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Abstract Solid nitrogen exhibits a panoply of phenomena ranging from complex molecular crystalline configurations to polymerization and closing band gap at higher densities. Among the elemental molecular solids, nitrogen stands apart for having phases, which can only be stabilized following particular pressure-temperature pathways, indicative of metastability and kinetic barriers. Here, through the combination of Raman spectroscopy and dynamic compression techniques, we find that the appearance of the whole nitrogen phase diagram is determined by the P-T paths taken below 2 GPa. We reveal the existence of the path- and phase-dependent triple point between the $$\beta$$ β - $$N_2$$ N 2 , $$\delta _{loc}$$ δ loc - $$N_2$$ N 2 and $$\gamma$$ γ - or $$\epsilon$$ ϵ - $$N_2$$ N 2 . We further show that the $$\beta$$ β - $$N_2$$ N 2 towards $$\gamma$$ γ - $$N_2$$ N 2 path below the triple point, that evades $$\delta$$ δ ( $$\delta _{loc}$$ δ loc )- $$N_2$$ N 2 , results in the formation of $$\gamma$$ γ - $$N_2$$ N 2 , which in turn becomes a dominant phase. We then demonstrate, that the $$\beta$$ β - $$N_2$$ N 2 through $$\delta$$ δ ( $$\delta _{loc}$$ δ loc )- $$N_2$$ N 2 above the triple point path leads to the formation of $$\epsilon$$ ϵ - $$N_2$$ N 2 and the “well-established” phase diagram. An additional pathway, which by-passes the rotationally inhibited modifications $$\delta$$ δ ( $$\delta _{loc}$$ δ loc )- $$N_2$$ N 2 , via rapid compression is found to produce $$\gamma$$ γ - $$N_2$$ N 2 at higher temperatures. We argue that the pathway and phase sensitive triple point and the compression rate dependent phase formation challenge our understanding of this archetypal dense molecular solid.

Abstract This study aimed to examine whether psychological distress was cross-sectionally associated with meeting World Cancer Research Fund (WCRF) recommendations in people living with and beyond cancer. Participants were adults living with and beyond breast, prostate and colorectal cancer, participating in the baseline wave of the Advancing Survivorship after Cancer Outcomes Trial (ASCOT). Anxiety/depression was assessed using the EQ-5D-5L and dichotomised into any/no problems. WCRF recommendations were assessed via pedometers, 24-h dietary recalls, self-reported alcohol intake (AUDIT-C), and self-reported smoking status. Participants were categorised as meeting WCRF recommendations using the following cut-offs: average daily steps (≥ 10,000/day), average weekly aerobic steps (≥ 15,000/day), fruit and vegetables (≥ 400 g/day), fibre (≥ 30 g/day), red meat (

Introduction Health interventions that require significant change to individual lifestyles or social norms can pose a challenge for widespread public acceptability and uptake. At the same time, over the last two decades, there has been increasing attention paid to the rise of populist movements globally, defined by ‘the people’ pushing against ‘an elite’ viewed as depriving the people of their sovereignty. To understand potential overlap in these two areas, this study aims to synthesise existing international evidence on linkages between populist attitudes and reduced uptake, acceptability, adherence and/or effectiveness of public health interventions. The goal of this work is to create a conceptual framework that can be used to inform policy strategies aimed at widening the impact of public health interventions.Methods and analysis A systematic review will be performed via searches across databases and websites relevant to public health and social science research, informed by preliminary searches on the topic. There will be no language restrictions, but included studies will be limited to those produced since 2008, the year of the global financial crisis, from which most current literature on populism dates. Risk of bias will be assessed using validated tools according to study design. Due to expected heterogeneity across included studies, this will be a systematic review without meta-analysis. Findings will be synthesised narratively, and the strength of the evidence will be assessed using the Grading of Recommendations Assessment, Development and Evaluation approach. The review will be reported according to the Systematic Reviews without Meta-Analysis reporting guidelines.Ethics and dissemination Ethical review is not required for this study. Public dissemination will be informed via consultation with our Patient and Public Involvement and Engagement Strategy Group, along with reporting via peer-reviewed publication, relevant international conferences, a policy brief and a workshop with public health and communications experts.PROSPERO registration number CRD42024513124.

Objectives We investigated the hypothetical impact of mandatory alcohol calorie labelling, comparing non-drinkers, low-risk and hazardous drinkers in terms of attitudes, knowledge about calorie content and hypothetical behaviour changes should labelling be introduced.Design Cross-sectional national telephone survey.Setting Community-dwelling adults in England between November 2022 and January 2023.Participants Data were collected from 4683 adults >18 years, of whom 24.7% were non-drinkers; 77.6% of alcohol drinkers were categorised as low-risk and 22.4% as hazardous drinkers according to the Alcohol Use Disorders Identification Test questionnaire.Primary outcome measures Attitudes to alcohol calorie labelling in shops and supermarkets and in hospitality venues, knowledge of the calorie content of alcoholic beverages (beer, wine, cider and spirits) and changes in drinking practices if calorie labelling was introduced.Results Comparisons were made between non-drinkers, low-risk drinkers and hazardous drinkers, with analyses adjusted for age, gender, ethnicity, socioeconomic status and education. Attitudes to calorie labelling were generally positive, but were less favourable among alcohol drinkers than non-drinkers. Hazardous drinkers were more accurate in their estimations of the calorie content of wine, cider and spirits than non-drinkers (p

Introduction Health research bodies recommend patient involvement and engagement in research and healthcare planning, although their implementation is not yet widespread. This deficiency extends to progressive pulmonary fibrosis (PPF), where crucial aspects remain unknown, including causal mechanisms, curative treatments and optimal symptom management. This study addresses these gaps by seeking stakeholders’ perspectives to guide research and treatment directions.Method A priority-setting partnership was established to explore stakeholders’ priorities in the diagnosis, treatment, management and care of PPF, including idiopathic pulmonary fibrosis which is the archetypal PPF. Stakeholders included people living with PPF, their carers, relatives and healthcare professionals involved in their management.Results Through an online open-ended survey, 2542 responses were collected from 638 stakeholders. Thematic analysis identified 48 specific research questions, which were then cross-referenced with academic literature to pinpoint research gaps. Following the evidence check, 44 unanswered questions were shortlisted by 834 stakeholders in a second online survey. Ultimately, a top 10 priority list was established through consensus.The prioritised research questions include (1) improved diagnosis accuracy and timing, (2) development of new treatments, (3) enhanced accuracy in primary care, (4) optimal timing for drug and non-drug interventions, (5) effective cough treatment, (6) early intervention for PPF, (7) improved survival rates, (8) symptom reduction, (9) impact of interventions on life expectancy and (10) new treatments with reduced side effects.Conclusion Stakeholders’ priorities can be summarised into five areas: early diagnosis, drug and non-drug treatments, survival and symptom management. Ideally, these topics should guide funding bodies and health policies.

Abstract Background The American Board of Psychiatry and Neurology (ABPN) and the Accreditation Council for Graduate Medical Education (ACGME) require that residency programs allow at least 6 weeks of parental leave. The American Medical Association (AMA) recommends 12 weeks of paid parental leave. Despite these recommendations, there is little information about parental leave policies across U.S. neurology residencies. The objective of our study was to assess parental leave policies in U.S. adult neurology residencies and barriers to increasing the duration of leave. Methods We distributed an anonymous online survey to U.S. adult neurology program directors (PDs) to assess demographics, components and length of parental leave, perceived impact on residents’ clinical training and academic development, and barriers to increasing the length of leave. Results We contacted 163 PDs and received 54 responses (response rate of 33%). 87% reported policies for both childbearing and non-childbearing residents. The average maximal length of leave allowed without extension of training was 8.5 weeks (range 0–13) for childbearing and 6.2 weeks (range 0–13) for non-childbearing residents. Most PDs felt that parental leave had a positive impact on resident wellness and neutral impact on clinical competency, academic opportunities, and career development. The most common barriers to providing a 12-week paid policy were concerns about equity in the program (82%), staffing of clinical services (80%), and impact on clinical training (78%). Conclusions Although most programs in our study have parental leave policies, there is significant variability. Policies to improve parental leave should focus on addressing common barriers, such as additional solutions to staffing clinical services.

