Body

When seeking the fastest pathway to a vaccine to prevent coronavirus disease 19 (COVID-19), defining the stakes and potential hurdles is critical, says Barney Graham in this Perspective. Because the human population is naïve to the virus that causes coronavirus disease 19 (COVID-19), the consequences of repeated epidemics will be unacceptably high, he writes. Therefore, the benefit of developing an effective vaccine is very great, and even greater if it can be deployed in time to prevent repeated or continuous epidemics. Finding the fastest pathway to vaccine availability includes the avoidance of safety pitfalls, with lessons learned from history. Although the potential risk of vaccine-induced antibody or T cell responses leading to adverse responses to natural SARS-CoV-2 infection should be carefully evaluated, Graham says, there is also a risk of delaying clinical trials in favor of prolonged evaluation of vaccines in animal models that do not fully recapitulate the pathogenesis of disease in humans. This happened with the respiratory syncytial virus vaccine, Graham notes. Judicious evaluation of candidate vaccines in healthy adults, in parallel with vaccine studies in animal models and coincident process development to scale-up production capacity, provides a path forward with minimal risk, and potentially tremendous benefit, to human subjects, he says.

A window on the body's internal workings

Computed tomography, or CT, utilizes computational processes to combine many X-ray measurements taken from different angles of the body to produce tomographic images. This non-invasive procedure, which provides a three-dimensional reconstructed view of organs or tissues, allows physicians to see inside the target without cutting.

"[This technique] helps experts to determine the presence of a tumour, its exact location, size and spread. It can also be used to diagnose muscle and bone disorders, infection or blood clots, heart disease, lung nodules, and liver masses," said Mohammad Mahdi Dehshibi, a postdoctoral researcher at the UOC's Scene Understanding and Artificial Intelligence laboratory (SUNAI), of the UOC's Faculty of Computer Science, Multimedia and Telecommunications, of the Pattern Research Centre in Teheran, Iran. "This technology is among the most common imaging tools used to guide biopsy and radiation therapy as well as monitoring the effectiveness of treatments like cancer treatment, internal injuries, and bleeding detection."

However, computed tomography involves the risk of damaging the structure of DNA and, subsequently, cancer due to the exposure of the body to high-dose X-rays. For example, in the course of a head CT scan, a person receives a dose of radiation equivalent to the total amount they are usually exposed to in 243 days of normal living.

A new algorithm to reduce radiation

In a search to reduce this radiation, the team led by Dehshibi has developed a new post-processing algorithm which increases the quality of reconstructed CT images. While conventional CT methods pick up only a part of the X-ray energy spectrum, the researchers tested a broader energy range, divided into intervals, to reach higher contrast. After testing it on constructed data using GATE/GEANT4 simulation software, they found that the algorithm enhances the quality of the images while reducing noise, which enables better discrimination between different types of tissue with lower doses of X-rays, according to their findings published in the Journal of Information Processing.

"Distinguishing between two different tissues (either normal or abnormal ones) in the same region is critical for physicians or radiologists to plan for further treatments, where this decision is dealing with the patients' lives," he said. "Having better tissue discrimination increases the success rate of the medicine's plan." The new method increases the capacity to distinguish between tissues by 60% in simulations compared to conventional CT.

"Our viewpoint was proposing a post-processing approach that does not need a substantial hardware reconfiguration and gives more freedom to imaging scientists for further exploration," Dehshibi said. "We hope that the findings of this study are later examined in the clinical setting to reduce the radioactive effect of irradiating with X-ray."

The novel radiopharmaceutical 18F-PSMA-1007 is both effective and readily available for detecting malignant prostate cancer lesions, according to research published in the April issue of The Journal of Nuclear Medicine. With this new option and 68Ga-PSMA-11, which is already widely used, nuclear medicine departments will have two effective options for staging of prostate cancer, potentially increasing availability for patients worldwide.

68Ga-PSMA is the most commonly used PSMA-labeled tracer in clinical practice for evaluating extent of disease in prostate cancer patients. However, it is produced by a specific generator and has a short half-life of 68 minutes. "The newly introduced 18F-PSMA-1007 has several advantages over the established 68Ga-PSMA," stated Einat Even-Sapir, MD, PhD, director of The Institute for Nuclear Medicine at Tel Aviv Sourasky Medical Center in Tel Aviv, Israel. "These include a longer half-life, favorable pharmacokinetics, central mass production and potentially better spatial resolution."

The prospective study aimed to compare the diagnostic accuracy of 18F-PSMA-1007 with 68Ga-PSMA-11 positron emission tomography (PET)/computed tomography (CT) in the same patients presenting with newly diagnosed intermediate- or high-risk prostate cancer. 18F-PSMA-1007 and 68Ga-PSMA-11 PET/CT were performed within 15 days of each other in sixteen patients with intermediate- or high-risk prostate cancer who were scheduled to undergo a radical prostatectomy. Findings from the two PET tracers were compared with histopathologic findings obtained from radical prostatectomy specimens, considered the gold standard.

Labeled PSMA-avid lesions in the prostate were identified in all 16 patients with almost perfect agreement between the two tracers regarding tumor location. Additionally, in four patients, a second positive focus, though less intense, was detected only by 18F-PSMA-1007. Three of these secondary foci were confirmed as areas of prostate cancer, while the fourth was shown on pathological examination to represent chronic prostatitis.

