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Newswise — LA JOLLA—Every year, more than 68,000 people end up with a clinical case of Japanese encephalitis. One in four of these patients will die. The mosquito-borne virus, which is most common in Southeast Asia, also causes severe neurological damage and psychiatric disorders.  There is no cure for Japanese encephalitis, but there are effective vaccines against Japanese encephalitis virus (JEV). The problem is that JEV’s range is spreading, and more and more people at risk of the disease also live in areas where viruses like Zika are prevalent. In a new study, published June 5, 2020, in the Journal of Experimental Medicine, scientists at La Jolla Institute for Immunology (LJI) shows that antibodies against JEV are “cross-reactive” and can also recognize Zika virus. Unfortunately, these antibodies can actually make Zika cases more severe. The research, conducted in mice, is the first to show that T cells can counteract this dangerous phenomenon. “This means we probably need to be developing a vaccine against both viruses that can elicit a good balance of antibodies and T cells,” says Associate Professor Sujan Shresta, Ph.D., who co-led the study in collaboration with Jinsheng Wen, Ph.D., of Ningbo University and Wenzhou Medical University, and Yanjun Zhang, Ph.D., of Zhejiang Provincial Center for Disease Control and Prevention. Shresta has spent much of her career studying flaviruses, a family of viruses which includes Zika, JEV, dengue, West Nile virus and yellow fever. These diseases have spread in recent years as more people around the world have moved to cities and climate change has allowed the mosquitoes that carry these diseases to expand their habitat. People in many countries now live at risk of encountering multiple harmful flaviviruses in their lives. “The immune responses to these viruses are very cross-reactive,” says Shresta. “The problem is that the immune response can be both good and bad.” In some cases, antibodies against one flavivirus can make a future flavivirus infection even worse by allowing the virus to enter host cells. Shresta and investigators worldwide have shown this process, called antibody-dependent enhancement (ADE), during Zika and dengue infections in animal models that recapitulate severe dengue or Zika disease in individuals with prior exposure to dengue or Zika virus. However, ADE of Zika disease in cases of previous JEV exposure, and the interplay between antibodies and infection-fighting immune cells called CD8+ T cells, had not been studied before. For the new study, Shresta and her colleagues took antibodies from JEV-infected mice or JEV-vaccinated people and injected them into healthy mice. The healthy mice were then exposed to Zika virus. These mice experienced ADE and had far more severe cases of Zika fever than mice with no antibodies against JEV. Shresta and her colleagues next focused their attention on CD8+ T cells from JEV-infected mice. They found that CD8+ T cells primed to fight JEV could counteract the harmful effects of cross-reactive antibodies. “These JEV-elicited T cells were indeed able to recognize and get rid of the Zika virus infection,” says Shresta.  In short, the mouse survival rate went up and their viral load went down, thanks to the CD8+ T cells. A future JEV vaccine would need to prompt a similar response from CD8+ T cells to help a person avoid ADE of Zika infection.  Shresta says this work can help shed light on how to fight the whole family of flaviviruses, which includes over 70 different species, and many countries are increasingly dealing with cocirculation of multiple flaviviruses. “Any of these viruses could cause a major, major outbreak,” says Shresta. “We need to look at deploying a combination Zika/JEV vaccine, and we may need to tailor vaccines to particular locations where we know both JEV and Zika pose a threat.” Shresta adds that research into cross-reactive antibodies and T cell responses is especially important today as scientists investigate whether exposure to common cold coronaviruses can leave a person with any immunity against SARS-CoV-2, the novel coronavirus. “This provides us with a really good model to learn about immune response,” Shresta says. The study, titled, “Japanese encephalitis virus-primed CD8+ T cells prevent antibody-dependent enhancement of Zika virus pathogenesis,” was supported by the K.C. Wong Magna Fund of Ningbo University, the Zhejiang Provincial Natural Science Foundation (LY17C010004), the National Natural Science Foundation of China (31870159) and institutional funds from the La Jolla Institute for Immunology.  Additional authors included Zhiliang Duan, Wenhua Zhou, Weiwei Zou, Shengwei Jin, Dezhou Li, Xinyu Chen, Yongchao Zhou, Lan Yang and Yanjun Zhang. DOI: 10.1084/jem.20192152

Newswise — Hamilton, ON (June 1, 2020) – A comprehensive review of existing evidence supports physical distancing of two metres or more to prevent person-to-person transmission of COVID-19, says an international team led by McMaster University and St. Joseph’s Healthcare Hamilton.  Face masks and eye protection decrease the risk of infection, too.  The systematic review and meta-analysis was commissioned by the World Health Organization. The findings were published today in The Lancet.  “Physical distancing likely results in a large reduction of COVID-19,” said lead author Holger Schünemann, professor of the departments of health research methods, evidence, and impact, and medicine at McMaster.  Schünemann is co-director of the World Health Organization (WHO) Collaborating Centre for Infectious Diseases, Research Methods and Recommendations. He also is director of Cochrane Canada and McMaster GRADE Centre.  “Although the direct evidence is limited, the use of masks in the community provides protection, and possibly N95 or similar respirators worn by health-care workers suggest greater protection than other face masks,” Schünemann said. “Availability and feasibility and other contextual factors will probably influence recommendations that organizations develop about their use. Eye protection may provide additional benefits.”  