Abstract Fucoidan has attracted considerable attention from scientists and pharmaceutical companies due to its antioxidant, anticoagulant, anti-inflammatory, anti-tumor, and health-enhancing properties. However, the extraction of fucoidan from seaweeds often involves the use of harsh chemicals, which necessitates the search for alternative solvents. Additionally, the high viscosity and low cell permeability of high molecular weight (Mw) fucoidan can limit its effectiveness in drug action, while lower Mw fractions exhibit increased biological activity and are also utilized as dietary supplements. The study aimed to (1) extract fucoidan from the seaweed Fucus vesiculosus (FV) using an environmentally friendly solvent and compare it with the most commonly used extraction solvent, hydrochloric acid, and (2) assess the impact of ultrasound-assisted depolymerization on reducing the molecular weight of the fucoidan extracts and examine the cytotoxic effect of different molecular weight fractions. The findings indicated that the green depolymerization solvent, in conjunction with a brief ultrasound treatment, effectively reduced the molecular weight. Moreover, a significant decrease in cell viability was observed in selected samples, indicating potential anticancer properties. As a result, ultrasound was determined to be an effective method for depolymerizing crude fucoidan from Fucus Vesiculosus seaweed.

Abstract Background Finding time in the medical curriculum to focus on motivational interviewing (MI) training is a challenge in many medical schools. We developed a software-based training tool, “Real-time Assessment of Dialogue in Motivational Interviewing” (ReadMI), that aims to advance the skill acquisition of medical students as they learn the MI approach. This human-artificial intelligence teaming may help reduce the cognitive load on a training facilitator. Methods During their Family Medicine clerkship, 125 third-year medical students were scheduled in pairs to participate in a 90-minute MI training session, with each student doing two role-plays as the physician. Intervention group students received both facilitator feedback and ReadMI metrics after their first role-play, while control group students received only facilitator feedback. Results While students in both conditions improved their MI approach from the first to the second role-play, those in the intervention condition used significantly more open-ended questions, fewer closed-ended questions, and had a higher ratio of open to closed questions. Conclusion MI skills practice can be gained with a relatively small investment of student time, and artificial intelligence can be utilized both for the measurement of MI skill acquisition and as an instructional aid.

AbstractAs the world’s population of adults greater than 60 years old continues to increase, it is important to manage nail disorders that may impact their daily lives. Nail disorders may have significant impact on quality of life due to decreased functionality, extreme pain, or social embarrassment. In this review, we discuss nail disorders affecting older patients, including physiologic, traumatic, drug-induced, infectious, environmental, inflammatory, and neoplastic conditions. Diagnosis of these conditions involves a detailed history, physical examination of all 20 nails, and depending on the condition, a nail clipping or biopsy and/or diagnostic imaging. Nails grow even more slowly in older adults compared to younger individuals, and therefore it is important for accurate diagnosis, and avoidance of inappropriate management and delay of treatment. Increased awareness of nail pathologies may help recognition and management of nail conditions in older adults.

Objective To provide contemporary data on cancer mortality rates within the context of incidence in the population with intellectual disabilities.Methods Scotland’s 2011 Census was used to identify adults with intellectual disabilities and controls with records linked to the Scottish Cancer Registry and death certificate data (March 2011–December 2019). The control cohort without intellectual disabilities and/or autism were used for indirect standardisation and calculation of crude incident rates/crude mortality rates, and age–sex standardised incident rate ratios/standardised mortality ratios (SIR/SMR), with 95% CIs.Results Adults with intellectual disabilities were most likely diagnosed cancers of digestive, specifically colorectal (14.2%), lung (9.3%), breast (female 22.9%), body of the uterus (female 9.3%) and male genital organs (male 17.6%). Higher incident cancers included metastatic cancer of unknown primary origin (female SIR=1.70, male SIR=2.08), body of uterus (female SIR=1.63), ovarian (female SIR=1.59), kidney (female SIR=1.85) and testicular (male SIR=2.49). SMRs were higher, regardless of a higher, similar or lower incidence (female SMR=1.34, male SMR=1.07). Excess mortality risk was found for colorectal (total SMR=1.54, male SMR=1.59), kidney (total SMR=2.01 u, female SMR=2.85 u), female genital organs (SMR=2.34 (ovarian SMR=2.86 u, body of uterus SMR=2.11), breast (female SMR=1.58) and metastatic cancer of unknown primary origin (female SMR=2.50 u, male SMR=2.84).Conclusions Adults with intellectual disabilities were more likely to die of cancer than the general population. Reasons for this may include later presentation/diagnosis (so poorer outcomes), poorer treatment/compliance or both. Accessible public health approaches are important for people with intellectual disabilities, and healthcare professionals need to be aware of the different cancer experiences faced by this population.

Introduction Dental caries among children is a major global health problem and is a particular public health challenge in Saudi Arabia. Dental caries cause pain, infection and negatively impact quality of life. As part of population oral health improvement efforts in Saudi Arabia, this project aims to evaluate the effectiveness of a supervised toothbrushing programme in kindergartens.Methods and analysis This study is a cluster randomised controlled trial. Enrolment began in September 2022, for two academic years (2022–2024) on 20 randomly selected kindergartens in Riyadh. The data collection phase will be completed in September 2024. Ten kindergartens are randomly allocated to supervised toothbrushing and 10 to treatment as usual, which is an annual oral health awareness visit. The primary endpoint will be the worsening of obvious decay experience as measured by decayed (into dentine), missing and filled teeth (d3mft) from baseline to the second year of follow-up. The secondary endpoint will be the increase in the number of teeth affected. A priori subgroups of the region of Riyadh, school type (public, private), child sex and presence/absence of prior decay at baseline, will be analysed. We require 244 evaluable endpoints using a power of 80% to meet the sample size requirement. In addition, questionnaires on behaviours, quality of life, process monitoring and cost analysis are being deployed.Ethics and dissemination Ethics approval for this study was given by the King Fahad Medical City Institutional Review Board in the Saudi Ministry of Health (22-083E/March 2022). The data analysis has been approved by the University of Glasgow Medical Veterinary and Life Sciences Research Ethical Committee (200220194/March 2023). The results of this study will be disseminated through presentations at scientific conferences and in scientific journals.Trial registration number NCT05512156.

Background Singing for lung health (SLH) is an arts-based breathing control and movement intervention for people with long-term respiratory conditions, intended to improve symptoms and quality of life. Online, remotely delivered programmes might improve accessibility; however, no previous studies have assessed the effectiveness of this approach.Methods We conducted an assessor-blind randomised controlled trial comparing the impact of 12 weeks of once-weekly online SLH sessions against usual care on health-related quality of life, assessed using the RAND 36-Item Short Form Health Survey (SF-36) Mental Health Composite (MHC) and Physical Health Composite (PHC) scores.Results We enrolled 115 people with stable chronic obstructive pulmonary disease (COPD), median (IQR) age 69 (62–74), 56.5% females, 80% prior pulmonary rehabilitation, Medical Research Council dyspnoea scale 4 (3–4), forced expiratory volume in 1 s % predicted 49 (35–63). 50 participants in each arm completed the study. The intervention arm experienced improvements in physical but not mental health components of RAND SF-36; PHC (regression coefficient (95% CI): 1.77 (95% CI 0.11 to 3.44); p=0.037), but not MHC (0.86 (95% CI −1.68 to 3.40); p=0.504). A prespecified responder analysis based on achieving a 10% improvement from baseline demonstrated a response rate for PHC of 32% in the SLH arm and 12.7% for usual care (p=0.024). A between-group difference in responder rate was not found in relation to the MHC (19.3% vs 25.9%; p=0.403).Discussion and conclusion A 12-week online SLH programme can improve the physical component of quality of life for people with COPD, but the overall effect is relatively modest compared with the impact seen in research using face-to-face group sessions. Further work on the content, duration and dose of online interventions may be useful.Trial registration number NCT04034212.

