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LA JOLLA--(January 5, 2021) Lithium is considered the gold standard for treating bipolar disorder (BD), but nearly 70 percent of people with BD don't respond to it. This leaves them at risk for debilitating, potentially life-threatening mood swings. Researchers at the Salk Institute have found that the culprit may lie in gene activity--or lack of it.

A new study led by Salk Professor and President Rusty Gage, which published in the journal Molecular Psychiatry on January 4, 2021, shows that decreased activation of a gene called LEF1 disrupts ordinary neuronal function and promotes hyperexcitability in brain cells--a hallmark of BD. The work could result in a new drug target for BD as well as a biomarker for lithium nonresponsiveness.

"Only one-third of patients respond to lithium with disappearance of the symptoms," says Renata Santos, co-first author on the study and a Salk research collaborator. "We were interested in the molecular mechanisms behind lithium resistance, what was blocking lithium treatment in nonresponders. We found that LEF1 was deficient in neurons derived from nonresponders. We were excited to see that it was possible to increase LEF1 and its dependent genes, making it a new target for therapeutic intervention in BD."

The study builds on the team's earlier findings, which reported that the neurons of people with BD who don't respond to lithium are larger, fire differently (are more easily stimulated, or hyperexcitable), and have increased potassium flow.

Subjects in the team's current study included lithium responders, nonresponders and people without BD (controls). Using stem-cell methods, the researchers grew neurons from the subjects' blood cells and compared the genetic disposition and behavior of the neurons for the three groups.

They looked at many genes across the board, but LEF1 stood out as one of the most different in nonresponders. Normally, LEF1 plays a decisive role in neuronal function by pairing with another protein called beta-catenin. The pairing typically activates other genes that regulate the level of activity in the neuron. In control or responding neurons, lithium enables beta-catenin to pair with LEF1. But in nonresponders, lithium is ineffective because LEF1 levels are too low for the pairing to occur, so there's no regulation of cell activity.

When the team administered valproic acid, a treatment often used for nonresponders, measurements showed increased levels of LEF1 and activation of the other relevant genes. And when the team silenced the LEF1 gene in control neurons, they found that the related genes were not activated. Together, these results indicate the critical role LEF1 plays in controlling neuronal hyperexcitability.

"When we silenced the LEF1 gene, the neurons became hyperexcitable," says Shani Stern, co-first author on the study and a Salk visiting scientist. "And when we used valproic acid, expression of LEF1 increased, and we lowered the hyperexcitability. That shows there is a causative relationship, and that's why we think LEF1 may be a possible target for drug therapy."

LEF1 may also help researchers develop a screening test for responsiveness. Currently, clinicians can only determine whether a patient is responsive to lithium by administering a complete course of treatment, which could take a year. Now, subdued activity of LEF1 may be an indicator that a patient won't respond to lithium, enabling a faster and more efficient way to approach therapy.

Team members already contemplating next steps. These include looking at other cell types, such as astrocytes and GABAergic neurons, to understand the bipolar neural network as a whole; identifying other genes that could be beneficial for nonresponders; and finding other drugs that can activate LEF1.

"LEF1 works in various ways in different parts of the body, so you can't just turn it on everywhere," says Carol Marchetto, co-corresponding author and Salk research collaborator. "You want to be more specific, either activating LEF1 on a targeted basis or activating downstream genes that are relevant for lithium nonresponsiveness."

Researchers at the Francis Crick Institute and the University of Western Australia have developed a new imaging method to see where antibiotics have reached bacteria within tissues. The method could be used to help develop more effective antibiotic treatments, reducing the risk of antibiotic resistance.

During bacterial infections like tuberculosis, bacteria enter human cells, which poses a challenge for treatment, as antibiotics must reach and enter all infected cells in order to be effective. If researchers could select for or develop more effective antibiotics based on where they reach, this may reduce the length of treatment needed, which in turn could reduce the risk of antibiotic resistance developing.

In their study, published in PLoS Biology the researchers developed a new imaging method to see where in infected tissues and in cells an antibiotic given to treat tuberculosis reaches the bacteria. The scientists are continuing to work on the method, adapting it for other types of antibiotic and to image multiple antibiotics at the same time.

Max Gutierrez, author and group leader of the Host-Pathogen Interactions in Tuberculosis Laboratory at the Crick, says: "In the case of tuberculosis, people need to be treated with at least three different antibiotics over six months. We don't yet fully understand why this extended treatment is needed. We hope that being able to more clearly see where antibiotics are going, will help us better understand this process and find ways to improve it."

To develop the imaging method, called CLEIMiT,* the researcher analysed lung tissue from mice infected with tuberculosis and treated with the antibiotic bedaquiline.

They combined a variety of imaging methods, including confocal laser scanning microscopy, 3D fluorescence microscopy, electron microscopy and nanoscale secondary ion mass spectrometry, to develop their new approach.

