CloudATAC: a cloud-based framework for ATAC-Seq data analysis.

Assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) generates genome-wide chromatin accessibility profiles, providing valuable insights into epigenetic gene regulation at both pooled-cell and single-cell population levels. Comprehensive analysis of ATAC-seq data involves the use of various interdependent programs. Learning the correct sequence of steps needed to process the data can represent a major hurdle. Selecting appropriate parameters at each stage, including pre-analysis, core analysis, and advanced downstream analysis, is important to ensure accurate analysis and interpretation of ATAC-seq data. Additionally, obtaining and working within a limited computational environment presents a significant challenge to non-bioinformatic researchers. Therefore, we present Cloud ATAC, an open-source, cloud-based interactive framework with a scalable, flexible, and streamlined analysis framework based on the best practices approach for pooled-cell and single-cell ATAC-seq data. These frameworks use on-demand computational power and memory, scalability, and a secure and compliant environment provided by the Google Cloud. Additionally, we leverage Jupyter Notebook's interactive computing platform that combines live code, tutorials, narrative text, flashcards, quizzes, and custom visualizations to enhance learning and analysis. Further, leveraging GPU instances has significantly improved the run-time of the single-cell framework. The source codes and data are publicly available through NIH Cloud lab https://github.com/NIGMS/ATAC-Seq-and-Single-Cell-ATAC-Seq-Analysis. This manuscript describes the development of a resource module that is part of a learning platform named ``NIGMS Sandbox for Cloud-based Learning'' https://github.com/NIGMS/NIGMS-Sandbox. The overall genesis of the Sandbox is described in the editorial NIGMS Sandbox [1] at the beginning of this Supplement. This module delivers learning materials on the analysis of bulk and single-cell ATAC-seq data in an interactive format that uses appropriate cloud resources for data access and analyses.

Engineered matrices reveal stiffness-mediated chemoresistance in patient-derived pancreatic cancer organoids.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by its fibrotic and stiff extracellular matrix. However, how the altered cell/extracellular-matrix signalling contributes to the PDAC tumour phenotype has been difficult to dissect. Here we design and engineer matrices that recapitulate the key hallmarks of the PDAC tumour extracellular matrix to address this knowledge gap. We show that patient-derived PDAC organoids from three patients develop resistance to several clinically relevant chemotherapies when cultured within high-stiffness matrices mechanically matched to in vivo tumours. Using genetic barcoding, we find that while matrix-specific clonal selection occurs, cellular heterogeneity is not the main driver of chemoresistance. Instead, matrix-induced chemoresistance occurs within a stiff environment due to the increased expression of drug efflux transporters mediated by CD44 receptor interactions with hyaluronan. Moreover, PDAC chemoresistance is reversible following transfer from high- to low-stiffness matrices, suggesting that targeting the fibrotic extracellular matrix may sensitize chemoresistant tumours. Overall, our findings support the potential of engineered matrices and patient-derived organoids for elucidating extracellular matrix contributions to human disease pathophysiology.

Safety of treating acute pulmonary embolism at home: an individual patient data meta-analysis.

BACKGROUND AND AIMS: Home treatment is considered safe in acute pulmonary embolism (PE) patients selected by a validated triage tool (e.g. simplified PE severity index score or Hestia rule), but there is uncertainty regarding the applicability in underrepresented subgroups. The aim was to evaluate the safety of home treatment by performing an individual patient-level data meta-analysis. METHODS: Ten prospective cohort studies or randomized controlled trials were identified in a systematic search, totalling 2694 PE patients treated at home (discharged within 24 h) and identified by a predefined triage tool. The 14- and 30-day incidences of all-cause mortality and adverse events (combined endpoint of recurrent venous thromboembolism, major bleeding, and/or all-cause mortality) were evaluated. The relative risk (RR) for 14- and 30-day mortalities and adverse events is calculated in subgroups using a random effects model. RESULTS: The 14- and 30-day mortalities were 0.11% [95% confidence interval (CI) 0.0-0.24, I2 = 0) and 0.30% (95% CI 0.09-0.51, I2 = 0). The 14- and 30-day incidences of adverse events were 0.56% (95% CI 0.28-0.84, I2 = 0) and 1.2% (95% CI 0.79-1.6, I2 = 0). Cancer was associated with increased 30-day mortality [RR 4.9; 95% prediction interval (PI) 2.7-9.1; I2 = 0]. Pre-existing cardiopulmonary disease, abnormal troponin, and abnormal (N-terminal pro-)B-type natriuretic peptide [(NT-pro)BNP] at presentation were associated with an increased incidence of 14-day adverse events [RR 3.5 (95% PI 1.5-7.9, I2 = 0), 2.5 (95% PI 1.3-4.9, I2 = 0), and 3.9 (95% PI 1.6-9.8, I2 = 0), respectively], but not mortality. At 30 days, cancer, abnormal troponin, and abnormal (NT-pro)BNP were associated with an increased incidence of adverse events [RR 2.7 (95% PI 1.4-5.2, I2 = 0), 2.9 (95% PI 1.5-5.7, I2 = 0), and 3.3 (95% PI 1.6-7.1, I2 = 0), respectively]. CONCLUSIONS: The incidence of adverse events in home-treated PE patients, selected by a validated triage tool, was very low. Patients with cancer had a three- to five-fold higher incidence of adverse events and death. Patients with increased troponin or (NT-pro)BNP had a three-fold higher risk of adverse events, driven by recurrent venous thromboembolism and bleeding.

