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Abstract Intratumoral heterogeneity is an important clinical challenge because low burden clones expressing specific genetic alterations drive therapeutic resistance mechanisms. We have developed CAVE (cancer-associated variant enrichment), a gene-agnostic computational tool to identify specific enrichment of low-burden cancer driver variants in next-generation sequencing (NGS) data. For this study, CAVE was applied to TP53 in chronic lymphocytic leukemia (CLL) as a cancer model. Indeed, as TP53 mutations are part of treatment decision-making algorithms and low-burden variants are frequent, there is a need to distinguish true variants from background noise. Recommendations have been published for reliable calling of low-VAF variants of TP53 in CLL and the assessment of the background noise for each platform is essential for the quality of the testing. CAVE is able to detect specific enrichment of low-burden variants starting at variant allele frequencies (VAFs) as low as 0.3%. In silico TP53 dependent and independent analyses confirmed the true driver nature of all these variants. Orthogonal validation using either ddPCR or NGS analyses of follow-up samples confirmed variant identification. CAVE can be easily deployed in any cancer-related NGS workflow to detect the enrichment of low-burden variants of clinical interest.

Abstract Understanding individuals’ distinct movement patterns is crucial for health, rehabilitation, and sports. Recently, we developed a machine learning-based framework to show that “gait signatures” describing the neuromechanical dynamics governing able-bodied and post-stroke gait kinematics remain individual-specific across speeds. However, we only evaluated gait signatures within a limited speed range and number of participants, using only sagittal plane (i.e., 2D) joint angles. Here we characterized changes in gait signatures across a wide range of speeds, from very slow (0.3 m/s) to exceptionally fast (above the walk-to-run transition speed) in 17 able-bodied young adults. We further assessed whether 3D kinematic and/or kinetic (ground reaction forces, joint moments, and powers) data would improve the discrimination of gait signatures. Our study showed that gait signatures remained individual-specific across walking speeds: Notably, 3D kinematic signatures achieved exceptional accuracy (99.8%, confidence interval (CI) 99.1–100%) in classifying individuals, surpassing both 2D kinematics and 3D kinetics. Moreover, participants exhibited consistent, predictable linear changes in their gait signatures across the entire speed range. These changes were associated with participants’ preferred walking speeds, balance ability, cadence, and step length. These findings support gait signatures as a tool to characterize individual differences in gait and predict speed-induced changes in gait dynamics.

Abstract HistoLens is an open-source graphical user interface developed using MATLAB AppDesigner for visual and quantitative analysis of histological datasets. HistoLens enables users to interrogate sets of digitally annotated whole slide images to efficiently characterize histological differences between disease and experimental groups. Users can dynamically visualize the distribution of 448 hand-engineered features quantifying color, texture, morphology, and distribution across microanatomic sub-compartments. Additionally, users can map differentially detected image features within the images by highlighting affected regions. We demonstrate the utility of HistoLens to identify hand-engineered features that correlate with pathognomonic renal glomerular characteristics distinguishing diabetic nephropathy and amyloid nephropathy from the histologically unremarkable glomeruli in minimal change disease. Additionally, we examine the use of HistoLens for glomerular feature discovery in the Tg26 mouse model of HIV-associated nephropathy. We identify numerous quantitative glomerular features distinguishing Tg26 transgenic mice from wild-type mice, corresponding to a progressive renal disease phenotype. Thus, we demonstrate an off-the-shelf and ready-to-use toolkit for quantitative renal pathology applications.

Abstract Differential diagnosis is a crucial aspect of medical practice, as it guides clinicians to accurate diagnoses and effective treatment plans. Traditional resources, such as medical books and services like UpToDate, are constrained by manual curation, potentially missing out on novel or less common findings. This paper introduces and analyzes two novel methods to mine etiologies from scientific literature. The first method employs a traditional Natural Language Processing (NLP) approach based on syntactic patterns. By using a novel application of human-guided pattern bootstrapping patterns are derived quickly, and symptom etiologies are extracted with significant coverage. The second method utilizes generative models, specifically GPT-4, coupled with a fact verification pipeline, marking a pioneering application of generative techniques in etiology extraction. Analyzing this second method shows that while it is highly precise, it offers lesser coverage compared to the syntactic approach. Importantly, combining both methodologies yields synergistic outcomes, enhancing the depth and reliability of etiology mining.

Abstract The impact of building morphology on building energy consumption has been extensively studied. However, research on how 3D building morphology affects energy consumption at a macroscopic scale is lacking. In this study, we measured the mean building height (BH), mean building volume (BV), and mean European nearest neighbor distance (MENN) of the city to quantify the 3D building morphology. We then used a spatial regression model to analyze the quantitative impact of urban 3D building morphology on per capita electricity consumption (PCEC). Results indicate that at the macroscopic scale of the city, the BH and the MENN have a significant positive impact on the PCEC, while the BV has a significant negative impact on the PCEC. Moreover, the inclusion of the 3D building morphology greatly improves the model’s ability to explain building energy efficiency, surpassing the impact of traditional economic factors. Considering the 3D building morphology indicators together, buildings with a lower height, a larger volume, and a more compact 3D morphology have greater potential for energy savings and are more conducive to electricity conservation. This study offers valuable insights for the energy-efficient arrangement of buildings.

Abstract Background A clear understanding of public perceptions of the social determinants of health remains lacking. This paper aimed to describe the relationship between income and urbanicity levels and public views of the determinants of health in eight middle-and high-income countries that varied across multiple characteristics. Methods We conducted a cross-sectional online survey in Brazil, China, Germany, Egypt, India, Indonesia, Nigeria, and the United States. Respondents were asked to select what they considered to be most important for health out of a list of ten determinants. We stratified the results by income and urbanicity levels and tested significance of differences between groups using two-tailed χ2 tests. Multivariable logistic regression models tested associations between demographic factors and the likelihood of respondents selecting the genetics, healthcare, income and wealth, or social support determinants. Results Here we show 8753 respondents across eight countries. Rankings of determinants are similar across income groups, except for two determinants. Respondents in the highest income group rank genetics in higher proportions (32.4%, 95%CI: 29.0%,35.8%) compared to other income groups. Conversely, those in lowest income group rank social support more frequently (27.9%, 95%CI: 25.3%,30.7%) than other income groups. Those living in urban settings rank healthcare in higher proportions (61.2%, 95%CI: 59.0%,63.4%) compared to non-urban respondents; meanwhile, higher proportions (26.6%, 95%CI: 24.9%,28.3%) of non-urban respondents rank social support as important for health compared to urban respondents. Conclusion Demographic factors play a role in shaping public views of what affects health. Advancing public understanding about determinants of health requires tailoring public health messaging to account for socioeconomic position within a population.

Abstract Background Definitive local therapy with stereotactic ablative radiation therapy (SABR) for ultracentral lung lesions is associated with a high risk of toxicity, including treatment related death. Stereotactic MR-guided adaptive radiation therapy (SMART) can overcome many of the challenges associated with SABR treatment of ultracentral lesions. Methods We retrospectively identified 14 consecutive patients who received SMART to ultracentral lung lesions from 10/2019 to 01/2021. Patients had a median distance from the proximal bronchial tree (PBT) of 0.38 cm. Tumors were most often lung primary (64.3%) and HILUS group A (85.7%). A structure-specific rigid registration approach was used for cumulative dose analysis. Kaplan-Meier log-rank analysis was used for clinical outcome data and the Wilcoxon Signed Rank test was used for dosimetric data. Results Here we show that SMART dosimetric improvements in favor of delivered plans over predicted non-adapted plans for PBT, with improvements in proximal bronchial tree DMax of 5.7 Gy (p = 0.002) and gross tumor 100% prescription coverage of 7.3% (p = 0.002). The mean estimated follow-up is 17.2 months and 2-year local control and local failure free survival rates are 92.9% and 85.7%, respectively. There are no grade ≥ 3 toxicities. Conclusions SMART has dosimetric advantages and excellent clinical outcomes for ultracentral lung tumors. Daily plan adaptation reliably improves target coverage while simultaneously reducing doses to the proximal airways. These results further characterize the therapeutic window improvements for SMART. Structure-specific rigid dose accumulation dosimetric analysis provides insights that elucidate the dosimetric advantages of SMART more so than per fractional analysis alone.