Using this method, they found that bedaquiline had not reached all infected cells in the lung tissue and also had not entered all infected areas within infected cells.

They also found this antibiotic was collecting in macrophages and in polymorphonuclear cells, both types of immune cell. This was a surprise as these cells have different environments and it wasn't thought that one antibiotic would be able to enter both.

Tony Fearns, author and senior laboratory research scientist in the Host-Pathogen Interactions in Tuberculosis Laboratory at the Crick, says: "Our approach could be used to help develop new antibiotics or to re-assess current antibiotics to judge how effectively they reach their targets. The more we learn about how drugs behave in the body, for example where they collect, the better we will be able to treat bacterial diseases like tuberculosis."

Brain metastases can only develop if cancer cells first exit the fine blood vessels and enter into the brain tissue. To facilitate this step, cancer cells influence blood clotting, as Heidelberg scientists from the German Cancer Research Center and from Heidelberg University Hospital have now been able to show in mice. The cancer cells actively promote the formation of clots, which helps them to arrest in the brain capillaries and then penetrate through the vessel wall. Drugs that inhibit the clotting factor thrombin were able to reduce the number of brain metastases in this experimental model.

Brain metastases are a feared complication of advanced cancers. Different cancers differ in their tendency to colonize the brain. Advanced-stage melanoma forms metastases in the brain in nearly half of all cases, and brain metastases are also very common in certain forms of breast cancer and lung cancer.

Brain metastases often cannot be removed surgically and frequently show no long-term response to treatments. "For patients with cancers that often spread to the brain, it would be extremely helpful if we had a treatment available that could prevent brain metastases from developing," explains Frank Winker, head of a research group at the German Cancer Research Center and managing senior physician at Heidelberg University Neurological Hospital.

It was already known from observational studies that antithrombotic drugs that inhibit blood clotting can have a favorable effect on the prognosis of certain cancers. It is possible that these agents influence metastasis. Winkler and his colleagues have now investigated in mice whether this also applies to brain metastases and, if so, how blood clotting and metastasis are linked. This study was made possible by a special microscopic technique (in vivo multiphoton laser-scanning microscopy) that allows the researchers to look deep into brain tissue and track individual cancer cells.

The mice were injected with melanoma or breast cancer cells into the bloodstream. Individuals of the circulating tumor cells then became arrested in the fine blood capillaries of the brain. Only if these cells now succeed in penetrating the vascular wall into the brain tissue can they grow into a brain metastasis. Winker and colleagues observed that blood clots (thrombi) frequently formed around the arrested tumor cells. Cancer cells around which no such clot formed did not manage to penetrate the capillary wall. "Apparently, the thrombus helps the cells hold on to the capillary for a long time in preparation for passage through the vessel wall," Winkler explains.

The Heidelberg researchers found that the tumor cells apparently intervene directly in the complex cascade of blood clotting and thus actively trigger the formation of the thrombi. They promote the formation of the clotting factor thrombin, which is required for the formation of the long-fiber protein fibrin, of which the network of the clot mainly consists.

Thrombus formation, the researchers realized, is the necessary prerequisite for tumor cells to leave the capillary and thus take the crucial first step toward forming a brain metastasis. An drug that inhibits thrombin would therefore have to suppress metastasis because it prevents the tumor cells from penetrating into the brain tissue. And indeed: mice that received the thrombin inhibitor dabigatran, which is already approved as a drug, developed significantly fewer metastases than untreated animals.

Inhibition of another blood clotting factor (von Willebrand factor) with specific antibodies also reduced the formation of thrombi in the mice - and subsequently the number of brain metastases that developed.

"These experiments show that it is primarily the influence of the cancer cells on the plasmatic coagulation factors that promotes the development of brain metastases. This is why a preventive drug should target precisely this process," explains Manuel Feinauer, first author of the current publication.

"Our goal is to identify drugs for the prevention of brain metastases in high-risk patients," says Winkler. "The studies in mice are a first step toward understanding exactly how theses substances can prevent tumor cells from colonizing the brain. In the long term, we then want to test these substances in clinical trials. To do this, we first need to better understand for which cancer subtypes this mechanism is particularly important, and also whether we can even better identify patients with a particularly high risk of brain metastases."

The researchers are optimistic because the drugs that inhibit thrombin have at least one already known advantage: they have long been prescribed for the prevention of strokes and are therefore considered to be comparatively well tolerated, even over long periods of time.

ANN ARBOR, Michigan -- Michael Green, M.D., Ph.D., noticed that when his patients had cancer that spread to the liver, they fared poorly - more so than when cancer spread to other parts of the body. Not only that, but transformative immunotherapy treatments had little impact for these patient.

Uncovering the reason and a possible solution, a new study, published in Nature Medicine, finds that tumors in the liver siphon off critical immune cells, rendering immunotherapy ineffective. But coupling immunotherapy with radiotherapy to the liver in mice restored the immune cell function and led to better outcomes.

