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With the National Eye Institute reporting that about 11 million older adults in the U.S. endure a condition that leads to progressive blindness, known as age-related macular degeneration, University of Maryland School of Medicine (UMSOM) researchers are starting to understand what goes wrong in the disease, in order to develop new therapies to treat it.

Using human tissue and mice in their new study, published on June 23 in
Nature Communications, they showed that the process which removes the eye's old, damaged light sensors is disrupted in macular degeneration.

Although more than 50 genes have been linked to the condition, the precise mechanism behind it is unknown. Most people have a form of the condition, for which there are no known effective treatments.

Previously, the senior author of a new study Zubair M. Ahmed, PhD, Professor of Otorhinolaryngology-Head & Neck Surgery and Ophthalmology at the University of Maryland School of Medicine, found out that many families with hearing disorders had genetic mutations in the gene for the CIB2 protein. In work published in 2012 in Nature Genetics, Dr. Ahmed also showed that CIB2 was needed for vision in a large human family, as well as in zebrafish. Now, in this latest study, his team built on that previous work to dissect the intricate cell mechanisms behind retinal degeneration.

The team compared healthy mouse eyes to those from a mouse engineered without the CIB2 protein. The researchers observed that the CIB2 mutant mice were not getting rid of their old light sensor proteins, called photoreceptors, like healthy mouse eyes did.

"Photoreceptors continue growing in tiny columns in the eye, but over time, light damages the photoreceptors. To combat this, support cells in the eye slowly munch on the old, damaged photoreceptors keeping the columns the correct length," says first author Saumil Sethna, PhD, Instructor of Otorhinolaryngology-Head & Neck Surgery at the University of Maryland School of Medicine. "If the photoreceptors are not removed or if the process is backed up due to slow digestion by the support cells, like in the CIB2 mutant mice, the undigested material builds up over time, which may contribute to blindness."

Next, the researchers identified several components in this photoreceptor recycling process, including a group of proteins collectively called mTORC1, which is involved in many human diseases, including cancer, obesity, and epilepsy.

As mTORC1 plays a central decision-maker role for many cellular functions including cleaning up cellular debris, the researchers looked at mTORC1's activity in the CIB2 mutant mice and saw that mTORC1 was overactive. They confirmed that mTORC1 was also overactive in human eye tissue samples from people with a form of age-related macular degeneration. By linking the results of the mouse studies to human disease, the researchers say their findings indicate that drugs against mTORC1 may be effective treatments for the most common type of age-related macular degeneration. mTOR, the core component can be found in two flavors each with different functions, known as complex 1 (as in mTORC1) or complex 2 (mTORC2).

"Researchers have tested many small molecules directed at mTORC1 to treat various diseases, but the problem is that mTOR is needed for so many other cell functions that there are major side-effects when you tinker with it," says Dr. Ahmed. "In our study, we found a backdoor way to regulate mTORC1 (and not mTORC2), which may bypass many of the unpleasant side-effects that normally occur with suppressing mTORC1. We think we may be able to use our new knowledge of this mechanism to develop treatments for age-related macular degeneration and other diseases as well."

The authors have filed a patent application to develop new therapies using CIB2's role in controlling mTOR (PCT/US2019/044745).

"Figuring out the cell mechanism behind age-related macular degeneration is the first step to being able to develop new treatments," says E. Albert Reece, MD, PhD, MBA, Executive Vice President for Medical Affairs, UM Baltimore, and the John Z. and Akiko K. Bowers Distinguished Professor and Dean, University of Maryland School of Medicine. "Using the evolving understanding of the mechanistic role of mTORC1, this study has provided great insights into new ways that researchers can begin to find ways to preserve, to treat, and/or improve macular degeneration, and thus improve the quality of life and independent living in many older adults."

Digital trial replicated and expanded upon results of traditional clinical trials

Developing virtual patient populations can speed up trials process

A study involving virtual rather than real patients was as effective as traditional clinical trials in evaluating a medical device used to treat brain aneurysms, according to new research.

The findings are proof of concept for what are called in-silico trials, where instead of recruiting people to a real-life clinical trial, researchers build digital simulations of patient groups, loosely akin to the way virtual populations are built in The Sims computer game.

In-silico trials could revolutionise the way clinical trials are conducted, reducing the time and costs of getting new medical devices and medicines developed, while reducing human and animal harm in testing.

The virtual patient populations are developed from clinical databases to reflect age, sex and ethnicity but they also simulate the way disease affects the human body: for example, the interactions between anatomy, physics, physiology, and blood biochemistry. Those simulations are then used to model the impact of therapies and interventions.

The international research, led by the University of Leeds and reported today (23 June) in the journal Nature Communications, investigated whether an in-silico trial could replicate the results of three, real-life clinical trials that assessed the effectiveness of a device called a flow diverter, used in the treatment of brain aneurysms, a disease where the wall of a blood vessel weakens and begins to bulge.

Flow diverter reduces blood flow into the aneurysm

A flow diverter is a small, flexible mesh tube which is guided to the site of the aneurysm by a doctor using a catheter. Once in place, the flow diverter directs blood along the blood vessel and reduces flow into the aneurysm, initiating a clotting process that eventually cuts the aneurysm off from blood circulation, thus healing it.

Without successful treatment, the aneurysm can burst causing a bleed on the brain and a stroke.

To establish their proof of concept, the researchers had to see if the results from their in-silico study agreed with the results from three previous major clinical trials into the effectiveness of flow diverters.

The 'participants' in the virtual trial

The researchers built a virtual population using real patient data drawn from clinical databases, ensuring that the anonymised virtual patients closely resembled the patients used in real flow diverter clinical trials in terms of age, sex and aneurysm characteristics.

The researchers then built a computational model that analysed how the implanted device would affect blood flow in each of the virtual patients. They were able to study different physiological conditions for each patient, such as normal and high blood pressure, and perform analyses on patient sub-groups, such as those with large aneurysms or aneurysms with a branch vessel.

