Body

Leesburg, VA, June 18, 2020--An open-access American Journal of Roentgenology (AJR) article exploring the diagnostic value of chest CT for coronavirus disease (COVID-19) pneumonia--especially for patients with negative initial results of reverse transcription-polymerase chain reaction (RT-PCR) testing--found that the less pulmonary consolidation on chest CT, the greater the possibility of negative initial RT-PCR results.

From January 19 to February 20, 2020, lead investigator Dandan Chen of Guangzhou First People's Hospital in China obtained the admission data of 21 patients (nine men, 12 women; age range, 26-90 years) with confirmed COVID-19 pneumonia from five nonspecialized infectious disease hospitals across Guangzhou.

After undergoing chest CT and swab RT-PCR tests within 3 days, patients were divided into two groups: seven patients with negative initial results (who were found to have positive results after a second RT-PCR test 2 days later) and 14 patients with initial positive results.

"Most of the COVID-19 lesions were located in multiple lobes (67%) in both lungs (72%) in our study," Chen et al. wrote, adding that the CT findings observed most frequently were ground-glass opacities (95%) and consolidation (72%) with subpleural distribution (100%). "Otherwise," they continued, "33% of patients had other lesions around the bronchovascular bundle."

Additional chest CT findings identified by Chen and colleagues included air bronchogram (57%), vascular enlargement (67%), interlobular septal thickening (62%), and pleural effusions (19%).

Ultimately, compared with the positive initial RT-PCR results group, CT of the group with negative initial RT-PCR results was less likely to indicate pulmonary consolidation (p

Acknowledging that RT-PCR detection can be affected by laboratory reagents, test method, and subjective operability, Chen noted that, theoretically, the multicenter nature of this study--five hospitals in four districts of Guangzhou (13 cases in Huadu, four in Baiyun, three in Yuexiu, one in Nansha)--should have reduced interference by such factors.

"When patients with suspected COVID-19 pneumonia who have an epidemiologic history and typical CT features have negative initial RT-PCR results," the authors of this AJR article concluded, "repeated RT-PCR tests and patient isolation should be considered."

Certain patients who receive hospital care for coronavirus infection (COVID-19) exhibit clinical and neurochemical signs of brain injury, a University of Gothenburg study shows. In even moderate COVID-19 cases, finding and measuring a blood-based biomarker for brain damage proved to be possible.

Some people infected with the coronavirus SARS-CoV-2 get only mild, cold-like symptoms, while others become severely ill and require hospital treatment. Among the latter, it has become clear that the patients sometimes show obvious signs of the brain not functioning as it should. These cases are not common, but do occur.

In a project at Sahlgrenska Academy, University of Gothenburg, blood samples were taken from 47 patients with mild, moderate and severe COVID-19 in the course of their hospital stay. These samples were analyzed by means of highly sensitive biomarkers for brain injury. The results were compared with those from a healthy control group comprising 33 people matched by age and sex.

Now that the research is being presented in the journal Neurology, it is evident that an increase in one of the biomarkers took place even with moderate COVID-19 -- that is, in patients admitted to hospital but not in need of ventilator support. This marker, known as GFAP (glial fibrillary acidic protein), is normally present in astrocytes, a star-shaped neuron-supportive cell type in the brain, but leaks out in the event of astrocytic injury or overactivation.

The second biomarker investigated was NfL (neurofilament light chain protein), which is normally to be found inside the brain's neuronal outgrowths, which it serves to stabilize, but which leaks out into the blood if they are damaged. Elevated plasma NfL concentrations were found in most of the patients who required ventilator treatment, and there was a marked correlation between how much they rose and the severity of the disease.

"The increase in NfL levels, in particular, over time is greater than we've seen previously in studies connected with intensive care, and this suggests that COVID-19 can in fact directly bring about a brain injury. Whether it's the virus or the immune system that's causing this is unclear at present, and more research is needed," says Henrik Zetterberg, Professor of Neurochemistry, whose research team at Sahlgrenska Academy performed the measurements.

Magnus Gisslén, Professor of Infectious Diseases at Sahlgrenska Academy and chief physician at the Department of Infectious Diseases, Sahlgrenska University Hospital, leads the Academy's clinical research on COVID-19.

In his view, blood tests for biomarkers associated with brain injury could be used for monitoring patients with moderate to severe COVID-19, to reduce the risk of brain injury.

"It would be highly interesting to see whether the NfL increase can be slowed down with new therapies, such as the new dexamethasone treatment that's now been proposed," Gisslén says.

In a Lancet Diabetes & Endocrinology review article Norbert Stefan from the German Center for Diabetes Research (DZD), the University Hospital of Tübingen and the Boston Children's Hospital, highlights why and to what extent a large hip circumference, an estimate of increased fat mass in the lower part of the body, protects from type 2 diabetes and cardiovascular diseases (CVD). He also provides new information that a high amount of hip and leg fat mass is very important to retain metabolic health. In addition, he discusses lifestyle modifications and pharmacological interventions that improve body fat distribution and exemplifies how a focus on lower body fat mass helps clinicians in risk assessment and patient communication.

An increased fat mass is an important risk factor for the worldwide increase in type 2 diabetes and CVD. However, for a given fat mass, there is a large variability in the risk of these cardiometabolic diseases. For example, some lean people unexpectedly have a risk of type 2 diabetes and CVD that is similar to the increased risk that is observed in most people who have obesity. What both of these phenotypes have in common is an increased upper body, and more specifically, an increased visceral (inside the belly), fat mass. As a result, much focus has been given on the strong predictive power of upper body obesity. However, comparisons to rare diseases such as lipodystrophy (dramatic rarefication of fat mass under the skin) and studying genetically determined fat distribution in the general population, suggest that an impaired ability to expand fat in the lower part of the body is also very important for predicting the incidence of these diseases.

