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This study evaluated the efficacy of an 8-week (two sessions/week; 60 min/session) adapted soccer intervention on skill performance and retention in 30 adults (18 men and 12 women) ages 17-40 years with autism spectrum disorder, Down syndrome, and intellectual disability. Of these 30 participants, 18 completed a 1-month retention test. The program included behavior supports and adaptations for participants with varying levels of behavioral needs. Dribbling, kicking a moving ball, kicking a stationary ball, throw-ins, trapping, and a composite skill score were examined. Linear mixed-effect regression revealed a significant time main effect with improvements from pretest to posttest and pretest to retention for all skills. In addition, modest offline gains (i.e., posttest < retention) were observed for throw-ins, kicking a moving ball, and the composite skill score. A significant main effect of diagnosis was observed such that participants with autism spectrum disorder had better performance on kicking a moving ball than those with Down syndrome and intellectual disability. Finally, a significant main effect of level of function was observed. This program enabled adults with various disabilities to acquire fundamental soccer skills that may lead to meaningful participation in community soccer programs.

The value of historical data for flood frequency analysis has been acknowledged and studied for a long time. A specific statistical framework must be used to comply with the censored nature of historical data, for which only floods large enough to induce written records or to trigger flood marks are usually recorded. It is assumed that all floods which exceeded a given perception threshold were recorded as written testimonies or flood marks. Conversely, all years without a flood record in the historical period are assumed to have had a maximum discharge below the perception threshold. This paper proposes a binomial model that explicitly recognizes the uncertain nature of both the perception threshold and the starting date of the historical period. This model is applied to a case study for the Rhône River at Beaucaire, France, where a long (1816–2020) systematic series of annual maximum discharges is available along with a collection of 13 historical floods from documentary evidence over 3 centuries (1500–1815). Results indicate that the inclusion of historical floods reduces the uncertainty of 100- or 1000-year flood quantiles, even when only the number of perception threshold exceedances is known. However, ignoring the uncertainty around the perception threshold leads to a noticeable underestimation of flood quantile uncertainty. A qualitatively similar conclusion is found when ignoring the uncertainty around the historical period length. However, its impact on flood quantile uncertainty appears to be much smaller than that of the perception threshold.

As the prevalence of autism spectrum disorder (ASD) increases, there is a growing need to develop physical activity interventions that address the behavioral challenges experienced by individuals with ASD. Physical education teachers have employed behavioral supports that add more structure and adapt the environment for individuals with ASD, which are associated with increased engagement for individuals with ASD during PE. The purpose of this study was to quantify motor engaged behaviors (i.e. motor appropriate (MA)), motor inappropriate (MI), motor supported (MS) during skill practice in 18 individuals with ASD (ages 7-19 years) participating in an adapted tennis program (ACEing Autism) using the Academic Learning Time in Physical Education (ALT-PE) instrument. Overall, the supports provided during the program may have enabled participants with ASD to spend more time in MA and MS than MI. Indeed, the participants spent over 50% of their time in MA during the program.

Introduction: Advanced mixed epithelial endometrial carcinomas are rare high-grade cancers with a poor prognosis. A clear cell component infers relative chemotherapy insensitivity, likely further increased by p53 wild type status and MMR deficiency. PD-1 inhibition for MMR deficient endometrial cancers has been recently added to first-line adjuvant treatment in combination with platinum-based chemotherapy. Information on de-escalation of adjuvant treatment to PD-1 inhibition alone without chemotherapy is sparse. Case Presentation: Here, we present a patient with advanced stage mixed epithelial endometrial carcinoma, a clear cell component and MMR deficiency who underwent de-escalated adjuvant treatment with PD-1 inhibition alone without simultaneous chemotherapy. Conclusion: Histotype-agnostic adjuvant monotherapy with checkpoint immune inhibitors alone appears to be a highly effective even in the rare mixed endometrial carcinomas if MMR protein deficient as described in this case report.

Abstract While brain size in primates and their relatives within Euarchontoglires is well-studied, less research has examined brain shape, or the allometric trajectories that underlie the relationship between size and shape. Defining these patterns is key to understanding evolutionary trends. 3D geometric morphometric analyses of endocranial shape were performed on 140 species of extant euarchontoglirans using digital cranial endocasts. Principal component analyses on Procrustes shape variables show a clear phylogenetic pattern in endocranial shape, supported by an ANOVA which identified significant differences in shape among several groups (e.g., Platyrrhini, Strepsirrhini, Scandentia, Rodentia, and Lagomorpha). ANOVAs of shape and size also indicate that allometry has a small but significant impact on endocranial shape across Euarchontoglires, with homogeneity of slopes tests finding significant differences in the scaling relationship between shape and size among these same groups. While most of these clades possess a distinct endocranial morphotype, the highly derived platyrrhines display the strongest relationship between size and shape. Rodents show the most diversity in endocranial shape, potentially attributed to their comparatively weak relationship between shape and size. These results suggest fundamental differences in how shape and size covary among Euarchontoglires, which may have facilitated the adaptive radiations that characterize members of this group.

