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Provincial and territorial governments should set clear rules for vaccinating health care workers against SARS-CoV-2, the virus that causes COVID-19, in public and private settings, and should not leave this task to employers, according to an analysis in CMAJ (Canadian Medical Association Journal).

"An effective vaccine provided to health care workers will protect both the health workforce and patients, reducing the overall burden of COVID-19 on services and ensuring adequate personnel to administer to people's health needs through the pandemic," writes Dr. Colleen M. Flood, University of Ottawa Research Chair in Health Law & Policy and a professor at the university, with coauthors.

The analysis, authored by legal scholars and a physician-researcher, describes legal precedents from attempts to mandate influenza vaccines for health care workers and how those precedents might apply to SARS-CoV-2 vaccination. It also describes the legal justification for mandating SARS-CoV-2 vaccination for health care workers and other legal considerations.

When creating policy for mandatory vaccination of health care workers, it will be important to include exemptions for people who cannot receive a vaccine because of underlying health issues or other reasons. These exemptions will help protect government mandates if there is a challenge under the Canadian Charter of Rights and Freedoms. Based on current evidence, these challenges would likely be unsuccessful if there are exemptions in place for employees. It is important to note that any vaccinate or stay at home order would not force a health care worker to be vaccinated.

"What is less clear is whether or not a health care worker could argue that they should be able, in lieu of vaccination, to wear personal protective equipment," says Dr. Flood. "Initially, even those vaccinated will continue to wear PPE, but we think courts should accept the application of the precautionary principle so as to require vaccination in most circumstances. It will, however, be essential to collect and weigh real-world evidence of the benefits of both vaccines and PPE."

The authors distinguish between overall mandated government actions that might qualify under the Charter and actions from nongovernmental organizations, such as a private long-term care home requiring its own health care workers to be vaccinated, in which case the Charter would not apply.

"This is an important issue to address with science and law working together," says Dr. Kumanan Wilson, senior scientist, The Ottawa Hospital, and Clinical Research Chair in Digital Health Innovation, University of Ottawa. "Given the rapid development of various COVID-19 vaccines and emerging evidence, new data will determine whether these policies will stay in effect or will be modified."

Support for people who may experience a rare adverse event from mandatory vaccination is important. "We applaud the recent announcement of a no-fault vaccine compensation scheme and await the implementation of the program. Although not a cure all, it does provide some security for health care workers obligated to vaccinate pursuant to carrying out their vital work," the authors write.

Listen to a podcast with Dr. Colleen M. Flood on the legal aspect of mandatory vaccination of health care workers
https://soundcloud.com/cmajpodcasts/202755-ana

Even prior to the pandemic, burnout among health care professionals was a pervasive public health concern, with some studies reporting burnout in more than 50% of clinicians. During the COVID-19 pandemic, health care professionals are required to work even longer hours in high stress situations. Understanding causes of burnout and factors that can protect against it can help improve quality of life for the health care workforce and quality of care for patients.

New research by faculty in George Mason University's College of Health and Human Services found that health care professionals with a greater personal ability to respond to change experienced lower rates of burnout when their work environments offered strong communication, teamwork, and leadership support. This is one of the first studies to look at both individual response to change and organizational capacity for change and how these factors affect burnout among health care professionals.

Dr. Debora Goldberg led the study published in the Journal of General Internal Medicine. Goldberg is an expert in primary care practice transformation, patient experience, and care for the underserved, with her current and upcoming research focused on workplace health and wellbeing.

"We know that health care work environments and job demands have a profound effect on the health and well-being of those delivering care, and they may even influence the quality of health care received by patients," explains Goldberg. "Especially as our health care professionals and systems are being pushed to the limit in response to the COVID-19 pandemic, it is imperative that we are more aware of the influences of the work environment and job demands on health care professionals' health and well-being."

Goldberg and colleagues surveyed 1,279 individuals in 154 primary care practices in Virginia. They measured the practices' capacity for change, individuals' change readiness, hours worked per week, and burnout. Participants were part of the Agency for Healthcare Research and Quality Heart of Virginia Healthcare (HVH) collaborative, which supported these practices with transformation and implementation of evidence-based cardiovascular care as they made major changes in operations and employee roles.

Burnout was measured with a single question on whether the health care professionals were experiencing burnout, a measure previously validated and used in workplace studies. Individual change readiness was measured with the Change Diagnostic Index©(CDI), which was developed by Dr. Victoria Grady in Mason's School of Business. Typically, the CDI is used in organizations that are planning for large change initiatives, and this is the first time it has been applied in primary care. The CDI measures individual attitudes toward organizational change in the areas of anxiety, frustration, delayed development, rejection of the environment, refusal to participate, withdrawal, and overall attitude. These individual attitudes can be indicators of larger organizational issues with morale, productivity, motivation, conflict, absenteeism, turnover, and overall organizational issues. The capacity of practices to change was measured by the practice adaptive reserve (PAR) instrument, which asks about an organization's communication, teamwork, relationship trust, leadership, work environment, adoption of innovations, and learning systems.

Consistent with their earlier work, the researchers found that providers were more likely to report burnout (25.5%) than other professionals (19.9% of clinical support staff, 17.5% of administrative staff).

Among all types of health care professionals (providers, clinical support staff, and administrative staff), both practice and individual factors were related to levels of burnout. Lower levels of burnout were reported among those who had higher scores for individual response to change as well as practices that had higher organizational capacity for change. As the change capacity of the practice increased, burnout in healthcare professionals decreased. As health care professionals had more positive responses to change, burnout decreased.

Higher levels of burnout were reported among those who worked more hours per week, were part of a larger practice (more than 10 clinicians) or were part of a single specialty practice.

"We found that the capacity of the practice to change influenced the relationship between individual response to change and burnout," added Goldberg. "Therefore, we recommend that physician practices and health care systems implement initiatives to reduce burnout by creating positive work environments through interprofessional teamwork, employee engagement, and enhanced communication."

Disasters in high-risk industries can have catastrophic environmental, financial and human safety consequences. One way these industries help prevent and mitigate disasters is formal procedures designed to standardize how work is done. These procedures typically come in the form of a written document workers use while performing a task.