"In view of the near-equal performance of the two tracers, this preliminary study suggests the routine use of 18F-PSMA-1007 in lieu of 68Ga-PSMA-11 for staging prostate cancer patients; clinicians can use either radiotracer based on availability," noted Jonathan Kuten, MD, MHA, nuclear medicine specialist at Tel Aviv Sourasky Medical Center in Tel Aviv, Israel. "It also adds to the collective growing database of evidence supporting the use of PSMA agents for staging intermediate and high-risk patients. We encourage researchers, in the future, to corroborate this study's results in larger cohorts."

Temperature and latitude do not appear to be associated with the spread of coronavirus disease 2019 (COVID-19), according to a study of many countries published in CMAJ (Canadian Medical Association Journal) http://www.cmaj.ca/lookup/doi/10.1503/cmaj.200920, but school closures and other public health measures are having a positive effect.

"Our study provides important new evidence, using global data from the COVID-19 epidemic, that these public health interventions have reduced epidemic growth," says Dr. Peter Jüni, Institute for Health Policy, Management and Evaluation, University of Toronto, and St. Michael's Hospital, Toronto, Ontario.

The Canadian study looked at 144 geopolitical areas -- states and provinces in Australia, the United States and Canada as well as various countries around the world -- and a total of more than 375 600 confirmed COVID-19 cases. China, Italy, Iran and South Korea were excluded because the virus was either waning in the case of China or in full disease outbreak at the time of the analysis in others. To estimate epidemic growth, researchers compared the number of cases on March 27 with cases on March 20, 2020, and determined the influence of latitude, temperature, humidity, school closures, restrictions of mass gatherings and social distancing measured during the exposure period of March 7 to 13.

They found little or no association between latitude or temperature with epidemic growth of COVID-19 and a weak association between humidity and reduced transmission. The results -- that hotter weather had no effect on the pandemic's progression -- surprised the authors.

"We had conducted a preliminary study that suggested both latitude and temperature could play a role," says Dr. Jüni. "But when we repeated the study under much more rigorous conditions, we got the opposite result."

The researchers did find that public health measures, including school closures, social distancing and restrictions of large gatherings, have been effective.

"Our results are of immediate relevance as many countries, and some Canadian provinces and territories, are considering easing or removing some of these public health interventions," says Dr. Jüni.

"Summer is not going to make this go away," says Prof. Dionne Gesink, a coauthor and epidemiologist at Dalla Lana School of Public Health. "It's important people know that. On the other hand, the more public health interventions an area had in place, the bigger the impact on slowing the epidemic growth. These public health interventions are really important because they're the only thing working right now to slow the epidemic."

The authors note several study limitations, such as differences in testing practices, the inability to estimate actual rates of COVID-19 and compliance with social distancing.

When deciding how to lift restrictions, governments and public health authorities should carefully weigh the impact of these measures against potential economic and mental health harms and benefits.

MERS, which struck South Korea in a 2015 outbreak, was caused by a coronavirus--the same family of viruses that is responsible for COVID-19 (disease: COVID-19, virus: SARS-CoV2). Recently, a Korean research team announced that it had developed a new vaccine platform using RNA-based adjuvants for the MERS coronavirus (MERS-CoV). The research team successfully conducted an experiment on nonhuman primates. It is expected that the new vaccine platform will soon be applicable to the development of a COVID-19 vaccine, an urgent global health priority.

MERS, which struck South Korea in a 2015 outbreak, was caused by a coronavirus--the same family of viruses that is responsible for COVID-19 (disease: COVID-19, virus: SARS-CoV2). Recently, a Korean research team announced that it had developed a new vaccine platform using RNA-based adjuvants for the MERS coronavirus (MERS-CoV). The research team successfully conducted an experiment on nonhuman primates. It is expected that the new vaccine platform will soon be applicable to the development of a COVID-19 vaccine, an urgent global health priority.

The Korea Institute of Science and Technology (KIST) recently released the results of the joint research on the RNA-based vaccine platform for MERS-CoV, conducted by a research team led by Dr. Keum Gyo-chang and Dr. Bang Eun-kyoung from the KIST's Center for Neuro-Medicine and a research team led by Professor Nam Jae-Hwan from the Catholic University of Korea (CUK, President Won Jong-chul). The vaccine platform uses RNA as an immunostimulatory agent known as an adjuvant and consists of compounds that maintain the stability of the RNA and *spike protein that the virus uses to invade the host cell. The new vaccine platform is expected to be used in the development of a vaccine for the COVID-19 virus, which is also a type of coronavirus.

*Spike protein : A surface protein that the MERS coronavirus uses to bind to a cell receptor

Recently, many protein-based vaccines have been developed as they are regarded as having a high level of safety. However, protein-based vaccines induce a weak immune response in antibody-producing cells. This requires the use of a highly stable adjuvant for a more balanced immune response.

The joint research team mixed the RNA of the **cricket paralysis virus, an adjuvant developed by the CUK research team, and an RNA stabilizer containing zinc complex, developed by the KIST research team. A vaccine was created using the mixture, along with the spike protein of the MERS-CoV, and administered to a group of mice. After just one inoculation, the vaccine was shown to have adequate protective efficacy (100% protective efficacy against lethal doses of the virus). The MERS-CoV infection was also suppressed through the induction of high ***neutralizing antibodies (PRNT80 titer > 1:2,560) when the same vaccine was administered to ****macaque monkeys, which are nonhuman primates. RNA adjuvant and stabilizer mixed together can be applied to most vaccine types, including protein-based vaccines and inactivated vaccines, meaning that they have a wide range of potential uses.

