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Abstract Background The use of surveillance technologies is becoming increasingly common in inpatient mental health settings, commonly justified as efforts to improve safety and cost-effectiveness. However, their use has been questioned in light of limited research conducted and the sensitivities, ethical concerns and potential harms of surveillance. This systematic review aims to (1) map how surveillance technologies have been employed in inpatient mental health settings, (2) explore how they are experienced by patients, staff and carers and (3) examine evidence regarding their impact. Methods We searched five academic databases (Embase, MEDLINE, PsycInfo, PubMed and Scopus), one grey literature database (HMIC) and two pre-print servers (medRxiv and PsyArXiv) to identify relevant papers published up to 19/09/2024. We also conducted backwards and forwards citation tracking and contacted experts to identify relevant literature. The Mixed Methods Appraisal Tool assessed quality. Data were synthesised narratively. Results Thirty-two studies met the inclusion criteria. They reported on CCTV/video monitoring (n = 13), Vision-Based Patient Monitoring and Management (n = 9), body-worn cameras (n = 6), GPS electronic monitoring (n = 2) and wearable sensors (n = 2). Sixteen papers (50.0%) were low quality, five (15.6%) medium quality and eleven (34.4%) high quality. Nine studies (28.1%) declared a conflict of interest. Qualitative findings indicate patient, staff and carer views of surveillance technologies are mixed and complex. Quantitative findings regarding the impact of surveillance on outcomes such as self-harm, violence, aggression, care quality and cost-effectiveness were inconsistent or weak. Conclusions There is currently insufficient evidence to suggest that surveillance technologies in inpatient mental health settings are achieving their intended outcomes, such as improving safety and reducing costs. The studies were generally of low methodological quality, lacked lived experience involvement, and a substantial proportion (28.1%) declared conflicts of interest. Further independent coproduced research is needed to more comprehensively evaluate the impact of surveillance technologies in inpatient settings. If they are to be implemented, all key stakeholders should be engaged in the development of policies, procedures and best practice guidance to regulate their use, prioritising patients’ perspectives.

Abstract This research explores the development and evaluation of breakfast cereals formulated from pearl millet (P-1) and finger millet (F-1) flours, with a focus on their nutritional composition and potential anti-obesity properties. The techno-functional properties were assessed, revealing that P-1 exhibited a bulk density of 0.40 ± 0.01 g/ml and a true density of 0.61 ± 0.03 g/ml, while F-1 showed a bulk density of 0.54 ± 0.03 g/ml and a true density of 0.65 ± 0.02 g/ml. The Carr index and Hausner ratio were significantly higher in P-1 (40.33 ± 0.41 and 1.68 ± 0.03, respectively) compared to F-1 (22.3 ± 0.3 and 1.31 ± 0.02, respectively). Both flours demonstrated comparable water absorption indices, but P-1 had superior foaming capacity and stability. Nutritional analysis indicated that P-1 contained 12.64% moisture, 6.02% fat, 10.29% protein, 63.94% carbohydrates, 2.38% ash, and 2.75% fibre, whereas F-1 had 8.92% moisture, 1.78% fat, 8.65% protein, 73.65% carbohydrates, 1.77% ash, and 4.04% fibre. Composite flours (PF-1, PF-2, PF-3) exhibited varying compositions: PF-1 had 9.86% moisture, 5.83% fat, 11.62% protein, 66.04% carbohydrates, 2.19% ash, and 3.03% fibre; PF-2 had 10.79% moisture, 3.87% fat, 10.01% protein, 68.97% carbohydrates, 2.05% ash, and 3.37% fibre; PF-3 had 9.87% moisture, 2.84% fat, 9.33% protein, 71.12% carbohydrates, 1.92% ash, and 3.74% Fiber. Antioxidant activity was higher in F-1 (80.63%) compared to P-1 (59.58%), with PF-1, PF-2, and PF-3 showing 64.84%, 70.14%, and 75.4%, respectively. Lipase and amylase inhibition capacities were 73.15% and 28.66% for P-1, 28.31% and 30.65% for F-1, and varied for composites: PF-1 (79.12% lipase, 46.41% amylase), PF-2 (50.75% lipase, 53.15% amylase), and PF-3 (39.51% lipase, 41.84% amylase). These findings underscore the distinct nutritional and functional properties of these flours, highlighting their potential in obesity management.

Abstract MYCN-amplified RB1 wild-type (MYCN amp RB1 +/+) retinoblastoma is a rare and aggressive subtype, often resistant to standard therapies. Identifying unique MRI features is crucial for diagnosing this subtype, as biopsy is not recommended. This study aimed to differentiate MYCN amp RB1 +/+ from the most prevalent RB1 -/- retinoblastoma using pretreatment MRI and radiomics. Ninety-eight unilateral retinoblastoma patients (19 MYCN cases and 79 matched controls) were included. Tumors on T2-weighted MR images were manually delineated and validated by experienced radiologists. Radiomics analysis extracted 120 features per tumor. Several combinations of feature selection methods, oversampling techniques and machine learning (ML) classifiers were evaluated in a repeated fivefold cross-validation machine learning pipeline to yield the best-performing prediction model for MYCN. The best model used univariate feature selection, data oversampling (duplicating MYCN cases), and logistic regression classifier, achieving a mean AUC of 0.78 (SD 0.12). SHAP analysis highlighted lower sphericity, higher flatness, and greater gray-level heterogeneity as predictive for MYCN amp RB1 +/+ status, yielding an AUC of 0.81 (SD 0.11). This study shows the potential of MRI-based radiomics to distinguish MYCN amp RB1 +/+ and RB1 -/- retinoblastoma subtypes.

Abstract Evidence suggests that maternal metabolome may be associated with child health outcomes. We analyzed the association between the maternal metabolome between 28–35 gestational weeks and child growth and development during the first year. A prospective cohort of 98 mother–child dyads was followed at birth, 1, 6, and 12 months. Maternal serum samples were collected for targeted LC–MS/MS analysis, which measured 132 metabolites. The child's growth and development were assessed at each time-point. Z-scores were calculated based on WHO growth standards, and the domains of development were assessed using the Ages and Stages Questionnaires (ASQ-3). Multiple linear mixed-effects models were performed and confounders were identified using a Diagram Acyclic Graph. The Benjamini–Hochberg correction was used for multiple comparison adjustments. We found a positive association between lysophosphatidylcholines (14:0; 16:0; 16:1; 17:0; 18:0; 18:1; 18:2; 20:4) with the z-score of weight-for-age, and lysophosphatidylcholines (14:0; 16:0; 16:1; 18:0) and taurine with the z-score of weight-for-length, and lysophosphatidylcholines (14:0; 16:0; 16:1; 17:0; 18:0; 18:1; 18:2; 20:4) and glycine with the z-score of BMI-for-age. The leucine, methionine, tryptophan, and valine were negatively associated with the fine motor skills domain. We observed an association between maternal metabolome and the growth and child's development throughout the first year.

Abstract Plant-based diets have gained attention for their potential benefits on both human health and environmental sustainability. The objective of this study was to investigate the association of plant-based dietary patterns with the endogenous metabolites of healthy individuals and identify metabolites that may act as mediators of the associations between dietary intake and modifiable disease risk factors. Adherence to plant-based dietary patterns was assessed for 170 healthy adults using plant-based diet indexes (PDI). Individuals with higher healthful PDI had lower BMI and fasting glucose and higher HDL-C, while those with higher unhealthful PDI had higher BMI, triacylglycerol and fasting glucose and lower HDL-C. Unhealthful PDI was associated with higher levels of several amino acids and biogenic amines previously associated with cardiometabolic diseases and an opposite pattern was observed for healthful PDI. Furthermore, healthful PDI was associated with higher levels of glycerophosphocholines containing very long-chain fatty acids. Glutamate, isoleucine, proline, tyrosine, α-aminoadipate and kynurenine had a statistically significant mediation effect on the associations between PDI scores and LDL-C, HDL-C and fasting glucose. These findings contribute to the growing evidence supporting the role of plant-based diets in promoting metabolic health and shed light on the potential mechanisms explaining their beneficial health effects.