Norbert Stefan highlights mechanisms that result in storage of energy in different fat depots of the body, or ectopically, in organs such as the liver, the pancreas and the heart. Then he discusses studies showing to what extent measurement of fat in the lower part of the body is helpful to estimate the risk of type 2 diabetes and CVD. In this respect recently published landmark studies provided genetic support that a low amount of estimated visceral fat and a high amount of lower body fat may be equally important to retain cardiometabolic health. He then provides novel information from a magnetic resonance imaging study supporting this hypothesis.

The author then discusses mechanisms that may drive a dramatic re-distribution of fat from the lower to the upper part of the body during aging. In this respect changes of sex hormone levels and signaling during lifetime are considered very important, both, in men and in women. He also highlights strategies, related to changes in lifestyle, or pharmacological treatment in diseases associated with disproportionate fat distribution, such as nonalcoholic fatty liver disease or a lipodystrophy-like phenotype, that help to hinder such fat-redistribution. Finally, he exemplifies how the focus on lower body fat mass helps health care providers to better assess the risk of cardiometabolic diseases and to communicate this risk with their patients.

The global COVID-19 pandemic has affected the physical lives of most people. But now there are also indications that the pandemic has negative consequences for the mental health of the people being infected, the healthcare professionals and the population as a whole.

This is shown in a new Danish review of 43 scientific articles that have studied the subject. The review was produced by researchers from the University of Copenhagen and the Mental Health Centre Copenhagen, Mental Health Services in the Capitol Region of Denmark.

'It is known from the previous SARS epidemic in 2002-2003, also called the bird flu, that mental health was affected among patients who survived the disease and among the healthcare professionals, treating the patients. Our recently published article systematically reviews current knowledge on symptoms among healthcare professionals and patients, and the same appears to be the case for the COVID-19 pandemic', says Professor Michael Eriksen Benros at the Department of Immunology and Microbiology at the University of Copenhagen and the Mental Health Centre Copenhagen.

Post-Traumatic Stress, Depression and Anxiety

The article is a review of 43 scientific studies. Of these, 20 studies have examined the mental health among healthcare professionals. An overweight of the studies found higher levels of anxiety and depression as well as mental stress and poor quality of sleep. 19 studies examined the mental health of the population as a whole. Here, too, it is the overall picture that the COVID-19 pandemic seems to be having a negative impact.

Only two studies have so far examined mental symptoms among patients with SARS-CoV-2 infection. The studies showed that 96% of seriously ill hospitalised patients with COVID-19 infection exhibited symptoms of post-traumatic stress. They also found an increased risk of developing depression after hospitalisation with COVID-19.

'Many more and better studies are needed, but the results are still relevant. The numerous reports of decreased sense of smell and taste during a COVID-19 infection might indicate an effect on the nervous system. It is therefore worrying that mental symptoms have been detected during and immediately after the infection. One contributing factor might be that the infection has affected the brain and caused the symptoms, either directly or through the induced immune response', says Michael Eriksen Benros.

Need for Better and More Studies

The researchers behind the review emphasise that significant reservations must be made because the included studies are of varying quality. The urgent societal and health crisis has led to faster than usual publication of scientific articles. In addition, most of the studies have been performed as online questionnaires and therefore do not have the same quality as thorough, clinical studies. Also, most studies are from Asia, and it is unclear whether the results can be transferred to a European context.

'We need more high-quality studies to make any final conclusions about a link between mental symptoms and COVID-19. However, our results indicate that COVID-19 may have an impact on the brain of those infected, and that there are derived effects of the pandemic on the mental health among both healthcare professionals and the population. Given that the previous SARS epidemic was also associated with mental symptoms, we believe that research in this area is extremely important, as knowledge is a prerequisite for dealing with any mental consequences of COVID-19', says PhD student and first author, Nina Vindegaard Sørensen, from the Department of Immunology and Microbiology at the University of Copenhagen and the Mental Health Centre Copenhagen

The previous SARS epidemic spread to 28 countries and sickened around 8,000 people, while eight million people in over 180 countries and regions have already been infected with SARS-CoV-2.

UConn associate professor of pharmaceutics Xiuling Lu, along with professor of chemistry Rajeswari M. Kasi, was part of a team that recently published a paper in Nature Cell Biology finding a commonly used chemotherapy drug may be repurposed as a treatment for resurgent or chemotherapy-resistant leukemia.

One of the largest problems with cancer treatment is the development of resistance to anticancer therapies. Few FDA-approved products directly target leukemia stem cells, which cause treatment-resistant relapses. The only known method to combat their presence is stem cell transplantation.

Leukemia presents unique treatment challenges due to the nature of this form of cancer. The disease affects bone marrow, which produces blood cells. Leukemia is a cancer of the early blood-forming cells, or stem cells. Most often, leukemia is a cancer of the white blood cells. The first step of treatment is to use chemotherapy to kill the cancerous white blood cells, but if the leukemia stem cells in the bone marrow persist, the cancer may relapse in a therapy-resistant form.

Fifteen to 20% of child and up to two thirds of adult leukemia patients experience relapse. Adults who relapse face a less-than 30% five-year survival rate. For children the five-year survival rate after relapse is around two thirds. When relapse occurs, chemotherapy does not improve the prognosis for these patients. There is a critical need for scientists to develop a therapy that can more effectively target chemotherapy-resistant cells.

