meet the definition."

In the publication, the group also makes a distinction between 'complementary synbiotics', in which a probiotic and prebiotic are combined but work separately, and 'synergistic synbiotics', in which the selectively utilized substrate specifically feeds the microorganisms that accompany it.

The expert panel was convened by the International Scientific Association for Probiotics and Prebiotics (ISAPP), the non-profit organization that previously led the scientific consensus definitions of both probiotics and prebiotics.

"Creating a definition of synbiotic is a first step," says Mary Ellen Sanders, ISAPP's Executive Science Officer. "From here, the scientific community can focus on designing and carrying out studies to test the health effects of these products."

Surveys indicate that consumers increasingly look for evidence that products on the market provide the benefits they claim to provide. Sanders says, "We expect that the scientific data on synbiotic health benefits will increase over time, alongside an increase in general awareness about synbiotics."

Toronto -- Taking advantage of a cancer cell's altered metabolism that drives its runaway growth, Princess Margaret researchers are zeroing in on these molecular changes to help them develop more precise drug targets for one of the most deadly breast cancers.

Triple negative breast cancer is a highly aggressive subtype of breast cancers, representing 15-20% of breast cancer cases, but accounting for 25% of breast cancer deaths. In addition, it has a higher metastatic rate within five years of diagnosis and poorer overall survival rate compared to receptor positive cancer subtypes.

Scientists don't know why, but this cancer is also more common among Black and younger women.

"This disease has no precision medicine," says Dr. Mathieu Lupien, Senior Scientist, Princess Margaret Cancer Centre, "so patients are treated with chemotherapy because we don't have a defined therapeutic target. Initially, it works for some patients, but close to a quarter of patients recur within five years from diagnosis, and many develop chemotherapy-resistant tumours.

"These savage statistics mean that we must improve our understanding of the molecular basis for this cancer's development to discover effective, precise targets for drugs, and a companion test to identify which patients are most likely to benefit the most from such a therapy."

In research led by Princess Margaret Senior Scientists Drs. Cheryl Arrowsmith and Mathieu Lupien published in Nature Communications, August 21, 2020, the scientific team found a promising approach with a protein biomarker that could potentially identify the best patients for more precise, targeted therapy in the future.

Using a collection of different patient-derived cell lines from triple negative breast cancer, researchers were able to test their sensitivity to 'chemical probes' (experimental, drug-like compounds) against inhibitors of a metabolic gatekeeper called GLUT1. They found a correlation or link between cells with varying levels of RB1, a protein involved in cell metabolism, as well as a long-established tumour suppressor protein, and decreased growth in these cancer cells.

Altered metabolism drives explosive cancer growth

All cancers have altered metabolic states, explains Dr. Arrowsmith, because their explosive growth requires huge amounts of energy, such as glucose, to nourish their survival and growth - despite being bombarded with chemotherapy in this specific cancer.

Having access to diverse cell models of triple-negative breast cancer allows us to distinguish where the potential drug will work, and where it won't, says Dr. Lupien, who is also an Associate Professor in the Department of Medical Biophysics. "Without this broad spectrum of samples, we might have missed the subset of triple-negative breast cancers that respond to our compound."

Specifically, the compound targets GLUT1, part of the pathway transporting glucose into a cell to increase metabolic energy in the subset of cancer cells with high levels of RB1 protein- in effect stopping them from growing.

Blocking this pathway "starved" the cancer cells, making them more responsive or sensitive to the chemical compound, demonstrating this as a promising target for new anticancer approaches.

This work shows that differing levels of RB1 can be used as a biological biomarker to discriminate between treatment responders and non-responders in the future, says Dr. Arrowsmith.

Major challenge in cancer research

Matching the right patient to the right drug is a major challenge in cancer research and treatment, says Dr. Arrowsmith, who is also Chief Scientist for the Structural Genomics Consortium Toronto laboratories and Professor of Medical Biophysics at the University of Toronto.

She points out that multiple changes in cancer cells drive their abnormal growth, including genetic, epigenetic, metabolic and chromosomal changes that mutate and change over time.

This heterogeneity in tumour cells, which is constantly changing and adapting over time, enables cancer cells to thrive and evade conventional therapies.

That's why many new potential drugs fail, says Dr. Arrowsmith, because these multiple combinations of changes in cancer cells are complex and dynamic.

"What we're trying to do is to understand in detail what subset of drugs are effective at targeting the minute molecular changes in the cancer cells.

"It's like whack-a-mole when you try and treat cancer with one drug. As soon as you figure out how to stop a mechanism that drives the cell rogue, the cancer cells adapt and keep on growing.

"That's the big challenge in treating cancer. The more we understand about the molecular complexity of cancer cells, the more we can target with precision.

"And the more we can build up a pharmacy of cancer drugs matched to specific changes in the cancer cell, the greater the chance of a cure."