Abstract Immunological adaptions during pregnancy play a crucial role in healthy fetal development. Aberrant immune modifications however contribute to adverse pregnancy outcomes, which may be driven by maternal factors such as previous pregnancies and BMI. This secondary analysis of the MicrobeMom2 RCT investigates the changes to maternal inflammatory biomarkers derived from serum and stimulated peripheral blood mononuclear cells (PBMCs) during pregnancy, and the effects of previous pregnancies (parity) and BMI on maternal immune responses. Changes in immune and metabolic biomarkers from early (11–15 weeks’ gestation) to late (28–32 weeks’ gestation) pregnancy were compared using paired t-tests. Participants were then split by parity (nulliparous, parous) and BMI (BMI = 25), and the relationship between parity and BMI with immune biomarker levels was examined using independent t-tests, paired t-tests, ANCOVA, and linear regression. Equivalent non-parametric tests were used for skewed data. Recruited women (n = 72) were on average 31.17 (SD ± 4.53) years of age and 25.11 (SD ± 3.82) BMI (kg/m2). Of these, 51 (70.8%) had a previous term pregnancy. Throughout gestation, PBMC cytokines displayed contrasting trends to serum, with a dampening of immune responses noted in PBMCs, and enhanced production of cytokines observed in the serum. Significant decreases in PBMC derived TNF-α, IL-10 and IFN-γ were seen from early to late pregnancy. Serum C3, IL-17A, IL-6, TNF-α, CD163, GDF-15 and leptin increased throughout gestation. First pregnancy was associated with higher levels of leptin in late pregnancy, while parous women showed significant decreases in PBMC derived TNF-α, IL10, and IFN-γ with gestation. Differences in levels of C3, IL-17A, TNF-α, GDF-15 and leptin were observed across BMI groups. Overall, serum-derived cytokines exhibit contrasting levels to those derived from stimulated PBMCs. Maternal immune responses undergo significant changes from early to late pregnancy, which are influenced by parity and BMI. These differences aid our understanding as to why first-time mothers are at greater risk of placental disease such as pre-eclampsia and fetal growth restriction.

Abstract Background Hypoglycaemia is the primary manifestation of all the hepatic types of glycogen storage disease (GSD). In 2008, Glycosade®, an extended-release waxy maize cornstarch, was reported as an alternative to uncooked cornstarch (UCCS) which could prolong the duration of fasting in the GSD population. To date, there has been minimal published experience in (a) young children, (b) the ketotic forms of GSD, and (c) with daytime dosing. The Glyde study was created as a prospective, global initiative to test the efficacy and tolerance of Glycosade use across a broader and more diverse population. Methods A randomised double-blind cross-over fasting study assessing the tolerance and efficacy of Glycosade compared with cornstarch was performed across disease types and ages. Participants and clinicians chose the product deemed superior, whilst still blinded. Participants were followed for 2 years to assess long-term metabolic control, growth, and quality of life. Results Sixty-one participants (age 2–62 years; 59% female) were enrolled, and 58 participants completed the fasting studies (28 GSD I; 30 GSD III, VI, IX). Glycosade improved duration of fasting in GSD I and duration of fasting without ketosis in the ketotic forms. Chronic Glycosade use was chosen by 69% of participants. Those treated with Glycosade for the 2-year chronic phase used fewer doses of therapy while markers of metabolic control remained stable. Conclusion The Glyde study is the first multi-centre international trial demonstrating the efficacy and tolerance of Glycosade in a large cohort of hepatic GSD patients across a diverse international population. The ability to use fewer doses of therapy per day and avoidance of overnight therapy may improve compliance, safety, and quality of life without sacrificing metabolic control.

AbstractPeople living with HIV (PLWH) who use drugs are hospitalized at higher rates than the general population and report receiving poor care during hospitalization. The patient experience of PLWH during hospitalization is influenced by the clinical practice of healthcare providers (HPs). However, there is a gap in the literature that articulates the perspectives of HPs who deliver care to this population. Semi-structured interviews were conducted with HPs on in-patient hospital units in Toronto and Ottawa, Canada. Structuration-theory-informed thematic analysis was used to explore the beliefs and rules identified and utilized by HPs that affect healthcare delivery during the hospital stay of PLWH who use drugs. Interviews were audio-recorded and transcribed verbatim. The participants included 26 hospital-based HPs (i.e. Physicians, Registered Nurses, Social Workers, Pharmacists, Dietician, and Nurse Practitioner) who deliver healthcare services to people who are living with HIV and who use drugs during the hospital admission. Most HPs stated that no explicit hospital rules exist to guide their clinical practice when engaging with people who use drugs and many indicate that providing care to this population is beyond their scope of practice. The lack of explicit rules results in implicit rules and actions that may negatively impact the delivery of equitable healthcare for PLWH who use drugs.

Addiction is commonly characterized by escalation of drug intake, compulsive drug seeking, and continued use despite harmful consequences. However, the factors contributing to the transition from moderate drug use to these problematic patterns remain unclear, particularly regarding the role of sex. Many preclinical studies have been limited by small sample sizes, low genetic diversity, and restricted drug access, making it challenging to model significant levels of intoxication or dependence and translate findings to humans. To address these limitations, we characterized addiction-like behaviors in a large sample of >500 outbred heterogeneous stock (HS) rats using an extended cocaine self-administration paradigm (6 hr/daily). We analyzed individual differences in escalation of intake, progressive ratio (PR) responding, continued use despite adverse consequences (contingent foot shocks), and irritability-like behavior during withdrawal. Principal component analysis showed that escalation of intake, progressive ratio responding, and continued use despite adverse consequences loaded onto a single factor that was distinct from irritability-like behaviors. Categorizing rats into resilient, mild, moderate, and severe addiction-like phenotypes showed that females exhibited higher addiction-like behaviors, with a lower proportion of resilient individuals compared to males. These findings suggest that, in genetically diverse rats with extended drug access, escalation of intake, continued use despite adverse consequences, and PR responding are highly correlated measures of a shared underlying construct. Furthermore, our results highlight sex differences in resilience to addiction-like behaviors.

We present a genome assembly from an individual Scomber scombrus (the Atlantic mackerel; Chordata; Actinopteri; Scombriformes; Scombridae). The genome sequence has a total length of 764.10 megabases. Most of the assembly is scaffolded into 24 chromosomal pseudomolecules. The mitochondrial genome has also been assembled and is 16.56 kilobases in length.

Objective To identify the types of conditions reported in peer-reviewed literature that result in chronic musculoskeletal lower limb pain in children and adolescents and explore the alignment of these conditions with the chronic pain reporting codes indexed in the International Classification of Diseases 11th Revision (ICD-11).Design This scoping review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.Data sources Five electronic databases were searched (Medline, EMBASE, PsycINFO, CINAHL and the Cochrane Library).Eligibility criteria Articles involving children and adolescents under 18 years and reporting on chronic musculoskeletal pain of the lower limb were included.Data extraction and synthesis We assigned an ICD-11 code to each condition based on details reported in the study. We recorded whether any of the presenting conditions were linked to an ICD-11 chronic pain manifestation code.Results From 12 343 records, 418 papers were included. There were 124 unique conditions associated with chronic lower limb pain, the most commonly reported being chronic widespread musculoskeletal pain (24 studies) and juvenile idiopathic arthritis (26 studies). Only 11.1% of presenting conditions were linked to an ICD-11 chronic pain manifestation code.Conclusion Most presenting conditions associated with chronic pain in the lower limb do not have a chronic pain manifestation code in the new global standard for recording health information. This means chronic pain associated with common lower limb conditions may remain invisible in global statistics.

Purpose Despite the volume of accumulating knowledge from prospective Aboriginal cohort studies, longitudinal data describing developmental trajectories in health and well-being is limited. The linkage of child and carer cohorts from a historical cross-sectional survey with longitudinal health-service and social-service administrative data has created a unique and powerful data resource that underpins the Western Australian Aboriginal Child Health Survey (WAACHS) linked data study. This study aims to provide evidence-based information to Aboriginal communities across Western Australia, governments and non-government agencies on the heterogeneous life trajectories of Aboriginal children and families.Participants This study comprises data from a historical cross-sectional household study of 5289 Aboriginal children from the WAACHS (2000–2002) alongside their primary (N=2113) and other (N=1040) carers, and other householders. WAACHS data were linked with Western Australia (WA) government administrative datasets up to 2020 including health, education, child protection, police and justice system contacts. The study also includes two non-Aboriginal cohorts from WA, linked with the same administrative data sources allowing comparisons of outcomes across cohorts in addition to between-group comparisons within the Aboriginal population.Findings to date Linked data coverage rates are presented for all WAACHS participants. Child health outcomes for the WAACHS children (Cohort 1) are described from birth into adulthood along with other outcomes including child protection and juvenile justice involvement.Future plans Analysis of data from both the child and carer cohorts will seek to understand the contribution of individual, family (intergenerational) and community-level influences on Aboriginal children’s developmental and health pathways, identify key developmental transitions or turning points where interventions may be most effective in improving outcomes, and compare service pathways for Aboriginal and non-Aboriginal children. All research is guided by Aboriginal governance processes and study outputs will be produced with Aboriginal leadership to guide culturally appropriate policy and practice for improving health, education and social outcomes.

