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Participants at the 6th Joint Science Conference of the Western Balkans Process have developed a "10 Point Plan" to control the coronavirus pandemic in the Western Balkans. Participants at the virtual two-day meeting also discussed priorities for the time after the pandemic in the Western Balkans and South East Europe. These include a decent healthcare system, climate neutrality, reduction of air and water pollution, and the digitalization of education, public administration, industry and healthcare. The conference was jointly organized by the German National Academy of Sciences Leopoldina and the Polish Academy of Sciences as part of the Western Balkans Process.

"We need to identify the lessons learned from this pandemic. The first logical consequence is to strengthen pandemic preparedness and crisis resilience," stated Professor (ETHZ) Dr Gerald Haug, President of the Leopoldina, at the virtual meeting.

In their "10 Point Plan", the participants recommend short-, mid-, and long-term measures for the next two years to control and contain the pandemic in South East Europe and on the European continent: Higher number of vaccines for the Western Balkan countries and accelerated vaccination, pan-European standards for travel and mobility in testing and forgery-proof use of the EU Digital COVID Certificate, and more humanitarian aid from the European Union (EU) as a sign of European solidarity.

The EU funds mobilized for the recovery and resilience of the Western Balkans should be primarily used to create an efficient health care system, to achieve the goal of climate neutrality with an emphasis on reducing air and water pollution, and to digitalize education, public administration, industry and health care. In order to achieve sustainable success, however, investments in education and science (research and innovation) in the Balkans are needed, especially to stop the "brain drain" from South East Europe. Therefore, the conference participants called for the "Western Balkans Research Fund" to be included as a new funding instrument in the EU's Horizon Europe framework programme.

The Western Balkans Process ? also known as the Berlin Process ? is a joint initiative of 16 European countries and the European Commission. It supports the efforts to integrate the region into the European Union and foster regional cooperation. The Process covers areas such as the resolution of bilateral disputes, endorsement of rule of law, connectivity, and economic development as well as strengthening the cooperation in education, science (research and innovation) and inter-societal dialogue. Seventeen parties are currently involved in the Process: Albania, Austria, Bosnia and Herzegovina, Bulgaria, Croatia, France, Germany, Greece, Italy, Kosovo, Montenegro, Northern Macedonia, Poland, Serbia, Slovenia, and the United Kingdom, as well as the European Commission.

BOSTON - A novel therapy recently approved by the U.S. Food and Drug Administration for patients with Alzheimer's disease amid considerable controversy should not be prescribed by physicians off-label for cerebral amyloid angiopathy (CAA), a similar cerebrovascular condition, according to Steven Greenberg, MD, PhD, director of the Hemorrhagic Stroke Research Program at Massachusetts General Hospital (MGH) and president of the International Cerebral Amyloid Angiopathy Association (ICAAA). In a letter published in The Lancet Neurology, Greenberg and eight other officers of the association wrote that there is no clinical evidence that the monoclonal antibody aducanumab is beneficial to patients with CAA, a condition in which proteins known as amyloid corrode arterial walls in the brain and can lead to bleeding and stroke.

"We believe that there are substantial uncertainties and concerns about both the safety and efficacy of aducanumab in patients diagnosed with CAA [and] therefore believe [it] should not be used for the purpose of treating CAA outside the context of a research trial," the letter stated.

The FDA approved aducanumab on June 7 under the FDA's accelerated approval process for drugs that treat serious conditions and fill an unmet medical need. While the approval was specifically for Alzheimer's disease, it opens the door for physicians to legally prescribe aducanumab off-label for cerebral amyloid angiopathy. Indeed, CAA is thought to be triggered, as in Alzheimer's, by a harmful accumulation of amyloid beta deposits in the brain. Unlike Alzheimer's, however, those deposits typically gather in the cerebral blood vessels, not the brain tissue itself. In giving the green light to aducanumab, the FDA took a position contrary to its own independent advisory committee, as well as many scientists and physicians, who contend there is no convincing evidence to show the drug helps patients.

Leading authorities in the field of cerebral amyloid angiopathy have now taken their own stand, recommending that aducanumab not be prescribed off-label for treatment of CAA. From an efficacy standpoint, the ICAAA officers noted that amyloid beta deposits in blood vessels of the brain appear to be more resistant to antibody-mediated treatment than plaque deposits in the brain tissue, and that insufficient evidence existed to suggest aducanumab was capable of clearing those blood vessels. The physicians cited a previous clinical trial of another anti-amyloid antibody, ponezumab, which found that blood vessel function in patients with CAA trended toward worsening rather than improving following three monthly infusions of the agent.

In terms of safety, the letter from Greenberg and his colleagues cited the fact that amyloid-related imaging abnormalities (ARIAs) had emerged as major adverse events in patients enrolled in trials of aducanumab and other anti-amyloid antibody drugs. ARIAs, which manifest as bleeding or swelling in the brain and are detectable through MRI imaging, are postulated to be triggered by CAA. What the physicians found worrisome was that these abnormalities might occur even more frequently in patients being treated for CAA than the high rates observed in patients treated for Alzheimer's disease.

