Proteomic prediction of diverse incident diseases: a machine learning-guided biomarker discovery study using data from a prospective cohort study.

BACKGROUND: Broad-capture proteomic technologies have the potential to improve disease prediction, enabling targeted prevention and management, but studies have so far been limited to very few selected diseases and have not evaluated predictive performance across multiple conditions. We aimed to evaluate the potential of serum proteins to improve risk prediction over and above health-derived information and polygenic risk scores across a diverse set of 24 outcomes. METHODS: We designed multiple case-cohorts nested in the EPIC-Norfolk prospective study, from participants with available serum samples and genome-wide genotype data, with more than 32 974 person-years of follow-up. Participants were middle-aged individuals (aged 40-79 years at baseline) of European ancestry who were recruited from the general population of Norfolk, England, between March, 1993 and December, 1997. We selected participants who developed one of ten less common diseases within 10 years of follow-up; we also subsampled a randomly drawn control subcohort, which also served to investigate 14 more common outcomes (n>70), including all-cause premature mortality (death before the age of 75 years; case numbers 71-437; controls 608-1556). Individuals were excluded from the current study owing to failed genotyping or proteomic quality control, relatedness, or missing information on age, sex, BMI, or smoking status. We used a machine learning framework to derive sparse predictive protein models for the onset of the the 23 individual diseases and all-cause premature mortality, and to derive a single common sparse multimorbidity signature that was predictive across multiple diseases from 2923 serum proteins. FINDINGS: Participants who developed one of ten less common diseases within 10 years of follow-up included 482 women and 507 men, with a mean age at baseline of 64·56 years (8·08). The random subcohort included 990 women and 769 men, with a mean age of 58·79 years (9·31). As few as five proteins alone outperformed polygenic risk scores for 17 of 23 outcomes (median dfference in concordance index [C-index] 0·13 [0·10-0·17]) and improved predictive performance when added over basic patient-derived information models for seven outcomes, achieving a median C-index of 0·82 (IQR 0·77-0·82). This included diseases with poor prognosis such as lung cancer (C-index 0·85 [+/- cross-validation error 0·83-0·87]), for which we identified unreported biomarkers such as C-X-C motif chemokine ligand 17. A sparse multimorbidity signature of ten proteins improved prediction across seven outcomes over patient-derived information models, achieving performances (median C-index 0·81 [IQR 0·80-0·82]) similar to those of disease-specific signatures. INTERPRETATION: We show the value of broad-capture proteomic biomarker discovery studies across multiple diseases of diverse causes, pointing to those that might benefit the most from proteomic approaches, and the potential to derive common sparse biomarker panels for prediction of multiple diseases at once. This framework could enable follow-up studies to explore the generalisability of proteomic models and to benchmark these against clinical assays, which are required to understand the translational potential of these findings. FUNDING: Medical Research Council, Health Data Research UK, UK Research and Innovation-National Institute for Health and Care Research, Cancer Research UK, and Wellcome Trust.

The association between device-measured sitting time and cardiometabolic health risk factors in children.

BACKGROUND: There is limited evidence of the associations between postural-derived sitting time, waist-worn derived sedentary time and children's health and the moderation effect of physical activity (PA). This study examined associations of children's device-measured sitting time with cardiometabolic health risk factors, including moderation by physical activity. METHODS: Cross-sectional baseline data from children (mean-age 8.2 ± 0.5 years) in Melbourne, Australia (2010) participating in the TransformUs program were used. Children simultaneously wore an activPAL to assess sitting time and an ActiGraph GT3X to assess sedentary time and physical activity intensity. Cardiometabolic health risk factors included: adiposity (body mass index [BMI], waist circumference [WC]), systolic and diastolic blood pressure (SBP, DBP), high-density lipoprotein (HDL), low-density lipoprotein (LDL), cholesterol, triglycerides, fasting plasma glucose (FPG), serum insulin, and 25-hydroxyvitaminD (25[OH]D). Linear regression models (n = 71-113) assessed associations between sitting time with each health risk factor, adjusted for different PA intensities (i.e. light [LIPA], moderate-vigorous intensities [MVPA], separately on each model), age, sex, adiposity, and clustering by school. Interaction terms examined moderation. The analyses were repeated using device-measured sedentary time (i.e. ActiGraph GT3X) for comparison. RESULTS: Sitting time was positively associated with SBP (b = 0.015; 95%CI: 0.004, 0.026), DBP (b = 0.012; 95%CI:0.004, 0.020), and FPG (b = 0.001; 95%CI: 0.000, 0.000), after adjusting for higher PA intensities. The association between sitting time and insulin (b = 0.003; 95%CI: 0.000, 0.006) was attenuated after adjusting for higher PA intensities. When the models were adjusted for LIPA and MVPA, there was a negative association with LDL (b=-0.001; 95%CI: -0.002, -0.000 and b=-0.001; 95%CI: -0.003, -0.000, respectively). There was a negative association of sedentary time with WCz (b=-0.003; 95%CI: -0.005, 0.000) and BMIz (b=-0.003; 95%CI: -0.006, -0.000) when the models were adjusted by MVPA. Sedentary time was positively associated with triglycerides (b = 0.001; 95%CI: 0.000, 0.001) but attenuated after adjusting for MVPA. No evidence of moderation effects was found. CONCLUSIONS: Higher volumes of sitting and sedentary time were associated with some adverse associations on some cardiometabolic health risk factors in children. These associations were more evident when sitting time was the predictor. This suggests that reducing time spent sitting may benefit some cardiometabolic health outcomes, but future experimental research is needed to confirm causal relationships and identify the biological mechanisms that might be involved. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12609000715279.