**Cricket paralysis virus: A virus that paralyzes and kills crickets

***Neutralizing antibody: An antibody that is bound to the biologically active substances, etc. of viruses or toxins and inhibits their pathogenicity or biologic activity

****Macaque monkey: A type of Old World primate that is widely used for testing vaccine efficacy

The joint research team was provided the coronavirus spike protein by Dr. Song Man-ki's research team at the International Vaccine Institute. For the research, Professor Lee Sang-myeong's research team at Chonbuk National University measured the amount of antibodies (*****neutralizing-antibody values) and conducted a virus challenge experiment, and Dr. Hong Jung-joo's research team at the National Primate Research Center, which is part of the Korea Research Institute of Bioscience and Biotechnology, investigated the immunity of nonhuman primates such as monkeys.

*****Neutralizing-antibody value: The measured value of the amount of antibodies contained in the unit capacity of antigen serum to suppress virus infection

Dr. Keum Gyo-chang from KIST said, "This RNA adjuvant formulated protein vaccine, which has shown efficacy against the MERS virus, has the advantage of rapid application to the development of a vaccine for COVID-19, which is caused by the same type of virus that causes MERS." Professor Nam Jae-Hwan from CUK further explained, "The nucleic acid (DNA or RNA)-based vaccines that have recently been reported, have not previously been produced as vaccine products and have not gone through large-scale clinical trials. In contrast, the protein based vaccine is mainly used vaccine platform. In this study, we added RNA as adjuvant to protein vaccine whose safety has already been proven. We expect that this new vaccine platform will enable the development of a safe vaccine."

Currently, the CUK research team is developing a COVID-19 vaccine and a vaccine for "severe fever with thrombocytopenia syndrome" (with research funds provided by Samkwang Labtree), using the vaccine platform. The research team has formed a consortium with SK Bioscience, to manage the development of a COVID-19 vaccine.

Exercise and physical therapy often are recommended to help people who have arthritis. Both can strengthen muscle -- a benefit that also can reduce joint pain. But building muscle mass and strength can take many months and be difficult in the face of joint pain from osteoarthritis, particularly for older people who are overweight. A new study in mice at Washington University School of Medicine in St. Louis, however, suggests gene therapy one day may help those patients.

The research shows that gene therapy helped build significant muscle mass quickly and reduced the severity of osteoarthritis in the mice, even though they didn't exercise more. The therapy also staved off obesity, even when the mice ate an extremely high-fat diet.

The study is published online May 8 in the journal Science Advances.

"Obesity is the most common risk factor for osteoarthritis," said senior investigator Farshid Guilak, PhD, the Mildred B. Simon Research Professor of Orthopaedic Surgery and director of research at Shriners Hospitals for Children -- St. Louis. "Being overweight can hinder a person's ability to exercise and benefit fully from physical therapy. We've identified here a way to use gene therapy to build muscle quickly. It had a profound effect in the mice and kept their weight in check, suggesting a similar approach may be effective against arthritis, particularly in cases of morbid obesity."

With the paper's first author, Ruhang Tang, PhD, a senior scientist in Guilak's laboratory, Guilak and his research team gave 8-week-old mice a single injection each of a virus carrying a gene called follistatin. The gene works to block the activity of a protein in muscle that keeps muscle growth in check. This enabled the mice to gain significant muscle mass without exercising more than usual.

Even without additional exercise, and while continuing to eat a high-fat diet, the muscle mass of these "super mice" more than doubled, and their strength nearly doubled, too. The mice also had less cartilage damage related to osteoarthritis, lower numbers of inflammatory cells and proteins in their joints, fewer metabolic problems, and healthier hearts and blood vessels than littermates that did not receive the gene therapy. The mice also were significantly less sensitive to pain.

One worry was that some of the muscle growth prompted by the gene therapy might turn out to be harmful. The heart, for example, is a muscle, and a condition called cardiac hypertrophy, in which the heart's walls thicken, is not a good thing. But in these mice, heart function actually improved, as did cardiovascular health in general.

Longer-term studies will be needed to determine the safety of this type of gene therapy. But, if safe, the strategy could be particularly beneficial for patients with conditions such as muscular dystrophy that make it difficult to build new muscle.

In the meantime, Guilak, who also co-directs the Washington University Center for Regenerative Medicine and is a professor of biomedical engineering and of developmental biology, said more traditional methods of muscle strengthening, such as lifting weights or physical therapy, remain the first line of treatment for patients with osteoarthritis.

"Something like this could take years to develop, but we're excited about its prospects for reducing joint damage related to osteoarthritis, as well as possibly being useful in extreme cases of obesity," he said.

The number of people evaluated for signs of stroke at U.S. hospitals has dropped by nearly 40% during the COVID-19 pandemic, according to a study led by researchers from Washington University School of Medicine in St. Louis who analyzed stroke evaluations at more than 800 hospitals across 49 states and the District of Columbia. The findings, published May 8 in the New England Journal of Medicine, are a troubling indication that many people who experience strokes may not be seeking potentially life-saving medical care.

