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Abstract The structure and design flexibility of aerogels make them promising for soft tissue engineering, though they tend to come with brittleness and low elasticity. While increasing crosslinking density may improve mechanics, it also imparts brittleness. In soft tissue engineering, resilience against mechanical loads from mobile tissues is paramount. We report a hybrid aerogel that consists of self-reinforcing networks of micro- and nanofibers. Nanofiber segments physically entangle microfiber pillars, allowing efficient stress distribution through the intertwined fiber networks. We show that optimized hybrid aerogels have high specific tensile moduli (~1961.3 MPa cm3 g−1) and fracture energies (~7448.8 J m−2), while exhibiting super-elastic properties with rapid shape recovery (~1.8 s). We demonstrate that these aerogels induce rapid tissue ingrowth, extracellular matrix deposition, and neovascularization after subcutaneous implants in rats. Furthermore, we can apply them for engineering soft tissues via minimally invasive procedures, and hybrid aerogels can extend their versatility to become magnetically responsive or electrically conductive, enabling pressure sensing and actuation.

The lateral parafacial area (pFL) is a crucial region involved in respiratory control, particularly in generating active expiration through an expiratory oscillatory network. Active expiration involves rhythmic abdominal (ABD) muscle contractions during late-expiration, increasing ventilation during elevated respiratory demands. The precise anatomical location of the expiratory oscillator within the ventral medulla’s rostro-caudal axis is debated. While some studies point to the caudal tip of the facial nucleus (VIIc) as the oscillator’s core, others suggest more rostral areas. Our study employed bicuculline (a γ-aminobutyric acid type A [GABA-A] receptor antagonist) injections at various pFL sites (–0.2 mm to +0.8 mm from VIIc) to investigate the impact of GABAergic disinhibition on respiration. These injections consistently elicited ABD recruitment, but the response strength varied along the rostro-caudal zone. Remarkably, the most robust and enduring changes in tidal volume, minute ventilation, and combined respiratory responses occurred at more rostral pFL locations (+0.6/+0.8 mm from VIIc). Multivariate analysis of the respiratory cycle further differentiated between locations, revealing the core site for active expiration generation with this experimental approach. Our study advances our understanding of neural mechanisms governing active expiration and emphasizes the significance of investigating the rostral pFL region.

Purpose: Standardization of x-ray cabinet irradiator dose, geometry, and calibration reporting is an ongoing process. Multi-tube designs have been introduced into the preclinical market and give a theoretical benefit but have not been widely assessed for use in preclinical irradiation conditions. The aim of this study was to report our experience commissioning a dual x-ray source cabinet irradiator (CIXD, Xstrahl Limited, United Kingdom) and assess the dose distribution for various experimental conditions. Methods and Materials: Half-value layer (HVL) measurement, profile measurements, and output calibration were performed using a calibrated ion chamber. Constancy measurements were performed twice daily over 2 weeks to assess output fluctuations. Film measurements were completed using solid water to assess percent depth dose and homogeneity within the field and within variable thicknesses of solid water and phosphate-buffered saline solution. Film measurements were repeated for various arrangements of petri dishes filled with phosphate-buffered saline or water and in a 3D-printed mouse phantom. Results: The x-ray tubes had a measured in-air output of 1.27 Gy/min. The HVL was 1.7 mm Cu. The upper and lower tubes both exhibited the heel effect, but when operated simultaneously, the effect was reduced. Ion chamber measurements revealed a 15% dose inhomogeneity within the tray area (18 × 18 cm2). Film measurements in the petri dishes indicated minor nonuniformities in the arrangements of the experimental apparatus. Measurements from the mouse phantom with film agreed with ion chamber measurements for various phantom placements and orientations. Conclusions: X-ray cell culture and animal irradiation with dual tube cabinet irradiation is efficient and robust when using established dosimetric tools to confirm output and homogeneity. The conditions assumed for calibrations are often not maintained during experiments. We have confirmed that inhomogeneities are present for single-tube use; however, they are reduced with simultaneous tube use. Additional dosimetric monitoring should be performed for each unique irradiation setup.

Retrocaval ureter is a rare congenital anomaly with few reported cases worldwide. In this case report, we describe a clinical presentation that demonstrates the stereotypical imaging features of a retrocaval ureter on ultrasound, computed tomography and nuclear imaging studies in a 38-year-old male patient who fits the classic reported patient demographics.

Abstract Cancer-associated immune dysfunction is a major challenge for effective therapies. The emergence of antibodies targeting tumor cell-surface antigens led to advancements in the treatment of hematopoietic malignancies, particularly blood cancers. Yet their impact is constrained against tumors of hematopoietic origin manifesting in the skin. In this study, we employ a clonality-supervised deep learning methodology to dissect key pathological features implicated in mycosis fungoides, the most common cutaneous T-cell lymphoma. Our investigations unveil the prominence of the IL-32β–major histocompatibility complex (MHC)-I axis as a critical determinant in tumor T-cell immune evasion within the skin microenvironment. In patients’ skin, we find MHC-I to detrimentally impact the functionality of natural killer (NK) cells, diminishing antibody-dependent cellular cytotoxicity and promoting resistance of tumor skin T-cells to cell-surface targeting therapies. Through murine experiments in female mice, we demonstrate that disruption of the MHC-I interaction with NK cell inhibitory Ly49 receptors restores NK cell anti-tumor activity and targeted T-cell lymphoma elimination in vivo. These findings underscore the significance of attenuating the MHC-I-dependent immunosuppressive networks within skin tumors. Overall, our study introduces a strategy to reinvigorate NK cell-mediated anti-tumor responses to overcome treatment resistance to existing cell-surface targeted therapies for skin lymphoma.

Abstract Carbons form critical components in biogas purification and energy storage systems and are used to modify polymer matrices. The environmental impact of producing carbons has driven research interest in biomass‐derived carbons, although these have yield, processing, and resource competition limitations. Naturally formed fungal filaments are investigated, which are abundantly available as food‐ and biotechnology‐industry by‐products and wastes as cost‐effective and sustainable templates for carbon networks. Pyrolyzed Agaricus bisporus and Pleurotus eryngii filament networks are mesoporous and microscale with a size regime close to carbon fibers. Their BET surface areas of ≈282 m2 g−1 and ≈60 m2 g−1, respectively, greatly exceed values associated with carbon fibers and non‐activated pyrolyzed bacterial cellulose and approximately on par with values for carbon black and CNTs in addition to pyrolyzed pinewood, rice husk, corn stover or olive mill waste. They also exhibit greater specific capacitance than both non‐activated and activated pyrolyzed bacterial cellulose in addition to YP‐50F (coconut shell based) commercial carbons. The high surface area and specific capacitance of fungal carbon coupled with the potential to tune these properties through species‐ and growth‐environment‐associated differences in network and filament morphology and inclusion of inorganic material through biomineralization makes them potentially useful in creating supercapacitors.