The systematic review was conducted by a large, international collaborative of researchers, front-line and specialist clinicians, epidemiologists, patients, public health and health policy experts of published and unpublished literature in any language.  They sought direct evidence on COVID-19 and indirect evidence on related coronaviruses causative of Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS). The team used Cochrane methods and the Grading of Recommendations, Assessment, and Evaluation (GRADE) approach which is used world-wide to assess the certainty of evidence.  They identified no randomized control trials addressing the three coronaviruses but 44 relevant comparative studies in health-care and non-health-care (community) settings across 16 countries and six continents from inception to early May 2020.  The authors noted more global, collaborative, well-conducted studies of different personal protective strategies are needed. For masks, large randomized trials are underway and are urgently needed.  The scientific lead is Derek Chu, a clinician scientist in the departments of health research methods, evidence, and impact, and medicine at McMaster and an affiliate of the Research Institute of St. Joe's Hamilton.  “There is an urgent need for all caregivers in health-care settings and non-health-care settings to have equitable access to these simple personal protective measures, which means scaling up production and consideration about repurposing manufacturing,” said Chu.  “However, although distancing, face masks, and eye protection were each highly protective, none made individuals totally impervious from infection and so, basic measures such as hand hygiene are also essential to curtail the current COVID-19 pandemic and future waves.”  The work was funded by the World Health Organization and involved close collaboration with the American University of Beirut, Lebanon and many international partners. Photo credit: by Gerli Sirk Caption: Holger Schünemann is a professor of the departments of health research methods, evidence, and impact, and medicine at McMaster. He is also co-director of the World Health Organization (WHO) Collaborating Centre for Infectious Diseases, Research Methods and Recommendations.

Tokyo, Jun 1, 2020 A team of scientists from Japan recently achieved more efficient degradation of the human serum albumin protein—an important protein in the blood—via high-intensity infrared irradiation, by attaching a zinc metal complex to the protein. Their findings indicate potential for future application of certain metal complexes to therapeutic interventions for diseases such as Alzheimer’s. Artificial metalloenzymes are hybrid compounds that are synthesized by attaching metal complexes to protein molecules. In the past few years, these compounds have garnered considerable attention in research communities because of their applicability as bio-inspired catalysts, in biofuel cells, and in therapeutic interventions such as targeted protein degradation and drug delivery. Advancing research on their application in targeted protein degradation, a team of scientists from the Tokyo University of Science, Japan, and Universidad Complutense de Madrid, Spain, examined the degradation of a specific metalloenzyme upon irradiation with high-energy infrared radiation. This metalloenzyme was one they had created by attaching a zinc metal complex (ZnL) to human serum albumin (HSA).  The use of high-energy infrared radiation to degrade proteins is not new. For instance, a previous study at the Tokyo University of Science used this technique to degrade several protein aggregates, including the protein aggregate whose buildup between neurons in the brain, called amyloid plaque, causes Alzheimer’s disease. What the present study finds, as Dr Takashiro Akitsu, lead scientist, explains, is that “when human serum albumin is conjugated with a zinc complex, protein damage is promoted upon irradiation with a mid-infrared free-electron laser.” A mid-infrared free-electron laser (IR-FEL) is the instrument that the scientists used to irradiate the hybrid. The team of scientists comprising Prof Akitsu, Prof Koichi Tsukiyama, Dr Takayasu Kawasaki, and Assistant Prof Tomoyuki Haraguchi, among others, from Japan and Prof Mauricio A. Palafox from Complutense de Madrid, Spain, first used infrared (IR) spectroscopy to verify the attachment of ZnL to HSA. The IR spectra they obtained also indicated the optimal wavelengths for degradation: these were 1537, 1652, and 1622 cm-1, corresponding to the two amide bonds in HSA and the carbon-nitrogen double bond of ZnL, respectively. The scientists created thin films of both the HSA and the HSA+ZnL hybrid and irradiated targeted portions of these films. They then compared the radiation damage caused by IR-FEL irradiation to the films, using a technique called Fourier transform infrared (FT-IR) microscopy and a program to evaluate changes in the protein secondary structure, called IR-SSE.  At 1622 cm-1, the HSA+ZnL hybrid structure did not dissociate. But, at the other two wavelengths, the protein structure of HSA, in both the pure HSA and hybrid forms, appeared significantly damaged. Further, in the latter cases, the hybrid compound was more degraded than pure HSA was. The scientists believe that the attachment of ZnL to the HSA protein destabilized the protein structure, allowing it to degrade more easily. Overall, this attachment of ZnL was feasible and assisted the degradation of the protein instead of alleviating it. These results are presented in a paper published in the International Journal of Molecular Sciences, in which the scientists highlight that “at present, the exact binding mechanism between the complex and the protein is unknown.” Further, Prof Akitsu clarifies that “research on various protein-metal complex pairs is ongoing.” The findings of this study cannot yet be generalized and until scientists have better insights, the applications of such metal complex-protein hybrids in therapeutic interventions or other areas of biotechnology will remain limited. Nevertheless, this study, in addition to the previous studies conducted at the Tokyo University of Science in this field, certainly makes us hopeful of a future in which diseases that