There are two cellular pathways, Wnt-β-catenin and PI3K-Akt, which play a key role in stem cell regulation and tumor regenesis. Cooperative activation of the Wnt- β-catenin and PI3K-Akt pathways drives self-renewal of cells that results in leukemic transformation, giving rise to cancer relapse. Previous studies have worked on targeting elements of these pathways individually, which has had limited success and often results in the growth of chemo-resistant clones.

The researchers screened hundreds of drugs to find one that may inhibit this interaction. They identified a commonly used chemotherapy drug, doxorubicin as the most viable target. While this drug is highly toxic and usually used with caution in clinical settings, the team found when used in multiple, low doses, it disrupts the Wnt-β-catenin and PI3K-Akt pathways' interaction, while potentially reducing toxicity.

Lu's lab contributed a nanoparticle which allowed the drug to be injected safely and released sustainably over time, a key to the experiment's success. The nanoparticle encasing doxorubicin enables slow release of the drug to the bone marrow to reduce the Akt-activated β-catenin levels in chemo-resistant leukemic stem cells and reduce the tumorigenic activity. In low doses, doxorubicin stimulated the immune system while typical clinical doses are immunosuppressive, inhibiting healthy immune cells.

Lu is the CEO of Nami Therapeutics, a startup which designs nanoparticles for drug delivery in a variety of clinical contexts including cancer treatment and vaccine delivery.

Because of its rate of drug release, Lu's patented nanoparticle was more effective than both a solution of the pure drug and a liposomal doxorubicin, the only commercially available version of a nanoparticle carrying doxorubicin.

"It's exciting that the whole research team identified this new mechanism to effectively inhibit leukemia stem cells," Lu says. "We are happy to see that our proprietary nanoparticle delivery system has such potential to help patients."

By using low, but more sustained, doses of this drug, leukemia-initiating activity of cancerous stem cells was effectively inhibited.

The researchers demonstrated clinical relevance by transplanting patient leukemic cells into mice and observing that low-dose doxorubicin's ability to disrupt these cells. Patient sample transplants with therapy-resistant leukemia stem cells rapidly developed leukemia. But the low-dose doxorubicin nanoparticle treatment improved survival by reducing the presence of leukemia stem cells.

Lu says the next steps for this research is to further validate the now-patented method and nanoparticle and eventually bring it into clinical usage. Lu and her collaborator, Rajeswari Kasi, also have two pending patents on copolymer-nanoparticles for drug delivery and methods for treating chemo-resistant cancer-initiating cells.

Vienna, Austria, June 18, 2020 - AFFiRiS AG, a clinical-stage biotechnology company developing novel disease-modifying specific active immunotherapies (SAITs), today announced that detailed results of the phase 1 clinical program with its lead candidate PD01 in early Parkinson's disease (PD) patients were published in the peer-reviewed journal The Lancet Neurology. The results of the long-term phase 1 trial series demonstrated that repeated immunisation with PD01A is safe and well-tolerated over an extended period of time. The data showed that active immunisation with PD01A leads to a positive antibody response specific for alpha-synuclein (aSyn), a protein that is believed to contribute to the pathogenesis of Parkinson's disease. Active immunisation also resulted in a substantial reduction (mean of 51%) in the levels of aSyn oligomers in the CSF of patients who received the high dose therapy, which is interpreted as a sign of in vivo target engagement.

Extensive evidences support the role of soluble aSyn oligomers as a causative factor in the development of Parkinson's disease and reducing the levels of aSyn oligomers could potentially have disease-modifying benefit in PD patients.

In the trial, the patients were randomised to receive four immunisations with two different doses of AFFiRiS' drug candidate and were followed for at least 3.5 years to assess the safety of the PD01A immunotherapeutic. In particular, this was the first study to assess the feasibility and safety of a specific active immunotherapy against aSyn.

The results of this phase 1 study demonstrated that immunisation with PD01A is safe when repeatedly administered and was well-tolerated over an extended time period. With the exception of expected local injection site reactions, most AEs were considered unrelated to study treatment. No patient discontinued due to treatment emergent adverse events. Immunisation resulted in a significant increase in IgG antibody against the immunizing AFFITOPE® PD01 peptide already after three priming injections with a maximum titre being achieved at Week 12. This led to a specific humoral immune response against the aSyn target epitope. Moreover, the priming immunisations resulted in a substantial memory effect for the aSyn target epitope as evidenced by the reactivation and augmentation of the antibody response following booster immunizations. This resulted in the persistence of the immune response until study end.

Although the study was not designed and not powered to evaluate clinical efficacy, clinical signals of efficacy were observed. In particular, MDS-UPDRS motor scores were generally stable across the study series, in contrast to published data which reports a worsening in MDS-UPDRS scores in a similar patient population.

"The PD01A safety profile and the substantial sustained aSyn antibody response targeting both the toxic oligomeric and fibrillar form of aSyn, which are believed to contribute to the pathology of PD, may offer a promising strategy for long-term management of PD, addressing an urgent medical need," said Dieter Volc MD, principal investigator of the study series and Head of the Parkinson Center at the Privatklinik Confraternitaet, Vienna.

"The encouraging results, including signals for clinical efficacy, warrant the further development of our drug for the treatment of PD in a phase 2 clinical trial," commented Noel Barrett, Ph.D., AFFiRiS's Chief Executive Officer. "Potentially, specific active immunization approaches such as with PD01A might overcome the limitations of passive antibody infusion approaches for PD, caused by their short in vivo half-lives, and circumvent frequent and high treatment costs by stimulating a self-produced, long-lasting immune reaction."

