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Abstract The emergence of SARS-CoV-2 into a highly susceptible global population was primarily driven by human mobility-induced introduction events. Especially in the early stages, understanding mobility was vital to mitigating the pandemic prior to widespread vaccine availability. We conducted a systematic review of studies published from January 1, 2020, to May 9, 2021, that used population-level human mobility data to understand SARS-CoV-2 transmission. Of the 5505 papers with abstracts screened, 232 were included in the analysis. These papers focused on a range of specific questions but were dominated by analyses focusing on the USA and China. The majority included mobile phone data, followed by Google Community Mobility Reports, and few included any adjustments to account for potential biases in population sampling processes. There was no clear relationship between methods used to integrate mobility and SARS-CoV-2 data and goals of analysis. When considering papers focused only on the estimation of the effective reproductive number within the US, there was no clear relationship identified between this measure and changes in mobility patterns. Our findings underscore the need for standardized, systematic ways to identify the source of mobility data, select an appropriate approach to using it in analysis, and reporting.

Abstract Although rare diseases (RDs) affect over 260 million individuals worldwide, low data quality and scarcity challenge effective care and research. This work aims to harmonise the Common Data Set by European Rare Disease Registry Infrastructure, Health Level 7 Fast Healthcare Interoperability Base Resources, and the Global Alliance for Genomics and Health Phenopacket Schema into a novel rare disease common data model (RD-CDM), laying the foundation for developing international RD-CDMs aligned with these data standards. We developed a modular-based GitHub repository and documentation to account for flexibility, extensions and further development. Recommendations on the model’s cardinalities are given, inviting further refinement and international collaboration. An ontology-based approach was selected to find a common denominator between the semantic and syntactic data standards. Our RD-CDM version 2.0.0 comprises 78 data elements, extending the ERDRI-CDS by 62 elements with previous versions implemented in four German university hospitals capturing real world data for development and evaluation. We identified three categories for evaluation: Medical Data Granularity, Clinical Reasoning and Medical Relevance, and Interoperability and Harmonisation.

Abstract This paper introduces the Welsh Advanced Neuroimaging Database (WAND), a multi-scale, multi-modal imaging dataset comprising in vivo brain data from 170 healthy volunteers (aged 18–63 years), including 3 Tesla (3 T) magnetic resonance imaging (MRI) with ultra-strong (300 mT/m) magnetic field gradients, structural and functional MRI and nuclear magnetic resonance spectroscopy at 3 T and 7 T, magnetoencephalography (MEG), and transcranial magnetic stimulation (TMS), together with trait questionnaire and cognitive data. Data are organised using the Brain Imaging Data Structure (BIDS). In addition to raw data, we provide brain-extracted T1-weighted images, and quality reports for diffusion, T1- and T2-weighted structural data, and blood-oxygen level dependent functional tasks. Reasons for participant exclusion are also included. Data are available for download through our GIN repository, a data access management system designed to reduce storage requirements. Users can interact with and retrieve data as needed, without downloading the complete dataset. Given the depth of neuroimaging phenotyping, leveraging ultra-high-gradient, high-field MRI, MEG and TMS, this dataset will facilitate multi-scale and multi-modal investigations of the healthy human brain.

Abstract Background Over the last decades, universal health coverage (UHC) has been promoted in south-east Asia (SEA), where many countries still need to ensure adequate financial protection to their populations. However, successful health financing reforms involve complex interactions among a range of stakeholders, as well as with context factors, including shocks and crises of different nature. In this article, we examine recent health financing reforms in Nepal, Thailand and Indonesia, using a political economy lens. The objective is to understand whether and how crises can be utilised to progress UHC and to analyse the strategies used by reformers to benefit from potential windows of opportunity. Methods The study adopted a retrospective, comparative case study design, using a shared framework and tools. The case studies mapped the contexts, including economic, political, social trends and any shocks which had recently occurred. A focal health financing reform was chosen in each setting to examine, probing the role of crisis in relation to it, through the key elements of the reform process, content and actors. Data sources were largely qualitative and included literature and document review (144 documents included across the three cases) and key informant interviews (26 in total). Results The findings, which bring out similarities and differences in the roles played by change teams across the settings, highlight the importance of working closely with political leaders and using a wide range of strategies to build coalitions and engage or block opponents. Changing decision rules to block veto points was significant in one case, and all three cases used participation and dialogue strategically to further reforms. More broadly, the links with context emerged as important, with prior conflicts and economic crises creating a sense of urgency about addressing health inequities, while in all countries appeal was made to underlying values to enhance the legitimacy of the reforms. Conclusion The lessons from these case studies include that technical teams can and should engage in Political Economy Analysis (PEA) thinking and strategizing, including being aware of and adaptable to the changing PEA landscape and prepared to take advantage of windows of opportunity, including, but not limited to, those emerging from crisis. There is a need for more empirical studies in this area and sharing of lessons to support future reforms to increase health coverage and financial protection, including in the face of likely shocks.