involve protein defects, such as Alzheimer’s, are curable. *** Reference Title of original paper: Degradation of Human Serum Albumin by Infrared Free Electron Laser Enhanced by Inclusion of a Salen-Type Schiff Base Zn (II) Complex Journal: International Journal of Molecular Sciences DOI: 10.3390/ijms21030874     About the Tokyo University of Science Tokyo University of Science (TUS) is a well-known and respected university, and the largest science-specialized private research university in Japan, with four campuses in central Tokyo and its suburbs and in Hokkaido. Established in 1881, the university has continually contributed to Japan's development in science through inculcating the love for science in researchers, technicians, and educators. With a mission of “Creating science and technology for the harmonious development of nature, human beings, and society", TUS has undertaken a wide range of research from basic to applied science. TUS has embraced a multidisciplinary approach to research and undertaken intensive study in some of today's most vital fields. TUS is a meritocracy where the best in science is recognized and nurtured. It is the only private university in Japan that has produced a Nobel Prize winner and the only private university in Asia to produce Nobel Prize winners within the natural sciences field.  Website: https://www.tus.ac.jp/en/mediarelations/ About Prof Takashiro Akitsu from the Tokyo University of Science Takashiro Akitsu is a Professor at the Faculty of Science at Tokyo University of Science. As an active researcher in the field of inorganic chemistry, he focuses particularly on coordination chemistry and materials science. He has a PhD from Osaka University, having focused his post-graduate research on coordination, crystal and bioinorganic chemistry. He was named Professor of the Year in 2018 for his teaching work on biomaterials, and holds a patent for an ultraviolet absorber since 2016.  Funding information This research was supported by the Japanese Ministry of Education, Culture, Sports, Science and Technology, under the Photon Beam Platform Project.

Coriell Life Sciences’ advanced data analytics examine individuals’ health history to identify those who are more likely to have severe or fatal outcomes if infected with novel coronavirus. Newswise — As more businesses and employees prepare to return to work around the country, Coriell Life Sciences (CLS) is rolling out a new tool in the fight against COVID-19: personalized COVID-19 Risk Scores.  Using proprietary, advanced data analytics, CLS analyzes information from medical records to identify the number of unique risk factors linked to poor COVID-19 outcomes an individual has.  Factors include thousands of potential risk elevators, from cardiovascular disease, diabetes and hypertension to allergies, anemia, and more.  The higher the number of risk factors, the higher the likelihood of experiencing severe or fatal symptoms if infected with the virus. “This type of intelligence has the power to play a pivotal role in protecting the most vulnerable among us,” says Jeffrey A. Shaman, PhD, Chief Science Officer at Coriell Life Sciences.  “It’s clear people who suffer from chronic medical conditions are far more likely to fare poorly if they have COVID-19, but it’s hardly that simple.  Other factors, such as blood type and medications used, are also showing evidence they may be related to negative outcomes.  By analyzing individuals’ health history against thousands of medical codes that are aligned to risk factors for poor COVID-19 outcomes, we can determine who has the greatest risk of requiring acute care and empower them to be more vigilant in protecting their health.” Individuals are eligible for COVID-19 risk scoring through participating employers.    “Beyond empowering individuals to better protect their health, this information can also be used to help business leaders strategically tackle the high-stakes complexities surrounding when and how to get their teams back to work safely,” notes Coriell Life Sciences’ President & CEO Scott Megill.  “Both are critical elements in lessening the impact of this pandemic on public health and our country’s economic health.  The bottom line is we must make better use of the information that’s available today while the global scientific community remains keenly focused on scaling diagnostics and developing effective therapeutics and a viable vaccine.” COVID-19 risk scoring is part of CLS’ new Return to Work Program.  This program provides an intelligence-driven solution designed to help organizations safely resume operations.  In addition to analyzing employee and facility data to illuminate risks and barriers to re-opening, the program offers businesses turnkey infrastructure for managing large-scale COVID-19 testing of employees in partnership with a network of laboratories across the country. A leader in genetic science, CLS also enables organizations to help employees advocate for their health by offering personalized COVID-19 Genetic Drug Safety Reports.  Based on preemptive DNA testing, this report reveals how an individual would likely respond to approximately 45 drugs that could be used during COVID-19 treatment and have known genetic implications.  This information can be provided to a physician or pharmacist to inform an effective treatment plan. “The reality is that some drugs just don’t work for some people,” notes Dr. Shaman.  “Some aren’t safe for one person but are completely fine for another.  Differences in our DNA are responsible for some of this variation.  Precision medicine enables us to determine which drugs will be both safe and effective for patients with COVID-19 – as well as many other conditions.”  To learn more, visit coriell.com.   About Coriell Life Sciences Coriell Life Sciences (CLS), a leader in genetic science, uses innovation in precision medicine to reduce healthcare costs and empower a healthier world.  With scientific expertise that spans six decades, CLS bridges the gap between genetic knowledge and clinical application and offers the most comprehensive medication risk management program on the market.  Visit coriell.com, email info@coriell.com or follow @CoriellLife.