"Our stroke team has maintained full capacity to provide emergency stroke treatment at all times, even during the height of the pandemic," said lead author Akash Kansagra, MD, an assistant professor of radiology at Washington University's Mallinckrodt Institute of Radiology (MIR). Kansagra sees stroke patients at Barnes-Jewish Hospital. "Nevertheless, we have seen a smaller number of stroke patients coming to the hospital and some patients arriving at the hospital after a considerable delay. It is absolutely heartbreaking to meet a patient who might have recovered from a stroke but, for whatever reason, waited too long to seek treatment."

Nearly 800,000 people in the U.S. experience a stroke every year. It is the fifth leading cause of death and the leading cause of long-term disability. With advances in stroke care such as better diagnostic tools, surgeries to remove blood clots or repair broken blood vessels, and clot-busting drugs, people have a better chance of recovering from a stroke today than ever before - as long as they receive treatment promptly. Clot-busting drugs are generally safe only within 4½ hours of symptom onset, and surgeries are only possible within 24 hours of symptom onset. The earlier the treatment is started, the more successful it is likely to be.

Worried by the low numbers of stroke patients being evaluated at Barnes-Jewish Hospital and hearing similar reports from colleagues at other institutions, Kansagra - along with co-authors Manu Goyal, MD, a Washington University assistant professor of radiology and neurology, and statistician Scott Hamilton, PhD, and neurologist Gregory Albers, MD, both of Stanford University - set out to determine how pervasive the problem was.

When patients arrive at a hospital and are showing signs of a stroke, they often get a brain scan so doctors can identify what kind of stroke has occurred and choose the most effective treatment. Many hospitals, including Barnes-Jewish Hospital, use software known as RAPID to analyze such brain scans. Kansagra and colleagues assessed how often the software was used in February, before the pandemic, and during a two-week period from March 26 to April 8, when much of the country was under shelter-in-place orders.

In total, the software was used for 231,753 patients at 856 hospitals representing the District of Columbia and all 50 states except New Hampshire. During February, the software was used for an average of 1.18 patients per day per hospital. During the pandemic period, software use per hospital averaged 0.72 patients per day, a drop of 39%.

"Across the board, everybody is affected by this decrease," said Kansagra, who is also an assistant professor of neurosurgery and of neurology. "It is not limited to just hospitals in urban settings or rural communities, small hospitals or large hospitals. It is not just the old or the young or the people with minor strokes who aren't showing up. Even patients with really severe strokes are seeking care at reduced rates. This is a widespread and very scary phenomenon."

There's no reason to believe people suddenly stopped having strokes. And the drop was large even in places where COVID-19 cases were few and hospitals were not overwhelmed, so patients should not have found it unusually difficult to obtain treatment.

"I suspect we are witnessing a combination of patients being reluctant to seek care out of fear that they might contract COVID-19, and the effects of social distancing," Kansagra said. "The response of family and friends is really important when a loved one is experiencing stroke symptoms. Oftentimes, the patients themselves are not in a position to call 911, but family and friends recognize the stroke symptoms and make the call. In an era when we are all isolating at home, it may be that patients who have strokes aren't discovered quickly enough."

Common signs of a stroke include the sudden onset of numbness or weakness in the face, arm or leg, especially on one side of the body; speech difficulty; confusion; difficulty seeing or walking; and severe headache.

Even during a pandemic, it is critically important for people who may be experiencing a stroke to receive care immediately, Kansagra said. The risk of delaying care for a stroke is much greater than the risk of contracting COVID-19.

"The effect of coming in too late is the same in many respects as not coming in at all," Kansagra said. "When patients come in too late, they may no longer be candidates for treatments that they would have qualified for just hours before. And as a result, they may not have access to treatments that are extremely effective in reducing death and disability."

A Texas A&M AgriLife Research team has good news for patients with copper-deficiency disorders, especially young children diagnosed with Menkes disease.

A team led by James Sacchettini, Ph.D. professor and Welch Chair of Science, and Vishal Gohil, Ph.D., associate professor, both from the Department of Biochemistry and Biophysics at Texas A&M University, published a paper in Science outlining their latest discoveries of how using the cancer drug elesclomol holds promise for treating copper deficiencies in Menkes disease.

The research funding was provided by the Chancellor's Research Initiative of The Texas A&M University System, the Welch Foundation and the National Institutes of Health.

"With all biology connected, it's great to see this innovative research from the agriculture and life sciences departments making a significant connection to an area of human health," said Patrick J. Stover, Ph.D., vice chancellor of Texas A&M AgriLife, dean of the College of Agriculture and Life Sciences and director of AgriLife Research.

Menkes disease

Menkes is a rare genetic disorder occurring in about 1 in every 50,000-300,000 births. Young children with the disorder typically die within three years of life due to a genetic mutation that limits their body's ability to absorb and utilize copper from their diet. The copper deficiency leads to severe brain damage and neuromuscular deficits.

"Experimental treatments have not been effective at overcoming the most severe symptoms of the disease or early mortality," Sacchettini said.

"Our current work documenting the efficacy of elesclomol in a mouse model of Menkes disease takes us one step closer to the clinical trials," Gohil said.

Copper deficiency

Normally, copper is acquired through diet from foods such as fish, organ meats, nuts and beans, said Liam Guthrie, a doctoral candidate in Sacchettini's lab and lead author of the paper. He explained that dietary copper is normally absorbed in the intestines, then exported to the liver for distribution throughout the body.