Abstract Understanding how the traits of lineages are related to diversification is key for elucidating the origin of variation in species richness. Here, we test whether traits are related to species richness among lineages of trees from all major biogeographical settings of the lowland wet tropics. We explore whether variation in mortality rate, breeding system and maximum diameter are related to species richness, either directly or via associations with range size, among 463 genera that contain wet tropical forest trees. For Amazonian genera, we also explore whether traits are related to species richness via variation among genera in mean species-level range size. Lineages with higher mortality rates—faster life-history strategies—have larger ranges in all biogeographic settings and have higher mean species-level range sizes in Amazonia. These lineages also have smaller maximum diameters and, in the Americas, contain dioecious species. In turn, lineages with greater overall range size have higher species richness. Our results show that fast life-history strategies influence species richness in all biogeographic settings because lineages with these ecological strategies have greater range sizes. These links suggest that dispersal has been a key process in the evolution of the tropical forest flora.

Abstract This study examined whether an emotion socialisation parenting program, Tuning in to Toddlers (TOTS), contributed to observed improvements in mother-toddler emotional availability. Parents of toddlers aged 18–36 months were recruited through childcare centres and maternal child health centres in Melbourne, Australia and were allocated to either an intervention or a waitlist control condition in a cluster-randomised controlled design. Parents in the intervention condition participated in 6 group sessions of TOTS. Baseline and 12-month follow up observation assessments for 99 mother-toddler dyads (intervention, n = 50; control, n = 49) were coded using the Emotional Availability Scales (4th edition) and analysed for between-group differences and clinically reliable change. Compared with the control condition, mothers in the intervention condition showed significant improvements in maternal sensitivity (p = 0.004). Further, significantly more intervention dyads reliably improved on maternal structuring (p =0 .013) and child responsiveness (p =0 .042), whereas those who received no intervention reliably deteriorated on maternal sensitivity (p = 0.001) and non-intrusiveness (p = 0.040). Thus, the preliminary evidence from this study indicates that an emotion socialisation program delivered to parents of toddlers may influence emotional availability.

Abstract Diffuse large B-cell lymphoma (DLBCL) is an aggressive hematopoietic neoplasm that affects humans as well as dogs. While previous studies on canine DLBCL (cDLBCL) have significantly advanced our understanding of the disease, the majority of this research has relied on whole-exome sequencing, which is limited in its ability to detect copy number aberrations and other genomic changes beyond coding regions. Furthermore, many of these studies lack sufficient clinical follow-up data, making it difficult to draw meaningful associations between genetic variants and patient outcomes. Our study aimed to characterize the mutational landscape of cDLBCL using whole-genome sequencing of matched tumor-normal samples obtained from a cohort of 43 dogs previously enrolled in a clinical trial for which longitudinal follow-up was available. We focused on identifying genes that were significantly or recurrently mutated with coding point mutations, copy number aberrations, and their associations with patient outcomes. We identified 26 recurrently mutated genes, 18 copy number gains, and 8 copy number losses. Consistent with prior studies, the most commonly mutated genes included TRAF3, FBXW7, POT1, TP53, SETD2, DDX3X and TBL1XR1. The most prominent copy number gain occurred on chromosome 13, overlapping key oncogenes such as MYC and KIT, while the most frequent deletion was a focal loss on chromosome 26, encompassing IGL, PRAME, GNAZ, RAB36, RSPH14, and ZNF280B. Notably, our set of recurrently mutated genes was significantly enriched with genes involved in epigenetic regulation. In particular, we identified hotspot mutations in two histone genes, H3C8, and LOC119877878, resulting in H3K27M alterations predicted to dysregulate gene expression. Finally, a survival analysis revealed that H3K27M mutations in H3C8 were associated with increased hazard ratios for progression-free survival. No copy number aberrations were associated with survival. These findings underscore the critical role of epigenetic dysregulation in cDLBCL and affirm the dog as a relevant large animal model for interrogating the biological activity of novel histone-modifying treatment strategies.