Renowned program led by James M. Wilson, MD, PhD, a leading expert in the technology platform used in the experimental vaccine, to conduct preclinical studies in joint research and development project with Massachusetts Eye and Ear and Massachusetts General Hospital. Newswise — The internationally-renowned Gene Therapy Program at the University of Pennsylvania is joining the AAVCOVID vaccine program led by Massachusetts Eye and Ear and Massachusetts General Hospital (MGH), members of Mass General Brigham for the joint research program. AAVCOVID is a unique gene-based vaccine candidate designed to protect against SARS-CoV-2, the virus that causes COVID-19. The AAVCOVID vaccine program was developed in the laboratory of Luk H. Vandenberghe, PhD, director of the Grousbeck Gene Therapy Center at Massachusetts Eye and Ear and Associate Professor of Ophthalmology at Harvard Medical School. AAVCOVID is a prophylactic gene-based immunization approach that uses an adeno-associated virus (AAV) vector to deliver and express gene fragments of SARS-CoV-2 virus to the body to elicit a protective immune response. The AAVCOVID vaccine is currently in preclinical development with a plan to begin clinical testing in humans later this year. Mason Freeman, MD, director and founder of the MGH Translational Research Center and a Professor of Medicine at Harvard Medical School, is leading the efforts to develop the clinical studies intended to establish safety and efficacy of the experimental vaccine. The AAVCOVID vaccine program will greatly benefit from the participation of Penn Medicine’s Gene Therapy Program, led by gene transfer pioneer James M. Wilson, MD, PhD, as the Gene Therapy Program’s involvement will enable the experimental vaccine to undergo additional rounds of critical preclinical studies that are required for the U.S. Food and Drug Administration investigational new drug (IND) application process. “We are leveraging the enormous clinical experience of AAV for gene therapy in this vaccine application. The capsid selected for this project was discovered when Luk was a graduate student in my lab. It has the unique properties of activating immune responses, which is important for its use as a genetic vaccine, rather than suppressing immune responses which characterizes most capsids used for gene therapy. I am absolutely delighted to team up with Luk and Mason for this important project.” says Dr. Wilson, who is the Rose H. Weiss Professor and Director of the Orphan Disease Center, and Professor of Medicine and Pediatrics at Penn’s Perelman School of Medicine.  Under the direction of Dr. Wilson, the Gene Therapy Program currently employs over 280 full-time employees with operations supported by a diverse group of public and private sponsors. “Dr. Wilson and his lab have made seminal contributions to the field of gene transfer for vaccines and therapy. The expertise and speed in pre-clinical development from this world-leading team joining the AAVCOVID project is a tremendous gain towards our ultimate goal of getting a vaccine into the clinic,” says Dr. Vandenberghe.  “We are grateful to the Gene Therapy Program at Penn Medicine and our collaborators in academia and industry for their shared commitment to battling the coronavirus pandemics.” About AAVCOVID Vaccine Program The AAVCOVID vaccine program is a gene-based vaccine strategy that seeks to deliver genetic sequences of the SARS-CoV-2 using an AAV vector. Vaccination delivers genetic DNA fragments from SARS-CoV-2 which generates an antigen protein, which is designed to elicit an immune response to prevent infection. This approach is supported by extensive data demonstrating safety of the AAV technology platform in other diseases, including two FDA-approved medications. The AAVCOVID project collaboration is led by principal investigator Dr. Vandenberghe, the Grousbeck Family Chair in Gene Therapy at Mass. Eye and Ear, who is a world-renowned leader and pioneer of viral gene transfer and therapeutic gene transfer. Dr. Vandenberghe and his laboratory began work on the vaccine in mid-January following the Wuhan outbreak and the first publication of genetic sequences of the new coronavirus. Using a specific AAV with desirable vaccine properties, the program seeks to induce immunity to prevent infection and disease in healthy populations, leveraging the existing manufacturing capabilities of the AAV industry. Dr. Vandenberghe is working in conjunction with Dr. Freeman at MGH, who serves as Director of the Translational Medicine Group of the MGH Center for Computational and Integrative Biology and is Professor of Medicine at Harvard Medical School. The project aims to enter clinical trials in the second half of 2020. AAV is also a rapidly adaptable technology. If a new strain of the SARS-CoV-2 virus emerges, the genetic code inside the AAVCOVID vaccine could be exchanged for an updated genetic code and processed into a new vaccine in weeks, according to the researchers. About Massachusetts Eye and Ear Massachusetts Eye and Ear, founded in 1824, is an international center for treatment and research and a teaching hospital of Harvard Medical School. A member of Mass General Brigham, Mass. Eye and Ear specializes in ophthalmology (eye care) and otolaryngology–head and neck surgery (ear, nose and throat care). Mass. Eye and Ear clinicians provide care ranging from the routine to the very complex. Also home to the world's largest community of hearing and vision researchers, Mass. Eye and Ear scientists are driven by a mission to discover the basic biology underlying conditions affecting the eyes, ears, nose, throat, head and neck and to develop new treatments and cures. In the 2019–2020 “Best Hospitals Survey,” U.S. News & World Report ranked Mass. Eye and Ear #4 in the nation for eye care and #2 for ear, nose and throat care. For more information about life-changing care and research at Mass. Eye and Ear, visit our blog, Focus, and follow us on Instagram, Twitter and Facebook. About Massachusetts General Hospital Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH Research Institute conducts the largest hospital-based research program in the nation, with an annual research budget of more than $1 billion and comprises more than 8,500 researchers working across more than 30 institutes, centers and departments. In August 2019 the