Hemolytic-uremic syndrome (HUS) is a rare complication of an infection with Shiga toxin (Stx)-producing Escherichia coli (STEC-HUS), characterized by severe acute kidney injury, thrombocytopenia and microangiopathic hemolytic anemia, and specific therapy is still lacking. Thrombomodulin (TM) is a multi-domain transmembrane endothelial cell protein and its N-terminal domain has been implicated in the pathophysiology of some cases of HUS. Indeed, the administration of recombinant human TM (rhTM) may have efficacy in HUS. We used a Stx-based murine model of HUS to characterize the role of the N-terminal domain of TM. We show that mice lacking that domain (TMLed (−/−)) are more sensitive to Stx, with enhanced HUS progression seen at 4 days and increased mortality at 7 days post-HUS induction. In spite of these changes, renal function was less affected in surviving Stx-challenged TMLed (−/−) mice compared to their wild-type counterparts TMLed (+/+) at 7 days. Contrary to few clinical case reports from Japan, the administration of rhTM (0.06 mg/kg) to wild-type mice (C57BL/6J) with HUS did not protect against disease progression. This overall promising, but also contradictory body of evidence, requires further systematic preclinical and clinical investigations to clarify the role of TM in HUS as a potential therapeutic strategy.

We present a genome assembly from an individual Danionella dracula (the Dracula fish; Chordata; Actinopterygii; Cypriniformes; Danionidae; Danioninae). The genome sequence is 665.21 megabases in span. This is a scaffold-level assembly, with a scaffold N50 of 10.29 Mb.

Introduction Trauma contributes to the greatest loss of disability-adjusted life-years for adolescents and young adults worldwide. In the context of global abdominal trauma, the trauma laparotomy is the most commonly performed operation. Variation likely exists in how these patients are managed and their subsequent outcomes, yet very little global data on the topic currently exists. The objective of the GOAL-Trauma study is to evaluate both patient and injury factors for those undergoing trauma laparotomy, their clinical management and postoperative outcomes.Methods We describe a planned prospective multicentre observational cohort study of patients undergoing trauma laparotomy. We will include patients of all ages who present to hospital with a blunt or penetrating injury and undergo a trauma laparotomy within 5 days of presentation to the treating centre. The study will collect system, patient, process and outcome data, following patients up until 30 days postoperatively (or until discharge or death, whichever is first). Our sample size calculation suggests we will need to recruit 552 patients from approximately 150 recruiting centres.Discussion The GOAL-Trauma study will provide a global snapshot of the current management and outcomes for patients undergoing a trauma laparotomy. It will also provide insight into the variation seen in the time delays for receiving care, the disease and patient factors present, and patient outcomes. For current standards of trauma care to be improved worldwide, a greater understanding of the current state of trauma laparotomy care is paramount if appropriate interventions and targets are to be identified and implemented.

Summary: Background: Clinical trials showed a single oral dose of doxycycline taken after sex protects against STIs among men who have sex with men (MSM) but not women. Pharmacokinetic data at vaginal, rectal and penile sites of STI exposure are lacking. We examined vaginal, rectal and urethral doxycycline concentrations in men and women to better inform STI prevention. Methods: Doxycycline pharmacokinetics in male and female participants 18–59 years of age were evaluated in blood and urine and on rectal and vaginal swabs collected at 1, 2, 4, 8, 24, 48, 72, 96 and 168 h after receiving a 200 mg oral doxycycline dose in a non-randomised single dose open label single centre study in Atlanta, Georgia. Rectal, vaginal, and cervical biopsies and male urethral swabs were collected 24 h after dosing (Trial registration: NCT04860505). Doxycycline was measured by liquid chromatography-mass spectrometry. Findings: Eleven male and nine female participants participated in the study. Doxycycline concentrations on rectal and vaginal swabs collected up to 96 h after dosing were approximately twice those of plasma and remained above minimum inhibitory concentrations (MICs) for at least four, three, and two days for Chlamydia trachomatis, Treponema pallidum, and tetracycline-sensitive Neisseria gonorrhoeae, respectively. Geometric mean doxycycline concentrations in male urethral secretions (1.166 μg/mL; 95% CI 0.568–2.394 μg/mL), male rectal (0.596 μg/g; 0.442–0.803 μg/g), vaginal (0.261 μg/g; 0.098–0.696 μg/g) and cervical tissue (0.410 μg/g; 0.193–0.870 μg/g) in biopsies collected 24 h after dosing exceeded MICs. Plasma and urine doxycycline levels defined adherence markers up to four and seven days postdosing, respectively. No adverse events were reported in this study. Interpretation: Doxycycline efficiently distributes to the rectum, vagina and urethra. Findings can help explain efficacy of STI prevention by doxycycline. Funding: Funded by CDC intramural funds, CDC contract HCVJCG-2020-45044 (to CFK).

Ongoing surveillance after pneumococcal conjugate vaccination (PCV) deployment is essential to inform policy decisions and monitor serotype replacement. We report serotype and disease severity trends in 3,719 adults hospitalized for pneumococcal disease in Bristol and Bath, United Kingdom, during 2006–2022. Of those cases, 1,686 were invasive pneumococcal disease (IPD); 1,501 (89.0%) had a known serotype. IPD decreased during the early COVID-19 pandemic but during 2022 gradually returned to prepandemic levels. Disease severity changed throughout this period: CURB65 severity scores and inpatient deaths decreased and ICU admissions increased. PCV7 and PCV13 serotype IPD decreased from 2006–2009 to 2021–2022. However, residual PCV13 serotype IPD remained, representing 21.7% of 2021–2022 cases, indicating that major adult PCV serotype disease still occurs despite 17 years of pediatric PCV use. Percentages of serotype 3 and 8 IPD increased, and 19F and 19A reemerged. In 2020–2022, a total of 68.2% IPD cases were potentially covered by PCV20.

Abstract Background The COVID-19 pandemic created a complex high-risk clinical research environment with clinical research activities significantly impacted. Clinical research stakeholders adapted rapidly to new clinical practices; PPE, infection control policies, all while engaging with a more unwell patient demographic. The aim of this study is to explore the experiences of conducting clinical research during COVID-19 with clinical research stakeholders. Methods This qualitative study of semi-structured interviews conducted with clinical research stakeholders in an acute Hospital setting across a variety of disciplines; Consultant Geriatrician, Clinical Research Nurse, Occupational Therapy, Physiotherapy. Interviews were fully transcribed prior to reflexive thematic analysis. NVivo software was used to support data management and analysis. Results Three main themes were produced; (1) The challenging COVID-19 clinical research landscape, (2) COVID-19 clinical research communication barriers, and (3) Adaptations and learnings from clinical research during COVID-19. Conclusions This study explored the experiences of conducting clinical research during COVID-19 with clinical research stakeholders examining challenges faced and adaptations required. The findings inform, equip and support clinical research stakeholders in the event of future adverse public health events.

For the one billion sufferers of respiratory disease, managing their disease with inhalers crucially influences their quality of life. Generic treatment plans could be improved with the aid of computational models that account for patient-specific features such as breathing pattern, lung pathology and morphology. Therefore, we aim to develop and validate an automated computational framework for patient-specific deposition modelling. To that end, an image processing approach is proposed that could produce 3D patient respiratory geometries from 2D chest X-rays and 3D CT images. We evaluated the airway and lung morphology produced by our image processing framework, and assessed deposition compared to in vivo data. The 2D-to-3D image processing reproduces airway diameter to 9% median error compared to ground truth segmentations, but is sensitive to outliers of up to 33% due to lung outline noise. Predicted regional deposition gave 5% median error compared to in vivo measurements. The proposed framework is capable of providing patient-specific deposition measurements for varying treatments, to determine which treatment would best satisfy the needs imposed by each patient (such as disease and lung/airway morphology). Integration of patient-specific modelling into clinical practice as an additional decision-making tool could optimise treatment plans and lower the burden of respiratory diseases.