"Patients with liver metastases receive little benefit from immunotherapy, a treatment that has been a game-changer for many cancers. Our research suggests that we can reverse this resistance using radiation therapy. This has potential to make a real difference in outcomes for these patients," says Green, assistant professor of radiation oncology at Michigan Medicine and corresponding author on the paper.

A multidisciplinary team from the University of Michigan Rogel Cancer Center looked at data from 718 patients who had received immunotherapy at the center. Patients had a variety of cancer types, including non-small cell lung cancer, melanoma, urothelial cancer and renal cell cancer, which had spread to different organs, including the liver and lungs.

Repeatedly, those with liver metastases had worse responses to immunotherapy. The issue was not just in the liver either: these patients had more cancer throughout their bodies, compared to similar patients whose cancer had spread but not to the liver.

"The liver is initiating a systemic immunosuppressive mechanism. The mechanism happens in the liver, but we see the systemic impact throughout the body," says corresponding study author Weiping Zou, M.D., Ph.D., Charles B. de Nancrede Professor of Surgery, Pathology, Immunology and Biology at the University of Michigan.

The liver is one of the most common site to which cancer metastasizes. It's known to interfere with immune response in autoimmune diseases, viral infections and organ transplants by suppressing certain critical immune cells.

This was playing out in metastatic cancer as oncologists observed a lack of immune response. Green notes that patients with liver metastases who received chemotherapy or targeted therapies did not have worse outcomes compared to those with other types of metastases. "It's unique to immunotherapy," he says.

Looking within the microenvironment of the liver metastases, researchers saw that the tumors were siphoning off the T cells - immune cells that should have been working to attack the cancer. Not only were the T cells being eliminated in the liver, but this was also creating an immune desert throughout the body. As a result, the immune system could not be activated to fight tumors at any sites.

Using mice with liver metastases, researchers delivered radiation therapy directly to the tumors in the liver. This stopped T cell death. With the T cells restored, an immune checkpoint inhibitor was then able to activate the immune system to eliminate the cancer throughout the body, on par with results seen in non-liver metastases.

"It's always a challenge to identify a novel mechanism of immune suppression and find a way to address it. With these promising results, we are now looking to open clinical trials in this space to better understand the mechanisms at play in human tumors," Green says.

COLUMBUS, Ohio - Scientists have developed a machine-learning method that crunches massive amounts of data to help determine which existing medications could improve outcomes in diseases for which they are not prescribed.

The intent of this work is to speed up drug repurposing, which is not a new concept - think Botox injections, first approved to treat crossed eyes and now a migraine treatment and top cosmetic strategy to reduce the appearance of wrinkles.

But getting to those new uses typically involves a mix of serendipity and time-consuming and expensive randomized clinical trials to ensure that a drug deemed effective for one disorder will be useful as a treatment for something else.

The Ohio State University researchers created a framework that combines enormous patient care-related datasets with high-powered computation to arrive at repurposed drug candidates and the estimated effects of those existing medications on a defined set of outcomes.

Though this study focused on proposed repurposing of drugs to prevent heart failure and stroke in patients with coronary artery disease, the framework is flexible - and could be applied to most diseases.

"This work shows how artificial intelligence can be used to 'test' a drug on a patient, and speed up hypothesis generation and potentially speed up a clinical trial," said senior author Ping Zhang, assistant professor of computer science and engineering and biomedical informatics at Ohio State. "But we will never replace the physician - drug decisions will always be made by clinicians."

The research is published today (Jan. 4, 2021) in Nature Machine Intelligence.

Drug repurposing is an attractive pursuit because it could lower the risk associated with safety testing of new medications and dramatically reduce the time it takes to get a drug into the marketplace for clinical use.

Randomized clinical trials are the gold standard for determining a drug's effectiveness against a disease, but Zhang noted that machine learning can account for hundreds - or thousands - of human differences within a large population that could influence how medicine works in the body. These factors, or confounders, ranging from age, sex and race to disease severity and the presence of other illnesses, function as parameters in the deep learning computer algorithm on which the framework is based.

That information comes from "real-world evidence," which is longitudinal observational data about millions of patients captured by electronic medical records or insurance claims and prescription data.

"Real-world data has so many confounders. This is the reason we have to introduce the deep learning algorithm, which can handle multiple parameters," said Zhang, who leads the Artificial Intelligence in Medicine Lab and is a core faculty member in the Translational Data Analytics Institute at Ohio State. "If we have hundreds or thousands of confounders, no human being can work with that. So we have to use artificial intelligence to solve the problem.

"We are the first team to introduce use of the deep learning algorithm to handle the real-world data, control for multiple confounders, and emulate clinical trials," Zhang said.

The research team used insurance claims data on nearly 1.2 million heart-disease patients, which provided information on their assigned treatment, disease outcomes and various values for potential confounders. The deep learning algorithm also has the power to take into account the passage of time in each patient's experience - for every visit, prescription and diagnostic test. The model input for drugs is based on their active ingredients.