MGH was once again named #2 in the nation by U.S. News & World Report in its list of "America’s Best Hospitals." About Harvard Medical School Department of Ophthalmology The Harvard Medical School Department of Ophthalmology is one of the leading and largest academic departments of ophthalmology in the nation. Composed of nine affiliates (Massachusetts Eye and Ear, which is home to Schepens Eye Research Institute; Massachusetts General Hospital; Brigham and Women’s Hospital; Boston Children’s Hospital; Beth Israel Deaconess Medical Center; Joslin Diabetes Center/Beetham Eye Institute; Veterans Affairs Boston Healthcare System; Veterans Affairs Maine Healthcare System; and Cambridge Health Alliance) and several international partners, the department draws upon the resources of a global team to pursue a singular goal—eradicate blinding diseases so that all children born today will see throughout their lifetimes. Formally established in 1871, the department is committed to its three-fold mission of providing premier clinical care, conducting transformational research, and providing world-class training for tomorrow’s leaders in ophthalmology. About Penn Medicine Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation’s first medical school) and the University of Pennsylvania Health System, which together form a $8.6 billion enterprise. The Perelman School of Medicine has been ranked among the top medical schools in the United States for more than 20 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $494 million awarded in the 2019 fiscal year. The University of Pennsylvania Health System’s patient care facilities include: the Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center—which are recognized as one of the nation’s top “Honor Roll” hospitals by U.S. News & World Report—Chester County Hospital; Lancaster General Health; Penn Medicine Princeton Health; and Pennsylvania Hospital, the nation’s first hospital, founded in 1751. Additional facilities and enterprises include Good Shepherd Penn Partners, Penn Home Care and Hospice Services, Lancaster Behavioral Health Hospital, and Princeton House Behavioral Health, among others.

ATS Researchers fail to find subphenotypes of COVID-19 ARDS. Newswise — May 27, 2020─ In a new paper published online in the Annals of the American Thoracic Society, researchers have been unable to produce two theorized subphenotypes of COVID-19 related acute respiratory distress syndrome (ARDS).  Scientists previously proposed that two phenotypes exist that differentiate patients with more severe COVID-19 and indicate that they should be treated differently. A phenotype is a set of characteristics used to classify  a patient, which may influence disease management.     In “Subphenotyping ARDS in COVID-19 Patients: Consequences for Ventilator Management,” Lieuwe D.J. Bos, MD, PhD, and co-authors report on a retrospective analysis of the first 38 patients with suspected COVID-19 who were admitted to the ICU of the Academic Medical Center of the University of Amsterdam, The Netherlands.  CT scans were done shortly after these patients were intubated and before they were admitted to the ICU.  The scans were analyzed and compared with each other to determine factors that might indicate different phenotypes of COVID-19 ARDS. “Our finding was that most patients do not fulfill the criteria of one phenotype or the other,” said Dr. Bos, clinician and researcher in respiratory medicine and intensive care, Amsterdam University Medical Center.  “I do not feel encouraged to spilt patients into the two proposed phenotypes to guide ventilator management, but rather treat patients with the uniform, high quality care that we always deliver to patients with lung injury.” Some scientists have hypothesized that patients can either develop typical ARDS, which has recently been called “H type,” or that they develop “L type” ARDS. In H type, a patient’s lung collapses easily (high elastance) resulting in higher lung weight due to pulmonary edema, a condition in which the lungs fill with fluid.  Blood flows through areas that are not ventilated (higher shunt) and collapsed lungs can be opened by using positive pressure ventilation.   The “L” phenotype would have low elastance, which means lung tissue does not collapse easily, and because of this, the weight of the lung is low (normal) and most of the blood flows through areas where there is ventilation (low shunt). The problem in these patients might be that blood vessels in the lungs dysfunction. Several steps have to be taken before subphenotype-targeted treatment can be put into clinical practice, the last step being a head-to-head comparison of subphenotype-directed treatment with standard of care in a randomized clinical trial.  Before this step is taken, however, the basic assumptions underlying the subclassifications of patients must be validated.  Dr. Bos and colleagues sought to invalidate this theory and hypothesized that patients with low elastance also show little consolidation on chest CT scan images – and vice versa.  The researchers performed CT scans right after intubation and before transport to the ICU.  They estimated lung consolidation area for patients classified as having either an H- or L-phenotype, classified lung morphology as focal (back side of lung) or non-focal, and conducted a number of other calculations.  They found that in patients with a non-focal lung morphology, lung weight and lower respiratory compliance were not related at all. The authors stated: “Based on these preliminary data, we conclude that compliance and an estimation of lung weight do not correlate in patients with COVID-19 related ARDS. Most patients could not be classified as either ‘H’ or ‘L’ subphenotype, but showed mixed features. “The presented data are the first independent test of proposed subphenotypes of COVID-19 related ARDS and highlight that features of the H- and L-subphenotypes are not mutually  exclusive.  Simultaneously, we validated the existence of heterogeneity in lung morphology known from non-COVID-19 related ARDS.  We need data-driven approaches to evaluate the existence of treatable traits to improve patient-centered care.  Until these data become  available, an evidence-based approach extrapolating data from ARDS not related to COVID-19 is the most reasonable approach for ICU care.”    