The data published in Lancet Neurology is the first report of an active anti-aSyn immunotherapy associated with reduction of CSF aSyn oligomers in PD patients and points to the possible development of this protein as a potential biomarker for disease progression.

Patients with cancer face a serious dilemma during the COVID-19 pandemic, as staying at home could increase their risk of cancer progression, while visiting the hospital for treatment could increase their risk of becoming infected with the virus that causes COVID-19. A new study published in Psycho-Oncology reveals how the pandemic has impacted such patients' quality of life.

The surveyed-based study, which included 260 patients with stage III and IV cancer undergoing chemotherapy when the pandemic hit, found that patients' quality of life during the pandemic was significantly lower than that of a reference group of 8,066 patients with stages III and IV cancer before the pandemic.

The differences in perceived quality of life concerned mainly social and cognitive functioning, which were significantly lower in patients during the COVID-19 pandemic. Physical and emotional functioning were similar between the two groups.

The study revealed that 20% of patients with cancer considered postponing chemotherapy and 5% consider abandoning further cancer treatment during the pandemic, despite a fear of cancer progression.

"During this extraordinary time, cancer patients are facing a war on two fronts having to struggle with the increased risk of COVID-19 morbidity and the risk of cancer progression with possible delays of diagnosis or treatment," said lead author Magdalena Ci??y?ska, PhD, of the Nicolaus Copernicus Multidisciplinary Centre for Oncology and Traumatology, in Poland. "Living with cancer at the time of pandemic does not mean that oncological care must be compromised. The oncology community, despite having to deal with unprecedented challenges in treating patients, at the same time identifies risk factors that deteriorate patients' quality of life to ensure that their safety and wellbeing are not affected."

Researchers at a major Boston academic medical center designed, fabricated, tested, and implemented a reusable face shield for front-line medical staff within a couple of weeks. The work, presented June 18 in the journal Med, was carried out at the Brigham and Women's Hospital Emergency Department in collaboration with members of the volunteer group Greater Boston Pandemic Fabrication Team (PanFab) and the local maker community.

The authors of the study say it provides an efficient and generally applicable approach for leveraging local manufacturing processes to quickly produce personal protective equipment (PPE) during public health emergencies. The paper provides all of the instructions and model files to produce the face shields.

"All of the designs and protocols generated through this effort are being freely shared for reuse and improvement, and the results of our testing in the emergency department at the Brigham are reported in full to facilitate the execution of similar face-shield efforts in other clinical settings," says co-senior study author Sherry Yu of the Brigham and Harvard Medical School. "We anticipate that this work will provide a framework for the design and implementation of similar approaches to PPE manufacturing for current and future shortages."

In the face of a rapidly expanding coronavirus disease 2019 (COVID-19) pandemic, severe PPE shortages have put both health care professionals and patients at increased risk of infection. The origins of these shortages reflect the fragility of medical supply chains, in which relatively few international vendors dominate critical medical product areas. Because many hospitals use just-in-time inventory management, supply-chain problems rapidly deplete hospital supplies and prevent restocking from traditional vendors. Two months into the COVID-19 pandemic in the US, traditional supply chains remain substantially disrupted, and much-advertised alternative sources of supply from large companies have not yet been widely distributed.

Faced with this crisis, many caregivers and medical centers have turned to local fabricators that use 3D printing to provide replacements for products such as face shields, filtering respirators, and even ventilator components. Recently, many public-domain designs for face shields have become available. Groups using these designs have found that introducing face shields and similar PPE into a healthcare setting is challenging. Despite their relatively simple design, face shields are regulated in the U.S. by the Centers for Disease Control and the Food and Drug Administration (FDA). In April, the FDA issued a letter stating that it "does not intend to object to individuals' distribution and use of improvised PPE when no alternatives, such as FDA-cleared masks or respirators, are available."

Still, no clear path exists for introducing a locally fabricated product into a clinical setting. "The FDA letter provides a legal framework in which to use locally fabricated, improvised PPE in the US, but it does not address the more general issue of introducing non-traditional PPE into a healthcare environment; what to do if emergency guidance is lacking, as it currently is in many countries; and how nontraditional devices should be introduced into the hospital supply chain in a rational, safe and controlled manner," says co-senior study author Nicole LeBoeuf of the Brigham and Harvard Medical School.

To address this need, Yu, LeBoeuf, and co-senior study author Peter Sorger of Harvard Medical School used a research protocol under supervision from the university's institutional review board to test a locally fabricated face shield as an investigational device. This allowed clinicians to participate in an iterative design process that was followed by real-world testing in an emergency department. Yu says this approach is unique because feedback was obtained in parallel, leading to faster implementation.

The researchers started with the 3D-printed Prusa RC2 face-shield design developed in the Czech Republic. They improved on this design to ensure limited aerosol and splatter exposure coming from the front and above, resistance to fogging, and suitable comfort for all-day wear in a high-intensity clinical setting. Overall, four substantial design modifications were made on the basis of clinical feedback, and the resulting design includes many features that are not present in disposable commercial face shields.

First, the researchers increased the width to maximize face protection without obstructing hearing or impeding a user's range of motion. Second, they used hook-and-loop Velcro to adapt each visor to individual users. Third, they reduced tightness by placing anchor points for the hook-and-loop strap in-line with the headbands.

