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We investigate the contrasting realities of the pandemic on psychosocial experiences and ways of coping among American Voices Project respondent surveys (N = 720) and interviews (N = 172). Despite similar levels of distress early in the pandemic, by late 2020 clear differences across education, race and ethnicity, and gender emerged, both quantitatively and qualitatively. Those with structural advantages reported greater gains from the pandemic, including self-improvement opportunities like therapy and time outdoors. In contrast, respondents without college degrees, Black and Hispanic individuals, and women reported experiencing greater psychosocial shocks into the later months of 2020 and feeling disproportionately undervalued, socially disconnected, and stressed, respectively. The former two groups also systematically differed in their coping strategies, which included hard work, emotion suppression, and faith.

Atmospheric effects, such as turbulence and background thermal noise, inhibit the propagation of light used in ON–OFF keying (OOK) free-space optical (FSO) communication. Here we present and experimentally validate a convolutional neural network (CNN) to reduce the bit error rate of FSO communication in post-processing that is significantly simpler and cheaper than existing solutions based on advanced optics. Our approach consists of two neural networks, the first determining the presence of bit sequences in thermal noise and turbulence and the second demodulating the bit sequences. All data used for training and testing our network is obtained experimentally by generating OOK bit streams, combining these with thermal light, and passing the resultant light through a turbulent water tank which we have verified mimics turbulence in the air to a high degree of accuracy. Our CNN improves detection accuracy over threshold classification schemes and has the capability to be integrated with current demodulation and error correction schemes.

Within psychology, efforts to address racial-ethnic disparities in students' academic outcomes have focused primarily on students themselves. But there is another important person in classrooms: the teacher. In the United States, most racial-ethnically minoritized students are taught by White teachers. Drawing on research on cross-race interactions, we argue that for White teachers--especially those new to the profession--this dynamic is likely to elicit psychological threat, which then undermines their relationships with students, their well-being, and their effectiveness as an instructor. We hypothesized that values affirmation, a technique to mitigate threat and stress, could improve these outcomes. We randomly assigned White public school teachers (N = 109) at schools serving predominantly minoritized students to complete a values affirmation exercise or a matched control exercise in the fall of their first year of teaching. Five months later, affirmed teachers reported greater well-being and better teacher-student relationships than their control counterparts, and their classrooms were rated as more rigorous and more supportive of students' academic growth by trained observers.

Typically 20–40 extreme cyclone events (sometimes called ‘weather bombs’) occur in the Arctic North Atlantic per winter season, with an increasing trend of 6 events/decade over 1979–2015, according to 6 hourly station data from Ny-Ålesund. This increased frequency of extreme cyclones is consistent with observed significant winter warming, indicating that the meridional heat and moisture transport they bring is a factor in rising temperatures in the region. The winter trend in extreme cyclones is dominated by a positive monthly trend of about 3–4 events/decade in November–December, due mainly to an increasing persistence of extreme cyclone events. A negative trend in January opposes this, while there is no significant trend in February. We relate the regional patterns of the trend in extreme cyclones to anomalously low sea-ice conditions in recent years, together with associated large-scale atmospheric circulation changes such as ‘blockinglike’ circulation patterns (e.g. Scandinavian blocking in December and Ural blocking during January–February).

Abstract Increasing number of Janus kinase (JAK) inhibitors have been approved for chronic haematopoietic neoplasms and inflammatory/autoimmune diseases. We aimed to assess safety of the first three approved JAK inhibitors: ruxolitinib, tofacitinib and baricitinib. In this retrospective observational study, pharmacovigilance data were extracted from the World Health Organization database. Adverse events are classified according to Medical Dictionary for Regulatory Activities hierarchy. Until February 28, 2021, all Individual Case Safety Reports [ICSRs] with the suspected drug ruxolitinib, tofacitinib or baricitinib were included. Disproportionality analysis was performed and the information component (IC) was estimated. Adverse events were considered a significant signal if the lower end of the 95% credibility interval of the IC (IC025) was positive. We identified 126,815 ICSRs involving JAK inhibitors. Ruxolitinib, tofacitinib and baricitinib were associated with infectious adverse events (IC025 1.7, especially with viral [herpes and influenza], fungal, and mycobacterial infectious disorders); musculoskeletal and connective tissue disorders (IC025 1.1); embolism and thrombosis (IC025 0.4); and neoplasms (IC025 0.8, especially malignant skin neoplasms). Tofacitinib was associated with gastrointestinal perforation events (IC025 1.5). We did not find a significant increase in the reporting of major cardiovascular events. We identified significant association between adverse events and ruxolitinib, tofacinitib and baricitinib in international pharmacovigilance database.

