Using Defence Engagement (Health) to progress the Women Peace and Security agenda.

Since the unanimous passing of United Nations Security Council Resolution 1325, which calls on member states to address gender inequality, many countries and the wider North Atlantic Treaty Organisation community have championed the Women Peace and Security agenda to empower women and reduce violence within fragile states. When women are empowered and actively involved in decision-making, there is less violence, and more peace and stability in that society, which benefits all members.Defence Medical Services are uniquely positioned to progress this agenda, particularly through its Defence Engagement activities. The UK's military medical community has more women in leadership than the wider military community. Our personnel can and should be used to model and empower military healthcare workers in partner nations. This paper forms part of a special issue of BMJ Military Health dedicated to Defence Engagement.

A systematic review of social-validity assessments in the Journal of Applied Behavior Analysis: 2010-2020.

We conducted a systematic review of studies published in the Journal of Applied Behavior Analysis between 2010 and 2020 to identify reports of social validity. A total of 160 studies (17.60%) published during this time included a measure of social validity. For each study, we extracted data on (a) the dimensions of social validity, (b) the methods used for collecting social-validity data, (c) the respondents, and (d) when social-validity data were collected. Most social-validity assessments measured the acceptability of intervention procedures and outcomes, with fewer evaluating goals. The most common method for collecting social validity data was Likert-type rating scales, followed by non-Likert-type questionnaires. In most studies, the direct recipients of the intervention provided feedback on social validity. Social-validity assessment data were often collected at the conclusion of the study. We provide examples of social-validity measurement methods, discuss their strengths and limitations, and provide recommendations for improving the future collection and reporting of social-validity data.

Decisions with patients, not for patients: Shared decision-making in allergy and immunology.

Shared Decision-Making (SDM) is an increasingly implemented patient-centred approach to navigating patient preferences regarding diagnostic and treatment options and supported decision-making. This therapeutic approach prioritizes the patient's perspectives, considering current medical evidence to provide a balanced approach to clinical scenarios. In light of numerous recent guideline recommendations that are conditional in nature, and are clinical scenarios defined by preference-sensitive care options, there is a tremendous opportunity for SDM and validated decision aids. Despite the expansion of the literature on SDM, formal acceptance among clinicians remains inconsistent. Surprisingly, a significant disparity exists between clinicians' self-reported adherence to SDM principles and patients' perceptions of its implementation during clinical encounters. This discrepancy underscores a fundamental issue in the delivery of healthcare, where clinicians may overestimate their integration of SDM, while patients' experiences suggest otherwise. This review critically examines the factors contributing to this inconsistency, including barriers within the healthcare system, clinician attitudes and behaviours, and patient expectations and preferences. By elucidating these factors in the fields of food allergy, asthma, eosinophilic esophagitis, and other allergic diseases, this review aims to provide insights into bridging the gap between clinician perception and patient experience in SDM. Addressing this discordance is crucial for advancing patient-centred care and ensuring that SDM is not merely a theoretical concept but a tangible reality in the practice of Allergy and Immunology.

Rationale and design for a pragmatic randomized trial to assess gene-based prescribing for SSRIs in the treatment of depression.

Specific selective serotonin reuptake inhibitors (SSRIs) metabolism is strongly influenced by two pharmacogenes, CYP2D6 and CYP2C19. However, the effectiveness of prospectively using pharmacogenetic variants to select or dose SSRIs for depression is uncertain in routine clinical practice. The objective of this prospective, multicenter, pragmatic randomized controlled trial is to determine the effectiveness of genotype-guided selection and dosing of antidepressants on control of depression in participants who are 8 years or older with ≥3 months of depressive symptoms who require new or revised therapy. Those randomized to the intervention arm undergo pharmacogenetic testing at baseline and receive a pharmacy consult and/or automated clinical decision support intervention based on an actionable phenotype, while those randomized to the control arm have pharmacogenetic testing at the end of 6-months. In both groups, depression and drug tolerability outcomes are assessed at baseline, 1 month, 3 months (primary), and 6 months. The primary end point is defined by change in Patient-Reported Outcomes Measurement Information System (PROMIS) Depression score assessed at 3 months versus baseline. Secondary end points include change inpatient health questionnaire (PHQ-8) measure of depression severity, remission rates defined by PROMIS score < 16, medication adherence, and medication side effects. The primary analysis will compare the PROMIS score difference between trial arms among those with an actionable CYP2D6 or CYP2C19 genetic result or a CYP2D6 drug-drug interaction. The trial has completed accrual of 1461 participants, of which 562 were found to have an actionable phenotype to date, and follow-up will be complete in April of 2024.