And fourth, the researchers added a visor above the headband to prevent fluid from entering the top of the face shield during high-risk procedures in which a clinician is required to lean forward. This includes endotracheal intubation for mechanical ventilation, one of the riskier procedures that must be performed on COVID-19 patients. They also added a plastic lip at the bottom of the visor so that any liquid that did fall on this area would be retained by the lip and would not spread down the front of the shield and affect a user's vision.

Among 92 surveyed staff members of the emergency department, most responded that the BWH/PanFab face shield was better in terms of splash protection (96%), sturdiness and reliability (92%), ease of use (78%), and comfort (87%). Moreover, 92% planned to continue using the BWH/PanFab face shield, and 99% responded they would be comfortable or very comfortable using this shield in a clinical scenario in which they had no other option.

The entire process of introducing a non-traditionally manufactured product into a hospital supply chain in a safe and controlled manner took only three weeks. With a design in hand and institutional support, others can deploy this process in two weeks or less, plus two to three days for clinical testing if design modifications are necessary because of material shortages. To date, the researchers have fabricated approximately 3,000 face shields, all of which remain in use. Currently, they are assessing various procedures for sterilizing and reusing face shields and similar PPE and clinically testing an alternative face-shield design that can be packed flat to facilitate shipping and storage.

Sorger says the changes in regulatory guidance are needed to facilitate the type of testing they used for their face shields. Moreover, hospital systems need staff their crisis and response teams with individuals who are specifically tasked with outreach to maker and manufacturing communities.

"The current crisis has shown that, when a pandemic is spreading, and health care workers are placed at high risk, we require a distributed and robust community-level approach to essential medical supplies," Sorger says. "The resulting devices, developed and produced largely by volunteers, not only are likely to decrease the risk of hospital infection but also send a powerful message to front-line medical staff that the local community stands behind them. Although a pandemic was required to galvanize these insights and promote rapid change, our hope is that the spirit of thoughtful collaboration and rapid innovation does not dissipate after the resolution of the current COVID-19 crisis."

A study of nearly 400 pregnant women in New York City is among the first to show that lower neighborhood socioeconomic status and greater household crowding increase the risk of becoming infected with SARS-CoV-2, the virus that causes COVID-19.

"Our study shows that neighborhood socioeconomic status and household crowding are strongly associated with risk of infection. This may explain why Black and Hispanic people living in these neighborhoods are disproportionately at risk for contracting the virus," says the study's leader Alexander Melamed, MD, MPH, assistant professor of obstetrics & gynecology at Columbia University Vagelos College of Physicians and Surgeons and a gynecologic oncologist at NewYork-Presbyterian/Columbia University Irving Medical Center.

What the Study Examined

The researchers examined the relationships between SARS-CoV-2 infection and neighborhood characteristics in 396 women who gave birth at NewYork-Presbyterian/Columbia University Irving Medical Center or NewYork-Presbyterian Allen Hospital during the peak of the COVID-19 outbreak in New York City.

Since March 22, all women admitted to the hospitals for delivery have been tested for the virus, which gave the researchers the opportunity to detect all infections -- including infections with no symptoms -- in a defined population.

Household Density Strongest COVID-19 Predictor

The strongest predictor of COVID-19 infection among these women was residence in a neighborhood where households with many people are common.

Women who lived in a neighborhood with high household membership were 3 times more likely to be infected with the virus.

Neighborhood poverty also appeared to be a factor: women were twice as likely to get COVID-19 if they lived in neighborhoods with a high poverty rate, although that relationship was not statistically significant due to the small sample size.

There was no association between infection and population density.

"New York City has the highest population density of any city in the United States, but our study found that the risks are related more to density in people's domestic environments rather than density in the city or within neighborhoods," says co-author Cynthia Gyamfi-Bannerman, MD, the Ellen Jacobson Levine and Eugene Jacobson Professor of Women's Health in Columbia's Department of Obstetrics and Gynecology and a maternal-fetal medicine specialist at NewYork-Presbyterian/Columbia University Irving Medical Center.

Public Health Implications

The study reveals information important for public health officials.

"One may think that because New York City is so dense, there's little that can slow the spread of the virus, but our study suggests the risk of infection is related to household, rather than urban, density," Gyamfi-Bannerman says.

"For our pregnant patients, that may mean counseling women about the risk of infection if they are considering bringing in other family members to help during pregnancy or postpartum," she says.

"The knowledge that SARS-CoV-2 infection rates are higher in disadvantaged neighborhoods and among people who live in crowded households," Melamed adds, "could help public health officials target preventive measures, like distributing masks or culturally competent educational information to these populations."

Madison, WI (June 18, 2020): In a paper published online this week in Autism Research, scientists at NeuroPointDX, a division of Stemina Biomarker Discovery, Inc., in collaboration with researchers at the UC Davis MIND Institute and academic and clinical institutions across the country, report new findings from the Children's Autism Metabolome Project or CAMP.

Analysis of blood samples from CAMP, the largest study yet undertaken of the metabolism of children with autism spectrum disorder (ASD), has now reproducibly identified unique metabolic signatures (called metabotypes) in over 50% of the children with autism in the study. This is an important step towards the goal of developing a panel of metabolomics tests that could form the basis for a biological screen of risk for ASD. Analysis of other potential blood-based biomarkers using CAMP study samples is ongoing. Validation of additional metabotypes of ASD is expected to result in the ability to detect a still higher percentage of children at risk of ASD using this approach.