Natal dispersal is a key demographic trait that affects population dynamics, and intraspecific variation in dispersal affects gene flow among populations and source-sink dynamics. However, relatively little is known about the selective pressures and trade-offs that animals face when departing their natal area due to the logistical difficulties associated with monitoring animals during this critical life stage. We used a randomized block design to examine the selective pressure that influence dispersal timing in juvenile burrowing owls (Athene cunicularia) by experimentally altering both food and ectoparasites at 135 nests. We also examined the effects of local food abundance, ectoparasite loads, and parental departure on natal dispersal timing. Juvenile burrowing owls varied widely in natal dispersal timing, and phenotypic plasticity in dispersal timing was evident in juvenile owls' response to our experimental treatments, local conditions, and their parents' departure from the natal area. Moreover, juveniles responded differently than their parents to experimental manipulation of food and ectoparasite loads. Juveniles typically dispersed shortly after their parents departed the natal area, but delayed dispersing more than 2 weeks after parental departure if they did not receive experimental food supplements during a low-food year. In contrast, the experimental food supplements did not affect the migratory departure decisions of adult owls in either year. Juveniles at nests treated for ectoparasites initiated dispersal at a younger age (and prior to adults in the high-food year) compared to juveniles at control nests. In contrast, parents at nests treated for ectoparasites departed later than parents at control nests. Our results suggest that unfavorable conditions (low food or high ectoparasite loads) caused juveniles to delay dispersal, but prompted adults to depart sooner. Our results highlight the extent of intraspecific variation in natal dispersal timing, and demonstrate that ecological conditions affect dispersal decisions of parents and offspring differently, which can create important trade-offs that likely affect life history strategies and responses to climatic changes.

Purpose: The etiopathogenesis of coronal nonsyndromic craniosynostosis (cNCS), a congenital condition defined by premature fusion of 1 or both coronal sutures, remains largely unknown. Methods: We conducted the largest genome-wide association study of cNCS followed by replication, fine mapping, and functional validation of the most significant region using zebrafish animal model. Results: Genome-wide association study identified 6 independent genome-wide-significant risk alleles, 4 on chromosome 7q21.3 SEM1-DLX5-DLX6 locus, and their combination conferred over 7-fold increased risk of cNCS. The top variants were replicated in an independent cohort and showed pleiotropic effects on brain and facial morphology and bone mineral density. Fine mapping of 7q21.3 identified a craniofacial transcriptional enhancer (eDlx36) within the linkage region of the top variant (rs4727341; odds ratio [95% confidence interval], 0.48[0.39-0.59]; P = 1.2E−12) that was located in SEM1 intron and enriched in 4 rare risk variants. In zebrafish, the activity of the transfected human eDlx36 enhancer was observed in the frontonasal prominence and calvaria during skull development and was reduced when the 4 rare risk variants were introduced into the sequence. Conclusion: Our findings support a polygenic nature of cNCS risk and functional role of craniofacial enhancers in cNCS susceptibility with potential broader implications for bone health.

Objectives As life expectancy increases, older people are living longer with multimorbidity (MM, co-occurrence of ≥2 chronic health conditions) and complex multimorbidity (CMM, ≥3 chronic conditions affecting ≥3 different body systems). We assessed the impacts of MM and CMM on healthcare service use in Australia, as little was known about this.Design Population-based cross-sectional data linkage study.Setting New South Wales, Australia.Participants 248 496 people aged ≥45 years who completed the Sax Institute’s 45 and Up Study baseline questionnaire.Primary outcome High average annual healthcare service use (≥2 hospital admissions, ≥11 general practice visits and ≥2 emergency department (ED) visits) during the 3-year baseline period (year before, year of and year after recruitment).Methods Baseline questionnaire data were linked with hospital, Medicare claims and ED datasets. Poisson regression models were used to estimate adjusted and unadjusted prevalence ratios for high service use with 95% CIs. Using a count of chronic conditions (disease count) as an alternative morbidity metric was requested during peer review.Results Prevalence of MM and CMM was 43.8% and 15.5%, respectively, and prevalence increased with age. Across three healthcare settings, MM was associated with a 2.02-fold to 2.26-fold, and CMM was associated with a 1.83-fold to 2.08-fold, increased risk of high service use. The association was higher in the youngest group (45–59 years) versus the oldest group (≥75 years), which was confirmed when disease count was used as the morbidity metric in sensitivity analysis.When comparing impact using three categories with no overlap (no MM/CMM, MM with no CMM, and CMM), CMM had greater impact than MM across all settings.Conclusion Increased healthcare service use among older adults with MM and CMM impacts on the demand for primary care and hospital services. Which of MM or CMM has greater impact on risk of high healthcare service use depends on the analytic method used. Ageing populations living longer with increasing burdens of MM and CMM will require increased Medicare funding and provision of integrated care across the healthcare system to meet their complex needs.

BackgroundExperiencing drug cravings is an aspect of substance use disorders that frequently compromises the recovery efforts of people who use drugs. Most treatment approaches that address drug cravings either involve cognitive strategies or medication. Few interventions directly address the physiological aspects of craving, such as increased heart rate. Previous research has demonstrated that slow-paced breathing may be effective in managing drug cravings by manipulating an individual's heart rate. The purpose of this paper is to describe a study protocol for an intervention that offers resonance frequency breathing training for managing cravings via a smartphone application (app).MethodsThis trial is registered in ClinicalTrials.gov (Identifier: NCT05830773). The intervention focuses on persons in recovery from opioid use disorder who receive services from the Texas Health and Human Service Commission Recovery Support Services division. Participants will be trained to use Camera Heart Rate Variability (CHRV), a resonance frequency breathing app. The CHRV app measures heart rate and the volumetric variations of blood circulation. When experiencing stress, anxiety, or cravings, participants will use the app to practice breathing exercises. Participants (N = 60) will also complete surveys at baseline, 4 weeks, and 8 weeks; the survey questions, covers demographic characteristics, personal trauma history, substance use experience, and utilization of substance use treatment services. The surveys will also include psychosocial measures of craving, stress, and anxiety to allow the study team to assess changes between baseline and study completion. Participants who complete the full 8-week intervention will be invited to participate in a 30-minute interview about their experience with the app. Interviews will provide details on implementation outcomes, including acceptability, appropriateness, and feasibility.ConclusionMany evidence-based interventions for opioid use require interpersonal communication with individuals in one's recovery network. However, individuals may be unable to engage others in their recovery network in the moments when they are experiencing cravings or stress- and anxiety-related triggers. Therefore, recovery support interventions that emphasize individual self-management of cravings, stress, and anxiety when they occur can empower individuals in recovery and enhance existing interventions.