Abstract Background In Mali, cancer patients are often diagnosed at stage III or IV. Tumor wounds are more frequent and associated with malodorous exudates, responsible for an altered quality of life and stigmatization of patients. Cinesteam® Cinnamon Dressing is an adsorbent dressing designed to reduce odors. This study aimed at demonstrating the feasibility of routine use of cinnamon dressing in the Malian context, and to assess its effect on tumor wound odors. Patients and methods This is a prospective observational pilot study conducted jointly by the oncology department of the Point G University hospital in Bamako and Médecins Sans Frontières France. Included patients suffered from a malignant malodourous wound and were treated with cinnamon dressing. The primary endpoint was wound odor. Secondary endpoints were appetite, duration of dressing efficacy and ease of use. Results Forty patients were included in this pilot study. Complete data and follow-up were available for 19 patients only. The odor score reported by patients was significantly decreased after 10 days of cinnamon dressing (odor score 1.7 versus 3.3, t-test 0.00003). Seventeen patients reported that the CINESTEAM® dressing was easy to use, even for patients receiving home-based palliative care in remote areas. The dressing provided an odor control that lasted more than 24 h. One year after inclusion, more than half of the patients had died of their cancer, indicating a very advanced stage at diagnosis. The cinnamon dressing had no effect on appetite, but most of the patients were undergoing palliative chemotherapy, which may account for this result. Conclusion The use of innovative dressings is feasible, even in very deprived contexts, and might decrease the discomfort linked with unpleasant odors in tumoral wounds. Odor management is crucial to restore self-esteem and to prevent patients’ stigma and isolation.

Abstract Background Globally, the increase in antimicrobial resistance is of great concern. In Denmark, the pig sector is accountable for the majority of antimicrobial usage in animals. As new-born piglets are at risk of developing infectious omphalitis, and many pigs are treated by antimicrobials within the first days of life, an early and accurate diagnosis of the disease is imperative to maintain animal welfare and reduce the antimicrobial usage. The aim of the present study was to compare histopathological and microbiological findings in piglets clinically diagnosed with and without omphalitis during the first three days after birth. Results A total of 98 case piglets with omphalitis and 98 control piglets without omphalitis, based on clinical examinations during the first three days of life, were included. Of the 196 piglets, 79 (38 cases and 41 controls) presented histopathological omphalitis. Post mortem, the volume of the umbilicus was significantly enlarged in cases compared to controls (p = 0.01). Except for a group of bacteria unidentified by matrix-assisted laser desorption ionisation time-of-flight (MALDI-TOF) (p = 0.02), no apparent association was found between histopathologically diagnosed omphalitis and the prevalence of specific pathogens (p > 0.05). The frequency of histopathologically diagnosed omphalitis tended to increase with increasing age in both cases and controls. The frequency of piglets with both histopathological omphalitis and arthritis/synovitis was significantly different among cases and controls (p = 0.05). This was due to all controls, and none of the cases, with arthritis/synovitis presented histopathological omphalitis. Conclusion The clinical differentiation between omphalitis cases and controls did not correspond to the histological diagnosis of omphalitis in zero-to-three days old piglets. An inaccurate clinical diagnosis complicates prudent use of antimicrobials in pig herds. In addition, animal welfare may be hampered in infected piglets due to lack of treatment and in healthy piglets due to the antimicrobial effect on the gut microbiome.

