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Abstract Background Staphylococcus aureus is the predominant pathogen isolated in diabetic foot infections. Recently, the skin commensal bacterium, Helcococcus kunzii, was found to modulate the virulence of this pathogen in an in vivo model. This study aims to elucidate the molecular mechanisms underlying the interaction between these two bacterial species, using a proteomic approach. Results Our results reveal that H. kunzii can coexist and proliferate alongside S. aureus in a Chronic Wound Media (CWM), thereby mimicking an in vitro chronic wound environment. We noted that the secreted proteome of H. kunzii induced a transcriptional effect on S. aureus virulence, resulting in a decrease in the expression level of agrA, a gene involved in quorum sensing. The observed effect could be ascribed to specific proteins secreted by H. kunzii including polysaccharide deacetylase, peptidoglycan DD-metalloendopeptidase, glyceraldehyde-3-phosphate dehydrogenase, trypsin-like peptidase, and an extracellular solute-binding protein. These proteins potentially interact with the agr system, influencing S. aureus virulence. Additionally, the virulence of S. aureus was notably affected by modifications in iron-related pathways and components of cell wall architecture in the presence of H. kunzii. Furthermore, the overall metabolism of S. aureus was reduced when cocultured with H. kunzii. Conclusion Future research will focus on elucidating the role of these excreted factors in modulating virulence.

Abstract Background In England, the number of takeaway food outlets (‘takeaways’) has been increasing for over two decades. Takeaway management zones around schools are an effective way to restrict the growth of new takeaways but their impacts on population health have not been estimated. Methods To model the impact of takeaway management zones on health, we used estimates of change in and exposure to takeaways (across home, work, and commuting buffers) based on a previous evaluation suggesting that 50% of new outlets were prevented from opening because of management zones. Based on previous cross-sectional findings, we estimated changes in body mass index (BMI) from changes in takeaway exposure, from 2018 to 2040. We used PRIMEtime, a proportional multistate lifetable model, and BMI change to estimate the impact of the intervention, in a closed-cohort of adults (25–64 years), on incidence of 12 non-communicable diseases, obesity prevalence, quality-adjusted life years (QALYs), and healthcare costs saved by 2040 in six local authorities (LAs) across the rural–urban spectrum in England (Wandsworth, Manchester, Blackburn with Darwen, Sheffield, North Somerset, and Fenland). Results By 2031, compared to no intervention, reductions in outlet exposure ranged from 3 outlets/person in Fenland to 28 outlets/person in Manchester. This corresponded to mean per person reductions in BMI of 0.08 and 0.68 kg/m2, respectively. Relative to no intervention, obesity prevalence was estimated to be reduced in both sexes in all LAs, including by 2.3 percentage points (PP) (95% uncertainty interval:2.9PP, 1.7PP) to 1.5PP (95%UI:1.9PP, 1.1PP) in males living in Manchester and Wandsworth by 2040, respectively. Model estimates showed reductions in incidence of disease, including type II diabetes (e.g. 964 (95% UI: 1565, 870) fewer cases/100,000 population for males in Manchester)), cardiovascular diseases, asthma, certain cancers, and low back pain. Savings in healthcare costs (millions) ranged from £1.65 (95% UI: £1.17, £2.25)/100,000 population in North Somerset to £2.02 (95% UI: £1.39, £2.83)/100,000 population in Wandsworth. Gains in QALYs/100,000 person were broadly similar across LAs. Conclusions Takeaway management zones in England have the potential to meaningfully contribute towards reducing obesity prevalence and associated healthcare burden in the adult population, at the local level and across the rural–urban spectrum.

Abstract Background Neighbourhood exposure to takeaways can contribute negatively to diet and diet-related health outcomes. Urban planners within local authorities (LAs) in England can modify takeaway exposure through denying planning permission to new outlets in management zones around schools. LAs sometimes refer to these as takeaway “exclusion zones”. Understanding the long-term impacts of this intervention on the takeaway retail environment and health, an important policy question, requires methods to forecast future takeaway growth and subsequent population-level exposure to takeaways. In this paper we describe a novel two-stage method to achieve this. Methods We used historic data on locations of takeaways and a time-series auto-regressive integrated moving average (ARIMA) model, to forecast numbers of outlets within management zones to 2031, based on historical trends, in six LAs with different urban/rural characteristics across England. Forecast performance was evaluated based on root mean squared error (RMSE) and mean absolute scaled error (MASE) scores in time-series cross-validation. Using travel-to-work data from the 2011 UK census, we then translated these forecasts of the number of takeaways within management zones into population-level exposures across home, work and commuting domains. Results Our ARIMA models outperformed exponential smoothing equivalents according to RMSE and MASE. The model was able to forecast growth in the count of takeaways up to 2031 across all six LAs, with variable growth rates by RUC (min–max: 39.4-79.3%). Manchester (classified as a non-London urban with major conurbation LA) exhibited the highest forecast growth rate (79.3%, 95% CI 61.6, 96.9) and estimated population-level takeaway exposure within management zones, increasing by 65.5 outlets per capita to 148.2 (95% CI 133.6, 162.7) outlets. Overall, urban (vs. rural) LAs were forecast stronger growth and higher population exposures. Conclusions Our two-stage forecasting approach provides a novel way to estimate long-term future takeaway growth and population-level takeaway exposure. While Manchester exhibited the strongest growth, all six LAs were forecast marked growth that might be considered a risk to public health. Our methods can be used to model future growth in other types of retail outlets and in other areas.

Purpose – The purpose of this article is to debut a novel initiative that could potentially optimize resources that are currently constrained but, if unleashed, could help ameliorate the science, technology, engineering and mathematics teacher shortage. The initiative involves the reconceptualization of the National Network for Educational Renewal (NNER) tripartite model, which evolved from the work of Goodlad (1994a) and promotes cooperation and partnerships between the three important players responsible for preparing succeeding generations of competent teachers: PK-12 schools, university colleges of education and university colleges of arts and sciences (Roselle, Hands, Marino, Kilgallen, & Howard, 2021; Goodlad, 1994a). Design/methodology/approach – The approach used in writing the article was narrative, offering a brief review of the various challenges that have had an impact on the national teacher shortage, particularly in the field of mathematics. Findings – The study suggests that a reconceptualized NNER tripartite model can be implemented to assuage the devastating effects of the coronavirus disease 2019 pandemic on learning, offer support to an overworked teacher workforce and provide a possible math teacher recruitment pipeline by forming a life-giving partnership between a college of education, a college of arts and sciences, a local elementary school and undergraduate math club members. Originality/value – This is an original application of the NNER tripartite model, particularly with math teacher recruitment in mind, and it is hoped that the model will be considered transferable to a variety of school-university contexts. However, additional study is required to explore the validity and replicability of this model.