Abstract Background Inflammatory bowel disease (IBD) treatment paradigms recommend objective disease activity assessment and reactive therapeutic drug monitoring (TDM) prior to changes in biologic therapy. We aimed to describe objective marker and TDM assessment in routine clinical practice prior to biologic therapeutic changes in adult IBD patients. Methods TARGET-IBD is a prospective longitudinal cohort of over 2100 IBD patients receiving usual care at 34 US academic or community centers enrolled between June 2017 and October 2019 who received biologic therapy and had a dose change or biologic discontinuation for lack of efficacy. Objective markers of disease activity within 12 weeks prior included fecal calprotectin, C-reactive protein (CRP), endoscopy, computed tomography (CT) and magnetic resonance imaging (MRI). TDM data for infliximab or adalimumab was obtained. Results 525 patients (71.4% Crohn’s disease [CD], 28.6% ulcerative colitis [UC]) receiving biologic therapy underwent dose change (55.6%) or discontinuation (44.4%) for lack of efficacy. The majority were Caucasian (85.7%), 18–39 years old (52.2%), privately insured (81.5%), and at academic centers (73.7%). For dose changes, 67.5% had at least one objective disease activity assessment or TDM in the 12 weeks prior (CD 67.9%, UC 66.2%; P = 0.79). The most common objective marker was CRP in both CD (39.1%) and UC (54.5%). CRP and calprotectin were used significantly more in UC (P = 0.02 and P = 0.03). TDM was obtained in 30.7% (28.8% UC, 31.4% CD; P = 0.72) prior to dose change. For biologic discontinuation, 79.4% patients underwent objective assessment or TDM prior. In CD, CRP (46.3%) was most common, and CT (P = 0.03) and MRI (P

Rationale and Objective: Chronic kidney disease is a risk enhancing factor for cardiovascular disease (CVD) and mortality, and the role of aspirin use is unclear in this population. We investigated the risk and benefits of aspirin use in primary and secondary prevention of CVD in the Chronic Renal Insufficiency Cohort Study. Study Design: Prospective observational cohort. Setting & Participants: 3,664 Chronic Renal Insufficiency Cohort participants. Exposure: Aspirin use in patients with and without preexisting CVD. Outcomes: Mortality, composite and individual CVD events (myocardial infarction, stroke, and peripheral arterial disease), kidney failure (dialysis and transplant), and major bleeding. Analytical Approach: Intention-to-treat analysis and multivariable Cox proportional hazards model to examine associations of time varying aspirin use. Results: The primary prevention group was composed of 2,578 (70.3%) individuals. Mean age was 57 ± 11 years, 46% women, 42% Black, and 47% had diabetes. The mean estimated glomerular filtration rate was 45 mL/min/1.73 m2. Median follow-up was 11.5 (IQR, 7.4-13) years. Aspirin was not associated with all-cause mortality in those without preexisting cardiovascular disease (CVD) (HR, 0.84; 95% CI, 0.7-1.01; P = 0.06) or those with CVD (HR, 0.88; 95% CI, 0.77-1.02, P = 0.08). Aspirin was not associated with a reduction of the CVD composite in primary prevention (HR, 0.97; 95% CI, 0.77-1.23; P = 0.79) and in secondary prevention because the original study design was not meant to study the effects of aspirin. Limitations: This is not a randomized controlled trial, and therefore, causality cannot be determined. Conclusions: Aspirin use in chronic kidney disease patients was not associated with reduction in primary or secondary CVD events, progression to kidney failure, or major bleeding.

Abstract Background Metastatic breast cancer is a deadly disease with a low 5-year survival rate. Tracking metastatic spread in living patients is difficult and thus poorly understood. Methods Via rapid autopsy, we have collected 30 tumor samples over 3 timepoints and across 8 organs from a triple-negative metastatic breast cancer patient. The large number of sites sampled, together with deep whole-genome sequencing and advanced computational analysis, allowed us to comprehensively reconstruct the tumor’s evolution at subclonal resolution. Results The most unique, previously unreported aspect of the tumor’s evolution that we observed in this patient was the presence of “subclone incubators,” defined as metastatic sites where substantial tumor evolution occurs before colonization of additional sites and organs by subclones that initially evolved at the incubator site. Overall, we identified four discrete waves of metastatic expansions, each of which resulted in a number of new, genetically similar metastasis sites that also enriched for particular organs (e.g., abdominal vs bone and brain). The lung played a critical role in facilitating metastatic spread in this patient: the lung was the first site of metastatic escape from the primary breast lesion, subclones at this site were likely the source of all four subsequent metastatic waves, and multiple sites in the lung acted as subclone incubators. Finally, functional annotation revealed that many known drivers or metastasis-promoting tumor mutations in this patient were shared by some, but not all metastatic sites, highlighting the need for more comprehensive surveys of a patient’s metastases for effective clinical intervention. Conclusions Our analysis revealed the presence of substantial tumor evolution at metastatic incubator sites in a patient, with potentially important clinical implications. Our study demonstrated that sampling of a large number of metastatic sites affords unprecedented detail for studying metastatic evolution.