A bispecific antibody targeting HLA-DQ2.5-gluten peptides potently blocks gluten-specific T cells induced by gluten ingestion in patients with celiac disease.

The gluten-free diet for celiac disease (CeD) is restrictive and often fails to induce complete symptom and/or mucosal disease remission. Central to CeD pathogenesis is the gluten-specific CD4+ T cell that is restricted by HLA-DQ2.5 in over 85% of CeD patients, making HLA-DQ2.5 an attractive target for suppressing gluten-dependent immunity. Recently, a novel anti-HLA-DQ2.5 antibody that specifically recognizes the complexes of HLA-DQ2.5 and multiple gluten epitopes was developed (DONQ52). OBJECTIVE: To assess the ability of DONQ52 to inhibit CeD patient-derived T-cell responses to the most immunogenic gluten peptides that encompass immunodominant T cell epitopes. METHODS: We employed an in vivo gluten challenge model in patients with CeD that affords a quantitative readout of disease-relevant gluten-specific T-cell responses. HLA-DQ2.5+ CeD patients consumed food containing wheat, barley, or rye for 3 days with collection of blood before (D1) and 6 days after (D6) commencing the challenge. Peripheral blood mononuclear cells were isolated and assessed in an interferon (IFN)-γ enzyme-linked immunosorbent spot assay (ELISpot) testing responses to gluten peptides encompassing a series of immunodominant T cell epitopes. The inhibitory effect of DONQ52 (4 or 40 µg/mL) was assessed and compared to pan-HLA-DQ blockade (SPVL3 antibody). RESULTS: In HLA-DQ2.5+ CeD patients, DONQ52 reduced T cell responses to all wheat gluten peptides to an equivalent or more effective degree than pan-HLA-DQ antibody blockade. It reduced T cell responses to a cocktail of the most immunodominant wheat epitopes by a median of 87% (IQR 72-92). Notably, DONQ52 also substantially reduced T-cell responses to dominant barley hordein and rye secalin derived peptides. DONQ52 had no effect on T-cell responses to non-gluten antigens. CONCLUSION: DONQ52 can significantly block HLA-DQ2.5-restricted T cell responses to the most highly immunogenic gluten peptides in CeD. Our findings support in vitro data that DONQ52 displays selectivity and broad cross-reactivity against multiple gluten peptide:HLA-DQ2.5 complexes. This work provides proof-of-concept multi-specific antibody blockade has the potential to meaningfully inhibit pathogenic gluten-specific T-cell responses in CeD and supports ongoing therapeutic development.

Deliberately introduced dung beetles in Australia: 12 years of occurrence and abundance records from 2001 to 2022.

Since 1968, the Australian Dung Beetle Project has carried out field releases of 43 deliberately introduced dung beetle species for the biological control of livestock dung and dung-breeding pests. Of these, 23 species are known to have become established. For most of these species, sufficient time has elapsed for population expansion to fill the extent of their potential geographic range through both natural and human-assisted dispersal. Consequently, over the last 20 years, extensive efforts have been made to quantify the current distribution of these introduced dung beetles, as well as the seasonal and spatial variation in their activity levels. Much of these data and their associated metadata have remained unpublished, and they have not previously been synthesized into a cohesive dataset. Here, we collate and report data from the three largest dung beetle monitoring projects from 2001 to 2022. Together, these projects encompass data collected from across Australia, and include records for all 23 species of established dung beetles introduced for biocontrol purposes. In total, these data include 22,718 presence records and 213,538 absence records collected during 10,272 sampling events at 546 locations. Most presence records (97%) include abundance data. In total, 1,752,807 dung beetles were identified as part of these data. The distributional occurrence and abundance data can be used to explore questions such as factors influencing dung beetle species distributions, dung beetle biocontrol, and insect-mediated ecosystem services. These data are provided under a CC-BY-NC 4.0 license and users are encouraged to cite this data paper when using the data.

Neural compass in the human brain during naturalistic virtual navigation.