Abstract Lung cancer is the leading cause of cancer-related deaths. An enhanced understanding of the immune microenvironments within these tumours may foster more precise and efficient treatment, particularly for immune-targeted therapies. The spatial architectural differences between lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) are relatively unexplored. Here, we applied imaging mass cytometry to a balanced cohort of LUAD and LUSC patients, matched for clinical factors such as age, sex, and smoking history, to analyze 204 histopathology images of tumours from 102 individuals with non-small cell lung cancer (NSCLC). By analyzing interactions and broader cellular networks, we interrogate the tumour microenvironment to understand how immune cells are spatially organized in clinically matched adenocarcinoma and squamous cell carcinoma subsets. This spatial analysis revealed distinct patterns of immune cell aggregation, particularly among macrophage populations, that correlated with patient prognosis differentially in adenocarcinoma and squamous cell carcinoma, suggesting potential new strategies for therapeutic intervention. Our findings underscore the importance of analyzing NSCLC histological subtypes separately when investigating the spatial immune landscape, as microenvironmental characteristics and cellular interactions differed by subtype. Recognizing these distinctions is essential for designing precision therapies tailored to each subtype’s unique immune architecture, ultimately enhancing patient outcomes.

Abstract Labelled compounds bearing hydrogen isotopes are keystones in diverse areas constituting a multi-billion dollar global market including drugs, diagnostics, biology, toxicology and smart materials. While hydrogen deuterium exchange (HDE) methods hold promise as relevant tools for the late-stage and one-step preparation of deuterium-labelled compounds, they often fall short in achieving sufficient isotopic purity combined either with a site-selectivity or with a full deuteration process, highlighting the need for further development and optimisation. This report pinpoints an approach to unlock the potential of HDE using the concept of iterative runs in continuous-flow technology (recirculation process). This closed-loop process grants access now to deuterated compounds with high isotopic purities, labelled at a precise site or perdeuterated on demand, in a fast, productive, and environmentally friendly way.

Abstract Perturbation of DNA replication, for instance by hydroxyurea-dependent dNTP exhaustion, often leads to stalling or collapse of replication forks. This triggers a replication stress response that stabilizes these forks, activates cell cycle checkpoints, and induces expression of DNA damage response genes. While several factors are known to act in this response, the full repertoire of proteins involved remains largely elusive. Here, we develop Replication-IDentifier (Repli-ID), which allows for genome-wide identification of regulators of DNA replication in Saccharomyces cerevisiae. During Repli-ID, the replicative polymerase epsilon (Pol ε) is tracked at a barcoded origin of replication by chromatin immunoprecipitation (ChIP) coupled to next-generation sequencing of the barcode in thousands of hydroxyurea-treated yeast mutants. Using this approach, 423 genes that promote Pol ε binding at replication forks were uncovered, including LGE1 and ROX1. Mechanistically, we show that Lge1 affects replication initiation and/or fork stability by promoting Bre1-dependent H2B mono-ubiquitylation. Rox1 affects replication fork progression by regulating S-phase entry and checkpoint activation, hinging on cellular ceramide levels via transcriptional repression of SUR2. Thus, Repli-ID provides a unique resource for the identification and further characterization of factors and pathways involved in the cellular response to DNA replication perturbation.

Abstract Background The TARGET Protein trial will evaluate the effect of greater enteral protein delivery (augmented protein) on clinical outcomes of critically ill adult patients when compared to usual care. Objective To describe the statistical analysis plan for the TARGET Protein trial. Methods TARGET Protein is a cluster randomized, cross-sectional, double cross-over, open-label, registry-embedded, pragmatic clinical trial conducted across Australia and New Zealand. The trial randomized eight intensive care units (ICU) to receive enteral formula containing either higher dose enteral protein (augmented protein) or usual dose protein in a 1:1 ratio. Each ICU received one trial formula for a 3-month period and then switched to the alternate formulae. This sequence was repeated, for a total trial length of 12 months. The primary outcome is the number of days free of the index hospital and alive at day 90. Secondary outcomes include proportion of patients alive at day 90, survivor-only analysis of days free of the index hospital at day 90, duration of invasive ventilation, ICU and hospital length of stay, incidence of tracheostomy insertion, renal replacement therapy, and discharge destination. The statistical methods and models which will be used to estimate the effects for the primary and secondary outcomes are described. All statistical models will account for the cluster-randomized cross-over design to ensure correct estimation of the 95% confidence intervals. Trial enrolment is complete with 3412 patients enrolled. Data linkage is ongoing. Conclusion This statistical analysis plan enables transparent reporting of the TARGET Protein trial. It will reduce the risk of potential selective reporting biases. Trial registration Australian New Zealand Clinical Trials Registry (ACTRN12621001484831). Registered on November 1, 2021.