While discouraging off-label use of aducanumab, Greenberg drew a distinction between patients diagnosed with cerebral amyloid angiopathy and those diagnosed with Alzheimer's disease. "We haven't taken a position on whether an Alzheimer's patient who also has markers of CAA should be prescribed aducanumab," he says. "What we are saying is that the drug shouldn't be prescribed for the purpose of treating CAA."

BOSTON -- As we age, our brains typically undergo a slow process of atrophy, causing less robust communication between various brain regions, which leads to declining memory and other cognitive functions. But a rare group of older individuals called "superagers" have been shown to learn and recall novel information as well as a 25-year-old. Investigators from Massachusetts General Hospital (MGH) have now identified the brain activity that underlies superagers' superior memory. "This is the first time we have images of the function of superagers' brains as they actively learn and remember new information," says Alexandra Touroutoglou, PhD, director of Imaging Operations at MGH's Frontotemporal Disorders Unit and senior author of the paper published in Cerebral Cortex.

In 2016, Touroutoglou and her fellow researchers identified a group of adults older than 65 with remarkable performance on memory tests. The superagers are participants in an ongoing longitudinal study of aging at MGH led by Bradford Dickerson, MD, director of the Frontotemporal Disorders Unit at MGH, and Lisa Feldman Barrett, PhD, a research scientist in Psychiatry at MGH. "Using MRI, we found that the structure of superagers' brains and the connectivity of their neural networks more closely resemble the brains of young adults; superagers had avoided the brain atrophy typically seen in older adults," says Touroutoglou.

In the new study, the investigators gave 40 adults with a mean age of 67 a very challenging memory test while their brains were imaged using functional magnetic resonance imaging (fMRI), which, unlike typical MRI, shows the activity of different brain areas during tasks. Forty-one young adults (mean age of 25) also took the same memory test while their brains were imaged. The participants first viewed 80 pictures of faces or scenes that were each paired with an adjective, such as a cityscape paired with the word "industrial" or a male face paired with the word "average." Their first task was to determine whether the word matched the image, a process called encoding. After 10 minutes, participants were presented with the 80 image-word pairs they had just learned, an additional 40 pairs of new words and images, and 40 rearranged pairs consisting of words and images they had previously seen. Their second task was to recall whether they had previously seen each specific word-picture pair, or whether they were looking at a new or rearranged pair.

While the participants were in the scanner, the researchers paid close attention to the visual cortex, which is the area of the brain that processes what you see and is particularly sensitive to aging. "In the visual cortex, there are populations of neurons that are selectively involved in processing different categories of images, such as faces, houses or scenes," says lead author Yuta Katsumi, PhD, a postdoctoral fellow in Psychiatry at MGH. "This selective function of each group of neurons makes them more efficient at processing what you see and creating a distinct memory of those images, which can then easily be retrieved."

During aging, this selectivity, called neural differentiation, diminishes and the group of neurons that once responded primarily to faces now activates for other images. The brain now has difficulty creating unique neural activation patterns for different types of images, which means it is making less distinctive mental representations of what the person is seeing. That's one reason older individuals have trouble remembering when they may have seen a television show, read an article, or eaten a specific meal.

But in the fMRI study, the superagers' memory performance was indistinguishable from the 25-year-olds', and their brains' visual cortex maintained youthful activity patterns. "The superagers had maintained the same high level of neural differentiation, or selectivity, as a young adult," says Katsumi. "Their brains enabled them to create distinct representations of the different categories of visual information so that they could accurately remember the image-word pairs."

An important question that researchers still must answer is whether "superagers' brains were always more efficient than their peers, or whether, over time, they developed mechanisms to compensate for the decline of the aging brain," says Touroutoglou.

Previous studies have shown that training can increase the selectivity of brain regions, which may be a potential intervention to delay or prevent the decline in neural differentiation in normal aging adults and make their brains more like those of superagers. Currently the researchers are conducting a clinical trial to evaluate whether noninvasive electromagnetic stimulation, which delivers an electrical current to targeted areas of the brain, can improve memory in older adults. The researchers also plan to study different brain regions to further understand how superagers learn and remember, and they will examine lifestyle and other factors that might contribute to superagers' amazing memory.

Pediatric melanoma is a rare disease with only around 400 cases diagnosed in the United States every year. To better understand this disease and how best to treat it, St. Jude Children's Research Hospital scientists created a registry called Molecular Analysis of Childhood MELanocytic Tumors (MACMEL). A paper on findings from the registry was published today in Cancer.

"What is different about the MACMEL registry is that it is prospective," said corresponding author Alberto Pappo, M.D., St. Jude Solid Tumor Division director. "We're seeing the vast majority of enrolled patients as part of the melanoma clinic at St. Jude. We can follow these patients and conduct detailed pathology and molecular analysis."