Applying what is called causal inference theory, the researchers categorized, for the purposes of this analysis, the active drug and placebo patient groups that would be found in a clinical trial. The model tracked patients for two years - and compared their disease status at that end point to whether or not they took medications, which drugs they took and when they started the regimen.

"With causal inference, we can address the problem of having multiple treatments. We don't answer whether drug A or drug B works for this disease or not, but figure out which treatment will have the better performance," Zhang said.

Their hypothesis: that the model would identify drugs that could lower the risk for heart failure and stroke in coronary artery disease patients.

The model yielded nine drugs considered likely to provide those therapeutic benefits, three of which are currently in use - meaning the analysis identified six candidates for drug repurposing. Among other findings, the analysis suggested that a diabetes medication, metformin, and escitalopram, used to treat depression and anxiety, could lower risk for heart failure and stroke in the model patient population. As it turns out, both of those drugs are currently being tested for their effectiveness against heart disease.

Zhang stressed that what the team found in this case study is less important than how they got there.

"My motivation is applying this, along with other experts, to find drugs for diseases without any current treatment. This is very flexible, and we can adjust case-by-case," he said. "The general model could be applied to any disease if you can define the disease outcome."

Osaka, Japan - A cancer-specific L-type amino acid transporter 1 (LAT1) is highly expressed in cancer tissues. Inhibiting the function of LAT1 has been known to have anti-tumor effects, but there has been limited progress in the development of radionuclide therapy agents targeting LAT1. Now, a multidisciplinary research team at Osaka University has established a targeted alpha-therapy with a novel drug targeting LAT1.

The researchers first produced the alpha-ray emitter 211Astatine, no easy task given that Astatine (At) is the rarest naturally occurring element on Earth. Targeted alpha-therapy selectively delivers α-emitters to tumors; the advantage over conventional β-therapy is that alpha decay is highly targeted and the high linear energy transfer causes double-strand breaks to DNA, effectively causing cell death. The short half-life and limited tissue penetration of alpha radiation ensures high therapeutic effects with few side-effects to surrounding normal cells.

Next, to carry the radioisotope into cancer cells, the researchers attached it to α-Methyl-L-tyrosine, which has high affinity for LAT1. This subterfuge exploits the elevated nutrient requirements of rapidly multiplying cancer cells.

"We found that 211At-labeled α-methyl-L-tyrosine (211At-AAMT) had high affinity for LAT1, inhibited tumor cells, and caused DNA double-strand breaks in vitro," reports Associate Professor Kazuko Kaneda-Nakashima, lead author. "Extending our research, we assessed the accumulation of 211At-AAMT and the role of LAT1 in an experimental mouse model. Further investigations on a human pancreatic cancer cell line showed that 211At-AAMT selectively accumulated in tumors and suppressed growth. At a higher dose, it even inhibited metastasis in the lung of a metastatic melanoma mouse model."

Professor Atsushi Shinohara, senior author, explains, "We could establish the efficacy of 211Astatine in the treatment of cancer including advanced and metastatic malignancies, as well as the utility of the amino acid transporter LAT1 as a vehicle for radionuclide therapy. As the drug is delivered cancer-specifically it can attack from inside the cell after being taken in as a nutrient."

Adding to efficacy is dosing convenience. As an injectable short-range radiopharmaceutical, 211At-AAMT may be administered in outpatient clinics, a huge advantage over conventional radiation protocols, and may even be an alternative to surgery in specific cancers. This approach has immense potential to revolutionize radionuclide therapy of not only pancreatic cancer but other malignancies that lack effective treatment including advanced or metastatic disease.

Brown fat is that magical tissue that you would want more of. Unlike white fat, which stores calories, brown fat burns energy and scientists hope it may hold the key to new obesity treatments. But it has long been unclear whether people with ample brown fat truly enjoy better health. For one thing, it has been hard to even identify such individuals since brown fat is hidden deep inside the body.

Now, a new study in Nature Medicine offers strong evidence: among over 52,000 participants, those who had detectable brown fat were less likely than their peers to suffer cardiac and metabolic conditions ranging from type 2 diabetes to coronary artery disease, which is the leading cause of death in the United States.

The study, by far the largest of its kind in humans, confirms and expands the health benefits of brown fat suggested by previous studies. "For the first time, it reveals a link to lower risk of certain conditions," says Paul Cohen, the Albert Resnick, M.D., Assistant Professor and senior attending physician at The Rockefeller University Hospital. "These findings make us more confident about the potential of targeting brown fat for therapeutic benefit."

A valuable resource

Although brown fat has been studied for decades in newborns and animals, it was only in 2009 that scientists appreciated it can also be also found in some adults, typically around the neck and shoulders. From then on, researchers have scrambled to study the elusive fat cells, which possess the power to burn calories to produce heat in cold conditions.