Abstract Background Systematic reviews are viewed as the best study design to guide clinical decision-making as they are the least biased publications assuming they are well-conducted and include well-designed studies. Cochrane was initiated in 1993 with an aim of conducting high-quality systematic reviews. We aimed to examine the publication rates of non-Cochrane systematic reviews (henceforth referred to simply as “systematic reviews”) and Cochrane reviews produced throughout Cochrane’s existence and characterize changes throughout the period. Methods This observational study collected data on systematic reviews published between 1993 and 2022 in PubMed. Identified Cochrane reviews were linked to data from the Cochrane Database of Systematic Reviews via their Digital Object Identifier. Systematic reviews and Cochrane reviews were analyzed separately. Two authors screened a random sample of records to validate the overall sample, providing a precision of 98%. Results We identified 231,602 (94%) systematic reviews and 15,038 (6%) Cochrane reviews. Publication of systematic reviews has continuously increased with a median yearly increase rate of 26%, while publication of Cochrane reviews has decreased since 2015. From 1993 to 2002, Cochrane reviews constituted 35% of all systematic reviews in PubMed compared with 3.5% in 2013–2022. Systematic reviews consistently had fewer authors than Cochrane reviews, but the number of authors increased over time for both. Chinese first authors conducted 15% and 4% of systematic reviews published from 2013–2022 and 2003–2012, respectively. Most Cochrane reviews had first authors from the UK (36%). The native English-speaking countries the USA, the UK, Canada, and Australia produced a large share of systematic reviews (42%) and Cochrane reviews (62%). The largest publishers of systematic reviews in the last 10 years were gold open access journals. Conclusions Publication of systematic reviews is increasing rapidly, while fewer Cochrane reviews have been published through the last decade. Native English-speaking countries produced a large proportion of both types of systematic reviews. Gold open access journals and Chinese first authors dominated the publication of systematic reviews for the past 10 years. More research is warranted examining why fewer Cochrane reviews are being published. Additionally, examining these systematic reviews for research waste metrics may provide a clearer picture of their utility.

Introducción: En Chile, la Enfermería de Práctica Avanzada (EPA) es un rol emergente. El propósito del estudio es comparar la satisfacción de los pacientes atendidos por una EPA en conjunto con un traumatólogo subespecialista de cadera, con pacientes atendidos en la consulta estándar del traumatólogo de cadera. Material y método: Estudio piloto cuasi-experimental. Se incluyeron pacientes mayores de 18 años que consultaron en un centro ambulatorio docente-asistencial entre los años 2020-2023. Se evaluaron dos grupos, en el grupo experimental la modalidad de atención fue mixta (EPA y un traumatólogo subespecialista de cadera) y en el control los pacientes recibieron atención estándar de un traumatólogo subespecialista de cadera. Se evaluó satisfacción mediante una encuesta de diez preguntas (escala numérica continua de 0 a 100). El instrumento midió la calidad de la atención, diagnóstico y tratamiento, si el paciente volvería a ser tratado bajo esta modalidad de atención y si lo recomendaría a otras personas. Se utilizó las prueba de chi-cuadrado y Mann-Whitney. Resultados: Se evaluaron 108 pacientes. El 49% de los pacientes fueron asignados al grupo de intervención (n=53). La mediana del puntaje de satisfacción total fue de 96,5 puntos (rango 79-100), sin diferencias significativas entre ambos grupos (p 0,26). No se observaron diferencias significativas en las puntuaciones de satisfacción en ninguna de las diez preguntas. Conclusión: No hubo diferencias en los puntajes de satisfacción entre ambas modalidades de atención. Esta es la primera experiencia reportada en Chile sobre la atención otorgada por una enfermera de práctica avanzada, en ortopedia.

Key Clinical Message Perianal alveolar rhabdomyosarcoma is a rare sarcoma that requires a high index of suspicion along with tissue biopsy for accurate diagnosis. Successful treatment, even in the setting of recurrence, requires a multidisciplinary approach.

HIV disease remains prevalent in the USA and chronic kidney disease remains a major cause of morbidity in HIV-1-positive patients. Host double-stranded RNA (dsRNA)-activated protein kinase (PKR) is a sensor for viral dsRNA, including HIV-1. We show that PKR inhibition by compound C16 ameliorates the HIV-associated nephropathy (HIVAN) kidney phenotype in the Tg26 transgenic mouse model, with reversal of mitochondrial dysfunction. Combined analysis of single-nucleus RNA-seq and bulk RNA-seq data revealed that oxidative phosphorylation was one of the most downregulated pathways and identified signal transducer and activator of transcription (STAT3) as a potential mediating factor. We identified in Tg26 mice a novel proximal tubular cell cluster enriched in mitochondrial transcripts. Podocytes showed high levels of HIV-1 gene expression and dysregulation of cytoskeleton-related genes, and these cells dedifferentiated. In injured proximal tubules, cell-cell interaction analysis indicated activation of the pro-fibrogenic PKR-STAT3-platelet-derived growth factor (PDGF)-D pathway. These findings suggest that PKR inhibition and mitochondrial rescue are potential novel therapeutic approaches for HIVAN.

Abstract Myelodysplastic syndrome is primarily characterized by dysplasia in the bone marrow (BM), presenting a challenge in consistent morphology interpretation. Accurate diagnosis through traditional slide-based analysis is difficult, necessitating a standardized objective technique. Over the past two decades, imaging flow cytometry (IFC) has proven effective in combining image-based morphometric analyses with high-parameter phenotyping. We have previously demonstrated the effectiveness of combining IFC with a feature-based machine learning algorithm to accurately identify and quantify rare binucleated erythroblasts (BNEs) in dyserythropoietic BM cells. However, a feature-based workflow poses challenges requiring software-specific expertise. Here we employ a Convolutional Neural Network (CNN) algorithm for BNE identification and differentiation from doublets and cells with irregular nuclear morphology in IFC data. We demonstrate that this simplified AI workflow, coupled with a powerful CNN algorithm, achieves comparable BNE quantification accuracy to manual and feature-based analysis with substantial time savings, eliminating workflow complexity. This streamlined approach holds significant clinical value, enhancing IFC accessibility for routine diagnostic purposes.

Abstract Friedreich’s ataxia is a degenerative and progressive multisystem disorder caused by mutations in the highly conserved frataxin (FXN) gene that results in FXN protein deficiency and mitochondrial dysfunction. While gene therapy approaches are promising, consistent induction of therapeutic FXN protein expression that is sub-toxic has proven challenging, and numerous therapeutic approaches are being tested in animal models. FXN (hFXN in humans, mFXN in mice) is proteolytically modified in mitochondria to produce mature FXN. However, unlike endogenous hFXN, endogenous mFXN is further processed into N-terminally truncated, extra-mitochondrial mFXN forms of unknown function. This study assessed mature exogenous hFXN expression levels in the heart and liver of C57Bl/6 mice 7–10 months after intravenous administration of a recombinant adeno-associated virus encoding hFXN (AAVrh.10hFXN) and examined the potential for hFXN truncation in mice. AAVrh.10hFXN induced dose-dependent expression of hFXN in the heart and liver. Interestingly, hFXN was processed into truncated forms, but found at lower levels than mature hFXN. However, the truncations were at different positions than mFXN. AAVrh.10hFXN induced mature hFXN expression in mouse heart and liver at levels that approximated endogenous mFXN levels. These results suggest that AAVrh.10hFXN can likely induce expression of therapeutic levels of mature hFXN in mice.