Intrahepatic cholangiocarcinoma (iCCA) is a highly heterogeneous and aggressive liver cancer with limited therapeutic options. Precise classification and immunotherapy are perspectives to improve the treatments. We reported the role of septin 9 in apico‐basal polarity and epithelial‐to‐mesenchymal transition (EMT). Here, we aim to elucidate its role in iCCA. We analyzed single‐cell transcriptomes from human iCCA tumor cells based on phenotype and cell state. Knockdown of the septin 9 gene (SEPT9) was done using small interfering RNA (siRNA); interferon‐γ (IFN‐γ) stimulation was performed using different CCA cells; gene expressions were analyzed by reverse transcription and real‐time PCR analysis (RT‐qPCR); and immunofluorescence, immunoblotting, and flow cytometry were performed to assess the expression of proteins. The differential distributions of SEPT9 and vimentin (VIM) gene expressions allowed us to define specific cellular trajectories of malignant cells and thus identified distinct clusters of iCCA cells. One cluster was enriched in VIM and extracellular‐matrix (ECM) remodeling molecules, and another had high expression of SEPT9 and genes from the ‘don't eat me’ signal involved in immune escape. This antagonism between SEPT9 and VIM was confirmed by in vitro experiments. Notably, SEPT9 and ‘don't eat me’ gene expressions were inversely correlated to those of vimentin and the EMT markers. SEPT9 expression was upregulated by IFN‐γ and SEPT9 knockdown decreased expression of ‘don't eat me’ signal genes and increased expression of mesenchymal markers. Cancer Cell Line Encyclopedia (CCLE) transcriptome database analyses confirmed that iCCA cells enriched in septin 9 exhibit epithelial‐like features. This study revealed septin 9 as a cytoskeleton element of iCCA epithelial‐like cells and a regulator of the immune system response. It also brings new insights into the enigmatic relationship between EMT and immune response. Notably, we decoded a potential mechanism that could sensitize patients to immunotherapies.

Abstract Whole genome sequencing (WGS) provides comprehensive, individualised cancer genomic information. However, routine tumour biopsies are formalin-fixed and paraffin-embedded (FFPE), damaging DNA, historically limiting their use in WGS. Here we analyse FFPE cancer WGS datasets from England’s 100,000 Genomes Project, comparing 578 FFPE samples with 11,014 fresh frozen (FF) samples across multiple tumour types. We use an approach that characterises rather than discards artefacts. We identify three artefactual signatures, including one known (SBS57) and two previously uncharacterised (SBS FFPE, ID FFPE), and develop an “FFPEImpact” score that quantifies sample artefacts. Despite inferior sequencing quality, FFPE-derived data identifies clinically-actionable variants, mutational signatures and permits algorithmic stratification. Matched FF/FFPE validation cohorts shows good concordance while acknowledging SBS, ID and copy-number artefacts. While FF-derived WGS data remains the gold standard, FFPE-samples can be used for WGS if required, using analytical advancements developed here, potentially democratising whole cancer genomics to many.

Abstract Introduction Niraparib first-line maintenance (1LM) therapy has demonstrated clinical benefit for patients with ovarian cancer (OC) in clinical trial and real-world settings, but data on factors associated with real-world patient outcomes remain limited. This analysis identified patient characteristics associated with time to next treatment (TTNT), a proxy for real-world progression-free survival, in patients with OC treated with 1LM niraparib monotherapy. Methods This retrospective observational study used a USA nationwide electronic health record-derived deidentified database and included adult patients diagnosed with OC who initiated 1LM niraparib monotherapy after first-line platinum-based chemotherapy. Patients were followed until the earliest occurrence of last clinical activity, death, or end of study period. TTNT was measured from 1LM niraparib initiation to the start of second-line treatment or death. Cox proportional hazards models assessed univariable and multivariable associations between baseline characteristics and TTNT. Results Of 7872 patients diagnosed with OC, 526 met the eligibility criteria and were included in this analysis. Median (IQR) duration of follow-up was 14.1 (7.4–23.6) months. In univariable analyses, age, BRCA/homologous recombination deficiency (HRD) status, socioeconomic status, stage at initial diagnosis, cytoreductive surgery type, and residual disease status were significantly associated with observed TTNT and were introduced into the multivariable model with other clinically relevant variables. In the multivariable analysis, BRCA/HRD status, cytoreductive surgery type, and residual disease status were significantly associated with observed TTNT after covariate adjustment. Conversely, age, Eastern Cooperative Oncology Group performance status, disease stage, niraparib starting dose status, and first-line bevacizumab use were not associated with observed TTNT. Conclusion This real-world, retrospective, observational analysis offers valuable insights on prognostic factors associated with TTNT in patients with OC treated with 1LM niraparib monotherapy after first-line platinum-based chemotherapy. Future studies are needed to examine how additional patient characteristics associated with clinical outcomes may guide treatment decisions and improve outcomes.

Abstract Introduction Clinical trials have demonstrated prolonged survival associated with niraparib first-line maintenance (1LM) therapy, compared with placebo, for patients with ovarian cancer (OC). However, data are limited on real-world 1LM niraparib monotherapy use, particularly as switch 1LM, following first-line (1L) combination chemotherapy plus bevacizumab. This real-world study aimed to describe patient demographics, clinical characteristics, and clinical outcomes of patients with OC receiving 1LM niraparib monotherapy following 1L combination chemotherapy plus bevacizumab. Methods This retrospective observational study used data from a US-based nationwide database of deidentified, electronic health record-derived data. Patients diagnosed with OC during the study period (1 January 2011–30 November 2022, inclusive) were eligible if they received 1L chemotherapy plus bevacizumab treatment followed by 1LM niraparib monotherapy, initiated between 1 January 2017 (inclusive) and 2 September 2022. Patients were followed from index date (initiation of niraparib 1LM) until the first occurrence of death, end of follow-up, or end of study. Clinical outcomes were time to treatment discontinuation (TTD) and time to next treatment (TTNT). Kaplan–Meier curves were used to estimate TTD, TTNT, and 95% confidence intervals (CIs). Results Among 93 patients selected, median age at index was 67 years (interquartile range [IQR] 60–72 years). Most patients had BRCA wild-type/homologous recombination (HR)-proficient or BRCA wild-type/HR unknown disease (75.3%). In all, 18 (19.4%) patients had HR-deficient disease. Five (5.4%) patients had unknown test results for both BRCA and HR deficiency status. Median follow-up time was 16.3 months (IQR 8.7–25.4 months), and median time from end of 1L therapy to 1LM initiation was 35.0 days (IQR 25.0–53.9 days). Median TTD was 9.3 months (95% CI 6.1–11.3 months). Median TTNT was 12.9 months (95% CI 11.5–19.0 months). Conclusions This real-world study provided insights into switch maintenance with 1LM niraparib monotherapy, which may be a viable treatment option for patients with advanced OC.

Degenerative cervical myelopathy (DCM) is the leading cause of spinal cord dysfunction in adults, representing substantial morbidity and significant financial and resource burdens. Typically, patients with progressive DCM will eventually receive surgical treatment. Nonetheless, despite advancements in pharmacotherapeutics, evidence for pharmacological therapy remains limited. Health professionals from various fields would find interest in pharmacological agents that could benefit patients with mild DCM or enhance surgical outcomes. This review aims to consolidate all clinical and experimental evidence on the pharmacological treatment of DCM. We conducted a comprehensive narrative review that presents all pharmacological agents that have been investigated for DCM treatment in both humans and animal models. Riluzole exhibits effectiveness solely in rat models, but not in treating mild DCM in humans. Cerebrolysin emerges as a potential neuroprotective agent for myelopathy in animals but had contradictory results in clinical trials. Limaprost alfadex demonstrates motor function improvement in animal models and exhibits promising outcomes in a small clinical trial. Glucocorticoids not only fail to provide clinical benefits but may also lead to adverse events. Cilostazol, anti-Fas ligand antibody, and Jingshu Keli display promise in animal studies, while erythropoietin, granulocyte colony-stimulating factor and limaprost alfadex exhibit potential in both animal and human research. Existing evidence mainly rests on weak clinical data and animal experimentation. Current pharmacological efforts target ion channels, stem cell differentiation, inflammatory, vascular, and apoptotic pathways. The inherent nature and pathogenesis of DCM offer substantial prospects for developing neurodegenerative or neuroprotective therapies capable of altering disease progression, potentially delaying surgical intervention, and optimizing outcomes for those undergoing surgical decompression.