Abstract Background There is conflicting evidence whether prediabetes is associated with adverse clinical outcomes in patients with chronic coronary syndrome. We aimed to assess the effect of prediabetes in patients with chronic coronary syndrome on clinical outcomes. Methods This is a secondary analysis of data from the ISCHEMIA and ISCHEMIA-CKD trials, including patients with chronic coronary syndrome determined by coronary computed tomography angiography or exercise-stress testing. Participants were assigned to the normoglycemia group (HbA1c

Abstract Therapeutic approaches targeting proteins on the surface of cancer cells have emerged as an important strategy for precision oncology. To capitalize on the potential impact of drugs targeting surface proteins, detailed knowledge about the expression patterns of the target proteins in tumor tissues is required. In castration-resistant prostate cancer (CRPC), agents targeting prostate-specific membrane antigen (PSMA) have demonstrated clinical activity. However, PSMA expression is lost in a significant number of CRPC tumors. The identification of additional cell surface targets is necessary to develop new therapeutic approaches. Here, we performed a comprehensive analysis of the expression heterogeneity and co-expression patterns of trophoblast cell-surface antigen 2 (TROP2), delta-like ligand 3 (DLL3), and carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) in CRPC samples from a rapid autopsy cohort. We show that DLL3 and CEACAM5 exhibit the highest expression in neuroendocrine prostate cancer (NEPC), while TROP2 is expressed across different CRPC molecular subtypes, except for NEPC. We further demonstrated that AR alterations were associated with higher expression of PSMA and TROP2. Conversely, PSMA and TROP2 expression was lower in RB1-altered tumors. In addition to genomic alterations, we show a tight correlation between epigenetic states, particularly histone H3 lysine 27 methylation (H3K27me3) at the transcriptional start site and gene body of TACSTD2 (encoding TROP2), DLL3, and CEACAM5, and their respective protein expression in CRPC patient-derived xenografts. Collectively, these findings provide insights into patterns and determinants of expression of TROP2, DLL3, and CEACAM5 with implications for the clinical development of cell surface targeting agents in CRPC.

Abstract Background Chronic kidney disease (CKD) affects 10% of the general population in Western countries. Currently, CKD cannot be cured and there are only few strategies to prevent the onset of CKD, to reverse early stages of CKD, and to prevent the progression of established CKD to end-stage kidney disease. Cigarette smoking is a preventable cause of CKD. Methods This narrative review analyses the cause–effect relationship between cigarette smoking and CKD and discusses the association of inhaled cadmium and smoking-induced kidney damage. Results Cigarette smoking places individuals at risk for incident CKD. It accelerates the progression (decline in glomerular filtration rate, aggravation of proteinuria) of CKD to end-stage kidney disease (ESKD), and is associated with shortened kidney transplant graft survival. These harmful effects on kidney function/structure are dependent on the dose and duration of cigarette smoking. Smoking abstinence decreases the higher risk for proteinuria and CKD progression. Inhaled cadmium may be the biologic link between cigarette smoking and kidney dysfunction. Recent studies indicate that accumulation of cadmium in the blood mediates progression of CKD and places smokers at higher risk for all-cause mortality. Conclusions Smoking cessation is an effective intervention to reduce the risk of onset and progression of CKD as well as to reduce smoking-attributable morbidity and mortality.

Abstract Histopathologic diagnosis and classification of cancer plays a critical role in guiding treatment. Advances in next-generation sequencing have ushered in new complementary molecular frameworks. However, existing approaches do not independently assess both site-of-origin (e.g. prostate) and lineage (e.g. adenocarcinoma) and have minimal validation in metastatic disease, where classification is more difficult. Utilizing gradient-boosted machine learning, we developed ATLAS, a pair of separate AI Tumor Lineage and Site-of-origin models from RNA expression data on 8249 tumor samples. We assessed performance independently in 10,376 total tumor samples, including 1490 metastatic samples, achieving an accuracy of 91.4% for cancer site-of-origin and 97.1% for cancer lineage. High confidence predictions (encompassing the majority of cases) were accurate 98–99% of the time in both localized and remarkably even in metastatic samples. We also identified emergent properties of our lineage scores for tumor types on which the model was never trained (zero-shot learning). Adenocarcinoma/sarcoma lineage scores differentiated epithelioid from biphasic/sarcomatoid mesothelioma. Also, predicted lineage de-differentiation identified neuroendocrine/small cell tumors and was associated with poor outcomes across tumor types. Our platform-independent single-sample approach can be easily translated to existing RNA-seq platforms. ATLAS can complement and guide traditional histopathologic assessment in challenging situations and tumors of unknown primary.