Abstract The present study aimed at evaluating the YF-specific neutralizing antibody profile besides a multiparametric analysis of phenotypic/functional features of cell-mediated response elicited by the 1/5 fractional dose of 17DD-YF vaccine, administered as a single subcutaneous injection. The immunological parameters of each volunteer was monitored at two time points, referred as: before (Day 0) [Non-Vaccinated, NV(D0)] and after vaccination (Day 30–45) [Primary Vaccinees, PV(D30–45)]. Data demonstrated high levels of neutralizing antibodies for PV(D30–45) leading to a seropositivity rate of 93%. A broad increase of systemic soluble mediators with a mixed profile was also observed for PV(D30–45), with IFN-γ and TNF-α presenting the highest baseline fold changes. Integrative network mapping of soluble mediators showed increased correlation numbers in PV(D30–45) as compared to NV(D0) (532vs398). Moreover, PV(D30–45) exhibited increased levels of Terminal Effector (CD45RA+CCR7−) CD4+ and CD8+ T-cells and Non-Classical memory B-cells (IgD+CD27+). Dimensionality reduction of Mass Cytometry data further support these findings. A polyfunctional cytokine profile (TNF-α/IFN-γ/IL-10/IL-17/IL-2) of T and B-cells was observed upon in vitro antigen recall. Mapping and kinetics timeline of soluble mediator signatures for PV(D30–45) further confirmed the polyfunctional profile upon long-term in vitro culture, mediated by increased levels of IFN-γ and TNF-α along with decreased production of IL-10. These findings suggest novel insights of correlates of protection elicited by the 1/5 fractional dose of 17DD-YF vaccine.

Abstract Data storage in DNA has recently emerged as a promising archival solution, offering space-efficient and long-lasting digital storage solutions. Recent studies suggest leveraging the inherent redundancy of synthesis and sequencing technologies by using composite DNA alphabets. A major challenge of this approach involves the noisy inference process, obstructing large composite alphabets. This paper introduces a novel approach for DNA-based data storage, offering, in some implementations, a 6.5-fold increase in logical density over standard DNA-based storage systems, with near-zero reconstruction error. Combinatorial DNA encoding uses a set of clearly distinguishable DNA shortmers to construct large combinatorial alphabets, where each letter consists of a subset of shortmers. We formally define various combinatorial encoding schemes and investigate their theoretical properties. These include information density and reconstruction probabilities, as well as required synthesis and sequencing multiplicities. We then propose an end-to-end design for a combinatorial DNA-based data storage system, including encoding schemes, two-dimensional (2D) error correction codes, and reconstruction algorithms, under different error regimes. We performed simulations and show, for example, that the use of 2D Reed-Solomon error correction has significantly improved reconstruction rates. We validated our approach by constructing two combinatorial sequences using Gibson assembly, imitating a 4-cycle combinatorial synthesis process. We confirmed the successful reconstruction, and established the robustness of our approach for different error types. Subsampling experiments supported the important role of sampling rate and its effect on the overall performance. Our work demonstrates the potential of combinatorial shortmer encoding for DNA-based data storage and describes some theoretical research questions and technical challenges. Combining combinatorial principles with error-correcting strategies, and investing in the development of DNA synthesis technologies that efficiently support combinatorial synthesis, can pave the way to efficient, error-resilient DNA-based storage solutions.

In high-income countries, outcomes following in hospital cardiac arrest have improved over the last two decades due to the introduction of rapid response teams, cardiac arrest teams, and advanced resuscitation training. However, in low-income countries, such as Rwanda, outcomes are still poor. This is due to multiple factors including lack of adequate resuscitation training, few trainers, and lack of equipment.To address this issue, the Initiative for Medical Equity and Global Health Equity (IMEGH), a training organization founded in 2018 by 5 local anesthesiologists has regularly taught resuscitation courses such as Basic Life Support, Advanced Cardiac Life Support, and Pediatric Advanced Life Support in hospitals throughout Rwanda. The aims of the organization include developing a sustainable model to offer context relevant resuscitation training courses, building a cadre of local instructors to teach on the courses, as well as engaging funding partners to help support the effort. From October 2018 until September 2022, 31 courses were run in 11 hospitals across Rwanda training 1,060 healthcare providers (mainly of non-physician anesthetists, nurses, midwives, and general practitioners). Ongoing challenges include lack of local protocols, inability to tracking resuscitation outcomes, and continued inaccessibility by many healthcare providers. Despite these challenges, the IMEGH program is an example of a successful context-relevant model and has potential to inform the design of resuscitation programs in other similar settings. This article describes the development of the IMEGH program, accomplishments as well as lessons learned, challenges, and next steps for expansion.

BackgroundAdolescents and young adults (AYAs) with cancer are at risk of poor psychosocial outcomes. AYAs grew up with the internet and digital technology, and mobile Health (mHealth) psychosocial interventions have the potential to overcome care access barriers. ObjectiveThis pilot randomized controlled trial (RCT) aimed to establish the feasibility, acceptability, and preliminary efficacy of a fully automated mobile app version of the Promoting Resilience in Stress Management intervention (mPRISM). Promoting Resilience in Stress Management is an evidence-based intervention developed in collaboration with AYAs, based on stress and coping theory, resilience theory, and evidence-based coping strategies. We hypothesized that mPRISM would be feasible, acceptable, and appropriate. MethodsThis is a parallel, 2-arm, single-site pilot RCT with a waitlist control design. The study will recruit 80 AYAs with cancer from a clinic. Eligible AYAs are aged 12 to 25 years, within 12 months of a new cancer diagnosis, receiving chemotherapy or radiation therapy, speak, read, or write in English, and are cognitively able to participate in study procedures. Recruitment by clinical research coordinators will occur remotely by phone, video, or text. Participants will be randomized to psychosocial usual care (UC) alone or UC plus mPRISM for an 8-week intervention period, and will remain unblinded to study condition. Enrolled participants will complete surveys at baseline before randomization, 8 weeks, and 3-month follow-up. Using a waitlist design, the UC arm will receive mPRISM upon completion of 3-month follow-up surveys. Those in the UC arm will complete 2 additional measurement points at immediate posttreatment and 3 months later. The primary outcomes of interest are feasibility, defined as ≥60% enrollment and ≥70% retention (ie, percentage of participants who completed the study), and “feasibility, acceptability, and appropriateness” as defined by cut-off scores ≥4/5 on 3 brief validated implementation outcome measures (feasibility of implementation measure, acceptability of intervention measure [AIM], intervention appropriateness measure [IAM]). We will apply top-box scoring for the implementation measures. Exploratory outcomes of interest include patient-reported health-related quality of life, resilience, distress, anxiety, depression, pain, and sleep. We will conduct an intention-to-treat analysis to compare the outcomes of the mPRISM arm versus the control arm with covariate-adjusted regression models. We will summarize individual digital usage metrics using descriptive statistics. ResultsSince September 2023, we have enrolled 20 participants and recruitment is ongoing. ConclusionsAlthough our previous work suggests AYAs with cancer are interested in mHealth psychosocial interventions, such interventions have not yet been sufficiently evaluated or implemented among AYA oncology patients. mPRISM may serve as a potential mHealth intervention to fill this gap. In this study, we will test the feasibility, acceptability, and preliminary efficacy of mPRISM. This work will inform future larger-scale RCTs powered for efficacy outcomes. Trial RegistrationClinicalTrials.gov NCT05842902; https://clinicaltrials.gov/study/NCT05842902 International Registered Report Identifier (IRRID)DERR1-10.2196/57950