More than one disease

Through such efforts as the St. Jude-Washington University Pediatric Cancer Genome Project, scientists learned that pediatric melanoma is really not one disease, but multiple diseases. These subgroups include:

Conventional melanoma: melanocytic lesions with features similar to adult melanoma that occur almost exclusively in adolescents. These tumors often have BRAF and TERT promoter mutations.

Spitz melanoma and atypical Spitz tumors: occur in younger patients and are characterized by copy number alterations. These tumors typically have kinase fusions involving MAP3K8, NTRK, ALK, ROS1, RET, BRAF or MET.

Giant congenital nevus melanomas: aggressive tumors that have NRAS mutations and upregulation of TERT.

No reliable clinical or morphologic features can accurately predict the clinical behavior of melanoma tumors in children. However, the registry provides the opportunity to better understand the natural history of these tumors and, potentially, treat them.

Registry findings

"What we're seeing from the registry's data is that these are incredibly diverse tumors. Some patients need drastic measures. For many others, masterful watching is the best option," said last author Armita Bahrami, M.D., formerly of St. Jude and now of Emory University. "It is critical for the care team to consider all available clinical, pathologic and genomic data in order to assign patients to the appropriate risk category."

The registry has been open and enrolling patients since 2016. The researchers analyzed data from the first 70 patients enrolled and categorized them as either one of the three recognized subgroups, or as "other." From the registry, the researchers were able to determine that most spitzoid melanomas have a gene fusion, most commonly involving MAP3K8. They also found that spitzoid melanomas that do not have a TERT mutation have a benign clinical course.

For conventional melanoma, the researchers found that the most common mutation was in the gene BRAF. Conventional melanoma patients with advanced disease did not do as well as those diagnosed with early stage disease. The study also showed that giant congential nevus melanomas all had NRAS mutations and all patients died of their disease.

A focus on rare disease

These results highlight the need to take into consideration the patient's age, pathology review and integrated genomic analysis not only to arrive at the right diagnosis but to anticipate the clinical behavior of these tumors.

"Now that we have all of this information available, we can be significantly more selective and integrate this information into treatment decision making," Pappo said. "It will help us provide the best information possible for the patient as far as prognosis, recurrence and the need for additional surgery or therapy."

A majority of the patients included in the registry were treated at St. Jude through a dedicated clinic for pediatric melanoma. The clinic is ongoing and has been held virtually during the COVID-19 pandemic.

Succinate dehydrogenase inhibitors (SDHIs) are a class of fungicides widely used to control many fungal diseases of crops. The relationship between SDHIs and fungi can be compared to finding the right key for the right lock. However, fungi are adaptable and develop resistance to fungicides often by changing the lock so that the SDHI is no longer able to open the door. Because of this adaptability, it is important to understand the biological mechanisms of fungicide resistance.

A recent collaboration between scientists in Michigan and Massachusetts as well as South Korea resulted in the development of a novel and broadly applicable molecular assay that used a model fungus to investigate how plant fungal pathogens circumvent the bioactivity of SDHIs. In other words, to study the interactions between different locks and keys. Through this analysis, they were able to successfully validate known mechanisms of fungicide resistance in several agriculturally important fungal pathogens.

Of note, they were also able to provide insights into the question: "Can newer SDHI fungicides overcome existing resistance mutations?" Their answer? Not necessarily! "We showed that the efficacy of fungicides developed in recent years will be heavily dependent on the history of fungicide application in each particular field site," said Jingyu Peng, one of the researchers involved with this study.

Their assay and resulting study are unique compared to other studies that focus on a specific fungus. "The molecular assay we developed enables a holistic interrogation of fungicide resistance mechanisms in various pathogenic fungi," Peng explained. "We hope our study will have a positive impact on future fungicide design as our approach is very scalable and can be implemented as a part of the resistance risk assessment protocol for future industrial fungicide discovery."

Using simple blood tests could help researchers identify children who have been misidentified as having severe malaria, according to a study published today in eLife.

Researchers are working to develop better ways to treat severe malaria, which kills about 400,000 children in Africa each year. The discovery could help expedite such research by helping them more accurately identify children with severe malaria. It also reinforces the importance of the World Health Organization's recommendation that all children being treated for severe malaria also receive antibiotics to ensure any misdiagnosed children receive life-saving care.

Diagnosing severe malaria in children in Africa is challenging because the parasites that cause malaria can be found in both healthy and severely ill children. This makes it difficult to tell if the parasites or some other condition is causing illness. In fact, many children diagnosed with severe malaria may have other life-threatening infections. In addition to potentially delaying life-saving antibiotic care, misdiagnosis can skew the results of studies of new treatments for malaria because children misdiagnosed with malaria will not respond, which could make drugs that work look ineffective.

"Inaccuracy in the diagnosis of severe malaria negatively impacts clinical studies, especially those trying to understand which genes may make people more vulnerable to severe disease, or which treatments are most effective," says co-first author James Watson, Senior Scientist at the Mahidol Oxford Tropical Medicine Research Unit (MORU) in Bangkok, Thailand. "We wanted to know whether complete blood count data, notably platelet counts and white blood cell counts, could help make the diagnosis of malaria more accurate."