Abstract Background Fear of falling (FoF) is estimated to be prevalent in over 50% of older adults and several studies suggest that it negatively affects health-related quality of life (HrQoL). Unlike previous studies that examined only few mediating variables, this study aimed to develop a more comprehensive path model explaining the association between FoF and HrQoL. Methods A theoretical path model was developed based on existing evidence and expert feedback and fitted to cross-sectional baseline data on 385 community-dwelling (pre-)frail older adults from the PromeTheus randomized controlled trial using robust weighted least squares estimation. FoF and HrQoL were operationalized by the Short Falls Efficacy Scale International and EQ-5D Index, respectively. The model included potential explanatory pathways through physical activity (German Physical Activity Questionnaire for middle-aged and older adults), physical capacity (Short Physical Performance Battery), physical performance (Late-Life Function and Disability Instrument [LLFDI] function component), disability (LLFDI disability component – short form), and affect (visual analogue scales on ‘happiness’, ‘sadness’, ‘calmness’ and ‘tension’). Age, sex, education, and previous falls were considered as covariates. Results The model demonstrated good fit to the data and the remaining direct effect of FoF on HrQoL was small (β=-0.05). Physical capacity and physical performance were the most important mediators (combined indirect effect of β=-0.17, accounting for > 50% of the total effect). Pathways of minor individual relevance (e.g. through disability or affect) contributed considerably to the total indirect effect when combined. Controlling for sociodemographic data and previous falls only had minor effects on model fit and path coefficients. Conclusion Physical capacity and physical performance are particularly important levers for reducing the impact of FoF on HrQoL through interventions. However, the other pathways also had a considerable influence when taken together. Hence, research on the association of FoF and HrQol should acknowledge the complexity of causal pathways that may explain this association and not neglect minor pathways. The proposed model should be tested on an alternative sample, using longitudinal data, and extended to include additional explanatory factors (e.g. activity avoidance). Trial registration German Clinical Trials Register, ID: DRKS00024638, https://drks.de/search/en/trial/DRKS00024638 , date of registration: March 11th 2021.

Abstract Obstructive sleep apnoea syndrome (OSAS) is a relatively common condition. It has a range of negative health and quality of life implications, but there are established tests to detect it, and recommended treatment pathways which have been well tested. OSAS is prevalent in people with severe mental illness (SMI), and research suggests it is under-detected in this group. This study aimed to examine and explore barriers and facilitators to the detection and treatment of OSAS in people with severe mental illnesses. Staff and patients with a range of relevant experiences were interviewed, and a large scale survey of potential OSAS referrers was conducted. Interviews were analysed thematically, survey responses were summarised descriptively, and results are presented together for comparison and enhanced interpretation. The results highlight a lack of awareness of OSAS outside of specialist sleep services, resulting in poor detection and treatment of OSAS in people with SMI. Comorbidities, symptoms and circumstances of this group may make the presence of OSAS less obvious, and can make diagnosis and adapting to treatment more difficult, but also emphasise the benefits of successful continuous positive airway pressure (CPAP) treatment in this group. The challenges of adapting to CPAP were described and acknowledged, but the impact of successful CPAP was for some life changing. The harm of delayed diagnosis was perceived as unjust. We recommend increased screening for OSAS in people with SMI, supported by increased education and training about OSAS in staff who work with people with severe mental illnesses, and increased awareness in service users and carers.