Camille Peres, associate professor at the Texas A&M University School of Public Health, said that there are two models of safety companies usually follow to varying degrees, whether they realize it or not. Safety model one "is very much a control paradigm," Peres said. "The idea the company has is that if they control absolutely everything that's going on, then they will be safe." This narrow, rule-following approach does not account for unexpected circumstances and broader system issues, such as safety climate.

Safety model two focuses on procedures as a tool for the worker, and the worker being sufficiently trained to know how and when to adjust to unforeseen circumstances.

"Safety model two involves empowering the workers to understand the risks and be able to adapt when necessary to unexpected situations," Peres said. "There is an acknowledgment that things don't always go according to plan, and there is constant feedback between workers and superiors about how best to accomplish work -- this often means improving procedures in an efficient and effective way."

Although safety model two seems like an effective way to prevent incidents from occurring, there has been little empirical evidence for it in the workplace. To fill this research gap, Peres and colleagues, including Joseph W. Hendricks, research associate at the School of Public Health, recently conducted a study to investigate how both safety models one and two influence safety in the workplace through individual and system-level characteristics.

Individual characteristics include amount of work experience, attitude toward procedure utility (or usefulness), and attitude toward procedure compliance. System-level characteristics include worker subjective judgments of procedure quality, safety climate, the efficiency of the procedure change process and the impact of procedure improvement.

The researchers' main findings were that the better the worker's attitude toward compliance and the utility of procedures, and fewer years' experience, the less likely they are to deviate from and actually use procedures.

Further, the researchers found that of the individual-level characteristics, attitudes toward procedure utility were found to be the best predictor of incidents and near-misses, suggesting that the better workers' attitudes regarding procedure utility, the fewer incidents and near-misses they were involved in per year.

"To have utility associated with incidents and near misses is a big deal," Peres said. "This tells industry that it's not enough to have high quality procedures -- you have to have procedures that help workers do their jobs." Specifically, they found that utility was the best predictor of procedure use, even after accounting for procedure quality.

As found in other studies, procedure quality was found to be important. The better the quality of the procedure, the fewer deviations there are, resulting in fewer incidents and near-misses per year.

This study is unique in that it demonstrates procedure quality to be a better predictor than all other predictors -- including individual characteristics. This supports the safety two model, as it suggests that the characteristics of the workers are not what is most predictive of procedure use, procedure deviation, incidents and near misses.

Peres said the study is not advocating for the abandonment of safety model one, but rather for the two models to be used together so that individual and system-level factors can be taken into account to design more effective procedural systems.

Further studies are needed to compare workers' performance in different experimental conditions. It will also be necessary to conduct longitudinal studies to determine how these variables change over time. Peres and Hendricks are working with industry partners as part of the Next Generation Advanced Procedures Consortium to conduct these studies.

New Rochelle, NY, January 19, 2021--Gene editing therapies, including CRISPR-Cas systems, offer the potential to correct mutations causing inherited retinal degenerations, a leading cause of blindness. Technological advances in gene editing, continuing safety concerns, and strategies to overcome these challenges are highlighted in the peer-reviewed journal Human Gene Therapy. Click here to read the full-text article free on the Human Gene Therapy website.

"Currently, the field is undergoing rapid development with a number of competing gene editing strategies, including allele-specific knock-down, base editing, prime editing, and RNA editing, are under investigation. Each offers a different balance of on-target editing efficiency versus off-target risks," state Kanmin Xue, University of Oxford, and coauthors. "Testing these newly-developed CRISPR technologies in human retinal tissue, organoids and in vivo will help to highlight the most-viable therapeutic approaches for treating inherited retinal diseases in the future."

Characterizing the rapidly evolving field of CRISPR-Cas based genome editing and current strategies for extending the capabilities of CRISPR-Cas9, the article also features epigenetic editing, the risks of retinal gene editing, and approaches in development to control Cas9 activity and improve safety.

"The eye is an ideal target for in vivo gene editing. Dr. Xue's review provides an excellent overview of the current state of the art," says Editor-in-Chief of Human Gene Therapy Terence R. Flotte, MD, Celia and Isaac Haidak Professor of Medical Education and Dean, Provost, and Executive Dep
uty Chancellor, University of Massachusetts Medical School.

A small pilot study suggests that early administration of ivermectin can reduce viral loads and symptom duration in patients with mild COVID-19, which in turn could help reduce viral transmission. The study, which is part of the SAINT project and has been led by the University of Navarra Clinic and the Barcelona Institute for Global Health (ISGlobal), an institution supported by the "la Caixa" Foundation, warrants further exploration in larger clinical trials. The findings of the pilot study have been published in EClinicalMedicine, a clinical journal published by The Lancet.

We already have two approved COVID-19 vaccines in the European Union, but immunising enough people worldwide to stop viral spread will require at least two years. Meanwhile, finding drugs that can treat or prevent infections remains a priority. "Many efforts are focusing on developing treatments for COVID-19, but few are addressing how to reduce viral transmission," affirms study coordinator Carlos Chaccour, researcher at ISGlobal and physician at the University of Navarra Clinic.

In this pilot study performed with patients from the Clinic and in facilities of the University of Navarra, Chaccour and his team evaluated whether the maximal dose of ivermectin recommended in Europe could have an impact on viral transmission when administered within the first days after symptom onset.

Ivermectin is an antiparasitic drug that has been shown to reduce SARS-CoV-2 replication in vitro (in cell lines), albeit at concentrations that exceed those recommended for human use. This, together with preliminary results from a trial in humans which used data of dubious origin and was never peer-reviewed, prompted the use of ivermectin in many Latin-American countries despite the lack of reliable evidence on its efficacy in treating or preventing infection.

The research team gave one single dose of ivermectin or placebo to 24 patients with confirmed infection and mild symptoms, within the first 72 hours after the first symptoms started. Nasal swabs and blood samples were taken at the moment of enrolment and 1, 2 and/or 3 weeks after treatment.