Newswise — Lawrenceville, NJ, USA—May 26, 2020—Value in Health, the official journal of ISPOR—the professional society for health economics and outcomes research, announced today the publication of a series of articles focused on methods for moving from the evaluation of precision medicine into practice and policy. The series was published in the May 2020 issue of Value in Health. “Precision medicine is an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle,” said Guest Editor Kathryn A. Phillips, PhD, Center for Translational and Policy Research on Personalized Medicine, University of California at San Francisco, San Francisco, CA, USA. “This approach allows clinicians and researchers to predict more accurately which treatments and prevention strategies for a particular disease will work in which groups of people.” The themed section highlights next-generation sequencing technologies, which are the fastest-growing type of precision medicine technology. These technologies include panels that test multiple genes for a single indication, whole exome sequencing tests that evaluate the entire exome (coding regions of the genome), and whole genome sequencing tests that evaluate the entire genome. In her introductory editorial, “Methods for Moving the Evaluation of Precision Medicine Into Practice and Policy,” Phillips provides historical perspective and introduces the other 5 articles in the series: “Being Precise About Precision Medicine: What Should Value Frameworks Incorporate to Address Precision Medicine? A Report of the Personalized Precision Medicine Special Interest Group,” by Eric Faulkner,Anke-Peggy Holtorf, Surrey Walton, Christine Y. Liu, Hwee Lin, Eman Bilta,j Diana Brixner, Charles Barr, Jennifer Oberg, Gurmit Shandhu, Uwe Siebert, Susan R. Snyder, Simran Tiwana, John Watkins, Maarten J. IJzerman, and Katherine Payne “Use of Real-World Evidence in US Payer Coverage Decision-Making for Next-Generation Sequencing–Based Tests: Challenges, Opportunities, and Potential Solutions,” by Patricia A. Deverka, Michael P. Douglas, and Kathryn A. Phillips, PhD “Insights From a Temporal Assessment of Increases in US Private Payer Coverage of Tumor Sequencing From 2015 to 2019,”by Julia R. Trosman, Michael P. Douglas, Su-Ying Liang, Christine B. Weldon, Allison W. Kurian, Robin K. Kelley, and Kathryn A. Phillips “Quantifying Downstream Healthcare Utilization in Studies of Genomic Testing,” by Zoë P. Mackay, Dmitry Dukhovny, Kathryn A. Phillips, Alan H. Beggs, Robert C. Green, Richard B. Parad, and Kurt D. Christensen “Addressing Challenges of Economic Evaluation in Precision Medicine Using Dynamic Simulation Modeling,” by Deborah A. Marshall, Luiza R. Grazziotin, Dean A. Regier, Sarah Wordsworth, James Buchanan, Kathryn A. Phillips, and Maarten Ijzerman “Much progress has been made in developing and applying methods to evaluate precision medicine,” said Phillips. “Nevertheless, new tests such as minimally invasive liquid biopsies and emerging approaches such as artificial intelligence and machine learning platforms will continue to require the development and adaptation of methods used to assess the value of precision medicine. The collective efforts of a society like ISPOR can bring together the wide range of disciplines and stakeholders that will be needed to continue to evolve the methods and approaches used to assess precision medicine.”

Newswise — Anopheles mosquitoes that have been genetically engineered with multiple anti-malaria molecules, acting at different stages of the malaria life cycle, are strongly resistant to the parasite that causes malaria and are unlikely to lose that resistance quickly, according to a study from scientists at Johns Hopkins Bloomberg School of Public Health. The study, published May 13 in the journal Science Advances, is an early-stage laboratory demonstration that will be followed by further testing. The findings suggest that releasing such mosquitoes in areas where malaria is endemic could dramatically reduce local, mosquito-borne transmission of malaria to humans for prolonged periods. “We were able to achieve a very efficient suppression of infection in the mosquitoes by combining antimalarial proteins that would be difficult for the parasite to evade,” says senior author George Dimopoulos, PhD, professor in the Department of Molecular Microbiology and Immunology at the Bloomberg School. Malaria is caused by Plasmodium parasites, which infect certain mosquito species and can be transmitted among humans and other mammals via mosquito “bites.” The disease continues to be one of the world’s top public health threats, accounting for about 200 million clinical cases and 400,000 deaths per year, mostly children under age five in sub-Saharan Africa. Decades of efforts towards a malaria vaccine have resulted so far in just one product. In a large clinical trial, the vaccine reduced serious malaria cases by only about 30 percent—far from the near-complete protection provided by modern vaccines against most viruses and bacteria. Antimalaria drugs are available but have significant side effects, provide incomplete protection against malaria symptoms, and do not prevent human infection by the parasite. A newer approach, inspired by the emergence of genetic engineering technology, is to create populations of mosquitoes that carry genes conferring resistance to malaria parasites. In theory, releasing such mosquitoes into the wild would lead to the spread of those genes in local mosquito populations, a consequent decline in Plasmodium infection in the mosquitoes, and thus a decline in mosquito-borne transmission of malaria to humans. Scientists since the late 1990s have reported numerous strategies for engineering malaria resistance into mosquitoes. However, the malaria parasite is a relatively large organism compared to bacteria and viruses; it has thousands of genes with which it can evolve ways to survive and keep proliferating in its mosquito or mammalian hosts despite attacks from antimalarial drugs or other factors. In