The in-silico trial had 82 virtual cases.

The traditional clinical trials (called PUFS, PREMIER and ASPIRe) had 109, 141 and?207?patients, respectively. Around half the cases in the traditional trials had high blood pressure.

The results of the in-silico trial predicted that 82.9% of the virtual patients with normal blood pressure would be successfully treated with a flow diverter. In the traditional clinical trials, the number of people who were successfully treated was 86.8%, 74.8% and 76.8%, respectively, thus showing that the in-silico trial replicated the traditional clinical trials results.

In-silico trials generate 'huge benefits'

Professor Alex Frangi, Diamond Jubilee Chair in Computational Medicine and Royal Academy of Engineering Chair in Emerging Technologies at the University of Leeds, who supervised the study, said: "The results demonstrate the huge potential of in-silico trials. We have shown that the approach can replicate the findings of traditional clinical trials - and they do that in a fraction of the time it normally takes, and at a fraction of the cost."

In the in-silico trial, the researchers were also able to adapt their computational model to investigate new hunches or emerging scientific findings.

By modelling the physics of blood flow and the biochemistry of blood clotting in aneurysms under different physiological conditions, they were able to identify sub-groups of patients at higher risk of stroke, with patients with large complex-shaped aneurysms at higher risk of haemorrhagic stroke and patients with hypertension at higher risk of ischaemic stroke.

Being able to rigorously analyse medical device performance in this way will allow biomedical engineers to optimise the device design and reduce the risks associated with treatment.

Clinical trials 'cut from years to months'

Professor Frangi said: "In-silico trials offer an opportunity to do virtual experiments that could explain concepts that are difficult to study in conventional clinical trials.

"The current approach to improve our understanding of new medical devices is slow, as conventional trials can easily take five to eight years, from their design to completion.

"In-silico trials could reduce this period to less than six months in some circumstances, making knowledge and therapeutic technologies safer and more promptly available to clinicians and patients."

The research involved an international collaboration of scientists from Leeds, the University of Oxford, Radbound University Medical Centre in the Netherlands, and KU Leuven in Belgium.

The paper - In-silico trial of intracranial flow diverters replicates and expands insights from conventional clinical trials - is published in the journal Nature Communications.

The research was funded through the Royal Academy of Engineering (INSILEX), @neurIST from the European Commission and the Engineering and Physical Sciences Research Council Centre for Doctoral Training on Fluid Dynamics.

As people go about their daily activities, complex fluctuations in their movement occur without conscious thought. These fluctuations -- known as fractal motor activity regulation (FMAR) -- and their changes are not readily detectable to the naked eye, but FMAR patterns can be recorded using a wristwatch-like device known as an actigraph. A new study, led by investigators at Brigham and Women's Hospital, the Massachusetts General Hospital (MGH) and Washington University at St. Louis, analyzed FMAR patterns in cognitively healthy adults who were also tested for established biomarkers of preclinical Alzheimer's disease (AD) pathology. The team found that FMAR was associated with preclinical AD pathology in women, suggesting that FMAR may be a new biomarker for AD before cognitive symptoms begin. Results are published in Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring.

"Our day-to-day movements that are subconscious can reveal changes in the brain that may occur many years before symptoms show," said co-first author Lei Gao, MD, assistant professor of Anesthesiology at MGH, and clinical director of the Medical Biodynamics Program in the Division of Sleep and Circadian Disorders at the Brigham. "If validated in future studies, this may provide a window of opportunity for early treatments and motivate the modification of existing risk factors."

For their study, the researchers assessed 178 cognitively normal adults from the Washington University Knight Alzheimer's disease Research Center. All participants underwent 7 to 14 days of home actigraphy. Pittsburgh Compound B (PiB) PET amyloid imaging was performed in 150 of the participants and cerebrospinal fluid (CSF) was obtained in 149 of them.

The team found that degradation of FMAR was significantly associated with both markers of preclinical AD. The relationship was independent of age, physical activity, circadian rest-activity pattern fragmentation and APOE-e4 carrier status (a gene variant predictive of risk of AD). When the researchers looked at differences between men and women, they found the relationship remained significant among women but not men.

"FMAR represents a non-invasive biomarker for testing and screening for AD," said Gao. "In addition, we focused on daytime activity, which removed sleep as a potential confounder. The results also remained after controlling for more established circadian disruption measures; this suggests that FMAR has unique pathways to AD pathology that require further study."

The authors note that study participants were relatively homogenous, so they were unable to fully consider race or ethnicity in their analyses, and that external validation and replication are needed.

"We're very excited to see FMAR applied for the early detection of AD," said co-senior author Kun Hu, PhD, director of the Brigham's Medical Biodynamics Program and a physiologist in the Division of Sleep and Circadian Disorders in the Departments of Medicine and Neurology at the Brigham. "This kind of approach could potentially guide research on AD and allow us to shift from focusing solely on cognition to improving motor functions that may link AD to other disorders, including sleep/circadian disorders."

People who have experienced childhood trauma get a more pleasurable "high" from morphine, new research suggests.

University of Exeter scientists compared the effects of morphine on 52 healthy people - 27 with a history of childhood abuse and neglect, and 25 who reported no such experiences in childhood.

Those with childhood trauma liked morphine (an opioid drug) more, felt more euphoric and had a stronger desire for another dose.

Those with no childhood trauma were more likely to dislike the effects and feel dizzy or nauseous.

"There are high rates of childhood trauma in people with addictions. Our findings show that these sorts of experiences can actually change how certain drugs feel," said lead author Dr Molly Carlyle, who conducted this research at Exeter and is now at the University of Queensland.

"To our knowledge, this is the first study to link childhood trauma with the effects of opioids in people without histories of addiction, suggesting that childhood trauma may lead to a greater sensitivity to the positive and pleasurable effects of opioids.

"This may explain the link between childhood trauma and vulnerability to opioid use disorder, with implications for treatments and the prescribing of opioids medically."