This study examines the unique challenges and transformations in higher education instruction during the COVID-19 pandemic, focusing on a strategic response from one chemistry department. The COVID-19 pandemic created many obstacles to providing quality instruction. To support chemistry instructors during the challenging transition to remote teaching, the leadership within one chemistry department created an initiative to ease feelings of isolation and support instructors in undergraduate teaching. Within this manuscript, we triangulate recordings of instructors’ discussions about remote teaching, course syllabi, and open-ended surveys to understand the teaching experiences of the instructors within this department during the COVID-19 pandemic. Our findings expose various points of tension instructors faced and demonstrate how the pandemic and the departmental initiative changed instructors’ teaching values. Despite the unfortunate context of the pandemic, these data reveal how this department-wide initiative has impacted the instructors and the department’s climate around teaching, which underscores the importance of collaborative efforts in navigating unprecedented educational challenges.

Introduction: Hypertension affects approximately 50 % of patients with hypertrophic cardiomyopathy (HCM) but clinical course in adults with co-occurring HCM and hypertension is underexplored. Management may be challenging as routine anti-hypertensive medications may worsen obstructive HCM, the most common HCM phenotype. In this scoping review, we sought to synthesize the available literature related to clinical course and outcomes in adults with both conditions and to highlight knowledge gaps to inform future research directions. Methods: We searched 5 electronic databases (PubMed, CINAHL, Scopus, Embase, Web of Science) to identify peer-reviewed articles, 2011–2023. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses-Scoping Review (PRISMA-ScR) guideline. Results: Eleven articles met eligibility. Adults with both conditions were older and had higher rates of obesity and diabetes than adults with HCM alone. Results related to functional class and arrhythmia were equivocal in cross-sectional studies. Only 1 article investigated changes in medical therapy among adults with both conditions. Hypertension was a predictor of worse functional class, but was not associated with all-cause mortality, heart failure-related mortality, or sudden-death. No data was found that related to common hypertension-related outcomes, including renal disease progression, nor patient-reported outcomes, including quality of life. Conclusions: Our results highlight areas for future research to improve understanding of co-occurring HCM and hypertension. These include a need for tailored approaches to medical management to optimize outcomes, evaluation of symptom burden and quality of life, and investigation of hypertension-related outcomes, like renal disease and ischemic stroke, to inform cardiovascular risk mitigation strategies.

Abstract Melanoma provides a primary benchmark for targeted drug therapy. Most melanomas with BRAFV600 mutations regress in response to BRAF/MEK inhibitors (BRAFi/MEKi). However, nearly all relapse within the first two years, and there is a connection between BRAFi/MEKi-resistance and poor response to immune checkpoint therapy. We reported that androgen receptor (AR) activity is required for melanoma cell proliferation and tumorigenesis. We show here that AR expression is markedly increased in BRAFi-resistant melanoma cells, and in sensitive cells soon after BRAFi exposure. Increased AR expression is sufficient to render melanoma cells BRAFi-resistant, eliciting transcriptional changes of BRAFi-resistant subpopulations, including elevated EGFR and SERPINE1 expression, of likely clinical significance. Inhibition of AR expression or activity blunts changes in gene expression and suppresses proliferation and tumorigenesis of BRAFi-resistant melanoma cells, promoting clusters of CD8+ T cells infiltration and cancer cells killing. Our findings point to targeting AR as possible co-therapeutical approach in melanoma treatment.

Abstract Multi-omics profiling by CITE-seq bridges the RNA-protein gap in single-cell analysis but has been largely applied to liquid biopsies. Applying CITE-seq to clinically relevant solid biopsies to characterize healthy tissue and the tumor microenvironment is an essential next step in single-cell translational studies. In this study, gating of cell populations based on their transcriptome signatures for use in cell type-specific ridge plots allowed identification of positive antibody signals and setting of manual thresholds. Next, we compare five skin dissociation protocols by taking into account dissociation efficiency, captured cell type heterogeneity and recovered surface proteome. To assess the effect of enzymatic digestion on transcriptome and epitope expression in immune cell populations, we analyze peripheral blood mononuclear cells (PBMCs) with and without dissociation. To further assess the RNA-protein gap, RNA-protein we perform codetection and correlation analyses on thresholded protein values. Finally, in a proof-of-concept study, using protein abundance analysis on selected surface markers in a cohort of healthy skin, primary, and metastatic melanoma we identify CD56 surface marker expression on metastatic melanoma cells, which was further confirmed by multiplex immunohistochemistry. This work provides practical guidelines for processing and analysis of clinically relevant solid tissue biopsies for biomarker discovery.

Electronic health records (EHR) data provides the researcher and physician with the opportunity to improve risk prediction by employing newer, more sophisticated modeling techniques. Rather than treating the impact of predictor variables on health trajectories as static, we explore the use of time-dependent variables in dynamically modeling time-to-event data through the use of landmarking (LM) data sets. We compare several different dynamic models presented in the literature that utilize LM data sets as the basis of their approach. These techniques include using pseudo-means, pseudo-survival probabilities, and the traditional Cox model. The models are primarily compared with their static counterparts using appropriate measures of model discrimination and calibration based on what summary measure is employed for the response variable.

BackgroundAn elevated shock index (SI) predicts worse outcomes in multiple clinical arenas. We aimed to determine whether the SI can aid in mortality risk stratification in unselected cardiac intensive care unit patients.MethodsWe included admissions to the Mayo Clinic from 2007 to 2015 and stratified them based on admission SI. The primary outcome was in-hospital mortality, and predictors of in-hospital mortality were analyzed using multivariable logistic regression.ResultsWe included 9,939 unique cardiac intensive care unit patients with available data for SI. Patients were grouped by SI as follows: < 0.6, 3,973 (40%); 0.6-0.99, 4,810 (48%); and ≥ 1.0, 1,156 (12%). After multivariable adjustment, both heart rate (adjusted OR 1.06 per 10 beats per minute higher; CI 1.02-1.10; p-value 0.005) and systolic blood pressure (adjusted OR 0.94 per 10 mmHg higher; CI 0.90-0.97; p-value < 0.001) remained associated with higher in-hospital mortality. As SI increased there was an incremental increase in in-hospital mortality (adjusted OR 1.07 per 0.1 beats per minute/mmHg higher, CI 1.04-1.10, p-Value < 0.001). A higher SI was associated with increased mortality across all examined admission diagnoses.ConclusionThe SI is a simple and universally available bedside marker that can be used at the time of admission to predict in-hospital mortality in cardiac intensive care unit patients.

Many political party strategists draw on Big Data to target specific groups of voters. This predominantly quantitative approach is useful for mobilising support, yet there are alternatives that help bring these voter segments to life. Pioneered in Australia (1996) and perfected in Canada (2006 to 2008), the use of personas in political marketing and communications holds several notable advantages. By personifying the segments – using names like “Phil and Jenny” or “Dougie” – strategists foster both internal cohesion and external consistency around their messaging. The technique is also useful for policy development. Grounded in an extensive review of campaigns and in-depth interviews, this article analyses the use of personas by the Conservative Party of Canada, pointing to the strengths and shortcomings of the approach.