Incorporating Noncovalent Interactions in Transfer Learning Gaussian Process Regression Models for Molecular Simulations.

FFLUX is a quantum chemical topology-based multipolar force field that uses Gaussian process regression machine learning models to predict atomic energies and multipole moments on the fly for fast and accurate molecular dynamics simulations. These models have previously been trained on monomers, meaning that many-body effects, for example, intermolecular charge transfer, are missed in simulations. Moreover, dispersion and repulsion have been modeled using Lennard-Jones potentials, necessitating careful parametrization. In this work, we take an important step toward addressing these shortcomings and show that models trained on clusters, in this case, a dimer, can be used in FFLUX simulations by preparing and benchmarking a formamide dimer model. To mitigate the computational costs associated with training higher-dimensional models, we rely on the transfer of hyperparameters from a smaller source model to a larger target model, enabling an order of magnitude faster training than with a direct learning approach. The dimer model allows for simulations that account for two-body effects, including intermolecular polarization and charge penetration, and that do not require nonbonded potentials. We show that addressing these limitations allows for simulations that are closer to quantum mechanics than previously possible with the monomeric models.

Clinical considerations for sexual and gender minorities with prostate cancer.

At every stage of the cancer continuum, the management of sexual and gender minorities with prostate cancer requires a thoughtful and multidisciplinary approach. For example, it is important to recognize that receptive anal intercourse, common among sexual minority men-i.e. gay and bisexual men-can potentially elevate prostate-specific antigen (PSA) leading to overdiagnosis and overtreatment. Additionally, it is important to understand that sexual minority men with prostate cancer might engage in insertive and/or receptive anal intercourse, as opposed to insertive vaginal intercourse, requiring a treatment conversation that expands beyond the usual discussion of sexual health in prostate cancer patients. For gender minorities-i.e. transgender women or trans feminine individuals (those recorded male at birth with feminine gender identities)-it is important to consider gender affirming hormones and pelvic surgeries as they can cause diagnostic and treatment challenges, including PSA suppression, more aggressive disease, and anatomical changes. Furthermore, it is essential to recognize that gender minorities are a diverse cohort and may or may not be on gender affirming hormone therapy and may or may not have received or intend to receive pelvic affirming surgery. In this seminar article, we highlight considerations for personalized management of prostate cancer in sexual and gender minorities to improve care for this understudied cohort and enhance health equity.

Use of Magnetic Resonance Direct Thrombus Imaging for the Diagnostic Management of Suspected Thrombosis in Routine Clinical Practice.

Background The noninvasive magnetic resonance direct thrombus imaging (MRDTI) technique can be used to diagnose acute deep vein thrombosis (DVT), without the use of intravenous contrast. MRDTI holds the potential to differentiate between acute and chronic DVT and could be helpful when diagnosing thrombosis is challenging. Objectives Our objective was to evaluate the application of MRDTI in clinical practice, including the frequency and indications of MRDTI scans performed in practice-based conditions, results, impact on treatment decisions, and associated patient outcomes. Methods A retrospective study was performed at the Leiden University Medical Center, the Netherlands. MRDTI scans performed since its implementation in patients aged ≥18 years as part of clinical practice for the diagnostic management of suspected thrombosis were evaluated. Results Between October 2015 and September 2023, 36 patients had undergone MRDTI for the diagnostic evaluation of thrombosis. MRDTI application increased since 2019 (five-eight scans per year). The most common indication was to differentiate between acute and chronic thrombosis, mainly for suspected recurrent ipsilateral DVT after inconclusive compression ultrasonography. In over a third of patients, acute thrombosis was confirmed by MRDTI. MRDTI results determined treatment decisions in all except two patients. One patient had symptomatic thrombosis of the lower extremity within 3 months after an MRDTI of the upper extremity without signs of acute thrombosis (1/23; 4.3%, 95% confidence interval: 0.77-21). Conclusion Over the past 4 years, MRDTI has been used increasingly in our hospital. MRDTI results guided treatment decisions, which confirms the clinical impact and feasibility of its application in daily practice.