Seven days after treatments, no difference was observed in the percentage of PCR-positive patients (100% of patients were positive in both groups). However, the mean viral load in the ivermectin-treated group was lower (around 3x lower at 4 days and up to 18x lower at 7 days post-treatment), although the difference was not statistically significant. Treated patients also showed a reduced duration of certain symptoms (of 50% for loss of smell and taste and of 30% for cough). All patients developed virus-specific IgG but, again, the mean level of antibodies in the treated group was lower than in the placebo group. "This could be the result of a lower viral load in these patients," explains Chaccour.

The fact that there was no effect on duration of symptoms or makers associated with inflammation suggests that ivermectin may act through mechanisms that do not involve a possible anti-inflammatory effect. The authors believe it could be interfering with viral entry in the cells, as suggested by another study performed in hamsters at the Pasteur Institute.

"Our findings are in line with those from recent assays conducted in Bangladesh and Argentina," says Chaccour. "Although our study is small and it is too early to draw conclusions, the trends observed in viral loads, symptom duration and antibody levels are encouraging and warrant further exploration in larger clinical trials with a higher diversity of patients," he adds.

ATLANTA - JANUARY 19, 2021 - Despite increases in overall suicide rates in the United States during the past two decades, cancer-related suicides declined by 2.8% per year, according to a new study by the American Cancer Society. The study, appearing in JNCI: The Journal of the National Cancer Institute, found that the largest declines in cancer-related suicide rates were among high-risk populations, suggesting an evolving role of psycho-oncology and palliative and hospice care for cancer patients and survivors during this period.

To examine the trends in cancer-related suicides compared to overall suicides in the U.S., investigators led by Xuesong Han, PhD, calculated average annual percentage change of suicide rates stratified by risk factors including age, sex, urban/rural status and cancer type. They found that of cancer-related suicides, lung cancer (18.2%), prostate cancer (15.4%), and colorectal cancer (9.1%) were the most common contributing causes. They also found that cancer-related suicide rates had large declines among those who were older, male, living in urban areas, and with prostate or lung cancer.

Although the gun and opioid epidemics emerged as major public health concerns during this period and overall suicide rates with firearm and drugs increased, the authors found that cancer-related suicide with firearms did not increase, and cancer-related suicides with drugs remained low. These results suggest different risk profiles of suicide for cancer patients compared to the general population.

"Advances in supportive care and policies ensuring equitable access to increased psychosocial care, and palliative and hospice care services are essential in delivering high quality cancer care to maximize patients and families' quality of life," the authors conclude.

Below please find summaries of new articles that will be published in the next issue of Annals of Internal Medicine. The summaries are not intended to substitute for the full articles as a source of information. This information is under strict embargo and by taking it into possession, media representatives are committing to the terms of the embargo not only on their own behalf, but also on behalf of the organization they represent.

1. Primary care physicians account for a minority of spending on low-value care
Abstract: https://www.acpjournals.org/doi/10.7326/M20-6257
URL goes live when the embargo lifts

Primary care physicians (PCPs) are seen as gatekeepers to reduce spending on low-value health care services, which have been estimated to cost the health care system up to $100 billion annually. A brief research report published in Annals of Internal Medicine analyzed how much low-value spending is directly related to PCPs' services and referral decisions.

Researchers from the American Board of Family Medicine, Harvard, Mount Sinai, and Stanford analyzed Medicare Part B claims between 2007 and 2014 to estimate the share of Medicare beneficiaries' low-value spending that was directly related to their PCP's services or referrals. Low-value services were identified using a consensus set of 31 services previously judged to be low-value by national physician societies, Medicare criteria, and clinical guidelines. Such services include imaging for non-specific back pain, PSA screening for men over the age of 75, and arthroscopic surgery for knee osteoarthritis.

The data showed that PCP services and referrals account for a small minority of spending on low-value care. For the majority of PCPs, services they performed or ordered accounted for less than 9% of their patients' low-value spending, which amounted to less than 0.3% of their total Medicare Part B spending. Similarly, for most PCPs, their referrals accounted for less than 16% of their patients' low-value spending, which amounted to less than 0.5% of their total Medicare Part B spending.

Media contacts: For an embargoed PDF, please contact Lauren Evans at laevans@acponline.org. The corresponding author, Aaron Baum, PhD, can be reached through Jane Ireland at jireland@theabfm.org.

2. Hypothetical case suggests genetic testing has significant limitations for predicting disease in a healthy patient
Abstract: https://www.acpjournals.org/doi/10.7326/M20-5713
URL goes live when the embargo lifts

Despite its utility as a diagnostic tool in patients with specific risk factors for genetic disease, genetic testing still has significant limitations for predicting disease in a healthy patient. Authors from Colombia University used a hypothetical case to illustrate differences between diagnostic testing and predictive genetic screening for prevention purposes, focusing on available clinical tests. Their case report is published in Annals of Internal Medicine.

Healthy patients increasingly inquire about genetic testing as a tool for predicting diseases, such as cancer, heart disease, or dementia. In practice, most genetic testing is done in affected persons as a diagnostic tool or in healthy persons at high risk for genetic disease based on family history. Much less is known about the predictive value of genetic tests to screen healthy persons with no clear risk for genetic disease.

The researchers summarized current knowledge using on the hypothetical case of a healthy 35-year-old woman requesting genetic testing to predict her future risk for disease. Her maternal aunt and a male cousin had coronary heart disease by age 50 and a paternal aunt died of breast cancer at age 56. The scope of the genetic test can be determined on the basis of the risk profile and family history as well as the patient's concerns about specific diseases. For this patient, several genetic tests would be available, yet their value for predicting future disease could be very limited.

According to the researchers, in the diagnostic framework, detection of a pathogenic variant consistent with a person's clinical condition can establish a diagnosis of genetic disease. In the predictive framework, interpretation of genetic results is more complicated given the large number of putative pathogenic variants and the paucity of information about their clinical consequences. Even if the patient's genetic test revealed a genetic risk to a specific illness or illnesses, in most cases, the likelihood that she would develop the disease is not known Based on what is currently known about genetic testing as a predictive tool, the researchers conclude that a Bayesian framework is useful for assessing future risk of disease and predictive testing in clinical practice should be limited to genes where there is strong evidence linking mutations to high risk of disease.