Abstract Metastatic uveal melanomas are highly resistant to all existing treatments. To address this critical issue, we performed a kinome‐wide CRISPR‐Cas9 knockout screen, which revealed the LKB1‐SIK2 module in restraining uveal melanoma tumorigenesis. Functionally, LKB1 loss enhances proliferation and survival through SIK2 inhibition and upregulation of the sodium/calcium (Na+/Ca2+) exchanger SLC8A1. This signaling cascade promotes increased levels of intracellular calcium and mitochondrial reactive oxygen species, two hallmarks of cancer. We further demonstrate that combination of an SLC8A1 inhibitor and a mitochondria‐targeted antioxidant promotes enhanced cell death efficacy in LKB1‐ and SIK2‐negative uveal melanoma cells compared to control cells. Our study also identified an LKB1‐loss gene signature for the survival prognostic of patients with uveal melanoma that may be also predictive of response to the therapy combination. Our data thus identify not only metabolic vulnerabilities but also new prognostic markers, thereby providing a therapeutic strategy for particular subtypes of metastatic uveal melanoma.

Abstract Immune checkpoint blockade therapy is beneficial and even curative for some cancer patients. However, the majority don’t respond to immune therapy. Across different tumor types, pre-existing T cell infiltrates predict response to checkpoint-based immunotherapy. Based on in vitro pharmacological studies, mouse models and analyses of human melanoma patients, we show that the cytokine GDF-15 impairs LFA-1/β2-integrin-mediated adhesion of T cells to activated endothelial cells, which is a pre-requisite of T cell extravasation. In melanoma patients, GDF-15 serum levels strongly correlate with failure of PD-1-based immune checkpoint blockade therapy. Neutralization of GDF-15 improves both T cell trafficking and therapy efficiency in murine tumor models. Thus GDF-15, beside its known role in cancer-related anorexia and cachexia, emerges as a regulator of T cell extravasation into the tumor microenvironment, which provides an even stronger rationale for therapeutic anti-GDF-15 antibody development.

Background: Immune checkpoint inhibitors (ICIs) and BRAF/MEK inhibitors (BRAF/MEKi) have drastically changed the outcomes of advanced melanoma patients in both the resectable/adjuvant and unresectable/metastatic setting. In this follow-up analysis of real-world data, we aimed to investigate the clinical management and outcomes of advanced melanoma patients in a tertiary referral center in Switzerland approximately a decade after the introduction of ICIs and BRAF/MEKi into clinical use. Moreover, we aimed to compare the results with seminal phase 3 trials and to identify areas of high unmet clinical need. Methods: This single-center retrospective cohort study analyzed the melanoma registry of the University Hospital Zurich, a tertiary cancer center in Switzerland, and included patients treated in the resectable/adjuvant (n = 331) or unresectable/metastatic setting (n = 375). Results: In the resectable setting, adjuvant anti-PD1 or BRAF/MEKi showed a 3-year relapse-free survival (RFS) of 53% and 67.6%, respectively, and the overall median RFS was 50 months. Patients with lymph node plus in-transit metastases or with distant metastases prior to commencing adjuvant treatment had a significantly reduced overall survival (OS). In 10.9% of patients, the treatment was stopped due to toxicity, which did not affect RFS/OS, unless the duration of the treatment was p = 0.018). In the unresectable setting, first-line anti-PD1, anti-CTLA4/PD1 combination, or BRAF/MEKi showed a 5-year OS of 46.5%, 52.4%, and 49.2%, respectively. In a multivariate analysis, elevated LDH levels or the presence of brain metastases substantially shortened OS (HR > 1.78, p < 0.035). There was a non-significant trend for the improved survival of patients treated with anti-CTLA4/PD1 compared to anti-PD1 (HR 0.64, p = 0.15). After a progression on first-line therapy, the median OS2 was reduced to below two years. Elevated LDH (HR 4.65, p < 0.001) levels and widespread disease with at least three metastatic sites, particularly bone metastases (HR 2.62, p = 0.026), affected OS2. Conclusion: Our study offers real-world insights into the clinical management, treatment patterns, and outcomes of advanced melanoma patients in both the adjuvant and unresectable setting. Early relapses in patients undergoing adjuvant treatment pose a particular challenge but these patients are generally excluded from first-line trials. The approved first-line metastatic treatments are highly effective in the real-world setting with 5-year OS rates around 50%. However, outcomes remain poor for patients with brain metastases or who fail first-line treatment.

Dendritic cell (DC) migration from peripheral tissues via afferent lymphatic vessels to draining lymph nodes (dLNs) is important for the organism’s immune regulation and immune protection. Several lymphatic endothelial cell (LEC)-expressed adhesion molecules have thus far been found to support transmigration and movement within the lymphatic vasculature. In this study, we investigated the contribution of CD112, an adhesion molecule that we recently found to be highly expressed in murine LECs, to this process. Performing in vitro assays in the murine system, we found that transmigration of bone marrow-derived dendritic cells (BM-DCs) across or adhesion to murine LEC monolayers was reduced when CD112 was absent on LECs, DCs, or both cell types, suggesting the involvement of homophilic CD112–CD112 interactions. While CD112 was highly expressed in murine dermal LECs, CD112 levels were low in endogenous murine dermal DCs and BM-DCs. This might explain why we observed no defect in the in vivo lymphatic migration of adoptively transferred BM-DCs or endogenous DCs from the skin to dLNs. Compared to murine DCs, human monocyte-derived DCs expressed higher CD112 levels, and their migration across human CD112-expressing LECs was significantly reduced upon CD112 blockade. CD112 expression was also readily detected in endogenous human dermal DCs and LECs by flow cytometry and immunofluorescence. Upon incubating human skin punch biopsies in the presence of CD112-blocking antibodies, DC emigration from the tissue into the culture medium was significantly reduced, indicating impaired lymphatic migration. Overall, our data reveal a contribution of CD112 to human DC migration.

Abstract Background Sinonasal inverted papillomas (IP) are benign tumours arising from the mucosal lining of the nasal cavity and paranasal sinuses with a high propensity for recurrence and malignant transformation. Advances in endoscopic surgery and improved radiologic navigation have increased the role of endoscopic surgical resection in the treatment of IPs. The current study aims to evaluate the rate of IP recurrence after endoscopic endonasal resection and to evaluate factors which impact recurrence. Methods This was a single-centre retrospective chart review of all patients who underwent endoscopic sinus surgery for management of IP between January 2009 and February 2022. Primary outcomes were the rate of IP recurrence and time to IP recurrence. Secondary outcome measures were patient and tumour factors that contributed to IP recurrence. Results Eighty-five patients were included. The mean age was 55.7 and 36.5% of patients were female. The mean follow-up time was 39.5 months. Of the 85 cases, 13 cases (15.3%) had recurrence of their IP and the median time to recurrence was 22.0 months. All recurrent tumours recurred at the attachment site of the primary tumour. The univariate analysis did not identify any significant demographic, clinical, or surgical predictors of IP recurrence. There were no significant changes in sinonasal symptoms at the time IP recurrence was detected. Conclusion Endoscopic endonasal resection of IPs represents an effective surgical approach, however, the relatively high rate of recurrence and lack of symptomatic changes at the time of recurrence necessitates long term follow up. Better delineation of risk factors for recurrence can help identify high-risk patients and inform postoperative follow up strategies.