Geographic access to fertility counseling among adolescent and young adult women with cancer in North Carolina.

BACKGROUND: Fertility counseling is recommended for adolescent and young adult (AYA) women facing gonadotoxic cancer therapy. However, fertility care is subspecialized medical care offered at a limited number of institutions, making geographic access a potential barrier to guideline-concordant care. We assessed the relationship between geographic access and receipt of fertility counseling among AYA women with cancer. METHODS: Using data from the North Carolina Central Cancer Registry, we identified women diagnosed with lymphoma, gynecologic cancer, or breast cancer at ages 15-39 years during 2004-2015. Eligible women were invited to complete an online survey on various topics, including fertility counseling. Geographic access was measured, using geocoded addresses, as vehicular travel time from residence to the nearest fertility clinic available at diagnosis. Multivariable regression models were used to examine the association between travel time and receipt of fertility counseling by provider type: health care provider vs fertility specialist. RESULTS: Analyses included 380 women. Median travel time to a fertility clinic was 31 (IQR: 17-71) minutes. Overall, 75% received fertility counseling from a health care provider and 16% by a fertility specialist. Women who lived ≥30 minutes from a clinic were 13% less likely to receive fertility counseling by a health care provider (PR:0.87; 95% CI:0.75-1.00) and 49% less likely to receive counseling by a fertility specialist (PR:0.51; 95% CI:0.28-0.93). CONCLUSIONS: Women who lived further away from fertility clinics were less likely to receive fertility counseling. IMPACT: Interventions to improve access to fertility counseling should include strategies to alleviate the burden of geographic access.

A fungal metabolic regulator underlies infectious synergism during Candida albicans-Staphylococcus aureus intra-abdominal co-infection.

Candida albicans and Staphylococcus aureus are two commonly associated pathogens that cause nosocomial infections with high morbidity and mortality. Our prior and current work using a murine model of polymicrobial intra-abdominal infection (IAI) demonstrates that synergistic lethality is driven by Candida-induced upregulation of functional S. aureus α-toxin leading to polymicrobial sepsis and organ damage. In order to determine the candidal effector(s) mediating enhanced virulence, an unbiased screen of C. albicans transcription factor mutants was undertaken revealing that zcf13Δ/Δ fails to drive augmented α-toxin or lethal synergism during co-infection. A combination of transcriptional and phenotypic profiling approaches shows that ZCF13 regulates genes involved in pentose metabolism, including RBK1 and HGT7 that contribute to fungal ribose catabolism and uptake, respectively. Subsequent experiments reveal that ribose inhibits the staphylococcal agr quorum sensing system and concomitantly represses toxicity. Unlike wild-type C. albicans, zcf13Δ/Δ did not effectively utilize ribose during co-culture or co-infection leading to exogenous ribose accumulation and agr repression. Forced expression of RBK1 and HGT7 in the zcf13Δ/Δ mutant fully restores pathogenicity during co-infection. Collectively, our results detail the interwoven complexities of cross-kingdom interactions and highlight how intermicrobial metabolism impacts polymicrobial disease pathogenesis with devastating consequences for the host.

Quantitative protein mass spectrometry for multiplex measurement of coagulation and fibrinolytic proteins towards clinical application: What, why and how?