The new publication, entitled "A metabolomics approach to screening for autism risk in the Children's Autism Metabolome Project" (Autism Research, 2020: doi: 10.1002/aur.2330) was authored by researchers from the UC Davis Mind Institute, Stemina Biomarker Discovery, Inc., University of Wisconsin-Madison, and the Cleveland Clinic.

"A primary goal of the CAMP study, which recruited 1,102 children ages 18 months to 48 months, was to generate a panel of validated biomarkers that, taken together, could detect a large proportion of young children at risk for ASD," said David Amaral, PhD, distinguished professor at the UC Davis MIND Institute and the Department of Psychiatry and Behavioral Sciences at UC Davis and senior author of the paper. "Our original analyses, published in Biological Psychiatry in 2019, identified and validated a set of metabotypes based on differences in branch chain amino acid metabolism; these metabotypes represented 17% of the children with autism in CAMP. This new research builds on that effort, resulting in an optimized set of 34 newly defined metabotypes based on amino acid and energy metabolism. Taken together, the test battery now detects 53% of subjects with ASD in the CAMP study with 91% specificity."

Robert Burrier, PhD, Chief Operating Officer of Stemina and co-author points out that "Using metabolomics to detect objective biomarkers of ASD is a promising approach because metabolism is sensitive to interactions among the genome, gastrointestinal microbiome, diet, and environmental factors that all contribute to risk of ASD."

"The CAMP study is the seminal study of the metabolism of children with autism. The study was carefully designed to allow discovery and validation of subpopulations of children with ASD who share common metabolic differences from typically developing children," said Elizabeth Donley, JD, MBA, MS, NeuroPointDX Chief Executive Officer and a co-author of the publication. "We strive to discover, validate and publish peer reviewed science from this ground-breaking study with the goal of building trust in the rigor of our science and its potential to change how autism is diagnosed and treated."

"While further research is needed, given the virtual absence of effective biomarkers to detect autism risk in very young children, we are optimistic that this approach has enormous potential for identifying children as early as possible," said Dr. Amaral. "Moreover, determining that an individual child has a particular pattern of metabolic alterations may offer the possibility of new targeted and personalized therapies. These opportunities and questions require further testing in the CAMP study. Fortunately, CAMP retains a repository of blood samples from our young participants that can be used for follow-up studies. The current paper represents an important stride in the research journey toward understanding the role of metabotypes and their potential as actionable clinical tools in the detection and treatment of ASD."

"These new findings from the CAMP study represent another step in our efforts to develop a metabolomics-based screening tool for ASD," Donley added. "While biomarkers of any kind cannot provide a definitive diagnosis of ASD, combining a metabolomics-based screen with behavioral testing increases the likelihood that those at risk for ASD can be detected as early as possible."

While the published findings are based on collection of blood samples from children 18 to 48-months-old, future research will be directed at validating this metabolomics approach in children younger than one year old when current diagnostic procedures are lacking. The researchers are also exploring whether these metabolic differences can lead to insights that enable more targeted treatment options for children with ASD.

A multi-institutional group of researchers led by Harvard Medical School and the Novartis Institutes for BioMedical Research has created an open-source machine learning tool that identifies proteins associated with drug side effects.

The work, published June 18 in the Lancet journal EBioMedicine, offers a new method for developing safer medicines by identifying potential adverse reactions before drug candidates reach human clinical trials or enter the market as approved medicines.

The findings also offer insights into how the human body responds to drug compounds at the molecular level in both desired and unintended ways.

"Machine learning is not a silver bullet for drug discovery, but I do believe it can accelerate many different aspects in the difficult and long process of developing new medicines," said paper co-first author Robert Ietswaart, research fellow in genetics in the lab of Stirling Churchman in the Blavatnik Institute at HMS. Churchman was not involved in the study.

"Although it cannot predict all possible adverse effects, we hope that our work will help researchers spot potential trouble early on and develop safer drugs in the future," Ietswaart said.

Drug side effects, technically known as adverse drug reactions, range from mild to fatal. They may occur either when taking a drug as prescribed or as a result of incorrect dosages, interaction of multiple medicines or off-label use (taking a drug for something other than what it was approved for). Adverse drug reactions are responsible for 2 million U.S. hospitalizations each year, according to the Department of Health and Human Services, and occur during 10 to 20 percent of hospitalizations, according to the Merck Manuals.

Researchers and health care providers have applied many tactics over the decades to avoid or at least minimize adverse drug reactions. But because a single drug often interacts with multiple proteins in the body--not always limited to the intended targets--it can be hard to predict what, if any, side effects a medicine may generate. And if a drug does end up causing an adverse reaction, it can be hard to identify which of its protein targets could be responsible.

In the new study, researchers took one existing database of reported adverse drug reactions and another database of 184 proteins that specific drugs are known to often interact with. Then they constructed a computer algorithm to connect the dots.

"Learning" from the data, the algorithm unearthed 221 associations between individual proteins and specific adverse drug reactions. Some were known and some were new.

The associations indicated which proteins likely represent drug targets that contribute to particular side effects and which others may be innocent bystanders.

Based on what it has already "learned," and strengthened by any new data that researchers feed it, the program may help doctors and scientists predict whether a new drug candidate is likely to cause a certain side effect on its own or when combined with particular medicines. The algorithm can help with these predictions before a drug is tested in humans, based on lab experiments that reveal which proteins the drug interacts with.

The hope is to raise the likelihood that a drug candidate will prove safe for patients before and after it reaches the market.

"This could reduce the risks that study participants face during the first in-human clinical trials and minimize risks for patients if a drug gains FDA approval and enters clinical use," said Ietswaart.