Abstract Sugar sweetened beverage consumption has been suggested as a risk factor for childhood asthma symptoms. We examined whether the UK Soft Drinks Industry Levy (SDIL), announced in March 2016 and implemented in April 2018, was associated with changes in National Health Service hospital admission rates for asthma in children, 22 months post-implementation of SDIL. We conducted interrupted time series analyses (2012-2020) to measure changes in monthly incidence rates of hospital admissions. Sub-analysis was by age-group (5-9,10-14,15-18 years) and neighbourhood deprivation quintiles. Changes were relative to counterfactual scenarios where the SDIL wasn’t announced, or implemented. Overall, incidence rates reduced by 20.9% (95%CI: 29.6-12.2). Reductions were similar across age-groups and deprivation quintiles. These findings give support to the idea that implementation of a UK tax intended to reduce childhood obesity may have contributed to a significant unexpected and additional public health benefit in the form of reduced hospital admissions for childhood asthma.

Indigenous knowledge is central to understanding environment and health sciences in the Arctic, yet limited research in these fields has explored the human–animal–environment interface from the unique perspectives of Inuit women. Using a community-led, Inuit-centred research approach, we characterized the use and meaning of country food in the context of community well-being for Inuit women in Nunavut, Canada. In-depth conversational interviews and focus groups (n = 16) were held with Inuit women (n = 10) who are knowledge holders in the Qikiqtani region that hold decades of country food knowledge. Data were analyzed using thematic analysis and constant comparative methods. Inuit women described country food in the context of (1) well-being, connection, and identity, (2) hunger, craving, and healing, (3) food security and nourishment, and (4) change and adaptation. Inuit women described a wide range of country food as central to physical and mental health, food security, identity, culture, healing and medicine. Adaptive strategies were discussed, such as eating more fish when caribou were scarce. This research highlights the critical role of country food for health and well-being for Inuit women and shares knowledge and perspective that is relevant to wildlife and environment researchers, public health practitioners, policy makers, and others interested in advancing health, well-being, and food sovereignty in Inuit communities.

Creatine transporter deficiency (CTD) is an inborn error of creatine (Cr) metabolism in which Cr is not properly distributed to the brain due to a mutation in the Cr transporter (CrT) SLC6A8 gene. CTD is associated with developmental delays and with neurological disability in children. Dodecyl creatine ester (DCE), as a Cr prodrug, is a promising drug to treat CTD after administration by the nasal route, taking advantage of the nose-to-brain pathway. In this study, the potential adaptive response to energy imbalance in glucose metabolism was investigated in CTD using both SLC6A8-deficient mice (CrT KO) and brain organoids derived from CTD patient cells. Longitudinal brain [18F]FDG PET imaging in CrT KO mice compared to wild-type mice demonstrated that CTD was associated with a significant loss and decline in brain glucose metabolism. In CrT KO mice, intranasal supplementation with DCE for a month significantly mitigated the decline in brain glucose metabolism compared to untreated (vehicle) animals. Mechanistic investigations in CrT KO mice and cerebral organoids derived from CTD patient cells suggest that intracellular trafficking of glucose transporter (Glut) may be altered by lack of activation of AMP-activated protein kinase (AMPK). Consistency between observations in the CrT KO mouse model and cerebral organoids derived from CTD patient cells supports the value of this new model for drug discovery and development. In addition, these results suggest that [18F]FDG PET imaging may offer a unique and minimally-invasive biomarker to monitor the impact of investigational treatment on CTD pathophysiology, with translational perspectives.

Background: Despite the widespread prevalence and substantial burden of mental disorders, they remain significantly underdiagnosed and undertreated. In low- and middle-income countries like Senegal, integrating mental health services into primary care represents the most feasible strategy to bridge the treatment gap. This study aimed to assess the effects of a mental health e-learning program on the knowledge, attitudes, and practices of allied and healthcare professionals in Senegal. Methods: An e-learning platform including 12 interactive modules was used to train 322 allied and healthcare professionals. We evaluated changes in knowledge, attitudes, and practices, as well as in satisfaction with knowledge and in self-assessed ability to diagnose and manage patients, by comparing data collected before and after the e-learning modules. Qualitative feedback on the satisfaction with the various components of the program was also collected via a post-training survey. Outcomes: Knowledge, attitudes and practices scores increased significantly for all modules. Additionally, scores related to satisfaction with knowledge and ability to diagnose and manage patients showed significant improvements (+77.0 % and +75.0 %, respectively), surpassing the gains observed in knowledge, attitudes, and practices scores (+19.2 %, +11.1 % and +15.0 %, respectively). Mean scores regarding participants' satisfaction with the various elements of the program ranged from 8.1 to 9.1, out of a maximum of 10. Conclusion: Although only a limited number of participants completed all 12 modules, the mental health e-learning program showed positive results on the knowledge, attitudes, and practices of participants. It also increased their confidence and was perceived as a very positive experience by learners.

Local and national policymakers are seeking innovative solutions to create healthier food environments around the world. Between 2009 and 2017, 35 local authorities across England (UK) adopted planning guidance designed to limit the proliferation of hot food takeaways near schools. Whilst these policies are intended to improve population health, they are also likely to have economic impacts. Often a decision to introduce such policies comes down to consideration of whether the short-term economic imperatives of allowing new takeaway outlets to open outweighs the potential long-term public health implications and associated economic consequences. These potential negative and positive economic impacts have not previously been clearly described and are summarised here. The aim of this paper is to provide an overview of the potential economic impacts of takeaway management zones. In particular, we present a Causal Loop Diagram (CLD) that outlines the possible economic impacts of takeaway management zones based on researcher knowledge of the interventions and the industry. Potential negative impacts fall across sectors and may include a loss of employment opportunities and reductions in local and national tax receipts, and may impact the economic vitality of local communities. In the longer term, there is the potential for positive impacts such as reductions in healthcare resource utilisation, social care expenditure and sickness-related absence from work. Part of a robust case would a better economic understanding, that would enable local authorities to improve understanding of the trade-offs associated with the policy, such as short-versus long-term, and business-related versus society-related health benefits and costs.

Abstract Objectives Artificial intelligence is evolving and significantly impacting health care, promising to transform access to medical information. With the rise of medical misinformation and frequent internet searches for health‐related advice, there is a growing demand for reliable patient information. This study assesses the effectiveness of ChatGPT in providing information and treatment options for chronic rhinosinusitis (CRS). Methods Six inputs were entered into ChatGPT regarding the definition, prevalence, causes, symptoms, treatment options, and postoperative complications of CRS. International Consensus Statement on Allergy and Rhinology guidelines for Rhinosinusitis was the gold standard for evaluating the answers. The inputs were categorized into three categories and Flesch–Kincaid readability, ANOVA and trend analysis tests were used to assess them. Results Although some discrepancies were found regarding CRS, ChatGPT's answers were largely in line with existing literature. Mean Flesch Reading Ease, Flesch–Kincaid Grade Level and passive voice percentage were (40.7%, 12.15%, 22.5%) for basic information and prevalence category, (47.5%, 11.2%, 11.1%) for causes and symptoms category, (33.05%, 13.05%, 22.25%) for treatment and complications, and (40.42%, 12.13%, 18.62%) across all categories. ANOVA indicated no statistically significant differences in readability across the categories (p‐values: Flesch Reading Ease = 0.385, Flesch–Kincaid Grade Level = 0.555, Passive Sentences = 0.601). Trend analysis revealed readability varied slightly, with a general increase in complexity. Conclusion ChatGPT is a developing tool potentially useful for patients and medical professionals to access medical information. However, caution is advised as its answers may not be fully accurate compared to clinical guidelines or suitable for patients with varying educational backgrounds. Level of evidence: 4.