Media contacts: For an embargoed PDF, please contact Lauren Evans at laevans@acponline.org. The corresponding author, Ali G. Gharavi, MD, can be contacted directly at ag2239@columbia.edu.

Also in this issue:

Corticosteroids and COVID-19: Calming the Storm?
Pearson
Hospitalist Commentary
https://www.acpjournals.org/doi/10.7326/M20-7671

Cancer and Deep Venous Thrombosis: A Serious Combination
Geno J. Merli, MD, Howard H. Weitz, MD
Consult Guys
https://www.acpjournals.org/doi/10.7326/W20-0017

Low Dose Steroids and Risk of Infection
Robert M. Centor, MD
Annals On Call Podcast
https://www.acpjournals.org/doi/10.7326/A20-0005

New research has demonstrated that a simple, cheap test can help identify who is at risk of developing colorectal cancer, aiding early diagnosis and potentially saving lives.

Led by the University of Exeter, and supported by the Peninsula and the Somerset, Wiltshire, Avon, and Gloucestershire Cancer Alliances, and by the Cancer Research UK CanTest Collaborative, a new study published today in the British Journal of Cancer examined data from nearly 4,000 patients aged 50 and over. The study involved all healthcare providers in the South West of England taking a new approach. Over six months, they provided the faecal immunochemical test (FIT), which costs round £4 and can pick up traces of hidden blood in faeces. The test was given to anyone with low-risk symptoms of colorectal cancer - that is, symptoms can be caused by bowel cancer but are also very often caused by other things - such as stomach ache, unexplained weight loss, or anaemia. Prior to this, there was no easy to do test available for people with low risk symptoms of colorectal cancer.

From June to December 2018, 3,890 patients received the FIT. Of those, 618 tested positive for blood in their faeces, 43 of whom had received a diagnosis of colorectal cancer within 12 months. In the group that tested negative, only eight were diagnosed with colorectal cancer a year later.

Dr Sarah Bailey, of the University of Exeter Medical School, who led the study, said: "Our findings are very exciting - we show that this simple and inexpensive test performs exceptionally well in this group of patients with low-risk symptoms, to quickly and accurately tell us who is likely to not have colorectal cancer, and who should be referred for investigation. At a time when hospital services face a backlog as a result of COVID-19 measures, making this decision quickly can ensure the right people are investigated and treated as quickly as possible, which can help save lives. We know that FIT has accelerated interest in how FIT can be used in other patients, such as those with symptoms that have a higher risk of being colorectal cancer and we are now calling for FIT to be evaluated for use across the entire healthcare spectrum, not just in primary care, and in combination with other clinical markers of cancer such as blood test results"

Colorectal cancer has a high mortality rate - each year, 1.8 million cases are diagnosed worldwide, and the disease causes global 900,000 deaths annually. Requests for urgent colorectal cancer investigations have more than doubled from 2012. This is in part because of awareness among clinicians that seemingly low-risk symptoms can later present as an emergency, with the lowest cancer survival.

Dr Joe Mays, of the Peninsula Cancer Alliance, which brings together leaders from different hospital trusts to improve cancer diagnosis and care in their area,, said: "The rapid and robust analysis has generated the evidence for doctors to use the FIT test with confidence. This led to a reduction in the expected rates of colonoscopy, and helped us build a business case for the ongoing commissioning of this service. Building confidence and familiarity with the test helped us to manage a crisis in endoscopy capacity caused by the COVID-19 pandemic. We're now keen to evidence the performance of the test in higher risk populations."

Dr Jodie Moffat, Cancer Research UK's head of early diagnosis, said: "FIT is already being used for people who don't have symptoms in the bowel screening programme. So it's fascinating to see how this test may also be used in patients with low risk symptoms to identify who needs further investigation. As with all tests, FIT isn't perfect and some cases can be missed so it's important that anyone whose symptoms persist, change or worsen contact their GP, even if they've recently had a negative FIT result."

Fried-food intake is linked to a heightened risk of major heart disease and stroke, finds a pooled analysis of the available research data, published online in the journal Heart.

And the risk rises with each additional 114 g weekly serving, the analysis indicates.

It's clear that the Western diet doesn't promote good cardiovascular health, but it's not clear exactly what contribution fried food might make to the risks of serious heart disease and stroke, say the researchers.

To shed some light on this, they trawled research databases, looking for relevant studies published up to April 2020, and found 19.

They pooled the data from 17, involving 562,445 participants and 36,727 major cardiovascular 'events', such as a heart attack or stroke, to assess cardiovascular disease risk.

And they pooled the data from six, involving 754,873 participants and 85,906 deaths over an average monitoring period of 9.5 years, to assess the potential link between fried food consumption and deaths from cardiovascular disease and from any cause.

Their analysis showed that compared with the lowest category of weekly fried food consumption, the highest was associated with a 28% heightened risk of major cardiovascular events; a 22% heightened risk of coronary heart disease; and a 37% heightened risk of heart failure.

These associations held true when stratified by various study and participant characteristics. What's more, a linear association emerged between fried food consumption and major cardiovascular events, coronary heart disease, and heart failure.

These risks substantially increased by 3%, 2%, and 12%, respectively, in tandem with each additional 114 g weekly serving.

Several studies included only one type of fried food, such as fried fish, potatoes, or snacks, rather than total fried food intake, which may have underestimated the associations found, suggest the researchers.

No associations were found for deaths from cardiovascular disease or from any cause, but this might be because of the relatively small numbers involved, say the researchers.

The design of the included studies varied considerably, added to which, they all relied on memory--factors that should be taken into consideration when interpreting the results, caution the researchers.

And how exactly fried foods might influence the development of cardiovascular disease isn't entirely clear, they point out, but suggesting several possible explanations.

Fried foods boost energy intake because of their fat content and they generate harmful trans fatty acids from the hydrogenated vegetable oils often used to cook them.