The future of work and the ever-changing skills demand in the labour market has been a constant debate and pressing challenge for higher education institutions (HEI’s), governments and industry. In the current context, HEI’s must increase the transformational effect of education on people’s employability, on organizations’ competitiveness and on society’s progress. This paper presents the design and development of a mock-up career guidance tool to empower lifelong learners through digital reskilling and upskilling. We discuss the methods used for designing a skills alignment tool and a smart catalogue for identifying stackable training pathways in two specific disciplinary domains. The skills alignment methodology features a skill gap analysis (SGA) in the occupational domains of Data Science and Chemistry, linked to the evolution and demand of the European labour market through an ESCO compatible tool. The smart program catalog presents the necessary program information to facilitate the creation of stackable training pathways. Considerations are made for the importance of virtual career guidance tools for lifelong learners as we face the ever-changing demand of the labor market and as we continue to embrace online education, micro-credentialing and the digital transformation of higher education.

Background: Substance use disorder (SUD) resolution typically involves a long-term, comprehensive process of change now widely referred to as “recovery.” Yet, definitions of recovery vary substantially, producing significant confusion. To support formal recovery definitions, we aimed to systematically identify recovery elements that are central to those in recovery and shared regardless of subgroup/pathway. Methods: Data were from the What is Recovery? Study, involving a diverse, national, online survey of people in recovery (N = 9341). Surveys included a 35-item recovery measure reflecting 4 domains; participants reported whether or not each element definitely belonged in their recovery definitions. Analyses examined item endorsements overall and among 30 subgroups defined a priori (by sociodemographics, substance use characteristics, and help-seeking history) to determine where items met study-specific centrality thresholds (ie, endorsement by ⩾80% and top-10 ranking, by endorsement level). We then classified items as “core” if meeting centrality thresholds both overall and for all 30 subgroups, and “prevalent” if meeting centrality thresholds overall and for 26 to 29 subgroups. Results: Four “core” recovery elements emerged, including a process of growth or development; being honest with oneself; taking responsibility for the things one can change; and reacting in a more balanced way. Four “prevalent” recovery elements also emerged, referencing the ability to enjoy life and handle negative feelings without substance use; abstinence and/or nonproblematic substance use; and living a life that contributes. Subgroups differing most in their endorsements included those reporting mild/moderate SUD severity; non-abstinent recovery; and no specialty treatment or mutual-help group attendance. Conclusions: Recovery elements identified here partially reflect some stakeholder definitions, but offer greater specificity and include novel elements (eg, personal integrity). Elements may point to areas of functioning that are damaged in the addiction process and can support an addiction-free life. Findings should inform institutional recovery definitions; SUD services and research; and communications about recovery.

Abstract Single‐cell proteomics aims to characterize biological function and heterogeneity at the level of proteins in an unbiased manner. It is currently limited in proteomic depth, throughput, and robustness, which we address here by a streamlined multiplexed workflow using data‐independent acquisition (mDIA). We demonstrate automated and complete dimethyl labeling of bulk or single‐cell samples, without losing proteomic depth. Lys‐N digestion enables five‐plex quantification at MS1 and MS2 level. Because the multiplexed channels are quantitatively isolated from each other, mDIA accommodates a reference channel that does not interfere with the target channels. Our algorithm RefQuant takes advantage of this and confidently quantifies twice as many proteins per single cell compared to our previous work (Brunner et al, PMID 35226415), while our workflow currently allows routine analysis of 80 single cells per day. Finally, we combined mDIA with spatial proteomics to increase the throughput of Deep Visual Proteomics seven‐fold for microdissection and four‐fold for MS analysis. Applying this to primary cutaneous melanoma, we discovered proteomic signatures of cells within distinct tumor microenvironments, showcasing its potential for precision oncology.

Congenital renal anomalies are common imaging findings and can often be detected antenatally. In some cases, these anomalies may go undetected and present in adulthood. We report a very rare case of unilateral renal agenesis in a 22-year-old male associated with an ipsilateral dilated blind-ended ureter that ectopically inserted into the seminal vesicle. This unique combination of developmental anomalies can lead to a variety of clinical presentations and requires careful monitoring and management.

Summary: Characterization of extracellular vesicles (EVs) holds great promise for biomarker discovery and understanding of diseases, including melanoma, the deadliest skin cancer type. Here, we describe a size-exclusion chromatography method to isolate and concentrate EVs from patient material including (1) patient-derived melanoma cell line supernatants and (2) plasma and serum biopsies. Additionally, we provide a protocol to analyze EVs by nano-flow cytometry. EV suspensions obtained with the presented protocol can be used for several downstream analyses including RNA sequencing and proteomics. : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

RNA editing refers to non-transient RNA modifications that occur after transcription and prior to translation by the ribosomes. RNA editing is more widespread in cancer cells than in non-transformed cells and is associated with tumorigenesis of various cancer tissues. However, RNA editing can also generate neo-antigens that expose tumour cells to host immunosurveillance. Global RNA editing in melanoma and its relevance to clinical outcome currently remain poorly characterized. The present study compared RNA editing as well as gene expression in tumour cell lines from melanoma patients of short or long metastasis-free survival, patients relapsing or not after immuno- and targeted therapy and tumours harbouring BRAF or NRAS mutations. Overall, our results showed that NTRK gene expression can be a marker of resistance to BRAF and MEK inhibition and gives some insights of candidate genes as potential biomarkers. In addition, this study revealed an increase in Adenosine-to-Inosine editing in Alu regions and in non-repetitive regions, including the hyperediting of the MOK and DZIP3 genes in relapsed tumour samples during targeted therapy and of the ZBTB11 gene in NRAS mutated melanoma cells. Therefore, RNA editing could be a promising tool for identifying predictive markers, tumour neoantigens and targetable pathways that could help in preventing relapses during immuno- or targeted therapies.

The presence of impurities above regulatory thresholds has been responsible for recent recalls of pharmaceutical drugs. Crystallization is one of the most used separation processes to control impurities in the final drug. A particular issue emerges when impurities are poorly soluble in the crystallization solvent and simultaneously precipitate with the product. This publication reports the development of a population balance model to investigate if the impurity crystallization kinetics can be selectively inhibited in a seeded batch crystallization system containing acetaminophen (ACM), a commonly used small-molecule active pharmaceutical ingredient (API), and curcumin (CUR), a simulated low-solubility/co-precipitating impurity. Raman spectroscopy was used in combination with a partial least squares (PLS) model for in situ monitoring of the crystallization process. The Raman data were integrated to calibrate a population balance model in gPROMS FormulatedProducts, to predict the evolution of the product’s purity throughout the process. Process optimization demonstrated that a high purity close to equilibrium is feasible within the first 2 h of crystallization, with ACM seed purity being the primary factor controlling this phenomenon. The optimal approach for kinetically rejecting impurities requires a low nucleation rate for the impurity, high product seed purities, and an adjustable crystallization time so the process can be stopped before equilibrium without allowing the impurity to nucleate. Overall, an improvement in product purity before equilibrium is attainable if there is enough difference in growth kinetics between the product and impurity, and if one can generate relatively pure seed crystals.