Watson, along with co-first author Carolyne Ndila, a researcher at The Kenya Medical Research Institute-Wellcome Trust Research Programme (KWTRP), in Kilifi, Kenya, and their colleagues developed a statistical model that could distinguish between severe malaria and other severe illnesses that can be mistaken as severe malaria. To develop the model they included data from over 1,500 children and adults diagnosed with severe malaria in Thailand and Bangladesh. In these countries, people are rarely misdiagnosed with severe malaria because it is much less common for healthy people to have malaria parasites in their blood.

They applied this model, which relied on platelet and white blood cell counts, to a large cohort of Kenyan children diagnosed with severe malaria. Based on their analysis, they estimate that in approximately one-third of the children, severe malaria was in fact a misdiagnosis.

"Our results support the current guideline that all children with suspected malaria should be given both antimalarials and broad-spectrum antibiotics, as many of the misdiagnosed children will likely have had bacterial sepsis, a severe blood infection," Ndila says.

Using their new model to reanalyse data from clinical studies that looked for potential genetic factors that protect against severe malaria, the team also found that people with glucose-6-phosphate dehydrogenase deficiency probably have some protection from malaria. This benefit was likely obscured in previous studies by the high rate of misdiagnoses.

"We hope our new model can be used by other scientists and clinicians to improve the accuracy of diagnosis in children suspected of having severe malaria," concludes senior author Nicholas White, Professor of Tropical Medicine at Mahidol University. "This will help studies trying to identify better treatments for these patients."

Des Plaines, IL - The Society for Academic Emergency Medicine (SAEM) is pleased to announce the release of the first publication in a series of Guidelines for Reasonable and Appropriate Care in the Emergency Department (GRACE), which focuses on low-risk chest pain. The article, titled "Guidelines for Reasonable and Appropriate Care in the Emergency Department (GRACE): Recurrent, Low-risk Chest Pain in the Emergency Department," will be published in the July issue of SAEM's peer reviewed journal, Academic Emergency Medicine (AEM).

Chest pain is the second most common chief complaint in the emergency department (ED), with only five percent of patients diagnosed with an acute, life-threatening condition. There are significant physician and institutional variations in diagnostic testing and admission of these patients, creating a need for clinical practice guidelines to aid in the evaluation and treatment specific to the ED population. The first SAEM GRACE team was assembled to address this critical need for evidence-based and expert-driven recommendations for the care of complaints associated with recurrent chest pain.

A multidisciplinary panel of experts assessed the certainty of evidence and strength of recommendations regarding eight priority questions for adults presenting to the ED with recurrent, low-risk chest pain. They then developed recommendations for testing, treatment, hospital admission, and screening tools and referrals for mental health management. To write this clinical practice guideline, the panel used Grading of Recommendations Assessment Development and Evaluation (GRADE) methodology, a framework for rating the quality of the best available evidence and developing clinical practice recommendations.

The lead author of the chest pain GRACE study is Paul Musey, Jr., MD, associate professor of emergency medicine in the department of emergency medicine at Indiana University School of Medicine in Indianapolis, Indiana.

In "GRACE-Recurrent Low Risk Chest Pain: A User's Guide," to be published alongside the GRACE study in the July issue of AEM, Courtney et al. summarize what emergency medicine physicians can take to the patient bedside and its possible effect in the ED,

"In patients with recurrent, low-risk chest pain and a normal stress test in the prior 12 months, it is not recommended to employ further routine stress testing to reduce subsequent 30-day Major Adverse Cardiac Events (MACE). In our opinion, the other important statement is that there is insufficient evidence to recommend hospitalization (either inpatient admission or observation) versus discharge as a strategy to mitigate 30-day MACE. Further recommendations including screening and referral for anxiety and depression, previously unexplored topics in the context of chest pain, should also be noted in this novel work."

"Endorsement and dissemination by multi-stakeholder organizations and societies could catapult these recommendations into decision support within electronic health records and implementation for millions of chest pain visits across the US and beyond, transforming them into shared decision-making with patients at the point of care."

The SAEM GRACE program addresses the best practices for the care of the most common chief complaints that can be seen on the tracking board of any emergency department in the country, based upon research and expert consensus. These guidelines are designed with de-implementation as a guiding principle to reasonably reduce wasteful testing, provide explicit criteria to reduce foreseeable risk, and define sensible and prudent medical care. In addition to GRACE for chest pain, SAEM research and writing teams will create guidelines for recurrent abdominal pain, acute dizziness, and non-opioid substance dependence.

In a commentary article, also in the July issue of AEM, titled "Navigating Uncertainty with GRACE: Society for Academic Emergency Medicine's Guidelines for Reasonable and Appropriate Care in the Emergency Department," Carpenter et al. further explain how and why GRACE guidelines were created,

"GRACE emerged to address the critical need for evidence-based and expert driven, trustworthy, and transparent recommendations for the clinical care of common chief complaints and syndromes, prioritizing those with demonstrable practice variability and significant malpractice angst that often elicit decisional conflict or treatment uncertainty."

