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BackgroundIndigenous people in Canada, the United States, Australia, and New Zealand experience an increased burden of chronic diseases compared to non-Indigenous people in these countries. Lack of necessary services and culturally relevant care for Indigenous people contributes to this burden. Many Indigenous communities have implemented systems, such as virtual care, to improve chronic disease management. Virtual care has extended beyond videoconferencing to include more advanced technologies, such as remote biometric monitoring devices. However, given the historical and ongoing Western intrusion into Indigenous day to day life, these technologies may seem more invasive and thus require additional research on their acceptability and utility within Indigenous populations. ObjectiveThe objective of this paper is to present the protocol for a scoping review, which aims to map existing evidence. This study is based on the following guiding research question: What are the characteristics of virtual care use by Indigenous adult populations in Canada, the United States, Australia, and New Zealand? The subquestions are related to the technology used, health conditions and nature of the virtual care, cultural safety, and key concepts for effective use. MethodsThis scoping review protocol is informed by the methodology described by the Joanna Briggs Institute and is supplemented by the frameworks proposed by Arksey and O’Malley and Levac et al. A search for published and gray literature, written in English, and published between 2000 and present will be completed utilizing electronic databases and search engines, including MEDLINE, CINAHL, Embase, Indigenous Peoples of North America, Australian Indigenous HealthInfoNet, Informit, and Native Health Database. Search results will be uploaded to the review software, Covidence, for title and abstract screening before full-text screening begins. This process will be repeated for gray literature. Upon completion, a data abstraction tool will organize the relevant information into categorical formations. ResultsThe search strategy has been confirmed, and the screening of titles and abstracts is underway. As of October 2020, we have identified over 300 articles for full-text screening. ConclusionsPrevious reviews have addressed virtual care within Indigenous communities. However, new virtual care technologies have since emerged; subsequently, additional literature has been published. Mapping and synthesizing this literature will inform new directions for research and discussion. International Registered Report Identifier (IRRID)PRR1-10.2196/21860

Abstract Fire agencies across the United States must make complex resource allocation decisions to manage wildfires using a national network of shared firefighting resources. Firefighters play a critical role in suppressing fires and protecting vulnerable communities. However, they are exposed to health and safety risks associated with fire, smoke inhalation, and infectious disease transmission. The COVID-19 pandemic further complicated these risks, prompting fire agencies to propose resource management adaptations to minimize COVID-19 exposure and transmission. It is unclear if and how the pandemic may have operationally influenced wildland firefighting personnel resource use given compounding wildfire and COVID-19 risks. Therefore, we developed generalized linear mixed models that were fit using multiple integrated datasets to detect changes in personnel resource use for years prior to and during the COVID-19 pandemic, while controlling for historical fire and landscape conditions, societal risks, and management objectives. Analyses of observed and predicted firefighting resource use revealed reductions in the mean personnel resources used per wildfire per day during the pandemic for models developed across the western U.S. and for various western U.S. fire regions. Notably, the Northern California and the Great Basin Coordination Centers showed statistically significant reductions in ground personnel use during the COVID-19 pandemic. Learning from wildland fire management strategies and resource use trends that occurred during the COVID-19 pandemic, fire agencies can better anticipate resource constraints that may arise during the compounding threats of severe wildland fire activity and infectious disease outbreaks to proactively prepare and adapt suppression management strategies.

Abstract Background Whole blood host transcript signatures show great potential for diagnosis of infectious and inflammatory illness, with most published signatures performing binary classification tasks. Barriers to clinical implementation include validation studies, and development of strategies that enable simultaneous, multiclass diagnosis of febrile illness based on gene expression. Methods We validated five distinct diagnostic signatures for paediatric infectious diseases in parallel using a single NanoString nCounter® experiment. We included a novel 3-transcript signature for childhood tuberculosis, and four published signatures which differentiate bacterial infection, viral infection, or Kawasaki disease from other febrile illnesses. Signature performance was assessed using receiver operating characteristic curve statistics. We also explored conceptual frameworks for multiclass diagnostic signatures, including additional transcripts found to be significantly differentially expressed in previous studies. Relaxed, regularised logistic regression models were used to derive two novel multiclass signatures: a mixed One-vs-All model (MOVA), running multiple binomial models in parallel, and a full-multiclass model. In-sample performance of these models was compared using radar-plots and confusion matrix statistics. Results Samples from 91 children were included in the study: 23 bacterial infections (DB), 20 viral infections (DV), 14 Kawasaki disease (KD), 18 tuberculosis disease (TB), and 16 healthy controls. The five signatures tested demonstrated cross-platform performance similar to their primary discovery-validation cohorts. The signatures could differentiate: KD from other diseases with area under ROC curve (AUC) of 0.897 [95% confidence interval: 0.822–0.972]; DB from DV with AUC of 0.825 [0.691–0.959] (signature-1) and 0.867 [0.753–0.982] (signature-2); TB from other diseases with AUC of 0.882 [0.787–0.977] (novel signature); TB from healthy children with AUC of 0.910 [0.808–1.000]. Application of signatures outside of their designed context reduced performance. In-sample error rates for the multiclass models were 13.3% for the MOVA model and 0.0% for the full-multiclass model. The MOVA model misclassified DB cases most frequently (18.7%) and TB cases least (2.7%). Conclusions Our study demonstrates the feasibility of NanoString technology for cross-platform validation of multiple transcriptomic signatures in parallel. This external cohort validated performance of all five signatures, including a novel sparse TB signature. Two exploratory multi-class models showed high potential accuracy across four distinct diagnostic groups.

Introduction: Recent policy changes in Washington State presented a unique opportunity to pair evidence-based interventions with first responder services to combat increasing opioid overdoses. However, little is known about how these interventions should be implemented. In partnership with the Research with Expert Advisors on Drug Use team, a group of academically trained and community-trained researchers with lived and living experience of substance use, we examined facilitators and barriers to adopting leave-behind naloxone, field-based buprenorphine initiation, and HIV and hepatitis C virus (HCV) testing for first responder programs. Methods: Our team completed semi-structured, qualitative interviews with 32 first responders, mobile integrated health staff, and emergency medical services (EMS) leaders in King County, Washington, from February–May 2022. Semi-structured interviews were recorded, transcribed, and coded using an integrated deductive and inductive thematic analysis approach grounded in community-engaged research principles. We collected data until saturation was achieved. Data collection and analysis were informed by the Consolidated Framework for Implementation Research. Two investigators coded independently until 100% consensus was reached. Results: Our thematic analysis revealed several perceived facilitators (ie, tension for change, relative advantage, and compatibility) and barriers (ie, limited adaptability, lack of evidence strength and quality, and prohibitive cost) to the adoption of these evidence-based clinical interventions for first responder systems. There was widespread support for the distribution of leave-behind naloxone, although funding was identified as a barrier. Many believed field-based initiation of buprenorphine treatment could provide a more effective response to overdose management, but there were significant concerns that this intervention could run counter to the rapid care model. Lastly, participants worried that HIV and HCV testing was inappropriate for first responders to conduct but recommended that this service be provided by mobile integrated health staff. Conclusion: These results have informed local EMS strategic planning, which will inform roll out of process improvements in King County, Washington. Future work should evaluate the impact of these interventions on the health of overdose survivors.

Abstract Background Final year medical students and postgraduate doctors regularly contend with feelings of under-preparedness when transitioning into new areas of clinical practice. This lack of confidence is most evident in the context of on-call work which frequently requires sound clinical prioritisation, rigorous decision making and the management of acutely unwell patients, often with reduced senior support and staffing. This has prompted the emergence of on-call simulation which seeks to enhance participant confidence in performing on-call tasks and facilitate the development of key clinical and non-technical skills. This narrative review examined the use of on-call simulation in medical student and newly qualified doctor cohorts, its effectiveness in achieving its stated outcomes and to identify novel areas for the development of existing models. Method A search strategy was developed in conjunction with a specialist medical librarian. OVID Medline and Embase searches identified articles related to the use and design of on-call simulation in medical education with no restrictions placed upon date or language of publication. Key findings from articles were summarised to develop comprehensive themes for discussion. Results Twenty Three unique publications were reviewed which unanimously reported that on-call simulation had a positive effect on self-reported participant confidence in performing on-call roles. Furthermore the value on-call simulation when used as an induction activity was also evident. However, there was limited evidence around improved patient and performance outcomes following simulation. It also remains resource intensive as an educational tool and there is a distinct absence of interprofessional education in current models. Conclusions We concluded that on-call simulation must adopt an interprofessional educational approach, incorporating other clinical roles. Further studies are needed to characterise the impact on patient outcomes. It remains highly useful as a confidence-boosting induction activity, particularly in specialities where clinical exposure is limited. Virtual and tabletop simulation formats, could potentially address the resource burden of manikin-based models, particularly with ever growing demands on medical educators and the expansion of training posts.

Abstract Yellowfin tuna, Thunnus albacares, represents an important component of commercial and recreational fisheries in the Gulf of Mexico (GoM). We investigated the influence of environmental conditions on the spatiotemporal distribution of yellowfin tuna using fisheries’ catch data spanning 2012–2019 within Mexican waters. We implemented hierarchical Bayesian regression models with spatial and temporal random effects and fixed effects of several environmental covariates to predict habitat suitability (HS) for the species. The best model included spatial and interannual anomalies of the absolute dynamic topography of the ocean surface (ADTSA and ADTIA, respectively), bottom depth, and a seasonal cyclical random effect. High catches occurred mainly towards anticyclonic features at bottom depths > 1000 m. The spatial extent of HS was higher in years with positive ADTIA, which implies more anticyclonic activity. The highest values of HS (> 0.7) generally occurred at positive ADTSA in oceanic waters of the central and northern GoM. However, high HS values (> 0.6) were observed in the southern GoM, in waters with cyclonic activity during summer. Our results highlight the importance of mesoscale features for the spatiotemporal distribution of yellowfin tunas and could help to develop dynamic fisheries management strategies in Mexico and the U.S. for this valuable resource.

Abstract Computational approaches for predicting the pathogenicity of genetic variants have advanced in recent years. These methods enable researchers to determine the possible clinical impact of rare and novel variants. Historically these prediction methods used hand-crafted features based on structural, evolutionary, or physiochemical properties of the variant. In this study we propose a novel framework that leverages the power of pre-trained protein language models to predict variant pathogenicity. We show that our approach VariPred (Variant impact Predictor) outperforms current state-of-the-art methods by using an end-to-end model that only requires the protein sequence as input. Using one of the best-performing protein language models (ESM-1b), we establish a robust classifier that requires no calculation of structural features or multiple sequence alignments. We compare the performance of VariPred with other representative models including 3Cnet, Polyphen-2, REVEL, MetaLR, FATHMM and ESM variant. VariPred performs as well as, or in most cases better than these other predictors using six variant impact prediction benchmarks despite requiring only sequence data and no pre-processing of the data.