Humans and animals maintain a consistent representation of their facing direction during spatial navigation. In rodents, head direction cells are believed to support this "neural compass", but identifying a similar mechanism in humans during dynamic naturalistic navigation has been challenging. To address this issue, we acquired fMRI data while participants freely navigated through a virtual reality city. Encoding model analyses revealed voxel clusters in retrosplenial complex and superior parietal lobule that exhibited reliable tuning as a function of facing direction. Crucially, these directional tunings were consistent across perceptually different versions of the city, spatially separated locations within the city, and motivationally distinct phases of the behavioral task. Analysis of the model weights indicated that these regions may represent facing direction relative to the principal axis of the environment. These findings reveal specific mechanisms in the human brain that allow us to maintain a sense of direction during naturalistic, dynamic navigation.

Individualized Dose-Response to Statins Associated with Cardiovascular Disease Outcomes.

Background: Statins reduce low-density lipoprotein cholesterol (LDL-C) and are efficacious in the prevention of atherosclerotic cardiovascular disease (ASCVD). Dose-response to statins varies among patients and can be modeled using three distinct pharmacological properties: (1) E0 (baseline LDL-C), (2) ED50 (potency: median dose achieving 50% reduction in LDL-C); and (3) Emax (efficacy: maximum LDL-C reduction). However, individualized dose-response and its association with ASCVD events remains unknown. Objective: We analyze the relationship between ED50 and Emax with real-world cardiovascular disease outcomes. Method: We leveraged de-identified electronic health record data to identify individuals exposed to multiple doses of the three most commonly prescribed statins (atorvastatin, simvastatin, or rosuvastatin) within the context of their longitudinal healthcare. We derived ED50 and Emax to quantify the relationship with a composite outcome of ASCVD events and all-cause mortality. Results: We estimated ED50 and Emax for 3,033 unique individuals (atorvastatin: 1,632, simvastatin: 1,089, and rosuvastatin: 312) using a nonlinear, mixed effects dose-response model. Time-to-event analyses revealed that ED50 and Emax are independently associated with the primary endpoint. Hazard ratios were 0.85 (p < 0.01), 0.83 (p < 0.01), and 0.87 (p = 0.10) for ED50 and 1.13 (p < 0.001), 1.06 (p < 0.001), and 1.15 (p = 0.009) for Emax in the atorvastatin, simvastatin, and rosuvastatin cohorts, respectively. Conclusion: The class-wide association of ED50 and Emax with clinical outcomes indicates that these measures influence the risk for ASCVD events in patients on statins.

Phenotypic Clusters and Multimorbidity in Hypermobile Ehlers-Danlos Syndrome.

Objective: To perform a retrospective clinical study in order to investigate phenotypic penetrance within a large registry of patients with hypermobile Ehlers-Danlos syndrome (hEDS) to enhance diagnostic and treatment guidelines by understanding associated comorbidities and improving accuracy in diagnosis. Patients and Methods: From May 1, 2021 to July 31, 2023, 2149 clinically diagnosed patients with hEDS completed a self-reported survey focusing on diagnostic and comorbid conditions prevalence. K-means clustering was applied to analyze survey responses, which were then compared across gender groups to identify variations and gain clinical insights. Results: Analysis of clinical manifestations in this cross-sectional cohort revealed insights into multimorbidity patterns across organ systems, identifying 3 distinct patient groups. Differences among these phenotypic clusters provided insights into diversity within the population with hEDS and indicated that Beighton scores are unreliable for multimorbidity phenotyping. Conclusion: Clinical data on the phenotypic presentation and prevalence of comorbidities in patients with hEDS have historically been limited. This study provides comprehensive data sets on phenotypic presentation and comorbidity prevalence in patients with hEDS, highlighting factors often overlooked in diagnosis. The identification of distinct patient groups emphasizes variations in hEDS manifestations beyond current guidelines and emphasizes the necessity of comprehensive multidisciplinary care for those with hEDS.

Degradation of the α-Carboxyl Terminus 11 Peptide: In Vivo and Ex Vivo Impacts of Time, Temperature, Inhibitors, and Gender in Rat.