Commentary on: Fitzcharles M-A, Cohen SP, Clauw DJ, Littlejohn G, Usui C, Häuser W. Chronic primary musculoskeletal pain: a new concept of non-structural regional pain. PAIN Reports 2022;7:e1024. See also: Treede R-D. Chronic musculoskeletal pain: traps and pitfalls in classification and management of a major global disease burden. PAIN Reports 2022;7:e1023.

Purpose: The addition of Pompe disease (Glycogen Storage Disease Type II) to the Recommended Uniform Screening Panel in the United States has led to an increase in the number of variants of uncertain significance (VUS) and novel variants identified in the GAA gene. This presents a diagnostic challenge, especially in the setting of late-onset Pompe disease when symptoms are rarely apparent at birth. There is an unmet need for validated functional studies to aid in classification of GAA variants. Methods: We developed an in vitro mammalian cell expression and functional analysis system based on guidelines established by the Clinical Genome Resource (ClinGen) Sequence Variant Interpretation Working Group for PS3/BS3. We validated the assay with 12 control variants and subsequently analyzed eight VUS or novel variants in GAA identified in patients with a positive newborn screen for Pompe disease without phenotypic evidence of infantile-onset disease.Results: The control variants were analyzed in our expression system and an activity range was established. The pathogenic controls had GAA activity between 0% and 11% of normal. The benign or likely benign controls had an activity range of 54%–100%. The pseudodeficiency variant had activity of 17%. These ranges were then applied to the variants selected for functional studies. Using the threshold of T and c.1103G > A) and provide further evidence to support the classification of likely pathogenic for two variants (c.1721T > C and c.1048G > A). One variant (c.1123C > T) was able to be reclassified based on other supporting evidence. We were unable to reclassify three variants (c.664G > A, c.2450A > G, and c.1378G > A) due to insufficient or conflicting evidence.Conclusion: We investigated eight GAA variants as proof of concept using our validated and reproducible in vitro expression and functional analysis system. While additional work is needed to further refine our system with additional controls and different variant types in order to apply the PS3/BS3 criteria at a higher level, this tool can be utilized for variant classification to meet the growing need for novel GAA variant classification in the era of newborn screening for Pompe disease.

The secreted enzyme interleukin four-induced gene 1 (IL4I1) is involved in the negative control of the adaptive immune response. IL4I1 expression in human cancer is frequent and correlates with poor survival and resistance to immunotherapy. Nevertheless, its mechanism of action remains partially unknown. Here, we identified transmembrane serine protease 13 (TMPRSS13) as an immune cell-expressed surface protein that binds IL4I1. TMPRSS13 is a paralog of TMPRSS2, of which the protease activity participates in the cleavage of SARS-CoV-2 spike protein and facilitates virus induced-membrane fusion. We show that TMPRSS13 is expressed by human lymphocytes, monocytes and monocyte-derived macrophages, can cleave the spike protein and allow SARS-CoV-2 spike pseudotyped virus entry into cells. We identify regions of homology between IL4I1 and spike and demonstrate competition between the two proteins for TMPRSS13 binding. These findings may be relevant for both interfering with SARS-CoV-2 infection and limiting IL4I1-dependent immunosuppressive activity in cancer.