Effectiveness of Intervention Strategies to Increase Adolescents' Physical Activity and Reduce Sedentary Time in Secondary School Settings, Including Factors Related to Implementation: A Systematic Review and Meta-Analysis.

BACKGROUND: Globally, just one in five adolescents meet physical activity guidelines and three-quarters of the school day is spent sitting. It is unclear which types of school-based interventions strategies increase physical activity and reduce sedentary time among adolescents, or how these interventions are implemented influences their effectiveness. OBJECTIVE: The three aims of our systematic review were to (a) identify intervention strategies used within secondary school settings to improve students' movement behaviours throughout school-based initiatives, delivered at or by the school; (b) determine the overall effect of the interventions (meta-analysis) on physical activity (all intensities), sedentary time, cognitive/academic, physical health and/or psychological outcomes; and (c) describe factors related to intervention implementation. METHODS: Searches were conducted in MEDLINE complete, EMBASE, CINAHL, SPORTDiscus, APA PsycINFO, and ERIC in January 2023 for studies that (a) included high school-aged adolescents; (b) involved a school-based intervention to increase physical activity and/or decrease sedentary time; and (c) were published in English. Reported effects were pooled in meta-analyses where sufficient data were obtained. RESULTS: Eighty-five articles, representing 61 interventions, met the inclusion criteria, with 23 unique intervention strategies used. Interventions that involved whole-school approaches (i.e., physical activity sessions, environmental modifications, teacher training, peer support and/or educational resources) were favourably associated with most of the outcomes. The meta-analyses showed: (a) non-significant effects for sedentary time (Standardized mean difference [SMD] = -0.02; 95%CI, -0.14, 0.11), physical activity at all intensities (light: SMD= -0.01; 95%CI, -0.08, 0.05; moderate: SMD = 0.06; 95%CI, -0.09, 0.22; vigorous: SMD = 0.08; 95%CI, -0.02, 0.18; moderate-to-vigorous: SMD = 0.05; 95%CI, -0.01, 0.12) and waist circumference (SMD = 0.09; 95%CI, -0.03, 0.21), and (b) a small statistically significant decrease in body mass index (SMD= -0.09, 95%CI -0.16, -0.0). Factors related to intervention implementation were reported in 51% of the articles. CONCLUSION: While some intervention approaches demonstrated promise, small or null effects were found in meta-analyses. Future school-based interventions should utilize a whole-school approach designed to increase adolescents' activity across the day. Consistent reporting of implementation will increase understanding of how interventions are adopted, implemented and sustained. REGISTRATION: PROSPERO (CRD42020169988).

Family caregivers improve the diagnostic accuracy of disorders of consciousness: from remote to near-bed auditory stimulation.

BACKGROUND: Family caregivers (FC) contribute to reducing the misdiagnosis rate in patients with disorders of consciousness (DOC). Unfortunately, the recent pandemic of COVID-19 imposed drastic restrictions that limited the access of FC to the sensory/cognitive stimulation protocols. Telemedicine approaches have been implemented to avoid discontinuity in care pathways and to ensure caregivers involvement in rehabilitation programs. AIM: The aim was to investigate whether the presence of FC remotely connected might help clinicians in eliciting higher cortically mediated behavioral responses in patients with DOC. DESIGN: Cross-sectional study. SETTING: Post-acute Unit of Neurorehabilitation. POPULATION: DOC due to severe brain injury. METHODS: Consecutive patients with DOC were assessed by means of the Coma Recovery Scale-Revised (CRS-R) by two expert examiners. Each patient underwent to five assessments in two weeks in three different conditions: 1) by the examiner only (standard); 2) with the verbal stimulation given by the FC remotely connected by PC tablet (caregiver in remote); and 3) with the verbal stimulation given by the FC physically present (caregiver in presence). RESULTS: Thirty patients with DOC (VS/UWS=10; MCS=20; mean age: 51, range: 21-79; vascular: 16; anoxic: 6; TBI=8) and their FC were enrolled. Higher total scores of CRS-R were recorded both in "caregiver in remote" and in "caregiver in presence" than in standard condition (standard vs. remote, Z=2.942, P=0.003; standard vs. presence, Z=3.736, P<0.001). Furthermore, the administration of the CRS-R with a FC, elicited higher levels of behavioral responses in MCS patients, than CRS-R performed in standard condition. In particular, 2 patients out of 30 (6.66%) showed higher scores and better diagnosis when the CRS-R was administered with FC in remote. Similarly, 5 out of 30 patients (16.66%) showed better diagnoses when the CRS-R was administered with FC in presence. Five patients changed diagnosis between standard and presence conditions (3 MCS- were diagnosed as MCS+; 2 MCS+ were diagnosed as conscious). CONCLUSIONS: Our findings add new evidence regarding the beneficial role of family members in the diagnosis of DOC, even mediated by telemedicine approach. CLINICAL REHABILITATION IMPACT: In future guidelines, FC should have an active and supporting role in the diagnostic and rehabilitative process of DOC.