The aim of this mixed-method study was to identify support needs, as well as barriers and facilitators to seeking support in a sample of Swedish fathers with a fear of childbirth (FOC). Participants completed an anonymous quantitative online survey ( N = 131), with three free-text items for those self-identifying as having an FOC ( N = 71) and five individual in-depth interviews. Data analysis included descriptive and chi-square analyses for quantitative data, and manifest content analysis for qualitative data. Those with a severe FOC were more likely to report having on-going mental health difficulties ( p = .039) and one fifth (21%) of the participants with severe FOC wanted to receive professional treatment, but only 8.1% received treatment. Most participants either preferred individual support or to receive support together with their partner. Fathers with severe FOC were more likely to report one or more barriers than those without FOC ( p = .005), where unwanted social stigma was the single largest barrier. Qualitative findings identified one main category: Expectant fathers missing and wishing for support for FOC composed four generic categories: (1) support in developing an understanding of their fear , (2) coping by being aware of feelings , (3) professional support through trust and respect , and (4) needing individualized support . To encourage healthy fathers, clinical professionals should find ways to support fathers, such as by providing them with their own perinatal appointments, asking them about their feelings, as well as screening, diagnosing, and treating fathers with severe FOC.

BackgroundSexual violence (SV) is a significant problem for sexual minorities, including men who have sex with men (MSM). The limited research suggests SV is associated with a host of syndemic conditions. These factors tend to cluster and interact to worsen one another. Unfortunately, while much work has been conducted to examine these factors in heterosexual women, there is a lack of research examining MSM, especially their SV risk perception. Further, MSM are active users of dating and sexual networking (DSN) mobile apps, and this technology has demonstrated usefulness for creating safe spaces for MSM to meet and engage partners. However, mounting data demonstrate that DSN app use is associated with an increased risk for SV, especially given the higher likelihood of using alcohol and other drugs before sex. By contrast, some researchers have demonstrated that DSN technology can be harnessed as a prevention tool for HIV; unfortunately, no such work has progressed regarding SV. ObjectiveThis study aims to (1) use qualitative and quantitative methods to tailor an existing laboratory paradigm of SV risk perception in women for MSM using a DSN mobile app framework and (2) subject this novel paradigm to a rigorous validation study to confirm its usefulness in predicting SV, with the potential for use in future prevention endeavors. MethodsTo tailor the paradigm for MSM, a team of computer scientists created an initial DSN app (G-Date) and incorporated ongoing feedback about the usability, feasibility, and realism of this tool from a representative sample of MSM. We used focus groups and interviews to assist in the development of G-Date, including by identifying relevant stimuli, developing the cover story, and establishing the appropriate study language. To confirm the paradigm’s usefulness, we are conducting an experimental study with web-based and face-to-face participants to determine the content, concurrent, and predictive validities of G-Date. We will evaluate whether certain correlates of SV informed by syndemics and minority stress theories (eg, history of SV and alcohol and drug use) affect the ability of MSM to detect SV risk within G-Date and how paradigm engagement influences behavior in actual DSN app use contexts. ResultsThis study received funding from the National Institute on Alcohol Abuse and Alcoholism on September 10, 2020, and ethics approval on October 19, 2020, and we began app development for aim 1 immediately thereafter. We began data collection for the aim 2 validation study in December 2022. Initial results from the validation study are expected to be available after December 2025. ConclusionsWe hope that G-Date will enhance our understanding of factors associated with SV risk and serve as a useful step in creating prevention programs for this susceptible population.

Background Women’s underage marriage (

Objective Although life events are clearly important to health, most of the scientific focus has been on baseline life events that occur prior to a study. Life events that occur after enrolment, that is, interval life events, have had almost no attention. The aim of this analysis of data was to develop a method for measuring interval life events that could be used in clinical trials and other longitudinal studies.Design Small Changes and Lasting Effects (SCALE) was a 12-month weight-loss randomised controlled trial (RCT). This was an analysis of the SCALE follow-up data.Setting Healthcare networks, outpatient clinics and community churches in the South Bronx and Harlem areas of New York City.Participants Overweight black and Latino adults. This analysis focuses on the 330 of the 405 patients who had >4 weeks of follow-up with at least one perceived stress score (PSS).Intervention The SCALE RCT was published elsewhere and involved positive affect and self-affirmation to increase behaviour change.Outcome 5% weight loss.Follow-up Over 12 months, up to 27 follow-ups were conducted that evaluated interval life events, eating and physical activity behaviour, weight and perceived stress. During these follow-ups, participants were asked two open-ended questions to capture interval life events. The interval life events were qualitatively coded into categories. The interval life events categories were compared with interval monthly measures of perceived stress using the 4-item PSS scale.Results During the interval follow-ups for the RCT, 70.6% of the 330 patients reported at least one interval life event, which occurred during a median of 15 follow-ups (95% CI: 5 to 24). The median number of interval events was 2 (95% CI: 0 to 8): 30.6% reported their own illness; 22%, death or bereavement; 21.8%, illness in the family and 13.1%, family conflicts. The mean perceived stress score (PSS-4) assessed over the year of follow-up was 3.2±2.7. Mean perceived stress (PSS-4) increased, especially for interval financial events, major conflict with a partner and unemployment, but by less for deaths, family illness and family conflict. Participants with the most interval life events had the greatest increase in interval perceived stress (p20) nor baseline depression (Patient Health Questionnaire-9 >10) were associated with higher interval life events (p>0.05); but those with lower social support had more events. However, those with either depression or stress had higher interval stress responses. Most participants had neither baseline nor interval events, and the percentage with both was small so that baseline events did not predict subsequent perceived stress.Conclusions This method provides a straightforward method of assessing interval life events, by asking two open-ended questions, that can be coded in a simple categorical framework. Such events can affect outcomes in longitudinal studies and trials in part by increasing perceived stress. This framework moves beyond the events identified as important in the 1950s and recognises that specific life events may have significantly different life impacts in different individuals.Trial registeration number NCT01198990; Post-results.

Objective To evaluate the long-term sustainability of response to the Janus kinase inhibitor upadacitinib among patients with rheumatoid arthritis and an inadequate response or intolerance to biological disease-modifying antirheumatic drugs (bDMARD-IR) in the SELECT-BEYOND phase 3 trial.Methods Patients on background conventional synthetic DMARDs (csDMARDs) were treated once daily with upadacitinib 15 mg or placebo. Patients who completed the week 24 visit could enter a long-term extension of up to 5 years. The sustainability of response was assessed based on achievement of Clinical Disease Activity Index (CDAI), Simplified Disease Activity Index (SDAI) and Disease Activity Score 28-joint count using C-reactive protein (DAS28 (CRP)) targets and evaluated up to week 260 in all patients receiving the approved upadacitinib 15 mg dose, including those randomised to upadacitinib 15 mg and those who switched from placebo to upadacitinib 15 mg at week 12.Results In this bDMARD-IR population, 45% (n=104/229) and 79% (n=172/219) of patients treated with upadacitinib 15 mg plus background csDMARD(s) achieved CDAI remission or CDAI low disease activity (LDA) at any point during the 5-year study, respectively. Of those who achieved CDAI remission/LDA, 25%/43% maintained their initial response through 240 weeks of follow-up after first achieving response. Most patients who lost remission or LDA were able to recapture that response by the cut-off date. Similar overall results were observed for SDAI and DAS28 (CRP). No strong predictors of response were identified.Conclusions Over three-quarters of bDMARD-IR patients achieved CDAI LDA with upadacitinib, and almost half of those maintained LDA through 240 weeks of follow-up. Remission was achieved by nearly half of all patients and maintained in approximately a quarter of those achieving remission.Trial registration number NCT02706847.

Background Left ventricular assist devices (LVADs) have emerged as a successful treatment option for patients with end-stage heart failure. Compared with the best medical therapy, LVADs improve survival and enhance functional capacity and quality of life. However, two major complications compromise this patient population’s outcomes: thrombosis and bleeding. Despite technological innovations and better hemocompatibility, these devices alter the rheology, triggering the coagulation cascade and, therefore, require antithrombotic therapy. Anticoagulation and antiplatelet therapies represent the current standard of care. Still, inconsistency in the literature exists, especially whether antiplatelet therapy is required, whether direct oral anticoagulants can replace vitamin K antagonists and even whether phosphodiesterase type 5 inhibitors with their antithrombotic effects could be added to the regimen of anticoagulation.Methods and analysis We will perform a living systematic review with network meta-analysis and indirect comparison between current antithrombotic therapies, which have and have not been directly compared within clinical trials and observational studies. We will systematically search the following electronic sources: Cochrane Central Register of Controlled Trials (CENTRAL), Medical Literature Analysis and Retrieval System Online (MEDLINE) and Excerpta Medica Database (EMBASE). We will exclusively examine studies published in English from 2016 to the present. Studies conducted before 2016 will be omitted since our primary focus is evaluating continuous flow devices. Two independent reviewers will assess the articles by title, abstract and full text; any disagreement will be resolved through discussion, and a third reviewer will be involved if necessary. The Cochrane Risk of Bias tool will be used to assess the risk of bias. We will then conduct a pairwise meta-analysis; if the assumption of transitivity is satisfied, we will proceed with network meta-analysis using Bayesian methodology.Ethics and dissemination Formal ethical approval is not required as no primary data are collected. This systematic review and network meta-analysis will delineate the risks of stroke, thromboembolic events, pump thrombosis, gastrointestinal bleeding and mortality in patients equipped with LVADs who are subjected to various antithrombotic regimens. The findings will be disseminated via a peer-reviewed publication and presented at conference meetings. This will enhance clinical practice and guide future research on anticoagulation strategies within this distinct patient cohort.PROSPERO registration number CRD42023465288.

Summary: Background: The ability to detect evidence of Mycobacterium tuberculosis (Mtb) infection within human tissues is critical to the study of Mtb physiology, tropism, and spatial distribution within TB lesions. The capacity of the widely-used Ziehl-Neelsen (ZN) staining method for identifying Mtb acid-fast bacilli (AFB) in tissue is highly variable, which can limit detection of Mtb bacilli for research and diagnostic purposes. Here, we sought to circumvent these limitations via detection of Mtb mRNA and secreted antigens in human tuberculous tissue. Methods: We adapted RNAscope, an RNA in situ hybridisation (RISH) technique, to detect Mtb mRNA in ante- and postmortem human TB tissues and developed a dual ZN/immunohistochemistry staining approach to identify AFB and bacilli producing antigen 85B (Ag85B). Findings: We identified Mtb mRNA within intact and disintegrating bacilli as well as extrabacillary mRNA. Mtb mRNA was distributed zonally within necrotic and non-necrotic granulomas. We also found Mtb mRNA within, and adjacent to, necrotic granulomas in ZN-negative lung tissue and in Ag85B-positive bronchiolar epithelium. Intriguingly, we observed accumulation of Mtb mRNA and Ag85B in the cytoplasm of host cells. Notably, many AFB were negative for Ag85B staining. Mtb mRNA was observed in ZN-negative antemortem lymph node biopsies. Interpretation: RNAscope and dual ZN/immunohistochemistry staining are well-suited for identifying subsets of intact Mtb and/or bacillary remnants in human tissue. RNAscope can identify Mtb mRNA in ZN-negative tissues from patients with TB and may have diagnostic potential in complex TB cases. Funding: Wellcome Leap Delta Tissue Program, Wellcome Strategic Core Award, the National Institutes of Health (NIH, USA), the Mary Heersink Institute for Global Health at UAB, the UAB Heersink School of Medicine.