Introduction Diarrhoea remains a leading cause of child morbidity and mortality. Systematically collected and analysed data on the aetiology of hospitalised diarrhoea in low-income and middle-income countries are needed to prioritise interventions.Methods We established the Global Pediatric Diarrhea Surveillance network, in which children under 5 years hospitalised with diarrhoea were enrolled at 33 sentinel surveillance hospitals in 28 low-income and middle-income countries. Randomly selected stool specimens were tested by quantitative PCR for 16 causes of diarrhoea. We estimated pathogen-specific attributable burdens of diarrhoeal hospitalisations and deaths. We incorporated country-level incidence to estimate the number of pathogen-specific deaths on a global scale.Results During 2017–2018, 29 502 diarrhoea hospitalisations were enrolled, of which 5465 were randomly selected and tested. Rotavirus was the leading cause of diarrhoea requiring hospitalisation (attributable fraction (AF) 33.3%; 95% CI 27.7 to 40.3), followed by Shigella (9.7%; 95% CI 7.7 to 11.6), norovirus (6.5%; 95% CI 5.4 to 7.6) and adenovirus 40/41 (5.5%; 95% CI 4.4 to 6.7). Rotavirus was the leading cause of hospitalised diarrhoea in all regions except the Americas, where the leading aetiologies were Shigella (19.2%; 95% CI 11.4 to 28.1) and norovirus (22.2%; 95% CI 17.5 to 27.9) in Central and South America, respectively. The proportion of hospitalisations attributable to rotavirus was approximately 50% lower in sites that had introduced rotavirus vaccine (AF 20.8%; 95% CI 18.0 to 24.1) compared with sites that had not (42.1%; 95% CI 33.2 to 53.4). Globally, we estimated 208 009 annual rotavirus-attributable deaths (95% CI 169 561 to 259 216), 62 853 Shigella-attributable deaths (95% CI 48 656 to 78 805), 36 922 adenovirus 40/41-attributable deaths (95% CI 28 469 to 46 672) and 35 914 norovirus-attributable deaths (95% CI 27 258 to 46 516).Conclusions Despite the substantial impact of rotavirus vaccine introduction, rotavirus remained the leading cause of paediatric diarrhoea hospitalisations. Improving the efficacy and coverage of rotavirus vaccination and prioritising interventions against Shigella, norovirus and adenovirus could further reduce diarrhoea morbidity and mortality.

Monosomy 7 and myelodysplastic syndrome (MDS) are two extremely rare medical conditions. Co-occurrence of these conditions is even less common and associated with an increased risk for an aggressive form of leukemia. Due to the rarity of these conditions, there is limited knowledge of morbidity, especially the impact on behavior and cognitive development in children. In this case series we present three siblings with monosomy 7/MDS who underwent neuropsychological assessments. A range of cognitive skills were assessed including intellectual functioning, verbal and nonverbal skills, memory, attention, executive functioning, academics and fine motor skills. In addition, behavioral and emotional symptoms were assessed with parent ratings. Verbal reasoning was found to be preserved, and none of the siblings were not found to demonstrate problems with externalizing behaviors. Despite these commonalities, there was significant variability in cognitive skills among siblings. Variability in presentation was considered with respect to age, intervention services, and treatment factors. Bone marrow transplantation and age at which the sibling received transplant may predict cognitive risk. Female sex may play a protective role against social difficulties associated with Autism Spectrum Disorder. Additional research is needed to further clarify potential contributing factors to cognitive and behavioral problems in order to inform monitoring and intervention guidelines.

High-grade serous ovarian cancer (HGSOC) is prone to developing resistance to treatment. Here, the authors use single-cell RNA-seq and an analysis of archetypes, and find that shifts in metabolism and proliferation are associated with the response to treatment and clonal heterogeneity in HGSOC.

Patients with chronic kidney disease are at risk of developing cardiovascular disease. To facilitate out-of-clinic evaluation, we piloted wearable device-based analysis of heart rate variability and behavioral readouts in patients with chronic kidney disease from the Chronic Renal Insufficiency Cohort and controls (n = 49). Time-specific partitioning of heart rate variability readouts confirm higher parasympathetic nervous activity during the night (mean RR at night 14.4 ± 1.9 ms vs. 12.8 ± 2.1 ms during active hours; n = 47, analysis of variance (ANOVA) q = 0.001). The α2 long-term fluctuations in the detrended fluctuation analysis, a parameter predictive of cardiovascular mortality, significantly differentiated between diabetic and nondiabetic patients (prominent at night with 0.58 ± 0.2 vs. 0.45 ± 0.12, respectively, adj. p = 0.004). Both diabetic and nondiabetic chronic kidney disease patients showed loss of rhythmic organization compared to controls, with diabetic chronic kidney disease patients exhibiting deconsolidation of peak phases between their activity and standard deviation of interbeat intervals rhythms (mean phase difference chronic kidney disease 8.3 h, chronic kidney disease/type 2 diabetes mellitus 4 h, controls 6.8 h). This work provides a roadmap toward deriving actionable clinical insights from the data collected by wearable devices outside of highly controlled clinical environments.

Abstract Advanced and metastatic estrogen receptor‐positive (ER+) breast cancers are often endocrine resistant. However, endocrine therapy remains the primary treatment for all advanced ER+ breast cancers. Treatment options that may benefit resistant cancers, such as add‐on drugs that target resistance pathways or switching to chemotherapy, are only available after progression on endocrine therapy. Here we developed an endocrine therapy prognostic model for early and advanced ER+ breast cancers. The endocrine resistance (ENDORSE) model is composed of two components, each based on the empirical cumulative distribution function of ranked expression of gene signatures. These signatures include a feature set associated with long‐term survival outcomes on endocrine therapy selected using lasso‐regularized Cox regression and a pathway‐based curated set of genes expressed in response to estrogen. We extensively validated ENDORSE in multiple ER+ clinical trial datasets and demonstrated superior and consistent performance of the model over clinical covariates, proliferation markers, and multiple published signatures. Finally, genomic and pathway analyses in patient data revealed possible mechanisms that may help develop rational stratification strategies for endocrine‐resistant ER+ breast cancer patients.