Large-scale studies of brown fat, however, have been practically impossible because this tissue shows up only on PET scans, a special type of medical imaging. "These scans are expensive, but more importantly, they use radiation," says Tobias Becher, the study's first author and formerly a Clinical Scholar in Cohen's lab. "We don't want to subject many healthy people to that."

A physician-scientist, Becher came up with an alternative. Right across the street from his lab, many thousands of people visit Memorial Sloan Kettering Cancer Center each year to undergo PET scans for cancer evaluation. Becher knew that when radiologists detect brown fat on these scans, they routinely make note of it to make sure it is not mistaken for a tumor. "We realized this could be a valuable resource to get us started with looking at brown fat at a population scale," Becher says.

Protective fat

In collaboration with Heiko Schoder and Andreas Wibmer at Memorial Sloan Kettering, the researchers reviewed 130,000 PET scans from more than 52,000 patients, and found the presence of brown fat in nearly 10 percent of individuals. (Cohen notes that this figure is likely an underestimate because the patients had been instructed to avoid cold exposure, exercise, and caffeine, all of which are thought to increase brown fat activity).

Several common and chronic diseases were less prevalent among people with detectable brown fat. For example, only 4.6 percent had type 2 diabetes, compared with 9.5 percent of people who did not have detectable brown fat. Similarly, 18.9 percent had abnormal cholesterol, compared to 22.2 percent in those without brown fat.

Moreover, the study revealed three more conditions for which people with brown fat have lower risk: hypertension, congestive heart failure, and coronary artery disease--links that had not been observed in previous studies.

Another surprising finding was that brown fat may mitigate the negative health effects of obesity. In general, obese people have increased risk of heart and metabolic conditions; but the researchers found that among obese people who have brown fat, the prevalence of these conditions was similar to that of non-obese people. "It almost seems like they are protected from the harmful effects of white fat," Cohen says.

More than an energy burning powerhouse

The actual mechanisms by which brown fat may contribute to better health are still unclear, but there are some clues. For example, brown-fat cells consume glucose in order to burn calories, and it's possible that this lowers blood glucose levels, a major risk factor for developing diabetes.

The role of brown fat is more mysterious in other conditions like hypertension, which is tightly connected to the hormonal system. "We are considering the possibility that brown fat tissue does more than consume glucose and burn calories, and perhaps actually participates in hormonal signaling to other organs," Cohen says.

The team plans to further study the biology of brown fat, including by looking for genetic variants that may explain why some people have more of it than others--potential first steps toward developing pharmacological ways to stimulate brown fat activity to treat obesity and related conditions.

"The natural question that everybody has is, 'What can I do to get more brown fat?'" Cohen says. "We don't have a good answer to that yet, but it will be an exciting space for scientists to explore in the upcoming years."

Amsterdam, NL, January 4, 2021 - The impact of the COVID-19 pandemic on children with disabilities has not received much attention, perhaps because the disease disproportionately affects older individuals. In this special issue of the Journal of Pediatric Rehabilitation Medicine experts assess the impact of the pandemic on pediatric patients with special needs, their caregivers, and healthcare providers. They also focus on the growing importance of telemedicine and provide insights and recommendations for mitigating the impact of the virus in the short and long term.

"Pediatric rehabilitation patients frequently have more access and therapy needs. As clinics were put on pause or cancelled during the pandemic, some patients who may have needed care did not receive it in a timely manner. These children should be a focus of evaluation and intervention to mitigate the negative consequences of COVID-19 and the resulting containment strategies. The need for more ethical and conscious decisions in the treatment of persons from disabled populations should be recognized and included in future crisis planning," emphasize Guest Editors Matthew J. McLaughlin, MD, MS, Children's Mercy - Kansas City, MO, USA, and Christian J. Vercler, MD, C.S. Mott Children's Hospital, University of Michigan, Ann Arbor, MI, USA.

Children comprise approximately 2% of cases of COVID-19 in the United States. In most cases the child is either asymptomatic or has mild symptoms. However, children with disabilities like cerebral palsy (CP) are more vulnerable and are at higher risk for respiratory complications. Some can present with multisystem inflammatory syndrome (MIS-C) and need supportive care.

This special issue addresses many aspects of COVID-19 in vulnerable children with special needs, including spasticity management, autism spectrum disorders, CP, neuromuscular disorders, tracheostomies, MIS-C, schooling, and how to deliver medicines safely and effectively. It also considers the impact of the pandemic on healthcare providers in training including the need for disability-conscious medical education, training, and practice; the disparate influence of the pandemic on Black, Latinx, and Native American marginalized populations; as well as the telemedicine experience and role of virtual education.