Background: Transforming growth factor β-activated protein kinase-1 (TAK1) plays an important role in MAPK and NFκB pathways and has been associated with colorectal cancer. The aim of this study was to determine how cytoplasmic and juxtanuclear punctate staining of TAK1 relates to immune checkpoint expression and cancer specific survival in colorectal cancer. Methods: Protein expression was assessed by immunohistochemistry on tissue microarrays from primary curative colorectal cancer resected specimens. Expression levels of cytoplasmic TAK1 by QuPath digital quantification and punctate TAK1 staining was scored using a manual point scoring technique and correlated with clinicopathological features, immune checkpoint expression and cancer-specific survival. Bulk RNA sequencing was performed in specimens to determine mutational profiles and differentially expressed genes. Results: A cohort of 875 patients who had undergone colorectal cancer resection were assessed for TAK1 expression. Higher levels of cytoplasmic TAK1 expression correlated with elevated PD1 and PD-L1 expression (p < 0.010). High punctate TAK1 expression was more commonly identified in poorly differentiated colorectal cancers (p = 0.036), had dysregulated mutational and transcriptional profiles with decreased insulin-like growth factor 2(IGF2) expression (p < 0.010), and independently predicted poor cancer-specific survival (HR 2.690, 95% CI 1.419–5.100, p = 0.002). The association of punctate TAK1 expression and recurrence remained after subgroup analysis for microsatellite-stable colorectal cancer (p = 0.028). Discussion: Punctate TAK1 expression is associated with worse cancer specific survival. TAK1 signalling may be an important pathway to investigate underlying mechanisms for recurrence in microsatellite-stable colorectal cancer.

ObjectivesThe prevalence of many psychiatric symptoms, including anxiety and depression, is higher in individuals born extremely preterm (EP) than in term-born individuals during childhood and adolescence. In this prospective study of adolescents born EP, we examined associations between early-life risk factors (prenatal maternal health conditions, socioeconomic and social factors) and anxiety and depression at 15 years of age.MethodsWe included 682 participants (53.2% White, 57.8% male) who were born

Background: There is no definitive evidence of the prognosis impact of histological variants (HVs) in patients who undergo surgical resection of a nonmetastatic renal cell carcinoma (nm-RCC) with venous tumor thrombus (TT). Objective: To investigate the impact of HVs on the prognosis of patients with nm-RCC with TT after radical surgery. Design, setting, and participants: Patients who underwent radical nephrectomy with the removal of the venous TT for an nm-RCC were included in a retrospective study. Outcome measurements and statistical analysis: Three groups were identified: clear cell (ccRCC), papillary (pRCC), and chromophobe (chRCC) RCC. The primary outcome measures (disease-free and overall survival [OS]) were assessed using the Kaplan-Meier method and compared using the log-rank test. Univariate and multivariate Cox proportional hazard models were used to study the impact of HVs on survival. Results and limitations: A total of 873 patients were included. The histological subtypes were distributed as follows: ccRCC in 780 cases, pRCC in 58 cases, and chRCC in 35 cases. At the time of data analysis, 612 patients were recurrence free and 228 had died. A survival analysis revealed significant differences in both OS and recurrence-free survival across histological subtypes, with the poorest outcomes observed in pRCC patients (p

Las técnicas de Gianni Rodari y Edward de Bono tienen gran importancia pues promueven el interés del estudiante en el proceso de producción de textos a través de la experimentación, que se logra al aplicar la metodología lúdica y el pensamiento creativo en las aulas. Por esta razón, la investigación tuvo como objetivo analizar las técnicas de Gianni Rodari y Edward De Bono como una estrategia de enseñanza para mejorar el proceso de escritura creativa en estudiantes de educación general básica en Ecuador. El escrito se elaboró empleando un enfoque deductivo, respaldado además por una investigación documental con enfoque cualitativo. No obstante, en cuanto a los resultados obtenidos, se evidenció a través del informe presentado por el Instituto Nacional de Evaluación Educativa en las pruebas Pisa que el promedio de Ecuador en lectura es de 409, lo que lo sitúa en nivel 2 que corresponde al nivel mínimo de competencias. Esto se debe al desconocimiento de técnicas y estrategias innovadoras en el ámbito escolar. Se concluyó que dichas técnicas estimulan la imaginación al tiempo que refuerza la confianza y autoestima del niño o niña, mejora la capacidad comunicativa y de escritura, y desarrolla el pensamiento crítico desde la expresión personal.

Abstract Assuming a toroidal space with finite volume, we derive analytically the full one-loop vacuum energy for a scalar field tunnelling between two degenerate vacua, taking into account discrete momentum. The Casimir energy is computed for an arbitrary number of dimensions using the Abel-Plana formula, while the one-loop instanton functional determinant is evaluated using the Green’s functions for the fluctuation operators. The resulting energetic properties are non-trivial: both the Casimir effect and tunnelling contribute to the Null Energy Condition violation, arising from a non-extensive true vacuum energy. We discuss the relevance of this mechanism to induce a cosmic bounce, requiring no modified gravity or exotic matter.

Abstract Background Adolescence is a pivotal developmental stage, where escalating rates of overweight and obesity have raised concerns about diet quality and its association with adverse health outcomes. Parents are known to have considerable influence on childhood diet, but how this influence changes as adolescents mature is unknown. This study investigates the association between parental fruit and vegetable (FV) intake and adolescent FV consumption, exploring how this changes across adolescence and when adolescents leave home. Methods Adolescents aged 10–30 years (n = 12,805) from the UK Household Longitudinal Study (UKHLS), and their parents, reported FV intakes every 2 years. Multilevel linear regression models were fitted to assess associations between parental and adolescent FV intakes, investigating interactions with age and living arrangement, and adjusting for sociodemographic covariates. Results Parental FV intake was positively associated with adolescent FV intake (β = 0.20 [95%CI:0.19,0.22] portions/day), with the strength of this association lowest during early adolescence (10–14 years) and peaking at 17–18 years (β = 0.30 [95%CI: 0.27,0.33] portions/day). When adolescents no longer lived in the parental home, the association of parental FV intake with adolescent FV consumption decreased, but a positive association was maintained up to age 30 years. Conclusions Our findings emphasise the enduring effect of parental FV consumption on adolescent FV consumption, highlighting the potential for interventions to promote increased FV intake, acknowledging the lasting influence of parental diet, even beyond the confines of the parental home.