Background: Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). Here, we report steroid-free efficacy and safety with tofacitinib among patients with UC who received corticosteroids at baseline of the maintenance study (OCTAVE Sustain). Methods: This analysis included patients with clinical response following OCTAVE Induction 1 and 2 who were re-randomized to receive placebo, or tofacitinib 5 or 10 mg twice daily (b.d.), in OCTAVE Sustain for 52 weeks and were receiving corticosteroids at OCTAVE Sustain baseline. Corticosteroid tapering was mandatory during OCTAVE Sustain. Rates of steroid-free remission, endoscopic improvement, and clinical response were assessed, stratified by baseline characteristics. Adverse events (AEs) were stratified by treatment and steroid-free remission status. Results: Overall, 289/593 patients had corticosteroid use at OCTAVE Sustain baseline. At week 52, steroid-free remission, endoscopic improvement, and clinical response rates were 10.9%, 11.9%, and 17.8% among patients receiving placebo, 27.7%, 29.7%, and 40.6% among patients receiving tofacitinib 5 mg b.d., and 27.6%, 29.9%, and 43.7% among patients receiving tofacitinib 10 mg b.d., respectively (non-responder imputation; all p

We developed and tested strategies for using spatial representations to help students understand core probability concepts, including the multiplication rule for computing a joint probability from a marginal and conditional probability, interpreting an odds value as the ratio of two probabilities, and Bayesian inference. The general goal of these strategies is to promote active learning by introducing concepts in an intuitive spatial format and then encouraging students to try to discover the explicit equations associated with the spatial representations. We assessed the viability of the proposed active-learning approach with two exercises that tested undergraduates’ ability to specify mathematical equations after learning to use the spatial solution method. A majority of students succeeded in independently discovering fundamental mathematical concepts underlying probabilistic reasoning. For example, in the second exercise, 76% of students correctly multiplied marginal and conditional probabilities to find joint probabilities, 86% correctly divided joint probabilities to get an odds value, and 69% did both to achieve full Bayesian inference. Thus, we conclude that the spatial method is an effective way to promote active learning of probability equations.

Abstract Background Neuroblastoma is the most common pediatric solid tumor. MYCN‐amplification is an important negative prognostic indicator and inherited genetic contributions to risk are incompletely understood. Genetic determinants of stature increase risk of several adult and childhood cancers, but have not been studied in neuroblastoma despite elevated neuroblastoma incidence in children with congenital overgrowth syndromes. Methods We investigated the association between genetic determinants of height and neuroblastoma risk in 1538 neuroblastoma cases, stratified by MYCN‐amplification status, and compared to 3390 European‐ancestry controls using polygenic scores for birth length (five variants), childhood height (six variants), and adult height (413 variants). We further examined the UK Biobank to evaluate the association of known neuroblastoma risk loci and stature. Results An increase in the polygenic score for childhood stature, corresponding to a ~0.5 cm increase in pre‐pubertal height, was associated with greater risk of MYCN‐amplified neuroblastoma (OR = 1.14, P = .047). An increase in the polygenic score for adult stature, corresponding to a ~1.7 cm increase in adult height attainment, was associated with decreased risk of MYCN‐amplified neuroblastoma (OR = 0.87, P = .047). These associations persisted in case‐case analyses comparing MYCN‐amplified to MYCN‐unamplified neuroblastoma. No polygenic height scores were associated with MYCN‐unamplified neuroblastoma risk. Previously identified genome‐wide association study hits for neuroblastoma (N = 10) were significantly enriched for association with both childhood (P = 4.0 × 10−3) and adult height (P = 8.9 × 10−3) in >250 000 UK Biobank study participants. Conclusions Genetic propensity to taller childhood height and shorter adult height were associated with MYCN‐amplified neuroblastoma risk, suggesting that biological pathways affecting growth trajectories and pubertal timing may contribute to MYCN‐amplified neuroblastoma etiology.

The process wherein dividing cells exhaust proliferative capacity and enter into replicative senescence has become a prominent model for cellular aging in vitro. Despite decades of study, this cellular state is not fully understood in culture and even much less so during aging. Here, we revisit Leonard Hayflick’s original observation of replicative senescence in WI-38 human lung fibroblasts equipped with a battery of modern techniques including RNA-seq, single-cell RNA-seq, proteomics, metabolomics, and ATAC-seq. We find evidence that the transition to a senescent state manifests early, increases gradually, and corresponds to a concomitant global increase in DNA accessibility in nucleolar and lamin associated domains. Furthermore, we demonstrate that senescent WI-38 cells acquire a striking resemblance to myofibroblasts in a process similar to the epithelial to mesenchymal transition (EMT) that is regulated by t YAP1/TEAD1 and TGF-β2. Lastly, we show that verteporfin inhibition of YAP1/TEAD1 activity in aged WI-38 cells robustly attenuates this gene expression program.