In Menkes disease, that process is disrupted. The copper absorbed by intestinal cells must be exported into the blood by a copper transport protein. If that protein is not functioning well, due to genetic mutations, the copper can't be distributed to various parts of the body. The brain, heart and other tissues thus become copper deficient.

And, when copper is deficient in these tissues, certain enzymes fail to activate, Gohil explained. One such enzyme is mitochondrial cytochrome oxidase complex, which is required for energy production.

"Mitochondrial cytochrome oxidase is an enzyme present in almost all cells in our body and uses a majority of the oxygen that we breathe," Gohil said.

This enzyme only works if it has copper in it, he explained. Without copper, the enzyme won't function, and the body stops working due to lack of energy production.

Finding the drug

Gohil began working on this project in 2012, and in 2014 his team began focusing on elesclomol and showed that it can deliver copper to mitochondria and restore the production of cytochrome oxidase protein complex in copper-deficient yeast and human cells, as well as in zebrafish.

In 2017, Gohil's graduate student Shivatheja Soma and postdoctoral fellow Mohammad Zulkifli, Ph.D., began collaborating with Guthrie, Andres Silva and others from the Sacchettini group. They began to translate the laboratory results into a preclinical mouse model of Menkes disease.

The team focused on developing procedures for using elesclomol to treat Menkes and optimizing treatment strategies to find the right doses.

"These were difficult and time-consuming experiments that required special precautions because we were working with very sick mice, ones that carried the same type of mutation as humans with severe Menkes disease," Guthrie said. "These mice showed very similar symptoms to babies with the disease. We had hope that if we could successfully treat these mice, we would be able to translate the discoveries to infants."

Sacchettini said the first step was to overcome the side effects of using a cancer drug to treat the disease. The major breakthrough came when their group came up with a new way to prepare the drug.

"We found that by mixing elesclomol with copper in a special formulation, we could keep the new form of the drug soluble prior to administration," he said. "With this approach we were able to dramatically increase survival of the mice and, importantly, to normalize their brain development."

The collaborators from the University of Maryland, led by Byung-Eun Kim, Ph.D., showed that elesclomol could overcome more than just defects in the transporter that causes Menkes disease. The medication also targeted a second copper transporter, one implicated in the development of hypertrophic heart and liver disorders in mice and humans--indicating the therapeutic applications of elesclomol may not be limited to Menkes disease.

Gohil's group and Michael Petris, Ph.D., from the University of Missouri, showed that elesclomol escorted copper to different tissues and delivered it to copper-utilizing enzymes like cytochrome c oxidase in mitochondria.

Promising results

Through this mechanism, elesclomol prevented brain damage and improved the survival of Menkes mice from a mere 14 days to over 200 days.

While there is still more work to do in preparation for treating infants with Menkes disease, Sacchettini and Gohil say they are confident they will soon be able to extend the survival and quality of life for those born with this devastating disease.

New guidance identifies patients with the greatest need for bariatric and metabolic surgery as experts warn delaying treatment could put them at a greater risk of complications from their disease as well as from COVID-19.

The recommendations, published today in The Lancet Diabetes & Endocrinology by experts from the multidisciplinary Diabetes Surgery Summit (DSS), led by Professor Francesco Rubino from King's College London, outline the surgical candidates at greatest risk of morbidity and mortality from type 2 diabetes or from severe obesity, for whom time-sensitive surgical therapy can be life-saving.

Bariatric and metabolic surgery, used to treat type 2 diabetes and obesity, has been suspended during the pandemic. This is to free up inpatient capacity for COVID-19 and reduce the risks of infection among patients and staff. However, experts warn the backlog of operations could increase risks of morbidity and mortality for patients awaiting surgery.

Professor Francesco Rubino, chair of bariatric and metabolic surgery at King's College London and a consultant surgeon at King's College Hospital, said: "In times of limited resources, patients with greatest risk of harm from untreated disease should be identified and prioritized for timely-access to the treatment they need. The misconception that bariatric surgery is a 'last resort', widespread stigma of obesity and inadequate criteria for patients' selection can penalize candidates for surgical treatment of obesity and diabetes."

Social distancing policies and lockdown might limit adherence to lifestyle interventions such as healthy diet and physical exercise, which can worsen the health of affected patients. Compared to non-surgical treatments, bariatric and metabolic surgery leads to greater long-term weight loss, reduction of cardiovascular risk, remission of diabetes and can improve survival.

Severe obesity, diabetes, hypertensions can increase risk for severe Covid-19 complications and bariatric/metabolic surgery can dramatically and rapidly improve these conditions. Delaying surgery may therefore leave many people vulnerable to severe consequences of SARS-Cov-2 infection.

Professor Paul Zimmet, from Monash University, Honorary President of the International Diabetes Federation and a co-author of the study, said: "These operations are called "elective" because they can be scheduled in advance not because the treatment they provide is less necessary. Metabolic surgery is a potentially lifesaving treatment for selected obese persons with type 2 diabetes."

Experts from the DSS recommend the following to have access to surgical treatment within 90 days:

Being at substantial risk of complications of diabetes such as cardiovascular disease or renal failure

Type 2 diabetes requiring insulin

Poor control of blood sugar levels despite taking multiple medications

Severe forms of obesity (BMI >60) or less severe obesity if there are at least three co-morbidities including liver, respiratory, renal or cardiac disease.

Need weight loss and/or metabolic improvement for other time sensitive treatments such as organ transplants.