Hack your side effects

The project was born at a quantitative science hackathon organized by Novartis Institutes for BioMedical Research (NIBR) in 2018.

Laszlo Urban, global head of preclinical secondary pharmacology at NIBR, presented on some of the problems his team faces when assessing the safety of new drug candidates. A group of Boston-area graduate students and postdocs at the hackathon jumped to apply their knowledge of data science and machine learning.

Most of the time, projects from the hackathon end as learning exercises, said Urban. On this rare occasion, however, a strong and lasting interaction of inspired scientists from different institutions resulted in a novel application published in a highly respected journal, he said.

Four members of the original hackathon group became co-first authors of the paper: Ietswaart at HMS, Seda Arat from The Jackson Laboratory, Amanda Chen of MIT and Saman Farahmand from the University of Massachusetts Boston. Arat is now at Pfizer. Another team member, Bumjun Kim of Northeastern University, is a co-author. Urban became senior author of the paper.

To tackle the problem, the team constructed its machine learning algorithm and applied it to two large data sets: one from Novartis with information about the proteins that each of 2,000 drugs interact with and one from the FDA with 600,000 physician reports of adverse drug reactions in patients.

The algorithm generated statistically robust information about how individual proteins contribute to documented adverse reactions, said Ietswaart.

"It suggests the physiological response to perturbing a particular protein--or the gene that makes it--at the molecular level," he said.

Many of the results supported previous observations, such as that binding to the protein hERG can cause cardiac arrhythmias. Findings like this strengthened the researchers' confidence that the algorithm was performing well.

Other results, however, were unexpected.

For instance, the algorithm suggested that the protein PDE3 is associated with over 40 adverse drug reactions. Doctors and researchers have known for years that PDE3 inhibitors--common anti-clotting treatments for acute heart failure, stroke prevention and a heart attack complication known as cardiogenic shock--can cause arrhythmias, low platelet counts and elevated levels of enzymes called transaminases, a possible indicator of liver damage. But it wasn't known that targeting PDE3 might raise the risk of so many other side effects, including some related to the muscles, bones, connective tissue, kidneys, urinary tract and ear.

Into the future

The algorithm also offered predictions on the likelihood that a particular drug would cause a certain adverse reaction.

How accurate were those new predictions? To find out, the researchers fed their algorithm updated information. Until then, the program had learned from adverse drug reactions reported through 2014. The team added reports gathered from 2014 through 2019, some of which revealed side effects that hadn't been observed before from particular drugs.

Sure enough, many of the algorithm's previously unproven predictions matched the recent real-world reports.

"What seemed like false-positive predictions proved not to be false at all when the new reports became available," said Ietswaart.

To make extra certain that the algorithm is reliable, the team compared its results to drug labels, conducted text mining of the scientific literature and used other validation techniques.

Although the researchers strengthened the model as much as they could, it still assesses less than 1 percent of the 20,000 genes in the human genome.

"Our work is by no means a complete understanding of adverse drug events because many other genes and proteins might contribute for which no assay is available or no drugs have been tested," said Ietswaart.

Scientists can use, improve and build upon the model, which is posted for free online at https://github.com/samanfrm/ADRtarget.

"This work has been a collaborative 'open science' spirit and team effort," said Ietswaart and Urban.

19 June 2020, Singapore - A study conducted by clinicians from KK Women's and Children's Hospital (KKH) and researchers at the Nanyang Technological University, Singapore (NTU), which evaluated and demonstrated the safety and effectiveness of a KKH-developed novel clinical protocol to screen and triage women with threatened miscarriages, has been published in the journal, Scientific Reports.

In the novel clinical protocol, a single serum progesterone (a blood test to measure the progesterone level in the body) is used to screen and triage women with threatened miscarriages, thereby guiding clinicians in the stratification and management of these patients. This screening protocol identified 240 high-risk pregnancies with a low progesterone level, with subsequent treatment and preventing a miscarriage in 70 (29.2%) high-risk pregnancies. 847 (77.9%) low-risk women with high progesterone level avoided the use of progestogens, with a miscarriage rate of less than 10%. This safe and effective clinical protocol has revolutionised the management of women with threatened miscarriage, and can be readily adapted for use in other healthcare institutions with only a single blood test.

Threatened miscarriage, which presents as vaginal bleeding in early pregnancy, affects up to 25% of all pregnancies, and 15% to 20% of threatened miscarriages progress to spontaneous miscarriage. There is currently no effective treatment available for a threatened miscarriage. However, progestogens, a medication to support pregnancies, in particular those with low progesterone levels, is given routinely by many healthcare institutions in the world including KKH, prior to the implementation of the novel clinical protocol.

Associate Professor Tan Hak Koon, Chairman, Division of Obstetrics and Gynaecology, KKH, said, "As the largest maternity hospital in Singapore, KKH manages an average of about 15 threatened miscarriages in a day, and therefore this validated novel clinical protocol marks a significant milestone for us, propelling us towards our goal of improving the health outcomes for generations of pregnant women and their babies. With this effective and safe screening and triage clinical protocol, pregnant women with risk of a threatened miscarriage can be detected early, receive timely intervention including anticipatory guidance, counselling, medical treatment, or monitored closely for adverse pregnancy outcomes throughout the rest of the pregnancy."

This study was recently published in the journal, Scientific Reports, and involved a total of 1,087 pregnant women presenting with a threatened miscarriage at the Urgent O&G Centre, KKH - Singapore's largest academic medical centre specialising in women's and children's health. The strength of this study is that it is the largest prospective cohort study of a novel clinical protocol.