CNES is currently carrying out a Phase A study to assess the feasibility of a future hyperspectral imaging sensor (10 m spatial resolution) combined with a panchromatic camera (2.5 m spatial resolution). This mission focuses on both high spatial and spectral resolution requirements, as inherited from previous French studies such as HYPEX, HYPXIM, and BIODIVERSITY. To meet user requirements, cost, and instrument compactness constraints, CNES asked the French hyperspectral Mission Advisory Group (MAG), representing a broad French scientific community, to provide recommendations on spectral sampling, particularly in the Short Wave InfraRed (SWIR) for various applications.This paper presents the tests carried out with the aim of defining the optimal spectral sampling and spectral resolution in the SWIR domain for quantitative estimation of physical variables and classification purposes. The targeted applications are geosciences (mineralogy, soil moisture content), forestry (tree species classification, leaf functional traits), coastal and inland waters (bathymetry, water column, bottom classification in shallow water, coastal habitat classification), urban areas (land cover), industrial plumes (aerosols, methane and carbon dioxide), cryosphere (specific surface area, equivalent black carbon concentration), and atmosphere (water vapor, carbon dioxide and aerosols). All the products simulated in this exercise used the same CNES end-to-end processing chain, with realistic instrument parameters, enabling easy comparison between applications. 648 simulations were carried out with different spectral strategies, radiometric calibration performances and signal-to-noise Ratios (SNR): 24 instrument configurations × 25 datasets (22 images + 3 spectral libraries).The results show that spectral sampling up to 20 nm in the SWIR range is sufficient for most applications. However, 10 nm spectral sampling is recommended for applications based on specific absorption bands such as mineralogy, industrial plumes or atmospheric gases. In addition, a slight performance loss is generally observed when radiometric calibration accuracy decreases, with a few exceptions in bathymetry and in the cryosphere for which the observed performance is severely degraded. Finally, most applications can be achieved with a realistic SNR, with the exception of bathymetry, shallow water classification, as well as carbon dioxide and methane estimation, which require the optimistic SNR level tested. On the basis of these results, CNES is currently evaluating the best compromise for designing the future hyperspectral sensor to meet the objectives of priority applications.

Anomalous right coronary artery (RCA) from the main pulmonary artery (ARCAPA) is a rare finding. Clinical presentations range from asymptomatic to sudden death. We present the case of ARCAPA in a septuagenarian initially suspected on a screening chest computed tomography (CT) and later confirmed on cardiac CT. A summary of important points related to this entity is also discussed.

OBJECTIVES/GOALS: Early HIV detection and treatment are key to reducing patient morbidity and mortality, yet 40% of people living with HIV do not know their status. “OPT-OUT” approaches to hiv testing, in which patients #_MSOCOM_1 are informed that an HIV test will be conducted unless they decline, are being increasingly recognized as a means to increase HIV testing. METHODS/STUDY POPULATION: the ed at Uhealth tower (UHT) implemented #_MSOCOM_1 the focus program that integrates routine “opt-out” HIV screening into the existing electronic medical record workflow to increase the number of individuals who know their HIV status, optimize linkage to care, and reduce stigma associated with HIV. the emr facilitates the opt-out screening model and maximizes the use of information systems to seamlessly integrate screening as a routine practice in a high-volume ed. our partnership with the florida department of health in miami dade (FDOH) allows uht to verify whether cases are new or known /out-of-care, link individuals immediately to care, and increase efficiencies with real-time data reconciliation. RESULTS/ANTICIPATED RESULTS: since implementation#_MSOCOM_1, from October 2019 - Dec 2022, the UHT ED screened 34, 314 eligible patients for HIV, of which, 17, 850 were tested. 228 people with hiv were identified; 37 were newly diagnosed. of HIV+ Diagnoses, 54.67% of HIV+ individuals were black and 36.89% HISPANIC. HIV+ individuals were referred to the doh with linkage to care at 81%. comparatively, before the onset of focus, the ED ordered 38 HIV tests, with one positive from Oct 2018 TO Sept. 2019. DISCUSSION/SIGNIFICANCE: UHT ED’s focus “OPT-OUT” HIV testing is a valuable conduit for HIV detection, prevention, and care. OPT-OUT screening removes the stigma associated with hiv testing, fosters earlier diagnoses and treatment, reduces health disparities, and decreases the risk of transmission.