Abstract Despite advancements in cancer immunotherapy, solid tumors remain formidable challenges. In glioma, profound inter- and intra-tumoral heterogeneity of antigen landscape hampers therapeutic development. Therefore, it is critical to consider alternative sources to expand the repertoire of targetable (neo-)antigens and improve therapeutic outcomes. Accumulating evidence suggests that tumor-specific alternative splicing (AS) could be an untapped reservoir of antigens. In this study, we investigated tumor-specific AS events in glioma, focusing on those predicted to generate major histocompatibility complex (MHC)-presentation-independent, cell-surface antigens that could be targeted by antibodies and chimeric antigen receptor-T cells. We systematically analyzed bulk RNA-sequencing datasets comparing 429 tumor samples (from The Cancer Genome Atlas) and 9166 normal tissue samples (from the Genotype-Tissue Expression project), and identified 13 AS events in 7 genes predicted to be expressed in more than 10% of the patients, including PTPRZ1 and BCAN, which were corroborated by an external RNA-sequencing dataset. Subsequently, we validated our predictions and elucidated the complexity of the isoforms using full-length transcript amplicon sequencing on patient-derived glioblastoma cells. However, analyses of the RNA-sequencing datasets of spatially mapped and longitudinally collected clinical tumor samples unveiled remarkable spatiotemporal heterogeneity of the candidate AS events. Furthermore, proteomics analysis did not reveal any peptide spectra matching the putative antigens. Our investigation illustrated the diverse characteristics of the tumor-specific AS events and the challenges of antigen exploration due to their notable spatiotemporal heterogeneity and elusive nature at the protein levels. Redirecting future efforts toward intracellular, MHC-presented antigens could offer a more viable avenue.

Sleep and circadian rhythm disturbance are predictors of poor physical and mental health, including dementia. Long-term digital technology-enabled monitoring of sleep and circadian rhythms in the community has great potential for early diagnosis, monitoring of disease progression, and assessing the effectiveness of interventions. Before novel digital technology-based monitoring can be implemented at scale, its performance and acceptability need to be evaluated and compared to gold-standard methodology in relevant populations. Here, we describe our protocol for the evaluation of novel sleep and circadian technology which we have applied in cognitively intact older adults and are currently using in people living with dementia (PLWD). In this protocol, we test a range of technologies simultaneously at home (7–14 days) and subsequently in a clinical research facility in which gold standard methodology for assessing sleep and circadian physiology is implemented. We emphasize the importance of assessing both nocturnal and diurnal sleep (naps), valid markers of circadian physiology, and that evaluation of technology is best achieved in protocols in which sleep is mildly disturbed and in populations that are relevant to the intended use-case. We provide details on the design, implementation, challenges, and advantages of this protocol, along with examples of datasets.

Abstract Abnormal cyclic motor pattern (CMP) activity is implicated in colonic dysfunction, but the only tool to evaluate CMP activity, high-resolution colonic manometry (HRCM), remains expensive and not widely accessible. This study aimed to validate body surface colonic mapping (BSCM) through direct correlation with HRCM. Synchronous meal-test recordings were performed in asymptomatic participants with intact colons. A signal processing method for BSCM was developed to detect CMPs. Quantitative temporal analysis was performed comparing the meal responses and motility indices (MI). Spatial heat maps were also compared. Post-study questionnaires evaluated participants’ preference and comfort/distress experienced from either test. 11 participants were recruited and 7 had successful synchronous recordings (5 females/2 males; median age: 50 years [range 38–63]). The best-correlating MI temporal analyses achieved a high degree of agreement (median Pearson correlation coefficient (Rp) value: 0.69; range 0.47–0.77). HRCM and BSCM meal response start and end times (Rp = 0.998 and 0.83; both p

Abstract Mental disorders are complex disorders influenced by multiple genetic, environmental, and biological factors. Specific microbiota imbalances seem to affect mental health status. However, the mechanisms by which microbiota disturbances impact the presence of depression, stress, anxiety, and eating disorders remain poorly understood. Currently, there are no robust biomarkers identified. We proposed a novel pyramid-layer design to accurately identify microbial/metabolomic signatures underlying mental disorders in the TwinsUK registry. Monozygotic and dizygotic twins discordant for mental disorders were screened, in a pairwise manner, for differentially abundant bacterial genera and circulating metabolites. In addition, multivariate analyses were performed, accounting for individual-level confounders. Our pyramid-layer study design allowed us to overcome the limitations of cross-sectional study designs with significant confounder effects and resulted in an association of the abundance of genus Parabacteroides with the diagnosis of mental disorders. Future research should explore the potential role of Parabacteroides as a mediator of mental health status. Our results indicate the potential role of the microbiome as a modifier in mental disorders that might contribute to the development of novel methodologies to assess personal risk and intervention strategies.

Abstract Arginine, a semi-essential amino acid, is critical for cell growth. Typically, de novo synthesis of arginine is sufficient to support cellular processes, however, it becomes vital for cancer cells that are unable to synthesise arginine due to enzyme deficiencies. Targeting this need, arginine depletion with enzymes such as arginase (ARG) has emerged as a potential cancer therapeutic strategy. Studies have proposed using high dose insulin to induce a state of hypoaminoacidaemia in the body, thereby further reducing circulating arginine levels. However, the mitogenic and metabolic properties of insulin could potentially counteract the therapeutic effects of ARG. Our study examined the combined impact of insulin and ARG on breast, lung, and ovarian cell lines, focusing on cell proliferation, metabolism, apoptosis, and autophagy. Our results showed that the influence of insulin on ARG uptake varied between cell lines but failed to promote the proliferation of ARG-treated cells or aid recovery post-ARG treatment. Moreover, insulin was largely ineffective in altering ARG-induced metabolic changes and did not prevent apoptosis. In vitro, at least, these findings imply that insulin does not offer a growth or survival benefit to cancer cells being treated with ARG.

Abstract Oilseed rape (Brassica napus) is an important global oil crop, with spring and winter varieties grown commercially. To understand the transcriptomic differences between these varieties, we collected transcriptomes from apex and leaf tissue from a spring variety, Westar, and a winter variety, Tapidor, before, during, and after vernalisation treatment, until the plants flowered. Large transcriptomic differences were noted in both varieties during the vernalisation treatment because of temperature and day length changes. Transcriptomic alignment revealed that the apex transcriptome reflects developmental state, whereas the leaf transcriptome is more closely aligned to the age of the plant. Similar numbers of copies of genes were expressed in both varieties during the time series, although key flowering time genes exhibited expression pattern differences. BnaFLC copies on A2 and A10 are the best candidates for the increased vernalisation requirement of Tapidor. Other BnaFLC copies show tissue-dependent reactivation of expression post-cold, with these dynamics suggesting some copies have retained or acquired a perennial nature. BnaSOC1 genes, also related to the vernalisation pathway, have expression profiles which suggest tissue subfunctionalisation. This understanding may help to breed varieties with more consistent or robust vernalisation responses, of special importance due to the milder winters resulting from climate change.

Abstract While obesity is a risk factor for post-acute sequelae of SARS-CoV-2 infection (PASC, "long-COVID"), the mechanism(s) underlying this phenomenon remains poorly understood. To address this gap in knowledge, we performed a 6-week longitudinal study to examine immune activity and gut microbiome dysbiosis in post-acute stage patients recovering from SARS-CoV-2 infection. Self-reported symptom frequencies and blood samples were collected weekly, with plasma assessed by ELISA and Luminex for multiple biomarkers and immune cell profiling. DNA from stool samples were collected at the early stage of recovery for baseline assessments of gut microbial composition and diversity using 16S-based metagenomic sequencing. Multiple regression analyses revealed obesity-related PASC linked to a sustained proinflammatory immune profile and reduced adaptive immunity, corresponding with reduced gut microbial diversity. In particular, enhanced signaling of the high mobility group box 1 (HMGB1) protein was found to associate with this dysregulation, with its upregulated levels in plasma associated with significantly impaired viral neutralization that was exacerbated with obesity. These findings implicate HMGB1 as a candidate biomarker of PASC, with potential applications for risk assessment and targeted therapies.

Abstract Controlling the dynamics of droplet evaporation is critical to numerous fundamental and industrial applications. The three main modes of evaporation so far reported on smooth surfaces are the constant contact radius (CCR), constant contact angle (CCA), and mixed mode. Previously reported methods for controlling droplet evaporation include chemical or physical modifications of the surfaces via surface coating. These often require complex multiple stage processing, which eventually enables similar droplet-surface interactions. By leveraging the change in the physicochemical properties of the outermost surface by different silicone oil grafting fabrication parameters, the evaporation dynamics and the duration of the different evaporation modes can be controlled. After grafting one layer of oil, the intrinsic hydrophilic silicon surface (contact angle (CA) ≈ 60°) is transformed into a hydrophobic surface (CA ≈ 108°) with low contact angle hysteresis (CAH). The CAH can be tuned between 1° and 20° depending on the fabrication parameters such as oil viscosity, volume, deposition method as well as the number of layers, which in turn control the duration of the different evaporation modes. In addition, the occurrence and strength of stick–slip behaviour during evaporation can be additionally controlled by the silicone oil grafting procedure adopted. These findings provide guidelines for controlling the droplet-surface interactions by either minimizing or maximising contact line initial pinning, stick–slip and/or constant contact angle modes of evaporation. We conclude that the simple and scalable silicone oil grafted coatings reported here provide similar functionalities to slippery liquid infused porous surfaces (SLIPSs), quasi-liquid surfaces (QLS), and/or slippery omniphobic covalently attached liquid (SOCAL) surfaces, by empowering pinning-free surfaces, and have great potential for use in self-cleaning surfaces or uniform particle deposition.

Abstract Background Tamoxifen is used in low dose concentrations (20–40 mg per day) as a therapy for breast cancer but is known to have ocular side effects. In this case report, the foveal cone integrity in a tamoxifen-treated patient who complained of a small central scotoma in the left eye while reading was examined using high resolution adaptive optics imaging. Case presentation Both eyes of a 54-year-old Caucasian, non-hispanic female who had been treated with tamoxifen for 1.5 years were examined using various imaging modalities including fundus photography, fundus autofluorescence, fluorescein angiography, spectral-domain optical coherence tomography, and adaptive optics scanning laser ophthalmoscopy. Clinical spectral-domain optical coherence tomography showed a very small disruption to the photoreceptor layer at the fovea in the left eye only. However, adaptive optics scanning laser ophthalmoscopy imaging revealed foveal cone loss in both eyes, but to a lesser extent in the right eye. Inner retinal changes were not observed in either eye. Conclusion The area of cone loss was similar in size to a single newsprint letter when projected onto the retina, matching the patient’s description of a scotoma in the left eye. Given the isolated loss of foveal cone photoreceptors with the absence of previously reported inner retinal and vascular changes, our results may indicate the earliest retinal changes associated with tamoxifen retinopathy.