Standard access to bariatric and metabolic surgery can be reserved for patients who are unlikely to deteriorate within 6 months, but these patients need to be optimised using intensive medical treatment to maintain optimal control.

The group also recommends mandatory COVID-19 screening pre-operatively for all patients considering metabolic surgery. Despite the theoretical higher risk of contagion for staff, the study found laparoscopic (keyhole) surgery remains the best approach, but appropriate personal protective equipment (PPE) should be used.

PHILADELPHIA - When Castleman Disease patients have a flare of their symptoms, they experience a cytokine storm inside their bodies - a hyper-response from the immune system that can cause a fever, organ failure, and even death. Now researchers at the Perelman School of Medicine at the University of Pennsylvania say they know what's happening at the cellular level of the immune system when these cytokine storms occur, and the answer not only informs future potential Castleman therapies but may also provide new insight into why similar events take place in COVID-19 patients. The researchers published their findings today in the Journal of Clinical Investigation Insight.
Castleman Disease isn't actually a single disease. The term describes a group of inflammatory disorders that share a common appearance under the microscope. It's diagnosed in about 5,000 people of all ages each year in the United States, which makes it roughly as common as Lou Gehrig's disease, also called Amyotrophic Lateral Sclerosis or ALS. Patients experience a range of symptoms - from a single abnormal lymph node with mild flu-like symptoms to abnormal lymph nodes located throughout their entire body, abnormal blood cell counts, and life-threatening failure of multiple organ systems, such as the kidneys, liver, heart, and lungs. The most severe subtype, idiopathic multicentric Castleman disease (iMCD), has similarities to autoimmune conditions, viral illnesses, and cancer. About 35 percent of patients with iMCD will die within five years of diagnosis.

"With iMCD, just as with COVID-19, it is the body's hyper-response that's deadly rather than the disease itself, and this study gives us new clues about why the immune cells are out of control and what we can do to rein them in," said the study's senior author David C. Fajgenbaum, MD, MBA, MSc, an assistant professor of Translational Medicine and Human Genetics, director of the Center for Study & Treatment of Lymphadenopathies & Cytokine Storms, executive director of the Castleman Disease Collaborative Network (CDCN), and a Castleman patient himself.

For this study, researchers took blood samples from iMCD patients who were asymptomatic and from those who were in flare to examine the differences in their immune cells. Previous research has shown the cytokine storm is tied to a cytokine, or inflammatory mediator, called interleukin-6 (IL-6), which in turn is connected to another pathway called mTOR. This study advanced these findings further and discovered a particular group of cytokines called Type-I Interferons are highly active when patients are in flare. They also found that another pathway called JAK seems to be a critical mediator of the cytokine storm.

"This deeper understanding of exactly what's causing the immune system's hyper-response strengthens the link between mTOR activation and cytokine storms, suggesting new treatment approaches for the patients in flare," said the study's lead author Ruth-Anne Langan Pai, a PhD candidate in Immunology and a member of the CDCN. Langan Pai performed the work as her doctoral thesis in Fajgenbaum's lab.

This alternative approach could address a vital clinical need. In 2014, the U.S Food and Drug Administration approved the drug siltuximab to treat iMCD, and studies have shown it can send between one-third and one-half of patients into a remission that generally lasts for years. However, patients who don't respond have limited options. They typically receive chemotherapy but often relapse.

Fajgenbaum and his team are currently testing treatment with mTOR inhibitors in a clinical trial (NCT03933904) at the University of Pennsylvania, with Sunita Nasta, MD, FACP, an associate professor of Hematology-Oncology, and Adam Cohen, MD, an assistant professor of Hematology-Oncology, enrolling and treating patients.

Fajgenbaum also says he hopes this work will prompt others in the field to consider different ways to approach the cytokine storms COVID-19 patients are experiencing. A provisional patent has been filed for a new treatment approach involving inhibition of JAK based on this work.

What Viewpoint Says: Methods for providing adolescents and young adults with reproductive health care during the COVID-19 pandemic are described.

Authors: Tracey A. Wilkinson, M.D., M.P.H., of the Indiana University School of Medicine in Indianapolis, 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/jamapediatrics.2020.1884)

Editor's Note:  The article includes conflict of interest 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.

May 7, 2020 - Reflecting research-driven changes in clinical practice, a revised set of evidence-based recommendations for the medical and surgical treatment of left-sided colonic diverticulitis has been published in Diseases of the Colon & Rectum (DC&R), the official journal of the American Society of Colon and Rectal Surgeons (ASCRS). The journal is published by Wolters Kluwer.

Developed by a panel of the ASCRS Clinical Practice Guidelines Committee, the new recommendations were posted today on the DC&R website and will appear in the journal's June issue. "As our understanding of diverticulitis has evolved, so have recommendations for the clinical management of these patients," according to the guideline statement. The lead author is Jason Hall, MD, MPH, of Boston University School of Medicine.

Shift Toward Outpatient Care, Non-Emergency Surgery for Diverticulitis
Colonic diverticulitis is a very common gastrointestinal disorder, accounting for hundreds of thousands of hospitalizations and emergency department visits each year - with costs of $1.6 billion or more. Diverticulitis occurs when small sacs or pouches in the colon wall (diverticula) become inflamed, causing symptoms such as abdominal pain or tenderness and fever. Some patients develop systemic infections or other serious complications, requiring surgical treatment.