One possible explanation for the differing responses to morphine is that childhood trauma affects the development of the endogenous opioid system (a pain-relieving system that is sensitive to chemicals including endorphins - our natural opioids).

"It's possible that childhood trauma dampens that system," Carlyle explained.

"When a baby cries and is comforted, endorphins are released - so if loving interactions like this don't happen, this system may develop differently and could become more sensitive to the rewarding effects of opioid drugs."

Professor Celia Morgan, of the University of Exeter, who leads the research group, said: "Our findings that people who have been traumatised as children are more likely to enjoy morphine might help to reduce stigma around heroin use.

"Many opioid addicts are people who were traumatised in early childhood, but it is still widely believed that addiction is a weakness and that addicts simply lack self-control.

"This research may be a step towards treating heroin addicts with more compassion, as we would children with histories of trauma.

"Our study also highlights the importance of interventions aimed at high-risk children and adolescents to protect against opioid use."

The study's participants, aged 18-65, had either reported experiencing severe childhood trauma (abuse or neglect, as measured by the Childhood Trauma Questionnaire) or reported no childhood trauma.

They each attended two sessions, a week apart, and received either an active dose of morphine (0.15mg/kg) or a negligible control dose (0.01mg/kg) in a randomised, double-blind crossover design.

People's experiences of morphine were measured by asking them a set of questions eight times - once before the morphine injections, then at regular intervals afterwards.

Pain was also measured by placing a hand in cold water and recording how long it took people to find this painful and how long they could tolerate leaving their hand in the water.

Morphine increased pain threshold and tolerance, but this did not differ between the trauma and non-trauma groups.

There was also a computerised button-pressing task that measured effort to obtain more morphine by button pressing for either a theoretical amount of money or morphine. No differences were found between the two groups during this task.

This may have been because money is highly rewarding in non-addicted groups and was not a suitable comparator for this task.

The testing was carried out at the Clinical Research Facility at the Royal Devon and Exeter Hospital.
The paper, published in the journal Addiction Biology, is entitled: "A randomised, double-blind study investigating the relationship between early childhood trauma and the rewarding effects of morphine."

Listening to music while running might be the key to improving people's performance when they feel mentally fatigued a study suggests.

The performance of runners who listened to a self-selected playlist after completing a demanding thinking task was at the same level as when they were not mentally fatigued, the research found.

The study is the first to investigate the effect of listening to music playlists on endurance running capacity and performance when mentally fatigued.

Researchers at the University of Edinburgh used two tests to study how listening to music affected the running performance of eighteen fitness enthusiasts.

One test looked at the effects on interval running capacity - alternating between high intensity running and lower intensity jogging - with a group of nine physically active exercisers, and the other on a 5km time-trial with a group of nine trained runners.

The groups completed a 30 minute computer based cognitive test which put them in a mentally fatigued state before completing high intensity exercise. The runners were tested with and without self-selected motivational music.

Researchers assisted participants in choosing motivational songs with a pre-test questionnaire asking them to rate the rhythm, style, melody, tempo, sound and beat of the music.

Examples of songs participants listened to were: Everyday by A$ap Rocky; Addicted To You by Avicii; Run This Town by Jay-Z; Power by Kanye West; No One Knows by Queens of the Stone Age; and Eye of the Tiger by Survivor.

During the exercise, heart rate and rating of perceived exertion were measured at multiple points.

The team took into account the results of a baseline test taken by participants which was without a mentally demanding test beforehand - and without the use of music.

The researchers found the interval running capacity among the mentally fatigued fitness enthusiasts was moderately greater with music compared to without music, and was the same as when the participants were not mentally fatigued.

The 5km time-trial performances also showed small improvements with self-selected music versus no music.

Researchers say the positive effects of music could potentially be due to altered perception of effort when listening to tunes.

Dr Shaun Phillips, of the University of Edinburgh's Moray House School of Education and Sport, said: "Mental fatigue is a common occurrence for many of us, and can negatively impact many of our day-to-day activities, including exercise. Finding safe and effective ways to reduce this negative impact is therefore useful.

"The findings indicate that listening to self-selected motivational music may be a useful strategy to help active people improve their endurance running capacity and performance when mentally fatigued. This positive impact of self-selected music could help people to better maintain the quality and beneficial impact of their exercise sessions."

Researchers say there are opportunities for further study into how listening to music while running affects larger and different groups of people, in different settings, and using different exercise challenges. Work in these areas is ongoing at the University of Edinburgh.

Researchers at the University of Cincinnati College of Medicine have developed a blueprint for a protein that plays an important role in the development and regulation of reproductive organs.

The knowledge advances our understanding of the protein anti-Müllerian hormone hormone (AMH), which helps form male reproductive organs and in females regulates follicle development and ovulation in the ovaries, explains Thomas Thompson, PhD, professor in the UC Department of Molecular Genetics, Biochemistry and Microbiology.

Scientists have been looking to regulate AMH because it might play a role in developing a novel contraceptive, aid in treatments for infertility and be useful in protecting the future fertility of women undergoing chemotherapy.

"AMH is unique in that it has a dedicated receptor," says Thompson. "This signaling module has a one-to-one relationship with a signaling receptor. What we have done in the study is define what that looks like and how those two interact. That helps us with trying to understand how we can therapeutically modulate the signaling molecule or the signaling receptor pair."

"When you introduce AMH signaling you can stop the ovarian follicles very early on from developing into eggs in the ovaries," says Thompson. "That's the angle where you have this for a potential contraceptive. If you can enhance AMH signaling you can stop the follicles from being selected for growth."

Researchers are also considering this for female cancer patients undergoing chemotherapy.

"Chemotherapy can damage follicles and cause less fertility over time," Thompson explains "If you can put the brakes on the reproductive process, you can actually protect the ovary and possibly maintain the ability to have children after chemotherapy."