Abstract Background The prescribing of antidepressants and antipsychotics to children has increased worldwide, but little is known about how changes in drug funding policy influence the practice. In 2018, Ontario introduced a universal pharmacare program (OHIP+) for children and youth, amending it in April 2019 to cover only those without private insurance. We examined the association of these policy changes with antipsychotic and antidepressant medication prescribing. Methods We conducted a population-based study of antidepressant and antipsychotic medication dispensing to children ≤ 18 years old between September 1, 2014, and February 29, 2020. We obtained dispensing data from the IQVIA Geographic Prescription Monitor database, and used interventional autoregressive integrated moving average models to examine whether the implementation of OHIP + and its subsequent revision were associated with changes in dispensing. Results The implementation of OHIP + was not associated with changes in the rate of antidepressants (-19.3 units per 1,000 population; 95% confidence interval [CI]: -41.7 to 3.1) or antipsychotics (+ 1.0 unit per 1,000 population; 95% CI: -5.4 to 7.5) dispensed. Similarly, subsequent changes to the program restricting coverage to children without private insurance were not associated with antidepressant (0.3 units per 1,000; 95% CI: -7.4 to 7.9) or antipsychotic (1.0 units per 1,000; 95% CI: -0.9 to 2.9) dispensing trends. Conclusion Implementation of a publicly-funded pharmacare program did not influence trends in antidepressant or antipsychotic medication dispensing among children.

In educational research, the complexity of interventions and the diversity of contexts challenge the adequacy of existing reporting standards, primarily tailored for health interventions and randomised controlled trials. Recognising the critical need for appropriate tools to support education research, we developed two checklists: the CheckList Of Standards of reporting in Education Research (CLOSER) and the Checklist for Intervention Description of Education Research (CIDER). CLOSER was designed to guide the comprehensive reporting of quantitative educational intervention research from the abstract to the discussion for multiple study designs. Concurrently, CIDER details the precise features of educational interventions. The final refinements of CLOSER and CIDER comprise of 34 and 17 items, respectively, developed through a five-stage process, including tool adaptation, expert feedback, a 2-round modified Delphi consensus survey, and final refinements. These checklists aim to enhance the clarity of educational intervention research findings, facilitating their replicability and subsequent meaningful translation into practice and policy. This addresses the gap in educational research reporting standards and sets the stage for a more robust, evidence-informed approach to educational intervention development and evaluation.

Abstract Underwater photogrammetry is routinely used to monitor large areas of complex and heterogeneous ecosystems, such as coral reefs. However, deriving data on benthic components (i.e. sand, rubble, coral and algae) from photogrammetry products has remained challenging due to the highly time‐consuming process of manual data extraction. We developed a machine learning approach to quantify benthic community composition in coral reefs from orthomosaics, which requires no manual delineation of benthic components for training or implementation. The current study presents RapidBenthos, an automated workflow that segments and classifies large‐area images. Our pipeline (1) uses a pre‐trained segmentation model, eliminating the need for manually generated fine‐scale segmented training data, and (2) classifies the resulting segments from multiple views using the underlying survey images, allowing for classification to fine taxonomic levels. Within a test photomosaic built from a coral reef area of 40 m−2, the model automatically detected 43 different benthic classes. Validation resulted in an overall classification accuracy of 0.96 and a segmentation accuracy of 0.87, when compared to a manually digitised replica. The RapidBenthos workflow was 195 times faster than manual segmentation and classification. Additional validation of 524 Acropora coral colonies from 11 additional test plots resulted in a segmentation accuracy of 0.92 and classification accuracy of 0.88 to the coarser ‘Acropora’ group. RapidBenthos has the capability to extract an unprecedented level of data from photomosaics of coral reefs or other complex environments, allowing to sustainably scale photogrammetric monitoring technique both in replicate and survey extent, which consequently can lead to new research questions and more informed ecosystem management.

Background and objective: Few longitudinal studies have described the prevalence and development of biochemical hypogonadism in aging testicular cancer survivors (TCSs) in comparison to men from the general population (control subjects). Methods: Serum total and free testosterone (Ttotal, Tfree) were measured in 593 TCSs median11 and 27 years after TC diagnosis (Survey-First; Survey-Last). Post-treatment adverse health outcomes (AHOs) were recorded. The results were compared to those in 578 control subjects. Treatment was stratified as surgery alone, radiotherapy alone, or platinum-based chemotherapy. Biochemical hypogonadism was defined as Ttotal