Plasma proteins involved in coagulation and fibrinolysis are essential to hemostasis. Consequently, their circulating levels and functionality are critical in bleeding and thrombosis development. Well-established laboratory tests to assess these are available; however, said tests do not allow high multiplicity, require large volumes of plasma and are often costly. A novel technology to quantify plasma proteins is quantitative protein mass spectrometry (QPMS). Aided by stable isotope-labeled internal standards a large number of proteins can be quantified in one single analytical run requiring <30 µL of plasma. This provides an opportunity to improve insight in the etiology and prognosis of bleeding and thrombotic disorders, in which the balance between different proteins plays a crucial role. This manuscript aims to give an overview of the QPMS potential applications in thrombosis and hemostasis research (quantifying the 38 proteins assigned to coagulation and fibrinolysis by the KEGG database), but also to explore the potential and hurdles if designed for clinical practice. Advantages and limitations of QPMS are described and strategies for improved analysis are proposed, using as an example the test requirements for antithrombin. Application of this technology in the future could represent a step towards individualized patient care.

Metabolic and Lipid Biomarkers for Pathogenic Algae, Fungi, Cyanobacteria, Mycobacteria, Gram-Positive Bacteria, and Gram-Negative Bacteria.

The utilization of metabolomics and lipidomics analytical platforms in the study of pathogenic microbes is slowly expanding. These research approaches will significantly contribute to the establishment of microbial metabolite and lipid databases of significant value to all researchers in microbiology. In this review, we present a high-level overview of some examples of biomarkers that can be used to detect the presence of microbes, monitor the expansion/decline of a microbe population, and add to our understanding of microbe biofilms and pathogenicity. In addition, increased knowledge of the metabolic functions of pathogenic microbes can contribute to our understanding of microbes that are utilized in diverse industrial applications. Our review focuses on lipids, secondary metabolites, and non-ribosomal peptides that can be monitored using electrospray ionization high-resolution mass spectrometry (ESI-HRMS).

Conversational presentation mode increases credibility judgements during information search with ChatGPT.

People increasingly use large language model (LLM)-based conversational agents to obtain information. However, the information these models provide is not always factually accurate. Thus, it is critical to understand what helps users adequately assess the credibility of the provided information. Here, we report the results of two preregistered experiments in which participants rated the credibility of accurate versus partially inaccurate information ostensibly provided by a dynamic text-based LLM-powered agent, a voice-based agent, or a static text-based online encyclopedia. We found that people were better at detecting inaccuracies when identical information was provided as static text compared to both types of conversational agents, regardless of whether information search applications were branded (ChatGPT, Alexa, and Wikipedia) or unbranded. Mediation analysis overall corroborated the interpretation that a conversational nature poses a threat to adequate credibility judgments. Our research highlights the importance of presentation mode when dealing with misinformation.

Comparison of skin prick test and prick-to-prick test with fruits and vegetables in the diagnosis of food allergy.

INTRODUCTION: Prick-to-prick (PTP) test with fresh food is accepted as a reliable tool for measuring sensitization to fruits and vegetables. Not all fruits and vegetables are available throughout the year. The objective of this study was to investigate whether skin prick test (SPT) performed with frozen juice of fruits and vegetables (FJFV) is a good alternative to PTP tests performed with fresh fruits and vegetables (FFV). METHODS: Adult patients suspected of having a food allergy to fruits and/or vegetables were included. A questionnaire was used to score symptoms after consumption of apple, kiwi, peach, tomato, and carrot. SPTs with FJFV, and PTP tests with FFV were performed. Intra-class correlation coefficients (ICC) between the SPT and PTP test results were calculated. The sensitivity and specificity of both diagnostic tests towards food allergen specific symptoms (FASS) were calculated. RESULTS: Thirty-six patients were included. FASS was positive in 75% for apple, 53% for kiwi, 44% for peach, 25% for tomato, and 22% for carrot. ICC between SPT and PTP test results were moderate for apple (0.72) and kiwi (0.71), strong for peach (0.75) and tomato (0.89), and very strong for carrot (0.94). Sensitivity was equal for the SPT and PTP tests for apple (0.93), peach (0.81), and carrot (1.00), and comparable for kiwi (0.50 resp. 0.70), and tomato (0.44 resp. 0.56). Specificity was equal for apple (0.33), peach (0.15), and carrot (0.41), and comparable for kiwi (0.29 resp. 0.21) and tomato (0.80 resp. 0.72). CONCLUSIONS: Results of SPT with FJFV and PTP test with FFV are comparable. SPT with FJFV is a good alternative in the daily practice of the allergists.

Iodine and other factors associated with fertility outcome following oil-soluble contrast medium hysterosalpingography: a prospective cohort study.