Cost-effectiveness of reducing children's sedentary time and increasing physical activity at school: the Transform-Us! intervention.

BACKGROUND: Improving physical activity and reducing sedentary behavior represent important areas for intervention in childhood in order to reduce the burden of chronic disease related to obesity and physical inactivity in later life. This paper aims to determine the cost-effectiveness of a multi-arm primary school-based intervention to increase physical activity and/or reduce sedentary time in 8-9 year old children (Transform-Us!). METHODS: Modelled cost-utility analysis, using costs and effects from a cluster randomized controlled trial of a 30-month intervention that used pedagogical and environmental strategies to reduce and break up sedentary behaviour (SB-I), promote physical activity (PA-I), or a combined approach (PA + SB-I), compared to current practice. A validated multiple-cohort lifetable model (ACE-Obesity Policy model) estimated the obesity and physical activity-related health outcomes (measured as change in body mass index and change in metabolic equivalent task minutes respectively) and healthcare cost-savings over the cohort's lifetime from the public-payer perspective, assuming the intervention was delivered to all 8-9 year old children attending Australian Government primary schools. Sensitivity analyses tested the impact on cost-effectiveness of varying key input parameters, including maintenance of intervention effect assumptions. RESULTS: Cost-effectiveness results demonstrated that, when compared to control schools, the PA-I and SB-I intervention arms were "dominant", meaning that they resulted in net health benefits and healthcare cost-savings if the intervention effects were maintained. When the costs and effects of these intervention arms were extrapolated to the Australian population, results suggested significant potential as obesity prevention measures (PA-I: 60,780 HALYs saved (95% UI 15,007-109,413), healthcare cost-savings AUD641M (95% UI AUD165M-$1.1B); SB-I: 61,126 HALYs saved (95% UI 11,770 - 111,249), healthcare cost-savings AUD654M (95% UI AUD126M-1.2B)). The PA-I and SB-I interventions remained cost-effective in sensitivity analysis, assuming the full decay of intervention effect after 10 years. CONCLUSIONS: The PA-I and SB-I Transform-Us! intervention arms represent good value for money and could lead to health benefits and healthcare cost-savings arising from the prevention of chronic disease in later life if intervention effects are sustained. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number (ISRCTN83725066). Australia and New Zealand Clinical Trials Registry Number (ACTRN12609000715279).

Hepatitis C Virus Testing, Infection, and Cases Reported Through Public Health Surveillance During Expanded Screening Recommendations, United States, 2013-2021.

OBJECTIVES: Hepatitis C virus (HCV) infection is the most common bloodborne infection in the United States. We assessed trends in HCV testing, infection, and surveillance cases among US adults. METHODS: We used Quest Diagnostics data from 2013-2021 to assess trends in the numbers tested for HCV antibody and proportion of positivity for HCV antibody and HCV RNA. We also assessed National Notifiable Diseases Surveillance System 2013-2020 data for trends in the number and proportion of hepatitis C cases. We applied joinpoint regression for trends testing. RESULTS: Annual HCV antibody testing increased from 1.7 million to 4.8 million from 2013 to 2021, and the positivity proportion declined (average, 0.2% per year) from 5.5% to 3.7%. The greatest percentage-point increase in HCV antibody testing occurred in hospitals and substance use disorder treatment facilities and among addiction medicine providers. HCV RNA positivity was stable at about 60% in 2013-2015 and declined to 41.0% in 2021 (2015-2021 average, -3.2% per year). Age-specific HCV RNA positivity was highest among people aged 40-59 years during 2013-2015 and among people aged 18-39 years during 2016-2021. The number of reported hepatitis C cases (acute and chronic) declined from 179 341 in 2015 to 105 504 in 2020 (average decline, -13 177 per year). The proportion of hepatitis C cases among those aged 18-39 years increased by an average of 1.4% per year during 2013-2020; among individuals aged 40-59 years, it decreased by an average of 2.3% per year during 2013-2018. CONCLUSIONS: HCV testing increased, suggesting improved universal screening. Various data sources are valuable for monitoring elimination progress.