"It is vital for (emergency medicine) EM organizations to foster EM-specific guidelines, created by EM clinical/academic experts, to serve ED patient needs. GRACE will accelerate the creation of new evidence-based recommendations for our specialty, with involvement and focus on patient-important outcomes and consideration of patients' values and preferences. Above all, GRACE aims to transparently report the decision process, as the focus on transparency facilitates understanding and implementation, and should empower patients and clinicians to make informed choices."

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. Infusion centers associated with substantially better outcomes than the ER for patients with acute pain events and sickle cell disease
Abstract: https://www.acpjournals.org/doi/10.7326/M20-7171
Editorial: https://www.acpjournals.org/doi/10.7326/M21-2650
Summary: https://www.acpjournals.org/doi/10.7326/P21-0005
URL goes live when the embargo lifts

A prospective cohort study found that treatment at an infusion center (IC) is associated with substantially better outcomes than treatment in the emergency department (ED) for patients with sickle cell disease (SCD) and uncomplicated vaso-occlusive crises. The findings are published in Annals of Internal Medicine.

Vaso-occlusive events are excruciatingly painful and the leading cause of hospital and ED use in SCD. Although SCD is considered a rare disease in the United States, the burden of ED care and subsequent hospitalization is high. As documented in a systematic review, patients presenting to the ED with severe pain from these events are often faced with structural and interpersonal racism and sub-par care.

Researchers from Johns Hopkins University School of Medicine studied 483 adults with sickle cell disease who lived within 60 miles of an IC in Baltimore, Milwaukee, Cleveland, or Baton Rouge between April 2015 and December 2016 to assess whether care in ICs or EDs would lead to better outcomes. They found that patients treated in an IC received parenteral pain medication an average of 70 minutes faster than those seen in the ED (62 minutes in the IC compared with 132 minutes in the ED). Patients in ICs were 3.8 times more likely to have their pain reassessed within 30 minutes of the first dose and 4 times more likely to be discharged home. These results suggest that ICs are more likely to provide guideline-based care than EDs and that care can improve overall outcomes.

According to the authors, these findings are important because adults with sickle cell disease have been historically underserved by the medical community. Better access to high-quality care should result in better outcomes for both the patient and the medical system.

Media contacts: For an embargoed PDF, please contact Angela Collom at acollom@acponline.org. To speak with the corresponding author, Sophie Lanzkron MD, MHS, please contact Patrick Smith at PJSmith@jhmi.edu.

2. Life expectancy gap closes dramatically between those with HIV and general population
Abstract: https://www.acpjournals.org/doi/10.7326/M21-0065
Editorial: https://www.acpjournals.org/doi/10.7326/M21-2586
URL goes live when the embargo lifts

An observational cohort study finds that mortality among persons entering HIV care decreased dramatically between 1999 and 2017, with the largest decrease seen between 2011 and 2017. Those entering HIV care remained at modestly higher risk for death in the years after starting care than comparable persons in the general U.S. population. The findings are published in Annals of Internal Medicine.

HIV-related mortality has been decreasing since the introduction of effective treatment in 1996 due to improving treatment options and evolving care guidelines, but the extent to which persons entering HIV care in the United States have a higher risk for death over the years after linkage to care than their peers in the general population over the same period remains unclear.

Researchers from the University of North Carolina at Chapel Hill used data from the National Center for Health Statistics to compare 5-year all-cause mortality between 82,766 adults entering HIV clinical care between 1999 and 2017 at 13 U.S. sites participating in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) and a matched subset of the U.S. population. The persons in the general population were matched to those in NA-ACCORD by calendar time, age, sex, race/ethnicity, and county of residence. The researchers found that the difference in mortality between people with HIV and the general population decreased over time, from 11.1% among those entering care between 1999 and 2004 to 2.7% among those entering care from 2011 to 2017. Of note, mortality decreased across all demographic subgroups studied and decreased more among non-Hispanic Black people than non-Hispanic White people.

According to the authors, the decrease in mortality among persons with HIV likely reflects advances in care and treatment, new guidelines indicating earlier treatment, greater engagement in care, higher levels of viral suppression, a trend toward linking persons with HIV to care earlier in the course of infection (that is, at higher CD4 cell counts), and evolving patient characteristics in the cohort over time. They say this study is important because understanding differences in mortality between persons entering HIV care and the matched U.S. population is critical to monitor opportunities to improve care.

Media contacts: For an embargoed PDF, please contact Angela Collom at acollom@acponline.org. The corresponding author, Jessie K. Edwards, PhD, can be reached directly at jkedwar@email.unc.edu.

Also new in this issue:

The importance of clinician-educators
Centor
Annals On Call
Abstract: https://www.acpjournals.org/doi/10.7326/A20-0016

Oncotarget published "Carcinoma cells that have undergone an epithelial-mesenchymal transition differentiate into endothelial cells and contribute to tumor growth" which reported that the authors investigated whether EMT can confer endothelial attributes upon carcinoma cells, augmenting tumor growth and vascularization.