Key Clinical Message Austrian Syndrome classically consists of meningitis, endocarditis, and pneumonia due to Streptococcus pneumonia bacteremia. A literature review, however, does not show variants of this triad. Our case highlights a unique variant of Austrian Syndrome with mastoiditis, meningitis, and endocarditis which requires immediate recognition and treatment to prevent devastating patient outcomes. Abstract Streptococcus pneumonia is responsible for more than 50% of all bacterial meningitis and has a case fatality rate of 22% in adults. In addition, Streptococcus pneumonia is also one of the most common causes of acute otitis media, a known cause of mastoiditis. However, in conjunction with bacteremia and endocarditis, limited evidence is able to be identified. This sequence of infections also closely relates to Austrian syndrome. Otherwise known as Osler's triad, Austrian syndrome is a rare phenomenon of meningitis, endocarditis, and pneumonia secondary to Streptococcus pneumonia bacteremia that was first delineated by Robert Austrian in 1956. The incidence of Austrian syndrome is reported to be less than

Introduction Hypertension affects 40%–60% of adults with hypertrophic cardiomyopathy (HCM), the most common inherited cardiac condition. It can be a diagnostic confounder for HCM, contributing to delayed diagnosis. Clinically, treatment of co-occurring hypertension and HCM poses challenges as first-line and second-line antihypertensive medications are often contraindicated in HCM. The clinical course in adults with hypertension and HCM is also not well understood, and studies examining patient outcomes in this population are equivocal. In this paper, we aim to outline the protocol of a scoping review, a type of literature review, to systematically synthesise existing knowledge on adults with co-occurring HCM and hypertension, highlighting knowledge and evidence gaps, and identifying future research directions to optimise outcomes in this population.Methods and analysis This review is guided by Arksey and O’Malley’s conceptual framework on conducting scoping reviews. We will search five electronic databases (PubMed, CINAHL, Scopus, Embase and Web of Science) and reference lists of publications to identify eligible articles focusing on medical therapy, clinical course or outcomes in adults with HCM and hypertension, between 2011 and 2023. Our search strategy and presentation of results will be guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses-Scoping Review guideline. First, two independent reviewers will screen articles, by title and abstract, followed by a full-text screen to identify eligible articles. Relevant data will be extracted and synthesised.Ethics and dissemination Ethical approval is not required for this review as it is a secondary data collection of published articles and does not involve human subject participation. We will present results of this review at relevant professional conferences and patient-centred educational events. Results will be published in a peer-reviewed journal.Trial registration number https://osf.io/cy8qb/?view_only=98197f4850584e51807ff9b62533a706.

Summary: Saccadic eye movements are known to cause saccadic suppression, a temporary reduction in visual sensitivity and visual cortical firing rates. While saccadic suppression has been well characterized at the level of perception and single neurons, relatively little is known about the visual cortical networks governing this phenomenon. Here we examine the effects of saccadic suppression on distinct neural subpopulations within visual area V4. We find subpopulation-specific differences in the magnitude and timing of peri-saccadic modulation. Input-layer neurons show changes in firing rate and inter-neuronal correlations prior to saccade onset, and putative inhibitory interneurons in the input layer elevate their firing rate during saccades. A computational model of this circuit recapitulates our empirical observations and demonstrates that an input-layer-targeting pathway can initiate saccadic suppression by enhancing local inhibitory activity. Collectively, our results provide a mechanistic understanding of how eye movement signaling interacts with cortical circuitry to enforce visual stability.

Melanomas are highly immunogenic tumors that have been shown to activate the immune response. Nonetheless, a significant portion of melanoma cases are either unresponsive to immunotherapy or relapsed due to acquired resistance. During melanomagenesis, melanoma and immune cells undergo immunomodulatory mechanisms that aid in immune resistance and evasion. The crosstalk within melanoma microenvironment is facilitated through the secretion of soluble factors, growth factors, cytokines, and chemokines. In addition, the release and uptake of secretory vesicles known as extracellular vesicles (EVs) play a key role in shaping the tumor microenvironment (TME). Melanoma-derived EVs have been implicated in immune suppression and escape, promoting tumor progression. In the context of cancer patients, EVs are usually isolated from biofluids such as serum, urine, and saliva. Nonetheless, this approach neglects the fact that biofluid-derived EVs reflect not only the tumor, but also include contributions from different organs and cell types. For that, isolating EVs from tissue samples allows for studying different cell populations resident at the tumor site, such as tumor-infiltrating lymphocytes and their secreted EVs, which play a central anti-tumor role. Herein, we outline the first instance of a method for EV isolation from frozen tissue samples at high purity and sensitivity that can be easily reproduced without the need for complicated isolation methods. Our method of processing the tissue not only circumvents the need for hard-to-acquire freshly isolated tissue samples, but also preserves EV surface proteins which allows for multiplex surface markers profiling. Tissue-derived EVs provide insight into the physiological role of EVs enrichment at tumor sites, which can be overlooked when studying circulating EVs coming from different sources. Tissue-derived EVs could be further characterized in terms of their genomics and proteomics to identify possible mechanisms for regulating the TME. Additionally, identified markers could be correlated to overall patient survival and disease progression for prognostic purposes.

Background Melanoma is an immune sensitive disease, as demonstrated by the activity of immune check point blockade (ICB), but many patients will either not respond or relapse. More recently, tumor infiltrating lymphocyte (TIL) therapy has shown promising efficacy in melanoma treatment after ICB failure, indicating the potential of cellular therapies. However, TIL treatment comes with manufacturing limitations, product heterogeneity, as well as toxicity problems, due to the transfer of a large number of phenotypically diverse T cells. To overcome said limitations, we propose a controlled adoptive cell therapy approach, where T cells are armed with synthetic agonistic receptors (SAR) that are selectively activated by bispecific antibodies (BiAb) targeting SAR and melanoma-associated antigens.Methods Human as well as murine SAR constructs were generated and transduced into primary T cells. The approach was validated in murine, human and patient-derived cancer models expressing the melanoma-associated target antigens tyrosinase-related protein 1 (TYRP1) and melanoma-associated chondroitin sulfate proteoglycan (MCSP) (CSPG4). SAR T cells were functionally characterized by assessing their specific stimulation and proliferation, as well as their tumor-directed cytotoxicity, in vitro and in vivo.Results MCSP and TYRP1 expression was conserved in samples of patients with treated as well as untreated melanoma, supporting their use as melanoma-target antigens. The presence of target cells and anti-TYRP1 × anti-SAR or anti-MCSP × anti-SAR BiAb induced conditional antigen-dependent activation, proliferation of SAR T cells and targeted tumor cell lysis in all tested models. In vivo, antitumoral activity and long-term survival was mediated by the co-administration of SAR T cells and BiAb in a syngeneic tumor model and was further validated in several xenograft models, including a patient-derived xenograft model.Conclusion The SAR T cell-BiAb approach delivers specific and conditional T cell activation as well as targeted tumor cell lysis in melanoma models. Modularity is a key feature for targeting melanoma and is fundamental towards personalized immunotherapies encompassing cancer heterogeneity. Because antigen expression may vary in primary melanoma tissues, we propose that a dual approach targeting two tumor-associated antigens, either simultaneously or sequentially, could avoid issues of antigen heterogeneity and deliver therapeutic benefit to patients.