Purpose Compared with older women diagnosed with breast cancer, younger women are more likely to die of breast cancer and more likely to suffer psychosocially in both the short-term and long term. The Young Women’s Breast Cancer Study (YWS) is a multisite prospective cohort study established to address gaps in our knowledge about this vulnerable and understudied population.Participants The YWS enrolled 1302 women newly diagnosed with stages 0–IV breast cancer at age 40 years or younger at 13 academic and community sites in North America between 2006 and 2016. Longitudinal patient-reported outcome data are complemented by clinical data abstraction and biospecimen collection at multiple timepoints.Findings to date Key findings related to fertility include that nearly 40% of participants were interested in pregnancy following diagnosis; of those who reported interest, 10% pursued fertility preservation. Overall, approximately 10% of YWS participants became pregnant in the first 5 years after diagnosis; follow-up is ongoing for pregnancies after 5 years. Studies focused on psychosocial outcomes have characterised quality of life, post-traumatic stress and fear of recurrence, with findings detailing the factors associated with the substantial psychosocial burden many young women face during and following active treatment. Multiple studies have leveraged YWS biospecimens, including whole-exome sequencing of tumour analyses that revealed that select somatic alterations occur at different frequencies in young (age≤35) versus older women with luminal A breast cancer, and a study that explored clonal hematopoiesis of indeterminate potential found it to be rare in young survivors.Future plans With a median follow-up of approximately 10 years, the cohort is just maturing for many relevant long-term outcomes and provides outstanding opportunities to further study and build collaborations to address gaps in our knowledge, with the ultimate objective to improve care and outcomes for young women with breast cancer.Trial registration number NCT01468246.

Objectives The objective of this study is to evaluate whether anti-neutrophil cytoplasmic antibody (ANCA) seropositivity and antigen specificity at diagnosis have predictive utility in paediatric-onset small vessel vasculitis.Methods Children and adolescents with small vessel vasculitis (n=406) stratified according to the absence (n=41) or presence of ANCA for myeloperoxidase (MPO) (n=129) and proteinase-3 (PR3) (n=236) were compared for overall and kidney-specific disease activity at diagnosis and outcomes between 1 and 2 years using retrospective clinical data from the ARChiVe/Paediatric Vasculitis Initiative registry to fit generalised linear models.Results Overall disease activity at diagnosis was higher in PR3-ANCA and MPO-ANCA-seropositive individuals compared with ANCA-negative vasculitis. By 1 year, there were no significant differences, based on ANCA positivity or specificity, in the likelihood of achieving inactive disease (~68%), experiencing improvement (≥87%) or acquiring damage (~58%). Similarly, and in contrast to adult-onset ANCA-associated vasculitis, there were no significant differences in the likelihood of having a relapse (~11%) between 1 and 2 years after diagnosis. Relative to PR3-ANCA, MPO-ANCA seropositivity was associated with a higher likelihood of kidney involvement (OR 2.4, 95% CI 1.3 to 4.7, p=0.008) and severe kidney dysfunction (Kidney Disease Improving Global Outcomes (KDIGO) stages 4–5; OR 6.04, 95% CI 2.77 to 13.57, p

Resumo: A inovação é um elemento fundamental para o desenvolvimento e crescimento, mas constituída por um processo demorado de acúmulo de conhecimento. Uma das formas de acelerar tal processo é por meio da transferência de tecnologia. Este artigo mapeou as particularidades da transferência de tecnologia para a vacina contra COVID-19, celebrado entre a AstraZeneca e o Instituto de Tecnologia em Imunobiológicos (Bio-Manguinhos), Fundação Oswaldo Cruz, bem como reconheceu os seus facilitadores, seus entraves e suas lacunas. Para tanto, foi realizada uma análise desde a etapa da seleção do parceiro mais adequado até a incorporação da nova tecnologia. A metodologia utilizada se baseou em uma ampla revisão bibliográfica sobre o tema, aliada ao estudo de caso. Os resultados apontaram que, apesar de muitas ações ainda precisarem ser realizadas para que os ganhos de capacidade tecnológica sejam potencializados, as lições aprendidas com o processo de transferência de tecnologia servirão de aprendizado e serão utilizadas nos acordos futuros e em andamento.

Abstract Ankle exoskeletons alter whole-body walking mechanics, energetics, and stability by altering center-of-mass (CoM) motion. Controlling the dynamics governing CoM motion is, therefore, critical for maintaining efficient and stable gait. However, how CoM dynamics change with ankle exoskeletons is unknown, and how to optimally model individual-specific CoM dynamics, especially in individuals with neurological injuries, remains a challenge. Here, we evaluated individual-specific changes in CoM dynamics in unimpaired adults and one individual with post-stroke hemiparesis while walking in shoes-only and with zero-stiffness and high-stiffness passive ankle exoskeletons. To identify optimal sets of physically interpretable mechanisms describing CoM dynamics, termed template signatures, we leveraged hybrid sparse identification of nonlinear dynamics (Hybrid-SINDy), an equation-free data-driven method for inferring sparse hybrid dynamics from a library of candidate functional forms. In unimpaired adults, Hybrid-SINDy automatically identified spring-loaded inverted pendulum-like template signatures, which did not change with exoskeletons (p > 0.16), except for small changes in leg resting length (p

Abstract Background Due to the abundant usage of chemotherapy in young triple-negative breast cancer (TNBC) patients, the unbiased prognostic value of BRCA1-related biomarkers in this population remains unclear. In addition, whether BRCA1-related biomarkers modify the well-established prognostic value of stromal tumor-infiltrating lymphocytes (sTILs) is unknown. This study aimed to compare the outcomes of young, node-negative, chemotherapy-naïve TNBC patients according to BRCA1 status, taking sTILs into account. Methods We included 485 Dutch women diagnosed with node-negative TNBC under age 40 between 1989 and 2000. During this period, these women were considered low-risk and did not receive chemotherapy. BRCA1 status, including pathogenic germline BRCA1 mutation (gBRCA1m), somatic BRCA1 mutation (sBRCA1m), and tumor BRCA1 promoter methylation (BRCA1-PM), was assessed using DNA from formalin-fixed paraffin-embedded tissue. sTILs were assessed according to the international guideline. Patients’ outcomes were compared using Cox regression and competing risk models. Results Among the 399 patients with BRCA1 status, 26.3% had a gBRCA1m, 5.3% had a sBRCA1m, 36.6% had tumor BRCA1-PM, and 31.8% had BRCA1-non-altered tumors. Compared to BRCA1-non-alteration, gBRCA1m was associated with worse overall survival (OS) from the fourth year after diagnosis (adjusted HR, 2.11; 95% CI, 1.18–3.75), and this association attenuated after adjustment for second primary tumors. Every 10% sTIL increment was associated with 16% higher OS (adjusted HR, 0.84; 95% CI, 0.78–0.90) in gBRCA1m, sBRCA1m, or BRCA1-non-altered patients and 31% higher OS in tumor BRCA1-PM patients. Among the 66 patients with tumor BRCA1-PM and ≥ 50% sTILs, we observed excellent 15-year OS (97.0%; 95% CI, 92.9–100%). Conversely, among the 61 patients with gBRCA1m and

The metastasis of poorly differentiated epithelioid carcinoma to the axillary node is uncommon. This tumor has heterogeneous expression and is challenging to diagnose with certainty. Often, it necessitates immunoperoxidase staining to ascertain the tumor lineage, and diagnosis is prolonged due to low suspicion. Herein, we present a case involving a 75-year-old male war veteran with a prior history of a gunshot wound complicated by colostomy that presented with an axillary mass, fecal and urinary incontinence, leg weakness, fevers, night sweats, and substantial weight loss. On admission, he had heightened leukocytosis (43K), anemia (hemoglobin 6.6), and thrombophilia (1000). This patient constantly picked at his back to remove recurrent “gun shrapnel” eruptions. An excisional biopsy of the axillary mass was performed for diagnosis and lymph node removal. Notably, after excision, there was marked improvement in the presenting symptoms. Diagnostic challenges arose due to the tumor cells’ inconsistent immunohistochemical marker expression. The staining patterns alluded to metastatic melanoma. Yet, the tumor displayed epithelial characteristics, supported by an immunophenotypic marker pattern indicative of poorly differentiated carcinoma. This case underscores the morphological and immunoperoxidase staining similarities between poorly differentiated carcinoma and dedifferentiated tumors of varying origins. It illustrates the intricate nature of these malignant metastatic tumors and their overlapping manifestations, which requires provider awareness. The timely diagnosis of poorly differentiated epithelial carcinoma remains paramount to early treatment and improved prognosis. Therefore, in patients manifesting with an axillary mass, fecal and urinary incontinence, and B-symptoms, poorly differentiated epithelial carcinoma should be included in the differential diagnosis.