Research findings from Thompson and lead author Kaitlin Hart, a doctoral student in UC Department of Pharmacology and Systems Physiology, are available online in the scholarly journal for the Proceedings of the National Academy of Sciences (PNAS).

Thompson and Hart worked closely with researchers from Harvard Medical School, including Nicholas Nagykery, Patricia Donahoe, MD, and David Pépin, PhD, who have tested AMH in animal models. Other collaborators from Monash University in Victoria, Melbourne, Australia, are William Stocker, PhD, Kelly Walton, PhD, and Craig Harrison, PhD.

"Preserving the fertility of women undergoing chemotherapy by protecting the follicles will have a big impact on the quality of life for women of reproductive age," says UC's Hart. "This becomes more important as more women have children at a later age and increased incidents of cancer occur in younger individuals."

Hart says a better understanding of how AMH interacts with its signaling receptor might also help scientists find a better treatment for polycystic ovary syndrome (PCOS), a hormonal disorder that leads to irregular menstrual periods, excess production of male hormones such as androgen and impeded ovulation in women of reproductive age.

The causes of PCOS are unknown, but it can also lead to Type 2 diabetes and heart disease. It's one of the most common causes of female infertility affecting up to 12% of women of reproductive age, according to the Centers for Disease Control and Prevention.

"There is no cure for PCOS and treatment options are extremely limited due to a lack of understanding of the disease," says Hart. "A group of researchers in France investigating AMH believe it is linked to PCOS with possibly too much AMH leading to infertility."

Animal well-being might also receive a boost with development of a contraceptive that uses AMH.

The knowledge UC researchers have advanced will benefit a project spearheaded by the Cincinnati Zoo & Botanical Garden to reduce the population of feral cats. Officials at the Cincinnati Zoo are working closely with the same researchers from Harvard Medical School who are collaborators on the research from Thompson's laboratory.

"They are developing AMH as a temporary nonsurgical sterilization option," explains Hart. "Instead of capturing cats to neuter, spay and release, you could deliver a therapy based on AMH that could achieve the same result with a single injection. We now understand the interaction between AMH and its receptor so we can contemplate targeted changes to the interfaces to increase that interaction and make AMH more potent."

Bill Swanson, DVM, PhD, director of animal research for the Cincinnati Zoo, adds that "early results have been promising and we are optimistic that this approach will be useful for reducing feral cat overpopulation."

“Workforce issues are the most significant challenges facing the long-term care industry,” states the opening editorial of a new special issue of The Gerontologist titled “Workforce Issues in Long-Term Care.”

The 17 articles contained within illustrate:

How policy and workplace practices might influence workforce size by attracting and retaining workers How social and policy contexts affect recruitment and retention How the day-to-day experiences of direct care workers might relate to quality of care

“Their rich and varied methodologies and perspectives also offer the field some glimpses of optimism that we can leverage diverse approaches to improve long-term care,” wrote Editor-in-Chief Suzanne Meeks, PhD, FGSA, and Editor: Social Media Howard B. Degenholtz, PhD, FGSA, in the editorial.

Overall, the collection addresses the long-term care workforce from the front line to the back office, from rigid hierarchies to flexible models that promote creativity.

“If the shared goal is that long-term care should provide both high-quality care and the opportunity for a good life, the resulting articles lay out many of the challenges faced by policymakers, practitioners, and providers,” Meeks and Degenholtz state. “At the same time, new models of care and new ways of thinking about and defining ‘work’ have perhaps moved us a few steps down the path. The COVID-19 pandemic has laid bare the need to reinvest in the long-term care workforce, and we hope that this collection will provide positive guidance for future research and policy.”

The studies include:

Workforce Issues in Long-Term Care: Is There Hope for a Better Way Forward? Retooling the Health Care Workforce for an Aging America: A Current Perspective It's Time to Resolve the Direct Care Workforce Crisis in Long-Term Care Impact of a New Home Care Payment Mechanism on Growth of the Home Care Workforce in Taiwan Maximizing Home Health Aide Retention: The Impact of Control and Support on the Job Organizational Factors Associated with Retention of Direct Care Workers: A Comparison of Nursing Homes and Assisted Living Facilities Long-Term Residential Care Policy Guidance for Staff to Support Resident Quality of Life “If They Don’t Like You, They Are Not Going to Eat for You”: Individual and Interpersonal Factors Affecting Certified Nursing Assistants’ Ability to Provide Mealtime Assistance to Residents with Dementia Not Just How Many but Who is on Shift: The Impact of Workplace Incivility and Bullying on Care Delivery in Nursing Homes Assistant Nurses’ Positioned Accounts for Prioritizations in Residential Care for Older People Comparing Occupational Adaptation-Based and Traditional Training Programs for Dementia Care Teams: An Embedded Mixed-Methods Study Medical Care Delivery in U.S. Nursing Homes: Current and Future Practice Medical Staffing Organization and Quality of Care Outcomes in Post-Acute Care Settings Nurse Practitioners Rising to the Challenge During the COVID-19 Pandemic in Long-Term Care Homes Measuring Caregiver Retention in Nursing Homes Deeply Discrediting: A Systematic Review Examining the Conceptualizations and Consequences of the Stigma of Working in Aged Care Assuring Quality in Nursing Homes: The Black Box of Administrative and Clinical Leadership--a Scoping Review

Persons suffering from the autoimmune disease multiple sclerosis can develop various neurological symptoms caused by damage to the nervous system. Especially in early stages, these may include sensory dysfunction such as numbness or visual disturbances. In most patients, MS starts with recurring episodes of neurological disability, called relapses or demyelinating events. These clinical events are followed by a partial or complete remission. Especially in the beginning, the symptoms vary widely, so that it is often difficult even for experienced doctors to interpret them correctly to arrive at a diagnosis of MS.

Above-average numbers of medical appointments

It has been evident for some time, however, that patients with MS show significantly higher numbers of physician visits and hospital admissions even years before the first diagnosis as compared to healthy control persons. In recent years, specialists have seen this pre-diagnosis period as a possible prodromal phase of the disease.