IntroductionThe worldwide incidence of melanoma has been increasing rapidly in recent decades with Switzerland having one of the highest rates in Europe. Ultraviolet (UV) radiation is one of the main risk factors for skin cancer. Our objective was to investigate UV protective behavior and melanoma awareness in a high-risk cohort for melanoma.MethodsIn this prospective monocentric study, we assessed general melanoma awareness and UV protection habits in at-risk patients (≥100 nevi, ≥5 dysplastic nevi, known CDKN2A mutation, and/or positive family history) and melanoma patients using questionnaires. ResultsBetween 01/2021 and 03/ 2022, a total of 269 patients (53.5% at-risk patients, 46.5% melanoma patients) were included. We observed a significant trend toward using a higher sun protection factor (SPF) in melanoma patients compared with at-risk patients (SPF 50+: 48% [n=60] vs. 26% [n=37]; p=0.0016). Those with a college or university degree used a high SPF significantly more often than patients with lower education levels (p=0.0007). However, higher educational levels correlated with increased annual sun exposure (p=0.041). Neither a positive family history for melanoma, nor gender or Fitzpatrick skin type influenced sun protection behavior. An age of ≥ 50 years presented as a significant risk factor for melanoma development with an odd’s ratio of 2.32. Study participation resulted in improved sun protection behavior with 51% reporting more frequent sunscreen use after study inclusion. DiscussionUV protection remains a critical factor in melanoma prevention. We suggest that melanoma awareness should continue to be raised through public skin cancer prevention campaigns with a particular focus on individuals with low levels of education.

Fresh vs. slow-frozen tissues from various malignancies are compared for the establishment of 2D, 3D and ex vivo cultures, as well as for scRNAseq analysis, and found to be comparable and suitable for cancer research.

Objective: To describe morphokinetic parameters and ploidy among low-quality blastocysts not meeting the criteria for clinical use. Design: Prospective cohort study. Setting: Academic medical center. Patient(s): Two hundred patients undergoing in vitro fertilization between February 2018 and November 2019. Intervention(s): All embryos were cultured in a time-lapse incubator. All expanded blastocysts underwent preimplantation genetic testing for aneuploidy using next-generation sequencing. Main Outcome Measure(s): Static blastocyst morphology grading; morphokinetic parameters, including time to each cell division (2-cell formation to 8-cell formation); time to morula formation; time to the start of blastulation; time to blastocyst formation; and preimplantation genetic testing for aneuploidy results. Result(s): A total of 1,306 embryos progressed to the expanded blastocyst stage; of these, 935 embryos met the criteria for clinical use and were designated as high quality, whereas 371 embryos were graded as low quality and did not meet the criteria for use. In morphokinetic evaluation, low-quality embryos developed more quickly to 5-cell formation (t5) 48.4 [42.4–48.7) vs 50.2 [46.3–50.1] hours, but progressed more slowly thereafter with tM 91.5 [85.9–92.3] vs 88.3 [82.1–88.3] and tB 114.0 [106.4–113.9] vs 106.9 [101.3–107.4] hours. Among the low-quality embryos, 75.5% were aneuploid, 22.4% were euploid, and 2.2% had undetermined chromosome copy number results. Morphokinetic parameters did not differ between the euploid and aneuploid low-quality embryos. Conclusion(s): Morphokinetic analysis did not distinguish between euploid and aneuploid low-quality embryos.

Abstract Biological soil crusts (BSC) are important contributors to nutrient cycling in arid environments such as the Sonoran Desert. BSC at an urban (University Indian Ruins) and at a non-urban site (Santa Rita Experimental Range) were compared to determine if their structure or function was influenced by proximity to an urban environment. The Step Point method was used in the field to determine ground cover; which was found to be similar between sites. However, the spatial distribution of the BSCs was significantly different, such that more BSCs were found under plants at the non-urban site (P

Leader-follower autonomy (LFA) systems have so far only focused on vehicles following other vehicles. Though there have been several decades of research into this topic, there has not yet been any work on human-vehicle leader-follower systems in the known literature. We present a system in which an autonomous vehicle—our ACTor 1 platform—can follow a human leader who controls the vehicle through hand-and-body gestures. We successfully developed a modular pipeline that uses artificial intelligence/deep learning to recognize hand-and-body gestures from a user in view of the vehicle’s camera and translate those gestures into physical action by the vehicle. We demonstrate our work using our ACTor 1 platform, a modified Polaris Gem 2. Results show that our modular pipeline design reliably recognizes human body language and translates the body language into LFA commands in real time. This work has numerous applications such as material transport in industrial contexts.

Viruses must balance their reliance on host cell machinery for replication while avoiding host defense. Influenza A viruses are zoonotic agents that frequently switch hosts, causing localized outbreaks with the potential for larger pandemics. The host range of influenza virus is limited by the need for successful interactions between the virus and cellular partners. Here we used immunocompetitive capture-mass spectrometry to identify cellular proteins that interact with human- and avian-style viral polymerases. We focused on the proviral activity of heterogenous nuclear ribonuclear protein U-like 1 (hnRNP UL1) and the antiviral activity of mitochondrial enoyl CoA-reductase (MECR). MECR is localized to mitochondria where it functions in mitochondrial fatty acid synthesis (mtFAS). While a small fraction of the polymerase subunit PB2 localizes to the mitochondria, PB2 did not interact with full-length MECR. By contrast, a minor splice variant produces cytoplasmic MECR (cMECR). Ectopic expression of cMECR shows that it binds the viral polymerase and suppresses viral replication by blocking assembly of viral ribonucleoprotein complexes (RNPs). MECR ablation through genome editing or drug treatment is detrimental for cell health, creating a generic block to virus replication. Using the yeast homolog Etr1 to supply the metabolic functions of MECR in MECR-null cells, we showed that specific antiviral activity is independent of mtFAS and is reconstituted by expressing cMECR. Thus, we propose a strategy where alternative splicing produces a cryptic antiviral protein that is embedded within a key metabolic enzyme.