Background At the beginning of the COVID-19 pandemic fears of severe disruptions to family planning (FP) and access to services abounded. This paper uses a unique data source, a special Supplement added to the 2021 round of the National Composite Index for Family Planning (NCIFP), to assess in depth the resilience of FP programs in the face of the COVID-19 pandemic across 70 countries spanning six regions. Methods The 2021 NCIFP included 961 key informants who were asked questions to assess interference in the countries’ ability to achieve objectives, ability to maintain commitment to FP, and availability of information and services. Open ended responses added context. Results All programs were affected; the magnitude of effects varies by region and country. While the average resilience score, at 47 out of 100, implies middling levels of resilience, further analysis showed that despite interference in many components of programming, with some exceptions, the COVID-19 pandemic generally did not diminish government commitment to FP and programs remained resilient in providing access to services. Common themes mentioned by 178 respondents (18.5% of respondents) included: fear of infection; disruption of services / difficulty with lockdown and travel restrictions; staff / facilities diverted to COVID-19; access to reproductive health services and contraceptive methods affected; shifts in services / outreach; interference with logistics & supplies, training & supervision, and M&E; lack of attention to FP/sexual reproductive health; financing reduced or diverted; and effects on existing partnerships. A strong enabling environment for FP, which the NCIFP is designed to measure, was positively correlated with continued government commitment and access to contraceptive methods during COVID-19. Conclusion These findings are instructive for programming: it will face challenges and ‘interference’ when unanticipated shocks like COVID-19 occur, with strong FP programs best prepared to exhibit resilience.

An animal entering a new environment typically faces three challenges: explore the space for resources, memorize their locations, and navigate towards those targets as needed. Here we propose a neural algorithm that can solve all these problems and operates reliably in diverse and complex environments. At its core, the mechanism makes use of a behavioral module common to all motile animals, namely the ability to follow an odor to its source. We show how the brain can learn to generate internal “virtual odors” that guide the animal to any location of interest. This endotaxis algorithm can be implemented with a simple 3-layer neural circuit using only biologically realistic structures and learning rules. Several neural components of this scheme are found in brains from insects to humans. Nature may have evolved a general mechanism for search and navigation on the ancient backbone of chemotaxis.

Abstract Background The aim of this work was to develop a basic treatment guideline set for late complications after treatment for colorectal and anal cancer. Furthermore, a prerequisite was that the guideline was appropriate and safe to use for all health care staff regardless of their educational level. Lastly, the set should cover the most common late complications for patients treated for colorectal and anal cancer, including stool, urinary, sexual, and depressive symptoms. Methods The treatment algorithms were developed by doctors in the Late Complication Clinic and afterward they were discussed to establish consensus with external experts in different fields such as surgery, gastroenterology, dietitian, gynecology, urology, sexology, general practice, anesthesiology, and psychiatry. Results We have developed a practical basic guideline set covering the most common late complications after colorectal and anal cancer treatment. The guideline set can be used by both nurses and doctors. The treatment algorithms are a combination of ordinary treatment principles and the best possible evidence in the field of late complications after colorectal and anal cancer. Conclusions We have developed a basic treatment guideline set for late complications after treatment for colorectal and anal cancers. There is generally little evidence in the field of late complications, and the evidence is mostly based on consensus. To establish higher‐level evidence for late complication treatment after colorectal and anal cancer, it is important to monitor and adjust the treatment algorithms.

Non-small cell lung cancer (NSCLC) is the most common pulmonary malignancy, frequently diagnosed at an advanced stage (III/IV). Patients in the Locally Advanced Stage Subgroup (IIIA) are relatively few, yet compose heterogenic phenotypes, posing a diagnostic and treating challenge, leading to a lack of clinical guidelines regarding the optimal standard of care. Several approaches exist, with a general agreement that a combined oncological and surgical modality approach is required. In this current retrospective descriptive study, patients with operable stage IIIA NSCLC who underwent surgery between 2013 and 2020 were evaluated on several aspects, including the initial diagnosis, neoadjuvant regimens, outcomes of surgical intervention, and overall survival at 2 years and 5 years following treatment. A total of 35 patients had neoadjuvant oncological treatment (mostly chemoradiation therapy) prior to surgery, out of which 28 patients were diagnosed with stage IIIA NSCLC. In post-operative assessment of pathological staging, downstaging was reported in 19 patients, of which 25% of cases were defined as a complete pathological response. The 2-year overall survival rate was 65% and the 5-year overall survival rate was 62%. The main pattern of disease recurrence was distant metastasis.

Se realizó un estudio con el objetivo de identificar un ecosistema de endemismo urbano que explique la persistencia del SARS-CoV-2 durante los primeros 18 meses de la pandemia en el municipio de Petrópolis, Río de Janeiro, Brasil. Se analizaron los registros oficiales de casos mensuales de COVID-19, georreferenciados según el domicilio de residencia de cada caso confirmado y se elaboraron mapas de calor mensuales que identifican puntos con diferentes densidades espaciales de la enfermedad mediante la aplicación de la metodología de kernel. Se identificaron puntos de calor con cinco niveles de intensidad para la densidad espacial de casos. Los puntos de mayor intensidad, conocidos como «hotspots», se mantuvieron constantes durante todo el período en un polígono de aproximadamente 4 km2 ubicado en el centro de la ciudad de Petrópolis. En conclusión, se encontró que la mayor concentración de casos se mantuvo en la misma ubicación a lo largo del tiempo, a pesar de la dispersión esporádica de los casos en el territorio municipal.

The Accelerating COVID-19 Therapeutic Interventions and Vaccines Therapeutic-Clinical Working Group members gathered critical recommendations in follow-up to lessons learned manuscripts released earlier in the COVID-19 pandemic. Lessons around agent prioritization, preclinical therapeutics testing, master protocol design and implementation, drug manufacturing and supply, data sharing, and public–private partnership value are shared to inform responses to future pandemics.

INTRODUCTION: The burden of injuries is high in low- and middle-income countries where pre-hospital systems are being developed to improve acute injury care. This study compares the characteristics and outcomes between trauma patients transported by formal emergency medical services (EMS) and by private transport to the emergency department (ED) of the Centre Hospitalier Universitaire de Kigali (CHUK) in Rwanda. METHODS: This retrospective cohort study analyzed a random sample of trauma patients presenting between 1 August 2015 and 30 July 2016. Descriptive analyses were performed, and differences in outcomes were assessed based on transport modalities via Pearson Chi-Squared or Fisher’s Exact tests. RESULTS: Of the 556 trauma patients analyzed, 87.1% were transported by private transport and the remainder by EMS. The median inpatient length of stay for private transport patients was 7 days (IQR:3-16 days), compared to 9.5 days for EMS patients (IQR:4-18 days) (p=0.301). More EMS-transported patients died in the ED (p=0.005), and more were admitted to the hospital. There was a higher mortality rate among patients admitted to the hospital who arrived by private transport, but the difference was not statistically significant. CONCLUSION: The higher ED death rate among EMS-transported patients and the higher in-hospital death rate among private transport patients suggest that major differences in the two groups may or may not be related to how trauma patients are brought to the ED.

