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Cerebral cavernous malformation (CCM) is a hemorrhagic neurovascular disease with no currently available therapeutics. Prior evidence suggests that different cell types may play a role in CCM pathogenesis. The contribution of each cell type to the dysfunctional cellular crosstalk remains unclear. Herein, RNA-seq was performed on fluorescence-activated cell sorted endothelial cells (ECs), pericytes, and neuroglia from CCM lesions and non-lesional brain tissue controls. Differentially Expressed Gene (DEG), pathway and Ligand-Receptor (LR) analyses were performed to characterize the dysfunctional genes of respective cell types within CCMs. Common DEGs among all three cell types were related to inflammation and endothelial-to-mesenchymal transition (EndMT). DEG and pathway analyses supported a role of lesional ECs in dysregulated angiogenesis and increased permeability. VEGFA was particularly upregulated in pericytes. Further pathway and LR analyses identified vascular endothelial growth factor A/ vascular endothelial growth factor receptor 2 signaling in lesional ECs and pericytes that would result in increased angiogenesis. Moreover, lesional pericytes and neuroglia predominantly showed DEGs and pathways mediating the immune response. Further analyses of cell specific gene alterations in CCM endorsed potential contribution to EndMT, coagulation, and a hypoxic microenvironment. Taken together, these findings motivate mechanistic hypotheses regarding non-endothelial contributions to lesion pathobiology and may lead to novel therapeutic targets. Ddgp6MUP9uoWsxMj-KUiCy Video Abstract

Introduction Despite trauma accounting 9% of global mortality, it has been demonstrated that undergraduate trauma teaching is inadequate nationally and worldwide. With COVID-19 exacerbating this situation, a scalable, accessible, and cost-effective undergraduate trauma teaching is required. Methods Our Continual Professional Development United Kingdom (CPUDK)-accredited University Hospitals Birmingham (UHB) Major Trauma Service (MTS) affiliated programme consisted of seven biweekly pre-recorded sessions that were delivered online through the Moodle educational platform to University of Birmingham students. Pre- and post-randomised session-specific multiple-choice questions (MCQs) and anonymous feedback forms were administered. Results There were 489 student responses, with 63 students completing all seven sessions. On an 8-point scale, students’ objective knowledge scores increased by a mean of 1.2 ( p  < 0.001). Using a 5-point Likert scale, students also showed improvement in subjective outcomes including their confidence in assessing trauma patient (absolute difference (AD) 1.38, p  < 0.001), advising initial investigations and formulating initial management plans (AD 1.78, p  < 0.001) and thereby their confidence to manage a trauma patient overall (AD 1.98, p  < 0.001). A total of 410 student responses endorsed the online delivery of SATMAS through Moodle and recommended SATMAS to future medical students. Conclusion SATMAS has demonstrated positive student feedback and extensive recruitment from only one centre, demonstrating that our programme can be an indispensable low-cost learning resource that prepares undergraduate medical students for their trauma exams and informs the implementation of clinical skills required by all doctors. We publish our pilot study findings to encourage similar teaching programmes to be adopted at other universities nationally and internationally, to synergistically benefit students, tutors, and ultimately patients, on a larger scale.

Despite the shift towards consultant-led care, many patients with trauma are still seen by junior doctors. Previous research has demonstrated that junior doctors feel unprepared to work in acute care but there is a paucity of recent research in trauma specifically. Thus, a national study is required to investigate the current state of undergraduate trauma teaching and identify specific areas for improvement. Between August and September 2020, a 35-item structured questionnaire was distributed among doctors who graduated from UK medical schools within the last 4 years. The questionnaire retrospectively assessed their experience of trauma teaching at medical school and their confidence to diagnose and manage patients with trauma. 398 responses were recorded from graduates of 39 UK medical schools. With 79.6% reporting only 0-5 hours of bedside trauma teaching and 51.8% reporting less than 20 hours in Accident and Emergency, graduates reported that trauma teaching was deficient compared with other specialties (78.1%). The majority of graduates were not confident in the initial assessment (72.9%) of a patient with trauma and almost all felt that a short course in trauma would be useful (93.7%). 77.4% of students felt that online learning would be beneficial and 92.9% felt that simulation would be useful. There is lack of standardised undergraduate trauma teaching nationally; a formal undergraduate teaching to ensure that new graduates are competent in the management of trauma would be supported by students. It is likely that a blended learning approach, incorporating e-learning with traditional teaching and clinical experience would be well received.