Although diverticulitis can occur anywhere in the colon (large intestine), the clinical practice guideline focuses on left-sided diverticulitis as this is the most common site of presentation. Recommendations reflect the "changing treatment paradigm" for diverticulitis: more patients being treated as outpatients and fewer undergoing emergency surgery, while more patients are undergoing elective or laparoscopic (minimally invasive) surgery. Key points include:

Recommendations for Initial evaluation of acute diverticulitis, emphasizing key physical examination findings and the results of computed tomography (CT) scanning of the abdomen and pelvis.
Approaches to medical management, including recent evidence that not all patients with acute diverticulitis need antibiotics. Higher-risk patients should receive antibiotics, while some patients with mild disease may not benefit from antibiotics.
Some patients with diverticulitis will develop associated abscesses and may benefit from antibiotics alone or a procedure to drain the infection.

Lifestyle changes to potentially reduce the risk of diverticulitis: tobacco cessation, reduced meat intake, physical activity, and weight loss.

Evaluation after recovery from complicated diverticulitis, including colonoscopy to confirm the diagnosis and exclude the possibility of colon cancer.
Guidelines for elective surgery: recommended for patients with complications such as fistula, obstruction, or strictures. For patients with recurrent episodes, elective surgery may improve quality of life.
Guidelines for emergency surgery: still required in 15 to 32 percent of patients hospitalized for diverticulitis. The guideline addresses factors to consider in deciding whether to create a stoma or restore bowel continuity in patients undergoing emergency surgery.

Other recommendations address technical considerations related to surgical treatment of left-sided diverticular disease. "When expertise is available, a minimal approach to colectomy [colon surgery] for diverticulitis is preferred," the Guideline Committee writes.

According to many observations, certain virus infections may play a part in the autoimmune attack that leads to type 1 diabetes. Researchers at Karolinska Institutet and at the universities of Jyväskylä and Tampere have now produced a vaccine for these viruses in the hope that it could provide protection against the disease. The study is published 6 May 2020 in the scientific journal Science Advances.

While an estimated 50,000 Swedes and 50, 000 Finns live with type 1 diabetes (sometimes known as juvenile diabetes) the causes of the disease remain unknown. There is a genetic component, but also environmental factors are needed for the disease to develop. One such factor believed to be significant in type 1 diabetes is infections caused by an extremely common group of enteroviruses. The sub-group in question is the Coxsackie B (CVB) family and it comprises of six strains that can give rise to the common cold. However, CVBs can also cause more serious infections leading to diseases including myocarditis and meningitis.

According to many scientific observations, one hypothesis suggests that CVBs play a part in the development of type 1 diabetes. The disease is characterised by an autoimmune attack on the insulin-producing beta cells in the pancreas and it is possible that the virus infection somehow initiates this attack by the immune system.

Epidemiological studies, in which children with a genetic risk profile for type 1 diabetes were monitored by blood tests over a period of many years, indicate that CVBs could be a pathogenic contributor. There are also autopsy observations suggesting that CVBs might be involved in the development of type 1 diabetes. This, however, remains hypothetical as the connection is yet to be proven, albeit it is a hypothesis that is well-established amongst diabetes researchers.

Vaccine protects against all six known strains of CVB

Researchers at Karolinska Institutet, Tampere University and University of Jyväskylä in Finland have now produced a vaccine that protects against all six known strains of CVB. The CVB serotypes to be used in the vaccine had been originally detected in the research performed in Vactech Oy in Tampere. The vaccine was tested in different animal models and was shown to protect mice infected with CVB from developing virus-induced type 1 diabetes.

The researchers then tested the vaccine in rhesus monkeys that have very similar genetics to humans. In these animals, the vaccine worked well and induced antibodies to CVB suggesting it could protect against the virus. An American pharmaceutical company is now going to perform clinical studies where they will test the vaccine in human subjects.

Assuming the vaccine is safe in initial trails, the plan is to use the vaccine in children with a genetic risk profile for type 1 diabetes. The researchers write that if the number of children that develop type 1 diabetes decreases after vaccination or if none develop the disease it will confirm that CVB are a triggering environmental factor.

"Our hope is that the vaccine will prove effective against CVB infections and that it will then be possible to administer it to children," says Malin Flodström-Tullberg, professor of type 1 diabetes at the Department of Medicine, Karolinska Institutet, Huddinge, and the study's corresponding author.

"It would be fantastic if the cases of type 1 diabetes that we currently suspect are caused by the Coxsackievirus could be prevented, though it's impossible right now to say what percentage of type 1 diabetes cases would be effected. At the same time, the vaccine would give protection against myocarditis, which can have a more severe course in both children and adults, and against many kinds of cold, which keep many people away from school and work."

"The research groups associated with this work have done fruitful collaboration already a longer time, to understand the infection mechanisms of enteroviruses and to develop vaccines and antivirals to combat enteroviruse infection", says Docent Varpu Marjomaki from the University of Jyvaskyla. Marjomaki is working also at Nanoscience Center at the University of Jyvaskyla.

From compact biosensors and spectrometers to invisible devices and quantum computers, applications related to integrated photonics are increasingly sought after. As in optical fibres, guiding light in integrated photonic circuits is achieved by a local increase of the refractive index (RI) of the material. Ultrafast laser writing is the only technology that allows three-dimensional RI modification in transparent materials, thus the direct fabrication of 3D photonic devices. Following the first laser writing of photonic channels in glass in the late 90s, it was believed that the technology would quickly become the tool of choice for the manufacture of integrated photonics. However, despite numerous efforts, the magnitude of the laser-induced RI change remains limited, preventing the fabrication of compact devices with bendy optical channels which require high RI changes.