Floods are a major natural hazard in the Mediterranean region, causing deaths and extensive damages. Recent studies have shown that intense rainfall events are becoming more extreme in this region but, paradoxically, without leading to an increase in the severity of floods. Consequently, it is important to understand how flood events are changing to explain this absence of trends in flood magnitude despite increased rainfall extremes. A database of 98 stations in southern France with an average record of 50 years of daily river discharge data between 1959 and 2021 was considered, together with a high-resolution reanalysis product providing precipitation and simulated soil moisture and a classification of weather patterns associated with rainfall events over France. Flood events, corresponding to an average occurrence of 1 event per year (5317 events in total), were extracted and classified into excess-rainfall, short-rainfall, and long-rainfall event types. Several flood event characteristics have been also analyzed: flood event durations, base flow contribution to floods, runoff coefficient, total and maximum event rainfall, and antecedent soil moisture. The evolution through time of these flood event characteristics and seasonality was analyzed. Results indicated that, in most basins, floods tend to occur earlier during the year, the mean flood date being, on average, advanced by 1 month between 1959–1990 and 1991–2021. This seasonal shift could be attributed to the increased frequency of southern-circulation weather types during spring and summer. An increase in total and extreme-event precipitation has been observed, associated with a decrease of antecedent soil moisture before rainfall events. The majority of flood events are associated with excess rainfall on saturated soils, but their relative proportion is decreasing over time, notably in spring, with a concurrent increased frequency of short rain floods. For most basins there is a positive correlation between antecedent soil moisture and flood event runoff coefficients that is remaining stable over time, with dryer soils producing less runoff and a lower contribution of base flow to floods. In a context of increasing aridity, this relationship is the likely cause of the absence of trends in flood magnitudes observed in this region and the change of event types. These changes in flood characteristics are quite homogeneous over the domain studied, suggesting that they are rather linked to the evolution of the regional climate than to catchment characteristics. Consequently, this study shows that even in the absence of trends, flood properties may change over time, and these changes need to be accounted for when analyzing the long-term evolution of flood hazards.

Background Stent thrombosis is a rare but deleterious event. Routine coronary angiography with percutaneous coronary intervention (PCI) is often deferred in the presence of laboratory markers of acute inflammation to prevent complications. The aim of this study was to investigate whether an acute inflammatory state is associated with an increased risk of early stent thrombosis. Methods and Results Within a prospective single‐center registry, the association between preprocedural acute inflammatory activation, defined as C‐reactive protein plasma levels >50 mg/L or a leukocyte count >12 g/L, and occurrence of early (≤30 days) stent thrombosis was evaluated. In total, 11 327 patients underwent PCI and of those, 6880 patients had laboratory results available. 49.6% of the study population received PCI for an acute coronary syndrome and 50.4% for stable ischemic heart disease. In patients with signs of acute inflammatory activation (24.9%), PCI was associated with a significantly increased risk for stent thrombosis (hazard ratio, 2.89; P

Abstract Background The predictive value of left ventricular (LV) global longitudinal strain (GLS) to predict outcomes in different left ventricular ejection fraction (LVEF) cohorts is not well known. We aimed to assess the role of LV GLS predicting outcomes in HF patients by LVEF. Methods In the Multicenter Automatic Defibrillator Implantation Trial Cardiac Resynchronization Therapy (MADIT‐CRT), we studied 1077 patients (59%) with 2D speckle tracking data available, 437 patients with LVEF > 30% and 640 with LVEF ≤ 30%. Baseline LV GLS was stratified in tertiles in both LVEF subgroups. The primary endpoint was ventricular tachycardia/fibrillation (VT/VF) or death; the secondary endpoint was heart failure (HF) or death. Results In patients with LVEF ≤ 30%, a higher tertile GLS (T3, less contractility) was associated with a higher rate of VT/VF/death (P 30% (P = 0.057). In patients with LVEF ≤ 30%, a higher tertile GLS was also associated with a higher rate of HF/death. In multivariable models, LV GLS predicted VT/VF or death in the LVEF ≤ 30% subgroup [T1 vs. T2/3 HR = 1.67 (1.16–2.38), P = 0.005], but not in those with LVEF > 30% [T1 vs. T2.3 HR = 1.32 (0.86–2.04), P = 0.21]. LV GLS predicted HF/death in the LVEF ≤ 30% subgroup [T1 vs T2/3 HR = 2.00 (1.30–3.13), P = 0.002], but not in in those with LVEF > 30%. Conclusions In this MADIT‐CRT sub‐study, LV GLS identified patients at higher risk of VT/VF, HF/death risk independently of conventional clinical parameters in patients with LVEF ≤ 30%, but not in patients with LVEF > 30%.