Abstract Background By analyzing the proteins which are the workhorses of biological systems, metaproteomics allows us to list the taxa present in any microbiota, monitor their relative biomass, and characterize the functioning of complex biological systems. Results Here, we present a new strategy for rapidly determining the microbial community structure of a given sample and designing a customized protein sequence database to optimally exploit extensive tandem mass spectrometry data. This approach leverages the capabilities of the first generation of Quadrupole Orbitrap mass spectrometer incorporating an asymmetric track lossless (Astral) analyzer, offering rapid MS/MS scan speed and sensitivity. We took advantage of data-dependent acquisition and data-independent acquisition strategies using a peptide extract from a human fecal sample spiked with precise amounts of peptides from two reference bacteria. Conclusions Our approach, which combines both acquisition methods, proves to be time-efficient while processing extensive generic databases and massive datasets, achieving a coverage of more than 122,000 unique peptides and 38,000 protein groups within a 30-min DIA run. This marks a significant departure from current state-of-the-art metaproteomics methodologies, resulting in broader coverage of the metabolic pathways governing the biological system. In combination, our strategy and the Astral mass analyzer represent a quantum leap in the functional analysis of microbiomes. Video Abstract

Abstract Colorectal cancer (CRC) is a heterogenous malignancy underpinned by dysregulation of cellular signaling pathways. Previous literature has implicated aberrant JAK/STAT3 signal transduction in the development and progression of solid tumors. In this study we investigate the effectiveness of inhibiting JAK/STAT3 in diverse CRC models, establish in which contexts high pathway expression is prognostic and perform in depth analysis underlying phenotypes. In this study we investigated the use of JAK inhibitors for anti-cancer activity in CRC cell lines, mouse model organoids and patient-derived organoids. Immunohistochemical staining of the TransSCOT clinical trial cohort, and 2 independent large retrospective CRC patient cohorts was performed to assess the prognostic value of JAK/STAT3 expression. We performed mutational profiling, bulk RNASeq and NanoString GeoMx® spatial transcriptomics to unravel the underlying biology of aberrant signaling. Inhibition of signal transduction with JAK1/2 but not JAK2/3 inhibitors reduced cell viability in CRC cell lines, mouse, and patient derived organoids (PDOs). In PDOs, reduced Ki67 expression was observed post-treatment. A highly significant association between high JAK/STAT3 expression within tumor cells and reduced cancer-specific survival in patients with high stromal invasion (TSPhigh) was identified across 3 independent CRC patient cohorts, including the TrasnSCOT clinical trial cohort. Patients with high phosphorylated STAT3 (pSTAT3) within the TSPhigh group had higher influx of CD66b + cells and higher tumoral expression of PDL1. Bulk RNAseq of full section tumors showed enrichment of NFκB signaling and hypoxia in these cases. Spatial deconvolution through GeoMx® demonstrated higher expression of checkpoint and hypoxia-associated genes in the tumor (pan-cytokeratin positive) regions, and reduced lymphocyte receptor signaling in the TME (pan-cytokeratin- and αSMA-) and αSMA (pan-cytokeratin- and αSMA +) areas. Non-classical fibroblast signatures were detected across αSMA + regions in cases with high pSTAT3. Therefore, in this study we have shown that inhibition of JAK/STAT3 represents a promising therapeutic strategy for patients with stromal-rich CRC tumors. High expression of JAK/STAT3 proteins within both tumor and stromal cells predicts poor outcomes in CRC, and aberrant signaling is associated with distinct spatially-dependant differential gene expression.

Abstract Background The ‘agentic demand’ of population health interventions (PHIs) refers to the capacity, resources and freedom to act that interventions demand of their recipients to benefit, which have a socio-economical pattern. Highly agentic interventions, e.g. information campaigns, rely on recipients noticing and responding to the intervention and thus might affect intervention effectiveness and equity. The absence of an adequate framework to classify agentic demands limits the fields’ ability to systematically explore these associations. Methods We systematically developed the Demands for Population Health Interventions (Depth) framework using an iterative approach: (1) developing the Depth framework by systematically identifying examples of PHIs aiming to promote healthier diets and physical activity, coding of intervention actors and actions and synthesising the data to develop the framework; (2) testing the Depth framework in online workshops with academic and policy experts and a quantitative reliability assessment. We applied the final framework in a proof-of-concept review, extracting studies from three existing equity-focused systematic reviews on framework category, overall effectiveness and differential socioeconomic effects and visualised the findings in harvest plots. Results The Depth framework identifies three constructs influencing agentic demand: exposure — initial contact with intervention (two levels), mechanism of action — how the intervention enables or discourages behaviour (five levels) and engagement — recipient response (two levels). When combined, these constructs form a matrix of 20 possible classifications. In the proof-of-concept review, we classified all components of 31 interventions according to the Depth framework. Intervention components were concentrated in a small number of Depth classifications; Depth classification appeared to be related to intervention equity but not effectiveness. Conclusions This framework holds potential for future research, policy and practice, facilitating the design, selection and evaluation of interventions and evidence synthesis.

Background: In 2022, the catchment area of the Fred Hutchinson/University of Washington/Seattle Children’s Cancer Consortium (the Consortium) grew from 13-counties in Western Washington State to include all 39 counties in Washington.Methods: Widening the catchment area provided new opportunities for the Consortium to monitor the cancer burden, identify cancer-related health disparities, use a bidirectional approach to develop cancer focused programming, and facilitate research in clinical and community settings.Results: In this commentary, we describe the exploratory process of catchment area change led by the Consortium’s Office of Community Outreach and Engagement and new initiatives that followed that growth.Discussion: We hope that by sharing the ongoing, data-driven community engagement approach in the Consortium’s current, statewide catchment area, our experience will be of value to other cancer centers looking to engage with communities and develop bidirectional partnerships in new areas.

Gene-editing technology provides promising opportunities for livestock industries by enabling precise genetic modifications that enhance desirable traits such as increased disease resistance, heat tolerance, and nutritional quality. With gene-edited beef products entering the market soon, understanding consumers’ acceptance is critical. Using structural equation modeling, the study aimed to determine how key psychological and social factors influence U.S. consumers’ attitudes toward gene editing and their behavioral intentions toward ground beef from gene-edited cattle. Results indicate that knowledge, subjective social norms, and perceived benefits positively influenced attitudes, while perceived risks and food technology neophobia negatively influenced attitudes. Subjective social norms, perceived benefits, and attitudes positively influenced behavioral intentions, while perceived risks and food technology neophobia negatively influenced intentions. Attitudes acted as a partial mediator, significantly mediating the effects of subjective social norms, perceived benefits, perceived risks, and food technology neophobia on behavioral intentions. Improving consumers’ behavioral intentions toward ground beef from gene-edited cattle hinges on cultivating more favorable attitudes toward the technology. Thus, collaborative efforts by scientists, producers, policymakers, extension agents, and agricultural communicators should seek to increase consumers’ perceived benefits and improve subjective social norms, as these factors were most influential.

In the United States, women account for one-fourth of people living with HIV. Most women living with HIV are Black or Hispanic and acquired HIV from heterosexual contact. Many face significant barriers to appropriate medical care, with lower retention in care and viral suppression than men who acquire HIV from male-to-male sexual contact. Many factors contribute to these disparities, including high rates of alcohol abuse, substance use, intimate partner violence, depression, and socioeconomic marginalisation. HIV, substance use, and violence each contribute independently to the collective health burden on women. The co-occurrence of these factors, termed the SAVA (substance abuse, violence, and HIV/AIDS) syndemic, is particularly hard to address, as the conditions act synergistically to negatively influence health outcomes. In addition, mental health conditions frequently coexist and further contribute to adverse outcomes. Unfortunately, clinician knowledge of this syndemic is low, and patients living with HIV and other elements of SAVA, including depression, are not recognised and referred for appropriate services. In this paper we describe our pilot educational and quality improvement program and the subsequent educational program we developed to increase knowledge of SAVA with the goal of improving health outcomes for women living with HIV.