This qualitative study aims to investigate the competencies and effectiveness of humor use in workplace leadership. By exploring the elements underlying successful and unsuccessful humor use, this research offers insights into the competencies required for leaders to leverage humor effectively. Adopting a qualitative inductive approach, fifteen individual semi-structured interviews were conducted, generating a dataset of 51 critical incidents of humor use. Reflexive thematic analysis was employed to identify key themes, resulting in the identification of five central elements: Reading the context, Intention and motivation, Judgement and decision, Skillful delivery, and Understanding reactions. These elements provide a comprehensive framework for understanding humor use in the context of workplace leadership, emphasizing the importance of cognitive and emotional intelligence / competencies. The study proposes a theoretical framework based on these findings, providing the foundation of a new paradigm for understanding and measuring humor use. This research contributes to a deeper understanding of the competencies and complexities involved in using humor as a leadership tool and provides practical implications for leaders aiming to enhance their leadership effectiveness through humor.

IntroductionDyadic care, which is the concurrent provision of care for a birthing person and their infant, is an approach that may improve disparities in postnatal health outcomes, but no synthesis of existing dyadic care studies has been conducted. This scoping review seeks to identify and summarize: 1) dyadic care studies globally, in which the birthing person-infant dyad are cared for together, 2) postnatal health outcomes that have been evaluated following dyadic care interventions, and 3) research and practice gaps in the implementation, dissemination, and effectiveness of dyadic care to reduce healthcare disparities.Materials and methodsEligible studies will (1) include dyadic care instances for the birthing person and infant, and 2) report clinical outcomes for at least one member of the dyad or intervention outcomes. Studies will be excluded if they pertain to routine obstetric care, do not present original data, and/or are not available in English or Spanish. We will search CINAHL, Ovid (both Embase and Medline), Scopus, Cochrane Library, PubMed, Google Scholar, Global Health, Web of Science Core Collection, gray literature, and WHO regional databases. Screening will be conducted via Covidence and data will be extracted to capture the study design, dyad characteristics, clinical outcomes, and implementation outcomes. The risk of bias will be assessed using the Joanna Briggs Institute Critical Appraisal Tool. A narrative synthesis of the study findings will be presented.DiscussionThis scoping review will summarize birthing person-infant dyadic care interventions that have been studied and the evidence for their effectiveness. This aggregation of existing data can be used by healthcare systems working to improve healthcare delivery to their patients with the aim of reducing postnatal morbidity and mortality. Areas for future research will also be highlighted.Trail registrationThis review has been registered at Open Science Framework (OSF, https://osf.io/5fs6e/).

The ADP-ribosylation factors (Arfs) constitute a family of small GTPases within the Ras superfamily, with a distinguishing structural feature of a hypervariable N-terminal extension of the G domain modified with myristate. Arf proteins, including Arf1, have roles in membrane trafficking and cytoskeletal dynamics. While screening for Arf1:small molecule co-crystals, we serendipitously solved the crystal structure of the non-myristoylated engineered mutation [L8K]Arf1 in complex with a GDP analogue. Like wild-type (WT) non-myristoylated Arf1•GDP, we observed that [L8K]Arf1 exhibited an N-terminal helix that occludes the hydrophobic cavity that is occupied by the myristoyl group in the GDP-bound state of the native protein. However, the helices were offset from one another due to the L8K mutation, with a significant change in position of the hinge region connecting the N-terminus to the G domain. Hypothesizing that the observed effects on behavior of the N-terminus affects interaction with regulatory proteins, we mutated two hydrophobic residues to examine the role of the N-terminal extension for interaction with guanine nucleotide exchange factors (GEFs) and GTPase Activating Proteins (GAPs. Different than previous studies, all mutations were examined in the context of myristoylated Arf. Mutations had little or no effect on spontaneous or GEF-catalyzed guanine nucleotide exchange but did affect interaction with GAPs. [F13A]myrArf1 was less than 1/2500, 1/1500, and 1/200 efficient as substrate for the GAPs ASAP1, ARAP1 and AGAP1; however, [L8A/F13A]myrArf1 was similar to WT myrArf1. Using molecular dynamics simulations, the effect of the mutations on forming alpha helices adjacent to a membrane surface was examined, yet no differences were detected. The results indicate that lipid modifications of GTPases and consequent anchoring to a membrane influences protein function beyond simple membrane localization. Hypothetical mechanisms are discussed.

BackgroundCash transfers are a promising but understudied intervention that may protect cognitive function in adults. Although South Africa has a rapidly ageing population, little is known about the nature of association between cash transfers and cognitive function in this setting.ObjectivesWe leveraged age-eligibility expansions to South Africa's Child Support Grant (CSG) to investigate the association between duration of CSG eligibility and cognitive function of biological mothers of child beneficiaries in South Africa.MethodsWe analysed 2014/2015 baseline data from 944 women, aged 40-59 years with at least one CSG-eligible child, enrolled in the population-representative HAALSI cohort in Agincourt, South Africa. Duration of CSG eligibility for each mother was calculated based on the birth dates of all their children and the CSG age-eligibility expansion years (2003-2012). Cognitive function was measured using a cognitive battery administered at the HAALSI baseline interview. Linear regression was used to estimate the association between duration of CSG eligibility, dichotomized as low (≤10 years) and high (>10 years) eligibility, and cognitive function z-scores of the mothers.ResultsHigh vs. low duration of CSG eligibility, was associated with higher cognitive function z-scores in the full sample [β: 0.15 SD units; 95% CI: 0.04, 0.26; p-value = 0.01]. In mothers with one to four lifetime children, but not five or more, high vs. low duration of CSG eligibility, was associated with higher cognitive function z-scores [β: 0.19 SD units; 95% CI: 0.05, 0.34, p-value = 0.02].ConclusionGovernment cash transfers given to support raising children may confer substantial protective effects on the subsequent cognitive function of mothers. Further studies are needed to understand how parity may influence this relationship. Our findings bring evidence to policymakers for designing income supplementation programmes to promote healthy cognitive ageing in low-income settings.

For the millions of people incarcerated in United States' prisons and jails during the COVID-19 pandemic, isolation took many forms, including medical isolation for those sick with COVID-19, quarantine for those potentially exposed, and prolonged facility-wide lockdowns. Incarcerated people's lived experience of isolation during the pandemic has largely gone undocumented. Through interviews with 48 incarcerated people and 27 staff at two jails and one prison in geographically diverse locations in the United States, we document the implementation of COVID-19 isolation policies from the perspective of those that live and work in carceral settings. Incarcerated people were isolated from social contact, educational programs, employment, and recreation, and lacked clear communication about COVID-19-related protocols. Being isolated, no matter the reason, felt like punishment and was compared to solitary confinement-with resultant long-term, negative impacts on health. Participants detailed isolation policies as disruptive, detrimental to mental health, and dehumanizing for incarcerated people. Findings point to several recommendations for isolation policy in carceral settings. These include integrating healthcare delivery into isolation protocols, preserving social relationships during isolation, promoting bidirectional communication about protocols and their effect between facility leadership and incarcerated people. Most importantly, there is an urgent need to re-evaluate the current approach to the use of isolation in carceral settings and to establish external oversight procedures for its use during pandemics.