Hypoxic regions, demarcated by HIF-1α staining, exhibited focal areas of E-cadherin loss and elevated levels of vimentin and the EMT-mediator FOXC2. Implantation of MCF-7 cells, co-mixed with human mammary epithelial cells overexpressing the EMT-inducer Snail, markedly potentiated tumor growth and vascularization, compared with MCF-7 cells injected alone or co-mixed with HMLE-vector cells.

Intra-tumoral vessels contained CD31-positive cells derived from either donor cell type.

FOXC2 knockdown abrogated the potentiating effects of HMLE-Snail cells on MCF-7 tumor growth and vascularization, and compromised endothelial transdifferentiation of mesenchymal cells cultured in endothelial growth medium.

Hence, cells that have undergone EMT can promote tumor growth and neovascularization either indirectly, by promoting endothelial transdifferentiation of carcinoma cells, or directly, by acquiring an endothelial phenotype, with FOXC2 playing key roles in these processes.

Cells that have undergone EMT can promote tumor growth and neovascularization either indirectly, by promoting endothelial transdifferentiation of carcinoma cells, or directly, by acquiring an endothelial phenotype, with FOXC2 playing key roles in these processes

Dr. Tapasree Roy Sarkar from The University of Texas MD Anderson Cancer Center as well as The Texas A&M University said, "Angiogenesis is a normal physiological process that entails the development of new blood vessels through remodeling of a pre-existing vasculature, underpinned by endothelial cell sprouting, proliferation, and fusion"

A fourth mechanism—termed vasculogenic mimicry—entails the de novo generation of microvessels, lined with highly invasive tumor cells embedded in a rich extracellular matrix, essentially mimicking a true vascular endothelium and, notably, lacking in the endothelial cell markers CD31 and CD34.

Finally, newly formed blood vessels may emerge through transdifferentiation of neoplastic or tumor stem-like cells into CD31-positive endothelial-like cells, as has been documented in neuroblastoma, B-cell lymphoma, and glioblastoma.

In addition, subcutaneous injection of B16 melanoma cells into Foxc2 haploinsufficient mice has been shown to lead to the impaired formation of tumor blood vessels and, accordingly, compromise tumor growth.

Given the inherent plasticity of cells that have undergone EMT and the involvement of hypoxia in EMT and angiogenesis, the authors sought to ascertain whether cells, undergoing EMT in the hypoxic milieu, can acquire endothelial cell attributes and augment tumor growth by directly contributing to the tumor vasculature.

These findings findings link the stemness, conferred through EMT, to the acquisition of endothelial cell traits and the augmentation of tumor angiogenesis in a FOXC2-dependent manner.

The Sarkar Research Team concluded in their Oncotarget Research Output that their findings are consistent with the notion that the phenotypic attributes of cells within growing tumors are eminently pliable and that, as tumor size and the oxygen deficit increase, carcinoma cells become progressively dedifferentiated towards a mesenchymal, stem-like phenotype.

Indeed, they have previously used mathematical modeling to show that exposure to hypoxia augments the rate of dedifferentiation of non-stem, differentiated epithelial cells resulting in a shift towards a stem-like, plastic phenotype with increased EMT features.

On the basis of the findings herein, we propose that the induction of EMT contributes to tumor neoangiogenesis in two different ways:

Firstly, indirectly, by modifying the tumor niche, through paracrine signaling or alterations in extracellular matrix deposition, to promote the endothelial transdifferentiation of epithelial tumor cells.

Secondly, by generating stem-like cells that can assume endothelial-like phenotypic and functional attributes and directly integrate into the nascent tumor vasculature.

They also report that FOXC2, a common denominator of multiple EMT pathways, plays a vital role in the acquisition of endothelial phenotypic and functional characteristics in vitro and in vivo, with the corollary that inhibition of FOXC2 signaling may compromise tumor neoangiogenesis.

During the large second wave of the COVID-19 pandemic in fall 2020, pulmonologist and critical care provider Juan C. Rojas, MD, reflected on how disproportionately members of minority populations were being affected by the disease. After hearing similar thoughts from colleagues in New Orleans and New York City, Rojas began to wonder how, if at all, state governments planned to ensure these disparities would be addressed when COVID-19 vaccines were rolled out to the public.

In a new study published July 2 in JAMA Network Open, Rojas and his team were surprised to find that while 43 states (out of 51, including all 50 states and Washington, D.C.) created a committee to develop a vaccine distribution plan, only 20 plans mentioned using a health equity committee to assist with plan development. Of those 20 health equity committees, only 8 actually included minority group representatives, with remaining members including physicians, government officials, ethicists and clergy.

"It wasn't surprising to find that there was variability across states, but it was surprising to find that most states didn't have a committee of diverse stakeholders to help address this equity problem," said Rojas, who was senior author on the study. "There weren't many places where patient advocates were included on the committee to add a voice about the additional challenges that might exist for these vulnerable patients."

Additionally, the team found that states used different high-risk criteria and medical conditions to determine which group would get priority vaccine access.