Introduction Traditional survey-based surveillance is costly, limited in its ability to distinguish diabetes types and time-consuming, resulting in reporting delays. The Diabetes in Children, Adolescents and Young Adults (DiCAYA) Network seeks to advance diabetes surveillance efforts in youth and young adults through the use of large-volume electronic health record (EHR) data. The network has two primary aims, namely: (1) to refine and validate EHR-based computable phenotype algorithms for accurate identification of type 1 and type 2 diabetes among youth and young adults and (2) to estimate the incidence and prevalence of type 1 and type 2 diabetes among youth and young adults and trends therein. The network aims to augment diabetes surveillance capacity in the USA and assess performance of EHR-based surveillance. This paper describes the DiCAYA Network and how these aims will be achieved.Methods and analysis The DiCAYA Network is spread across eight geographically diverse US-based centres and a coordinating centre. Three centres conduct diabetes surveillance in youth aged 0–17 years only (component A), three centres conduct surveillance in young adults aged 18–44 years only (component B) and two centres conduct surveillance in components A and B. The network will assess the validity of computable phenotype definitions to determine diabetes status and type based on sensitivity, specificity, positive predictive value and negative predictive value of the phenotypes against the gold standard of manually abstracted medical charts. Prevalence and incidence rates will be presented as unadjusted estimates and as race/ethnicity, sex and age-adjusted estimates using Poisson regression.Ethics and dissemination The DiCAYA Network is well positioned to advance diabetes surveillance methods. The network will disseminate EHR-based surveillance methodology that can be broadly adopted and will report diabetes prevalence and incidence for key demographic subgroups of youth and young adults in a large set of regions across the USA.

Summary: Background: In spite of new treatments, the incidence of type 2 diabetes (T2D) and its morbidities continue to rise. The key feature of T2D is resistance of adipose tissue and other organs to insulin. Approaches to overcome insulin resistance are limited due to a poor understanding of the mechanisms and inaccessibility of drugs to relevant intracellular targets. We previously showed in mice and humans that CD248, a pre/adipocyte cell surface glycoprotein, acts as an adipose tissue sensor that mediates the transition from healthy to unhealthy adipose, thus promoting insulin resistance. Methods: Molecular mechanisms by which CD248 regulates insulin signaling were explored using in vivo insulin clamp studies and biochemical analyses of cells/tissues from CD248 knockout (KO) and wild-type (WT) mice with diet-induced insulin resistance. Findings were validated with human adipose tissue specimens. Findings: Genetic deletion of CD248 in mice, overcame diet-induced insulin resistance with improvements in glucose uptake and lipolysis in white adipose tissue depots, effects paralleled by increased adipose/adipocyte GLUT4, phosphorylated AKT and GSK3β, and reduced ATGL. The insulin resistance of the WT mice could be attributed to direct interaction of the extracellular domains of CD248 and the insulin receptor (IR), with CD248 acting to block insulin binding to the IR. This resulted in dampened insulin-mediated autophosphorylation of the IR, with reduced downstream signaling/activation of intracellular events necessary for glucose and lipid homeostasis. Interpretation: Our discovery of a cell-surface CD248-IR complex that is accessible to pharmacologic intervention, opens research avenues toward development of new agents to prevent/reverse insulin resistance. Funding: Funded by Canadian Institutes of Health Research (CIHR), Natural Sciences and Engineering Research Council of Canada (NSERC), Canada Foundations for Innovation (CFI), the Swedish Diabetes Foundation, Family Ernfors Foundation and Novo Nordisk Foundation.

Objective Mesothelioma varies in clinical phenotype and survival. Clinical trials are unavoidably affected by selection bias, reducing generalisability. ASSESS-meso is a UK, multicentre, prospective, mesothelioma cohort study (ISRCTN61861764). This pre-specified interim analysis, conducted when recruitment reached 25% of target, summarised participant characteristics and evaluated external validity through comparison with real-world and clinical trial cohorts. Methods The study took place at 14 hospitals across the UK. People diagnosed with mesothelioma, at any anatomical site, were eligible. Clinical, radiological and biochemical data were collected at enrolment. In this interim report, the external validity of the cohort was investigated through comparison of baseline demographic data with populations included in the 2020 UK National Mesothelioma Audit (real-world cohort), and CHECKMATE-743 and MAPS trials (clinical trial cohorts). Results 244 patients were enrolled between 7 April 2017 and 1 March 2022. The cohort was predominantly male (195 out of 244; 80%) with a median age of 74 years. Pleural disease and epithelioid subtypes were most prevalent. ASSESS-meso participants were more similar to the real-world population with regard to age, performance status, disease site and stage than the clinical trial population. ASSESS-meso participants were more likely to be formally staged and less likely to have undifferentiated histology compared with the real-world cohort, possibly reflecting high rates of discussion of ASSESS-meso participants at regional mesothelioma multidisciplinary team meetings. As expected, poorer performance status, non-epithelioid histology and neutrophil–lymphocyte ratio were associated with shorter survival in the adjusted analysis. Conclusion ASSESS-meso is representative of the UK mesothelioma population. Future outputs from the cohort will help characterise different mesothelioma phenotypes with high external validity.

Abstract Explosive caldera-forming eruptions eject voluminous magma during the gravitational collapse of the roof of the magma chamber. Caldera collapse is known to occur by rapid decompression of a magma chamber at shallow depth, however, the thresholds for magma chamber decompression that promotes caldera collapse have not been tested using examples from actual caldera-forming eruptions. Here, we investigated the processes of magma chamber decompression leading to caldera collapse using two natural examples from Aira and Kikai calderas in southwestern Japan. The analysis of water content in phenocryst glass embayments revealed that Aira experienced a large magmatic underpressure before the onset of caldera collapse, whereas caldera collapse occurred with a relatively small underpressure at Kikai. Our friction models for caldera faults show that the underpressure required for a magma chamber to collapse is proportional to the square of the depth to the magma chamber for calderas of the same horizontal size. This model explains why the relatively deep magma system of Aira required a larger underpressure for collapse when compared with the shallower magma chamber of Kikai. The distinct magma chamber underpressure thresholds can explain variations in the evolution of caldera-forming eruptions and the eruption sequences for catastrophic ignimbrites during caldera collapse.

Introduction Feeding practices developed in early life can impact a child’s nutrition, growth, dental health, cognitive development and lifetime risk of chronic diseases. Substantial evidence suggests ethnic health inequalities, and non-recommended complementary infant feeding practices among UK’s South Asian (SA) population. Nurture Early for Optimal Nutrition aims to use women’s group participatory learning and action (PLA) cycles to optimise infant feeding, care and dental hygiene practices in SA infants

Artificial intelligence, machine learning, and digital health innovations have tremendous potential to advance patient-centred, data-driven mental healthcare. To enable the clinical application of such innovations, the Krembil Centre for Neuroinformatics at the Centre for Addiction and Mental Health, Canada's largest mental health hospital, embarked on a journey to co-create a digital learning health system called the BrainHealth Databank (BHDB). Working with clinicians, scientists, and administrators alongside patients, families, and persons with lived experience (PFLE), this hospital-wide team has adopted a systems approach that integrates clinical and research data and practices to improve care and accelerate research. PFLE engagement was intentional and initiated at the conception stage of the BHDB to help ensure the initiative would achieve its goal of understanding the community's needs while improving patient care and experience. The BHDB team implemented an evolving, dynamic strategy to support continuous and active PFLE engagement in all aspects of the BHDB that has and will continue to impact patients and families directly. We describe PFLE consultation, co-design, and partnership in various BHDB activities and projects. In all three examples, we discuss the factors contributing to successful PFLE engagement, share lessons learned, and highlight areas for growth and improvement. By sharing how the BHDB navigated and fostered PFLE engagement, we hope to motivate and inspire the health informatics community to collectively chart their paths in PFLE engagement to support advancements in digital health and artificial intelligence.