Generating photonic cluster states using a single non-heralded source and a single entangling gate would optimise scalability and reduce resource overhead. Here, the authors generate up to 4-photon cluster states using a quantum dot coupled to a fibre loop, with a fourfold generation rate of 10 Hz.

A novel classification technique based on definition of unique spectral relations (such as slopes among spectral bands) for all land cover types named (SSF Significant Spectral Features) is presented in the article.A large slopes combination between spectral band pairs is calculated and spectral characterizations that emphasizes the best spectral land cover separation is sought. Increasing in dimensionality of spectral representations is balanced by the simplicity of calculations. The technique has been examined on data acquired by a flown hyperspectral scanner (AISA). The spectral data was narrowed into the equivalent 8 world-view2 channels. The research area was in the city of “Hadera”, Israel, which included 10 land cover types in an urban area, open area and road infrastructure. The comparison between the developed SSF technique and common techniques such as: SVM (Support Vector Machine) and ML (Maximum Likelihood) has shown a clear advantage over ML technique, while produced similar results as SVM. The poorest results of using SSF technique was achieved in an herbaceous area (70%). However, the simplicity of the method, the well-defined parameters it produces for interpreting the results, makes it intuitive over using techniques such as SVM, which is considered as a not explicit classifier.

Abstract Background Although the 21-gene recurrence score (RS) assay is widely used to predict distant recurrence risk and benefit from adjuvant chemotherapy among women with hormone receptor-positive (HR+) breast cancer, the relationship between the RS and isolated locoregional recurrence (iLRR) remains poorly understood. Therefore, we examined the association between the RS and risk of iLRR for women with stage I-II, HR+ breast cancer. Methods We identified 1758 women captured in the national prospective Breast Cancer-Collaborative Outcomes Research Database who were diagnosed with stage I-II, HR+ breast cancer from 2006 to 2012, treated with mastectomy or breast-conserving surgery, and received RS testing. Women who received neoadjuvant therapy were excluded. The association between the RS and risk of iLRR was examined using competing risks regression. Results Overall, 19% of the cohort (n = 329) had a RS ≥25. At median follow-up of 29 months, only 22 iLRR events were observed. Having a RS ≥25 was not associated with a significantly higher risk of iLRR compared to a RS

Abstract Background The number of cases from the coronavirus disease 2019 (COVID-19) global pandemic has overwhelmed existing medical facilities and forced clinicians, patients, and families to make pivotal decisions with limited time and information. Main body While machine learning (ML) methods have been previously used to augment clinical decisions, there is now a demand for “Emergency ML.” Throughout the patient care pathway, there are opportunities for ML-supported decisions based on collected vitals, laboratory results, medication orders, and comorbidities. With rapidly growing datasets, there also remain important considerations when developing and validating ML models. Conclusion This perspective highlights the utility of evidence-based prediction tools in a number of clinical settings, and how similar models can be deployed during the COVID-19 pandemic to guide hospital frontlines and healthcare administrators to make informed decisions about patient care and managing hospital volume.

Abstract Background Endothelial progenitor cells (EPCs) are non-differentiated endothelial cells (ECs) present in blood circulation that are involved in neo-vascularization and correction of damaged endothelial sites. Since EPCs from patients with vascular disorders are impaired and inefficient, allogenic sources from adult or cord blood are considered as good alternatives. However, due to the reaction of immune system against allogenic cells which usually lead to their elimination, we focused on the exact role of EPCs on immune cells, particularly, T cells which are the most important cells applied in immune rejection. TNFα is one of the main activators of EPCs that recognizes two distinct receptors. TNFR1 is expressed ubiquitously and its interaction with TNFα leads to differentiation and apoptosis, whereas, TNFR2 is expressed predominantly on ECs, immune cells and neural cells and is involved in cell survival and proliferation. Interestingly, it has been shown that different immunosuppressive cells express TNFR2 and this is directly related to their immunosuppressive efficiency. However, little is known about immunological profile and function of TNFR2 in EPCs. Methods Using different in-vitro combinations, we performed co-cultures of ECs and T cells to investigate the immunological effect of EPCs on T cells. We interrupted in the TNFα/TNFR2 axis either by blocking the receptor using TNFR2 antagonist or blocking the ligand using T cells derived from TNFα KO mice. Results We demonstrated that EPCs are able to suppress T cell proliferation and modulate them towards less pro-inflammatory and active phenotypes. Moreover, we showed that TNFα/TNFR2 immune-checkpoint pathway is critical in EPC immunomodulatory effect. Conclusions Our results reveal for the first time a mechanism that EPCs use to suppress immune cells, therefore, enabling them to form new immunosuppressive vessels. Furthermore, we have shown the importance of TNFα/TNFR2 axis in EPCs as an immune checkpoint pathway. We believe that targeting TNFR2 is especially crucial in cancer immune therapy since it controls two crucial aspects of tumor microenvironment: 1) Immunosuppression and 2) Angiogenesis. Video Abstract. (MP4 46355 kb)