the new study, Dimopoulos and his team engineered Anopheles mosquitoes with a combination of multiple antimalarial effector proteins that block infection. This strategy minimizes the parasite’s chances of developing resistance to the effector proteins and resume the parasite’s ability to be transmitted to and infect humans. One element of the strategy was a single artificial gene, or transgene, encoding five proteins that are known to kill malaria parasites; these included Shiva 1, a toxin from spider venom; Scorpine, a toxin from scorpion venom; and Melittin, a toxin from bee venom. The scientists combined this five-in-one transgene with another transgene encoding an antibody-plus-toxin molecule that homes in on the late, sporozoite stage of the parasite. As an alternative strategy, the scientists combined the antibody-toxin transgene with a transgene that stimulates the early mosquito immune defense against malaria infection. The transgenes in each case were designed to become active whenever the host mosquito had a blood meal. The scientists found that both of these combination approaches succeeded in greatly suppressing infection of mosquitoes by Plasmodium falciparum, the parasite species that causes most of the serious cases of malarial illness and nearly all malaria deaths. The degree of suppression was more than enough, in principle, to eliminate or greatly reduce malaria transmission to humans by such engineered mosquitoes. Mosquitoes carrying the foreign, insect-venom genes were found to have suffered a slight “fitness cost” in terms of reduced lifespan, which in the wild would result in the loss of these genes from the mosquito gene pool over time. However, in practice, antimalarial transgenes can be engineered into mosquitoes with so-called “gene drives” that overcome normal mechanisms of heredity and essentially force the antimalarial transgenes into a high percentage of mosquito offspring. This strategy, if proven successful, could one day convert a malaria-transmitting mosquito population to one that can’t transmit the parasite. Dimopoulos and his team now plan to follow up by integrating their antimalarial transgenes into gene drive systems and by modeling the effects on malaria transmission of releasing these engineered mosquitoes in the wild. “Ultimately, transgenic mosquito -based strategies like ours probably will advance to the point that there will be test releases of engineered mosquitoes under controlled conditions,” Dimopoulos says. “Once those studies show there is no danger, then I think that people will be more open to this type of approach to malaria prevention.“Versatile transgenic multi-stage effector-gene combinations for Plasmodium falciparum suppression in Anopheles” was written by Yuemei Dong, Maria L. Simões, and George Dimopoulos. Support for the research was provided by the National Institutes of Health (R01AI061576, R01AI061576, R01AI122743, R01AI122743), the Bloomberg Philanthropies, and the Johns Hopkins Malaria Research Institute.

Cellular processes happen every day in humans and plants, such as homeostasis and photosynthesis The cells involved in the process are so complex it’s challenged human understanding, especially how they act in different environments A bioelectrical conceptualisation of cells could be the key to researching how cells operate, researchers at the School of Life Sciences, University of Warwick argue If the genetics, physics and physiology can be grounded on bioelectrical conceptualisation of cells it could have implications for research in conditions related to cellular processes Newswise — We use cells to breathe, to moderate body temperature, to grow and many other every day processes, however the cells in these processes are so complex its left scientists perplexed into how they develop in different environments. Researchers from the University of Warwick say future research needs to look into the bioelectrical composition of cells for answers. Cellular processes happen every day for survival, form homeostasis to photosynthesis and anaerobic respiration to aerobic respiration. However the complexity of cells has fascinated and challenged human understanding for centuries. It’s cellular “machinery” responsible for key functions have been the focus of biology research, and despite previous research exploring the molecular and genetic basis of these processes showing unprecedented insights, we still can’t fully understand and predict cell behaviour when challenged to different conditions. In particular, the basis of heterogeneity in single-cell behaviour and the initiation of many different metabolic, transcriptional or mechanical responses to environmental stimuli remain largely unexplained. Researchers from the School of Life Sciences at the University of Warwick have today, the 20th May had the paper ‘Bioelectrical understanding and engineering of cell biology’ published in the journal Royal Society Interface, in which they have gone beyond the status quo of understanding cell behaviours, and argue a combination of genetics, physics and physiology can be grounded on a bioelectrical conceptualisation of cells. They argue that a bioelectrical view can provide predictive biological understanding, which can open up novel ways to control cell behaviours by electrical and electrochemical means, setting the stage for the emergence of bioelectrical engineering. Dr Orkun Soyer, from the School of Life Sciences at the University of Warwick comments: “When looking at the underlying chemistry of this “machinery” it is easy to recognise the importance of electricity in biological phenomena. “Here we advocate that the understanding of cells as electrical entities will pave the way to fully understand, predict and modulate cellular function. When cellular functions are understood it could have a huge impact on healthcare, as conditions related to, for example, homeostasis such as heart failure or diabetes, could have new treatments researched if we can manipulate the bioelectricity in the cells.”