Background Little is known about who uses online food delivery services and how use of these services is associated with social inequalities in food purchasing and diet-related health. This study explored associations between social position and use of online takeaway food and grocery delivery services, and its association with weight status.Methods Data were obtained from households in a consumer research panel living in London and the north of England (n=1521) in February 2019. Use of online grocery delivery services was determined via recorded purchases, and takeaway food delivery app use via survey responses. Social position was approximated through occupation-based social grade and household income. We used logistic regression to estimate the association between social position and use of online delivery services, and the relationship between online delivery service use and weight status.Results Overall, 13.2% of respondents used takeaway food delivery apps over a 7-day period and 15.6% of households used online grocery delivery services over a 4-week period. High-income households were more likely to use online grocery delivery services than low-income households (OR 2.01, 95% CI 1.22 to 3.34). In contrast, households with lower social grade were more likely to use takeaway food delivery apps compared with households in the highest grade (OR 2.31, 95% CI 1.38 to 3.87). While takeaway food delivery app use was positively associated with living with obesity (relative risk ratio 1.84, 95% CI 1.20 to 2.82), use of online grocery delivery services was not.Discussion Findings indicate that use of online food delivery services is patterned by markers of social position and weight status, which may lead to dietary inequalities. The potential impact of increased and differential usage of online delivery services on diet and dietary inequalities warrants further research.

The NFκB pathway, known as the central regulator of inflammation, has a well-established role in colorectal cancer (CRC) initiation, progression, and therapy resistance. Due to the pathway's overarching roles in CRC, there have been efforts to characterise NFκB family members and target the pathway for therapeutic intervention. Initial research illustrated that the canonical NFκB pathway, driven by central kinase IKKβ, was a promising target for drug intervention. However, dose limiting toxicities and specificity concerns have resulted in failure of IKKβ inhibitors in clinical trials. The field has turned to look at targeting the less dominant kinase, IKKα, which along with NFκB inducing kinase (NIK), drives the lesser researched non-canonical NFκB pathway. However prognostic studies of the non-canonical pathway have produced conflicting results. There is emerging evidence that IKKα is involved in other signalling pathways, which lie outside of canonical and non-canonical NFκB signalling. Evidence suggests that some of these alternative pathways involve a truncated form of IKKα, and this may drive poor cancer-specific survival in CRC. This review aims to explore the multiple components of NFκB signalling, highlighting that NIK may be the central kinase for non-canonical NFκB signalling, and that IKKα is involved in novel pathways which promote CRC.

BackgroundHealth statistics on dengue are virtually non-existent, despite the fact that the virus is circulating in Togo. This study aimed to assess the knowledge, attitudes, and practices (KAP) of health professionals in the Kara health region.MethodsA cross-sectional study was conducted from March to June 2022 among healthcare professionals who had worked in the Kara region of northern Togo were selected using an exhaustive recruitment method. Data were collected by trained resident doctors with a face-to-face interview using a standardized, pretested questionnaire based on the WHO 2009 dengue guide. Three multivariate regression models were utilized to investigate factors associated with knowledge, attitudes and, and practices.ResultsA total of 464 respondents (37.1% female), median age 35 years, interquartile range (29–43 years) were included. Only (3.0%) of the participants had received training on dengue fever diagnosis, treatment and prevention in the last 3 years, and 10.3% had dengue rapid diagnostic tests available at their hospital. Half of the respondents (49.1%) had good knowledge of dengue fever, compared with 30.0% who had positive attitudes. Of a total of 256 professionals who had encountered a case of dengue fever in their practice, only 24 (9.4%) had appropriate practices for diagnosing and treating dengue fever. In multivariate analysis, the healthcare professionals who had taken part in ongoing training on dengue fever were more likely to have adequate dengue diagnosis and treatment practice aOR = 8.1; CI 95% = [1.7–36.0].ConclusionStrengthening healthcare professionals' dengue-related skills through ongoing training and the provision of dengue diagnostic tests could help improve early detection practices and management of dengue fever in Togo.

Many acquired bleeding and thrombotic complications are provoked by autoantibodies to blood coagulation factors, or to hemostasis inhibitors and regulatory proteins. If occurrence of those antibodies remains rare or ultra-rare, affected patients are not always well-identified and associated pathologies are not always understood. Today, autoantigens tend to be better characterized. New available methods allow investigating structural changes of body components, responsible for auto-immunization. This renders it possible to develop laboratory assays for detecting autoantibodies and estimating their blood concentration. This review analyzes the major autoantibodies reported to be associated with hemorrhagic or thrombotic pathologies and their possible inducing causes when known. Pathogenicity is strongly patient- and context-dependent and is related to autoantibodies’ concentration, avidity, and capacity to bind to autoantigen structures in-vivo, misdirecting the immune system to the own body’s cells or organs. Identification of autoantigens allows for developing laboratory methods for testing autoantibodies and following their evolution kinetics. In-vitro investigations concern functional assays, to evaluate autoantibody’s capacity to inhibit physiological activities, or autoantigen-capture-based assays to detect autoantibodies, like with enzyme-linked immuno-sorbent assay (ELISA) methods. Exploring patients with autoimmune complications remains difficult as few specific assays are available. They mainly concern diseases with the highest incidence, like anti-phospholipid antibodies, lupus anticoagulants, or heparin-dependent antibodies. The present understanding suggests that antibodies to ubiquitous components, like phospholipids or polysaccharides, are actually targeted to proteins with a strong affinity binding to those components: Autoantibodies are not directed to phospholipids, but to phospholipid-binding proteins, and heparin-dependent antibodies are not directed to anticoagulant polysaccharides, but to platelet factor 4. Most pathogenic autoantibodies are of immunoglobulin G (IgG) isotype, but in some cases, IgM or IgA isotypes can be involved. Identification and characterization of autoantibodies associated to hemorrhagic or thrombotic pathologies remains complex at the laboratory level, although they are of high relevance for the right management of concerned patients.

Construction professionals are at the forefront in reinforcing the soil with the use and application of methods and materials that help increase its bearing capacity, since one of the main causes of building collapse and settlement is soft soil. For this study, a five-story reinforced concrete building was designed using structural software and a soil-structure interaction analysis was performed. Immediate and differential settlements were calculated with the application of loads from the structure. Four reinforcement analysis models were considered: 1) without improvement; 2) with soil replacement; 3) with geogrids; and 4) with geogrids and footing width reduction. The bearing capacity was estimated using data from soil studies and material parameters from quarries near the study area in Portoviejo, Ecuador. An adaptation to the formulas of Meyerhof & Hanna (1978) was applied for the soil substitution alternative, while the formulas of Huang & Meng (1997) were used and applied for the geogrids. The aim of this analysis is to obtain a high bearing capacity value of the soil that leads to savings in foundation material and at the same time to achieve low numbers of settlements that are deduced to the safety of the structure. The results of the reinforcement in relation to the natural soil revealed a considerable increase for the geogrid alternatives compared to soil substitution, and a reduction in settlements. The percentages obtained after analysis and calculations demonstrate the benefits of using geogrids under this type of structure.