Abstract Background The majority of eyewitness lineup studies are laboratory-based. How well the conclusions of these studies, including the relationship between confidence and accuracy, generalize to real-world police lineups is an open question. Signal detection theory (SDT) has emerged as a powerful framework for analyzing lineups that allows comparison of witnesses’ memory accuracy under different types of identification procedures. Because the guilt or innocence of a real-world suspect is generally not known, however, it is further unknown precisely how the identification of a suspect should change our belief in their guilt. The probability of guilt after the suspect has been identified, the posterior probability of guilt (PPG), can only be meaningfully estimated if we know the proportion of lineups that include a guilty suspect, P(guilty). Recent work used SDT to estimate P(guilty) on a single empirical data set that shared an important property with real-world data; that is, no information about the guilt or innocence of the suspects was provided. Here we test the ability of the SDT model to recover P(guilty) on a wide range of pre-existing empirical data from more than 10,000 identification decisions. We then use simulations of the SDT model to determine the conditions under which the model succeeds and, where applicable, why it fails. Results For both empirical and simulated studies, the model was able to accurately estimate P(guilty) when the lineups were fair (the guilty and innocent suspects did not stand out) and identifications of both suspects and fillers occurred with a range of confidence levels. Simulations showed that the model can accurately recover P(guilty) given data that matches the model assumptions. The model failed to accurately estimate P(guilty) under conditions that violated its assumptions; for example, when the effective size of the lineup was reduced, either because the fillers were selected to be poor matches to the suspect or because the innocent suspect was more familiar than the guilty suspect. The model also underestimated P(guilty) when a weapon was shown. Conclusions Depending on lineup quality, estimation of P(guilty) and, relatedly, PPG, from the SDT model can range from poor to excellent. These results highlight the need to carefully consider how the similarity relations between fillers and suspects influence identifications.

We introduce the statistical concept of 'compensatory selection', which arises when selecting a subset of applicants based on multiple predictors, such as when standardized test scores are used in combination with other predictors required in a school application (e.g., previous grades, references letters, and personal statements). Post-hoc analyses often fail to find a positive correlation between test scores and subsequent success, and this failure is sometimes taken as evidence against the predictive validity of the standardized test. The present analysis reveals that the failure to find a negative correlation indicates that the standardized test is in fact a valid predictor of success. This is due to compensation between predictors during selection: Some students are admitted despite a low test score because their application is exceptional in other respects, while other students are admitted primarily based on a high test score despite weakness in the rest of their application. This compensatory selection process introduces a negative correlation between test scores and other predictors among those admitted (a 'collider bias' or 'Berkson's paradox' effect). If test scores are valid predictors of success, this negative correlation between the predictors counteracts the positive correlation between test scores and success that would have been observed if all applicants were admitted. If test scores are not predictive of success, but were nevertheless used in a compensatory selection process, there would be a spurious negative correlation between test scores and success (i.e., an admitted student with a weak application except for a high test score would be unlikely to succeed). The selection effect that is described here is fundamentally different from the well-known 'restricted range' problem and can powerfully alter results even in situations that accept most applicants.