Abstract Background Hereditary angioedema (HAE) is characterized by unpredictable and often severe cutaneous and mucosal swelling that affects the extremities, face, larynx, gastrointestinal tract, or genitourinary area. Introduction of novel long-term prophylactic treatment options (lanadelumab, berotralstat, and C1-esterase inhibitor SC [human]) into the treatment armamentarium has substantially reduced HAE attacks, allowing patients to be attack free for longer with improvements to their quality of life. Using data drawn from a wide-ranging survey of patients with HAE, we examined the relationship between duration of time attack free and health-related quality of life (HRQoL), exploring the possibility that there is an association between observed improvement in HRQoL and attack-free duration. Methods A survey among patients with HAE on long-term prophylaxis (LTP) in six countries (the US, Australia, Canada, UK, Germany, and Japan) assessed the relationship between attack-free duration and mean Angioedema Quality of Life (AE-QoL) scores, quality of life benefits, and rescue medication used. Analysis of covariance (ANCOVA) was used to assess the roles of LTP and attack-free period (

Abstract Health care workers have been exposed to COVID-19 more than people in other professions, which may have led to stigmatization, discrimination, and violence toward them, possibly impacting their mental health. We investigated (1) factors associated with stigma, discrimination, and violence, (2) the association of stigma, discrimination, and violence with mental health, (3) everyday experiences of stigmatization, discrimination, and violence. We chose a combination of a quantitative approach and qualitative content analysis to analyze data collected at three time points: in 2020, 2021 and 2022. A higher age was associated with lower odds of experiencing stigma, discrimination, and violence, whereas female gender was related to more negative experiences. The intensity of exposure to COVID-19 was associated with greater experience with stigmatization, discrimination, and violence across all three years (for example in 2022: odds ratio, 95% confidence interval: 1.74, 1.18–2.55 for mild exposure; 2.82, 1.95–4.09 for moderate exposure; and 5.74, 3.55–9.26 for severe exposure, when compared to no exposure). Stigma, discrimination, and violence were most strongly associated with psychological distress in 2020 (odds ratio = 2.97, 95% confidence interval 2.27–3.88) and with depressive symptoms in 2021 (odds ratio = 2.78, 95% confidence interval 2.12–3.64). Attention should be given to the destigmatization of contagious diseases and the prevention of discrimination, violence, and mental health problems, both within workplaces and among the public.

Several metabolites have been shown to have independent and at times unexpected biological effects outside of their metabolic pathways. These include succinate, lactate, fumarate, and 2-hydroxyglutarate. 2-Hydroxybutyrate (2HB) is a byproduct of endogenous cysteine synthesis, produced during periods of cellular stress. 2HB rises acutely after exercise; it also rises during infection and is also chronically increased in a number of metabolic disorders. We show here that 2HB inhibits branched-chain aminotransferase enzymes, which in turn triggers a SIRT4-dependent shift in the compartmental abundance of protein ADP-ribosylation. The 2HB-induced decrease in nuclear protein ADP-ribosylation leads to a C/EBPβ-mediated transcriptional response in the branched-chain amino acid degradation pathway. This response to 2HB exposure leads to an improved oxidative capacity in vitro. We found that repeated injection with 2HB can replicate the improvement to oxidative capacity that occurs following exercise training. Together, we show that 2-HB regulates fundamental aspects of skeletal muscle metabolism.

Background Respiratory syncytial virus (RSV) bronchiolitis contributes to a large morbidity and mortality burden globally. While emerging evidence suggests that airway microRNA (miRNA) is involved in the pathobiology of RSV infection, its role in the disease severity remains unclear.Methods In this multicentre prospective study of infants (aged

Objective: To determine if librarian collaboration was associated with improved database search quality, search reproducibility, and systematic review reporting in otolaryngology systematic reviews and meta-analyses. Methods: In this retrospective cross-sectional study, PubMed was queried for systematic reviews and meta-analyses published in otolaryngology journals in 2010, 2015, and 2021. Two researchers independently extracted data. Two librarians independently rated search strategy reproducibility and quality for each article. The main outcomes include association of librarian involvement with study reporting quality, search quality, and publication metrics in otolaryngology systematic reviews and meta-analyses. Categorical data were compared with Chi-Squared tests or Fisher’s Exact tests. Continuous variables were compared via Mann Whitney U Tests for two groups, and Kruskal-Wallis Tests for three or more groups. Results: Of 559 articles retrieved, 505 were analyzed. More studies indicated librarian involvement in 2021 (n=72, 20.7%) compared to 2015 (n=14, 10.4%) and 2010 (n=2, 9.0%) (p=0.04). 2021 studies showed improvements in properly using a reporting tool (p

Objective Optic neuritis (ON) is an acute focal inflammation of the optic nerve routinely treated with glucocorticoids. We aimed to compare adverse events (AE) among glucocorticoid-treated and untreated patients in the real world to guide clinical decision making about treatment tradeoffs.Design Retrospective, longitudinal cohort study.Setting Claims study from a large, private insurer in the USA (2005–2019).Participants Adults≥18 years old with ≥1 ICD9/10 ON diagnosis with an evaluation/management visit code, and ≥6 months continuous enrolment prior to and following ON diagnosis.Intervention Glucocorticoid prescription exposure.Primary and secondary outcome measures Primary outcome was any AE within 90 days of glucocorticoid prescription. Secondary outcome was AE assessment by severity. Generalised estimating equations with logit link assessed relationships between glucocorticoid prescription and AEs. High-dimensional propensity score analyses accounted for potential confounding (eg, sociodemographics and comorbidities). Sensitivity analyses restricted the cohort to high-dose prescriptions (≥100 mg prednisone equivalent, injection/infusion), AEs within 30 days, highly specific ON definition and traditional propensity score match.Results Of the 14 311 people with 17 404 ON claims, 66.3% were women (n=9481), predominantly White (78.2%; n=9940), with median age (IQR)=48 (37,60) years. Within 90 days of the claim, 15.7% (n=2733/17 404) were prescribed glucocorticoids. The median (IQR) prescription duration=10 (6,20) days. Any and severe AEs were higher among patients prescribed glucocorticoids versus none (any AEs: n=437/2733 (16.0%) vs n=1784/14 671 (12.2%), adjusted OR 1.33 (95% CI: 1.18 to 1.50); severe AEs: n=72/2733 (2.6%) vs n=273/14 671 (1.9%), adjusted OR 1.82 (95% CI: 1.37 to 2.35)). Sensitivity analyses were similar.Conclusions Real-world glucocorticoid prescriptions among ON patients were short-term, associated with a 30% relative increase in potentially serious AEs captured within healthcare encounters, including those not previously observed, such as VTE. These results can inform treatment decisions, particularly for ON patients likely to experience only marginal benefits.

Abstract The aim of this study was to investigate the ability of shell (coating) formulations comprised of alginate and glucono delta lactone (GDL) to encapsulate a mixture of green tea and turmeric extracts. Three concentrations of alginate and GDL were used at 0.5%, 0.75%, and 1%, w/v and their solid ratio was varied using a factorial design. A response surface model was applied to optimize the retention of catechin and curcuminoid contents, to determine encapsulation efficiency, and to minimize undesirable flavor and taste. Increasing the concentration of alginate and GDL significantly increased the retention of catechin and curcuminoid contents, encapsulation efficiency, and consumer acceptance (p

Abstract Pathogenic loss-of-function variants in BGN, an X-linked gene encoding biglycan, are associated with Meester-Loeys syndrome (MRLS), a thoracic aortic aneurysm/dissection syndrome. Since the initial publication of five probands in 2017, we have considerably expanded our MRLS cohort to a total of 18 probands (16 males and 2 females). Segregation analyses identified 36 additional BGN variant-harboring family members (9 males and 27 females). The identified BGN variants were shown to lead to loss-of-function by cDNA and Western Blot analyses of skin fibroblasts or were strongly predicted to lead to loss-of-function based on the nature of the variant. No (likely) pathogenic missense variants without additional (predicted) splice effects were identified. Interestingly, a male proband with a deletion spanning the coding sequence of BGN and the 5’ untranslated region of the downstream gene (ATP2B3) presented with a more severe skeletal phenotype. This may possibly be explained by expressional activation of the downstream ATPase ATP2B3 (normally repressed in skin fibroblasts) driven by the remnant BGN promotor. This study highlights that aneurysms and dissections in MRLS extend beyond the thoracic aorta, affecting the entire arterial tree, and cardiovascular symptoms may coincide with non-specific connective tissue features. Furthermore, the clinical presentation is more severe and penetrant in males compared to females. Extensive analysis at RNA, cDNA, and/or protein level is recommended to prove a loss-of-function effect before determining the pathogenicity of identified BGN missense and non-canonical splice variants. In conclusion, distinct mechanisms may underlie the wide phenotypic spectrum of MRLS patients carrying loss-of-function variants in BGN.