According to the 2021 Extension Master Gardener (EMG) National Summary, the EMG Volunteer Program had an estimated 84,700 volunteers throughout the United States. These volunteers helped communities garden and grow food, provided opportunities to engage in activities that improved physical and mental health, and worked on projects that addressed environmental issues. In total, these programs contributed 3.1 million hours of education to local communities and $88 million dollars in value to the public. However, the COVID-19 pandemic presented challenges for the program, with many states implementing reduced requirements and increased flexibility for volunteers. The workshop “Dynamic Volunteer Engagement and Impactful Educational Outreach Taking Us Into the Next 50 Years of the EMG Program” at the 2022 ASHS conference discussed how to engage EMG volunteers despite the limitations of limited in-person contact. The workshop featured three Extension educators and EMG coordinators who shared their experiences and strategies for engaging volunteers during the pandemic. Topics discussed included engaging volunteers in local food systems and community gardens, engaging students in horticulture at an earlier age, and digital volunteer opportunities. Overall, the workshop provided valuable insights and facilitated discussions on how to adapt and continue the EMG program during challenging times.

Recent inroads into percutaneous-based options for the treatment of tricuspid valve disease has brought to light how little we know about the behavior of the right ventricle in both health and disease and how incomplete our assessment of right ventricular (RV) physiology and function is using current non-invasive technology, in particular echocardiography. The purpose of this review is to provide an overview of what three-dimensional echocardiography (3DE) can offer currently to enhance RV evaluation and what the future may hold if we continue to improve the 3D evaluation of the right heart.

Background: Left atrial volume (LAV) has prognostic value. Guidelines propose indexation to body surface area (BSA), however studies demonstrate this can overcorrect for body size. Limited studies investigate indexation across different ethnicities. We sought to evaluate the effect of ethnicity on indexation. Methods: Using data from the World Alliance of Societies of Echocardiography (WASE) cohort, healthy subjects were classified by race as White, Black, Asian, or Other. Biplane LAV was indexed to traditional isometric measurements (BSA, height, weight, ideal body weight (IBW) and IBW derived BSA (IBSA)), as well as previously-derived allometric height exponents (2.7 and 1.72). Additionally, an allometric height exponent for our cohort was derived (linear regression of the logarithmic transformation of LAV = a(height)b) as 1.87. All indices were then assessed using Spearman correlation, with a good index retaining correlation of LAV/index to raw LAV (r∼1), while avoiding overcorrection by the index (r∼0). Results: There were 1366 subjects (White: 524, Black: 149, Asian: 523, Other: 170; median age 44 years, 653 females (47.8%)). In the entire group, BSA, IBSA, height1.87 and height1.72 performed well with retaining correlation to raw LAV (r > 0.9 for all), and minimising overcorrection to body size (r

Abstract Aims Secondary, or functional, mitral regurgitation (FMR) was recently recognized as a separate clinical entity, complicating heart failure with reduced ejection fraction (HFrEF) and entailing particularly poor outcome. Currently, there is a lack of targeted therapies for FMR due to the fact that pathomechanisms leading to FMR progression are incompletely understood. In this study, we sought to perform metabolomic profiling of HFrEF patients with severe FMR, comparing results to patients with no or mild FMR. Methods and results Targeted plasma metabolomics and untargeted eicosanoid analyses were performed in samples drawn from HFrEF patients (n = 80) on optimal guideline‐directed medical therapy. Specifically, 17 eicosanoids and 188 metabolites were analysed. Forty‐seven patients (58.8%) had severe FMR, and 33 patients (41.2%) had no or non‐severe FMR. Comparison of eicosanoid levels between groups, accounting for age, body mass index, and sex, revealed significant up‐regulation of six eicosanoids (11,12‐EET, 13(R)‐HODE, 12(S)‐HETE, 8,9‐DiHETrE, metPGJ2, and 20‐HDoHE) in severe FMR patients. Metabolites did not differ significantly. In patients with severe FMR, but not in those without severe FMR, levels of 8,9‐DiHETrE above a cut‐off specified by receiver‐operating characteristic analysis independently predicted all‐cause mortality after a median follow‐up of 43 [interquartile range 38, 48] months [hazard ratio 12.488 (95% confidence interval 3.835–40.666), P

Abstract The energy crisis is forcing Germany and other EU countries to reconsider and, if necessary, adjust energy policy decisions. New perspectives envisage a rapid expansion of renewable energies in the next few years. In the short term, Germany is considering reactivating coal-fired power plants from the reserve and revising decisions to decommission coal-fired and nuclear power plants in the coming years. This brief study analyses the price effects for the years 2024 and 2027 to shed light on both the short-term challenges and the medium-term prospects.