Frying also boosts the production of chemical by-products involved in the body's inflammatory response, while foods, such as fried chicken and French fries, are usually high in added salt, and often accompanied by sugar-sweetened drinks, particularly when served in fast food restaurants, they say.

Scientists in Australia have developed a method for the rapid synthesis of safe vaccines, an approach that can be used to test vaccine strategies against novel pandemic pathogens such as SARS-CoV-2, the virus that causes COVID-19.

Led by Professor Richard Payne at the University of Sydney and Professor Warwick Britton at the Centenary Institute, the team has demonstrated application of the method with a new vaccine for use against tuberculosis (TB), which has generated a powerful protective immune response in mice.

Researchers are keen to develop the vaccine strategy further to assist in the rapid pre-clinical testing of new vaccines, particularly for respiratory illnesses.

"Tuberculosis infects 10 million and kills more than 1.4 million people every year," said joint first author Dr Anneliese Ashhurst from the University of Sydney. "Historically, it is the leading cause of death worldwide from a single infectious agent. So far, a TB vaccine that is highly effective and safe to use in all populations has eluded medical science."

The only current vaccine for tuberculosis, the Bacille Calmette-Guerin vaccine, uses an injected live bacterium. It is effective in infants but has reduced effectiveness in adolescents and adults and poses significant health risks for immunocompromised patients, particularly for people living with HIV/AIDS.

Protein-based vaccines have been shown to be very safe, but they must be mixed with enhancers, or adjuvants, to make them effective, which is not straightforward.

Dr Ashhurst said: "The challenge is to ensure that our immune cells see both the protein and adjuvant simultaneously. To overcome this difficulty, for the first time we have developed a method that synthesises the protein with an attached adjuvant as a single molecule."

The vaccine strategy and synthetic technology could be deployed to rapidly generate new vaccines for pre-clinical testing for a range of diseases, the researchers say, including the respiratory pathogen that causes COVID-19.

Their results are published today in the Proceedings of the National Academy of Sciences of the United States of America.

HOW IT WORKS

In order for vaccines to be effective, they need to stimulate behaviour in protective T-cells that allows them to recognise the pathogen as an antigen, or foreign body. In the case of tuberculosis, our immune system needs to respond quickly to the bacteria that causes TB - Mycobacterium tuberculosis - to reduce infection in lungs.

Using the method developed by the Sydney scientists, an inhaled vaccine provides a low-dose immune-stimulating molecule - containing a synthesised bacterial protein attached directly to an adjuvant - to the immune cells in the lungs.

A major hurdle overcome by the scientists was the difficulty in fusing hydrophobic (water-repellent) adjuvants with a water-soluble protein antigen.

"We got around this problem of keeping hydrophobic and hydrophilic molecules together in a vaccine by developing a way to permanently bind the protein and adjuvant together as a single molecule using synthetic chemistry. Our approach overcomes the solubility problems faced by other methods," said Professor Payne from the School of Chemistry and Deputy Director of the ARC Centre for Innovations in Peptide & Protein Science (CIPPS).

The team says that synthesising an entire bacterial protein with attached adjuvant has not been achieved before.

Professor Britton from the Tuberculosis Research Program at the Centenary Institute said: "As well as providing a rapid method to develop a range of vaccines for pre-clinical testing, we expect that this pulmonary vaccination approach will be particularly beneficial for protecting against respiratory diseases."

He said: "We hope that an inhaled vaccine for tuberculosis using a protein-based immunisation will allow us to develop a universal and safe approach to combatting this deadly disease."

The other major advantage with this method is that vaccines for a range of diseases can be developed rapidly and safely in the laboratory.

"We don't need to grow the actual pathogen in the lab to make the vaccine," said Dr Ashhurst, who holds a joint position in the School of Chemistry and the School of Medical Sciences. "Using this new method, we can rapidly and safely synthesise highly pure vaccines in the lab and take them straight into animal models for pre-clinical testing."

Targeted neuromodulation tailored to individual patients' distinctive symptoms is an increasingly common way of correcting misfiring brain circuits in people with epilepsy or Parkinson's disease. Now, scientists at UC San Francisco's Dolby Family Center for Mood Disorders have demonstrated a novel personalized neuromodulation approach that -- at least in one patient -- was able to provide relief from symptoms of severe treatment-resistant depression within minutes.

The approach is being developed specifically as a potential treatment for the significant fraction of people with debilitating depression who do not respond to existing therapies and are at high risk of suicide.

"The brain, like the heart, is an electrical organ, and there is a growing acceptance in the field that the faulty brain networks that cause depression -- just like epilepsy or Parkinson's disease -- could be shifted into a healthier state by targeted stimulation," said Katherine Scangos, MD, PhD, an assistant professor in the Department of Psychiatry and Behavioral Sciences and corresponding author of the new study. "Prior attempts to develop neuromodulation for depression have always applied stimulation in the same site in all patients, and on a regular schedule that fails to specifically target the pathological brain state. We know depression affects different people in very different ways, but the idea of mapping out individualized sites for neuromodulation that match a patient's particular symptoms had not been well explored."

In a case study published January 18, 2021 in Nature Medicine, Scangos and colleagues mapped the effects of mild stimulation of several mood-related brain sites in a patient with severe treatment-resistant depression. They found that stimulation at different sites could alleviate distinct symptoms of the brain disease -- reducing anxiety, boosting energy levels, or restoring pleasure in everyday activities -- and, notably, that the benefits of different stimulation sites depended on the patient's mental state at the time.

The proof-of-concept study lays the groundwork for a major five-year clinical trial Scangos is leading, called the PRESIDIO trial, that will evaluate the effectiveness of personalized neuromodulation in 12 patients with severe treatment-resistant depression. The trial will build on the current study by identifying brain signatures that reflect individual participants' symptoms. With this information, neuromodulation devices can be programmed to respond in real time to these faulty network states with targeted stimulation that brings patients' brain circuits back into balance.