Abstract Background Doctors’ unwillingness to share responsibility acts as a major barrier to interprofessional collaboration (IPC). Educating both doctors and allied health professionals in taking on or relinquishing responsibility could enhance IPC. Yet there is no evidence that these educational efforts increase IPC willingness. This study aims to (1) compare the willingness to take on or relinquish responsibility for decision-making in patient care and their willingness to strengthen IPC between members of five main health professions, and (2) investigate associations between the willingness to take on or relinquish responsibility and the willingness to strengthen IPC. Methods We conducted a cross-sectional survey targeting pharmacists, doctors, medical practice assistants, nurses, and physiotherapists in Switzerland. Group differences were assessed, and associations were examined using multivariable logistic regression analyses. Results Overall, 3670 health professionals participated. Members of all allied health professions were highly willing to take on more responsibility for decision-making for patient care (ranging from 74.3% to 86.5%). Medical practice assistants (52.3%) and nurses (46.8%) were highly willing to relinquish responsibility, less so pharmacists (34.2%) and physiotherapists (37.8%); doctors were torn between high (49.2%) and neither high nor low willingness (38%). Members of all professions were highly willing to strengthen IPC (ranging from 76.4 to 91.2%). We found a strong, statistically significant relationship between willingness to take on more responsibility and willingness to strengthen IPC (OR = 5.30, p

Abstract Background Mirtazapine is used to treat depression worldwide, and the effects of mirtazapine on depression rating scales are well-known. Our primary objective was to assess the risks of adverse events with mirtazapine for major depressive disorder. Methods We searched relevant sources from inception to 7 March 2024 for randomised clinical trials comparing mirtazapine versus placebo in adults with major depressive disorder. The primary outcomes were suicides or suicide attempts, serious adverse events, and non-serious adverse events. Data were synthesised using meta-analysis and Trial Sequential Analysis. Results We included 17 trials randomising 2,131 participants to mirtazapine versus placebo. All results were at high risk of bias, and the certainty of the evidence was very low. The included trials assessed outcomes at a maximum of 12 weeks after randomisation. Meta-analysis and Trial Sequential Analysis showed insufficient information to determine the effects of mirtazapine on the risks of suicides or suicide attempts and serious adverse events. Meta-analyses showed that mirtazapine increased the risks of somnolence, weight gain, dry mouth, dizziness, and increased appetite but decreased the risk of headaches. Conclusions There is a lack of evidence on the effects of mirtazapine on suicides and serious adverse events. Mirtazapine increases the risks of somnolence, weight gain, dry mouth, dizziness, and increased appetite. Mirtazapine might decrease the risk of headaches. The long-term effects of mirtazapine are unknown. Prospero id CRD42022315395.

Abstract Background The large language model ChatGPT can now accept image input with the GPT4-vision (GPT4V) version. We aimed to compare the performance of GPT4V to pretrained U-Net and vision transformer (ViT) models for the identification of the progression of multiple sclerosis (MS) on magnetic resonance imaging (MRI). Methods Paired coregistered MR images with and without progression were provided as input to ChatGPT4V in a zero-shot experiment to identify radiologic progression. Its performance was compared to pretrained U-Net and ViT models. Accuracy was the primary evaluation metric and 95% confidence interval (CIs) were calculated by bootstrapping. We included 170 patients with MS (50 males, 120 females), aged 21–74 years (mean 42.3), imaged at a single institution from 2019 to 2021, each with 2–5 MRI studies (496 in total). Results One hundred seventy patients were included, 110 for training, 30 for tuning, and 30 for testing; 100 unseen paired images were randomly selected from the test set for evaluation. Both U-Net and ViT had 94% (95% CI: 89–98%) accuracy while GPT4V had 85% (77–91%). GPT4V gave cautious nonanswers in six cases. GPT4V had precision (specificity), recall (sensitivity), and F1 score of 89% (75–93%), 92% (82–98%), 91 (82–97%) compared to 100% (100–100%), 88 (78–96%), and 0.94 (88–98%) for U-Net and 94% (87–100%), 94 (88–100%), and 94 (89–98%) for ViT. Conclusion The performance of GPT4V combined with its accessibility suggests has the potential to impact AI radiology research. However, misclassified cases and overly cautious non-answers confirm that it is not yet ready for clinical use. Relevance statement GPT4V can identify the radiologic progression of MS in a simplified experimental setting. However, GPT4V is not a medical device, and its widespread availability highlights the need for caution and education for lay users, especially those with limited access to expert healthcare. Key Points Without fine-tuning or the need for prior coding experience, GPT4V can perform a zero-shot radiologic change detection task with reasonable accuracy. However, in absolute terms, in a simplified “spot the difference” medical imaging task, GPT4V was inferior to state-of-the-art computer vision methods. GPT4V’s performance metrics were more similar to the ViT than the U-net. This is an exploratory experimental study and GPT4V is not intended for use as a medical device. Graphical Abstract