BackgroundThe mental health of military personnel has garnered increased attention over the last few decades; however, the impacts of perpetuating, observing, or failing to prevent acts that transgress deeply held moral standards, referred to as moral injuries, are less understood, particularly in relation to encounters with children during deployment. This paper describes a multiphased research protocol that centers around the lived experiences of Canadian Armed Forces (CAF) Veterans to understand how encounters with children during military deployments impact the well-being and mental health of military personnel. ObjectiveThis study has four objectives: (1) highlight the lived experiences of CAF Veterans who encountered children during military deployments; (2) improve understanding of the nature of experiences that military personnel faced that related to observing or engaging with children during military service; (3) improve understanding of the mental health impacts of encountering children during military service; and (4) use participatory action research (PAR) to develop recommendations for improving preparation, training, and support for military personnel deployed to contexts where encounters with children are likely. MethodsThe research project has 2 main phases where phase 1 includes qualitative interviews with CAF Veterans who encountered children during military deployments and phase 2 uses PAR to actively engage Canadian Veterans with lived experiences of encountering children during military deployments, as well as health professionals and researchers to identify recommendations to better address the mental health effects of these encounters. ResultsAs of January 26, 2024, a total of 55 participants and research partners have participated in the 2 phases of the research project. A total of 16 CAF Veterans participated in phase 1 (qualitative interviews), and 39 CAF Veterans, health professionals, and researchers participated in phase 2 (PAR). The results for phase 1 have been finalized and are accepted for publication. Data collection and analysis are ongoing for phase 2. ConclusionsPrioritizing and valuing the experiences of CAF Veterans has deepened our understanding of the intricate nature and impacts of potentially morally injurious events involving children during military deployments. Together with health professionals and researchers, the PAR approach empowers CAF Veterans to articulate important recommendations for developing and improving training and mental health support. This support is crucial not only during the deployment cycle but also throughout the military career, helping lessen the effects of moral injury among military personnel. International Registered Report Identifier (IRRID)DERR1-10.2196/57146

Objectives Mycophenolate mofetil (MMF) and azathioprine (AZA) are immunomodulatory treatments in interstitial lung disease (ILD). This systematic review aimed to evaluate the efficacy of MMF or AZA on pulmonary function in ILD.Design Population included any ILD diagnosis, intervention included MMF or AZA treatment, outcome was delta change from baseline in per cent predicted forced vital capacity (%FVC) and gas transfer (diffusion lung capacity of carbon monoxide, %DLco). The primary endpoint compared outcomes relative to placebo comparator, the secondary endpoint assessed outcomes in treated groups only.Eligibility criteria Randomised controlled trials (RCTs) and prospective observational studies were included. No language restrictions were applied. Retrospective studies and studies with high-dose concomitant steroids were excluded.Data synthesis The systematic search was performed on 9 May. Meta-analyses according to drug and outcome were specified with random effects, I2 evaluated heterogeneity and Grading of Recommendations, Assessment, Development and Evaluation evaluated certainty of evidence. Primary endpoint analysis was restricted to RCT design, secondary endpoint included subgroup analysis according to prospective observational or RCT design.Results A total of 2831 publications were screened, 12 were suitable for quantitative synthesis. Three MMF RCTs were included with no significant effect on the primary endpoints (%FVC 2.94, 95% CI −4.00 to 9.88, I2=79.3%; %DLco −2.03, 95% CI −4.38 to 0.32, I2=0.0%). An overall 2.03% change from baseline in %FVC (95% CI 0.65 to 3.42, I2=0.0%) was observed in MMF, and RCT subgroup summary estimated a 4.42% change from baseline in %DLCO (95% CI 2.05 to 6.79, I2=0.0%). AZA studies were limited. All estimates were considered very low certainty evidence.Conclusions There were limited RCTs of MMF or AZA and their benefit in ILD was of very low certainty. MMF may support preservation of pulmonary function, yet confidence in the effect was weak. To support high certainty evidence, RCTs should be designed to directly assess MMF efficacy in ILD.PROSPERO registration number CRD42023423223.

Introduction Wildfires and deforestation potentially have direct effects on multiple health outcomes as well as indirect consequences for climate change. Tropical rainforest areas are characterised by high rainfall, humidity and temperature, and they are predominantly found in low-income and middle-income countries. This study aims to synthesise the methods, data and health outcomes reported in scientific papers on wildfires and deforestation in these locations.Methods and analysis We will carry out a scoping review according to the Joanna Briggs Institute’s (JBI) manual for scoping reviews and the framework proposed by Arksey and O’Malley, and Levac et al. The search for articles was performed on 18 August 2023, in 16 electronic databases using Medical Subject Headings terms and adaptations for each database from database inception. The search for local studies will be complemented by the manual search in the list of references of the studies selected to compose this review. We screened studies written in English, French, Portuguese and Spanish. We included quantitative studies assessing any human disease outcome, hospitalisation and vital statistics in regions of tropical rainforest. We exclude qualitative studies and quantitative studies whose outcomes do not cover those of interest. The text screening was done by two independent reviewers. Subsequently, we will tabulate the data by the origin of the data source used, the methods and the main findings on health impacts of the extracted data. The results will provide descriptive statistics, along with visual representations in diagrams and tables, complemented by narrative summaries as detailed in the JBI guidelines.Ethics and dissemination The study does not require an ethical review as it is meta-research and uses published, deidentified secondary data sources. The submission of results for publication in a peer-reviewed journal and presentation at scientific and policymakers’ conferences is expected.Study registration Open Science Framework (https://osf.io/pnqc7/).

Ikaros is a transcriptional factor required for conventional T cell development, differentiation, and anergy. While the related factors Helios and Eos have defined roles in regulatory T cells (Treg), a role for Ikaros has not been established. To determine the function of Ikaros in the Treg lineage, we generated mice with Treg-specific deletion of the Ikaros gene (Ikzf1). We find that Ikaros cooperates with Foxp3 to establish a major portion of the Treg epigenome and transcriptome. Ikaros-deficient Treg exhibit Th1-like gene expression with abnormal production of IL-2, IFNg, TNFa, and factors involved in Wnt and Notch signaling. While Ikzf1-Treg-cko mice do not develop spontaneous autoimmunity, Ikaros-deficient Treg are unable to control conventional T cell-mediated immune pathology in response to TCR and inflammatory stimuli in models of IBD and organ transplantation. These studies establish Ikaros as a core factor required in Treg for tolerance and the control of inflammatory immune responses.

Background: Our aim was to implement and evaluate a novel social determinants of health (SDoH) curriculum into the required fourth-year emergency medicine (EM) course at the University of Vermont Larner College of Medicine with the goal to teach students how to assess and address SDoH in clinical practice. The objectives were as follows: 1. Assess the SDoH, risk factors, and barriers to healthcare facing patients from diverse socioeconomic and cultural backgrounds in the ED. 2. Examine how social work consult services operate in the ED setting and how to identify appropriate referrals, resources, and treatment plans for patients in the ED. 3. Examine and interpret the impact health disparities have on patients in the ED and develop potential solutions to reduce these disparities to improve health outcomes. 4. Analyze the experiences and lessons learned and use them to inform future patient interactions. Curricular Design: The curriculum was developed by a workgroup that considered the following: scope; target learners; overall structure; instructional and delivery methods; and session scheduling. The curriculum consisted of four components that took place over the four-week EM course. Students completed a required end-of-course survey. Survey results underwent a mixed-methods analysis to assess student attitudes and the impact of the curriculum. Impact/Effectiveness: We received a 78.7% (74/94) completion rate for the 2021-2022 academic year. Of all respondents, 92% (68/74) indicated that they would apply lessons learned from the SDoH components of the curriculum; 74% (54/74) rated the SDoH curriculum as good, very good, or excellent; and 81% (60/74) felt that the EM course increased their understanding of diversity, equity, and inclusion as it relates to the practice of medicine. The thematic analyses revealed four main themes: 1) general comments; 2) course design; 3) interprofessional collaboration; and 4) expanding the scope of the curriculum. Conclusion: Social medicine integration into core EM courses is a generalizable approach to experiential and collaborative exposure to the social determinants of health. Of student respondents, 92% indicated they will use lessons learned from this curriculum in their future practice. This can improve the way future generations of physicians identify SDoH and address the social needs that affect their patients, thereby advancing and promoting health equity.

BackgroundTo address needs for emotional well-being resources for Californians during the COVID-19 pandemic, the Together for Wellness/Juntos por Nuestro Bienestar (T4W/Juntos) website was developed in collaboration with multiple community partners across California, funded by the California Department of Health Care Services Behavioral Health Division federal emergency response. ObjectiveThis qualitative study was designed to explore and describe the perspectives of participants affiliated with California organizations on the T4W/Juntos website, understand their needs for web-based emotional health resources, and inform iterative website development. MethodsAfter providing informed consent and reviewing the website, telephone interviews were conducted with 29 participants (n=21, 72% in English and n=8, 28% in Spanish) recruited by partnering community agencies (October 2021-February 2022). A 6-phase thematic analysis was conducted, enhanced using grounded theory techniques. The investigators wrote reflexive memos and performed line-by-line coding of 12 transcripts. Comparative analyses led to the identification of 15 overarching codes. The ATLAS.ti Web software (ATLAS.ti Scientific Software Development GmbH) was used to mark all 29 transcripts using these codes. After examining the data grouped by codes, comparative analyses led to the identification of main themes, each with a central organizing concept. ResultsFour main themes were identified: (1) having to change my coping due to the pandemic, (2) confronting a context of shifting perceptions of mental health stigma among diverse groups, (3) “Feels like home”—experiencing a sense of inclusivity and belonging in T4W/Juntos, and (4) “It’s a one-stop-shop”—judging T4W/Juntos to be a desirable and useful website. Overall, the T4W/Juntos website communicated support and community to this sample during the pandemic. Participants shared suggestions for website improvement, including adding a back button and a drop-down menu to improve functionality as well as resources tailored to the needs of groups such as older adults; adolescents; the lesbian, gay, bisexual, transgender, and queer community; police officers; and veterans. ConclusionsThe qualitative findings from telephone interviews with this sample of community members and service providers in California suggest that, during the COVID-19 pandemic, the T4W/Juntos website was well received as a useful, accessible tool, with some concerns noted such as language sometimes being too “professional” or “clinical.” The look, feel, and content of the website were described as welcoming due to pictures, animations, and videos that showcased resources in a personal, colorful, and inviting way. Furthermore, the content was perceived as lacking the stigma typically attached to mental health, reflecting the commitment of the T4W/Juntos team. Unique features and diverse resources, including multiple languages, made the T4W/Juntos website a valuable resource, potentially informing dissemination. Future efforts to develop mental health websites should consider engaging a diverse sample of potential users to understand how to tailor messages to specific communities and help reduce stigma.

With diminishing returns and high clinical failure rates from traditional preclinical and animal-based drug discovery strategies, more emphasis is being placed on alternative drug discovery platforms. Ex vivo approaches represent a departure from both more traditional preclinical animal-based models and clinical-based strategies and aim to address intra-tumoural and inter-patient variability at an earlier stage of drug discovery. Additionally, these approaches could also offer precise treatment stratification for patients within a week of tumour resection in order to direct tailored therapy. One tumour group that could significantly benefit from such ex vivo approaches are high-grade gliomas, which exhibit extensive heterogeneity, cellular plasticity and therapy-resistant glioma stem cell (GSC) niches. Historic use of murine-based preclinical models for these tumours has largely failed to generate new therapies, resulting in relatively stagnant and unacceptable survival rates of around 12-15 months post-diagnosis over the last 50 years. The near universal use of DNA damaging chemoradiotherapy after surgical resection within standard-of-care (SoC) therapy regimens provides an opportunity to improve current treatments if we can identify efficient drug combinations in preclinical models that better reflect the complex inter-/intra-tumour heterogeneity, GSC plasticity and inherent DNA damage resistance mechanisms. We have therefore developed and optimised a high-throughput ex vivo drug screening platform; GliExP, which maintains GSC populations using immediately dissociated fresh surgical tissue. As a proof-of-concept for GliExP, we have optimised SoC therapy responses and screened 30+ small molecule therapeutics and preclinical compounds against tumours from 18 different patients, including multi-region spatial heterogeneity sampling from several individual tumours. Our data therefore provides a strong basis to build upon GliExP to incorporate combination-based oncology therapeutics in tandem with SoC therapies as an important preclinical alternative to murine models (reduction and replacement) to triage experimental therapeutics for clinical translation and deliver rapid identification of effective treatment strategies for individual gliomas.