"We've developed a framework for how to go about personalizing treatment in a single individual, showing that the distinctive effects of stimulating different brain areas are reproducible, long-lasting and state-dependent," said Andrew Krystal, MD, director of UCSF's Dolby Center and co-senior author on the new study. "Our trial is going to be groundbreaking in that every person in the study is potentially going to get a different, personalized treatment, and we will be delivering treatment only when personalized brain signatures of a depressed brain state indicate treatment is needed."

Epilepsy Studies Laid Groundwork for Depression Neuromodulation Trial

Depression is among the most common psychiatric disorders, affecting as many as 264 million people worldwide and leading to hundreds of thousands of deaths per year. But as many as 30 percent of patients do not respond to standard treatments such as medication or psychotherapy. Some of these individuals respond positively to electroconvulsive therapy (ECT), but stigma and side effects make ECT undesirable for many, and one in ten patients experience little benefit even from ECT.

Previous research by Edward Chang, MD, co-senior author of the new study, has demonstrated the potential of brain mapping to identify promising sites for mood-boosting brain stimulation. These studies were conducted at UCSF Epilepsy Center in patients with and without clinical depression who already had electrode arrays implanted in their brains to map seizures ahead of epilepsy surgery.

"Our prior work showed a proof of principle for targeted stimulation across brain areas to treat mood symptoms, but an outstanding question has been whether the same approach would hold true for patients with depression alone," said Chang, who is the Joan and Sanford I. Weill Chair of the UCSF Department of Neurological Surgery and Jeanne Robertson Distinguished Professor.

Brain Mapping Case Study Illustrates Personalized Neuromodulation and Symptom Relief

In the new study, the UCSF team demonstrated the use of a similar brain-mapping approach to identify patient-specific therapeutic stimulation sites as the first phase of the PRESIDIO trial.

The team used a minimally invasive approach called stereo-EEG to place 10 intracranial electrode leads into the brain of the first patient enrolled in the trial -- a 36-year-old woman who has experienced multiple episodes of severe treatment-resistant depression since childhood. The patient then spent 10 days at the UCSF Helen Diller Medical Center at Parnassus Heights while researchers systematically mapped effects of mild stimulation across a number of brain regions that prior research had shown were likely to have an effect on mood.

The researchers found that 90-second stimulation of a several different brain sites could reliably produce an array of distinctive positive emotional states, as measured by a set of clinical scales that were used to assess the patient's mood and depression severity throughout the study. For example, after stimulation of one region, the patient reported "tingles of pleasure," while stimulation of a second area resulted in a feeling of "neutral alertness ... less cotton and cobwebs." Stimulation of a third area -- a region called orbitofrontal cortex (OFC) that had been identified in Chang's earlier studies -- produced a sensation of calm pleasure "like ... reading a good book."

The team then tested more prolonged (three- to 10-minute) stimulation of these three areas to attempt longer-lasting relief of the patient's depression symptoms. To their surprise, they found that stimulation of each of the three sites improved her symptoms in different ways, depending on the patient's mental state at the time of stimulation. For example, when she was experiencing anxiety, the patient reported stimulation of the OFC as positive and calming, but if the same stimulation was delivered when she was experiencing decreased energy, it worsened her mood and made her feel excessively drowsy. The opposite pattern was observed in the other two regions, where stimulation increased the patient's arousal and energy level.

"I've tried literally everything, and for the first few days I was a little worried that this wasn't going to work," the patient recalled. "But then when they found the right spot, it was like the Pillsbury Doughboy when he gets poked in the tummy and has that involuntary giggle. I hadn't really laughed at anything for maybe five years, but I suddenly felt a genuine sense of glee and happiness, and the world went from shades of dark gray to just--grinning."

The researchers focused in on an area known as the ventral capsule/ventral striatum, which seemed to best address this particular patient's primary symptoms of low energy and loss of pleasure in everyday activities.

"As they kept playing with that area, I gradually looked down at the needlework I had been doing as a way to keep my mind off negative thoughts and realized I enjoyed doing it, which was a feeling I haven't felt for years," she said. "It struck me so clearly in that moment that my depression wasn't something I was doing wrong or just needed to try harder to snap out of -- it really was a problem in my brain that this stimulation was able to fix. Every time they'd stimulate, I felt like, 'I'm my old self, I could go back to work, I could do the things I want to do with my life.'"

The researchers found that the effects of stimulation could be tailored to the patient's mood, and that positive effects lasted for hours, well beyond the 40-minute window designed into the study protocol. The patient's symptoms also got significantly better over the course of the 10-day study, leading to a temporary remission lasting 6 weeks.

"The fact that we could eliminate this patient's symptoms for hours with just a few minutes of targeted stimulation was remarkable to see," Krystal said. "It emphasizes that even the most severe depression is a brain circuit disease that may just need a targeted nudge back into a healthy state. Unlike antidepressant drugs, which might not have an effect for one to three months, probably by altering brain circuits in ways we don't understand, our hope is that this approach will be effective precisely because it only requires brief, mild stimulation when the undesired brain state we want to change is present."

Promising Initial Results of Real-Time, Targeted Neuromodulation Seen in Ongoing Trial

When the patient's symptoms returned after her initial remission, the researchers proceeded to the next phase of the PRESIDIO trial -- implanting a responsive neuromodulatory device called the NeuroPace RNS System. This device is widely used for seizure control in epilepsy patients, in whom it can detect signs of oncoming seizures in real time and initiate brief, targeted stimulation that cancels them out. In the PRESIDIO trial, the device instead detects signature patterns of brain activity that indicate that a participant is moving towards a highly depressed state, and then provides mild, undetectable levels of stimulation to a targeted brain region to counteract this downswing.

"We hope that providing gentle neuromodulation throughout each day will be able to prevent patients from falling into long-lasting depressive episodes," said Scangos, who was recently awarded a 1907 Research Trailblazer Award for her work to understand depression's neural circuitry. "The idea is that keeping neural circuit activity functioning along the correct track, the pathways that support pathological negative thought processes in depression can be unlearned."

The NeuroPace device was implanted in June of 2020 and activated in August, and so far, the study participant has reported that her symptoms -- which in the past seven years had made it impossible for her to hold a job or even drive -- have almost completely vanished, despite significant life stressors like a COVID exposure, helping her parents move out of state, and caring for her mother after a fall.