Abstract Background Although polygenic risk score (PRS) has emerged as a promising tool for predicting cancer risk from genome-wide association studies (GWAS), the individual-level accuracy of lung cancer PRS and the extent to which its impact on subsequent clinical applications remains largely unexplored. Methods Lung cancer PRSs and confidence/credible interval (CI) were constructed using two statistical approaches for each individual: (1) the weighted sum of 16 GWAS-derived significant SNP loci and the CI through the bootstrapping method (PRS-16-CV) and (2) LDpred2 and the CI through posteriors sampling (PRS-Bayes), among 17,166 lung cancer cases and 12,894 controls with European ancestry from the International Lung Cancer Consortium. Individuals were classified into different genetic risk subgroups based on the relationship between their own PRS mean/PRS CI and the population level threshold. Results Considerable variances in PRS point estimates at the individual level were observed for both methods, with an average standard deviation (s.d.) of 0.12 for PRS-16-CV and a much larger s.d. of 0.88 for PRS-Bayes. Using PRS-16-CV, only 25.0% of individuals with PRS point estimates in the lowest decile of PRS and 16.8% in the highest decile have their entire 95% CI fully contained in the lowest and highest decile, respectively, while PRS-Bayes was unable to find any eligible individuals. Only 19% of the individuals were concordantly identified as having high genetic risk (> 90th percentile) using the two PRS estimators. An increased relative risk of lung cancer comparing the highest PRS percentile to the lowest was observed when taking the CI into account (OR = 2.73, 95% CI: 2.12–3.50, P-value = 4.13 × 10−15) compared to using PRS-16-CV mean (OR = 2.23, 95% CI: 1.99–2.49, P-value = 5.70 × 10−46). Improved risk prediction performance with higher AUC was consistently observed in individuals identified by PRS-16-CV CI, and the best performance was achieved by incorporating age, gender, and detailed smoking pack-years (AUC: 0.73, 95% CI = 0.72–0.74). Conclusions Lung cancer PRS estimates using different methods have modest correlations at the individual level, highlighting the importance of considering individual-level uncertainty when evaluating the practical utility of PRS.

Abstract Background Addressing childhood stunting is a priority and an important step in the attainment of Global Nutrition Targets for 2025 and Sustainable Development Goals (SDGs). In Rwanda, the prevalence of child stunting remains high despite concerted efforts to reduce it. Methods Utilizing the United Nations International Children’s Emergency Fund (UNICEF) framework on maternal and child nutrition, this study systematically evaluated the determinants of child stunting in Rwanda and identified available gaps. Twenty-five peer-reviewed papers and five Demographic and Health Surveys (DHS) reports were included in the final selection of our review, which allowed us to identify determinants such as governance and norms including wealth index, marital status, and maternal education, while underlying determinants were maternal health and nutrition factors, early initiation of breastfeeding, water treatment and sanitation, and immediate factors included infections. Results A total of 75% of the overall inequality in stunting was due to the difference in the social determinants of stunting between poor and nonpoor households. Maternal education (17%) and intergenerational transfer (31%) accounted for most of the inequalities in stunting, and an increase in gross domestic product per capita contributed to a reduction in its prevalence. There is a paucity of information on the impact of sociocultural norms, early life exposures, maternal health and nutrition, and Rwandan topography. Conclusion The findings of this study suggest that improving women’s status, particularly maternal education and health; access to improved water, sanitation, and hygiene-related factors; and the socioeconomic status of communities, especially those in rural areas, will lay a sound foundation for reducing stunting among under-5 children.

Reviews of the disciplines of law, medicine, engineering, and math/science teaching in Australia examined five issues concerning continuing professional education: (1) importance; (2) purpose; (3) relationship to preservice training; (4) mandatory/voluntary options; and (5) delivery. (SK)

There is an increasing need for valid, rapid diet screening tools. A significant association between the Prime Diet Quality Score (PDQS) and reduced risk of cardiovascular disease (CVD) has been demonstrated in the US but evidence of its use in Europe is lacking. The aim of this study was to amend the PDQS for a UK/Irish population and determine validity and reliability in those at risk of CVD. Participants were recruited via online adverts across the island of Ireland. The PDQS was amended for a UK/Irish population and participants completed PDQS and reference measure (4-day food diary (FD)) on two occasions. PDQS score was calculated directly from PDQS and indirectly from FDs. Validity was determined using Spearman correlation coefficients (SCCs) (r), intraclass correlation coefficients (ICCs) and weighted kappa. Reliability was determined using SCCs (r), ICCs, weighted kappa and coefficient of variation.

Objective To estimate the cost-effectiveness of craniotomy, compared with decompressive craniectomy (DC) in UK patients undergoing evacuation of acute subdural haematoma (ASDH).Design Economic evaluation undertaken using health resource use and outcome data from the 12-month multicentre, pragmatic, parallel-group, randomised, Randomised Evaluation of Surgery with Craniectomy for Patients Undergoing Evacuation-ASDH trial.Setting UK secondary care.Participants 248 UK patients undergoing surgery for traumatic ASDH were randomised to craniotomy (N=126) or DC (N=122).Interventions Surgical evacuation via craniotomy (bone flap replaced) or DC (bone flap left out with a view to replace later: cranioplasty surgery).Main outcome measures In the base-case analysis, costs were estimated from a National Health Service and Personal Social Services perspective. Outcomes were assessed via the quality-adjusted life-years (QALY) derived from the EuroQoL 5-Dimension 5-Level questionnaire (cost-utility analysis) and the Extended Glasgow Outcome Scale (GOSE) (cost-effectiveness analysis). Multiple imputation and regression analyses were conducted to estimate the mean incremental cost and effect of craniotomy compared with DC. The most cost-effective option was selected, irrespective of the level of statistical significance as is argued by economists.Results In the cost-utility analysis, the mean incremental cost of craniotomy compared with DC was estimated to be −£5520 (95% CI −£18 060 to £7020) with a mean QALY gain of 0.093 (95% CI 0.029 to 0.156). In the cost-effectiveness analysis, the mean incremental cost was estimated to be −£4536 (95% CI −£17 374 to £8301) with an OR of 1.682 (95% CI 0.995 to 2.842) for a favourable outcome on the GOSE.Conclusions In a UK population with traumatic ASDH, craniotomy was estimated to be cost-effective compared with DC: craniotomy was estimated to have a lower mean cost, higher mean QALY gain and higher probability of a more favourable outcome on the GOSE (though not all estimated differences between the two approaches were statistically significant).Ethics Ethical approval for the trial was obtained from the North West—Haydock Research Ethics Committee in the UK on 17 July 2014 (14/NW/1076).Trial registration number ISRCTN87370545.

BackgroundIn Australian remote communities, First Nations children with otitis media (OM)-related hearing loss are disproportionately at risk of developmental delay and poor school performance, compared to those with normal hearing. Our objective was to compare OM-related hearing loss in children randomised to one of 2 pneumococcal conjugate vaccine (PCV) formulations.Methods and findingsIn 2 sequential parallel, open-label, randomised controlled trials (the PREVIX trials), eligible infants were first allocated 1:1:1 at age 28 to 38 days to standard or mixed PCV schedules, then at age 12 months to PCV13 (13-valent pneumococcal conjugate vaccine, +P) or PHiD-CV10 (10-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine, +S) (1:1). Here, we report prevalence and level of hearing loss outcomes in the +P and +S groups at 6-monthly scheduled assessments from age 12 to 36 months. From March 2013 to September 2018, 261 infants were enrolled and 461 hearing assessments were performed. Prevalence of hearing loss was 78% (25/32) in the +P group and 71% (20/28) in the +S group at baseline, declining to 52% (28/54) in the +P groups and 56% (33/59) in the +S group at age 36 months. At primary endpoint age 18 months, prevalence of moderate (disabling) hearing loss was 21% (9/42) in the +P group and 41% (20/49) in the +S group (difference -19%; (95% confidence interval (CI) [-38, -1], p = 0.07) and prevalence of no hearing loss was 36% (15/42) in the +P group and 16% (8/49) in the +S group (difference 19%; (95% CI [2, 37], p = 0.05). At subsequent time points, prevalence of moderate hearing loss remained lower in the +P group: differences -3%; (95% CI [-23, 18], p = 1.00 at age 24 months), -12%; (95% CI [-30, 6], p = 0.29 at age 30 months), and -9%; (95% CI [-23, 5], p = 0.25 at age 36 months). A major limitation was the small sample size, hence low power to reach statistical significance, thereby reducing confidence in the effect size.ConclusionsIn this study, we observed a high prevalence and persistence of moderate (disabling) hearing loss throughout early childhood. We found a lower prevalence of moderate hearing loss and correspondingly higher prevalence of no hearing loss in the +P group, which may have substantial benefits for high-risk children, their families, and society, but warrant further investigation.Trial registrationClinicalTrials.gov NCT01735084 and NCT01174849.