Every country has a unique style regarding the parliamentary system they follow. This parliamentary system may experience changes or developments that differ from the initial concept. It is expected because each country has other political, cultural, social, and economic conditions. It is normative legal research with a historical and conceptual approach, then conducted in a comparative study. The results of this study found that the French parliamentary system is included in the category of Medium-Strength bicameralism with asymmetrical and incongruent characteristics. The Dutch parliament belongs to medium-strength bicameralism with symmetrical and harmonious features. The Austrian legislature, known as the Bundesrat, does not have the same power as the Nationalrat, so the management of the two chambers of parliament is asymmetrical. Meanwhile, the parliamentary system in Indonesia can be classified as medium-strength bicameralism with asymmetrical and incongruent buildings. The parliamentary system can indirectly affect the effectiveness of the legislature's performance. Sometimes, the system adopted can make parliament an effective and efficient institution or vice versa. A small example is France, which can complete over 50% of proposed legislation in one year. Meanwhile, from 2020-2024, only 17 draft laws were constructed in Indonesia out of 215 registered. This figure is only 7.9% of the total proposed bill. Suppose the parliamentary system adopted has yet to bring parliament into a better, transparent, efficient, and open legislative body. In that case, the system can be re-evaluated by considering the existing ideal parliamentary concept.

Abstract Dopaminergic degeneration is a central feature of Parkinson’s disease (PD), but glial dysfunction may accelerate or trigger neuronal death. In fact, astrocytes play a key role in the maintenance of the blood–brain barrier and detoxification. 6-hydroxydopamine (6OHDA) is used to induce PD in rodent models due to its specific toxicity to dopaminergic neurons, but its effect on astrocytes has been poorly investigated. Here, we show that 6OHDA dose-dependently impairs autophagy in human U373 cells and primary murine astrocytes in the absence of cell death. LC3II downregulation was observed 6 to 48 h after treatment. Interestingly, 6OHDA enhanced NRH:quinone oxidoreductase 2 (NQO2) expression and activity in U373 cells, even if 6OHDA turned out not to be its substrate. Autophagic flux was restored by inhibition of NQO2 with S29434, which correlated with a partial reduction in oxidative stress in response to 6OHDA in human and murine astrocytes. NQO2 inhibition also increased the neuroprotective capability of U373 cells, since S29434 protected dopaminergic SHSY5Y cells from 6OHDA-induced cell death when cocultured with astrocytes. The toxic effects of 6OHDA on autophagy were attenuated by silencing NQO2 in human cells and primary astrocytes from NQO2−/− mice. Finally, the analysis of Gene Expression Omnibus datasets showed elevated NQO2 gene expression in the blood cells of early-stage PD patients. These data support a toxifying function of NQO2 in dopaminergic degeneration via negative regulation of autophagy and neuroprotection in astrocytes, suggesting a potential pharmacological target in PD.

Characterizing Management Units (MUs) with tree-level data is instrumental for a comprehensive understanding of forest structure and for providing information needed to support forest management decision-making. Airborne Laser Scanning (ALS) data may enhance this characterization. While some studies rely on Individual Tree Detection (ITD) methods using ALS data to estimate tree diameters within stands, these methods often face challenges when the goal is to characterize MUs in dense forests. This study proposes a methodology that simulates diameter distributions from LiDAR data using an Area-Based Approach (ABA) to overcome these limitations. Focusing on maritime pine (Pinus pinaster Ait.) MUs within a forest intervention zone in northern Portugal, the research initially assesses the suitability of two highly flexible Probability Density Functions (PDFs), Johnson’s SB and Weibull, for simulating diameter distribution in maritime pine stands in Portugal using the PINASTER database. The selected PDF is then used in conjunction with ABA to derive the variables needed for parameter recovery, enabling the simulation of diameter distributions within each MU. Monte Carlo Simulation (MCS) is applied to generate a sample list of tree diameters from the simulated distributions. The results indicate that this methodology is appropriate to estimate diameter distributions within maritime pine MUs by using ABA combined with Johnson’s SB and Weibull PDFs.

The emergence of pathological manifestations on facades persists globally, with recurring failures occurring often due to repeated construction details or design decisions. This study selected a building with a recurring architectural design and evaluated the stain pattern on its facade using a UAV with an infrared thermal camera. The results showed that advanced technology offers a non-invasive and efficient approach for comprehensive inspections, enabling early detection and targeted interventions to preserve architectural assets without requiring ancillary infrastructure or risking workers at height. The precise identification of damage clarified the real causes of the observed pathological manifestations. Capturing the images allowed accurate inspection, revealing hollow and damp spots not visible to the human eye. Novel results highlight patterns in the appearance of dirt on facades, related to water flow that could have been redirected through proper geometric element execution. The presented inspection methodology, staining standards, and construction details can be easily applied to any building, regardless of location. Sills, drip pans, and flashings must have drip cuts, adequate inclination, and projections to prevent building degradation.

Despite the many potential applications of an accurate indoor positioning system (IPS), no universal, readily available system exists. Much of the IPS research to date has been based on the use of radio transmitters as positioning beacons. Visible light positioning (VLP) instead uses LED lights as beacons. Either cameras or photodiodes (PDs) can be used as VLP receivers, and position estimates are usually based on either the angle of arrival (AOA) or the strength of the received signal. Research on the use of AOA with photodiode receivers has so far been limited by the lack of a suitable compact receiver. The quadrature angular diversity aperture receiver (QADA) can fill this gap. In this paper, we describe a new QADA design that uses only three readily available parts: a quadrant photodiode, a 3D-printed aperture, and a programmable system on a chip (PSoC). Extensive experimental results demonstrate that this design provides accurate AOA estimates within a room-sized test chamber. The flexibility and programmability of the PSoC mean that other sensors can be supported by the same PSoC. This has the potential to allow the AOA estimates from the QADA to be combined with information from other sensors to form future powerful sensor-fusion systems requiring only one beacon.

Viruses in the subfamily Serpentovirinae (order Nidovirales, family Tobaniviridae) can cause significant morbidity and mortality in captive snakes, but documented infections have been limited to snakes of the Boidae, Colubridae, Homalopsidae, and Pythonidae families. Infections can either be subclinical or associated with oral and/or respiratory disease. Beginning in June 2019, a population of over 150 confiscated snakes was screened for serpentovirus as part of a quarantine disease investigation. Antemortem oropharyngeal swabs or lung tissue collected postmortem were screened for serpentovirus by PCR, and 92/165 (56.0%) of snakes tested were positive for serpentovirus. Serpentoviruses were detected in fourteen species of Viperidae native to Asia, Africa, and South America and a single species of Elapidae native to Australia. When present, clinical signs included thin body condition, abnormal behavior or breathing, stomatitis, and/or mortality. Postmortem findings included variably severe inflammation, necrosis, and/or epithelial proliferation throughout the respiratory and upper gastrointestinal tracts. Genetic characterization of the detected serpentoviruses identified four unique viral clades phylogenetically distinct from recognized serpentovirus genera. Pairwise uncorrected distance analysis supported the phylogenetic analysis and indicated that the viper serpentoviruses likely represent the first members of a novel genus in the subfamily Serpentovirinae. The reported findings represent the first documentation of serpentoviruses in venomous snakes (Viperidae and Elapidae), greatly expanding the susceptible host range for these viruses and highlighting the importance of serpentovirus screening in all captive snake populations.