There is concern that the virus could have a disparate impact on children with disabilities when viewed through the lens of race and equity. In the US, early data reported from multiple jurisdictions showed that there is a disproportionate impact of COVID-19 when measuring death rates and infection rates in Black, Native American, and Latinx individuals compared with White populations in multiple areas of the country. The risk of children with disabilities contracting coronavirus is directly related to caregivers and/or family members that share their living arrangements, explains Maurice G. Sholas, MD, PhD, Principal and Pediatric Physiatrist, Sholas Medical Consulting, LLC, New Orleans, LA, USA. He presents a number of measures to mitigate the problems, concluding that "Individual providers, health systems and policy interventions must be accountable and active to ensure that marginalized communities do not continue to be disproportionately impacted."

Patients with pre-existing respiratory disorders such as CP are at greater risk for respiratory complications if they contract COVID-19, notes Joline E. Brandenburg, MD, Department of Physical Medicine and Rehabilitation, and Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA, and colleagues in a review of research on respiratory function and diaphragm muscle force generation in children with CP. They compare and integrate clinical work and basic science research investigating phrenic motor neuron and diaphragm motor unit dysfunction in an animal model and discuss the potential for individuals with CP to experience severe respiratory symptoms from COVID-19.

"We need to be vigilant in encouraging and supporting families of children with CP and individuals who have CP to practice physical distancing, good hand hygiene, minimizing trips to public places such as stores and restaurants, and thorough cleaning of any equipment that is used outside the home (i.e., walkers and wheelchairs) in order to reduce the risk of contracting COVID-19," advises Dr. Brandenburg.

COVID-19 has accelerated the adoption of telehealth across many medical specialties and is a special focus of this issue. "There has been an expansion of telemedicine offerings by many different pediatric rehabilitation providers," explain Dr. McLaughlin and Dr. Vercler. "Historically, pediatric rehabilitation patients are more difficult to transport, may come from a more challenged socioeconomic background, and have more medical co-morbidities than the general pediatric population. By more clinics offering telemedicine appointments, this may limit exposures to COVID-19 and decrease the caregiver burden if medical care can be provided within the home setting."

A survey of pediatric physiatrists by Anton Dietzen, MD, DC, Marianjoy Rehabilitation Hospital, Northwestern Medicine, Lombard, IL, USA, and colleagues, showed a significant increase in telehealth utilization since COVID-19, from less than 15% to 97%. More than 80% of respondents reported feeling comfortable using telehealth, 77% felt confident in the quality of the care provided, and 91% believed patients were satisfied with telehealth visits.

"Responses indicate that telehealth is expected to play a role in future pediatric physiatry and interest in telehealth continuing medical education is prevalent. Most pediatric physiatrists plan to continue or expand telehealth offerings after COVID-19," notes Dr. Dietzen.

The Guest Editors add that "the benefit of telemedicine and its expanded use may continue to benefit patients with rehabilitation needs, although we need to be aware that procedures such as intrathecal baclofen refills or botulinum toxin injections will require in person visits."

"Through this issue of the Journal of Pediatric Rehabilitation Medicine we are disseminating a wealth of information on COVID-19 and the effect that it has on our pediatric rehabilitation caregivers, providers and those with special needs," comments Editor-in-Chief Elaine L. Pico, MD, FAAP, FAAPM&R, UCSF Benioff Children's Hospital, Oakland, CA, USA. "It is my belief that this type of worldwide outreach and exchange of information is an essential part of the global solution to help mitigate the spread of this deadly virus.

What The Study Did: In this observational study of 5,256 U.S. nursing home residents with COVID-19, increased age, male sex and impaired cognitive and physical function were independent risk factors for all-cause 30-day mortality.

Authors: Orestis A. Panagiotou, M.D., Ph.D., of the Brown University School of Public Health in Providence, Rhode Island, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamainternmed.2020.7968)

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

What The Study Did: Changes were assessed in abortions performed and at what gestational age following a Texas order postponing nonmedically necessary surgeries due to the COVID-19 pandemic compared with abortions performed during the same months in 2019.

Authors: Kari White, Ph.D., M.P.H., of the University of Texas at Austin, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jama.2020.24096)

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

LOS ANGELES -- A growing number of women forgoing reconstruction after a mastectomy say they're satisfied with their choice, even as some did not feel supported by their physician, according to a study led by researchers at the UCLA Jonsson Comprehensive Cancer Center.

The study, published in the Journal Annals of Surgical Oncology, surveyed 931 women who had a unilateral or bilateral mastectomy without current breast mound reconstruction to assess the motivating factors for forgoing the procedure and to measure whether surgeons provided adequate information and support for "going flat."

Out of the women surveyed, 74% were satisfied with their outcome and 22% experienced "flat denial," where the procedure was not initially offered, the surgeon did not support the patient decision, or intentionally left additional skin in case the patient changed her mind.

The team also explored reasons given for the choice and found women pointed to a desire for a faster recovery, avoidance of a foreign body placement and the belief that breast mound reconstruction was not important for their body image.

"Undergoing a mastectomy with or without reconstruction is often a very personal choice," said Dr. Deanna Attai, an assistant clinical professor of surgery at the David Geffen School of Medicine at UCLA, and senior author of the study. "We found that for a subset of women, 'going flat' is a desired and intentional option, which should be supported by the treatment team and should not imply that women who forgo reconstruction are not concerned with their post-operative appearance."