In previous research, a synthetic α-carboxyl terminus 1 (αCT1) peptide derived from connexin 43 (Cx43) and its variant (αCT11) showed beneficial effects in an ex vivo ischemia-reperfusion (I/R) heart injury model in mouse. In an in vivo mouse model of cryo-induced ventricular injury, αCT1 released from adhesive cardiac patches reduced Cx43 remodeling and arrhythmias, as well as maintained cardiac conduction. Whether intravenous injection of αCT1 or αCT11 produces similar outcomes has not been investigated. Given the possibility of peptide degradation in plasma, this study utilized in vivo I/R cardiac injury and ex vivo blood plasma models to examine factors that may limit the therapeutic potential of peptide therapeutics in vivo. Following tail vein administration of αCT11 (100 µM) in blood, no effect on I/R infarct size was observed in adult rat hearts on day 1 (D1) and day 28 (D28) after injury (p > 0.05). There was also no difference in the echocardiographic ejection fraction (EF%) between the control and the αCT11 groups (p > 0.05). Surprisingly, αCT11 in blood plasma collected from these rats was undetectable within ∼10 min after tail vein injection. To investigate factors that may modulate αCT11 degradation in blood, αCT11 was directly added to blood plasma isolated from normal rats without I/R and peptide levels were measured under different experimental conditions. Consistent with in vivo observations, significant αCT11 degradation occurred in plasma within 10 min at 22 and 37 °C and was nearly undetectable by 30 min. These responses were reduced by the addition of protease/phosphatase (PTase/PPTase) inhibitors to the isolated plasma. Interestingly, no significant differences in αCT11 degradation in plasma were noted between male and female rats. We conclude that fast degradation of αCT11 is likely the reason that no beneficial effects were observed in the in vivo I/R model and inhibition or shielding from PTase/PPTase activity may be a strategy that will assist with the viability of peptide therapeutics.

Canadian Undergraduate Perspectives on Medical Assistance in Dying for Mental Illness: Does Psychiatric Illness Type, Age, and Exposure to Information Influence Acceptance of MAiD?

BACKGROUND AND OBJECTIVES: In 2027, Canadians whose only medical condition is an untreatable mental illness and who otherwise meet all eligibility criteria will be able to request Medical Assistance in Dying (MAiD). This study investigates the attitudes of undergraduate students towards widening the scope of MAiD for physical illness for certain psychiatric conditions. We were interested in understanding if age, information, and type of mental illness influenced undergraduates' acceptance or rejection of MAiD for mental illness (MAiD-MI). METHOD: 413 undergraduate students participated in this study which examined the factors that correlate with the acceptance or rejection of MAiD-MI. Four scenarios were presented in which age (older or younger) and illness type (depression or schizophrenia) were manipulated. Demographic questions and measures assessing personality, religion, and attitudes towards euthanasia were administered. Questions assessing participants' general understanding of MAiD and their life experiences with death and suicide were also asked. RESULTS: Most of the participants accepted MAiD-MI for both depression and schizophrenia. As hypothesized, support for MAiD-MI was higher for patients with schizophrenia than for depression. Also as hypothesized, support was higher for older patients than for younger patients. Variables such as religion, personality and political affiliation were also associated with acceptance or rejection of MAiD-MI. Finally, consistent with our hypotheses, participants' understanding of MAiD and experiences with death and suicide was predictive of support for MAiD-MI.

REFORMS: Consensus-based Recommendations for Machine-learning-based Science.

Machine learning (ML) methods are proliferating in scientific research. However, the adoption of these methods has been accompanied by failures of validity, reproducibility, and generalizability. These failures can hinder scientific progress, lead to false consensus around invalid claims, and undermine the credibility of ML-based science. ML methods are often applied and fail in similar ways across disciplines. Motivated by this observation, our goal is to provide clear recommendations for conducting and reporting ML-based science. Drawing from an extensive review of past literature, we present the REFORMS checklist (recommendations for machine-learning-based science). It consists of 32 questions and a paired set of guidelines. REFORMS was developed on the basis of a consensus of 19 researchers across computer science, data science, mathematics, social sciences, and biomedical sciences. REFORMS can serve as a resource for researchers when designing and implementing a study, for referees when reviewing papers, and for journals when enforcing standards for transparency and reproducibility.

hyve, a compositional visualisation engine for brain imaging data.

Visualisations facilitate the interpretation of geometrically structured data and results. However, heterogeneous geometries-such as volumes, surfaces, and networks-have traditionally mandated different software approaches. We introduce hyve, a Python library that uses a compositional functional framework to enable parametric implementation of custom visualisations for different brain geometries. Under this framework, users compose a reusable visualisation protocol from geometric primitives for representing data geometries, input primitives for common data formats and research objectives, and output primitives for producing interactive displays or configurable snapshots. hyve also writes documentation for user-constructed protocols, automates serial production of multiple visualisations, and includes an API for semantically organising an editable multi-panel figure. Through the seamless composition of input, output, and geometric primitives, hyve supports creating visualisations for a range of neuroimaging research objectives.