Das nur wenige Kilometer nördlich von Longyearbyen auf der anderen Seite des Adventfjords gelegene Advent City war die erste Steinkohlemine auf Spitzbergen, die ganzjährig in Betrieb war und bereits fünf Jahre nach der Aufnahme der Arbeiten aufgrund mangelnder Profitabilität wieder aufgegeben wurde. Während Teile der Siedlung seit über hundert Jahren dem Verfall überlassen werden, wurden viele der Gebäude schon kurz nach der Aufgabe der Bergbautätigkeit an anderer Stelle wiederrichtet und stehen größtenteils heute noch an ihrer neuen Position. Neben den Überresten von Gebäuden und technischen Installationen vor Ort sowie den noch erhaltenen Holzhütten, haben sich eine ganze Reihe von historischen Photographien erhalten, die uns ein sehr genaues Bild der Siedlung zeigen. Aus den unterschiedlichen Quellen wurde ein vollständiges 3D-Modell von Advent City entwickelt, das die britische Mine zum Zeitpunkt ihres Betriebs Anfang des 20. Jahrhunderts zeigt. Dieses Modell wurde anschließend in eine Virtual Reality Anwendung überführt, welche dem Nutzer das immersive Erleben der Siedlung erlaubt. Wir werden in unserem Beitrag die Genese des 3D-Modells sowie der VR-Umgebung eingehend besprechen und anschließend den Nutzen einer derartigen digitalen Welt für die Vermittlung der Ergebnisse der polararchäologischen Forschung Studierende, Lehrende, Schülerinnen und Schüler sowie die interessierte Öffentlichkeit diskutieren.

Abstract Background Rates of potentially traumatic events (PTEs) and other forms of adversity among children are high globally, resulting in the development of a number of evidence-based interventions (EBIs) to address the adverse outcomes stemming from these experiences. Though EBIs are intended to be delivered according to set parameters, these EBIs are frequently adapted. However, little is known about existing adaptations of EBIs for children who experienced PTEs or other adversities. As such, this review aimed to determine: (1) why existing EBIs designed to address PTEs and other adversities experienced by children are adapted, (2) what processes are used to determine what elements should be adapted, and (3) what components of the intervention are adapted. Methods Nine academic databases and publicly available search engines were used to identify academic and grey literature. Initial screening, full-text review, data extraction, and quality determinations were completed by two members of the research team. Data were synthesized narratively for each adapted EBI by research question. Results Forty-two studies examining the adaptations of nine different EBIs were located, with Trauma-Focused Cognitive Behavioral Therapy and Cognitive Behavioral Intervention for Trauma in Schools being the most commonly adapted EBIs. Most frequently, EBIs were adapted to improve fit with a new population and to address cultural factors. Most commonly, researchers in combination with others made decisions about adapting interventions, though frequently who was involved in these decisions was not described. Common content adaptations included the addition of intervention elements and the tailoring/tweaking/refining of intervention materials. Common contextual adaptations included changes to the intended population, changes to the channel of treatment delivery, and changes to who administered the intervention. Conclusions Most published studies of EBI adaptions have been developed to improve fit and address cultural factors, but little research is available about adaptations made by clinicians in day-to-day practice. Efforts should be made to evaluate the various types of adaptations and especially whether adaptations improve access to services or improve child outcomes in order to ensure that all children exposed to trauma can access effective treatment. Trial registration The protocol for this systematic review was published with PROSPERO (CRD42020149536).

A comprehensive characterisation of Omicron-BA.1 and VOC Delta in numerous in vitro and in vivo models uncovers the factors that led to its global dominance.

Abstract DNA mutations in specific genes can confer preferential benefit from drugs targeting those genes. However, other molecular perturbations can “phenocopy” pathogenic mutations, but would not be identified using standard clinical sequencing, leading to missed opportunities for other patients to benefit from targeted treatments. We hypothesized that RNA phenocopy signatures of key cancer driver gene mutations could improve our ability to predict response to targeted therapies, despite not being directly trained on drug response. To test this, we built gene expression signatures in tissue samples for specific mutations and found that phenocopy signatures broadly increased accuracy of drug response predictions in-vitro compared to DNA mutation alone, and identified additional cancer cell lines that respond well with a positive/negative predictive value on par or better than DNA mutations. We further validated our results across four clinical cohorts. Our results suggest that routine RNA sequencing of tumors to identify phenocopies in addition to standard targeted DNA sequencing would improve our ability to accurately select patients for targeted therapies in the clinic.