Hyperglycemia increases the heart sensitivity to ischemia-reperfusion (IR), but the underlying cellular mechanisms remain unclear. Mitochondrial dynamics (the processes that govern mitochondrial morphology and their interactions with other organelles, such as the reticulum), has emerged as a key factor in the heart vulnerability to IR. However, it is unknown whether mitochondrial dynamics contributes to hyperglycemia deleterious effect during IR. We hypothesized that (i) the higher heart vulnerability to IR in hyperglycemic conditions could be explained by hyperglycemia effect on the complex interplay between mitochondrial dynamics, Ca2+ homeostasis, and reactive oxygen species (ROS) production; and (ii) the activation of DRP1, a key regulator of mitochondrial dynamics, could play a central role. Using transmission electron microscopy and proteomic analysis, we showed that the interactions between sarcoplasmic reticulum and mitochondria and mitochondrial fission were increased during IR in isolated rat hearts perfused with a hyperglycemic buffer compared with hearts perfused with a normoglycemic buffer. In isolated mitochondria and cardiomyocytes, hyperglycemia increased mitochondrial ROS production and Ca2+ uptake. This was associated with higher RyR2 instability. These results could contribute to explain the early mPTP activation in mitochondria from isolated hearts perfused with a hyperglycemic buffer and in hearts from streptozotocin-treated rats (to increase the blood glucose). DRP1 inhibition by Mdivi-1 during the hyperglycemic phase and before IR induction, normalized Ca2+ homeostasis, ROS production, mPTP activation, and reduced the heart sensitivity to IR in streptozotocin-treated rats. In conclusion, hyperglycemia-dependent DRP1 activation results in higher reticulum-mitochondria calcium exchange that contribute to the higher heart vulnerability to IR.

Abstract Proteogenomic methodologies have enabled the identification of protein sequences in wild species without annotated genomes, shedding light on molecular mechanisms affected by pollution. However, proteomic resources for sentinel species are limited, and organ-level investigations are necessary to expand our understanding of their molecular biology. This study presents proteomic resources obtained from proteogenomic analyses of key organs (hepatopancreas, gills, hemolymph) from three established aquatic sentinel invertebrate species of interest in ecotoxicological/ecological research and environmental monitoring: Gammarus fossarum, Dreissena polymorpha, and Palaemon serratus. Proteogenomic analyses identified thousands of proteins for each species, with over 90% of them being annotated to putative function. Functional analysis validated the relevance of the proteomic atlases by revealing similarities in functional annotation of catalogues of proteins across analogous organs in the three species, while deep contrasts between functional profiles are delimited across different organs in the same organism. These organ-level proteomic atlases are crucial for future research on these sentinel animals, aiding in the evaluation of aquatic environmental risks and providing a valuable resource for ecotoxicological studies.

Background and objectives On 6 April 2022, the UK government implemented mandatory kilocalorie (kcal) labelling regulations for food and drink products sold in the out-of-home food sector (OHFS) in England. Previous assessments of kcal labelling practices in the UK OHFS found a low prevalence of voluntary implementation and poor compliance with labelling recommendations. This study aimed to examine changes in labelling practices preimplementation versus post implementation of mandatory labelling regulations in 2022.Methods In August–December 2021 (preimplementation) and August–November 2022 (post implementation), large OHFS businesses (250 or more employees) subject to labelling regulations were visited. At two time points, a researcher visited the same 117 food outlets (belonging to 90 unique businesses) across four local authorities in England. Outlets were rated for compliance with government regulations for whether kcal labelling was provided at any or all point of choice, provided for all eligible food and drink items, provided per portion for sharing items, if labelling was clear and legible and if kcal reference information was displayed.Results There was a significant increase (21% preimplementation vs 80% post implementation, OR=40.98 (95% CI 8.08 to 207.74), p

We studied the effect of microstructural abnormalities in the corpus callosum on language development in 348 infants born very prematurely. We discovered that the fractional anisotropy of the corpus callosum anterior midbody was a significant predictor of standardized language scores at 2 years, independent of clinical and social risk factors.

BackgroundThe soft drinks industry levy (SDIL) in the United Kingdom has led to a significant reduction in household purchasing of sugar in drinks. In this study, we examined the potential medium- and long-term implications for health and health inequalities among children and adolescents in England.Methods and findingsWe conducted a controlled interrupted time series analysis to measure the effects of the SDIL on the amount of sugar per household per week from soft drinks purchased, 19 months post implementation and by index of multiple deprivation (IMD) quintile in England. We modelled the effect of observed sugar reduction on body mass index (BMI), dental caries, and quality-adjusted life years (QALYs) in children and adolescents (0 to 17 years) by IMD quintile over the first 10 years following announcement (March 2016) and implementation (April 2018) of the SDIL. Using a lifetable model, we simulated the potential long-term impact of these changes on life expectancy for the current birth cohort and, using regression models with results from the IMD-specific lifetable models, we calculated the impact of the SDIL on the slope index of inequality (SII) in life expectancy. The SDIL was found to have reduced sugar from purchased drinks in England by 15 g/household/week (95% confidence interval: -10.3 to -19.7). The model predicts these reductions in sugar will lead to 3,600 (95% uncertainty interval: 946 to 6,330) fewer dental caries and 64,100 (54,400 to 73,400) fewer children and adolescents classified as overweight or obese, in the first 10 years after implementation. The changes in sugar purchasing and predicted impacts on health are largest for children and adolescents in the most deprived areas (Q1: 11,000 QALYs [8,370 to 14,100] and Q2: 7,760 QALYs [5,730 to 9,970]), while children and adolescents in less deprived areas will likely experience much smaller simulated effects (Q3: -1,830 QALYs [-3,260 to -501], Q4: 652 QALYs [-336 to 1,680], Q5: 1,860 QALYs [929 to 2,890]). If the simulated effects of the SDIL are sustained over the life course, it is predicted there will be a small but significant reduction in slope index of inequality: 0.76% (95% uncertainty interval: -0.9 to -0.62) for females and 0.94% (-1.1 to -0.76) for males.ConclusionsWe predict that the SDIL will lead to medium-term reductions in dental caries and overweight/obesity, and long-term improvements in life expectancy, with the greatest benefits projected for children and adolescents from more deprived areas. This study provides evidence that the SDIL could narrow health inequalities for children and adolescents in England.

BackgroundReducing healthcare disparities among children is extremely important given the potential impact of these disparities on long-term health-related quality of life (HRQL). Race and parental socioeconomic status (SES) are associated with child HRQL, but these associations have not been studied in infants born extremely preterm (EP), a population at increased risk for physical, cognitive, and psychosocial impairments. Achieving health equity for infants born EP across their life course requires identifying the impact of racism and SES on HRQL.ObjectiveWe aimed to evaluate the association between self-reported maternal race, SES factors, and HRQL among 10-year-old children born EP.Design/methodsParticipants were identified from an ongoing multicenter prospective longitudinal study of Extremely Low Gestational Age Newborns (ELGAN Study), born between 2002 and 2004, and evaluated at 10 years of age using the Pediatric quality of life (QoL) Inventory completed by their parent or guardian, assessing physical, emotional, social, school, and total (composite) QoL domains. Multivariable regression models were used to evaluate the relationship between QoL scores and self-identified maternal race, adjusting for SES factors (education level, marital status, and public insurance).ResultsOf 1,198 study participants who were alive at 10 years of age, 863 (72.0%) were evaluated at 10 years of age. Differences in mean 10-year QoL scores across racial groups were observed and were significant on univariate analysis. However, these associations attenuated when adjusted for the marital status, public insurance status, and education status of mothers. A comparison of children with English as the primary language spoken at home vs. any other language revealed a significant difference only in school QoL, in which non-English language was associated with more favorable school QoL scores.ConclusionsAmong 10-year-old children born EP, differences in parent-reported QoL were associated with maternal SES factors but not with race. Our results suggest that interventions designed to improve the SES of mothers may enhance the QoL of children born EP. Furthermore, these results underscore that race is a social construct, rather than a biological variable, as we work toward greater equity in care provision.