MS often begins far in advance of the diagnosis

A new study carried out by a team working with the neurologist Prof. Bernhard Hemmer at TUM suggests that many complaints prior to diagnosis might not represent a prodromal phase. "Instead, we suspect that unrecognized MS relapses cause these individuals to seek medical attention," says Prof. Hemmer. "That is because we have found that the physician appointments and hospital admissions frequently involved complaints indicating typical MS symptoms. We believe that many complaints that have been attributed to a prodromal phase are in fact caused by ongoing disease. We therefore believe that, although the disease has not yet been diagnosed, it is fully active and not in a preliminary or prodromal phase."

A path to an earlier diagnosis

The results of the study could also open up possibilities to optimize MS treatment: "The sooner MS is recognized, the better we can treat the disease," says first author Dr. Christiane Gasperi, a physician and researcher at the Neuro-Head Center at the TUM Klinikum rechts der Isar. "We now need to take a closer look at which early symptoms of MS might be overlooked. This could allow us to recognize the disease at an earlier stage and thus enable earlier treatment initiation."

Less frequent respiratory tract infections

Along with the more frequent complaints in the years before an MS diagnosis, the results of the study also showed that persons with MS were actually less likely to seek medical attention for upper respiratory tract infections. "This was unexpected, in view of the fact that MS relapses have sometimes been associated with infections," says co-first author and Adjunct Teaching Professor Dr. Alexander Hapfelmeier of the TUM Institute of General Practice and Health Services Research. "However, future studies will be needed to determine whether there is a causal link between MS and a degree of protection against certain infections, or whether the health data we analyzed reflect protective behavior adopted by persons with MS."

Philadelphia, June 22, 2021 - Vivid photos of the red "COVID arm" rash and reports of facial swelling in patients who have received dermatological fillers after Pfizer-BioNTech or Moderna vaccination for COVID-19 may increase patients' concerns about mRNA vaccine side effects and contribute to vaccine hesitancy. A comprehensive review in Clinics in Dermatology, conducted by University of Connecticut School of Medicine researchers and published by Elsevier, confirms that almost all cutaneous reactions are largely self-limited and should not discourage getting the vaccine.

The authors reviewed literature published as of May 2021 describing cutaneous side effects from the currently authorized m-RNA vaccines and supplemented their analysis with data from the Centers for Disease Control and Prevention's Vaccine Adverse Event Reporting System (CDC-VAERS).

"Usually, the cutaneous reactions described are not a cause for concern," explained co-author Christian Gronbeck, MD, UConn School of Medicine, Farmington, CT, USA. "Existing reports should reassure patients of the overall compelling safety profiles and benignity of skin reactions following mRNA COVID-19 vaccination."

Local injection site reactions may occur shortly after vaccine administration and may take the form of swelling, redness/erythema, and/or pain. The incidence rate reported in studies reviewed by Dr. Gronbeck and his coauthor Jane M. Grant-Kels, MD, UConn School of Medicine Department of Dermatology, Farmington, CT, USA, range from 5.5 percent to 23.7 percent. The published reports agree that these reactions are harmless, transient, and largely resolve within two to five days. It is important to distinguish these reactions from immediate allergic-type hypersensitivity reactions, such as angioedema, respiratory distress, or anaphylaxis that occur within four hours of vaccination. However, existing studies provide reassurance to patients and providers because dermatological symptoms are transient and rarely associated with anaphylaxis.

Delayed local reactions, typically erythema with mild hardening of the tissue at the injection site, occur days rather than hours, after injection with the Moderna vaccine. They are temporary and may be less frequent after the second dose. They likely represent T-cell-mediated hypersensitivity, and the authors agree that they likely do not lessen vaccine safety. "Recognition of delayed reactions is nonetheless important," Dr. Gronbeck and Dr. Grant-Kels said, "to both guide patient expectations and avoid unnecessary medical treatment."

Rarely reported and more unusual cutaneous reactions to the mRNA COVID-19 vaccines have occurred, although reports are very limited and it is difficult to identify overall incidence rates. Crusted, vesicular, painful skin lesions, consistent with herpes zoster reactivation, have been reported following both the Pfizer and Moderna vaccines. It has been postulated that immunomodulary effects of the COVID-19 vaccines may have promoted zoster reactivation and further studies are needed. In the meantime, the authors suggest heightened monitoring for patients with risk factors.

Several cases of facial swelling in patients with a history of dermatological fillers have been reported after COVID-19 vaccination. Although rare, these events are important to recognize amidst the expansion of vaccines to the general population and the growing popularity of dermal fillers.

The CDC-VAERS currently lists 260 reports of immune thrombocytopenia (ITP), a disorder characterized by excessive bruising and bleeding caused by lowered platelet levels. Case reports suggest that it may present differently and occur in varying patient populations. Some studies hypothesize that the cause may be immune-mediated platelet destruction following the COVID vaccine. However, given the overall rarity, researchers have also considered that underlying autoimmune or another disease may play a role. Optimal treatment must be further studied, given that aggressive immunosuppression may dampen the desired immune response from the vaccines.

The authors observed that most studies and the VAERS data do not include incidence rates among all vaccinated individuals, making it difficult to estimate the specific frequency of each reaction. Also, many studies reported reactions in healthcare workers, which may not reflect the broader population. Despite these shortcomings, Dr. Grant-Kels said, "We propose several reassuring clinical considerations for those who are hesitant to be vaccinated. First, the reported reactions are largely self-limited, and the most frequent reactions were also found in the clinical trials of the drugs, which have been authorized for use in the general population. Allergic-type symptoms are transient and rarely associated with anaphylaxis. The development of uncommon reactions such as herpes zoster, dermal filler reactions, and ITP were seldom serious in nature but justify clinical monitoring."

The authors noted that while further studies are needed to understand the reaction mechanisms and management approaches for cutaneous vaccination reactions, the research published to date should provide reassurance to all regarding the safety of these vaccines vis-à-vis the skin.