A DNA damage-inducible mutagenic gene cassette has been implicated in the emergence of drug resistance in Mycobacterium tuberculosis during anti-tuberculosis (TB) chemotherapy. However, the molecular composition and operation of the encoded ‘mycobacterial mutasome’ – minimally comprising DnaE2 polymerase and ImuA′ and ImuB accessory proteins – remain elusive. Following exposure of mycobacteria to DNA damaging agents, we observe that DnaE2 and ImuB co-localize with the DNA polymerase III β subunit (β clamp) in distinct intracellular foci. Notably, genetic inactivation of the mutasome in an imuBAAAAGG mutant containing a disrupted β clamp-binding motif abolishes ImuB–β clamp focus formation, a phenotype recapitulated pharmacologically by treating bacilli with griselimycin and in biochemical assays in which this β clamp-binding antibiotic collapses pre-formed ImuB–β clamp complexes. These observations establish the essentiality of the ImuB–β clamp interaction for mutagenic DNA repair in mycobacteria, identifying the mutasome as target for adjunctive therapeutics designed to protect anti-TB drugs against emerging resistance.

Abstract Chronic thromboembolic pulmonary hypertension (CTEPH) is successfully treatable with pulmonary endarterectomy (PEA), balloon pulmonary angioplasty, and medical therapy. Registry to Evaluate Early and Long‐Term Pulmonary Arterial Hypertension Disease Management risk score (RRS) is able to predict long‐term outcome in inoperable patients or in patients with residual PH after surgery. We performed a post hoc analysis of RRS in patients who were enrolled in the CTREPH study (NCT01416636), a randomized, double‐blind clinical trial comparing high‐dose and low‐dose subcutaneous (SC) treprostinil in patients with severe CTEPH that was classified by an interdisciplinary CTEPH team as nonoperable, or as persistent or recurrent pulmonary hypertension after PEA. Baseline mean RRS was similar in both treatment groups (8.7 in high‐dose arm vs. 8.6 in low‐dose arm), but mean RRS change from baseline to Week 24 was greater in the high‐dose treprostinil group than in the low‐dose treprostinil group (−0.88 vs. −0.17). The difference in RRS change from baseline to Week 24 between high dose versus low dose was statistically significant with mean difference of −0.70 (95% confidence interval: −1.36 to −0.05, p = 0.0352), and was driven mainly by improvement of World Health Organization functional class and N‐terminal pro‐brain natriuretic peptide concentration. SC treprostinil therapy administered in standard dose had positive effect on the risk profile measured by RRS in patients with inoperable or persistent/recurrent severe CTEPH. Although our study was limited by the small sample size and post hoc nature, assessment of risk profile is of great importance to this particular patient population with very poor prognosis.

Abstract The Russian attack on Ukraine and the German energy industry’s dependence on Russian gas are currently leading to a very tight supply situation, which could worsen in the coming winter. In the medium term, too, the import price for natural gas is likely to be significantly above historical levels as Europe becomes independent of Russian gas. These developments call for a reassessment of German energy policy, including for the energy transition in the power sector.

Loss of HLA-I gene expression in prostate cancer is associated with repressive chromatin states, which can be reversed by pharmacological DNMT and HDAC inhibition leading to increased activation of co-cultured tumor-specific CD8+ T-cells.

Background: While the detrimental impact of negative emotions on the clinical course of inflammatory bowel disease (IBD) and quality of life has been extensively investigated, evidence for a potential impact of positive emotions is scarce. Objectives: We aim to analyse contributing factors of positive affect and their predictive value for disease course in IBD patients. Design: In this retrospective cohort study, epidemiological, psychosocial and IBD disease characteristics of Swiss IBD cohort study patients were analysed longitudinally. Methods: Epidemiological, psychosocial and disease characteristics were extracted from the database of the Swiss IBD cohort study. Participants’ positive emotions were assessed cross-sectionally with the seven-item Marburg questionnaire (range 1–6) addressing positive affect in different aspects of daily life. Predictors of positive emotions were identified by linear regression. The quantitative longitudinal impact of positive emotions on the further disease course was analysed using a multivariable Cox proportional hazards model. Results: Among 702 IBD patients, those reporting more positive emotions were found to have significantly less intense medical treatment, less pain and fewer depressive symptoms ( p 3.5) experienced longer flare-free survival, also after adjusting for confounders (adjusted hazard ratio: 0.39, p