Hepatitis B Care Continuum Models-Data to Inform Public Health Action.

The application of a care continuum model (CCM) can identify gaps in diagnosis, care, and treatment of populations with a common condition, but challenges are inherent in developing a CCM for chronic hepatitis B. In contrast with treatment for HIV or hepatitis C, treatment is not indicated for all people with chronic hepatitis B, clinical endpoints are not clear for those receiving treatment, and those for whom treatment is not indicated remain at risk for complications. This topical review examines the data elements necessary to develop and apply chronic hepatitis B CCMs at the jurisdictional health department level. We conducted a nonsystematic review of US-based publications in Ovid MEDLINE (1946-present), Ovid Embase (1974-present), and Scopus (not date limited) databases, which yielded 724 publications for review. Jurisdictional health departments, if properly supported, could develop locale-specific focused CCMs using person-level chronic hepatitis B registries, updated longitudinally using electronic laboratory reporting data and case reporting data. These CCMs could be applied to identify disparities and improve rates in testing and access to care and treatment, which are necessary to reduce liver disease and chronic hepatitis B mortality. Investments in public health surveillance infrastructure, including substantial enhancements in electronic laboratory reporting and case reporting and the use of supplementary data sources, could enable jurisdictional health departments to develop modified CCMs for chronic hepatitis B that focus, at least initially, on "early" CCM steps, which emphasize optimization of hepatitis B diagnosis, linkage to care, and ongoing clinical follow-up of diagnosed people, all of which can lead to improved outcomes.

Frequency of Children Diagnosed with Perinatal Hepatitis C, United States, 2018-2020.

We describe hepatitis C testing of 47 (2%) of 2,266 children diagnosed with perinatal hepatitis C who were exposed during 2018-2020 in 7 jurisdictions in the United States. Expected frequency of perinatal transmission is 5.8%, indicating only one third of the cases in this cohort were reported to public health authorities.

Effects of dietary supplementation with 3-nitrooxypropanol on enteric methane production, rumen fermentation, and performance in young growing beef cattle offered a 50:50 forage:concentrate diet.

There is an urgent requirement internationally to reduce enteric methane (CH4) emissions from ruminants to meet greenhouse gas emissions reduction targets. Dietary supplementation with feed additives is one possible strategy under investigation as an effective solution. The effects of the CH4 inhibitor 3-nitrooxypropanol (3-NOP) at reducing CH4 emissions in beef have been shown mainly in adult cattle consuming backgrounding and high-energy finishing diets. In this study, the effects of dietary supplementation of young growing (≤6 mo) beef cattle with 3-NOP were examined in a 50:50 forage:concentrate diet. A total of 68 Dairy × Beef (Aberdeen Angus and Hereford dairy cross) male calves (≤6 mo of age at the start of experiment, body weight: 147 ±â€…38 kg) underwent a 3-wk acclimatization period and were then assigned to one of two treatments in a completely randomized block design. Dietary treatments were (1) control, placebo (no 3-NOP), and (2) 3-NOP applied at 150 mg kg-1 DM. Calves were fed a partial mixed ration for 12 wk. Body weight was recorded weekly and feed intake daily using the Calan Broadbent feeding system. Methane and hydrogen emissions were measured using the GreenFeed system. Total weight gained, dry matter intake (DMI), and average daily gain were not affected by 3-NOP (P > 0.05) supplementation. On average, the inclusion of 3-NOP decreased (P < 0.001) CH4 emissions: g d-1; g kg-1 DMI; by 30.6% and 27.2%, respectively, during the study with a greater reduction occurring over time. Incorporating 3-NOP into beef cattle diets is an efficient solution to decrease CH4 emissions during indoor feeding and when offered 50:50 forage:concentrate diet.

Enteric methane (CH4) is a by-product from the fermentation of feed in the digestive tract of cattle. The production of CH4 is responsible for the loss of 2% to 12% of the animal's gross energy intake. A potent greenhouse gas, CH4 from ruminant systems accounts for 30% of international anthropogenic CH4 emissions. As a result, a significant effort has been made internationally to reduce CH4 emissions from ruminants in order to achieve reductions in global greenhouse gas emissions. The supplementation of additives in the feed has been demonstrated to be an effective strategy in reducing CH4 emitted from livestock. The purpose of this research was to investigate the effects of supplementing young growing cattle with the CH4 inhibitor, 3-nitrooxypropanol (3-NOP), consuming a 50:50 forage:concentrate diet. A total of 68 Dairy × Beef (Aberdeen Angus and Hereford dairy cross) male calves (≤6 mo of age at the start of the experiment) were assigned to one of two treatments: control (no 3-NOP) and 3-NOP. Animals received their diets for 12 wk. Animal performance was recorded weekly, with CH4 and hydrogen (H2) emissions recorded daily. Dry matter intake and animal performance were not affected by the inclusion of 3-NOP. Over the duration of this study, the inclusion of 3-NOP decreased daily CH4 emissions by 30.6%, with a 227% increase in daily H2 emissions.