Summary: Background: Carpal tunnel syndrome (CTS) is a common disorder caused by compression of the median nerve in the wrist, resulting in pain and numbness throughout the hand and forearm. While multiple behavioural and physiological factors influence CTS risk, a growing body of evidence supports a strong genetic contribution. Recent genome-wide association study (GWAS) efforts have reported 53 independent signals associated with CTS. While GWAS can identify genetic loci conferring risk, it does not determine which cell types drive the genetic aetiology of the trait, which variants are “causal” at a given signal, and which effector genes correspond to these non-coding variants. These obstacles limit interpretation of potential disease mechanisms. Methods: We analysed CTS GWAS findings in the context of chromatin conformation between gene promoters and accessible chromatin regions across cellular models of bone, skeletal muscle, adipocytes and neurons. We identified proxy variants in high LD with the lead CTS sentinel SNPs residing in promoter connected open chromatin in the skeletal muscle and bone contexts. Findings: We detected significant enrichment for heritability in skeletal muscle myotubes, as well as a weaker correlation in human mesenchymal stem cell-derived osteoblasts. In myotubes, our approach implicated 117 genes contacting 60 proxy variants corresponding to 20 of the 53 GWAS signals. In the osteoblast context we implicated 30 genes contacting 24 proxy variants coinciding with 12 signals, of which 19 genes shared. We subsequently prioritized BZW2 as a candidate effector gene in CTS and implicated it as novel gene that perturbs myocyte differentiation in vitro. Interpretation: Taken together our results suggest that the CTS genetic component influences the size, integrity, and organization of multiple tissues surrounding the carpal tunnel, in particular muscle and bone, to predispose the nerve to being compressed in this disease setting. Funding: This work was supported by NIH Grant UM1 DK126194 (SFAG and WY), R01AG072705 (SFAG & KDH) and the Center for Spatial and Functional Genomics at CHOP (SFAG & ADW). SFAG is supported by the Daniel B. Burke Endowed Chair for Diabetes Research. WY is supported by the Perelman School of Medicine of the University of Pennsylvania.

Background Overnight desaturation predicts poor prognosis across interstitial lung diseases (ILDs). The aim of the present study was to investigate whether nocturnal desaturation is associated with pulmonary vasculopathy and mortality. Methods A retrospective single centre study of 397 new ILD patients was carried out including patients with idiopathic pulmonary fibrosis (IPF) (n=107) and patients with non-IPF fibrotic ILD (n=290). This is the largest study to date of the effect of significant nocturnal desaturation (SND) (≥10% of total sleep time with oxygen saturation ≤90% measured by pulse oximetry). Results The prevalence of SND was 28/107 (26.2%) in IPF and 80/290 (27.6%) in non-IPF ILD. The prevalence of SND was higher in non-IPF ILDs than in IPF (p=0.025) in multivariate analysis. SND was associated with noninvasive markers of pulmonary hypertension (PH): tricuspid regurgitation velocity (TRV) (p4% in 6-min walking test (p