Poly-ADP ribose polymerase inhibitors (PARPi) are an emerging therapeutic option for the treatment of prostate cancer. Their primary mechanism of action is via induction of synthetic lethality in cells with underlying deficiencies in homologous recombination repair (HRR). In men with metastatic castrate-resistant prostate cancer (mCRPC) and select HRR pathway alterations, PARPi treatment has been shown to induce objective tumor responses as well as improve progression free and overall survival. Presently, there are two PARPi, olaparib and rucaparib, that are FDA approved in the treatment of mCRPC. Ongoing research is focused on identifying which HRR alterations are best suited to predict response to PARPi so that these therapies can be most effectively utilized in the clinic. While resistance to PARPi remains a concern, combination therapies may represent a mechanism to overcome or delay resistance.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare major vessel pulmonary vascular disease that is characterised by fibrotic obstructions deriving from an organised clot. Recent advances in treatments for CTEPH have significantly improved outcomes. Apart from classical surgical pulmonary endarterectomy, balloon pulmonary angioplasty (BPA) and vasodilator drugs that were tested in randomised controlled trials of non-operable patients are now available. In Europe, CTEPH affects males and females equally. In the first European CTEPH Registry, women with CTEPH underwent pulmonary endarterectomy less frequently than men, especially at low-volume centres. In Japan, CTEPH is more common in females and is predominantly treated by BPA. More data on gender-specific outcomes are expected from the results of the International BPA Registry (NCT03245268).

Precision oncology is important for patient treatment. Here the authors review the current applications of microfluidic systems to cancer precision medicine, and discuss the issues that must be addressed prior to getting these technologies into the clinic.

European flood frequency and intensity change on a multidecadal scale. Floods were more frequent in the 19th (central Europe) and early 20th century (western Europe) than during the mid-20th century and again more frequent since the 1970s. The causes of this variability are not well understood and the relation to climate change is unclear. Palaeoclimate studies from the northern Alps suggest that past flood-rich periods coincided with cold periods. In contrast, some studies suggest that more floods might occur in a future, warming world. Here we address the contribution of atmospheric circulation and of warming to multidecadal flood variability. For this, we use long series of annual peak streamflow, daily weather data, reanalyses, and reconstructions. We show that both changes in atmospheric circulation and moisture content affected multidecadal changes of annual peak streamflow in central and western Europe over the past two centuries. We find that during the 19th and early 20th century, atmospheric circulation changes led to high peak values of moisture flux convergence. The circulation was more conducive to strong and long-lasting precipitation events than in the mid-20th century. These changes are also partly reflected in the seasonal mean circulation and reproduced in atmospheric model simulations, pointing to a possible role of oceanic variability. For the period after 1980, increasing moisture content in a warming atmosphere led to extremely high moisture flux convergence. Thus, the main atmospheric driver of flood variability changed from atmospheric circulation variability to water vapour increase.

Abstract Introduction PD-L1 expression in non-small cell lung cancer (NSCLC) predicts response to immune checkpoint blockade, however is an imperfect biomarker given tumor heterogeneity, and the antigen presentation pathway requiring other components including HLA I expression. HLA I downregulation may contribute to resistance, warranting its evaluation in attempts to guide patient selection. In addition, earlier detection of acquired resistance could prompt earlier change in treatment and prolong patient survival. Analysis of circulating tumor cells (CTCs) captures heterogeneity across multiple sites of metastases, enables detection of changes in tumor burden that precede radiographic response, and can be obtained in serial fashion. Methods To quantify the expression of both PD-L1 and HLA I on CTCs, we developed exclusion-based sample preparation technology, achieving high-yield with gentle magnetic movement of antibody-labeled cells through virtual barriers of surface tension. To achieve clinical-grade quantification of rare cells, we employ high quality fluorescence microscopy image acquisition and automated image analysis together termed quantitative microscopy. Results In preparation for clinical laboratory implementation, we demonstrate high precision and accuracy of these methodologies using a diverse set of control materials. Preliminary testing of CTCs isolated from patients with NSCLC demonstrate heterogeneity in PD-L1 and HLA I expression and promising clinical value in predicting PFS in response to PD-L1 targeted therapies. Conclusions By confirming high performance, we ensure compatibility for clinical laboratory implementation and future application to better predict and detect resistance to PD-L1 targeted therapy in patients with NSCLC.