Newswise — (New York, NY – May 19, 2020) – Mount Sinai researchers are the first in the country to use artificial intelligence (AI) combined with imaging, and clinical data to analyze patients with coronavirus disease (COVID-19). They have developed a unique algorithm that can rapidly detect COVID-19 based on how lung disease looks in computed tomography (CT scans) of the chest, in combination with patient information including symptoms, age, bloodwork, and possible contact with someone infected with the virus. This study, published in the May 19 issue of Nature Medicine, could help hospitals across the world quickly detect the virus, isolate patients, and prevent it from spreading during this pandemic. “AI has huge potential for analyzing large amounts of data quickly, an attribute that can have a big impact in a situation such as a pandemic. At Mount Sinai, we recognized this early and were able to mobilize the expertise of our faculty and our international collaborations to work on implementing a novel AI model using CT data from coronavirus patients in Chinese medical centers. We were able to show that the AI model was as accurate as an experienced radiologist in diagnosing the disease, and even better in some cases where there was no clear sign of lung disease on CT,” says one of the lead authors, Zahi Fayad, PhD, Director of the BioMedical Engineering and Imaging Institute (BMEII) at the Icahn School of Medicine at Mount Sinai. “We’re now working on how to use this at home and share our findings with others—this toolkit can easily be deployed worldwide to other hospitals, either online or integrated into their own systems.” This research expands on a previous Mount Sinai study that identified a characteristic pattern of disease in the lungs of COVID-19 patients and showed how it develops over the course of a week and a half.The new study involved scans of more than 900 patients that Mount Sinai received from institutional collaborators at hospitals in China. The patients were admitted to 18 medical centers in 13 Chinese provinces between January 17 and March 3, 2020. The scans included 419 confirmed COVID-19-positive cases (most either had recently traveled to Wuhan, China, where the outbreak began, or had contact with an infected COVID-19 patient) and 486 COVID-19-negative scans. Researchers also had patients’ clinical information, including blood test results showing any abnormalities in white blood cell counts or lymphocyte counts as well as their age, sex, and symptoms (fever, cough, or cough with mucus). They focused on CT scans and blood tests since doctors in China use both of these to diagnose patients with COVID-19 if they come in with fever or have been in contact with an infected patient. The Mount Sinai team integrated data from those CT scans with the clinical information to develop an AI algorithm. It mimics the workflow a physician uses to diagnose COVID-19 and gives a final prediction of positive or negative diagnosis. The AI model produces separate probabilities of being COVID-19-positive based on CT images, clinical data, and both combined. Researchers initially trained and fine-tuned the algorithm on data from 626 out of 905 patients, and then tested the algorithm on the remaining 279 patients in the study group (split between COVID-19-positive and negative cases) to judge the test’s sensitivity; higher sensitivity means better detection performance. The algorithm was shown to have statistically significantly higher sensitivity (84 percent) compared to 75 percent for radiologists evaluating the images and clinical data. The AI system also improved the detection of COVID-19-positive patients who had negative CT scans. Specifically, it recognized 68 percent of COVID-19-positive cases, whereas radiologists interpreted all of these cases as negative due to the negative CT appearance. Improved detection is particularly important to keep patients isolated if scans don’t show lung disease when patients first present symptoms (since the previous study showed that lung disease doesn’t always show up on CT in the first few days) and COVID-19 symptoms are often nonspecific, resembling a flu or common cold, so it can be difficult to diagnose. CT scans are not widely used for diagnosis of COVID-19 in the United States; however, Dr. Fayad explains that imaging can still play an important role. “Imaging can help give a rapid and accurate diagnosis—lab tests can take up to two days, and there is the possibility of false negatives—meaning imaging can help isolate patients immediately if needed, and manage hospital resources effectively. The high sensitivity of our AI model can provide a ‘second opinion’ to physicians in cases where CT is either negative (in the early course of infection) or shows nonspecific findings, which can be common. It’s something that should be considered on a wider scale, especially in the United States, where currently we have more spare capacity for CT scanning than in labs for genetic tests,” said Dr. Fayad, who is also a Professor of Diagnostic, Molecular and Interventional Radiology at the Icahn School of Medicine at Mount Sinai. “This study is important because it shows that an artificial intelligence algorithm can be trained to help with early identification of COVID-19, and this can be used in the clinical setting to triage or prioritize the evaluation of sick patients early in their admission to the emergency room,” says Matthew Levin, MD, Director of the Mount Sinai Health System’s Clinical Data Science Team, and a member of the Mount Sinai COVID Informatics Center. “This is an early proof concept that we can apply to our own patient data to further develop algorithms that are more specific to our region and diverse populations.” Mount Sinai researchers are now focused on further developing the model to find clues about how well patients will do based on subtleties in their CT data and clinical information. They say this could be important to optimize treatment and improve outcomes. Xueyan Mei, a trainee in the Graduate School of Biological Sciences at the Icahn School of Medicine at Mount Sinai, and Yang Yang, PhD, Assistant Professor of Radiology at the Icahn School of Medicine at Mount Sinai, also contributed to this work.   Image credit: BioMedical Engineering and Imaging Institute (BMEII) at the Icahn School of Medicine at Mount Sinai