Background Interstitial lung disease frequently complicates systemic autoimmune disorders including scleroderma, idiopathic inflammatory myositis and mixed connective tissue disease, resulting in considerable morbidity and mortality. Based on the results of trials undertaken in scleroderma, cyclophosphamide is the standard of care for individuals with severe or progressive connective tissue disease-associated interstitial lung disease. Observational studies suggest that the anti-CD20 monoclonal antibody, rituximab is an effective rescue therapy in treatment of refractory connective tissue disease-associated interstitial lung disease, but it has not been studied as first-line therapy in clinical trials. Objectives To compare the safety and efficacy of rituximab against that of cyclophosphamide as treatment for individuals with severe, progressive interstitial lung disease associated with scleroderma, idiopathic inflammatory myositis or mixed connective tissue disease. Methods This was a Phase IIb, multicentre, randomised, double-blind, double-dummy study assessing the superiority of rituximab compared with cyclophosphamide, conducted in rheumatology or interstitial lung disease units at 11 UK centres. The study recruited individuals with extensive and/or progressive connective tissue disease-associated interstitial lung disease, excluding those with significant comorbidities, including airflow obstruction. Participants were randomised 1 : 1 to receive either rituximab 1 g given intravenously, twice at an interval of 2 weeks, or intravenous cyclophosphamide given monthly for 6 months at a dose of 600 mg/m2 body surface area. The primary end point for the study was the change in forced vital capacity at 24 weeks. Secondary end points included safety and tolerability, corticosteroid exposure, forced vital capacity change at 48 weeks and patient-reported quality of life. A cost-effectiveness analysis was undertaken to assess the impact of rituximab use in the United Kingdom National Health Service. Results One hundred and one subjects (70 females) with a mean age of 56.3 years were randomised; 51 to rituximab and 50 to cyclophosphamide. Ninety-seven were included in the modified intention-to-treat population for the primary and secondary efficacy analyses (49 in the rituximab group and 48 in the cyclophosphamide group). 38.6% had scleroderma, 44.6% idiopathic inflammatory myositis and 16.8% mixed connective tissue disease. Four subjects withdrew prior to the first dose of therapy (two in each arm). At 24 weeks, both rituximab and cyclophosphamide improved forced vital capacity from baseline [(mean ± standard deviation) 97 ± 234 and 99 ± 329 ml, respectively]. Using an adjusted mixed-effects model corrected for diagnosis and baseline forced vital capacity the difference in forced vital capacity at 24 weeks between rituximab and cyclophosphamide was −40 ml (95% CI −153 to 74 ml), p = 0.49. Other physiological and quality-of-life parameters improved in both arms following treatment but were not statistically significantly different between groups. Numerically fewer adverse events were reported by subjects receiving rituximab. Corticosteroid exposure over the 48 weeks of the trial was numerically less in the rituximab arm [13,291 (±14,657) mg of hydrocortisone equivalent per subject in the cyclophosphamide arm versus 11,469 (±10,041) mg per subject in the rituximab group; these differences did not reach statistical significance]. Limitations of the study include a disproportionate number of subjects being recruited from a single centre and insufficient subjects in each subgroup to determine whether there were treatment differences between individual connective tissue diseases. Based on the results of the trial, from a UK healthcare payer perspective, rituximab is more cost-effective than cyclophosphamide as a treatment for severe or progressive connective tissue disease-interstitial lung disease. Conclusions Rituximab improved forced vital capacity and patient-reported quality of life at 24 weeks but was not superior to cyclophosphamide. Rituximab should be considered as a therapeutic alternative to cyclophosphamide in individuals with connective tissue disease-associated interstitial lung disease requiring systemic therapy. Future work should explore the role of repeated dosing of rituximab and the use of rituximab earlier in the course of connective tissue disease-associated interstitial lung disease. Trial registration This trial is registered as ISRCTN16474148. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation Programme (NIHR award ref: 11/116/03) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 4. See the NIHR Funding and Awards website for further award information. Plain language summary Interstitial lung disease, a condition characterised by inflammation and scarring of the lungs, is the leading cause of death in systemic sclerosis (an autoimmune disease that typically causes thickening and scarring of the skin and which is associated with internal organ problems such as interstitial lung disease and kidney failure), and a major cause of morbidity (illness) in many other connective tissue diseases; a group of conditions that are caused by over activity of the immune system. When interstitial lung disease associated with connective tissue disease gets worse over time, treatment such as intravenous cyclophosphamide is required to slow down lung scarring. Occasionally, standard immunosuppressive drugs fail to control lung inflammation and scaring and this can result in death. Rituximab, a novel therapy, has been proven to be of benefit in suppressing inflammation associated with immune system over activity. Observational studies suggest that rituximab may be an effective treatment for pulmonary inflammation in connective tissue diseases. The study was designed to determine how well rituximab works compared to cyclophosphamide in treating patients with severe connective tissue disease-associated interstitial lung disease. We recruited 101 participants from 11 hospitals throughout the UK who were randomly allocated to one of two groups. Those in the first group were given rituximab on day 1 of the study and then on day 14. They were then given a placebo every 4 weeks for the next 18 weeks. Those in the second group were given cyclophosphamide every 4 weeks from day 1 of the study to week 20. On day 14, they were given a placebo. Lung function for all participants was assessed at 24 weeks. Our results suggest that rituximab improved lung function and quality of life but was not better than cyclophosphamide. Rituximab was associated with fewer unexpected medical events and a trend towards reduction in corticosteroid use and should be considered as a therapeutic alternative to cyclophosphamide. Scientific summary Background Interstitial lung disease (ILD) is characterised by inflammation and/or fibrosis within the parenchymal compartment bounded by the alveolar epithelium and capillary endothelium and frequently results in breathlessness progressing over time to respiratory failure. Autoimmune injury to the lung is a frequent cause of ILD. As such, the connective tissue diseases (CTDs), including systemic sclerosis (SSc), the inflammatory myopathies and mixed connective tissue disease (MCTD), are important causes of ILD. For individuals with CTD the development of ILD is an important cause of morbidity and mortality; for people with scleroderma, ILD is now the leading cause of death. Despite this there are few evidence-based treatments for CTD-associated ILD. At the time of planning this research there were no approved therapies available for CTD-ILD and all of the trial data which existed had been generated in the context of scleroderma-associated ILD. The Scleroderma Lung Study I assessed the efficacy of 52 weeks of treatment with oral cyclophosphamide (CP) compared to placebo in individuals with systemic sclerosis-associated ILD and evidence of an active inflammatory cell infiltrate on bronchoalveolar lavage. The trial demonstrated a positive effect of CP at 52 weeks but the drug was poorly tolerated and the benefit compared with placebo had disappeared by 2 years. A smaller 52-week study, also conducted in individuals with scleroderma-associated ILD, compared placebo to once-monthly intravenous CP given for 6 months followed by azathioprine and low dose prednisolone for the subsequent 6 months and showed a trend towards benefit in the active treatment arm. In the absence of treatment guidelines or evidence generated in other forms of CTD-ILD, most centres in the UK were routinely using intravenous CP as first-line therapy for individuals with clinically advanced or rapidly progressive ILD arising in the context of CTD. Rituximab, a chimeric (human/mouse) monoclonal antibody with a high affinity for the CD20 surface antigen expressed on B-lymphocytes, results in rapid depletion of B cells from the peripheral circulation for 6–9 months. Evidence for the efficacy of B cell depletion exists in a number of immune-mediated conditions, including rheumatoid arthritis, antineutrophil cytoplasmic antibody-associated vasculitis and immune thrombocytopenic purpura. Several case series suggest rituximab may also be effective in ILD occurring in the context of immunological over-activity, with favourable responses reported in antisynthetase-associated ILD and SSc-ILD. Our own clinical experience suggested that rituximab is an effective, potentially life-saving therapeutic intervention in the treatment of very severe, progressive CTD-ILD unresponsive to conventional immunosuppression. In head-to-head studies in the context of other autoimmune diseases rituximab has been shown to have a favourable safety and tolerability profile compared to CP. The absence of high-quality evidence to guide treatment of CTD-ILD provided an opportunity to assess the efficacy of rituximab compared to the accepted standard of care, CP. Objectives The primary objective of the study was to demonstrate that intravenous rituximab has superior efficacy compared to current best treatment (intravenous CP) for CTD-ILD as measured by assessment of change in forced vital capacity (FVC) at 24 weeks. Secondary objectives were: to compare the safety profile of rituximab to intravenous CP in individuals with CTD-ILD to assess the health economic benefits of rituximab compared to current standard of care for CTD-ILD – including measurements of healthcare utilisation, quality of life (QoL) and carer burden to evaluate a range of exploratory biomarkers for disease severity, prognosis and treatment response in CTD-ILD. Methods The study was a Phase IIb, UK multicentre, prospective, randomised, double-blind, double-dummy trial of intravenous rituximab compared with intravenous CP in patients with severe, progressive CTD-ILD. Patients were randomised 1 : 1 to two groups, both groups received placebo to match the different regimens. Patients were followed for 48 weeks after first treatment; after 24 weeks subjects were permitted additional immunotherapy as determined by their treating physician. Study settings The study was conducted in rheumatology or ILD units at 11 UK centres. Participant inclusion criteria A diagnosis of CTD, based on internationally accepted criteria, in one of the following categories: systemic sclerosis idiopathic interstitial myopathy (including polymyositis/dermatomyositis) MCTD. Severe and/or progressive ILD associated with the underlying CTD. Chest high-resolution computer tomography performed within 12 months of randomisation. Intention of the caring physician to treat the ILD with intravenous CP. Able to provide written informed consent. Participant exclusion criteria Previous treatment with rituximab and/or intravenous CP. Age 80 years. Known hypersensitivity to rituximab or CP or their components. Significant (in the opinion of the investigator) other organ comorbidity including cardiac, hepatic or renal impairment. Coexistent obstructive pulmonary disease (e.g. asthma, chronic obstructive pulmonary disease, emphysema) with pre-bronchodilator forced expiratory volume in 1 second (FEV1) and FVC ratio < 70%. Patients at significant risk for infectious complications following immunosuppression including those with human immunodeficiency virus positive or other immunodeficiency syndromes (including hypogammaglobulinemia). Suspected or proven untreated tuberculosis. Viral hepatitis. Infection requiring antibiotic treatment in the preceding 4 weeks. Unexplained neurological symptoms (which may be suggestive of progressive multifocal leucoencephalopathy). Neurological symptoms arising because of the underlying CTD do not necessitate exclusion. Other investigational therapy (participation in research trial) received within 8 weeks of randomisation. Immunosuppressive or CTD modifying therapy (other than corticosteroids) received within 2 weeks of the first intravenous treatment. Pregnant or breastfeeding women, or women of child-bearing potential, not using a reliable contraceptive method for up to 12 months following IMP. Unexplained haematuria, or previous bladder carcinoma. Computerised tomography scan > 12 months from randomisation. Unable to provide informed written consent. Interventions Patients were randomised to receive either: Rituximab 1000 mg for two doses at day 0 and day 14. Placebo was administered monthly from week 4 to week 20. CP given at a dose of 600 mg/m2 body surface area rounded to the nearest 100 mg every 4 weeks from day 0 to week 20. Placebo was given at day 14. Patients were pre-medicated on day 0 with hydrocortisone, paracetamol, chlorpheniramine and mesna, at day 14 with hydrocortisone, paracetamol and chlorpheniramine and at visits from week 4 to 20 with mesna. Measurements Wherever possible, even if treatment could not be given, spirometry was undertaken at the time of each planned visit and performed according to standards outlined in the American Thoracic Society/European Respiratory Society guidelines. Lung function tests (plethysmography and gas transfer) were measured at screening, baseline, week 12, week 24 and week 48. Assessment for adverse events (AEs) and clinical end points began from randomisation and continued for the individual patient until they completed their follow-up at 48 weeks. At each study visit the investigator or designee made an assessment of safety and reviewed the clinical history and investigation findings with regard to the occurrence of adverse or serious adverse events (SAEs). Peripheral blood was taken at the time of each planned visit. Collection of blood for laboratory analyses included full blood count, erythrocyte sedimentation rate, urea and electrolytes, glucose, hepatitis A, B and C serology (screening only) and liver function tests. Blood for lymphocyte subsets and biomarker analysis was taken at day 0, week 12, 24 and 48 only. Quality of life was assessed by self-administered validated questionnaires undertaken at baseline and repeated at the primary end point visit at 24 weeks and at the final follow-up visit at 48 weeks. The instruments used were: the Short Form 36 (SF36) questionnaire EuroQol-5 Dimensions (EQ-5D) St George’s Respiratory Questionnaire (SGRQ) King’s Brief Interstitial Lung Disease (K-BILD) Scleroderma Health Assessment (SHA) Questionnaire which was disease-specific. For individuals with scleroderma, assessment of skin thickening was undertaken using the modified Rodnan skin score at baseline, 24 and 48 weeks. Sample size The primary outcome was changed in FVC at 24 weeks. The trial was designed to have 90% power to detect a 5% difference in 24-week FVC between treatment groups with a significance level (alpha) of 0.05 (two-tailed). The target sample size was 116 with the anticipation that 52 patients would reach the end-of-study in each arm with an expected 10% drop out. Because of the COVID-19 pandemic and an anticipated prolonged interruption to recruitment, trial enrolment was halted in March 2020 after randomisation of 101 subjects. Statistical analysis No formal interim analysis was planned. A statistical analysis plan was produced and agreed prior to analysis. Analysis of the primary outcome was by modified intention to treat. In other words, data were included in respect of all subjects who met all the entry criteria for the trial and had been randomised and received at least one dose of study drug. Results The study recruitment period was from December 2014 until March 2020 from 11 sites. In total 145 subjects were assessed for eligibility and of these 104 participants were enrolled. Three of these failed screening and were excluded. One hundred and one subjects were therefore randomised and 97 subjects received at least one dose of study drug and were included in the modified intention-to-treat population for the primary and secondary efficacy analyses (49 in the rituximab group and 48 in the CP group). Overall, baseline characteristics between the rituximab and CP arms were well balanced albeit with slightly more male participants in the rituximab arm. For the total cohort the mean ± S.D. age was 56 ± 11.4 years. Seventy subjects (69.3%) were female, 70 (69.3%) were white, 16 (15.8%) Asian and 12 (11.9%) black. The most frequently encountered CTD was idiopathic inflammatory myopathy (44.6%), followed by scleroderma (38.6%) and then MCTD (16.8%). Primary outcome At week 24 the unadjusted mean [± standard deviation (SD)] change in FVC in the CP treatment arm was a gain of 99 ± 329 ml. In the rituximab arm the change was 97 ± 234 ml. The relative change from baseline for each arm was 4.35 ± 15.67% for CP and for rituximab 4.31 ± 11.80%. Using a mixed-effects model adjusted for baseline FVC and diagnosis the difference (and 95% confidence interval) at 24 weeks between rituximab and CP was −40 ml [95% confidence interval (CI) −153 to 74 ml], p = 0.49. Secondary outcomes The unadjusted change in FVC at 48 weeks was 138 ± 440 ml in the CP arm and 112 ± 249 ml in the rituximab group. In relative terms, over 48 weeks, the improvement in the CP group was 5.08 ± 19.96% and in the rituximab group 4.22 ± 10.31%. An adjusted mixed-effects model demonstrated a −58 (95% CI −178 to 62) ml difference at 48 weeks between the rituximab and CP arms (p = 0.251). At week 24 the mean relative change in diffusing capacity of the lung for carbon monoxide (DLco) in the CP arm was 1.43 ± 23.05% compared to 6.98 ± 17.19% in the rituximab arm. At 48 weeks the changes in DLco were 3.00 ± 31.35% and 7.43 ± 16.08% in the CP and rituximab arms, respectively. For 6-minute walk distance the 24-week change in the CP and rituximab arms was 10.4 ± 78.6 and 10.9 ± 74.2 m, respectively. At week 48 the changes were 15.1 ± 82.8 and −6.8 ± 69.8 m. Using an adjusted mixed-effects model the differences between the rituximab and CP arms were −0.72 (−24.76 to 23.32) m, p = 0.953 at 24 weeks and −22.46 (−48.43 to 3.51) m, p = 0.090 at 48 weeks. Quality of life was assessed using the K-BILD questionnaire. Change at 24 weeks was 9.4 ± 20.8 in the CP arm and 8.8 ± 17.0 in the rituximab arm. At 48 weeks the difference compared to baseline was 5.6 ± 25.6 and 6.4 ± 16.2 in the CP and rituximab arms, respectively. Analysis in an adjusted mixed-effects model showed the difference between rituximab and CP was 0.4 (−5.73 to 6.52) and 1.15 (−5.34 to 7.64) at weeks 24 and 48, respectively. Survival Over the 48-week course of the study there were five deaths. All were deemed to be due to complications of either CTD or ILD. Three occurred in subjects receiving rituximab and two in subjects receiving CP. There was no difference between groups in time to death as assessed by an adjusted Cox proportional hazards model [hazard ratio (HR) 1.72 (95% CI 0.311 to 9.56, p = 0.534)]. The rates of progression-free survival [HR 1.11 (95% CI 0.625 to 1.99, p = 0.715)], and time to treatment failure [HR 1.25 (95% CI 0.34 to 4.65, p = 0.742)] did not differ between treatment arms. Corticosteroids The mean per-subject total steroid exposure during the study (measured in hydrocortisone equivalents) was 13,291 (±14,657) mg in the CP and 11,469 (±10,041) mg in the rituximab group; a 12% reduction in corticosteroid exposure in the rituximab arm. The daily mean dose per patient was 42.89 mg hydrocortisone/day in the CP and 37.61 mg hydrocortisone/day in the rituximab group. Safety All subjects in both arms experienced at least one AE. There were more AEs reported in the CP arm (646) than in the rituximab arm (445). The imbalance was less marked for SAEs with 33 and 29 in the CP and rituximab arms, respectively. Gastrointestinal disorders (170 vs. 71), general disorders and administration site reactions (91 vs. 52) and nervous system disorders (72 vs. 35) were more common in the CP arm. The frequency of other AEs was balanced between groups including infections and infestations (50 vs. 46). One patient in each arm withdrew because of side effects. There were no reported cases of COVID-19 during the trial. Cost-effectiveness Over the 48-week trial period treatment with CP was associated with a cost of £94,338 compared with a cost of £93,227 for rituximab; a difference of £1110 in favour of rituximab. Rituximab was associated with a 0.022 gain in quality-adjusted life-years over that seen with CP. The incremental net monetary benefit was significantly higher in the rituximab group under a wide range of monetary values and quality-adjusted life-years. Conclusion This study demonstrated that both rituximab and CP improve FVC and QoL in patients with CTD-ILD. There were numerically fewer AEs and a trend towards reduction in corticosteroid exposure in the rituximab-treated subjects. Rituximab should therefore be considered as a treatment option in patients with severe or rapidly progressive CTD-associated ILD. Implications for health care Although this study failed to show superiority of rituximab over CP in improving FVC when used as first-line treatment for CTD-ILD, the consistent positive effects of rituximab on physiological end points, QoL, and corticosteroid requirements support the clinical use of this drug in what is a population of patients with high unmet need (especially in situations where CP is contraindicated or likely to cause deleterious effects such as gonad failure or bladder malignancy). Implications for research Further trials will be necessary to confirm whether repeated dosing with rituximab confers additional benefit as compared to a single baseline dose. Similarly, additional studies are necessary to confirm findings in individual CTDs and to assess the optimal longer-term therapeutic regimen following initial intravenous therapy. Trial registration This trial is registered as ISRCTN16474148. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation Programme (NIHR award ref: 11/116/03) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 4. See the NIHR Funding and Awards website for further award information.