The results challenge past studies showing that patients who chose not to undergo breast reconstruction tend to have a poorer quality of life compared with those who do have the surgery.

Attai and her team found that a majority of patients who elected to go flat were in fact satisfied with their surgical outcome. The authors believe the survey tool commonly used to asses outcomes was biased towards reconstruction. To avoid that bias, Attai partnered with patient advocates to develop a unique survey to assess reasons for going flat, satisfaction with their decision, and factors associated with satisfaction. They also identified concerns unique to these patients not captured by other validated surveys.

While a majority of the women surveyed reported they were satisfied with their surgical outcomes, 27% of patients surveyed reported not being satisfied with the appearance of their chest wall.

"Some patients were told that excess skin was intentionally left -- despite a preoperative agreement to perform a flat chest wall closure -- for use in future reconstruction, in case the patient changed her mind," said Attai, who is a member of the UCLA Jonsson Comprehensive Cancer Center. "We were surprised that some women had to struggle to receive the procedure that they desired."

Surgeons may hesitate to recommend mastectomy without reconstruction surgeons due to being less confident that they can provide a cosmetically acceptable result for patients who desire a flat chest wall, noted Attai.

"We hope that the results of this study will serve to inform general and breast surgeons that going flat is a valid option for patients, and one that needs to be offered as an option," said Attai. "We also hope the results may help inform patients that going flat is an option, and to empower them to seek out surgeons who offer this option and respect their decision."

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. State laws promoting flu vaccination for hospital workers may help prevent deaths from flu and pneumonia
Abstract: https://www.acpjournals.org/doi/10.7326/M20-0413
URL goes live when the embargo lifts

Research suggests that state laws promoting influenza vaccination for hospital workers can be effective in preventing deaths from pneumonia and influenza, particularly among the elderly. Findings from a quasi-experimental observational study are published in Annals of Internal Medicine.

Seasonal influenza vaccines are a key defense against infection, but they can be less effective in elderly adults and chronically ill persons who are at the greatest risk. The Centers for Disease Control and Prevention (CDC) has long recommended vaccinating health care workers and several states passed laws requiring that hospitals provide influenza vaccination onsite for their employees. The effect of these laws on pneumonia and influenza mortality is unknown.

Researchers from the University of Georgia, Montana State University, and Monash University used quasi-experimental, state-level, longitudinal study designs to estimate the association of state hospital worker influenza vaccination laws with influenza and pneumonia mortality rates. In one design, the researchers conducted a synthetic control analysis to estimate a separate treatment effect for each of the 14 states that adopted a vaccination law between 2002 and 2014. In the other design, they estimated an average treatment effect using a state-level, longitudinal model in which they controlled for national time fixed effects, state fixed effects, and state-specific time trends. Each of these approaches compared differences in mortality rates between states with and without laws in place, before and after law implementation.

The researchers found that the implementation of a state vaccination law was associated with a 2.5% reduction in monthly pneumonia and influenza mortality rates during the years when the vaccine was well matched to the circulating strains. This implies that during the 2016-2017 influenza year (when 15 states had implemented laws), approximately 1,822 pneumonia and influenza deaths were averted because of the laws. The largest effects occurred among elderly persons and during peak influenza months. According to the researchers, these findings suggest that vaccination laws may be a good way to protect the country's most vulnerable populations.

Media contacts: For an embargoed PDF, please contact Angela Collom at acollom@acponline.org. To reach the corresponding author, Emily Lawler, PhD, please contact Caroline Paris Paczkowski at cparis@uga.edu.

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Abstract: https://www.acpjournals.org/doi/10.7326/A20-0004

The Asian tiger mosquito does not pose a major risk for Zika virus epidemics, according to a study published December 31 in the open-access journal PLOS Pathogens by Albin Fontaine of the Institut de Recherche Biomédicale des Armées, and colleagues.

Zika virus has triggered large outbreaks in human populations, in some cases causing congenital deformities, fetal loss, or neurological problems in adults. While the yellow fever mosquito Aedes aegypti is considered the primary vector of Zika virus, the Asian tiger mosquito Aedes albopictus has been shown experimentally to transmit the virus and was involved in several transmissions of the virus in France in 2019. Originating from Southeast Asia, Ae. aegypti is an aggressive biter that has invaded the world and is now present on all inhabited continents, including temperate Europe, due to its ability to endure harsh winter conditions. As the second most important vector of human viral pathogens, Ae. albopictus is displacing Ae. aegypti populations due to competitive advantages. But it is not known if Ae. albopictus could trigger large-scale Zika virus epidemics.