Introduction Index case testing (ICT) is an evidence-based approach that efficiently identifies persons in need of HIV treatment and prevention services. In Malawi, delivery of ICT has faced challenges due to limited technical capacity of healthcare workers (HCWs) and clinical coordination. Digitisation of training and quality improvement processes presents an opportunity to address these challenges. We developed an implementation package that combines digital and face-to-face modalities (blended learning) to strengthen HCWs ICT skills and enhance quality improvement mechanisms. This cluster randomised controlled trial will assess the impact of the blended learning implementation package compared with the standard of care (SOC) on implementation, effectiveness and cost-effectiveness outcomes.Methods and analysis The study was conducted in 33 clusters in Machinga and Balaka districts, in Southern Malawi from November 2021 to November 2023. Clusters are randomised in a 2:1 ratio to the SOC versus blended learning implementation package. The SOC is composed of: brief face-to-face HCW ICT training and routine face-to-face facility mentorship for HCWs. The blended learning implementation package consists of blended teaching, role-modelling, practising, and providing feedback, and blended quality improvement processes. The primary implementation outcome is HCW fidelity to ICT over 1 year of follow-up. Primary service uptake outcomes include (a) index clients who participate in ICT, (b) contacts elicited, (c) HIV self-test kits provided for secondary distribution, (d) contacts tested and (e) contacts identified as HIV-positive. Service uptake analyses will use a negative binomial mixed-effects model to account for repeated measures within each cluster. Cost-effectiveness will be assessed through incremental cost-effectiveness ratios examining the incremental cost of each person tested.Ethics and dissemination The Malawi National Health Science Research Committee, the University of North Carolina and the Baylor College of Medicine Institutional Review Boards approved the trial. Study findings will be disseminated through peer-reviewed journals and conference presentations.Trial registration number NCT05343390.

This retrospective study evaluated a commercial deep learning (DL) software for chest radiographs and explored its performance in different scenarios. A total of 477 patients (284 male, 193 female, mean age 61.4 (44.7–78.1) years) were included. For the reference standard, two radiologists performed independent readings on seven diseases, thus reporting 226 findings in 167 patients. An autonomous DL reading was performed separately and evaluated against the gold standard regarding accuracy, sensitivity and specificity using ROC analysis. The overall average AUC was 0.84 (95%-CI 0.76–0.92) with an optimized DL sensitivity of 85% and specificity of 75.4%. The best results were seen in pleural effusion with an AUC of 0.92 (0.885–0.955) and sensitivity and specificity of each 86.4%. The data also showed a significant influence of sex, age, and comorbidity on the level of agreement between gold standard and DL reading. About 40% of cases could be ruled out correctly when screening for only one specific disease with a sensitivity above 95% in the exploratory analysis. For the combined reading of all abnormalities at once, only marginal workload reduction could be achieved due to insufficient specificity. DL applications like this one bear the prospect of autonomous comprehensive reporting on chest radiographs but for now require human supervision. Radiologists need to consider possible bias in certain patient groups, e.g., elderly and women. By adjusting their threshold values, commercial DL applications could already be deployed for a variety of tasks, e.g., ruling out certain conditions in screening scenarios and offering high potential for workload reduction.

Background: At the beginning of the COVID-19 pandemic fears of severe disruptions to family planning (FP) and access to services abounded. This paper uses a unique data source, a special Supplement added to the 2021 round of the National Composite Index for Family Planning (NCIFP), to assess in depth the resilience of FP programs in the face of the COVID-19 pandemic across 70 countries spanning six regions. Methods: The 2021 NCIFP included 961 key informants who were asked questions to assess interference in the countries’ ability to achieve objectives, ability to maintain commitment to FP, and availability of information and services. Open ended responses added context. Results: All programs were affected; the magnitude of effects varies by region and country. While the average resilience score, at 47 out of 100, implies middling levels of resilience, further analysis showed that despite interference in many components of programming, with some exceptions, the COVID-19 pandemic generally did not diminish government commitment to FP and programs remained resilient in providing access to services. Common themes mentioned by 178 respondents (18.5% of respondents) included: fear of infection; disruption of services / difficulty with lockdown and travel restrictions; staff / facilities diverted to COVID-19; access to reproductive health services and contraceptive methods affected; shifts in services / outreach; interference with logistics & supplies, training & supervision, and M&E; lack of attention to FP/sexual reproductive health; financing reduced or diverted; and effects on existing partnerships. A strong enabling environment for FP, which the NCIFP is designed to measure, was positively correlated with continued government commitment and access to contraceptive methods during COVID-19. Conclusion: These findings are instructive for programming: it will face challenges and ‘interference’ when unanticipated shocks like COVID-19 occur, with strong FP programs best prepared to exhibit resilience.

Abstract Random forests are a popular type of machine learning model, which are relatively robust to overfitting, unlike some other machine learning models, and adequately capture non-linear relationships between an outcome of interest and multiple independent variables. There are relatively few adjustable hyperparameters in the standard random forest models, among them the minimum size of the terminal nodes on each tree. The usual stopping rule, as proposed by Breiman, stops tree expansion by limiting the size of the parent nodes, so that a node cannot be split if it has less than a specified number of observations. Recently an alternative stopping criterion has been proposed, stopping tree expansion so that all terminal nodes have at least a minimum number of observations. The present paper proposes three generalisations of this idea, limiting the growth in regression random forests, based on the variance, range, or inter-centile range. The new approaches are applied to diabetes data obtained from the National Health and Nutrition Examination Survey and four other datasets (Tasmanian Abalone data, Boston Housing crime rate data, Los Angeles ozone concentration data, MIT servo data). Empirical analysis presented herein demonstrate that the new stopping rules yield competitive mean square prediction error to standard random forest models. In general, use of the intercentile range statistic to control tree expansion yields much less variation in mean square prediction error, and mean square prediction error is also closer to the optimal. The Fortran code developed is provided in the Supplementary Material.

Abstract Chromosomal microarray analysis (CMA) has been recommended and practiced routinely since 2010 both in the USA and Europe as the first-tier cytogenetic test for patients with unexplained neurodevelopmental delay/intellectual disability, autism spectrum disorders, and/or multiple congenital anomalies. However, in Brazil, the use of CMA is still limited, due to its high cost and complexity in integrating the results from both the private and public health systems. Although Brazil has one of the world’s largest single-payer public healthcare systems, nearly all patients referred for CMA come from the private sector, resulting in only a small number of CMA studies in Brazilian cohorts. To date, this study is by far the largest Brazilian cohort (n = 5788) studied by CMA and is derived from a joint collaboration formed by the University of São Paulo and three private genetic diagnostic centers to investigate the genetic bases of neurodevelopmental disorders and congenital abnormalities. We identified 2,279 clinically relevant CNVs in 1886 patients, not including the 26 cases of UPD found. Among detected CNVs, the corresponding frequency of each category was 55.6% Pathogenic, 4.4% Likely Pathogenic and 40% VUS. The diagnostic yield, by taking into account Pathogenic, Likely Pathogenic and UPDs, was 19.7%. Since the rational for the classification is mostly based on Mendelian or highly penetrant variants, it was not surprising that a second event was detected in 26% of those cases of predisposition syndromes. Although it is common practice to investigate the inheritance of VUS in most laboratories around the world to determine the inheritance of the variant, our results indicate an extremely low cost–benefit of this approach, and strongly suggest that in cases of a limited budget, investigation of the parents of VUS carriers using CMA should not be prioritized.

There is increasing attention to suicides that occur in view of others, as these deaths can cause significant psychological impact on witnesses. This study illuminates characteristics of witnessed suicides and compares characteristics of these deaths to non-witnessed suicides. We develop a codable definition of what constitutes witnessed (vs. non-witnessed) suicide. Our data include a sample of 1200 suicide descriptions from the 2003–2017 National Violent Death Reporting System (NVDRS). We first developed criteria to identify probable cases of witnessed suicide. The coding scheme achieved 94.5% agreement and identified approximately 10% (n = 125) of suicides as witnessed. Next, we examined differences between witnessed and non-witnessed suicides in demographics, manner of death, and social/environmental factors using bivariate Chi-squared tests, multivariate logistic regression, and ANOVA. Witnessed suicide decedents were significantly more likely than non-witnessed suicide decedents to be male, younger, and members of a sexual minority, and to have died in living spaces by means of a firearm. Two thirds of witnesses were strangers to the decedents, while 23.2% were romantic partners or ex-partners of the decedents. Our coding method offers a reliable approach to identify witnessed suicides. While witnessed suicides are relatively infrequent, these deaths have profound impact on witnesses. Articulating the features of witnessed suicides may contribute to identifying potential risk mitigation strategies.