BackgroundDelay discounting quantifies an individual’s preference for smaller, short-term rewards over larger, long-term rewards and represents a transdiagnostic factor associated with numerous adverse health outcomes. Rather than a fixed trait, delay discounting may vary over time and place, influenced by individual and contextual factors. Continuous, real-time measurement could inform adaptive interventions for various health conditions. ObjectiveThe goals of this paper are 2-fold. First, we present and validate a novel, short, ecological momentary assessment (EMA)–based delay discounting scale we developed. Second, we assess this tool’s ability to reproduce known associations between delay discounting and health behaviors (ie, substance use and craving) using a convenience-based sample. MethodsParticipants (N=97) were adults (age range 18-71 years), recruited on social media. In phase 1, data were collected on participant sociodemographic characteristics, and delay discounting was evaluated via the traditional Monetary Choice Questionnaire (MCQ) and our novel method (ie, 7-item time-selection and 7-item monetary-selection scales). During phase 2 (approximately 6 months later), participants completed the MCQ, our novel delay discounting measures, and health outcomes questions. The correlations between our method and the traditional MCQ within and across phases were examined. For scale reduction, a random number of items were iteratively selected, and the correlation between the full and random scales was assessed. We then examined the association between our time- and monetary-selection scales assessed during phase 2 and the percentage of assessments that participants endorsed using or craving alcohol, tobacco, or cannabis. ResultsIn total, 6 of the 7 individual time-selection items were highly correlated with the full scale (r>0.89). Both time-selection (r=0.71; P0.94). Greater delay discounting measured via the time-selection measure (adjusted mean difference=5.89, 95% CI 1.99-9.79), but not the monetary-selection scale (adjusted mean difference=–0.62, 95% CI –3.57 to 2.32), was associated with more past-hour tobacco use endorsement in follow-up surveys. ConclusionsThis study evaluated a novel EMA-based scale’s ability to validly and reliably assess delay discounting. By measuring delay discounting with fewer items and in situ via EMA in natural environments, researchers may be better able to identify individuals at risk for poor health outcomes.

Background Congenital heart conditions are among the most common non-communicable diseases in children and young people (CYP), affecting 13.9 million CYP globally. While survival rates are increasing, support for young people adjusting to life with a heart condition is lacking. Furthermore, one in three CYP with heart conditions also experiences anxiety, depression or adjustment disorder, for which little support is offered. While adults are offered cardiac rehabilitation (CR) to support their mental and physical health, this is not offered for CYP.One way to overcome this is to evaluate a CR programme comprising exercise with mental health support (CardioActive; CA) for CYP with heart conditions. The exercise and mental health components are informed by the metacognitive model, which has been shown to be effective in treating anxiety and depression in CYP and associated with improving psychological outcomes in adult CR.Method and analysis The study is a single-blind parallel randomised feasibility trial comparing a CR programme (CA) plus usual care against usual care alone with 100 CYP (50 per arm) aged 11–16 diagnosed with a heart condition. CA will include six group exercise, lifestyle and mental health modules. Usual care consists of routine outpatient management. Participants will be assessed at three time points: baseline, 3-month (post-treatment) and 6-month follow-up. Primary outcomes are feasibility and acceptability (ie, referral rates, recruitment and retention rates, attendance at the intervention, rate of return and level of completion of follow-up data). Coprimary symptom outcomes (Strength and Difficulties Questionnaire and Paediatric Quality of Life) and a range of secondary outcomes will be administered at each time point. A nested qualitative study will investigate CYP, parents and healthcare staff views of CR and its components, and staff’s experience of delivering CA. Preliminary health economic data will be collected to inform future cost-effectiveness analyses. Descriptive data on study processes and clinical outcomes will be reported. Data analysis will follow intention to treat. Qualitative data will be analysed using thematic analysis and the theoretical framework of acceptability.Ethics and dissemination Ethical approval was granted on 14 February 2023 by the Greater Manchester East Research Ethics Committee (22/NW/0367). The results will be disseminated through peer-reviewed journals, conference presentations and local dissemination.Trial registration number ISRCTN50031147; NCT05968521.

BackgroundHIV or sexually transmitted infections remain a significant public health concern in the United States, with adolescents affected disproportionately. Adolescents engage in HIV/STI risk behaviors, including drug use and condomless sex, which increase the risk for HIV/STIs. At-risk adolescents, many of whom are racial minorities, experience HIV/STI disparities. Although at-risk adolescents are disproportionately affected by HIV/STI risk behaviors and infections and although the Centers for Disease Control and Prevention recommends routine HIV/STI testing for adolescents, relatively few adolescents report having ever been tested for HIV/STI. With expected increases in health clinic visits as a result of the Affordable Care Act combined with technological advances, health clinics and mobile health (mHealth), including apps, provide innovative contexts and tools to engage at-risk adolescents in HIV/STI prevention programs. Yet, there is a dearth of efficacious mHealth interventions in health clinics to prevent and reduce both condomless sex and drug use and increase HIV/STI testing for at-risk adolescents. ObjectiveTo address this gap in knowledge, we developed a theory-driven, culturally congruent mHealth intervention (hereon referred to as S4E [Storytelling 4 Empowerment]) that has demonstrated feasibility and acceptability in a clinical setting. The next step is to examine the preliminary efficacy of S4E on adolescent HIV/STI testing and risk behaviors. This goal will be accomplished by 2 aims: the first aim is to develop a cross-platform and universal version of S4E. The cross-platform and universal version of S4E will be compatible with both iOS and Android operating systems and multiple mobile devices, aimed at providing adolescents with ongoing access to the intervention once they leave the clinic, and the second aim is to evaluate the preliminary efficacy of S4E, relative to usual care control condition, in preventing or reducing drug use and condomless sex and increasing HIV/STI testing in a clinical sample of at-risk adolescents aged 14-21 years living in Southeast Michigan. MethodsIn this study, 100 adolescents recruited from a youth-centered community health clinic will be randomized via blocked randomization with random sequences of block sizes to one of the 2 conditions: S4E mHealth intervention or usual care. Theory-driven and culturally congruent, S4E is an mHealth adaptation of face-to-face storytelling for empowerment, which is registered with the Substance Abuse and Mental Health Services Administration's National Registry of Evidence-Based Programs and Practices. ResultsThis paper describes the protocol of our study. The recruitment began on May 1, 2018. This study was registered on December 11, 2017, in ClinicalTrials.gov. All participants have been recruited. Data analysis will be complete by the end of March 2024, with study findings available by December 2024. ConclusionsThis study has the potential to improve public health by preventing HIV/STI and substance use disorders. Trial RegistrationClinicalTrials.gov NCT03368456; https://clinicaltrials.gov/study/NCT03368456 International Registered Report Identifier (IRRID)DERR1-10.2196/47216

Patients face numerous health-related decisions once advanced chronic kidney disease (CKD) is diagnosed. Yet, when patients are underprepared to navigate and discuss health-related decisions, they can make choices inconsistent with their expectations for the future. This pilot study, guided by the multiphase optimization strategy and community-engaged research principles, aimed to explore the acceptability of a developed patient component to a decision-support training intervention called ImPart (Improving Decisional Partnership of CKD Dyads). CKD patients and their family caregivers were recruited from an urban, academic medical center. Eligibility criteria for patients included a diagnosis of stage 3 or higher CKD (on chart review), and caregivers participated in interview sessions only. Patients without a caregiver were not eligible. The intervention was lay coach, telephone-delivered, and designed to be administered in 1-2 week intervals for 4 sessions. An interview guide, developed in collaboration with an advisory group, was designed to ascertain participants' experiences with the intervention. Caregiver interviews focused on changes in the patient's decision ability or engagement. Thirteen patients and eleven caregivers were interviewed. The program was viewed as "good" or "beneficial." Three themes capture the intervention's impact- 1) Frequent and deliberate disease-focused communication, 2) Future planning activation, and 3) Coaching relationship. The piloted intervention was successfully delivered, acceptable to use, and found to promote enhanced disease and future planning communication. By undergoing this work, we ensure that the patient component is feasible to use and meets the needs of participants before implementation in a larger factorial trial.

IntroductionChemical contamination and pollution are an ongoing threat to human health and the environment. The concern over the consequences of chemical exposures at the global level continues to grow. Because resources are constrained, there is a need to prioritize interventions focused on the greatest health impact. Data, especially related to chemical exposures, are rarely available for most substances of concern, and alternate methods to evaluate their impact are needed.Structured expert judgment (sej) processA Structured Expert Judgment (Research Outreach, 2021) process was performed to provide plausible estimates of health impacts for 16 commonly found pollutants: asbestos, arsenic, benzene, chromium, cadmium, dioxins, fluoride, highly hazardous pesticides (HHPs), lead, mercury, polycyclic-aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), Per- and Polyfluorinated Substances (PFAs), phthalates, endocrine disrupting chemicals (EDCs), and brominated flame retardants (BRFs). This process, undertaken by sector experts, weighed individual estimations of the probable global health scale health impacts of each pollutant using objective estimates of the expert opinions' statistical accuracy and informativeness.Main findingsThe foremost substances, in terms of mean projected annual total deaths, were lead, asbestos, arsenic, and HHPs. Lead surpasses the others by a large margin, with an estimated median value of 1.7 million deaths annually. The three other substances averaged between 136,000 and 274,000 deaths per year. Of the 12 other chemicals evaluated, none reached an estimated annual death count exceeding 100,000. These findings underscore the importance of prioritizing available resources on reducing and remediating the impacts of these key pollutants.Range of health impactsBased on the evidence available, experts concluded some of the more notorious chemical pollutants, such as PCBs and dioxin, do not result in high levels of human health impact from a global scale perspective. However, the chemical toxicity of some compounds released in recent decades, such as Endocrine Disrupters and PFAs, cannot be ignored, even if current impacts are limited. Moreover, the impact of some chemicals may be disproportionately large in some geographic areas. Continued research and monitoring are essential; and a preventative approach is needed for chemicals.Future directionsThese results, and potential similar analyses of other chemicals, are provided as inputs to ongoing discussions about priority setting for global chemicals and pollution management. Furthermore, we suggest that this SEJ process be repeated periodically as new information becomes available.

Violence against children in schools harms the affected children, limits their learning and educational attainment, and extends its harms to families and the broader communities. However, to date, comparable cross-country data on violence against children in schools has not been available. We utilize the Violence Against Children and Youth Surveys (VACS) to estimate school-related violence against children in seven countries (Honduras, Kenya, Malawi, Nigeria, Tanzania, Uganda, and Zambia). Leveraging the unique comparability of the surveys, we are able to estimate both physical and sexual violence experienced in childhood and adolescence among youth aged 13-24. Where possible, we also disaggregate by gender and perpetrator type. Overall, within our sample seven countries, we find that 12.11-44.63% of females and 14.28-53.85% of males experienced at least one form of violence. Males experience higher levels of school-related violence and a significant portion of this is due to experiencing physical violence perpetrated by male classmates.