Objectives It is important that allied health professionals (AHPs) are prepared for clinical practice from the very start of their working lives to provide quality care for patients, for their personal well-being and for retention of the workforce. The aim of this study was to understand how well newly qualified AHPs were prepared for practice in the UK.Design Systematic review.Data sources Embase, MEDLINE, CINAHL, ERIC and BEI were searched from 2012 to 2024. Grey literature searching and citation chasing were also conducted.Eligibility criteria We included primary studies reporting the preparedness for practice of UK graduates across 15 professions; all study types; participants included graduates who were up to 2 years postgraduation, their supervisors, trainers, practice educators and employers; and all outcome measures.Data extraction and synthesis A standardised data extraction form was used. Studies were quality assessed using the Quality Appraisal for Diverse Studies tool. 10% of articles were independently double-screened, extracted and quality assessed; 90% was completed by one researcher.Results 14 reports were included (9 qualitative, 3 mixed-method and 2 quantitative). Six papers focused on radiographers, three on a mixture of professions, two on paramedics, and one each on physiotherapists, clinical psychologists and orthotists. An important finding of the review is the paucity and low-medium quality of research on the topic. The narrative synthesis tentatively suggests that graduates are adequately prepared for practice with different professions having different strengths and weaknesses. Common areas of underpreparedness across the professions were responsibility and decision-making, leadership and research. Graduates were generally well prepared in terms of their knowledge base.Conclusion High-quality in-depth research is urgently needed across AHPs to elucidate the specific roles, their nuances and the areas of underpreparedness. Further work is also needed to understand the transition into early clinical practice, ongoing learning opportunities through work, and the supervision and support structures in place.PROSPERO registration number CRD42022382065.

Objectives This study aimed to understand how staff in children’s hospitals view their responsibility to reduce health inequalities for the children and young people who access their services.Design We conducted an exploratory qualitative study.Setting The study took place at nine children’s hospitals in England.Participants 217 members of staff contributed via interviews and focus groups conducted January–June 2023. Staff were represented at all levels of the organisations, and all staff who volunteered to contribute were included in the study.Analysis Data were analysed using Rapid Research Evaluation and Appraisal (RREAL) methodology for rapid assessment procedures (RAP).Results All of the children’s hospitals were taking some action to reduce health inequalities. Two key themes were identified. First, it was clear that reducing health inequalities was seen as something that was of vital import and should be part of staff’s day-to-day activity, framed as ‘everyone’s business.’ Many staff felt that there was an obligation to intervene to ensure that children and young people receiving hospital treatment were not further disadvantaged by, for example, food poverty. Second, however, the deeply entrenched and intersectional nature of health inequalities sometimes meant that these inequalities were complex to tackle, with no clear impetus to specific actions, and could be framed as ‘no-one’s responsibility’. Within a complex health and social care system, there were many potential actors who could take responsibility for reducing health inequalities, and staff often questioned whether it was the role of a children’s hospital to lead these initiatives.Conclusions Broadly speaking, senior leaders were clear about their organisational role in reducing health inequalities where they impacted on access and quality of care, but there was some uncertainty about the perceived boundaries of responsibility. This led to fragility in the sustainability of activity, and a lack of joined-up intervention. Most hospitals were forging ahead with activity, considering that it was more important to work to overcome health inequalities rather than debate whose job it was.

Current treatment of metabolic dysfunction-associated steatotic liver disease focuses on adjusting patients’ lifestyles, including promoting weight loss and physical activity. Here, we suggest adopting a holistic preventive hepatology approach encompassing social nutrition, social prescribing and broader societal changes to facilitate individuals’ engagement with behavioural modifications.

Purpose: Current guidelines recommend debriefing following medical resuscitations to improve patient outcomes. The goal of this study was to describe national trends in postresuscitation debriefing practices among pediatric critical care medicine (PCCM) fellows to identify potential gaps in fellow education. Methods: A 13-item survey was distributed to fellows in all 76 ACGME-accredited PCCM programs in the United States in the spring of 2021. The online survey addressed frequency and timing of debriefings following medical resuscitations, whether formal training is provided, which medical professionals are present, and providers’ comfort level leading a debriefing. Results were analyzed using descriptive statistics. Results: A total of 102 responses (out of a possible N of 536) were gathered from current PCCM fellows. All fellows (100%) reported participation in a medical resuscitation. Only 21% stated that debriefings occurred after every resuscitation event, and 44% did not follow a structured protocol for debriefing. While 66% reported feeling very or somewhat comfortable leading the debriefing, 19% felt either somewhat uncomfortable or very uncomfortable. A vast majority (92%) of participating fellows believed that debriefing would be helpful in improving team member performance during future resuscitations, and 92% expressed interest in learning more about debriefing. Conclusions: The majority of PCCM fellows do not receive formal training on how to lead a debriefing. Given that 74% of fellows in our study did not feel very comfortable leading a debriefing but almost universally expressed that this practice is useful for provider well-being and performance, there is a clear need for increased incorporation of debriefing training into PCCM curricula across the United States.

Abstract Despite broad interest, experimental evidence for gender differences in social abilities remains inconclusive. Two important factors may have limited previous results: (i) a lack of clear distinctions between empathy (sharing another's feelings), compassion (a feeling of concern toward others), and Theory of Mind (ToM; inferring others’ mental states), and (ii) the absence of robust, naturalistic social tasks. Overcoming these limitations, in Study 1 (N = 295) we integrate three independent, previously published datasets, each using a dynamic and situated, video-based paradigm which disentangles ToM, empathy, and compassion, to examine gender differences in social abilities. We observed greater empathy and compassion in women compared to men, but found no evidence that either gender performed better in ToM. In Study 2 (n = 226) we extend this paradigm to allow participants to engage in prosocial donations. Along with replicating the findings of Study 1, we also observed greater prosocial donations in women compared to men. Additionally, we discuss an exploratory, novel finding, namely that ToM performance is positively associated with prosocial donations in women, but not men. Overall, these results emphasize the importance of establishing experimental designs that incorporate dynamic, complex stimuli to better capture the social realities that men and women experience in their daily lives.

Abstract Background Elevated standardised mortality ratio of cardiovascular diseases (CVD) in patients with brain tumours may result from differences in the CVD incidences and cardiovascular risk factors. We compared the risk of CVD among patients with a primary malignant or non-malignant brain tumour to a matched general population cohort, accounting for other co-morbidities. Methods Using data from the Secured Anonymised Information Linkage (SAIL) Databank in Wales (United Kingdom), we identified all adults aged ≥ 18 years in the primary care database with first diagnosis of malignant or non-malignant brain tumour identified in the cancer registry in 2000–2014 and a matched cohort (case-to-control ratio 1:5) by age, sex and primary care provider from the general population without any cancer diagnosis. Outcomes included fatal and non-fatal major vascular events (stroke, ischaemic heart disease, aortic and peripheral vascular diseases) and venous thromboembolism (VTE). We used multivariable Cox models adjusted for clinical risk factors to compare risks, stratified by tumour behaviour (malignant or non-malignant) and follow-up period. Results There were 2869 and 3931 people diagnosed with malignant or non-malignant brain tumours, respectively, between 2000 and 2014 in Wales. They were matched to 33,785 controls. Within the first year of tumour diagnosis, malignant tumour was associated with a higher risk of VTE (hazard ratio [HR] 21.58, 95% confidence interval 16.12–28.88) and stroke (HR 3.32, 2.44–4.53). After the first year, the risks of VTE (HR 2.20, 1.52–3.18) and stroke (HR 1.45, 1.00–2.10) remained higher than controls. Patients with non-malignant tumours had higher risks of VTE (HR 3.72, 2.73–5.06), stroke (HR 4.06, 3.35–4.93) and aortic and peripheral arterial disease (HR 2.09, 1.26–3.48) within the first year of diagnosis compared with their controls. Conclusions The elevated CVD and VTE risks suggested risk reduction may be a strategy to improve life quality and survival in people with a brain tumour.