Summary: Background: While vaccines have established utility against COVID-19, phase 3 efficacy studies have generally not comprehensively evaluated protection provided by previous infection or hybrid immunity (previous infection plus vaccination). Individual patient data from US government-supported harmonized vaccine trials provide an unprecedented sample population to address this issue. We characterized the protective efficacy of previous SARS-CoV-2 infection and hybrid immunity against COVID-19 early in the pandemic over three-to six-month follow-up and compared with vaccine-associated protection. Methods: In this post-hoc cross-protocol analysis of the Moderna, AstraZeneca, Janssen, and Novavax COVID-19 vaccine clinical trials, we allocated participants into four groups based on previous-infection status at enrolment and treatment: no previous infection/placebo; previous infection/placebo; no previous infection/vaccine; and previous infection/vaccine. The main outcome was RT-PCR-confirmed COVID-19 >7–15 days (per original protocols) after final study injection. We calculated crude and adjusted efficacy measures. Findings: Previous infection/placebo participants had a 92% decreased risk of future COVID-19 compared to no previous infection/placebo participants (overall hazard ratio [HR] ratio: 0.08; 95% CI: 0.05–0.13). Among single-dose Janssen participants, hybrid immunity conferred greater protection than vaccine alone (HR: 0.03; 95% CI: 0.01–0.10). Too few infections were observed to draw statistical inferences comparing hybrid immunity to vaccine alone for other trials. Vaccination, previous infection, and hybrid immunity all provided near-complete protection against severe disease. Interpretation: Previous infection, any hybrid immunity, and two-dose vaccination all provided substantial protection against symptomatic and severe COVID-19 through the early Delta period. Thus, as a surrogate for natural infection, vaccination remains the safest approach to protection. Funding: National Institutes of Health.

BackgroundIn most countries, men are more likely to die by suicide than women. Adherence to dominant masculine norms, such as being self-reliant, is linked to suicide in men in Western cultures. We created a suicide prevention media campaign, “Boys Do Cry,” designed to challenge the “self-reliance” norm and encourage help-seeking in men. A music video was at the core of the campaign, which was an adapted version of the “Boys Don’t Cry” song from “The Cure.” There is evidence that suicide prevention media campaigns can encourage help-seeking for mental health difficulties. ObjectiveWe aimed to explore the reach, engagement, and themes of discussion prompted by the Boys Do Cry campaign on Twitter. MethodsWe used Twitter analytics data to investigate the reach and engagement of the Boys Do Cry campaign, including analyzing the characteristics of tweets posted by the campaign’s hosts. Throughout the campaign and immediately after, we also used Twitter data derived from the Twitter Application Programming Interface to analyze the tweeting patterns of users related to the campaign. In addition, we qualitatively analyzed the content of Boys Do Cry–related tweets during the campaign period. ResultsDuring the campaign, Twitter users saw the tweets posted by the hosts of the campaign a total of 140,650 times and engaged with its content a total of 4477 times. The 10 highest-performing tweets by the campaign hosts involved either a video or an image. Among the 10 highest-performing tweets, the first was one that included the campaign’s core video; the second was a screenshot of the tweet posted by Robert Smith, the lead singer of The Cure, sharing the Boys Do Cry campaign’s video and tagging the campaign’s hosts. In addition, the pattern of Twitter activity for the campaign-related tweets was considerably higher during the campaign than in the immediate postcampaign period, with half of the activity occurring during the first week of the campaign when Robert Smith promoted the campaign. Some of the key topics of discussions prompted by the Boys Do Cry campaign on Twitter involved users supporting the campaign; referencing the original song, band, or lead singer; reiterating the campaign’s messages; and having emotional responses to the campaign. ConclusionsThis study demonstrates that a brief media campaign such as Boys Do Cry can achieve good reach and engagement and can prompt discussions on Twitter about masculinity and suicide. Such discussions may lead to greater awareness about the importance of seeking help and providing support to those with mental health difficulties. However, this study suggests that longer, more intensive campaigns may be needed in order to amplify and sustain these results.

Abstract Objective APPEASE is a phase I study to assess the safety, dosing, and efficacy of rivoceranib (a selective, small-molecule inhibitor of VEGFR2) in combination with pembrolizumab. We aimed to treat patients with metastatic malignancies who have progressed through at least first-line therapy, with pembrolizumab 200 mg every 3 weeks, as well as escalating doses of rivoceranib until disease progression or unacceptable toxicity. Results Five patients were enrolled on the starting dose of rivoceranib 300 mg once daily. There were no dose-limiting toxicities observed in combination with pembrolizumab. The dose of rivoceranib was not escalated due to study closure. We note a treatment related grade 3 adverse event (AE) rate of 40%, predominantly in urothelial cancer patients, with no deaths related to treatment related AEs. The disease control rate was 75% (3 of 4) and the median progression free survival (PFS) was 3.6 months. Tumor shrinkage was noted in patients who were previously progressing on pembrolizumab alone. Apatinib 300 mg is safe and demonstrates anti-tumor activity in advanced solid tumors in combination with pembrolizumab. Further dose escalation and efficacy need to be investigated in larger disease-specific patient populations. Trial registration number: Clinical trial registration number: NCT03407976. Date of registration: January 17, 2018.

Abstract With global progress towards malaria reduction stalling, further analysis of epidemiology is required, particularly in countries with the highest burden. National surveys have mostly analysed infection prevalence, while large-scale data on parasite density and different developmental forms rarely available. In Nigeria, the country with the largest burden globally, blood slide microscopy of children up to 5 years of age was conducted in the 2018 National Demographic and Health Survey, and parasite prevalence previously reported. In the current study, malaria parasite density measurements are reported and analysed for 7783 of the children sampled across the 36 states within the six geopolitical zones of the country. Asexual and sexual stages, and infections with different malaria parasite species are analysed. Across all states of Nigeria, there was a positive correlation between mean asexual parasite density within infected individuals and prevalence of infection in the community (Spearman’s rho = 0.39, P = 0.02). Asexual parasite densities were highest in the northern geopolitical zones (geometric means > 2000 μL−1), extending the evidence of exceptionally high infection burden in many areas. Sexual parasite prevalence in each state was highly correlated with asexual parasite prevalence (Spearman’s rho = 0.70, P

Abstract Theory of mind (ToM), the ability to represent the mental states of oneself and others, is argued to be central to human social experience, and impairments in this ability are thought to underlie several psychiatric and developmental conditions. To examine the accuracy of mental state inferences, a novel ToM task was developed, requiring inferences to be made about the mental states of ‘Targets’, prior participants who took part in a videoed mock interview. Participants also made estimates of the Targets’ personality traits. These inferences were compared to ground-truth data, provided by the Targets, of their true traits and mental states. Results from 55 adult participants demonstrated that trait inferences were used to derive mental state inferences, and that the accuracy of trait estimates predicted the accuracy of mental state inferences. Moreover, the size and direction of the association between trait accuracy and mental state accuracy varied according to the trait—mental state combination. The accuracy of trait inferences was predicted by the accuracy of participants’ understanding of trait covariation at the population level. Findings are in accordance with the Mind-space theory, that representation of the Target mind is used in the inference of their mental states.

Abstract Improving maternal nutrition during pregnancy/lactation is a promising strategy to maximise the intestinal health of piglets undergoing abrupt weaning under commercial production conditions. This experiment investigated the effects of maternal supplementation of a casein hydrolysate and yeast β-glucan (CH-YBG) from day 83 of gestation until weaning (day 28) on sow faecal microbial populations and measures of piglet gastrointestinal health parameters at weaning. Sows (n = 10 sows/group) were assigned to: (1) control diet, and (2) control diet + CH-YBG. Maternal supplementation increased the abundance of the phylum Firmicutes, including members Lactobacillus in the sows faeces, with a concomitant increase in the caecal abundance of Lactobacillus in the weaned piglets compared to the controls. Piglets weaned from the supplemented sows had increased villus height in the duodenum (P

Influenza A virus (IAV) infection is commonly complicated by secondary bacterial infections that lead to increased morbidity and mortality. Our recent work demonstrates that IAV disrupts airway homeostasis, leading to airway pathophysiology resembling cystic fibrosis disease through diminished cystic fibrosis transmembrane conductance regulator (CFTR) function. Here, we use human airway organotypic cultures to investigate how IAV alters the airway microenvironment to increase susceptibility to secondary infection with Streptococcus pneumoniae (Spn). We observed that IAV-induced CFTR dysfunction and airway surface liquid acidification is central to increasing susceptibility to Spn. Additionally, we observed that IAV induced profound transcriptional changes in the airway epithelium and proteomic changes in the airway surface liquid in both CFTR-dependent and -independent manners. These changes correspond to multiple diminished host defense pathways and altered airway epithelial function. Collectively, these findings highlight both the importance of CFTR function during infectious challenge and demonstrate a central role for the lung epithelium in secondary bacterial infections following IAV.