In a new paper published in Light: Science & Applications, Dr Jerome Lapointe from the Centre for Optics, Photonics and Lasers (COPL), Laval University, Canada and colleagues discovered a physical phenomenon related to the electronic resonance of laser processed materials which addresses the RI change issue. Using the new concept, the scientists demonstrated photonic channels with micron-size bending radii, which was not achieved in three dimensions before. The new technology has the potential to significantly miniaturize 3D photonics circuits, allowing denser integration of photonic applications on a same chip or increasing optical quantum computer capacity, for example. These scientists explain their discovery:

"We have discovered that femtosecond laser pulses can locally and permanently modify the electronic resonance of a material. By mathematical definition, the RI exponentially depends on the electronic resonance of the material as a function of light frequencies (or colors). We then demonstrated that photonic circuits could take advantage of this phenomenon in a transparent region of the material. In this region, the change in RI (which is the basis of the photonic circuits) can reach a very large positive value, which allows light guiding in miniaturized photonic circuits."

"European scientists recently fabricated quantum computer components using laser writing. The quantum devices are 5 to 10 centimeters long. Our discovery suggests that the same quantum devices could be over 10 times smaller. This is very promising since the computing capacity of any computer is directly proportional to the quantity of components on a same chip." they added.

Surprisingly, the scientists observed that the circuits are invisible when red light is shone through them. They found that the circuits become invisible for certain colors depending on the material and the laser writing conditions. The scientists explain the phenomenon using the same theory implying the electronic resonance variation. This new concept paves the way to invisible photonic applications, which could be placed on phone screens, car windshields, and industrial displays.

"We found that the positive RI change induced by the electronic resonance variation can exactly compensate the negative RI change induced by a structural expansion (both caused by the laser writing), resulting in a zero RI change for certain colors. To our knowledge, this is a new concept of direct fabrication of invisible structures. The beneficial combination of high RI change for operating frequencies and the invisibility for the rainbow frequencies may help to enable several invisible applications in phone screens, for example." the scientists forecast.

Clear, positive, messaging that is segmented by age, culture, and geography is key to helping the public stick to social distancing measures to stop the spread of Covid-19 infection, say behavioural experts in a commentary accepted for publication in the Journal of Epidemiology and Community Health.

Messaging that is authoritarian and/or punitive in tone and socially divisive will have the opposite effect, say the nine authors, led by Professor Chris Bonell of the London School of Hygiene and Tropical Medicine.

As the prospect of lockdown easing draws closer, and in the absence of other hard evidence on how best to curb the spread of COVID-19, they set out a series of 11 key communication principles that are informed by a body of behavioural science and the study of other infections, such as SARS and MERS.

These principles, which aim to guide governments on how to help people stick to social distancing measures, "could ensure that interventions are more likely to achieve their intended outcomes and less likely to generate unintended consequences," they suggest.

The 11 principles are:

Clear and specific guidance

'Protect each other'

'Stand together'

'This is who we are'

Avoid messages based on fear or disgust

Avoid authoritarian messages

Make a plan and review it regularly

'Make it possible '

Style of messaging

Theory of change

Co-design

First and foremost, information by itself won't always secure mass behaviour change, say the authors. But it's still important and, crucially, the public needs clear, specific, and consistent guidance on exactly what behaviours they need to adopt for social distancing.

Messaging needs to focus on the importance of how behaviour change protects everyone, including the most vulnerable, key workers, and loved ones. And it should include concrete examples, powerful images, and the actual voices of those most in need of protection.

A one size fits all approach will fail to recognise the impact of age, income, and ethnicity on the sacrifices required to stick to social distancing rules, advise the authors.

And "'Protect yourself' messages will have limited overall impact among the general public because many consider themselves at low risk of severe consequences from COVID-19 infection and are unlikely to be persuaded otherwise," they note.

The 'stand together' principle emphasises membership of groups, from families to nation, but all linked by a sense of duty, solidarity, and inclusion, irrespective of creed or culture.

Messages should come from trusted peers, including social media influencers and celebrities, rather than from those regarded as partisan or self interested. And it's worth tailoring them by age, gender, cultural beliefs, and geography, suggest the authors.

The 'This is who we are' principle draws on the informal rules (social norms) that govern group culture and behaviour, but messaging should avoid focusing on undesirable behaviours, such as 'don't panic buy' or 'don't bend the rules.'

Messaging should avoid invoking fear or disgust at others' behaviour and not adopt an authoritarian tone. "Messages based on coercion and authority can in some circumstances achieve large changes in the short term, but can be hard to sustain in the longer term," the authors point out.

Plans are important because they help people anticipate what helps and hinders committing to social distancing, while carrots, such as financial and mental health support and opening up green spaces, are more effective than sticks, such as punishment and fines.

Messaging should be communicated through professionally designed and appealing mass media and social media campaigns, focusing on the positive and inclusivity.

And each campaign should be regarded as an intervention, with clearly defined objectives and reach, informed by the evidence and principles of behavioural change. And it should consider the potential for unintended consequences.

And lastly, interventions should be designed and piloted with members of the public and properly evaluated so that the learning can be taken on board for the future, say the authors.