Objective: To examine factors associated with fertility following hysterosalpingography (HSG) using an oil-soluble contrast medium (OSCM). Design: In a prospective cohort study on 196 women undergoing OSCM HSG, we showed that iodine excess was almost universal (98%) and mild subclinical hypothyroidism was frequent (38%). Here, we report the analyses of secondary outcomes examining factors associated with the likelihood of pregnancy following the HSG. Setting: Auckland, New Zealand (2019-2021). Sample: 196 women with primary or secondary infertility who underwent OSCM HSG. Methods: Baseline and serial urine iodine concentrations (UIC) and thyroid function tests were measured over six months following the HSG. Pregnancy and treatment with levothyroxine during the study period were documented. Results: Following OSCM HSG, pregnancy rates were 49% in women aged <40 years (77/158) but considerably lower (16%) among those ≥40 years (6/38). Similarly, live birth rates were markedly lower in women ≥40 years (17%; 1/6) versus <40 years (73%; 56/77). 29% of participants were iodine deficient at baseline despite advice recommending iodine fortification. Following HSG, the likelihood of pregnancy in women with moderate iodine deficiency was 64% higher than in women with normal iodine levels (p=0.048). Among women aged <40 years who had subclinical hypothyroidism (n=75), levothyroxine treatment was associated with higher pregnancy rates compared to untreated women [63% (26/48) vs 37% (10/27), respectively; p=0.047]. Conclusion: OSCM HSG was associated with higher pregnancy rates in women ≤40 than in those aged >40 years. Iodine deficiency was relatively common in this cohort, and increased iodine levels from OSCM exposure may contribute to the improved fertility observed with this procedure. Trial registration: This study is registered with the Australian New Zealand Clinical Trials Registry (ANZCTR: 12620000738921) https://anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12620000738921.

AKT-dependent nuclear localization of EPRS1 activates PARP1 in breast cancer cells.

Glutamyl-prolyl-tRNA synthetase (EPRS1) is a bifunctional aminoacyl-tRNA-synthetase (aaRS) essential for decoding the genetic code. EPRS1 resides, with seven other aaRSs and three noncatalytic proteins, in the cytoplasmic multi-tRNA synthetase complex (MSC). Multiple MSC-resident aaRSs, including EPRS1, exhibit stimulus-dependent release from the MSC to perform noncanonical activities distinct from their primary function in protein synthesis. Here, we show EPRS1 is present in both cytoplasm and nucleus of breast cancer cells with constitutively low phosphatase and tensin homolog (PTEN) expression. EPRS1 is primarily cytosolic in PTEN-expressing cells, but chemical or genetic inhibition of PTEN, or chemical or stress-mediated activation of its target, AKT, induces EPRS1 nuclear localization. Likewise, preferential nuclear localization of EPRS1 was observed in invasive ductal carcinoma that were also P-Ser473-AKT+. EPRS1 nuclear transport requires a nuclear localization signal (NLS) within the linker region that joins the catalytic glutamyl-tRNA synthetase and prolyl-tRNA synthetase domains. Nuclear EPRS1 interacts with poly(ADP-ribose) polymerase 1 (PARP1), a DNA-damage sensor that directs poly(ADP-ribosyl)ation (PARylation) of proteins. EPRS1 is a critical regulator of PARP1 activity as shown by markedly reduced ADP-ribosylation in EPRS1 knockdown cells. Moreover, EPRS1 and PARP1 knockdown comparably alter the expression of multiple tumor-related genes, inhibit DNA-damage repair, reduce tumor cell survival, and diminish tumor sphere formation by breast cancer cells. EPRS1-mediated regulation of PARP1 activity provides a mechanistic link between PTEN loss in breast cancer cells, PARP1 activation, and cell survival and tumor growth. Targeting the noncanonical activity of EPRS1, without inhibiting canonical tRNA ligase activity, provides a therapeutic approach potentially supplementing existing PARP1 inhibitors.

Molecular and Serological Surveillance for Mycobacterium leprae and Mycobacterium lepromatosis in Wild Red Squirrels (Sciurus vulgaris) from Scotland and Northern England.