Pancreatic ductal adenocarcinoma (PDAC) presents at advanced stages and is refractory to most treatment modalities. Wnt signaling activation plays a critical role in proliferation and chemotherapeutic resistance. Minimal media conditions, growth factor dependency, and Wnt dependency were determined via Wnt inhibition for seven patient derived organoids (PDOs) derived from pancreatic tumor organoid libraries (PTOL). Organoids demonstrating response in vitro were assessed in vivo using patient-derived xenografts. Wnt (in)dependent gene signatures were identified for each organoid. Panc269 demonstrated a trend of reduced organoid growth when treated with ETC-159 in combination with paclitaxel or gemcitabine as compared with chemotherapy or ETC-159 alone. Panc320 demonstrated a more pronounced anti-proliferative effect in the combination of ETC-159 and paclitaxel but not with gemcitabine. Panc269 and Panc320 were implanted into nude mice and treated with ETC-159, paclitaxel, and gemcitabine as single agents and in combination. The combination of ETC-159 and paclitaxel demonstrated an anti-tumor effect greater than ETC-159 alone. Extent of combinatory treatment effect were observed to a lesser extent in the Panc320 xenograft. Wnt (in)dependent gene signatures of Panc269 and 320 were consistent with the phenotypes displayed. Gene expression of several key Wnt genes assessed via RT-PCR demonstrated notable fold change following treatment in vivo. Each pancreatic organoid demonstrated varied niche factor dependencies, providing an avenue for targeted therapy, supported through growth analysis following combinatory treatment of Wnt inhibitor and standard chemotherapy in vitro. The clinical utilization of this combinatory treatment modality in pancreatic cancer PDOs has thus far been supported in our patient-derived xenograft models treated with Wnt inhibitor plus paclitaxel or gemcitabine. Gene expression analysis suggests there are key Wnt genes that contribute to the Wnt (in)dependent phenotypes of pancreatic tumors, providing plausible mechanistic explanation for Wnt (in)dependency and susceptibility or resistance to treatment on the genotypic level.

Biliary atresia is a neonatal disease characterized by damage, inflammation, and fibrosis of the liver and bile ducts and by abnormal bile metabolism. It likely results from a prenatal environmental exposure that spares the mother and affects the fetus. Our aim was to develop a model of fetal injury by exposing pregnant mice to low-dose biliatresone, a plant toxin implicated in biliary atresia in livestock, and then to determine whether there was a hepatobiliary phenotype in their pups. Pregnant mice were treated orally with 15 mg/kg/d biliatresone for 2 days. Histology of the liver and bile ducts, serum bile acids, and liver immune cells of pups from treated mothers were analyzed at P5 and P21. Pups had no evidence of histological liver or bile duct injury or fibrosis at either timepoint. In addition, growth was normal. However, serum levels of glycocholic acid were elevated at P5, suggesting altered bile metabolism, and the serum bile acid profile became increasingly abnormal through P21, with enhanced glycine conjugation of bile acids. There was also immune cell activation observed in the liver at P21. These results suggest that prenatal exposure to low doses of an environmental toxin can cause subclinical disease including liver inflammation and aberrant bile metabolism even in the absence of histological changes. This finding suggests a wide potential spectrum of disease after fetal biliary injury.

ObjectiveGlycolytic inhibition via 2-deoxy-D-glucose (2DG) has potential therapeutic benefits for a range of diseases, including cancer, epilepsy, systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA), and COVID-19, but the systemic effects of 2DG on gene function across different tissues are unclear.MethodsThis study analyzed the transcriptional profiles of nine tissues from C57BL/6J mice treated with 2DG to understand how it modulates pathways systemically. Principal component analysis (PCA), weighted gene co-network analysis (WGCNA), analysis of variance, and pathway analysis were all performed to identify modules altered by 2DG treatment.ResultsPCA revealed that samples clustered predominantly by tissue, suggesting that 2DG affects each tissue uniquely. Unsupervised clustering and WGCNA revealed six distinct tissue-specific modules significantly affected by 2DG, each with unique key pathways and genes. 2DG predominantly affected mitochondrial metabolism in the heart, while in the small intestine, it affected immunological pathways.ConclusionsThese findings suggest that 2DG has a systemic impact that varies across organs, potentially affecting multiple pathways and functions. The study provides insights into the potential therapeutic benefits of 2DG across different diseases and highlights the importance of understanding its systemic effects for future research and clinical applications.

Atlantic tarpon (Megalops atlanticus) are capable of long-distance migrations (hundreds of kilometers) but also exhibit resident behaviors in estuarine and coastal habitats. The aim of this study was to characterize the spatial distribution of juvenile tarpon and identify migration pathways of adult tarpon in the northern Gulf of Mexico. Spatial distribution of juvenile tarpon was investigated using gillnet data collected by Texas Parks and Wildlife Department (TPWD) over the past four decades. Generalized additive models (GAMs) indicated that salinity and water temperature played a significant role in tarpon presence, with tarpon occurrences peaking in the fall and increasing over the past four decades in this region. Adult tarpon caught off Texas (n = 40) and Louisiana (n = 4) were tagged with acoustic transmitters to characterize spatial and temporal trends in their movements and migrations. Of the 44 acoustic transmitters deployed, 18 of the individuals were detected (n = 16 west of the Mississippi River Delta and n = 2 east of the Mississippi River Delta). Tarpon tagged west of the Mississippi River Delta off Texas migrated south in the fall and winter into areas of south Texas and potentially into Mexico, while individuals tagged east of the delta migrated into Florida during the same time period, suggesting the presence of two unique migratory contingents or subpopulations in this region. An improved understanding of the habitat requirements and migratory patterns of tarpon inhabiting the Gulf of Mexico is critically needed by resource managers to assess the vulnerability of each contingent to fishing pressure, and this information will guide multi-state and multi-national conservation efforts to rebuild and sustain tarpon populations.

Background Nintedanib slows progression of lung function decline in patients with progressive fibrosing (PF) interstitial lung disease (ILD) and was recommended for this indication within the United Kingdom (UK) National Health Service in Scotland in June 2021 and in England, Wales and Northern Ireland in November 2021. To date, there has been no national evaluation of the use of nintedanib for PF-ILD in a real-world setting. Methods 26 UK centres were invited to take part in a national service evaluation between 17 November 2021 and 30 September 2022. Summary data regarding underlying diagnosis, pulmonary function tests, diagnostic criteria, radiological appearance, concurrent immunosuppressive therapy and drug tolerability were collected via electronic survey. Results 24 UK prescribing centres responded to the service evaluation invitation. Between 17 November 2021 and 30 September 2022, 1120 patients received a multidisciplinary team recommendation to commence nintedanib for PF-ILD. The most common underlying diagnoses were hypersensitivity pneumonitis (298 out of 1120, 26.6%), connective tissue disease associated ILD (197 out of 1120, 17.6%), rheumatoid arthritis associated ILD (180 out of 1120, 16.0%), idiopathic nonspecific interstitial pneumonia (125 out of 1120, 11.1%) and unclassifiable ILD (100 out of 1120, 8.9%). Of these, 54.4% (609 out of 1120) were receiving concomitant corticosteroids, 355 (31.7%) out of 1120 were receiving concomitant mycophenolate mofetil and 340 (30.3%) out of 1120 were receiving another immunosuppressive/modulatory therapy. Radiological progression of ILD combined with worsening respiratory symptoms was the most common reason for the diagnosis of PF-ILD. Conclusion We have demonstrated the use of nintedanib for the treatment of PF-ILD across a broad range of underlying conditions. Nintedanib is frequently co-prescribed alongside immunosuppressive and immunomodulatory therapy. The use of nintedanib for the treatment of PF-ILD has demonstrated acceptable tolerability in a real-world setting.

BackgroundStress during pregnancy is detrimental to maternal health, pregnancy and birth outcomes and various preventive relaxation interventions have been developed. This systematic review and meta-analysis aimed to evaluate their effectiveness in terms of maternal mental health, pregnancy and birth outcomes.MethodThe protocol for this review is published on PROSPERO with registration number CRD42020187443. A systematic search of major databases was conducted. Primary outcomes were maternal mental health problems (stress, anxiety, depression), and pregnancy (gestational age, labour duration, delivery mode) and birth outcomes (birth weight, Apgar score, preterm birth). Randomized controlled trials or quasi-experimental studies were eligible. Meta-analyses using a random-effects model was conducted for outcomes with sufficient data. For other outcomes a narrative review was undertaken.ResultWe reviewed 32 studies comprising 3,979 pregnant women aged 18 to 40 years. Relaxation interventions included yoga, music, Benson relaxation, progressive muscle relaxation (PMR), deep breathing relaxation (BR), guided imagery, mindfulness and hypnosis. Intervention duration ranged from brief experiment (~10 minutes) to 6 months of daily relaxation. Meta-analyses showed relaxation therapy reduced maternal stress (-4.1 points; 95% Confidence Interval (CI): -7.4, -0.9; 9 trials; 1113 participants), anxiety (-5.04 points; 95% CI: -8.2, -1.9; 10 trials; 1965 participants) and depressive symptoms (-2.3 points; 95% CI: -3.4, -1.3; 7 trials; 733 participants). Relaxation has also increased offspring birth weight (80 g, 95% CI: 1, 157; 8 trials; 1239 participants), explained by PMR (165g, 95% CI: 100, 231; 4 trials; 587 participants) in sub-group analysis. In five trials evaluating maternal physiological responses, relaxation therapy optimized blood pressure, heart rate and respiratory rate. Four trials showed relaxation therapy reduced duration of labour. Apgar score only improved significantly in two of six trials. One of three trials showed a significant increase in birth length, and one of three trials showed a significant increase in gestational age. Two of six trials examining delivery mode showed significantly increased spontaneous vaginal delivery and decreased instrumental delivery or cesarean section following a relaxation intervention.DiscussionWe found consistent evidence for beneficial effects of relaxation interventions in reducing maternal stress, improving mental health, and some evidence for improved maternal physiological outcomes. In addition, we found a positive effect of relaxation interventions on birth weight and inconsistent effects on other pregnancy or birth outcomes. High quality adequately powered trials are needed to examine impacts of relaxation interventions on newborns and offspring health outcomes.ConclusionIn addition to benefits for mothers, relaxation interventions provided during pregnancy improved birth weight and hold some promise for improving newborn outcomes; therefore, this approach strongly merits further research.

Seedling root traits impact plant establishment under challenging environments. Pearl millet is one of the most heat and drought tolerant cereal crops that provides a vital food source across the sub-Saharan Sahel region. Pearl millet’s early root system features a single fast-growing primary root which we hypothesize is an adaptation to the Sahelian climate. Using crop modeling, we demonstrate that early drought stress is an important constraint in agrosystems in the Sahel where pearl millet was domesticated. Furthermore, we show that increased pearl millet primary root growth is correlated with increased early water stress tolerance in field conditions. Genetics including genome-wide association study and quantitative trait loci (QTL) approaches identify genomic regions controlling this key root trait. Combining gene expression data, re-sequencing and re-annotation of one of these genomic regions identified a glutaredoxin-encoding gene PgGRXC9 as the candidate stress resilience root growth regulator. Functional characterization of its closest Arabidopsis homolog AtROXY19 revealed a novel role for this glutaredoxin (GRX) gene clade in regulating cell elongation. In summary, our study suggests a conserved function for GRX genes in conferring root cell elongation and enhancing resilience of pearl millet to its Sahelian environment.