"Some states prioritized people over 65, while others prioritize people over 75," said Rojas. "Diabetes and obesity were the most common high-risk conditions listed in the plans we looked at. But then, sickle cell disease, which is much more common in African-Americans than in other ethnicities, was only listed as a high-risk condition in 72% of plans. But a high-risk condition is high-risk, no matter what state you live in. This shows that we could do better as a country to develop consistent parameters for these kinds of situations."

The researchers analyzed early versions of these plans, and acknowledge that most remained in "draft" status throughout their analysis since each state's task force continued to adjust and update vaccine rollout efforts. In future studies, the team hopes to investigate how those plans translated to outcomes in vaccine distribution.

"Now that we have more vaccine available, how have these states performed?" said Rojas. "We're looking county by county, and state by state, to see if the equity planning done by individual states actually bore out in better vaccination rates for those high-risk patient populations."

Rojas hopes that this work can be used to help inform ongoing COVID-19 vaccination efforts, but more importantly, that it can help guide policies for potential future healthcare crises.

"The important takeaway here is that having a standardized process in which states and the country can use to roll out something as valuable and complicated as a vaccine to our citizens, with an acknowledgement of existing healthcare disparities," he said. "There need to be conversations about equitable distribution, first by acknowledging that these disparities exist, and then by thinking about how we can create policies that will ensure adequate and equitable access to these vaccines."

Fast facts:

Nanobodies have been shown to inhibit the dysfunction of key proteins involved with various diseases such as rheumatoid arthritis, osteoarthritis, psoriasis, B-cell lymphoma, and breast cancer

Understanding the structure of a nanobody helps to better understand its disease-fighting potential

Typically, the protein structure is determined from solid samples. Researchers at NYUAD used a liquid state technique to determine protein structure.

Abu Dhabi, UAE: For the first time in the UAE, researchers at NYU Abu Dhabi have used nuclear magnetic resonance techniques to determine the structure of a specific nanobody, Nb23, potentially leading to a better understanding of how this small protein derived from an antibody type, found only in camelids (i.e camels, llamas, and alpacas) and sharks, can fight diseases ranging from rheumatoid arthritis, lupus and psoriasis to lymphoma and breast cancer.

In a new study, published in the journal Molecules, Visiting Professor of Chemistry Gennaro Esposito, and his collaborators, Mathias Percipalle and Yamanappa Hunashal, at the NYUAD Nuclear Magnetic Resonance (NMR) laboratory detail how they utilized NMR spectroscopy to determine the structure of the Nb23 nanobody in water.

This is unique because scientists typically determine protein structure from solid samples, namely from crystals using X-ray or from frozen solutions using electron microscopy. However, crystals are sometimes difficult to obtain, and, most significantly, proteins work in liquid state where their mobility and sometimes their shape differ from the solid state, especially for small species.

By using the NMR spectroscopy, the researchers can map the factors relevant for nanobody function, recognize the changes that occur when the nanobody binds to its target protein, and prevents, as in the case of Nb23, the formation of abnormal protein aggregation (amyloid) that leads to degenerative or functional diseases.

Researchers are eager to explore the potential of nanobodies over disease-fighting monoclonal antibodies, the laboratory-made proteins that mimic the immune system's ability to fight off harmful antigens such as viruses but are difficult to handle and conserve and often hardly penetrate solid tissues due to their size. Nanobodies, instead, are tenfold smaller in size than antibodies, offer more stability, strong binding affinity, good solubility and biocompatibility because of their natural origin, representing a promising alternative for therapeutic use.

"Our team is studying several nanobodies, including two in particular, Nb23 and Nb24, that bind to a key protein of the immune system called beta2-microglobulin and prevent its pathological transformation into fibrillar deposits such as those involved with degenerative or functional diseases, including Alzheimer's, Parkinson's and type-2 diabetes," said Esposito. "Elucidating the structure of Nb23 and other important nanobodies is a critical step in improving our understanding of how they can bind to target proteins and help prevent the onset of these diseases."

What The Study Did: Researchers in this study aimed to determine how each state and the District of Columbia planned to ensure equitable COVID-19 vaccine distribution.

Authors: Juan C. Rojas, M.D., of the University of Chicago, 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/jamanetworkopen.2021.15653)

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 in the use of women's preventive health services during the COVID-19 pandemic, including screening for sexually transmitted infections, breast and cervical cancer, and obtaining contraceptives from pharmacies are described by researchers in this study.

Authors: Nora V. Becker, M.D., Ph.D., of the University of Michigan Medical School in Ann Arbor, 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/jamahealthforum.2021.1408)

Editor's Note: The article includes conflict of interest 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: This study investigates whether different risk factors identify the same hospitals caring for a high proportion of disadvantaged patients using seven definitions of social risk.

Authors: Susannah M. Bernheim, M.D., M.H.S., of the Yale University School of Medicine in New Haven, Connecticut, 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/jamahealthforum.2021.1323)

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.