Leprosy is a poverty-associated infectious disease in humans caused by Mycobacterium leprae or M. lepromatosis, often resulting in skin and peripheral nerve damage, which remains a significant public health concern in isolated areas of low- and middle-income countries. Previous studies reported leprosy in red squirrels in the British Isles, despite the fact that autochthonous human cases have been absent for centuries in this region. To investigate the extent of M. leprae and M. lepromatosis presence in wild red squirrels in the northern UK, we analyzed 220 blood/body cavity fluid samples from opportunistically sampled red squirrels (2004-2023) for specific antibodies against phenolic glycolipid-I, a cell wall component specific for these leprosy bacilli. Additionally, we assessed bacillus-derived DNA by real-time PCR (qPCR) in 250 pinnae from the same cohort. M. lepromatosis and M. leprae DNA were detected by qPCR in 20.4% and 0.8% of the squirrels, respectively. No cases of co-detection were observed. Detectable levels of anti-PGL-I antibodies by UCP-LFA were observed in 52.9% of animals with the presence of M. lepromatosis determined by qPCR, and overall in 15.5% of all animals. In total, 22.6% (n = 296) of this UK cohort had at least some exposure to leprosy bacilli. Our study shows that leprosy bacilli persist in red squirrels in the northern UK, emphasizing the necessity for ongoing molecular and serological monitoring to study leprosy ecology in red squirrels, gain insight into potential zoonotic transmission, and to determine whether the disease has a conservation impact on this endangered species.

Hepatitis B Vaccine Refusal Trends in Washington, DC, Newborns, 2017-2022.

This cross-sectional study evaluates trends in rates of hepatitis B vaccine birth dose refusals in Washington, DC, from 2017 to 2022.

The role of microbial communities in biogeochemical cycles and greenhouse gas emissions within tropical soda lakes.

Although anthropogenic activities are the primary drivers of increased greenhouse gas (GHG) emissions, it is crucial to acknowledge that wetlands are a significant source of these gases. Brazil's Pantanal, the largest tropical inland wetland, includes numerous lacustrine systems with freshwater and soda lakes. This study focuses on soda lakes to explore potential biogeochemical cycling and the contribution of biogenic GHG emissions from the water column, particularly methane. Both seasonal variations and the eutrophic status of each examined lake significantly influenced GHG emissions. Eutrophic turbid lakes (ET) showed remarkable methane emissions, likely due to cyanobacterial blooms. The decomposition of cyanobacterial cells, along with the influx of organic carbon through photosynthesis, accelerated the degradation of high organic matter content in the water column by the heterotrophic community. This process released byproducts that were subsequently metabolized in the sediment leading to methane production, more pronounced during periods of increased drought. In contrast, oligotrophic turbid lakes (OT) avoided methane emissions due to high sulfate levels in the water, though they did emit CO2 and N2O. Clear vegetated oligotrophic turbid lakes (CVO) also emitted methane, possibly from organic matter input during plant detritus decomposition, albeit at lower levels than ET. Over the years, a concerning trend has emerged in the Nhecolândia subregion of Brazil's Pantanal, where the prevalence of lakes with cyanobacterial blooms is increasing. This indicates the potential for these areas to become significant GHG emitters in the future. The study highlights the critical role of microbial communities in regulating GHG emissions in soda lakes, emphasizing their broader implications for global GHG inventories. Thus, it advocates for sustained research efforts and conservation initiatives in this environmentally critical habitat.

Association between precipitation and mortality due to diarrheal diseases by climate zone: A multi-country modeling study.

Background: Precipitation could affect the transmission of diarrheal diseases. The diverse precipitation patterns across different climates might influence the degree of diarrheal risk from precipitation. This study determined the associations between precipitation and diarrheal mortality in tropical, temperate, and arid climate regions. Methods: Daily counts of diarrheal mortality and 28-day cumulative precipitation from 1997 to 2019 were analyzed across 29 locations in eight middle-income countries (Argentina, Brazil, Costa Rica, India, Peru, the Philippines, South Africa, and Thailand). A two-stage approach was employed: the first stage is conditional Poisson regression models for each location, and the second stage is meta-analysis for pooling location-specific coefficients by climate zone. Results: In tropical climates, higher precipitation increases the risk of diarrheal mortality. Under extremely wet conditions (95th percentile of 28-day cumulative precipitation), diarrheal mortality increased by 17.8% (95% confidence interval [CI] = 10.4%, 25.7%) compared with minimum-risk precipitation. For temperate and arid climates, diarrheal mortality increases in both dry and wet conditions. In extremely dry conditions (fifth percentile of 28-day cumulative precipitation), diarrheal mortality risk increases by 3.8% (95% CI = 1.2%, 6.5%) for temperate and 5.5% (95% CI = 1.0%, 10.2%) for arid climates. Similarly, under extremely wet conditions, diarrheal mortality risk increases by 2.5% (95% CI = -0.1%, 5.1%) for temperate and 4.1% (95% CI = 1.1%, 7.3%) for arid climates. Conclusions: Associations between precipitation and diarrheal mortality exhibit variations across different climate zones. It is crucial to consider climate-specific variations when generating global projections of future precipitation-related diarrheal mortality.