In the study, pregnant women with threatened miscarriages were triaged and stratified into two groups - the high-risk group (77.9%) consists of pregnant women who had serum progesterone

23.1% of pregnant women experienced a spontaneous miscarriage before 16 weeks of pregnancy. Among the women who received progesterone treatment, 29.2% of women in the high-risk group and 90.4% of women in the low-risk group continued with their pregnancies beyond 16 weeks. Miscarriages despite progesterone treatment may be attributable to other causes, such as chromosomal abnormalities, infections and maternal diseases, regardless of serum progesterone levels.

Co-author of the study, Dr Ku Chee Wai, Division of Obstetrics and Gynaecology, KKH, said, "The novel clinical protocol in the study has been established to be effective and accurate in predicting pregnant outcomes at 16 weeks of gestation amongst the two risk- stratified groups. Through early intervention, we were able to prevent a miscarriage in about 70 (29.2%) pregnancies. We have also avoided the use of progestogens in 847 (77.9%) pregnant women, without increasing their risk of miscarriage. This further reduces the potential side effects or adverse outcomes associated with medical therapy, with increased financial savings for the patient. Women with normal progesterone levels are further reassured that they will have a high chance of having a successful pregnancy, leading to less anxiety and a positive pregnancy experience."

KKH and NTU had also conducted another related study2, published earlier this year. The KKH-led study, 'Characterisation of serum progesterone and progesterone-induced blocking factor (PIBF) levels across trimesters in healthy pregnant women', published in the journal, Scientific Reports, in March 2020, showed that serum progesterone and PIBF levels play important roles in healthy pregnancies, with increasing progesterone and PIBF concentrations seen in advancing trimesters and increasing gestational age. This may lead to the development of reference ranges for progesterone and PIBF to predict the viability in all three trimesters of pregnancy, and support further research on the role of progesterone and PIBF in the maintenance of healthy pregnancies.

What The Study Did: Researchers examined what demographic and clinical factors are associated with the decision to withdraw life-supporting treatment in patients with severe traumatic brain injury using data from more than 825 trauma centers in the U.S.

Authors: Theresa Williamson, M.D., of Duke University Medical Center in Durham, North Carolina, 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/jamasurg.2020.1790)

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

What The Study Did: Whether the prone position is associated with improved oxygenation and decreased risk for intubation in spontaneously breathing patients with severe COVID-19 hypoxemic respiratory failure is investigated in this observational study.

Authors: Sanja Jelic, M.D., of the Columbia University Vagelos College of Physicians and Surgeons in New York, 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/jamainternmed.2020.3030)

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

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Kilchberg/Switzerland: Disease-related, profound fatigue impairs the quality of life of many people with rheumatic and musculoskeletal diseases. A Belgian study (1) has now concluded that early intensive treatment combining methotrexate with a bridging scheme of prednisone can reduce the onerous fatigue - this also applies to patients at low risk of a severe course. The European League against Rheumatism (EULAR) therefore recommends, that even in so-called low-risk patients, early consideration should be given to whether intensive treatment should be initiated.

Patients with rheumatoid arthritis (RA) suffer from chronically inflamed joints. The inflammatory processes in the body can lead to a feeling of weakness, exhaustion, and lassitude - this abnormal tiredness is called "fatigue". Such fatigue is poorly helped by resting and can accompany patients constantly or at least over long distances.

"In addition to pain, profound fatigue reduces the quality of life for many people, even more than the swelling of the joints", explains EULAR President Professor Dr. Iain B. McInnes from Glasgow, Scotland, UK. However, doctors often do not pay sufficient attention to this fact and do not adjust the therapy accordingly.

A recent Belgian two-year study has now examined the question of whether early intensive treatment of RA directly after diagnosis has a positive influence on the course of the disease and offers an opportunity to manage the fatigue. Using the same approach, it also examined whether these mechanisms also apply to patients who have a lower risk of a severe disease progression.

"Up to 90 percent of patients with rheumatoid arthritis report profound fatigue," says Dr. Diederik De Cock, Katholieke Universiteit Leuven, Belgium, who conducted the study together with his team. Fatigue has a major impact on patients' lives and is perceived by many as difficult to manage. "The early course of the disease could provide an opportunity to manage fatigue."

Eighty patients with a low risk profile were selected for the study - this risk profile is based, among other things, on a low disease activity status. Randomized into two groups of 38 and 42 patients, the subjects received, directly after diagnosis of RA, monotherapy with 15 mg methotrexate weekly or a combination therapy of 15 mg methotrexate weekly plus cortisone (prednisone) starting at 30 mg but tapered weekly to 5mg. Methotrexate suppresses the disease and acute inflammatory reaction, while prednisone has a strong anti-inflammatory effect and is suitable for reducing pain and inflammation of the joints very quickly.

The result: Patients who received intensive treatment with the combination therapy of both drugs for two years were less tired than the patients in the monotherapy control group - even though the disease activity in both groups were comparable over time. The levels of fatigue seemed to differ more and more over time between groups.

"This underlines the importance of initiating optimal, intensive treatment early on, even in so-called low-risk patients," says EULAR Scientific Chair of the Congress, Professor Dr. John Isaacs from Newcastle University, UK. Unfortunately, this is not yet standard practice. The study clearly shows how fatigue levels in early RA can be significantly improved, the congress president concludes. About one percent of all people worldwide suffer from rheumatoid arthritis - according to figures published by EULAR in the run-up to its annual congress (2).