Multi-omic prediction of incident type 2 diabetes.

AIMS/HYPOTHESIS: The identification of people who are at high risk of developing type 2 diabetes is a key part of population-level prevention strategies. Previous studies have evaluated the predictive utility of omics measurements, such as metabolites, proteins or polygenic scores, but have considered these separately. The improvement that combined omics biomarkers can provide over and above current clinical standard models is unclear. The aim of this study was to test the predictive performance of genome, proteome, metabolome and clinical biomarkers when added to established clinical prediction models for type 2 diabetes. METHODS: We developed sparse interpretable prediction models in a prospective, nested type 2 diabetes case-cohort study (N=1105, incident type 2 diabetes cases=375) with 10,792 person-years of follow-up, selecting from 5759 features across the genome, proteome, metabolome and clinical biomarkers using least absolute shrinkage and selection operator (LASSO) regression. We compared the predictive performance of omics-derived predictors with a clinical model including the variables from the Cambridge Diabetes Risk Score and HbA1c. RESULTS: Among single omics prediction models that did not include clinical risk factors, the top ten proteins alone achieved the highest performance (concordance index [C index]=0.82 [95% CI 0.75, 0.88]), suggesting the proteome as the most informative single omic layer in the absence of clinical information. However, the largest improvement in prediction of type 2 diabetes incidence over and above the clinical model was achieved by the top ten features across several omic layers (C index=0.87 [95% CI 0.82, 0.92], Δ C index=0.05, p=0.045). This improvement by the top ten omic features was also evident in individuals with HbA1c <42 mmol/mol (6.0%), the threshold for prediabetes (C index=0.84 [95% CI 0.77, 0.90], Δ C index=0.07, p=0.03), the group in whom prediction would be most useful since they are not targeted for preventative interventions by current clinical guidelines. In this subgroup, the type 2 diabetes polygenic risk score was the major contributor to the improvement in prediction, and achieved a comparable improvement in performance when added onto the clinical model alone (C index=0.83 [95% CI 0.75, 0.90], Δ C index=0.06, p=0.002). However, compared with those with prediabetes, individuals at high polygenic risk in this group had only around half the absolute risk for type 2 diabetes over a 20 year period. CONCLUSIONS/INTERPRETATION: Omic approaches provided marginal improvements in prediction of incident type 2 diabetes. However, while a polygenic risk score does improve prediction in people with an HbA1c in the normoglycaemic range, the group in whom prediction would be most useful, even individuals with a high polygenic burden in that subgroup had a low absolute type 2 diabetes risk. This suggests a limited feasibility of implementing targeted population-based genetic screening for preventative interventions.

Prioritizing a research agenda on built environments and physical activity: a twin panel Delphi consensus process with researchers and knowledge users.

BACKGROUND: The growth of urban dwelling populations globally has led to rapid increases of research and policy initiatives addressing associations between the built environment and physical activity (PA). Given this rapid proliferation, it is important to identify priority areas and research questions for moving the field forward. The objective of this study was to identify and compare research priorities on the built environment and PA among researchers and knowledge users (e.g., policy makers, practitioners). METHODS: Between September 2022 and April 2023, a three-round, modified Delphi survey was conducted among two independent panels of international researchers (n = 38) and knowledge users (n = 23) to identify similarities and differences in perceived research priorities on the built environment and PA and generate twin 'top 10' lists of the most important research needs. RESULTS: From a broad range of self-identified issues, both panels ranked in common the most pressing research priorities including stronger study designs such as natural experiments, research that examines inequalities and inequities, establishing the cost effectiveness of interventions, safety and injuries related to engagement in active transportation (AT), and considerations for climate change and climate adaptation. Additional priorities identified by researchers included: implementation science, research that incorporates Indigenous perspectives, land-use policies, built environments that support active aging, and participatory research. Additional priorities identified by knowledge users included: built environments and PA among people living with disabilities and a need for national data on trip chaining, multi-modal travel, and non-work or school-related AT. CONCLUSIONS: Five common research priorities between the two groups emerged, including (1) to better understand causality, (2) interactions with the natural environment, (3) economic evaluations, (4) social disparities, and (5) preventable AT-related injuries. The findings may help set directions for future research, interdisciplinary and intersectoral collaborations, and funding opportunities.