Associations between physicians' SDM behaviour and participation of older patients and family members in triadic decision-making: An observational study.

Background: Medical consultations with older patients often include triadic conversations and decision-making processes involving physicians, patients, and family members. The presence of family members may change the communication dynamics and therefore increase the complexity of the consultation and decision-making process. Objective: This study explored associations between physicians' shared decision-making (SDM) behaviour and patients' and family members' participation in the decision-making process. Methods: Using an observational design, we analysed 95 recorded consultations between medical specialists, patients aged ≥65 years, and accompanying family members at a Dutch hospital. The OPTIONMCC was used to assess the physicians' SDM behaviour and patients' and family members' levels of involvement in SDM. Results: We found a strong positive correlation between physicians' behaviour and patients' and family members' participation in SDM (0.68 and 0.64, respectively, p < .01). Family members were more involved in SDM for patients aged 80 and older. Conclusion: While not asserting causation, our study suggests physicians potentially play a facilitating role in shaping the SDM process together with proactive contributions from patients and family members. Innovation: The results offer new insights into triadic SDM and provide suggestions for refining the OPTIONMCC. Further research is recommended into participants' mutual directional influences in triadic SDM.

Attentional Biases and Nonsuicidal Self-Injury Urges in Adolescents.

Importance: Nonsuicidal self-injury (NSSI) is a significant clinical concern among adolescents. Exposure to NSSI-related content on social media platforms has been suspected to potentially act as a trigger for NSSI. Objective: To use free-viewing eye-tracking and dot-probe paradigms to examine attentional bias and psychophysiological responses to NSSI-related pictorial and textual stimuli in adolescents with and without a history of NSSI. Design, Setting, and Participants: From June 2022 to April 2023, adolescent participants in Vienna, Austria with and without a history of NSSI were exposed to NSSI-related stimuli in this nonrandomized controlled trial. Data were analyzed from December 2023 to January 2024. Exposure: Exposure to NSSI-related stimuli. Main Outcomes and Measures: During both tasks, subjective arousal, NSSI urges, and autonomic nervous system activity were assessed. Results: A total of 50 adolescents in 2 groups, 25 who engaged in NSSI (mean [SD] age 15.86 [1.14] years; 19 female participants [76%]) and 25 who did not (mean [SD] age 16.40 [1.71] years; 19 female participants [76%]) were included. Adolescents with a history of NSSI-but not those without a history of NSSI-showed a clear attentional bias toward NSSI-related images during eye-tracking, as indicated by increased initial fixations (500 ms stimulus presentation mean difference, 28.64%; 95% CI, 18.31%-38.98%; P < .001; 1000 ms stimulus presentation mean difference, 18.50%; 95% CI, 9.05%-27.95%; P < .001) and longer fixation durations (500 ms mean difference, 29.51 ms; 95% CI, 4.3-54.72 ms; P < .001; 1000 ms mean difference, 39.83 ms; 95% CI, 6.90-72.76 ms; P < .001), regardless of stimulus duration. This bias was associated with a heightened urge to engage in NSSI (d = 1.22; 95% CI, 0.69-1.73; P < .001), a trend not seen in adolescents without a history of NSSI. Similarly, in the dot-probe task, only the NSSI group showed an attentional bias toward NSSI images but not toward trauma images, emphasizing the specificity of their attentional bias. Physiological measures revealed no significant differences, suggesting that viewing NSSI images is not associated with increased autonomic arousal. Textual NSSI content did not provoke an attentional bias or heighten NSSI urges in either group. Conclusions and Relevance: In this nonrandomized controlled trial of 50 adolescents, results highlighted a specific attentional bias toward NSSI-related pictorial stimuli in adolescents with a history of NSSI, particularly a difficulty in disengaging from NSSI images. These findings contribute to understanding maladaptive information processing in NSSI and suggest implications for clinical management and cognitive models addressing NSSI triggers. Trial Registration: German Clinical Trials Register identifier: DRKS00025905.