We sought to examine whether and how landlord-related forced moves (inclusive of, but not limited to, legal eviction) were associated with emergency department (ED) use over time.We used survey data collected between 2017 and 2019 among 283 low-income participants in New Haven, CT to examine whether experiencing a legal eviction or other landlord-related forced move (T0) was associated with increased odds of ED use 6 months (T1) and 12 months (T2) later. We conducted bootstrapped mediation analyses to examine indirect effects of post-traumatic stress symptoms.One-fifth of participants (n = 61) reported a recent forced move at baseline (T0); half of these were legally evicted. Landlord-related forced moves were associated with ED use at T1 (AOR = 2.06, 95 % CI: 1.04–4.06) and T2 (AOR = 3.05, 95 % CI: 1.59–5.88). After adjustment for sociodemographic factors and other health-related confounders, legal eviction was not significantly associated with ED use at T1 (AOR = 1.61, 95 % CI: 0.68–3.81), but was significantly associated with ED use at T2 (AOR = 3.58, 95 % CI: 1.58–8.10). Post-traumatic stress symptoms accounted for 15.1% of forced moves’ association with ED use (p

Visually guided behaviors require the brain to transform ambiguous retinal images into object-level spatial representations and implement sensorimotor transformations. These processes are supported by the dorsal ‘where’ pathway. However, the specific functional contributions of areas along this pathway remain elusive due in part to methodological differences across studies. We previously showed that macaque caudal intraparietal (CIP) area neurons possess robust 3D visual representations, carry choice- and saccade-related activity, and exhibit experience-dependent sensorimotor associations (Chang et al., 2020b). Here, we used a common experimental design to reveal parallel processing, hierarchical transformations, and the formation of sensorimotor associations along the ‘where’ pathway by extending the investigation to V3A, a major feedforward input to CIP. Higher-level 3D representations and choice-related activity were more prevalent in CIP than V3A. Both areas contained saccade-related activity that predicted the direction/timing of eye movements. Intriguingly, the time course of saccade-related activity in CIP aligned with the temporally integrated V3A output. Sensorimotor associations between 3D orientation and saccade direction preferences were stronger in CIP than V3A, and moderated by choice signals in both areas. Together, the results explicate parallel representations, hierarchical transformations, and functional associations of visual and saccade-related signals at a key juncture in the ‘where’ pathway.

E1 and E2 (E1E2), the fusion proteins of Hepatitis C Virus (HCV), are unlike that of any other virus yet described, and the detailed molecular mechanisms of HCV entry/fusion remain unknown. Hypervariable region-1 (HVR-1) of E2 is a putative intrinsically disordered protein tail. Here, we demonstrate that HVR-1 has an autoinhibitory function that suppresses the activity of E1E2 on free virions; this is dependent on its conformational entropy. Thus, HVR-1 is akin to a safety catch that prevents premature triggering of E1E2 activity. Crucially, this mechanism is turned off by host receptor interactions at the cell surface to allow entry. Mutations that reduce conformational entropy in HVR-1, or genetic deletion of HVR-1, turn off the safety catch to generate hyper-reactive HCV that exhibits enhanced virus entry but is thermally unstable and acutely sensitive to neutralising antibodies. Therefore, the HVR-1 safety catch controls the efficiency of virus entry and maintains resistance to neutralising antibodies. This discovery provides an explanation for the ability of HCV to persist in the face of continual immune assault and represents a novel regulatory mechanism that is likely to be found in other viral fusion machinery.

Objectives Agitation, defined as excessive psychomotor activity leading to aggressive or violent behaviour, is prevalent in the emergency department (ED) due to rising behavioural-related visits. Experts recommend use of verbal de-escalation and avoidance of physical restraint to manage agitation. However, bedside applications of these recommendations may be limited by system challenges in emergency care. This qualitative study aims to use a systems-based approach, which considers the larger context and system of healthcare delivery, to identify sociotechnical, structural, and process-related factors leading to agitation events and physical restraint use in the ED.Design Qualitative study using a grounded theory approach to triangulate interviews of patients who have been physically restrained with direct observations of agitation events.Setting Two EDs in the Northeast USA, one at a tertiary care academic centre and the other at a community-based teaching hospital.Participants We recruited 25 individuals who experienced physical restraint during an ED visit. In addition, we performed 95 observations of clinical encounters of agitation events on unique patients. Patients represented both behavioural (psychiatric, alcohol/drug use) and non-behavioural (medical, trauma) chief complaints.Results Three primary themes with implications for systems-based practice of agitation events in the ED emerged: (1) pathways within health and social systems; (2) interpersonal contexts as reflections of systemic stressors on behavioural emergency care and (3) systems-based and patient-oriented strategies and solutions.Conclusions Agitation events represented manifestations of patients’ structural barriers to care from socioeconomic inequities and high burden of emotional and physical trauma as well as staff members’ simultaneous exposure to external stressors from social and healthcare systems. Potential long-term solutions may include care approaches that recognise agitated patients’ exposure to psychological trauma, improved coordination within the mental health emergency care network, and optimisation of physical environment conditions and organisational culture.

Background: Nucleic acid binding proteins are frequently targeted as autoantigens in systemic lupus erythematosus (SLE) and other interferon (IFN)-linked rheumatic diseases. The AIM-like receptors (ALRs) are IFN-inducible innate sensors that form supramolecular assemblies along double-stranded (ds)DNA of various origins. Here, we investigate the ALR absent in melanoma 2 (AIM2) as a novel autoantigen in SLE, with similar properties to the established ALR autoantigen interferon-inducible protein 16 (IFI16). We examined neutrophil extracellular traps (NETs) as DNA scaffolds on which these antigens might interact in a pro-immune context. Methods: AIM2 autoantibodies were measured by immunoprecipitation in SLE and control subjects. Neutrophil extracellular traps were induced in control neutrophils and combined with purified ALR proteins in immunofluorescence and DNase protection assays. SLE renal tissues were examined for ALR-containing NETs by confocal microscopy. Results: AIM2 autoantibodies were detected in 41/131 (31.3%) SLE patients and 2/49 (4.1%) controls. Our SLE cohort revealed a frequent co-occurrence of anti-AIM2, anti-IFI16, and anti-DNA antibodies, and higher clinical measures of disease activity in patients positive for antibodies against these ALRs. We found that both ALRs bind NETs in vitro and in SLE renal tissues. We demonstrate that ALR binding causes NETs to resist degradation by DNase I, suggesting a mechanism whereby extracellular ALR-NET interactions may promote sustained IFN signaling. Conclusions: Our work suggests that extracellular ALRs bind NETs, leading to DNase resistant nucleoprotein fibers that are targeted as autoantigens in SLE. Funding: These studies were funded by NIH R01 DE12354 (AR), P30 AR070254, R01 GM 129342 (JS), K23AR075898 (CM), K08AR077100 (BA), the Jerome L. Greene Foundation and the Rheumatology Research Foundation. Dr. Antiochos and Dr. Mecoli are Jerome L. Greene Scholars. The Hopkins Lupus Cohort is supported by NIH grant R01 AR069572. Confocal imaging performed at the Johns Hopkins Microscopy Facility was supported by NIH Grant S10 OD016374.