Abstract Background The prognosis for patients with head and neck cancer (HNC) is poor and has improved little in recent decades, partially due to lack of therapeutic options. To identify effective therapeutic targets, we sought to identify molecular pathways that drive metastasis and HNC progression, through large-scale systematic analyses of transcriptomic data. Methods We performed meta-analysis across 29 gene expression studies including 2074 primary HNC biopsies to identify genes and transcriptional pathways associated with survival and lymph node metastasis (LNM). To understand the biological roles of these genes in HNC, we identified their associated cancer pathways, as well as the cell types that express them within HNC tumor microenvironments, by integrating single-cell RNA-seq and bulk RNA-seq from sorted cell populations. Results Patient survival-associated genes were heterogenous and included drivers of diverse tumor biological processes: these included tumor-intrinsic processes such as epithelial dedifferentiation and epithelial to mesenchymal transition, as well as tumor microenvironmental factors such as T cell-mediated immunity and cancer-associated fibroblast activity. Unexpectedly, LNM-associated genes were almost universally associated with epithelial dedifferentiation within malignant cells. Genes negatively associated with LNM consisted of regulators of squamous epithelial differentiation that are expressed within well-differentiated malignant cells, while those positively associated with LNM represented cell cycle regulators that are normally repressed by the p53-DREAM pathway. These pro-LNM genes are overexpressed in proliferating malignant cells of TP53 mutated and HPV + ve HNCs and are strongly associated with stemness, suggesting that they represent markers of pre-metastatic cancer stem-like cells. LNM-associated genes are deregulated in high-grade oral precancerous lesions, and deregulated further in primary HNCs with advancing tumor grade and deregulated further still in lymph node metastases. Conclusions In HNC, patient survival is affected by multiple biological processes and is strongly influenced by the tumor immune and stromal microenvironments. In contrast, LNM appears to be driven primarily by malignant cell plasticity, characterized by epithelial dedifferentiation coupled with EMT-independent proliferation and stemness. Our findings postulate that LNM is initially caused by loss of p53-DREAM-mediated repression of cell cycle genes during early tumorigenesis.

Abstract Social support can mitigate the impact of distressing events. Such stress buffering elicits activity in many brain regions, but it remains unclear (1) whether this activity constitutes a stable brain signature, and (2) whether brain activity can predict buffering across people. Here, we developed a neural signature that predicted social buffering of negative emotion in response to real life stressors. During neuroimaging, participants (n = 95) responded to stressful autobiographical memories either naturally, or by imagining a conversation with a peer. Using supervised dimensionality reduction and machine learning techniques, we identified a spatio-temporal neural signature that distinguished between these two trials. Activation of this signature was associated with less negative affect across trials, and people who most activated the signature reported more supportive social connections and lower loneliness outside the lab. Together, this work provides a behaviorally relevant neurophysiological marker for social support that underlies stress buffering.

Abstract Background Incomplete reporting about what systematic reviewers did and what they found prevents users of the report from being able to fully interpret the findings and understand the limitations of the underlying evidence. Reporting guidelines such as the PRISMA statement and its extensions are designed to improve reporting. However, there are important inconsistencies across the various PRISMA reporting guidelines, which causes confusion and misinterpretation. Coupled with this, users might need to consult multiple guidelines to gain a full understanding of the guidance. Furthermore, the current passive strategy of implementing PRISMA has not fully brought about needed improvements in the completeness of systematic review reporting. Methods The PRISMATIC (‘PRISMA, Technology, and Implementation to enhance reporting Completeness’) project aims to use novel methods to enable more efficient and effective translation of PRISMA reporting guidelines into practice. We will establish a working group who will develop a unified PRISMA statement that harmonises content across the main PRISMA guideline and several of its extensions. We will then develop a web application that generates a reporting template and checklist customised to the characteristics and methods of a systematic review (‘PRISMA-Web app’) and conduct a randomised trial to evaluate its impact on authors’ reporting. We will also develop a web application that helps peer reviewers appraise systematic review manuscripts (‘PRISMA-Peer app’) and conduct a diagnostic accuracy study to evaluate its impact on peer reviewers’ detection of incomplete reporting. Discussion We anticipate the novel guidance and web-based apps developed throughout the project will substantively enhance the completeness of reporting of systematic reviews of health evidence, ultimately benefiting users who rely on systematic reviews to inform health care decision-making.

Background: The COVID-19 pandemic has exacerbated existing healthcare disparities among American Indian/Alaska Native (AI/AN) populations rooted in historical traumas and systemic marginalization. Methods: This study conducted at a single Indian Health Service (IHS) clinic in central Michigan evaluates two educational interventions for enhancing COVID-19 knowledge and attitudes in a sample AI/AN population. Utilizing a pre/post-intervention prospective study design, participants received either a video or infographic educational intervention, followed by a survey assessing their COVID-19 knowledge and attitudes. Results: The results indicate significant improvements in knowledge and attitudes post-intervention, with both modalities proving effective. However, specific factors such as gender, political affiliation, and place of residence influenced COVID-19 attitudes and knowledge, emphasizing the importance of tailored interventions. Conclusions: Despite limitations, this study highlights the critical role of educational interventions in addressing vaccine hesitancy and promoting health equity within AI/AN communities. Moving forward, comprehensive strategies involving increased Indian Health Service funding, culturally relevant interventions, and policy advocacy are crucial in mitigating healthcare disparities and promoting health equity within AI/AN communities.

Abstract The continuous growth of annual production and consumption of polyethylene terephthalate (PET) is coined with increasing waste that leaks into the environment, landfills and oceans as microplastics and nano plastics fragments. Upcycling the recycled PET to make a feedstock for the fast-growing material-extrusion additive manufacturing (MEX-AM) technology can contribute to the solution and supports the concept of sustainable materials. In this work, extrudable filaments comprising recycled polyethylene terephthalate (rPET) with low-cost additives, such as pyromellitic dianhydride (PMDA) as a chain extender, styrene-ethylene-butylene-styrene terpolymer functionalized with maleic anhydride (SEBS-g-MA), a thermal modifier and toughening agent, ethylene-ethyl acrylate-glycidyl methacrylate terpolymer (E-EA-GMA), a functional reactive elastomeric impact modifier and ethylene-ethyl-acrylate (EEA), a non-reactive elastomeric impact modifier, have been fabricated using the twin-screw extruder. The optimum extrusion process parameters for producing uniform filaments of different rPET compounded formulations have been identified, this includes the extrusion die temperature of 280 °C and the screw speed of 150 ± 3 rpm. The compounded filaments are then printed into standard ASTM test specimens for thermal characterization and mechanical characterization, including glass transition and melting temperatures, crystallinity and crystallization temperature, tensile strength, tensile modulus, ductility, flexural strength, and Izod impact energy. Furthermore, the melt flow index for the filaments was measured. More significantly, the experimental data showed that compounding rPET with such additives in the reactive twin-screw extrusion process results in uniform filaments that display advantageous thermal and mechanical properties and can be used as a feedstock in the MEX-AM technology. This study suggests that compounding the recycled PET pellets with low-cost additives while extruding them into filaments for MEX-AM offers excellent potential to make high-value-added customized products from a sustainable polymer feedstock, such as prototyping, tooling, testing components or end-use internal components for small machines and cars.

Abstract We estimate the US prevalence of uncorrectable visual impairment in 2050 accounting for the changing distribution of both age and myopia. Age projections of the US population (from an estimated total of 379 million in 2050), were taken from the US census website. The distribution of myopia, by severity, was calculated from literature-derived prevalence estimates of 58.4% (≤ − 0.50 D, 2050 projection) and 33.1% (≤ − 1.00 D, 1999–2004 estimate) to provide predicted and conservative estimates, respectively. Uncorrectable visual impairment as a function of age and refractive error was modelled by multiple linear regression. Finally, the likely number of individuals in the US with visual impairment in 2050 was calculated. For a projected myopia prevalence of 58.4%, 222 million are projected to be myopic and 48 million will have high myopia (− 5 D or worse). The projected total number with uncorrectable visual impairment is 11.4 million of which 4.9 million cases (43%) of visual impairment will be directly attributed to increased risk of eye disease associated with myopia. For a projected myopia prevalence of 33.1%, 8.9 million are projected to have uncorrectable visual impairment of which 2.4 million cases (27%) will be directly attributed to myopia. It is predicted that between 27 and 43% of uncorrectable visual impairment in the US population in 2050 will be directly attributable to myopia. Failure to account for the increasing prevalence of myopia among the aging population leads to a substantial underestimate of the prevalence of visual impairment.