To address this question, the researchers exposed Ae. albopictus to Zika virus and assessed infection rates in experiments, modeled the dynamics of Zika virus infection within individual humans, and used epidemiological simulations. The highest risk of transmission occurred during the pre-symptomatic stage of the disease. At this dose, mosquito infection probability was estimated to be 20%, and 21 days were required to reach median systemic infection rates. Despite these unfavorable characteristics for transmission, Ae. albopictus was still able to trigger large outbreaks in a simulated environment in the presence of sufficiently high mosquito densities and biting rates. According to the authors, active surveillance and eradication programs should be implemented in territories occupied by Ae. albopictus to maintain the low risk of Zika virus outbreaks.

The authors conclude, "The complementary combination of dose-dependent experimental infection, modeling of intra-human viremia dynamics, and in silico epidemiological simulations confirms the low epidemic potential of Aedes albopictus for Zika virus."

Multiple bouts of blood feeding by mosquitoes shorten the incubation period for malaria parasites and increase malaria transmission potential, according to a study published December 31 in the open-access journal PLOS Pathogens by Lauren Childs of Virginia Tech, Flaminia Catteruccia of the Harvard T.H. Chan School of Public Health, and colleagues. Given that mosquitoes feed on blood multiple times in natural settings, the results suggest that malaria elimination may be substantially more challenging than suggested by previous experiments, which typically involve a single blood meal.

Malaria remains a devastating disease for tropical and subtropical regions, accounting for an estimated 405,000 deaths and 228 million cases in 2018. In natural settings, the female Anopheles gambiae mosquito -- the major malaria vector -- feeds on blood multiple times in her lifespan. Such complex behavior is regularly overlooked when mosquitoes are experimentally infected with malaria parasites, limiting our ability to accurately describe potential effects on transmission. In the new study, the researchers examine how additional blood feeding affects the development and transmission potential of Plasmodium falciparum malaria parasites in An. gambiae females.

"We wanted to capture the fact that, in endemic regions, malaria-transmitting mosquitoes are feeding on blood roughly every 2-3 days", says W. Robert Shaw, a lead author of this study. "Our study shows that this natural behavior strongly promotes the transmission potential of malaria parasites, in previously unappreciated ways".

The results show that an additional blood feed three days after infection with P. falciparum accelerates the growth of the malaria parasite, thereby shortening the incubation period required before transmission to humans can occur. Incorporating these data into a mathematical model across sub-Saharan Africa reveals that malaria transmission potential is likely higher than previously thought, making disease elimination more difficult. In addition, parasite growth is accelerated in genetically modified mosquitoes with reduced reproductive capacity, suggesting that control strategies using this approach, with the aim of suppressing Anopheles populations, may inadvertently favor malaria transmission. The data also suggest that parasites can be transmitted by younger mosquitoes, which are less susceptible to insecticide killing, with negative implications for the success of insecticide-based strategies. Taken together, the results suggest that younger mosquitoes and those with reduced reproductive ability may provide a larger contribution to infection than previously thought.

According to the authors, the findings have important implications for accurately understanding malaria transmission potential and estimating the true impact of current and future mosquito control measures.

The discovery of new drugs is vital to achieving the eradication of neglected tropical diseases (NTDs) in Africa and around the world. Now, researchers reporting in PLOS Neglected Tropical Diseases have identified traditional Ghanaian medicines which work in the lab against schistosomiasis, onchocerciasis and lymphatic filariasis, three diseases endemic to Ghana.

The major intervention for NTDs in Ghana is currently mass drug administration of a few repeatedly recycled drugs, which can lead to reduced efficacy and the emergence of drug resistance. Chronic infections of schistosomiasis, onchocerciasis and lymphatic filariasis can be fatal. Schistosomiasis is caused by the blood flukes Schistosome haematobium and S. mansoni. Onchocerciasis, or river blindness, is caused by the parasitic worm Onchocerca volvulus. Lymphatic filariasis, also called elephantiasis, is caused by the parasitic filarial worm Wuchereria bancrofti.

In the new work, Dorcas Osei-Safo of the University of Ghana, and colleagues obtained--from the Ghana Federation of Traditional Medicines Practitioners Association--15 traditional medicines used for treating NTDs in local communities. The medicines were available in aqueous herbal preparations or dried powdered herbs. In all cases, crude extracts were prepared from the herbs and screened in the laboratory for their ability to treat various NTDs.

Two extracts, NTD-B4-DCM and NTD-B7-DCM, displayed high activity against S. mansoni adult worms, decreasing the movement of the worms by 78.4% and 84.3% respectively. A different extract, NTD-B2-DCM, was the most active against adult Onchocera onchengi worms, killing 100% of males and more than 60% of females. Eight of 26 crude extracts tested, including NTD-B4-DCM and NTD-B2-DCM, also exhibited good activity against trypanosomes--parasites that cause other human diseases but weren't the original targets of the traditional medicines.

"By embracing indigenous knowledge systems which have evolved over centuries, we can potentially unlock a wealth of untapped research and shape it by conducting sound scientific investigations to produce safe, efficacious and good quality remedies," the researchers say.