Summary:. Beyond being aesthetically unpleasing, metatarsal defects have been known to lead to several patient concerns such as intermetatarsal malpositioning and metatarsalgia. There are several reconstructive techniques that have been utilized for reconstruction of bony defects in the foot, including the free dorsal toe flap and dorsal metatarsal perforator flap. Our institution has utilized the free fibular flap for surgical management pertaining to tarsal reconstruction. Our study looks to evaluate the work of a single plastic surgeon and identify patient postoperative outcomes. A retrospective chart review was conducted at Beaumont Health System, Royal Oak for patients who underwent first metatarsal reconstruction with a free fibular flap between the years 2015 and 2022. Demographic data, operative details, complications, medical comorbidities, and patient outcomes were retrospectively gathered and analyzed. A total of two patients were isolated after chart review. Both patients were found to have tolerated the procedure well and had no intraoperative complications. In addition, all patients had clinically viable flaps and were satisfied with their surgical results. The free fibular flap may be used effectively in the management of metatarsal defects that have failed prior therapy. In our study, both patients who underwent surgical management with a free fibular flap were noted to have successful long-term results. With the right expertise and patient population, a free fibular flap can be highly successful in the repair of metatarsal defects.

Background:. Ankle arthrodesis has become a common surgical procedure for individuals with end-stage ankle arthritis, chronic infection, and bony misalignment. Although arthrodesis is typically managed with arthrodesis in situ or realignment, reconstruction may be utilized for patients with more complicated cases that involve metatarsal defects. Our institution utilizes both the pedicled and free fibula flaps for surgical management pertaining to ankle arthrodesis. Our study looks to evaluate the work of a single plastic surgeon and identify patient postoperative outcomes. Methods:. A retrospective chart review was conducted at Beaumont Health System, Royal Oak, for patients who underwent ankle arthrodesis with a pedicled fibula flap for nonunion or avascular necrosis of the talus between the years 2014 and 2022. Demographic data, operative details, complications, medical comorbidities, and patient outcomes were retrospectively gathered and analyzed. Results:. A total of six patients were isolated, with three patients undergoing a free fibula approach and three patients undergoing the pedicled fibula approach. All patients were found to have tolerated the procedure well and had no intraoperative complications. In addition, all patients had clinically viable flaps and were satisfied with their surgical result. Conclusions:. Both free and pedicled free fibula flaps may be used effectively in the management of ankle arthrodesis in patients who have failed prior therapy. In our study, free fibula flaps were utilized in a medial approach, while the pedicled fibula flap was utilized in a lateral approach. With the right expertise and patient population, the free and pedicled fibula flaps can be highly successful in the repair of ankle defects.

The school reliance on exclusionary discipline drives behavioral inequities and sustains the marginalization of youth in schools. The narratives of punishment often extend beyond the walls of the school system and may be reinforced by news media discourse. Never-the-less, the relationship between news media discourse and the school disciplinary structure is an understudied area of research. Using critical discourse techniques--with a theoretical framework of critical race and news framing theories--we analyze news coverage of exclusionary discipline across (N = 64) newspaper articles. Our findings underscore news discourse with a hyper-focus on youth deficits, stigmatizing portrayals of violence and blame, and teacher resistance to discipline alternatives and reform. Discursive absence included a lack of youth and family voices and perspectives, and a disconnection from the systemic mechanisms that shape the disciplinary structure. We conclude with implications for educators, policymakers, and scholars--as we advocate for a re-invigorated focus to-ward the equitable support and inclusion of youth.

John Busby,1 David Price,2– 4 Riyad Al-Lehebi,5 Sinthia Bosnic-Anticevich,6– 8 Job FM van Boven,9 Benjamin Emmanuel,10 J Mark FitzGerald,11 Mina Gaga,12 Susanne Hansen,13,14 Mark Hew,15,16 Takashi Iwanaga,17 Désirée Larenas Linnemann,18 Bassam Mahboub,19,20 Patrick Mitchell,21 Daniela Morrone,22 Jonathan Pham,15,23 Celeste Porsbjerg,14 Nicolas Roche,24,25 Eileen Wang,26,27 Neva Eleangovan,2,3 Liam G Heaney28 1Centre for Public Health, Queen’s University Belfast, Belfast, Northern Ireland; 2Optimum Patient Care, Cambridge, UK; 3Observational and Pragmatic Research Institute, Singapore, Singapore; 4Centre of Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Aberdeen, UK; 5Department of Pulmonology, King Fahad Medical City, Riyadh, Saudi Arabia; 6Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia; 7Woolcock Institute of Medical Research, The University of Sydney, Sydney, Australia; 8Central Sydney Local Area Health District, Sydney, Australia; 9Department of Clinical Pharmacy & Pharmacology, Groningen Research Institute for Asthma and COPD (GRIAC), University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; 10BioPharmaceuticals Medical, AstraZeneca, Gaithersburg, MD, USA; 11Department of Medicine, The University of British Columbia, Vancouver, Canada; 12 7th Respiratory Medicine Department and Asthma Centre, Athens Chest Hospital, Athens, Greece; 13Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark; 14Respiratory Research Unit, Bispebjerg University Hospital, Copenhagen, Denmark; 15Allergy, Asthma & Clinical Immunology Service, Alfred Health, Melbourne, Australia; 16Public Health and Preventive Medicine, Monash University, Melbourne, Australia; 17Center for General Medical Education and Clinical Training, Kindai University Hospital, Osakasayama, Japan; 18Directora Centro de Excelencia en Asma y Alergia, Hospital Médica Sur, Ciudad de México, Mexico; 19College of Medicine, University of Sharjah, Sharjah, United Arab Emirates; 20Rashid Hospital, Dubai Health Authority, Dubai, United Arab Emirates; 21Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; 22Personalized Medicine, Asthma and Allergy, Humanitas Clinical and Research Center, IRCCS, Rozzano, Italy; 23Allergy and Lung Health Unit, Centre for Epidemiology and Biostatistics, Melbourne School of Population & Global Health, The University of Melbourne, Melbourne, Australia; 24Respiratory Medicine, Cochin Hospital, APHP.Centre, Paris, France; 25University of Paris, Cochin Institute (UMR1016), Paris, France; 26Division of Allergy & Clinical Immunology, Department of Medicine, National Jewish Health, Denver, CO, USA; 27Division of Allergy & Clinical Immunology, Department of Internal Medicine, University of Colorado School of Medicine, Aurora, CO, USA; 28Wellcome-Wolfson Centre for Experimental Medicine, Queen’s University Belfast, Belfast, Northern IrelandCorrespondence: David PriceCentre of Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Polwarth Building, Foresterhill, Aberdeen, AB25 2ZD, UKTel +65 6962 3627Email dprice@opri.sgIntroduction: Asthma morbidity and health-care utilization are known to exhibit a steep socioeconomic gradient. Further investigation into the modulators of this effect is required to identify potentially modifiable factors.Methods: We identified a cohort of patients with asthma from the Optimum Patient Care Research Database (OPCRD). We compared demographics, clinical variables, and health-care utilization by quintile of the UK 2011 Indices of Multiple Deprivation based on the location of the patients’ general practice. Multivariable analyses were conducted using generalized linear models adjusting for year, age, and sex. We conducted subgroup analyses and interaction tests to investigate the impact of deprivation by age, sex, ethnicity, and treatment step.Results: Our analysis included 127,040 patients with asthma. Patients from the most deprived socio-economic status (SES) quintile were more likely to report uncontrolled disease (OR: 1.54, 95% CI: 1.16, 2.05) and to have an exacerbation during follow-up (OR: 1.27, 95% CI: 1.13, 1.42) than the least deprived quintile. They had higher blood eosinophils (ratio: 1.03; 95% CI: 1.00, 1.06) and decreased peak flow (ratio: 0.95, 95% CI: 0.94, 0.97) when compared to those in the least deprived quintile. The effect of deprivation on asthma control was greater among those aged over 75 years (OR = 1.81, 95% CI: 1.20, 2.73) compared to those aged less than 35 years (OR: 1.22, 95% CI: 0.85, 1.74; pinteraction=0.019). Similarly, socioeconomic disparities in exacerbations were larger among those from ethnic minority groups (OR: 1.94, 95% CI: 1.40, 2.68) than white patients (OR: 1.24, 95% CI: 1.10, 1.39; pinteraction=0.012).Conclusion: We found worse disease control and increased exacerbation rates among patients with asthma from more deprived areas. There was evidence that the magnitude of socioeconomic disparities was elevated among older patients and those from ethnic minority groups. The drivers of these differences require further exploration.Keywords: asthma, socioeconomic status, disparities