Abstract Background There is increasing evidence from human and animal studies that cortical spreading depression (CSD) is the neurophysiological correlate of migraine aura and a trigger of migraine pain mechanisms. The mechanisms of initiation of CSD in the brain of migraineurs remain unknown, and the mechanisms of initiation of experimentally induced CSD in normally metabolizing brain tissue remain incompletely understood and controversial. Here, we investigated the mechanisms of CSD initiation by focal application of KCl in mouse cerebral cortex slices. Methods High KCl puffs of increasing duration up to the threshold duration eliciting a CSD were applied on layer 2/3 whilst the membrane potential of a pyramidal neuron located very close to the site of KCl application and the intrinsic optic signal were simultaneously recorded. This was done before and after the application of a specific blocker of either NMDA or AMPA glutamate receptors (NMDARs, AMPARs) or voltage-gated Ca2+ (CaV) channels. If the drug blocked CSD, stimuli up to 12–15 times the threshold were applied. Results Blocking either NMDARs with MK-801 or CaV channels with Ni2+ completely inhibited CSD initiation by both CSD threshold and largely suprathreshold KCl stimuli. Inhibiting AMPARs with NBQX was without effect on the CSD threshold and velocity. Analysis of the CSD subthreshold and threshold neuronal depolarizations in control conditions and in the presence of MK-801 or Ni2+ revealed that the mechanism underlying ignition of CSD by a threshold stimulus (and not by a just subthreshold stimulus) is the CaV-dependent activation of a threshold level of NMDARs (and/or of channels whose opening depends on the latter). The delay of several seconds with which this occurs underlies the delay of CSD initiation relative to the rapid neuronal depolarization produced by KCl. Conclusions Both NMDARs and CaV channels are necessary for CSD initiation, which is not determined by the extracellular K+ or neuronal depolarization levels per se, but requires the CaV-dependent activation of a threshold level of NMDARs. This occurs with a delay of several seconds relative to the rapid depolarization produced by the KCl stimulus. Our data give insights into potential mechanisms of CSD initiation in migraine.

Abstract Antibodies with similar amino acid sequences, especially across their complementarity-determining regions, often share properties. Finding that an antibody of interest has a similar sequence to naturally expressed antibodies in healthy or diseased repertoires is a powerful approach for the prediction of antibody properties, such as immunogenicity or antigen specificity. However, as the number of available antibody sequences is now in the billions and continuing to grow, repertoire mining for similar sequences has become increasingly computationally expensive. Existing approaches are limited by either being low-throughput, non-exhaustive, not antibody specific, or only searching against entire chain sequences. Therefore, there is a need for a specialized tool, optimized for a rapid and exhaustive search of any antibody region against all known antibodies, to better utilize the full breadth of available repertoire sequences. We introduce Known Antibody Search (KA-Search), a tool that allows for the rapid search of billions of antibody variable domains by amino acid sequence identity across either the variable domain, the complementarity-determining regions, or a user defined antibody region. We show KA-Search in operation on the $$\sim $$ ∼ 2.4 billion antibody sequences available in the OAS database. KA-Search can be used to find the most similar sequences from OAS within 30 minutes and a representative subset of 10 million sequences in less than 9 seconds. We give examples of how KA-Search can be used to obtain new insights about an antibody of interest. KA-Search is freely available at https://github.com/oxpig/kasearch .

BackgroundDigital tools may support people to self-manage their heart failure (HF). Having previously outlined the human-centered design development of a digital tool to support self-care of HF, the next step was to pilot the tool over a period of time to establish people’s acceptance of it in practice. ObjectiveThis study aims to conduct an observational pilot study to examine the usability, adherence, and feasibility of a digital health tool for HF within the Irish health care system. MethodsA total of 19 participants with HF were provided with a digital tool comprising a mobile app and the Fitbit Charge 4 and Aria Air smart scales for a period of 6 months. Changes to their self-care were assessed before and after the study with the 9-item European HF Self-care Behavior Scale (EHFScBS) and the Minnesota Living with HF Questionnaire (MLwHFQ) using a Wilcoxon signed rank test. After the study, 3 usability questionnaires were implemented and descriptively analyzed: the System Usability Scale (SUS), Wearable Technology Motivation Scale (WTMS), and Comfort Rating Scale (CRS). Participants also undertook a semistructured interview regarding their experiences with the digital tool. Interviews were analyzed deductively using the Theoretical Domains Framework. ResultsParticipants wore their devices for an average of 86.2% of the days in the 6-month testing period ranging from 40.6% to 98%. Although improvements in the EHFScBS and MLwHFQ were seen, these changes were not significant (P=.10 and P=.70, respectively, where P>.03, after a Bonferroni correction). SUS results suggest that the usability of this system was not acceptable with a median score of 58.8 (IQR 55.0-60.0; range 45.0-67.5). Participants demonstrated a strong motivation to use the system according to the WTMS (median 6.0, IQR 5.0-7.0; range 1.0-7.0), whereas the Fitbit was considered very comfortable as demonstrated by the low CRS results (median 0.0, IQR 0.0-0.0; range 0.0-2.0). According to participant interviews, the digital tool supported self-management through increased knowledge, improved awareness, decision-making, and confidence in their own data, and improving their social support through a feeling of comfort in being watched. ConclusionsThe digital health tool demonstrated high levels of adherence and acceptance among participants. Although the SUS results suggest low usability, this may be explained by participants uncertainty that they were using it fully, rather than it being unusable, especially given the experiences documented in their interviews. The digital tool targeted key self-management behaviors and feelings of social support. However, a number of changes to the tool, and the health service, are required before it can be implemented at scale. A full-scale feasibility trial conducted at a wider level is required to fully determine its potential effectiveness and wider implementation needs.

Objectives Quantifying area-level inequalities in population health can help to inform policy responses. We describe an approach for estimating quality-adjusted life expectancy (QALE), a comprehensive health expectancy measure, for local authorities (LAs) in Great Britain (GB). To identify potential factors accounting for LA-level QALE inequalities, we examined the association between inclusive economy indicators and QALE.Setting 361/363 LAs in GB (lower tier/district level) within the period 2018–2020.Data and methods We estimated life tables for LAs using official statistics and utility scores from an area-level linkage of the Understanding Society survey. Using the Sullivan method, we estimated QALE at birth in years with corresponding 80% CIs. To examine the association between inclusive economy indicators and QALE, we used an open access data set operationalising the inclusive economy, created by the System Science in Public Health and Health Economics Research consortium.Results Population-weighted QALE estimates across LAs in GB were lowest in Scotland (females/males: 65.1 years/64.9 years) and Wales (65.0 years/65.2 years), while they were highest in England (67.5 years/67.6 years). The range across LAs for females was from 56.3 years (80% CI 45.6 to 67.1) in Mansfield to 77.7 years (80% CI 65.11 to 90.2) in Runnymede. QALE for males ranged from 57.5 years (80% CI 40.2 to 74.7) in Merthyr Tydfil to 77.2 years (80% CI 65.4 to 89.1) in Runnymede. Indicators of the inclusive economy accounted for more than half of the variation in QALE at the LA level (adjusted R2 females/males: 50%/57%). Although more inclusivity was generally associated with higher levels of QALE at the LA level, this association was not consistent across all 13 inclusive economy indicators.Conclusions QALE can be estimated for LAs in GB, enabling further research into area-level health inequalities. The associations we identified between inclusive economy indicators and QALE highlight potential policy priorities for improving population health and reducing health inequalities.

Objectives Occupational moral injury and post-traumatic embitterment disorder (PTED) describe the psychological distress caused by exposure to injustice at work. This meta-analysis aims to determine the prevalence of occupational moral injury and PTED and establish whether prevalence estimates differ depending on occupation.Design A systematic review and meta-analysis.Data sources Google Scholar, PubMed, APA PsycINFO, Web of Science Core Collection, Scopus, ScienceDirect and Sage Journals Online were searched in June 2020 and updated in November 2022.Eligibility criteria for selecting studies Observational studies that measured prevalence or average scores of moral injury, or PTED in any occupational group and any geographical location.Data extraction and synthesis Two independent reviewers screened and coded eligible studies. Study design, participant demographics, sampling method, location, measurement tool and prevalence or average scores were extracted. Risk of bias was assessed using the Quality Assessment Checklist for Prevalence Studies tool. Meta-analysis was conducted using random effects models. Results that could not be combined were summarised qualitatively in a narrative synthesis using the Guidance for Systematic Reviews.Results In total, 88 studies across armed forces and veterans, healthcare, first responders, educators, journalists, child protection service employees, the unemployed, public-sector employees and mixed occupations were included. Studies included in each separate meta-analysis based on the measure used ranged from 2 to 30. The pooled prevalence of clinically relevant moral injury in healthcare professionals was 45%, and exposure to any potentially morally injurious event (PMIE) across occupations was 67%. Exposure to transgressions by others and betrayal was significantly lower in the armed forces than civilian occupations. Pooled prevalence of PTED across occupations was 26%.Conclusion Exposure to PMIEs, moral injury symptoms and PTED are prevalent at work and exposure to transgressions by others and betrayal are more likely in civilian occupations than the armed forces.PROSPERO registration number CRD42020191766.