Seminoma and dysgerminoma: evidence for alignment of clinical trials and de-escalation of systemic chemotherapy.

Malignant germ cell tumours are a group of rare cancers whose incidence peaks in late adolescence and early adulthood. Dysgerminomas of the ovary and seminomas of the testis are analogous diseases, but seminomas have a 10-fold higher incidence. The two tumours are morphologically identical and are only differentiated by surrounding organ-specific tissue or testicular germ cell neoplasia in situ. They share genetic features including KIT and RAS mutations, amplification of chromosome 12p, and expression of pluripotency markers (NANOG (Nanog homeobox), OCT3/4 (Octamer-binding transcription factor 3/4), and SAL4 (Spalt-like trascription factor 4)). Both histologies are exquisitely sensitive to platinum chemotherapy, and the combination of bleomycin, etoposide, and cisplatin (BEP) yields survival rates greater than 90%. However, BEP causes significant, lifelong toxicity (cardiovascular, renal, respiratory, and neurological) in these young patients with an expectation of cure. Here, we comprehensively review the biological features of dysgerminoma and seminoma to demonstrate that they are biologically analogous diseases. We present available clinical trial data supporting de-escalation of chemotherapy treatment. Finally, we propose that future trials should enrol men, women, and children to benefit all patients regardless of age or sex.

The Impact of COVID-19 on Knowledge, Beliefs, and Practices of Ni-Vanuatu Health Workers Regarding Antibiotic Prescribing and Antibiotic Resistance, 2018 and 2022: A Mixed Methods Study.

Antimicrobial resistance (AMR) is included in the ten most urgent global public health threats. Global evidence suggests that antibiotics were over prescribed during the early waves of the COVID-19 pandemic, particularly in low- and middle-income countries. Inappropriate use of antibiotics drives the emergence and spread of antibiotic resistance. This study aimed to examine the impact of COVID-19 on Ni-Vanuatu health worker knowledge, beliefs, and practices (KBP) regarding antibiotic prescribing and awareness of antibacterial AMR. A mixed methods study was conducted using questionnaires and in-depth interviews in 2018 and 2022. A total of 49 respondents completed both baseline (2018) and follow-up (2022) questionnaires. Knowledge scores about prescribing improved between surveys, although health workers were less confident about some prescribing activities. Respondents identified barriers to optimal hand hygiene performance. More than three-quarters of respondents reported that COVID-19 influenced their prescribing practice and heightened their awareness of ABR: "more careful", "more aware", "stricter", and "need more community awareness". Recommendations include providing ongoing continuing professional development to improve knowledge, enhance skills, and maintain prescribing competency; formalising antibiotic stewardship and infection, prevention, and control (IPC) programmes to optimise prescribing and IPC practices; and raising community awareness about ABR to support more effective use of medications.

Scaling up a school-based intervention to increase physical activity and reduce sedentary behaviour in children: protocol for the TransformUs hybrid effectiveness-implementation trial.

INTRODUCTION: Efficacious programmes require implementation at scale to maximise their public health impact. TransformUs is an efficacious behavioural and environmental intervention for increasing primary (elementary) school children's (5-12 years) physical activity and reducing their sedentary behaviour within school and home settings. This paper describes the study protocol of a 5-year effectiveness-implementation trial to assess the scalability and effectiveness of the TransformUs programme. METHODS AND ANALYSIS: A type II hybrid implementation-effectiveness trial, TransformUs is being disseminated to all primary schools in the state of Victoria, Australia (n=1786). Data are being collected using mixed methods at the system (state government, partner organisations), organisation (school) and individual (teacher, parent and child) levels. Evaluation is based on programme Reach, Effectiveness, Adoption, Implementation and Maintenance (RE-AIM) framework. RE-AIM domains are being measured using a quasi-experimental, pre/post, non-equivalent group design, at baseline, 12 and 24 months. Effectiveness will be determined in a subsample of 20 intervention schools (in Victoria) and 20 control schools (in New South Wales (NSW), Australia), at baseline, 12 and 24 months. Primary outcomes include TransformUs Reach, Adoption, Implementation and organisational Maintenance (implementation trial), and children's physical activity and sedentary time assessed using accelerometers (effectiveness trial). Secondary outcomes include average sedentary time and moderate to vigorous-intensity physical activity on weekdays and during school hours, body mass index z-scores and waist circumference (effectiveness trial). Linear mixed-effects models will be fitted to compare outcomes between intervention and control participants accounting for clustering of children within schools, confounding and random effects. ETHICS AND DISSEMINATION: The trial was approved by the Deakin University Human Research Ethics Committee (HEAG-H 28_2017), Victorian Department of Education, the NSW Department of Education, Australian Catholic University (2017-145R), Melbourne Archdiocese Catholic Schools and Catholic Schools NSW. Partners, schools/teachers and parents will provide an informed signed consent form prior to participating. Parents will provide consent for their child to participate in the effectiveness trial. Findings will be disseminated via peer-reviewed publications, scientific conferences, summary reports to schools and our partner organisations, and will inform education policy and practice on effective and sustainable ways to promote physical activity and reduce sedentary behaviours population-wide. TRIAL REGISTRATION NUMBER: Australian Clinical Trials Registration Registry (ACTRN12617000204347).