Lugano, Switzerland, 2 July 2021 - Obese patients with colorectal cancer receive lower cumulative doses of adjuvant chemotherapy, relative to their body surface area (BSA), than non-obese patients, show results from a large meta-analysis reported at the ESMO World Congress on Gastrointestinal Cancer 2021 (1). Further findings showed that cumulative relative chemotherapy dose was associated with survival so may explain the poorer survival that has been seen in obese patients receiving adjuvant chemotherapy for colorectal cancer. (2)

"Adjuvant chemotherapy is dosed according to a person's body surface area, which is calculated from their height and weight. But in obese patients (with a high body mass index (BMI), and who are more likely to have high BSAs), doses are often capped, or based on an idealised weight, because of concern that large doses might increase side-effects. This means that obese patients may receive proportionately lower doses of chemotherapy" reported lead author Corinna Slawinski, from the Division of Cancer Sciences, University of Manchester, UK.

"Our study has demonstrated an association between increasing body mass index and modest reductions in the cumulative relative dose of adjuvant chemotherapy in patients with colorectal cancer. And we also saw an association between increased cumulative relative dose and improved survival," she said. "This supports the recently published ASCO guidance that full, weight-based chemotherapy doses should be used to treat obese adult patients" (3)

Commenting on the findings, Elizabeth Smyth, Addenbrooke's Hospital in Cambridge, UK, member of the ESMO Faculty for Gastrointestinal tumours, said: "Dose reductions for high BMI may be associated with lower cure rates in resected colon cancer treated with adjuvant chemotherapy." She added: "Adjuvant chemotherapy has the potential to cure patients with residual micrometastatic disease following curative surgery, so it is important that we maximise the benefits for all patients."

A number of previous studies have shown that obese patients with colorectal cancer have worse outcomes than non-obese patients. But limitations with these studies made it difficult to draw conclusions as to whether having a higher body mass index was directly associated with survival or if the association was due to other factors such as treatment (i.e. dose administered).

"One important factor is how chemotherapy doses are calculated for individual patients. We carried out our study to better understand the relationship between BMI, chemotherapy dosing and survival in colorectal cancer," explained Slawinski.

The OCTOPUS study analysed data for 7269 patients receiving adjuvant chemotherapy after curative surgery for colon and/or rectal cancer in four large, randomised trials. The researchers examined the relationship between BMI and chemotherapy dosing and the relationship between chemotherapy dosing and survival.

"We looked at two ways of measuring how much chemotherapy had been received as a proportion of actual-to-expected standard doses: average cumulative relative dose (ACRD) and average relative dose intensity (ARDI)." ACRD is the proportion of the total expected standard dose (per unit of body surface area) over the whole chemotherapy course that has actually been received. ARDI however, also takes into account the duration of treatment, and is the proportion of the expected standard dose intensity (the total dose per unit of BSA, divided by the number of weeks of treatment) that has actually been received. With both measures averaged over the number of drugs in the regimen, and expressed as a percentage.

Results showed that 5% increments in ACRD were significantly associated with improvements in disease-free survival (hazard ratio 0.953, 95% confidence interval 0926, 0.980, p=0.001). Overall survival was also associated with ACRD. However, there was no significant association with ARDI. Slawinski suggested that the lack of association between survival and ARDI may be because ARDI is a less sensitive measure of reductions in total (cumulative) dose of chemotherapy.

Further findings showed that each BMI increase of 5kg/m2 was associated with a 2% reduction in the relative dose of chemotherapy in the first cycle of chemotherapy and 1% reductions in both ACRD and ARDI. This means an obese patient with a BMI of 37.5kg/m2 would have a 3% reduction of ACRD and ARDI compared to a non-obese patient with a BMI of 22.5kg/m2.

"These results showed that elevated BMI is associated with a reduced relative dose of chemotherapy in the first treatment cycle and a modest reduction in ACRD. These indirect effects through sub-optimal treatment might explain poorer survival in obese patients, rather than direct effects of obesity resulting from, for example, tumour biology," concluded Slawinski. "Our results so far support giving obese patients a full dose of chemotherapy based on their body weight. But we are still exploring toxicity data, examining the relationship between BMI, dose capping, toxicity and survival," she cautioned. "Toxicity has the potential to reduce quality of life and can be life threatening. And there may also be other reasons for reducing chemotherapy doses, such as comorbidities, so it is important that dosing and treatment decisions are individualised to the patient."

Smyth agreed: "The main message from this study is that we should consider whether dose reductions are necessary in patients with a high BMI when treating them with adjuvant chemotherapy." But she added: "Dosing chemotherapy is complex and includes not only weight but fitness, co-morbidities including renal function and dihydropyrimidine dehydrogenase (DPD) testing results."

Smyth considered that more studies are needed before changing practice. "Prospective studies examining the impact of higher doses of chemotherapy may be needed, especially as there is an increase in the proportion of patients diagnosed with cancer and who are obese." For now, she concluded: "We should take all aspects of the patient into account when making chemotherapy dosing decisions. Dose reductions do seem to be associated with less good survival in this study, but these may still be required for safety."