Summary: Background: Tumour-promoting inflammation is a “hallmark” of cancer and conventional epidemiological studies have reported links between various inflammatory markers and cancer risk. The causal nature of these relationships and, thus, the suitability of these markers as intervention targets for cancer prevention is unclear. Methods: We meta-analysed 6 genome-wide association studies of circulating inflammatory markers comprising 59,969 participants of European ancestry. We then used combined cis-Mendelian randomization and colocalisation analysis to evaluate the causal role of 66 circulating inflammatory markers in risk of 30 adult cancers in 338,294 cancer cases and up to 1,238,345 controls. Genetic instruments for inflammatory markers were constructed using genome-wide significant (P 70% was employed to indicate support for shared causal variants across inflammatory markers and cancer outcomes. Findings were replicated in the FinnGen study and then pooled using meta-analysis. Findings: We found strong evidence to support an association of genetically-proxied circulating pro-adrenomedullin concentrations with increased breast cancer risk (OR: 1.19, 95% CI: 1.10–1.29, q-value = 0.033, PPH4 = 84.3%) and suggestive evidence to support associations of interleukin-23 receptor concentrations with increased pancreatic cancer risk (OR: 1.42, 95% CI: 1.20–1.69, q-value = 0.055, PPH4 = 73.9%), prothrombin concentrations with decreased basal cell carcinoma risk (OR: 0.66, 95% CI: 0.53–0.81, q-value = 0.067, PPH4 = 81.8%), and interleukin-1 receptor-like 1 concentrations with decreased triple-negative breast cancer risk (OR: 0.92, 95% CI: 0.88–0.97, q-value = 0.15, PPH4 = 85.6%). These findings were replicated in pooled analyses with the FinnGen study. Though suggestive evidence was found to support an association of macrophage migration inhibitory factor concentrations with increased bladder cancer risk (OR: 2.46, 95% CI: 1.48–4.10, q-value = 0.072, PPH4 = 76.1%), this finding was not replicated when pooled with the FinnGen study. For 22 of 30 cancer outcomes examined, there was little evidence (q-value ≥0.20) that any of the 66 circulating inflammatory markers examined were associated with cancer risk. Interpretation: Our comprehensive joint Mendelian randomization and colocalisation analysis of the role of circulating inflammatory markers in cancer risk identified potential roles for 4 circulating inflammatory markers in risk of 4 site-specific cancers. Contrary to reports from some prior conventional epidemiological studies, we found little evidence of association of circulating inflammatory markers with the majority of site-specific cancers evaluated. Funding: Cancer Research UK (C68933/A28534, C18281/A29019, PPRCPJT∖100005), World Cancer Research Fund (IIG_FULL_2020_022), National Institute for Health Research (NIHR202411, BRC-1215-20011), Medical Research Council (MC_UU_00011/1, MC_UU_00011/3, MC_UU_00011/6, and MC_UU_00011/4), Academy of Finland Project 326291, European Union's Horizon 2020 grant agreement no. 848158 (EarlyCause), French National Cancer Institute (INCa SHSESP20, 2020-076), Versus Arthritis (21173, 21754, 21755), National Institutes of Health (U19 CA203654), National Cancer Institute (U19CA203654).

Background and objectiveTwo decades ago, an international initiative (GEMINI) was launched in a high-risk, low-resource region in Northeast Iran, aiming to investigate incidence, etiology, early detection, and treatment of esophageal squamous cell carcinoma (ESCC). An earlier report from this area, highlighted poor ESCC survival rates, with a 5-year survival probability of 3.3% and the median survival time of 7 months. Our study assesses whether ESCC survival has improved since the implementation of the GEMINI initiative in this region.Material and methods490 adult patients with histologically-confirmed ESCC were recruited from the Atrak clinic, Golestan, Iran, between 2007 and 2018. At recruitment, information on demographics and various exposures were collected. Active (telephone surveys) and passive (linkage to Golestan population-based cancer and death registries) follow-up methods were used to determine patients' vital status though March 2019. Survival estimates were obtained by Kaplan-Meier method and Cox proportional hazards regression models.ResultsOver the study period 340 deaths were recorded. Five-year ESCC survival probability was 23% (95% Confidence Interval: 19% to 28%), and the median survival time was 19 months. Five-year survival probability was higher among individuals who were younger (35% in 70-year-olds, pConclusionOver the last two decades, ESCC survival in this population has significantly improved, highlighting the potential of enhancing healthcare infrastructure and ensuring access to affordable medical care in resource-limited, high-risk regions. Older age at diagnosis, Turkman ethnicity, opium use, and untreated cases (indicative of advanced disease at diagnosis) were identified as the main ESCC prognostic factors in this population.

Ticks represent important vectors of a number of bacterial and viral disease agents, owing to their hematophagous nature and their questing behavior (the process in which they seek new hosts). Questing activity is notably seasonal with spatiotemporal dynamics that needs to be understood in detail as part of mediating and mitigating tick-borne disease risk. Models of the geography of tick questing activity developed to date, however, have ignored the temporal dimensions of that behavior; more fundamentally, they have often not considered the sampling underlying available occurrence data. Here, we have addressed these shortfalls for Amblyomma americanum, the most commonly encountered tick in the central Great Plains, via (1) detailed, longitudinal sampling to characterize the spatiotemporal dimensions of tick questing activity; (2) randomization tests to establish in which environmental dimensions a species is manifesting selective use; and (3) modeling methods that include both presence data and absence data, taking fullest advantage of the information available in the data resource. The outcome was a detailed picture of geographic and temporal variation in suitability for the species through the two-year course of this study. Such models that take full advantage of available information will be crucial in understanding the risk of tick-borne disease into the future.

Abstract Background: Cervical cancer screening rates in the USA fall behind national targets, requiring innovation to circumvent screening barriers. Cervical cancer screening where human papillomavirus (HPV) testing is performed on vaginal samples collected by the patients themselves (self-sampling) are effective and acceptable, and patient-operated rapid HPV tests (self-testing) are currently under development. It is unclear why there is ambivalence toward HPV self-sampling and self-testing among clinicians, an important stakeholder group. We conducted a mixed convergent quantitative and qualitative study to identify the factors influencing clinicians’ attitudes toward self-sampling and self-testing. Methods: A survey of Midwest clinicians distributed by professional group media and a market research firm between May and November 2021 was analyzed (n = 248) alongside in-depth interviews with Midwest clinicians from professional groups (n = 23). Logistic regression models examined willingness to support self-sampling and self-testing across respondent characteristics. Results: We report that family practice physicians and those in rural areas were more willing to adopt HPV self-sampling (adjusted OR (aOR) = 3.16 [1.43–6.99]; aOR = 2.17 [1.01–4.68]). Clinician willingness to support self-testing was positively associated with current use of self-testing for other conditions and negatively associated with performing 10 or more monthly cervical cancer screenings (aOR = 2.02 [1.03–3.95], aOR = 0.42 [0.23–0.78]). Qualitative data contextualize how clinical specialty and experience with self-sampling and self-testing for other conditions inform clinician perspectives. Conclusion: These data suggest clinician populations most accepting of initiatives to implement self-sampling and self-testing for cervical cancer screening and highlight that experience with other forms of self-testing could facilitate more widespread adoption for cervical cancer.

Understanding how post-acute sequelae of SARS-CoV-2 infection (PASC) affects communities disproportionately affected by HIV is critically needed. This study aimed to identify the prevalence of PASC symptoms among Medicaid enrollees at risk for or living with HIV. Through a web survey, we received 138 valid responses from Medicaid-managed plan members who had received a COVID diagnosis. Participants' mean age was 45.4 years (SD = 11.9) and most were non-Hispanic Black (43.5%) or Hispanic (39.1%). Almost thirty-two percent reported inadequate incomes and 77.5% were HIV-positive. In the overall population, the frequently reported symptoms included neck/back/low back pain, brain fog/difficulty concentrating, bone/joint pain, muscle aches, and fatigue. Findings indicate that there is no statistically significant difference in the prevalence and intensity of PASC symptoms lasting 6 months or more between individuals living with and without HIV. Multiple regression analysis found that the number of PASC symptoms 6 months or longer was independently associated with inadequate incomes and comorbidities (cardiac problems, cancer, fibromyalgia) (R2 = .34). Those with inadequate incomes and comorbidities have more numerous PASC symptoms. Implications for health care delivery and long-term COVID services will be discussed.

[This corrects the article DOI: 10.1371/journal.pone.0228677.].