In a cancer that has not seen new targeted therapies for over 20 years, MUSC Hollings Cancer Center researcher and oncologist Nancy Klauber-DeMore, M.D., is pioneering new discoveries.

Using a combination of personal passion and expertise, Klauber-DeMore shifted her knowledge of the pro-angiogenic protein SFRP2 in breast cancer to address the lack of treatment options for patients with aggressive metastatic osteosarcoma. The results of the combination treatment with SFRP2 and PD-1 antibodies in a preclinical model were published in Cancers.

Osteosarcoma expert William Tap, M.D., chief of the Sarcoma Medical Oncology Service at Memorial Sloan Kettering Cancer Center said, "Osteosarcoma is an area of great unmet medical need which unfortunately has seen few clinical advances in the last 30 years. The work of Dr. Klauber-DeMore and colleagues, which targets SFRP2, provides a spark of hope in creating novel clinical inroads against this terrible disease while providing unique insight into the application and effects of anti-SFRP2 therapies in cancer."

One focus of clinical research for Klauber-DeMore, a surgical oncologist and the BMW Endowed Chair in Cancer Research at MUSC, is centered around understanding how tumors hijack the development of new blood vessels, a process known as angiogenesis, to fuel their own growth. Tumors need to develop their own blood supplies to facilitate the exchange of nutrients. Blocking the angiogenesis-promoting molecules that tumors secrete has been a cancer treatment strategy for over a decade.

According to Klauber-DeMore, VEGF, the first angiogenesis factor that was targeted with an antibody, does not always slow cancer growth. "A decade ago, while I was exploring the issue of targeted VEGF treatment failing, I realized that there must be other factors promoting angiogenesis that overcame the lack of VEGF. My research in human breast cancer led me to the protein called SFRP2, which also promotes new blood vessel growth in cancers," explained Klauber-DeMore.

While breast cancer is Klauber-DeMore's specialty, both in the clinic and in the lab, personal experience and scientific discovery led to her research in pediatric osteosarcoma. In 2015, Weston Mallard, the son of close family friends, was diagnosed with osteosarcoma the week before he started eighth grade in Durham, North Carolina.

Osteosarcoma is a bone cancer that has a particularly poor prognosis once the cancer spreads to other organs. "Immunotherapy is one of the newer and more promising therapies for many cancers; however, it is not effective in osteosarcoma and effective treatments are lacking," said Klauber-DeMore.

Weston's mother, Jennifer Mallard, said it was a horrible time. "Weston was started on treatments right away. They were awful. They made him so sick. This disease really destroyed his life from the beginning."

Sadly, Weston passed away in 2017 after the cancer metastasized to his lungs. "It is easy to remember how I felt when we got to the point in the treatment where there was nothing to do. A year into the treatment, even though we had a great team of doctors at UNC, there were no promising treatment options left for him," said Mallard.

"Not being in the medical field, we did not want to jump to conclusions. But it felt like everyone was talking about adult cancers and the advancements. But no one was talking about pediatric cancer advancements," said Mallard. This painful journey and the lack of options resonated with Klauber-DeMore. Weston was one of her daughter's best friends.

During Weston's battle with osteosarcoma, Jason Yustein, M.D., Ph.D., at Baylor College of Medicine, published research showing that SFRP2 may be a therapeutic target in osteosarcoma. Klauber-DeMore contacted Yustein and started a collaboration to study the use of Klauber-DeMore's novel antibody, hSFRP2 mAb, in a preclinical metastatic osteosarcoma model.

The team's research revealed the role of SFRP2 in immune cells, which are becoming an important counterpart in improving cancer treatments. The addition of the SFRP2 molecule causes an increase in two molecules, CD38 and PD-1, on T-cells. Klauber-DeMore's hSFRP2 mAb stopped the increase of CD38 and PD-1 on T-cells.

One of the paper's co-authors, Hollings Cancer Center researcher Shikhar Mehrotra, Ph.D., previously found that PD-1 immunotherapy is not effective when there are high CD38 levels on T-cells. Blocking CD38 allows PD-1 immunotherapy to work.

"A previous study showed that PD-1 immunotherapy did not work in osteosarcoma. We now know that osteosarcoma produces a lot of the SFRP2 molecule, which causes an increase of CD38 and PD-1 on the T-cells," said Klauber-DeMore.

"We found an additive beneficial effect using the hSFRP2 mAb and PD-1 -- the combination blocked metastasis in our preclinical osteosarcoma model." Since SFRP2 is mainly on active T-cells and tumors, there is the hope that this combination treatment will be well tolerated and effective, she said.

Klauber-DeMore is working with Innova Therapeutics to get this treatment into clinical trials for osteosarcoma and, eventually, other cancers in an attempt to provide a more effective option for patients.

A group of health care leaders, including a University of Massachusetts Amherst nurse innovator, has published a national call to action to prevent non-ventilator-associated, hospital-acquired pneumonia (NVHAP).

This call to action was developed by a joint task force of key national healthcare stakeholders, including the Centers for Disease Control and Prevention (CDC), the Veterans Health Administration, The Joint Commission on Accreditation of Healthcare Organizations, the American Dental Association, the Patient Safety Movement Foundation, Oral Health Nursing Education and Practice, Teaching Oral-Systemic Health and academia.

In a commentary paper published in the journal Infection Control & Hospital Epidemiology (ICHE), the joint task force, which included UMass Amherst's Karen K. Giuliano, lays out their recommendations for improved research and prevention efforts to reduce harm from NVHAP.

According to the National Organization to Prevent Hospital-acquired Pneumonia (NOHAP), most hospitals do not track, report or have initiatives to actively prevent NVHAP, even though it's the most common hospital-acquired infection.

The negative patient outcomes associated with NVHAP include 15-30% mortality, extended hospital length of stay, unexpected ICU admission of up to 46% and increased risk for hospital readmission within 30 days, according to the ICHE paper.