Antarctic terrestrial biodiversity occurs almost exclusively in ice-free areas that cover less than 1% of the continent. Climate change will alter the extent and configuration of ice-free areas, yet the distribution and severity of these effects remain unclear. Here we quantify the impact of twenty-first century climate change on ice-free areas under two Intergovernmental Panel on Climate Change (IPCC) climate forcing scenarios using temperature-index melt modelling. Under the strongest forcing scenario, ice-free areas could expand by over 17,000 km 2 by the end of the century, close to a 25% increase. Most of this expansion will occur in the Antarctic Peninsula, where a threefold increase in ice-free area could drastically change the availability and connectivity of biodiversity habitat. Isolated ice-free areas will coalesce, and while the effects on biodiversity are uncertain, we hypothesize that they could eventually lead to increasing regional-scale biotic homogenization, the extinction of less-competitive species and the spread of invasive species. Permanently ice-free areas, home to almost all of Antarctica’s biodiversity, are projected, in the worst case, to expand by over 17,000 km 2 as a result of climate change by the end of this century, with potentially deleterious consequences for the continent’s biodiversity. Ice loss threatens biodiversity hotspots Permanently ice-free areas are home to almost all of Antarctica's biodiversity. Jasmine Lee and colleagues model the potential effect of climate change on the extent of ice-free areas in Antarctica over the coming century, under moderate and severe forcing scenarios. Ice-free areas are projected to expand by over 17,000 km 2 under the strongest forcing scenario. The greatest change can be expected in the Antarctic Peninsula, where a threefold increase in ice-free area is projected. The authors suggest that the expansion and eventual merging of ice-free areas could have harmful consequences for the biodiversity of the continent by facilitating the homogenization of biodiversity across regions.

Brain metastases (BMs) are an emerging challenge in oncology due to increasing incidence and limited treatments. Here, we present results of a single-arm, open-label, phase 2 trial evaluating intracranial efficacy of pembrolizumab, a programmed cell death protein 1 inhibitor, in 9 patients with untreated BMs (cohort A) and 48 patients with recurrent and progressive BMs (cohort B) across different histologies. The primary endpoint was the proportion of patients achieving intracranial benefit, defined by complete response, partial response or stable disease. The primary endpoint was met with an intracranial benefit rate of 42.1% (90% confidence interval (CI): 31–54%). The median overall survival, a secondary endpoint, was 8.0 months (90% CI: 5.5–8.7 months) across both cohorts, 6.5 months (90% CI: 4.5–18.7 months) for cohort A and 8.1 months (90% CI: 5.3–9.6 months) for cohort B. Seven patients (12.3%), encompassing breast, melanoma and sarcoma histologies, had overall survival greater than 2 years. Thirty patients (52%; 90% CI: 41–64%) had one or more grade-3 or higher adverse events that were at least possibly treatment related. Two patients had grade-4 adverse events (cerebral edema) that were deemed at least possibly treatment related. These results suggest that programmed cell death protein 1 blockade may benefit a select group of patients with BMs, and support further studies to identify biomarkers and mechanisms of resistance. ClinicalTrials.gov identifier: NCT02886585 In a phase 2 trial of patients with untreated, recurrent and progressive brain metastases treated with an anti-programmed cell death protein 1 inhibitor, the overall intracranial benefit rate was 42.1%, which met the prespecified primary endpoint.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in December 2019 in Wuhan city, Hubei province, China. This is the third and largest coronavirus outbreak since the new millennium after SARS in 2002 and Middle East respiratory syndrome (MERS) in 2012. Over 3 million people have been infected and the COVID-19 has caused more than 217 000 deaths. A concern exists regarding the vulnerability of patients who have been treated with immunosuppressive drugs prior or during this pandemic. Would they be more susceptible to infection by the SARS-CoV-2 and how would their clinical course be altered by their immunosuppressed state? This is a question the wider medical fraternity—including ophthalmologists, rheumatologists, gastroenterologist and transplant physicians among others—must answer. The evidence from the SARS and MERS outbreak offer some degree of confidence that immunosuppression is largely safe in the current COVID-19 pandemic. Preliminary clinical experiences based on case reports, small series and observational studies show the morbidity and mortality rates in immunosuppressed patients may not differ largely from the general population. Overwhelmingly, current best practice guidelines worldwide recommended the continuation of immunosuppression treatment in patients who require them except for perhaps high-dose corticosteroid therapy and in patients with associated risk factors for severe COVID-19 disease.

Background Pleural malignant mesothelioma (MM) is a deadly tumour predominantly associated with asbestos exposure. A reliable diagnostic and prognostic marker for MM will significantly enhance clinical care and is an area of intense research. Soluble mesothelin is the most studied and an FDA-approved biomarker for MM. A recent report showed promising results using fibulin-3 as a new diagnostic marker. The aim of this study was to compare the utility of fibulin-3 versus mesothelin, singly or in combination. Methods Fibulin-3 and soluble mesothelin were determined by ELISA in the plasma and pleural fluid of 153 patients presenting with a pleural effusion including 82 with MM, 36 with non-MM malignant effusions and 35 with benign effusions. Biomarker concentrations were determined in the plasma of an additional 49 cases with benign asbestos-related disease. Results Mesothelin provides better diagnostic accuracy than fibulin-3 for MM whether measured in plasma or pleural effusion: area under the curve (AUC) for plasma was 0.822 (95% CI 0.76 to 0.87) compared with 0.671 (0.61 to 0.73), respectively, and for pleural fluid AUC was 0.815 (0.74 to 0.87) compared with 0.588 (0.51 to 0.67), respectively. Effusion fibulin-3 was an independent significant prognostic factor for survival in MM patients; HR 2.08 (1.14 to 3.82), p=0.017. MM patients with effusion fibulin-3 levels below the median survived significantly longer than those with levels above the median (14.1 vs 7.9 months, p=0.012). Mesothelin and neutrophil to lymphocyte ratio were not significant prognostic markers. Conclusions Soluble mesothelin is a superior diagnostic biomarker for MM compared with fibulin-3, whereas fibulin-3 provides superior prognostic information compared with mesothelin.