"2020 was terrible for everyone, and I've had some particularly stressful life events, but for the first time in a long time, I feel like I can bob back up again," she said. "I can't tell exactly when the device turns on, but I generally feel more of a sense of clarity, an ability to look at my emotions rationally and apply the tools that I've worked on through psychotherapy, and that is so far from where I was before."

In the trial's next phase, the patient will switch between six weeks with the device turned on and six weeks with it off, without being aware of which is which, in order to assess possible placebo effects.

HOUSTON — In an effort to address a major challenge when analyzing large single-cell RNA-sequencing datasets, researchers from The University of Texas MD Anderson Cancer Center have developed a new computational technique to accurately differentiate between data from cancer cells and the variety of normal cells found within tumor samples. The work was published today in Nature Biotechnology.

The new tool, dubbed CopyKAT (copy number karyotyping of aneuploid tumors), allows researchers to more easily examine the complex data obtained from large single-cell RNA-sequencing experiments, which deliver gene expression data from many thousands of individual cells.

CopyKAT uses that gene expression data to look for aneuploidy, or the presence of abnormal chromosome numbers, which is common in most cancers, said study senior author Nicholas Navin, Ph.D., associate professor of Genetics and Bioinformatics & Computational Biology. The tool also helps to identify distinct subpopulations, or clones, within the cancer cells.

"We developed CopyKAT as a tool to infer genetic information from the transcriptome data. By applying this tool to several datasets, we showed that we could unambiguously identify, with about 99% accuracy, tumor cells versus the other immune or stromal cells present in a mixed tumor sample," Navin said. "We could then go one step further to discover the subclones present and understand their genetic differences."

Historically, tumors have been studied as a mixture of all cells present, many of which are not cancerous. The advent of single-cell RNA sequencing in recent years has enabled researchers to analyze tumors in much greater resolution, examining the gene expression of each individual cell to develop a picture of the tumor landscape, including the surrounding microenvironment.

However, it's not easy to distinguish between cancer cells and normal cells without a reliable computational approach, Navin explained. Former postdoctoral fellow Ruli Gao, Ph.D., now assistant professor of Cardiovascular Sciences at Houston Methodist Research Institute, developed the CopyKAT algorithms, which improve upon older techniques by increasing accuracy and adjusting for the newest generation of single-cell RNA-sequencing data.

The team first benchmarked its tool by comparing results to whole-genome sequencing data, which showed high accuracy in predicting copy number changes. In three additional datasets from pancreatic cancer, triple-negative breast cancer and anaplastic thyroid cancer, the researchers showed that CopyKAT was accurate in distinguishing between tumor cells and normal cells in mixed samples.

These analyses were made possible through collaborations with Stephen Y. Lai, M.D., Ph.D., professor of Head and Neck Surgery, as well as Stacy Moulder, M.D., professor of Breast Medical Oncology, and the Breast Cancer Moon Shot®, part of MD Anderson's Moon Shots Program®, a collaborative effort to rapidly develop scientific discoveries into meaningful clinical advances that save patients' lives.

In analyzing these samples, the researchers also showed the tool is effective in identifying subpopulations of cancer cells within the tumor based on copy number differences, as confirmed by experiments in triple-negative breast cancers.

"By using CopyKAT, we were able to identify rare subpopulations within triple-negative breast cancers that have unique genetic alterations not widely reported, including those with potential therapeutic implications," Gao said. "We hope this tool will be useful to the research community to make the most of their single-cell RNA-sequencing data and to drive new discoveries in cancer."

The tool is freely available to researchers here. The authors note that the tool is not applicable to the study of all cancer types. Aneuploidy, for example, is relatively rare in pediatric and hematologic cancers.

Philadelphia, January 18, 2021 - A new study comparing the incidence of sudden deaths occurring outside the hospital across New York City's highly diverse neighborhoods with the percentage of positive SARS-CoV-19 tests found that increased sudden deaths during the pandemic correlate to the extent of virus infection in a neighborhood. The analysis appears in Heart Rhythm, the official journal of the Heart Rhythm Society, the Cardiac Electrophysiology Society, and the Pediatric & Congenital Electrophysiology Society, published by Elsevier.

"Our research shows the highly diverse regional distribution of out-of-hospital sudden death during the COVID-19 pandemic surge and follows the geographic distribution of seroconversion to SARS-CoV-2 in New York City," explains lead investigator Stavros E. Mountantonakis, MD, FHRS, Northwell Health-Lenox Hill Hospital, Department of Cardiac Electrophysiology, New York, NY, USA. "This finding adds to the previously reported association between out-of-hospital sudden death and COVID-19 presumed deaths and further supports an association between out-of-hospital sudden death and SARS-COV-2 epidemiologic burden."

The investigators collected results of all antibody tests reported to the New York City Department of Health between March 3 and August 20, 2020 for all New York City zip codes, excluding eight commercial districts. New York City requires mandatory reporting of all tests. Data from March 20 to April 22, 2020, during the height of the pandemic, were obtained from the Fire Department of New York City on the number of patients pronounced dead at the scene from sudden cardiac arrest, the classification the Department uses for out-of-hospital sudden death. For comparison, they collected data for the same period in 2019. Census data were used to examine the possible influence of factors including age, race, access to medical insurance, education, and immigration status.

The investigators found that sudden death during the pandemic varied widely among neighborhoods and there was a moderate positive association between the rate of sudden death in a neighborhood and the percentage of positive antibody tests to SARS-CoV-2. The rate of sudden death in 2019 was also predictive of increased sudden deaths in a neighborhood during the first pandemic surge in New York City.

The investigators note that it is unclear whether this association is causative, or if there are factors that affect the geographic distribution of sudden death and SARS-CoV-2 infection similarly.

Dr. Mountantonakis observes, "The epidemiological data is a direct surrogate of viral burden and indirectly associated with people dying suddenly at home. It remains to be seen whether this is due to cardiac complications related to the virus or poor access to healthcare in neighborhoods that suffered the most during the first wave of the COVID-19 pandemic."