Unlike ventilator-associated pneumonia (VAP) and other device-associated hospital-acquired infections, NVHAP is not recognized as one of the National Database of Nursing Quality indicators, nor do the Centers for Medicare and Medicaid Services (CMS) require hospitals to report cases to the CDC National Healthcare Safety Network or include it in pay-for-reporting or performance programs.

NVHAP is one focus of Giuliano's ongoing research, for which she received the Association for Professionals in Infection Control and Epidemiology's 2020 award for publication excellence.

"The hidden harm from NVHAP in acute care is a significant patient safety issue. NVHAP should be elevated to the same level of concern, attention and effort as prevention of VAP in hospitals," says Giuliano, who holds a joint position as an associate professor in the College of Nursing and the Institute for Applied Life Sciences (IALS), and is co-director of the recently launched Center for Nursing and Engineering Innovation.

In addition to raising awareness about NVHAP, the paper recommends educating patients, health care professionals and students about prevention measures, including standardized, therapeutic oral care for all patients; implementing surveillance strategies; and supporting research to develop new strategies for both surveillance and prevention.

"Adding NVHAP to these lists of high-stakes conditions is one way to draw hospitals' attention to NVHAP, to catalyze the discovery of optimized prevention initiatives and implementation strategies, and drive down NVHAP incidence and morbidity," the white paper concludes.

In rare cases, adults who have recovered from COVID-19 may develop multisystem inflammatory syndrome, and clinicians should consider this possibility in adults with specific symptoms, as physicians describe in a case published in CMAJ (Canadian Medical Association Journal) https://www.cmaj.ca/lookup/doi/10.1503/cmaj.210232.

A 60-year-old man, who had tested positive for SARS-CoV-2 four weeks before, visited hospital for a range of symptoms, including prolonged shortness of breath, high fever, swelling and severe fatigue. Testing found an enlarged heart and lung swelling as well as other issues.

"Given the patient's recent history of SARS-CoV-2 infection, fevers without localizing symptoms, oral mucosal changes, cervical lymphadenopathy, conjunctivitis and lower extremity changes, we suspected inflammatory post-COVID-19 syndrome. The presentation was similar to reported cases of an uncommon but severe complication in children and adolescents infected with SARS-CoV-2, called multisystem inflammatory syndrome in children (MIS-C), as well as to Kawasaki-like illness," write Drs. Genevieve Kerkerian and Stephen Vaughan, infectious disease specialists, Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta.

Prompt initiation of medication helped the patient to recover.

Previous cases of the syndrome in adults have been documented in people younger than 50. The authors suggest that age should not limit the potential diagnosis.

Much is unknown about multisystem inflammatory syndrome in adults (MIS-A).

"Unlike for MIS-C, there is currently no requirement to report cases of MIS-A to provincial or state authorities, but this should be encouraged to facilitate research and improve patient outcomes," the authors conclude.

Alexandria, VA, and New Rochelle, NY, June 17, 2021--Catherine F. Sinclair, MD, has been appointed the next Editor-in-Chief of VideoEndocrinology™, published by Mary Ann Liebert, Inc.

"I am honored and delighted to have been selected as the next EIC of VideoEndocrinology. I look forward to helping promote novel concepts and techniques in thyroidology and to assisting the wider community in navigating the rapidly evolving landscape of surgical and non-surgical management options for thyroid disease. I eagerly anticipate the opportunity to work with colleagues from multiple disciplines to showcase the work being done worldwide to advance our field," said Dr. Sinclair.

"The American Thyroid Association® (ATA®) is excited to announce that Catherine Sinclair, MD has been selected as the Editor-in-Chief of VideoEndocrinology. Dr. Sinclair was selected from an extremely competitive group of candidates secondary to her evident abilities to include experience with video-based education, audiovisual production and presentation, as well as her vision for the future of VideoEndocrinology. The strength of the field of candidates for this position speaks to the importance of VideoEndocrinology, particularly to surgeons involved in the field of thyroid, parathyroid, and endocrine related procedures," said, Victor J. Bernet, MD, President of the ATA, and Associate Professor of Medicine, Mayo Clinic, Jacksonville, FL. "With Catherine's leadership we look forward to continued growth and stature of this pioneering videojournal, continuing the trajectory established by its previous Editor-in-Chiefs, most recently William B. Inabnet III."

Dr. Sinclair graduated from the Flinders University School of Medicine in Australia with the Dean's prize in Medicine, the Staff Prize in Surgery, and the Australia Medical Association (SA) medal. She was subsequently awarded the Gordon-Gordon Taylor Medal and the Clinical Committee Prize by the Royal Australasian College of Surgeons during Basic Surgical Training. She completed her Otolaryngology Head and Neck Surgery training in Melbourne, Australia, before travelling to the United States to pursue dual fellowships in head and neck surgery and laryngology. For the past decade she has worked in New York where she has served as the Director of Division of Head and Neck Surgery, Mount Sinai West Hospital. Dr. Sinclair is an internationally recognized expert in surgical management of neck endocrine diseases. In 2016, she developed and implemented a novel methodology for intraoperative neuromonitoring of the recurrent laryngeal and vagus nerves. She has been an early adopter of radiofrequency ablation for treatment of benign thyroid nodules and has helped advance the field of thermal ablative technologies. In August 2019, she performed the first radiofrequency ablation for a benign thyroid nodule in New York and, in April 2021, she performed the first radiofrequency ablation in Australia. Dr Sinclair has authored multiple peer-reviewed journal articles and book chapters and has been the guest editor for a number of journals on topics relating to thyroid cancer and environmental exposures, thermal ablation, and neuromonitoring. She is an active member of many national committees including the Guidelines and Statements Committee of the American Thyroid Association and the Executive Committee of the Endocrine Section of the American Head and Neck Society. She lectures throughout the world and was inducted into the Triological Society in 2020.

"We are very pleased to welcome Dr. Catherine Sinclair as the next Editor-in-Chief of VideoEndocrinology, and look forward to working with her," says Mary Ann Liebert, President of the company that bears her name.