Understanding the distribution of pathogens causing acute febrile illness (AFI) is important for clinical management of patients in resource-poor settings. We evaluated the proportion of AFI caused by specific pathogens among outpatients in Bangladesh. During May 2019-March 2020, physicians screened patients aged ≥2 years in outpatient departments of four tertiary level public hospitals. We randomly enrolled patients having measured fever (≥100.4°F) during assessment with onset within the past 14 days. Blood and urine samples were tested at icddr,b through rapid diagnostic tests, bacterial culture, and polymerase chain reaction (PCR). Acute and convalescent samples were sent to the Centers for Disease Control and Prevention (USA) for Rickettsia and Orientia (R/O) and Leptospira tests. Among 690 patients, 69 (10%) had enteric fever (Salmonella enterica serotype Typhi orSalmonella enterica serotype Paratyphi), 51 (7.4%) Escherichia coli, and 28 (4.1%) dengue detected. Of the 441 patients tested for R/O, 39 (8.8%) had rickettsioses. We found 7 (2%) Leptospira cases among the 403 AFI patients tested. Nine patients (1%) were hospitalized, and none died. The highest proportion of enteric fever (15%, 36/231) and rickettsioses (14%, 25/182) was in Rajshahi. Dhaka had the most dengue cases (68%, 19/28). R/O affected older children and young adults (IQR 8-23 years) and was detected more frequently in the 21-25 years age-group (17%, 12/70). R/O was more likely to be found in patients in Rajshahi region than in Sylhet (aOR 2.49, 95% CI 0.85-7.32) between July and December (aOR 2.01, 1.01-5.23), and who had a history of recent animal entry inside their house than not (aOR 2.0, 0.93-4.3). Gram-negative Enterobacteriaceae were the most common bacterial infections, and dengue was the most common viral infection among AFI patients in Bangladeshi hospitals, though there was geographic variability. These results can help guide empiric outpatient AFI management.

After introduction of rotavirus vaccine, other pathogens might become leading causes of hospitalizations for severe diarrhea among children

Abstract Ocular surface squamous neoplasia is the most common tumour of the ocular surface. It is a spectrum of disease from intraepithelial dysplasia to invasive squamous cell carcinoma. Recent years have seen an increase in the use of topical chemotherapeutic agents to treat this condition, often as primary treatment without full-thickness biopsy. This practical approach provides a critical appraisal of the evidence base with the goal being to aid the clinician in the management of these patients.

Abstract Conjunctival melanoma is a rare malignant condition of the ocular surface. It is potentially lethal, with regional lymph node spread often preceding distant solid-organ metastasis. Due to its rarity and the long latency between treatment and local recurrence or the development of metastases, it is difficult to study. The literature is composed entirely of case series of varying quality, and there is significant variability in the management of this condition. This commentary attempts to distil the evidence base to provide practical management tips for the clinician.

The SARS-CoV-2 Delta variant emerged shortly after COVID-19 vaccines became available in 2021. We describe SARS-CoV-2 breakthrough infections in a highly vaccinated, well-monitored US Embassy community in Kampala, Uganda. Defining breakthrough infection rates in highly vaccinated populations can help determine public health messaging, guidance, and policy globally.

Newly discovered anti-cancer immunotherapies, such as immune checkpoint inhibitors and chimeric antigen receptor T cells, focus on spurring the anti-tumor effector T cell (Teff) response. Although such strategies have already demonstrated a sustained beneficial effect in certain malignancies, a substantial proportion of treated patients does not respond. CD4+FOXP3+ regulatory T cells (Tregs), a suppressive subset of T cells, can impair anti-tumor responses and reduce the efficacy of currently available immunotherapies. An alternative view that has emerged over the last decade proposes to tackle this immune brake by targeting the suppressive action of Tregs on the anti-tumoral response. It was recently demonstrated that the tumor necrosis factor alpha (TNF-α) tumor necrosis factor receptor 2 (TNFR2) is critical for the phenotypic stabilization and suppressive function of human and mouse Tregs. The broad non-specific effects of TNF-α infusion in patients initially led clinicians to abandon this signaling pathway as first-line therapy against neoplasms. Previously unrecognized, TNFR2 has emerged recently as a legitimate target for anti-cancer immune checkpoint therapy. Considering the accumulation of pre-clinical data on the role of TNFR2 and clinical reports of TNFR2+ Tregs and tumor cells in cancer patients, it is now clear that a TNFR2-centered approach could be a viable strategy, once again making the TNF-α pathway a promising anti-cancer target. Here, we review the role of the TNFR2 signaling pathway in tolerance and the equilibrium of T cell responses and its connections with oncogenesis. We analyze recent discoveries concerning the targeting of TNFR2 in cancer, as well as the advantages, limitations, and perspectives of such a strategy.

In the context of the global covid-19 pandemic, educators at all levels had to re-imagine their teaching practices to respond to the necessity of conducting all courses on-line. This article reports on the collaboration of two university instructors to create a trans-national model of learning in the context of the covid-19 pandemic. By virtue of this collaboration, the efl students based at a large public university in Colombia were engaged in four online sessions and paired with teacher candidates taking an esl endorsement course in the United States. This online collaboration afforded the Colombian efl students an authentic opportunity to practice their English learning and the us teacher candidates a meaningful context in which to conduct authentic language assessments. Using interview and questionnaire data, this qualitative case study explored the experiences of the efl students. The data demonstrate that online exchanges can afford students meaningful opportunities for language development. The results further show that online learning can be enriched through mutually beneficial collaborations across universities and transnational contexts.