Novel treatment modalities comprising immune checkpoint inhibitors and targeted therapies have revolutionized treatment of metastatic melanoma. Still, some patients suffer from rapid progression and decease within months after a diagnosis of stage IV melanoma. We aimed to assess whether genomic alterations may predict survival after the development of stage IV disease, irrespective of received therapy. We analyzed tumor samples of 79 patients with stage IV melanoma using a custom next-generation gene-sequencing panel, MelArray, designed to detect alterations in 190 melanoma-relevant genes. We classified the patients: first, as short survivors (survival ≤6 months after stage IV disease, n = 22) and long survivors (survival >6 months, n = 57); second, by using a cut-off of one year; and third, by comparing the longest surviving 20 patients to the shortest surviving 20. Among analyzed genes, no individual gene alterations, or combinations of alterations, could be dichotomously associated with survival. However, the cohort’s mutational profiles closely matched three known mutational signatures curated by the Catalog of Somatic Mutations in Cancer (COSMIC): UV signature COSMIC_7 (cosine-similarity 0.932), clock-like signature COSMIC_5 (cosine-similarity 0.829), and COSMIC_30 (cosine-similarity 0.726). Patients with UV signature had longer survival compared to patients with clock-like and COSMIC 30 (p < 0.0001). Subgroup dichotomization at 6 months showed that 75% of patients with UV signature survived longer than 6 months, and about 75% of patients with clock-like signature survived less than 6 months after development of stage IV disease. In our cohort, clock-like COSMIC_5 mutational signature predicted poor survival while a UV signature COSMIC_7 predicted longer survival. The prognostic value of mutational signatures should be evaluated in prospective studies.

This article responds to the rise of the micro-credential movement. It evidences the heightened attention politicians, policy-makers and educational leaders are giving to micro-credentials by framing the discussion in several recent high-level policy developments, an exponential growth in the number of academic publications and the increasing level of interest shown by popular media. It follows that micro-credentials appear to be high on the change agenda for many higher education institutions (HEIs), especially in the post-COVID-19 environment. However, the emergence of the micro-credential raises several crucial questions for educational leaders, set against fear of missing out. Importantly, the paper identifies a significant gap in the literature regarding leadership and strategic institutional responses to micro-credentials. Indeed, there is a dearth of literature. Leadership is crucial to the success of any educational change or innovation, so five key questions are presented for institutional leaders. They challenge institutions to make strategic decisions around how they engage with and position micro-credentials. If micro-credentials are part of an HEI’s change agenda, then serious consideration needs to be given to the type of leadership and internal structures required to develop and execute a successful micro-credential strategy. Consideration must also be given to fit-for-purpose business models and how to mitigate potential risks. We hope to bring these strategic questions to the table as institutions plan, envision and develop their micro-credential strategies.

Urban areas are increasingly vulnerable to the effects of climate change. Stormwater Green infrastructure (SWGI) is seen as an approach to increase the climate resilience of urban areas, because they can buffer precipitation changes brought on by climate change. However, SWGI features themselves need to be resilient to climate change to be able to contribute to the resilience of cities. Thus, we aimed to develop a SWGI resilience assessment framework that could be used to identify challenges and to inform decisionmakers’ efforts to enhance resilience. We developed a resilience assessment framework based upon a resilience matrix approach to recognize effective resilience categories for SWGI by reviewing the literature on critical functionality and barriers to implementation and operation. These categories for SWGI included policy, design, maintenance, economic factors and social factors that influence SWGI functionality. We then identified specific aspects under each category that could be used for assessing SWGI resilience, recognizing that SWGI has critical functionalities and factors controlling its viability. Unlike other SWGI assessment frameworks that are focused on ecosystem services as a final outcome, we worked from a socio-ecological perspective in order to include socio-economic and policy factors and design and planning aspects that affect service provision. Developing a resilience assessment framework is critical for management because it can reveal the specific challenges facing SWGI resilience that have traditionally been overlooked, such as maintenance and social factors. This specific framework can also lead to efficient planning and management by identifying interrelations and hierarchical relationships of categories that influence resilience. Application of this framework will rely upon expert input to connect broad dimensions with specific indicators for SWGI to local priorities in resilience planning.

Abstract Background Findings have been mixed as to whether brief intervention (BI) is appropriate and effective for individuals with more severe alcohol use problems. Motivation to change drinking has been supported as a mechanism of behavior change for BI. This exploratory study examined aspects of motivation as mechanisms of clinical response to BI and alcohol problem severity as a moderator of treatment effects. Methods Non-treatment-seeking heavy drinkers (average age = 35 years; 57% male) were randomized to receive BI (n = 27) or attention-matched control (n = 24). Three indices of motivation to change were assessed at baseline and post-intervention: importance, confidence, and readiness. Moderated mediation analyses were implemented with treatment condition as the focal predictor, changes in motivation as mediator, 1-month follow-up drinks per day as the outcome, and an alcohol severity factor as second-stage moderator. Results Analysis of importance displayed a significant effect of intervention condition on importance (p

Melanoma cells can switch between proliferative and invasive phenotypes. Here the authors show that the embryonic stem cell factor Sall4 is a negative regulator of melanoma phenotype switching where its loss leads to the acquisition of an invasive phenotype, due to derepression of invasiveness genes.

Abstract Pulmonary hypertension (PH) associated with interstitial lung disease (ILD) is an attractive target for clinical trials of PH medications. There are many factors that need to be considered to prime such studies for success. The patient phenotype most likely to respond to the intervention requires weighing the extent of the parenchymal lung disease against the severity of the hemodynamic impairment. The inclusion criteria should not be too restrictive, thus enabling recruitment. The trial should be of sufficient duration to meet the chosen endpoint which should reflect how the patient feels, functions, or survives. This paper summarizes prior studies in PH‐ILD and provides a framework of the type of studies to be considered. Inclusion criteria, clinical trial endpoints, and pharmacovigilance in the context of PH‐ILD trials are also addressed. Through lessons learnt from prior studies, suggestions and guidance for future clinical trials in PH‐ILD are also provided.