We have investigated the potential of the GTP synthesis pathways as chemotherapeutic targets in the human pathogen Cryptococcus neoformans, a common cause of fatal fungal meningoencephalitis. We find that de novo GTP biosynthesis, but not the alternate salvage pathway, is critical to cryptococcal dissemination and survival in vivo. Loss of inosine monophosphate dehydrogenase (IMPDH) in the de novo pathway results in slow growth and virulence factor defects, while loss of the cognate phosphoribosyltransferase in the salvage pathway yielded no phenotypes. Further, the Cryptococcus species complex displays variable sensitivity to the IMPDH inhibitor mycophenolic acid, and we uncover a rare drug-resistant subtype of C. gattii that suggests an adaptive response to microbial IMPDH inhibitors in its environmental niche. We report the structural and functional characterization of IMPDH from Cryptococcus, revealing insights into the basis for drug resistance and suggesting strategies for the development of fungal-specific inhibitors. The crystal structure reveals the position of the IMPDH moveable flap and catalytic arginine in the open conformation for the first time, plus unique, exploitable differences in the highly conserved active site. Treatment with mycophenolic acid led to significantly increased survival times in a nematode model, validating de novo GTP biosynthesis as an antifungal target in Cryptococcus.

Background We designed a survey to evaluate preferences of facial appearance in transgender male (TM), transgender female (TF) and gender nonbinary patients to better inform goals of facial gender affirming surgery (FGAS) in gender nonbinary patients. Methods TM/TF and nonbinary patients > 18 years old were identified via retrospective chart review and distributed an anonymized survey via email from October 3 to December 31, 2022. To assess facial preferences, AI-generated and open-source portraits were edited to create five image sets with a range of features from masculine to feminine for the forehead, mandible/chin and hairline. Data were analyzed using Fisher’s exact tests and ANOVA in R-Studio. Results Survey response rate was 32% (180 patients identified via chart review, 58 respondents; TM = 5, TF = 39, nonbinary = 14). TM and TF patients as well as TF and nonbinary patients had significantly different preferences for all regions ( p  < 0.005; all series), while TM and nonbinary patients did not ( p => 0.05; all series). TF patients consistently selected 4s with neutral or more feminine features. TM and nonbinary patients, however, demonstrated no consistent preference for either male or female features but rather a range of responses spanning extremes of both masculine and feminine options. When stratified by sex assigned at birth, nonbinary patients consistently identified preferences opposite to their assigned gender. Conclusion Gender nonbinary and TM patients appear to have uniquely individual preferences regarding facial appearance that do not fit into classically masculine or feminine patterns/phenotypes. As a result, we recommend individualized preoperative planning for FGAS to achieve the optimal result in these patient populations. Level of Evidence IV This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Mutations in nucleotide-binding oligomerization domain-containing protein 2 (NOD2) cause Blau syndrome, an inflammatory disorder characterized by uveitis. The antimicrobial functions of Nod2 are well-established, yet the cellular mechanisms by which dysregulated Nod2 causes uveitis remain unknown. Here, we report a non-conventional, T cell-intrinsic function for Nod2 in suppression of Th17 immunity and experimental uveitis. Reconstitution of lymphopenic hosts with Nod2 −/− CD4 + T cells or retina-specific autoreactive CD4 + T cells lacking Nod2 reveals a T cell-autonomous, Rip2-independent mechanism for Nod2 in uveitis. In naive animals, Nod2 operates downstream of TCR ligation to suppress activation of memory CD4 + T cells that associate with an autoreactive-like profile involving IL-17 and Ccr7. Interestingly, CD4 + T cells from two Blau syndrome patients show elevated IL-17 and increased CCR7. Our data define Nod2 as a T cell-intrinsic rheostat of Th17 immunity, and open new avenues for T cell-based therapies for Nod2-associated disorders such as Blau syndrome. How mutations in the microbial receptor NOD2 induce Blau syndrome in humans and related uveitis is unclear. Here the authors show, using Nod2-deficient mice and experimental uveitis, that Nod2 negatively regulates T cell activation and transcription of autoimmunity-related genes to suppress Th17 responses and uveitis.