Abstract During their annual migration, avian migrants alternate stopover periods, for refuelling, with migratory flight bouts. We hypothesise that European Nightjars (Caprimulgus europaeus) adapt their daily migration tactics in association with biomes. We tracked the autumn migration of 24 European Nightjars, from breeding populations in Mongolia, Belgium and UK, using GPS-loggers and multi-sensor data loggers. We quantified crepuscular and nocturnal migration and foraging probabilities, as well as daily travel speed and flight altitude during active migration in response to biomes. Nightjars adopt a rush tactic, reflected in high daily travel speed, flight altitude and high migration probabilities at dusk and at night, when travelling through ecological barriers. Migration is slower in semi-open, hospitable biomes. This is reflected in high foraging probabilities at dusk, lower daily travel speed and lower migration probabilities at dusk. Our study shows how nightjars switch migration tactics during autumn migration, and suggest nightjars alternate between feeding and short migratory flight bouts within the same night when travelling through suitable habitats. How this may affect individuals’ fuel stores and whether different biomes provide refuelling opportunities en route remains to be investigated, to understand how future land-use change may affect migration patterns and survival probabilities.

Abstract We present a model for the petrogenesis of magma with adakitic affinity in an old subduction zone, which does not involve slab melting and is constrained by new geochronological and geochemical data for Mt. Popa, the largest of three Quaternary volcanoes in central Myanmar (Popa, Monywa and Singu). The edifice is composed of Popa Plateau (0.8–0.6 Ma) with high-K rocks and a stratovolcano ( 40). The distinct K contents indicate that the adakitic magmas cannot be derived from Popa high-K rocks, but they share trace-element signatures and Sr–Nd isotope ratios with medium-K basalts from Monywa volcano. Our estimation of water contents in Popa magma reveals that primary magma for medium-K basalts was generated by partial melting of wedge mantle with normal potential temperature (TP 1330–1340 °C) under wet conditions (H2O 0.25–0.54 wt%). Its melting was probably induced by asthenospheric upwelling that is recognized by tomographic images. Mafic adakitic magma (Mg# ~ 63, Sr/Y ~ 64) was derived from the medium-K basaltic magma in fractional crystallization of a garnet-bearing assemblage at high pressure, and felsic adakitic rocks (Mg# ~ 45, Sr/Y ~ 50) were produced by assimilation-fractional crystallization processes at mid-crustal depths.

Traffic congestion is ubiquitous in major cities around the world. Congestion is associated with a slew of negative effects, including delays and local air pollution. Because of the negative effects of congestion, governments invest billions of dollars into the highway system to try to reduce congestion and accommodate peak-hour automobile travel demand. The COVID-19 pandemic presented a significant disruption to transportation systems globally. One impact was a drastic reduction in travel, leading to free-flowing traffic conditions in many previously-congested cities. As lockdowns eased, traffic volumes returned to near-normal levels. However, the temporal pattern of demand may differ, due to increased remote work or other factors. In this article, we examine the temporal distribution of highway demand in California, using data from over 3,500 traffic sensors. We find that peak-hour automobile travel is spreading in the post-lockdown period. In addition to decreased traffic congestion, this finding also has implications for infrastructure investment. Roadways are generally sized based on peak-hour demand. As the peaks spread, some highway construction project may prove unnecessary. It may be possible to reallocate road space to other uses with fewer tradeoffs in terms of traffic congestion.

Background: Shift work is essential in society but can be detrimental to health and quality of life and is associated with decreased productivity and increased risk of accidents. Interventions to reduce these consequences are needed, but the extent and range of trial evidence for interventions for those most affected by their shift-work schedules is unclear. We therefore carried out a scoping review to assess the availability of evidence to inform the development and evaluation of future interventions. Methods: We aimed to identify clinical trials of any intervention for shift work-related sleep disturbance that included a comparator group, where the intervention was delivered in an occupational setting. We searched Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, CINAHL, EMBASE, Medline and Science Citation Index from inception to 30th March 2020 for relevant citations. Citations were screened by two independent reviewers, a third reviewer resolved disagreements. Data were extracted by two independent reviewers. Results: From 1250 unique citations, 14 studies met inclusion criteria for comparative trials of treatment in an occupational setting. There were five trials of hypnotics, five trials of stimulants, and four trials of non-pharmacological therapies (cognitive behavioural therapy, light therapy, aromatherapy and herbal medicine). Outcomes included sleep parameters, day-time sleepiness, and quality of life. There were no consistently reported outcomes across trials. Conclusions: Interventions fell into three distinct groups investigated in distinct time periods without progression from efficacy trials to wider-scale interventions. The lack of consistent patient-reported outcome measures limits synthesising findings. Some trials focussed on optimising sleep, others on reducing wake-time sleepiness. Adequately powered trials of existing interventions are needed, with the development and testing of novel combination treatments in patients with well-defined shift work sleep disorder. A core set of clinically relevant outcomes will develop and standardise the evidence-base for shift work sleep disorder.

BackgroundPaediatric trials must contend with many challenges that adult trials face but often bring additional obstacles. Decentralised trials, where some or all trial methods occur away from a centralised location, are a promising strategy to help meet these challenges. This scoping review aims to (a) identify what methods and tools have been used to create and conduct entirely online-decentralised trials with children and (b) determine the gaps in the knowledge in this field. This review will describe the methods used in these trials to identify their facilitators and the gaps in the knowledge.MethodsThe methods were informed by guidance from the Joanna Briggs Institute and the PRISMA extension for scoping reviews. We systematically searched MEDLINE, CENTRAL, CINAHL, and Embase databases, trial registries, pre-print servers, and the internet. We included randomised and quasi-randomised trials conducted entirely online with participants under 18 published in English. A risk of bias assessment was completed for all included studies.ResultsTwenty-one trials met our inclusion criteria. The average age of participants was 14.6 years. Social media was the most common method of online recruitment. Most trials employed an external host website to store and protect their data. Duration of trials ranged from single-session interventions up to ten weeks. Fourteen trials compensated participants. Eight trials involved children in their trial design process; none reported compensation for this. Most trials had a low risk of bias in "random sequence generation", "selective reporting", and "other". Most trials had a high risk of bias in "blinding participants and personnel", "blinding of outcome assessment", and "incomplete outcome data". "Allocation concealment" was unclear in most studies.ConclusionsThere was a lack of transparent reporting of the recruitment, randomisation, and retention methods used in many of the trials included in this review. Patient and public involvement (PPI) was not common, and the compensation of PPI partners was not reported in any study. Consent methods and protection against fraudulent entries to trials were creative and thoroughly discussed by some trials and not addressed by others. More work and thorough reporting of how these trials are conducted is needed to increase their reproducibility and quality.Ethics and disseminationEthical approval was not necessary since all data sources used are publicly available.

Edge effects resulting from adjacent land uses are poorly understood in agroecosystems yet understanding above and belowground edge effects is crucial for maintaining ecosystem function. The aim of our study was to examine impacts of land management on aboveground and belowground edge effects, measured by changes in plant community, soil properties, and soil microbial communities across agroecosystem edges. We measured plant composition and biomass, soil properties (total carbon, total nitrogen, pH, nitrate, and ammonium), and soil fungal and bacterial community composition across perennial grassland-annual cropland edges. Edge effects due to land management were detected both aboveground and belowground. The plant community at the edge was distinct from the adjacent land uses, where annual, non-native, plant species were abundant. Soil total nitrogen and carbon significantly decreased across the edge (P < 0.001), with the highest values in the perennial grasslands. Both bacterial and fungal communities were different across the edge with clear changes in fungal communities driven directly and indirectly by land management. A higher abundance of pathogens in the more heavily managed land uses (i.e. crop and edge) was detected. Changes in plant community composition, along with soil carbon and nitrogen also influenced the soil fungal community across these agroecosystems edges. Characterizing edge effects in agroecosystem, especially those associated with soil microbial communities, is an important first step in ensuring soil health and resilience in these managed landscapes.