These findings emphasize the importance of preserving access to healthcare, especially in neighborhoods that suffered disproportionally in the first COVID-19 pandemic wave.

Writing in an accompanying editorial, John R. Giudicessi, MD, PhD, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA, notes that regardless of the ultimate breakdown between direct and indirect effects of COVID-19 on out-of-hospital sudden death incidence, the precipitous rise in New York City and other metropolitan areas is indisputable. "It appears increasingly likely that most areas will have to endure one or more additional surges before the benefits of vaccination efforts take hold," he comments. "There is hope that maintaining safe access to routine and emergency health services, avoidance of ineffective treatment strategies, and improvements in how COVID-19 patients are monitored and treated in the outpatient setting may help reduce the incidence of out of hospital cardiac arrest and death."

The researchers published their report in the Journal Nature Communications from 15 January 2021.

When the communication breaks down

Spinal cord injuries caused by sports or traffic accidents often result in permanent disabilities such as paraplegia. This is caused by damage to nerve fibers, so-called axons, which carry information from the brain to the muscles and back from the skin and muscles. If these fibers are damaged due to injury or illness, this communication is interrupted. Since severed axons in the spinal cord can't grow back, the patients suffer from paralysis and numbness for life. To date, there are still no treatment options that could restore the lost functions in affected patients.

Designer protein stimulates regeneration

In their search for potential therapeutic approaches, the Bochum team has been working with the protein hyper-interleukin-6. "This is a so-called designer cytokine, which means it doesn't occur like this in nature and has to be produced using genetic engineering," explains Dietmar Fischer. His research group already demonstrated in a previous study that hIL-6 can efficiently stimulate the regeneration of nerve cells in the visual system.

In their current study, the Bochum team induced nerve cells of the motor-sensory cortex to produce hyper-Interleukin-6 themselves. For this purpose, they used viruses suitable for gene therapy, which they injected into an easily accessible brain area. There, the viruses deliver the blueprint for the production of the protein to specific nerve cells, so-called motoneurons. Since these cells are also linked via axonal side branches to other nerve cells in other brain areas that are important for movement processes such as walking, the hyper-interleukin-6 was also transported directly to these otherwise difficult to access essential nerve cells and released there in a controlled manner.

Applied in one area, effective in several areas

"Thus, gene therapy treatment of only a few nerve cells stimulated the axonal regeneration of various nerve cells in the brain and several motor tracts in the spinal cord simultaneously," points out Dietmar Fischer. "Ultimately, this enabled the previously paralyzed animals that received this treatment to start walking after two to three weeks. This came as a great surprise to us at the beginning, as it had never been shown to be possible before after full paraplegia."

The research team is now investigating to what extent this or similar approaches can be combined with other measures to optimize the administration of hyper-Interleukin-6 further and achieve additional functional improvements. They are also exploring whether hyper-interleukin-6 still has positive effects in mice, even if the injury occurred several weeks previously. "This aspect would be particularly relevant for application in humans," stresses Fischer. "We are now breaking new scientific ground. These further experiments will show, among other things, whether it will be possible to transfer these new approaches to humans in the future."

Philadelphia, January 14, 2021--In a large study of pediatric cancer patients, researchers from Children's Hospital of Philadelphia (CHOP) have analyzed the frequency, fusion partners, and clinical outcome of neurotrophic tyrosine receptor kinase (NTRK) fusions, which are clinical biomarkers that identify patients suitable for treatment with FDA-approved TRK inhibitors. The researchers found that NTRK fusions are more common in pediatric tumors and also involve a wider range of tumors than adult cancers, information that could help prioritize screening for NTRK fusions in pediatric cancer patients who might benefit from treatment with TRK inhibitors.

The findings were published in JCO Precision Oncology.

"Our findings demonstrate that NTRK fusions are far more frequently seen in pediatric tumors than in adult tumors and involve a broader panel of fusion partners and wider range of pediatric tumors than previously recognized," said senior author Marilyn M. Li, MD, Vice Chief of the Division of Genomic Diagnostics and Director of Cancer Genomic Diagnostics at CHOP. "With the recent FDA approval of larotrectinib and entrectinib for the treatment of adult and pediatric NTRK-positive, unresectable solid tumors, identification of these fusions directly impacts patient care."

Previous studies have shown that rearrangements of NTRK genes drive tumor growth in a diverse range of cancers. This led to the development of the first generation oral NTRK inhibitors, larotrectinib and entrectinib, and have spurred the development of other NTRK inhibitors, which are currently in clinical development. Ongoing clinical trials hope to identify optimal use of these drugs in children.

Given that in children, certain cancers like infantile fibrosarcoma (IF) and secretory carcinoma have very high incidence of NTRK fusions (>90%), whereas other cancers like melanoma and acute leukemia rarely involve NTRK fusions, the researchers sought to better understand the frequency of these gene fusions across all pediatric cancers.

To do so, they analyzed 1,347 consecutive pediatric tumors from 1,217 patients who underwent tumor genomic profiling using custom-designed DNA and RNA next generation sequencing panels. The researchers identified NTRK fusions in 29 tumors from 27 patients, with a positive yield of 2.22% for all tumors and 3.08% for solid tumors. NTRK fusions were detected in 13% of papillary thyroid carcinomas (PTCs), 1.9% of central nervous system (CNS) tumors, 1.8% of non-CNS, non-PTC solid tumors, and 0.4% of hematologic malignancies.

Patients in the study were followed for up to 46 months, and in almost all cases, the detection of an NTRK fusion confirmed the diagnosis of the lesion type, including five cases where the final tumor diagnosis was largely based on the discovery of an NTRK fusion. In one patient, the diagnosis was changed due to the identification of an NTRK fusion. In a separate case, a 6-month-old infant with a mass in his upper left extremity due to IF, which would have required extremely complex surgery to remove, was treated with larotrectinib and achieved complete pathologic remission.

"The identification of these NTRK fusions has facilitated precision cancer diagnosis and TRK inhibitor targeted therapy," Li said. "Our experience highlights the clinical utility of screening NTRK fusions for all pediatric tumors."