Police Harassment and Psychiatric, Sexual, and Substance Use Risk Among Black Sexual Minority Men and Black Transgender Women in the HIV Prevention Trials 061 Cohort.

BACKGROUND: Black sexual minority men and Black transgender women (BSMM/BTW) experience disproportionate levels of HIV/STI-related risk factors as well as police harassment (PH). PH is linked to psychiatric risk and could play a role in substance use, sexual risk behavior, and HIV/STI risk. METHODS: We used data from the HIV Prevention Trials Network 061(HPTN 061) study to examine associations between PH and HIV/STI-related outcomes. Using PH exposure measured at baseline and 6-month study visits, we examined an ordinal exposure (PH reported at both visits, PH reported at either visit, versus PH reported at neither baseline nor 6 months) and a binary exposure of persistent PH reported at both visits (yes versus no). We estimate risk ratios (RR) for associations between PH and depression, use of alcohol and methamphetamine, multiple partnerships, condomless sex, and syphilis. RESULTS: Persistent PH (binary) was associated with a 20% or greater increase in the risk of depression (RR, 1.26 (1.07, 1.47)) and multiple partnerships (RR, 1.20 (1.05, 1.39)). There was evidence that ordinal PH was associated with elevated risk of alcohol use (RR, 1.17 (1.00, 1.36)); the point estimate for the association between persistent PH and alcohol use was similar but the imprecision was greater (RR, 1.16 (0.95, 1.42)). CONCLUSION: PH may influence not only mental health but also behavioral risks that contribute to HIV/STI among BSMM/BTW, highlighting the potential wide-ranging and downstream effects of PH on health. Further research is required to confirm associations and elucidate pathways through which PH may influence HIV/STI among BSMM/BTW.

Impact of analytic decisions on test-retest reliability of individual and group estimates in functional magnetic resonance imaging: a multiverse analysis using the monetary incentive delay task.

Empirical studies reporting low test-retest reliability of individual blood oxygen-level dependent (BOLD) signal estimates in functional magnetic resonance imaging (fMRI) data have resurrected interest among cognitive neuroscientists in methods that may improve reliability in fMRI. Over the last decade, several individual studies have reported that modeling decisions, such as smoothing, motion correction and contrast selection, may improve estimates of test-retest reliability of BOLD signal estimates. However, it remains an empirical question whether certain analytic decisions consistently improve individual and group level reliability estimates in an fMRI task across multiple large, independent samples. This study used three independent samples ( N s: 60, 81, 119) that collected the same task (Monetary Incentive Delay task) across two runs and two sessions to evaluate the effects of analytic decisions on the individual (intraclass correlation coefficient [ICC(3,1)]) and group (Jaccard/Spearman rho ) reliability estimates of BOLD activity of task fMRI data. The analytic decisions in this study vary across four categories: smoothing kernel (five options), motion correction (four options), task parameterizing (three options) and task contrasts (four options), totaling 240 different pipeline permutations. Across all 240 pipelines, the median ICC estimates are consistently low, with a maximum median ICC estimate of .43 - .55 across the three samples. The analytic decisions with the greatest impact on the median ICC and group similarity estimates are the Implicit Baseline contrast, Cue Model parameterization and a larger smoothing kernel. Using an Implicit Baseline in a contrast condition meaningfully increased group similarity and ICC estimates as compared to using the Neutral cue. This effect was largest for the Cue Model parameterization, however, improvements in reliability came at the cost of interpretability. This study illustrates that estimates of reliability in the MID task are consistently low and variable at small samples, and a higher test-retest reliability may not always improve interpretability of the estimated BOLD signal.

Factors Associated With Service Referrals and Uptake in Early Head Start: The Importance of Care Setting.

Secondary analysis of the Early Head Start Family and Child Experiences Survey 2018 data set (Baby FACES 2018) explored links between family risk events and referral-making and referral uptake among families receiving Early Head Start (EHS) services. Referrals to both behavioral health and entitlement programs were considered. Results showed that referrals to behavioral health programs were much more likely to be given to families receiving care from home-based care than center-based care, and that referrals were slightly more likely to be given to families who did not have any family risk events. Several factors also moderated the relationship between family risk and referrals, including perceived closeness of the parent/caregiver-EHS staff relationship, family conflict, and caregiver depression. There were no observed effects for referrals to entitlement programs. Caregiver depression weakened the link between family risk and service uptake for entitlement programs.