IntroductionWe are conducting a multicenter study to identify classifiers predictive of disease-specific survival in patients with primary melanomas. Here we delineate the unique aspects, challenges, and best practices for optimizing a study of generally small-sized pigmented tumor samples including primary melanomas of at least 1.05mm from AJTCC TNM stage IIA-IIID patients. We also evaluated tissue-derived predictors of extracted nucleic acids' quality and success in downstream testing. This ongoing study will target 1,000 melanomas within the international InterMEL consortium.MethodsFollowing a pre-established protocol, participating centers ship formalin-fixed paraffin embedded (FFPE) tissue sections to Memorial Sloan Kettering Cancer Center for the centralized handling, dermatopathology review and histology-guided coextraction of RNA and DNA. Samples are distributed for evaluation of somatic mutations using next gen sequencing (NGS) with the MSK-IMPACTTM assay, methylation-profiling (Infinium MethylationEPIC arrays), and miRNA expression (Nanostring nCounter Human v3 miRNA Expression Assay).ResultsSufficient material was obtained for screening of miRNA expression in 683/685 (99%) eligible melanomas, methylation in 467 (68%), and somatic mutations in 560 (82%). In 446/685 (65%) cases, aliquots of RNA/DNA were sufficient for testing with all three platforms. Among samples evaluated by the time of this analysis, the mean NGS coverage was 249x, 59 (18.6%) samples had coverage below 100x, and 41/414 (10%) failed methylation QC due to low intensity probes or insufficient Meta-Mixed Interquartile (BMIQ)- and single sample (ss)- Noob normalizations. Six of 683 RNAs (1%) failed Nanostring QC due to the low proportion of probes above the minimum threshold. Age of the FFPE tissue blocks (pConclusionOur experience with many archival tissues demonstrates that with careful management of tissue processing and quality control it is possible to conduct multi-omic studies in a complex multi-institutional setting for investigations involving minute quantities of FFPE tumors, as in studies of early-stage melanoma. The study describes, for the first time, the optimal strategy for obtaining archival and limited tumor tissue, the characteristics of the nucleic acids co-extracted from a unique cell lysate, and success rate in downstream applications. In addition, our findings provide an estimate of the anticipated attrition that will guide other large multicenter research and consortia.

Awake craniotomies provide unique and invaluable scientific opportunities for neurophysiological experimentation in consenting human subjects. While such experimentation carries a long history, rigorous reporting of methodologies focusing on synchronizing data across multiple platforms is not universally reported and often not translatable to across operating rooms, facilities, or behavioral tasks. Therefore, here we detail an intraoperative data synchronization methodology designed to work across multiple commercially available platforms to collect behavioral and surgical field videos, electrocorticography, brain stimulation timing, continuous finger joint angles, and continuous finger force production. Our technique was developed to be nonobstructive to operating room (OR) staff and generalizable to a variety of hand-based tasks. We hope that the detailed reporting of our methods will support the scientific rigor and reproducibility of future studies, as well as aid other groups interested in performing related experiments.

We describe the MalariaGEN Pf7 data resource, the seventh release of Plasmodium falciparum genome variation data from the MalariaGEN network. It comprises over 20,000 samples from 82 partner studies in 33 countries, including several malaria endemic regions that were previously underrepresented. For the first time we include dried blood spot samples that were sequenced after selective whole genome amplification, necessitating new methods to genotype copy number variations. We identify a large number of newly emerging crt mutations in parts of Southeast Asia, and show examples of heterogeneities in patterns of drug resistance within Africa and within the Indian subcontinent. We describe the profile of variations in the C-terminal of the csp gene and relate this to the sequence used in the RTS,S and R21 malaria vaccines. Pf7 provides high-quality data on genotype calls for 6 million SNPs and short indels, analysis of large deletions that cause failure of rapid diagnostic tests, and systematic characterisation of six major drug resistance loci, all of which can be freely downloaded from the MalariaGEN website.

The use of cannabis for medicinal purposes has increased globally over the past decade since patient access to medicinal cannabis has been legislated across jurisdictions in Europe, the United Kingdom, the United States, Canada, and Australia. Yet, evidence relating to the effect of medical cannabis on the management of symptoms for a suite of conditions is only just emerging. Although there is considerable engagement from many stakeholders to add to the evidence base through randomized controlled trials, many gaps in the literature remain. Data from real-world and patient reported sources can provide opportunities to address this evidence deficit. This real-world data can be captured from a variety of sources such as found in routinely collected health care and health services records that include but are not limited to patient generated data from medical, administrative and claims data, patient reported data from surveys, wearable trackers, patient registries, and social media. In this systematic scoping review, we seek to understand the utility of online user generated text into the use of cannabis as a medicine. In this scoping review, we aimed to systematically search published literature to examine the extent, range, and nature of research that utilises user-generated content to examine to cannabis as a medicine. The objective of this methodological review is to synthesise primary research that uses social media discourse and internet search engine queries to answer the following questions: (i) In what way, is online user-generated text used as a data source in the investigation of cannabis as a medicine? (ii) What are the aims, data sources, methods, and research themes of studies using online user-generated text to discuss the medicinal use of cannabis. We conducted a manual search of primary research studies which used online user-generated text as a data source using the MEDLINE, Embase, Web of Science, and Scopus databases in October 2022. Editorials, letters, commentaries, surveys, protocols, and book chapters were excluded from the review. Forty-two studies were included in this review, twenty-two studies used manually labelled data, four studies used existing meta-data (Google trends/geo-location data), two studies used data that was manually coded using crowdsourcing services, and two used automated coding supplied by a social media analytics company, fifteen used computational methods for annotating data. Our review reflects a growing interest in the use of user-generated content for public health surveillance. It also demonstrates the need for the development of a systematic approach for evaluating the quality of social media studies and highlights the utility of automatic processing and computational methods (machine learning technologies) for large social media datasets. This systematic scoping review has shown that user-generated content as a data source for studying cannabis as a medicine provides another means to understand how cannabis is perceived and used in the community. As such, it provides another potential 'tool' with which to engage in pharmacovigilance of, not only cannabis as a medicine, but also other novel therapeutics as they enter the market.

Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are two common systemic inflammatory conditions with a combined lifetime risk of approximately 3.5% in women and 1.5% in men. They are intimately associated with the aging process, virtually never occurring prior to 50 years of age and becoming more common over time. The reasons for this are unclear, but likely relate in part to factors related to aging of the immune system. The treatment of both GCA and PMR is traditionally based on glucocorticoids, frequently requiring a prolonged treatment course over long periods of time. Other medications are belatedly entering our treatment armamentarium, but their exact place in treatment algorithms remains to be fully defined and it is likely glucocorticoids will remain a cornerstone of our treatment in GCA and PMR for the foreseeable future. As a result, people with GCA and PMR will continue to be exposed to a significant cumulative glucocorticoid burden with all of the attendant potential adverse events, including osteoporosis. The predominantly post-menopausal female population that most commonly develops PMR and GCA is also the population that is most affected by osteoporosis. Given the risk of glucocorticoid-induced osteoporosis and subsequent fragility fractures, a planned treatment approach from glucocorticoid initiation is needed in these conditions. For the majority of patients, this will entail ensuring sufficiency of calcium and vitamin D as well as antiresorptive treatments. In this article, we discuss considerations around optimisation of metabolic bone health in GCA and PMR.