In recent years, the use of medical cannabis to treat sick kids is on the rise, although questions remain about the benefits and safety of such treatments. Now, a team of researchers from the Hebrew University of Jerusalem (HU) has completed a first-ever meta-analysis of pediatric patients treated with medical cannabis to better understand the risks and benefits of cannabis use among young patients.

The meta-review was led by Professor Ilan Matok at HU's School of Pharmacy and the David R. Bloom Center for Pharmacy, along with and PhD candidate Nir Treves. They will present their findings at the 31st Annual International Cannabinoid Research Society Symposium (ICRS) being held in Jerusalem this week, for the first time ever. The conference host is HU's Multidisciplinary Center for Cannabinoid Research (MCCR), a leading research center on cannabinoids, endocannabinoids, and medicinal cannabis.

Matok and his team found that medical cannabis is particularly successful at treating severe epilepsy and chemotherapy's pernicious side effects. However, the side effects of these treatments in kids is still an open question. As Matok explained, "since medical cannabis isn't widely recognized as an accepted or regulated drug, there simply haven't been enough studies to know whether it's appropriate for children."

The team looked at seven clinical studies involving approximately 500 young patients (under 18 years of age). Despite the limited number of participants, they were able to glean both positive and negative effects of medical cannabis use on kids' mental and physical health. For example, the team found that CBD (cannabidiol) is effective at decreasing the number of severe seizures in children, especially those with hard-to-treat epilepsy. However, CBD also greatly suppresses their appetites. They also found that several cannabis plant ingredients used in medical treatments adversely affect children's mental state, causing fatigue, apathy, dizziness, and lethargy.

"Children aren't small adults," shared Matok. "Medical cannabis affects kids differently, and doctors need to pay close attention to those differences". On the plus side, medical cannabis proved very helpful for children undergoing chemotherapy, reducing the severity of the nausea and vomiting which often accompanies this treatment.

The study of medical cannabis in children is still in its infancy. Since cannabis is not registered as a medication, it is often prescribed to children on as-needed basis with limited clinical evidence. "Whereas Pfizer and Moderna were able to conduct clinical trials for their COVID-19 vaccine on kids, few top-notch clinical trials exist for cannabis use in children. The goal of our meta-analysis is to shed light on this area and provide doctors and parents with a more informed view of the potential of cannabis to help or harm their young patients," Matok concluded.

Matok's next research project is to study the effect? of medical marijuana on young patients, looking specifically at whether it raises their rates of depression, cardiovascular incidents and involvement in car accidents.

Dissatisfaction with married life raises the risk of dying from a cerebrovascular accident: A new Tel Aviv University study reveals that perceiving marriage as unsuccessful is a significant predictor of death from a CVA and premature death among men, no less that well-known risk factors such as smoking and lack of physical activity. The study was based on extensive health data from more than 30 years of research that tracked the deaths of 10,000 Israeli men.

The study was led by researchers from the School of Public Health at the Sackler Faculty of Medicine, Tel Aviv University: Prof. Uri Goldbort from the Department of Epidemiology and Preventive Medicine, who initiated and managed the long-term study; Dr. Shahar Lev-Ari, the head of the Department of Health Promotion; and Dr. Yiftah Gapner, from the Department of Epidemiology and Preventive Medicine. The article was published in the Journal of Clinical Medicine.

As part of the study, the researchers conducted statistical analyses of a database that started gathering data in the 1960s and, for 32 years, tracked the health and behavior of 10,000 men, all Israeli state employees, with special attention paid to death from strokes and premature death in general. At the beginning of the study, most of the participants were in their 40s. Since then, 64 percent died from a range of illnesses. "We wanted to analyze the data gathered longitudinally using various parameters to identify behavioral and psychosocial risk factors that can predict death from a CVA and premature death for any reason," Dr. Lev-Ari explains.

The researchers say that, early in the 32-year long study, participants in the longitudinal study were asked to rank their level of marriage satisfaction on a scale of 1 (marriage is very successful) to 4 (marriage is unsuccessful).

To the researchers' surprise, the analysis showed that this scale was a predictive factor vis-à-vis life expectancy, very similar to smoking and lack of physical activity. For example, the number of deceased from a stroke was 69 percent higher among those who ranked their marriage satisfaction at 4 (i.e. marriage is unsuccessful) compared to those who ranked their marriage satisfaction very highly - 40.6 dead among the very dissatisfied versus 24.0 among the very satisfied. [1] (Statistical analysis: see footnote)

When it came to death from any cause, the gap was 19 percent in favor of the happily married. The data show that while among the unhappily married there were 295.3 deaths for any reason (see footnote 1), among the very happily married there were only 248.5 (see footnote 1). The researchers note that the gaps were even larger among men who were relatively young (under 50) at the beginning of the study.

In addition, the researchers conducted a statistical analysis of all known risk factors contributing to death from cardiovascular diseases, such as diabetes, hypertension, excessive BMI, and socioeconomic status. Here, too, the data was highly surprising. It turns out that the relative risk for death for any reason among the unhappily married versus the happily married was 1.21 higher among those dissatisfied with their marriages. This rates is similar to data in the literature regarding smokers and those leading a sedentary life.

Dr. Lev-Ari summarizes: "Our study shows that the quality of marriage and family life has health implications for life expectancy. Men who reported they perceived their marriage as failure died younger than those who experienced their marriages as very successful. In other words, the level of satisfaction with marriage has emerged as a predictive factor for life expectancy at a rate comparable with smoking (smokers versus non-smokers) and physical activity (activity versus inactivity). Furthermore, it's important to note that we observed a higher risk among relatively young men, under the age of 50. At a higher age, the gap is smaller, perhaps due to processes of adjustment that life partners go through over time. These findings were consistent with other studies that have shown the effectiveness of educational programs fostering good life partnerships as part of a national strategy to promote health and wellness for the public at large."