Socioeconomic position as a predictor of youth's movement trajectory profiles between ages 10 and 14 years.

BACKGROUND: Combinations of movement behaviors (i.e., physical activity, sedentary behavior, sleep) are associated with health and developmental outcomes in youth. Youth vary in how they accumulate these behaviors, both in volume and specific domains (e.g., sedentary time spent on recreational screen activities vs homework). The aim of this study was to examine how youth's combined general and domain-specific movement trajectories differ by socioeconomic position. METHODS: We conducted a longitudinal, group-based multi-trajectory analysis to identify general and domain-specific movement trajectory profiles for 2457 youth from age 10 to 14 years from the Longitudinal Study of Australian Children from 2014-2018. We used multinomial logistic regression to test if socioeconomic position predicted profile membership. RESULTS: We identified three general movement trajectory profiles for both sexes, four domain-specific profiles for males, and five for females. For general movement trajectories, females from lower socioeconomic positions were more likely to be a combination of less active and more sedentary than females from higher socioeconomic positions. Males across socioeconomic positions spend similar amounts of time in physical activity, sedentary time, and sleep. For domain-specific movement trajectories, youth from lower socioeconomic positions were likely to spend a combination of less time in education-based sedentary behavior and more time in recreational screen activities than their higher socioeconomic position peers. CONCLUSION: Our results indicate that socioeconomic position predicted in which domains youth accumulate their movements. Future observational research and interventions targeting different socioeconomic groups should therefore consider domain-specific movement trajectories.

Defining and reporting activity patterns: a modified Delphi study.

BACKGROUND: Despite significant interest in assessing activity patterns in different populations, there has been no consensus concerning the definition and operationalisation of this term. This has limited the comparability, interpretability, and synthesis of study findings to date. The aim of this study was to establish a consensus regarding the way in which activity patterns and activity pattern components are defined and reported. METHODS: The activity patterns literature was searched to identify experts to be invited to participate and to develop a proposed definition of activity patterns and activity pattern components. A three-round modified Delphi survey was conducted online (November 2021 to May 2022). In Round 1, participants were asked to rate their agreement with a proposed activity patterns definition, which also included six activity pattern components (e.g., activity intensity, activity bout, transitions), six examples of activity patterns (e.g., frequency of postural transitions in discrete time periods) and eight items for reporting activity patterns in future research (n = 21 items). Open-ended questions enabled participants to provide further comments and suggestions for additional items. Consensus was defined a priori as ≥ 80% participants rating their agreement with an item. In Round 2, participants were asked to rate their agreement with 25 items (13 original items, eight amended, and four new). In Round 3, participants rated their agreement with 10 items (five original items, four amended, and one new). RESULTS: Twenty experts in activity patterns research participated in Round 1, with response rates of 80% and 60% in Rounds 2 and 3, respectively. The proposed activity pattern definition, all activity pattern components definitions, four of the six activity pattern examples, and 10 items in the activity patterns reporting framework achieved consensus. The removal of one activity component item between Rounds 1 and 2 achieved consensus. CONCLUSION: This modified Delphi study achieved consensus for defining and reporting activity patterns for the first time. This consensus definition enables standardisation of activity patterns terminology, which is important given the significant interest in quantifying how individuals accumulate their physical activity and sedentary behaviour across the lifespan to inform the development of future public health guidelines and interventions efforts.

Fib-4 score is able to predict intra-hospital mortality in 4 different SARS-COV2 waves.

Increased values of the FIB-4 index appear to be associated with poor clinical outcomes in COVID-19 patients. This study aimed to develop and validate predictive mortality models, using data upon admission of hospitalized patients in four COVID-19 waves between March 2020 and January 2022. A single-center cohort study was performed on consecutive adult patients with Covid-19 admitted at the Fondazione Policlinico Gemelli IRCCS (Rome, Italy). Artificial intelligence and big data processing were used to retrieve data. Patients and clinical characteristics of patients with available FIB-4 data derived from the Gemelli Generator Real World Data (G2 RWD) were used to develop predictive mortality models during the four waves of the COVID-19 pandemic. A logistic regression model was applied to the training and test set (75%:25%). The model's performance was assessed by receiver operating characteristic (ROC) curves. A total of 4936 patients were included. Hypertension (38.4%), cancer (12.15%) and diabetes (16.3%) were the most common comorbidities. 23.9% of patients were admitted to ICU, and 12.6% had mechanical ventilation. During the study period, 762 patients (15.4%) died. We developed a multivariable logistic regression model on patient data from all waves, which showed that the FIB-4 score > 2.53 was associated with increased mortality risk (OR = 4.53, 95% CI 2.83-7.25; p ≤ 0.001). These data may be useful in the risk stratification at the admission of hospitalized patients with COVID-19.

Causal associations between cardiorespiratory fitness and type 2 diabetes.

Higher cardiorespiratory fitness is associated with lower risk of type 2 diabetes. However, the causality of this relationship and the biological mechanisms that underlie it are unclear. Here, we examine genetic determinants of cardiorespiratory fitness in 450k European-ancestry individuals in UK Biobank, by leveraging the genetic overlap between fitness measured by an exercise test and resting heart rate. We identified 160 fitness-associated loci which we validated in an independent cohort, the Fenland study. Gene-based analyses prioritised candidate genes, such as CACNA1C, SCN10A, MYH11 and MYH6, that are enriched in biological processes related to cardiac muscle development and muscle contractility. In a Mendelian Randomisation framework, we demonstrate that higher genetically predicted fitness is causally associated with lower risk of type 2 diabetes independent of adiposity. Integration with proteomic data identified N-terminal pro B-type natriuretic peptide, hepatocyte growth factor-like protein and sex hormone-binding globulin as potential mediators of this relationship. Collectively, our findings provide insights into the biological mechanisms underpinning cardiorespiratory fitness and highlight the importance of improving fitness for diabetes prevention.

Magnetic and Magnetocaloric Properties of the A2LnSbO6 Lanthanide Oxides on the Frustrated fcc Lattice.

Frustrated lanthanide oxides are promising candidates for cryogen-free magnetic refrigeration due to their suppressed ordering temperatures and high magnetic moments. While much attention has been paid to the garnet and pyrochlore lattices, the magnetocaloric effect in frustrated face-centered cubic (fcc) lattices remains relatively unexplored. We previously showed that the frustrated fcc double perovskite Ba2GdSbO6 is a top-performing magnetocaloric material (per mol Gd) because of its small nearest-neighbor interaction between spins. Here we investigate different tuning parameters to maximize the magnetocaloric effect in the family of fcc lanthanide oxides, A2LnSbO6 (A = {Ba2+, Sr2+} and Ln = {Nd3+, Tb3+, Gd3+, Ho3+, Dy3+, Er3+}), including chemical pressure via the A site cation and the magnetic ground state via the lanthanide ion. Bulk magnetic measurements indicate a possible trend between magnetic short-range fluctuations and the field-temperature phase space of the magnetocaloric effect, determined by whether an ion is a Kramers or a non-Kramers ion. We report for the first time on the synthesis and magnetic characterization of the Ca2LnSbO6 series with tunable site disorder that can be used to control the deviations from Curie-Weiss behavior. Taken together, these results suggest fcc lanthanide oxides as tunable systems for magnetocaloric design.

Attachment-focused iMAgery therapy for PSychosis (A-iMAPS): A case series targeting psychosis-related trauma.

OBJECTIVES: The experience of psychosis and its sequelae (including treatment experiences) can be traumatic and affect feelings of safety and security. Until relatively recently, trauma therapy has been avoided with psychosis populations due to concerns about additional harm. Intervention-based research is growing, but focus on psychosis-related trauma is limited. Engendering psychological safety may support engagement with trauma-focused therapy, for which attachment theory provides a strong foundation. Imagery can enhance felt security and is an effective modality for working with trauma. Therefore, this study aimed to examine feasibility and preliminary outcomes of a novel attachment-focused imagery therapy (A-iMAPS) addressing psychosis-related trauma. METHODS: A multiple baseline case series: Participants received between two and five baseline assessments then engaged in the six-session A-iMAPS intervention. Participants completed weekly measures of trauma symptoms and felt security. Further measures were completed pre- and post-intervention. RESULTS: Twelve clinical participants were recruited from NHS services in Northwest England and eight retained through baseline and intervention to the end-of-therapy assessment (attending all sessions). A significant improvement was seen for felt security between baseline and intervention phases. Other measures of trauma symptoms, core schemas, paranoia and attachment varied in change from baseline to end of therapy, but some promising preliminary results were seen. CONCLUSIONS: This study shows that a brief attachment-focused imagery therapy is a promising intervention for targeting psychosis-related trauma, for which there are currently no other specific intervention studies. Utilizing an attachment-informed framework when working with trauma in psychosis should be considered in future intervention studies.