Abstract Introduction Group Interpersonal Therapy (IPT), an evidence-based treatment of depression recommended by the WHO mhGAP Intervention Guide, was implemented through a task-shifting approach in Senegal, as a treatment for depressed people living with HIV (PLWH). Since a description of the resources used and the implementation costs incurred is necessary to inform policymakers better, this study aimed to estimate the costs associated with its implementation. Methods Intervention costs were analyzed using an “ingredients-based costing approach” from the provider’s perspective. We identified and described the start-up and implementation costs for the initial phase and a projection over 5 years (implementation at capacity). We estimated total annual costs and cost per beneficiary. We conducted a scenario analysis to highlight some cost uncertainties and their impacts. Results The total annual costs were estimated at $4064 for the initial phase and $8161 for the implementation at capacity. The training was the main cost driver representing approximately 60% of the total annual costs. The cost per beneficiary receiving group IPT was estimated at $65 for the implementation at capacity. The scenario analysis also illustrated the importance of parameters like the screening strategy, training activities, and allocation to cover transport costs mobilized by participants. Conclusion This cost analysis highlighted the costs and cost allocations required to implement group IPT in Senegal to treat depression in PLWH. This preliminary work should enable policymakers to identify the optimal resources to be mobilized to implement and ensure the sustainability of this therapy in HIV at a country-level program.

Abstract Background In moderate-to-high malaria transmission regions, the World Health Organization recommends intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) alongside insecticide-treated bed nets to reduce the adverse consequences of pregnancy-associated malaria. Due to high-grade Plasmodium falciparum resistance to SP, novel treatment regimens need to be evaluated for IPTp, but these increase pill burden and treatment days. The present qualitative study assessed the acceptability of IPTp-SP plus dihydroartemisinin-piperaquine (DP) in Papua New Guinea, where IPTp-SP was implemented in 2009. Methods Individual in-depth interviews (IDIs) and focus group discussions were conducted at health facilities where a clinical trial evaluated IPTp-SP plus DP (three-day regimen) versus IPTp-SP plus DP-placebo. IDIs were conducted with: (1) trial participants at different stages of engagement with ANC and IPTp, e.g. first antenatal clinic visit, subsequent antenatal clinic visits and postpartum; (2) local health workers (nurses, community health workers, midwives, health extension officers, doctors); and (3) representatives of district, provincial and national health authorities involved in programming ANC and IPTp. Focus group discussions comprised pregnant women only, including those engaged in the clinical trial and those receiving routine ANC outside of the trial. All interviews were audio recorded and transcribed. Transcripts were analysed using inductive and deductive thematic analysis applying a framework assessing: affective attitude, burden, ethicality, intervention coherence, opportunity costs, perceived effectiveness, and self-efficacy. Results Women expressed positive feelings and attitudes towards SP plus DP/DP-placebo; reported limited side effects; and found the size, number, colour, and taste of study medicines acceptable. Health workers and policymakers were concerned that, compared to SP alone, additional tablets, frequency (three-day regimen), and tablet size might be barriers to acceptability for users outside a non-trial setting. There was a high perceived effectiveness of SP plus DP; most women reported that they did not get malaria or felt sick during pregnancy. Broader healthcare benefits received through trial participation and the involvement of health workers, relatives and community members in the clinical trial enabled antenatal clinic attendance and perceived acceptability of this IPTp regimen. Conclusions In the trial context, IPTp-SP plus DP was acceptable to both users and providers. Healthcare providers were concerned about the realities of acceptability and adherence to SP plus DP outside a clinical trial setting.

Abstract Background Caregiver concern is the main driver to paediatric emergency departments visits. Understanding caregiver worries is crucial to guide patients to the most appropriate healthcare setting. Previous research shows mixed findings on the accordance between caregiver assessment and professional triage. Methods We assessed data from two questionnaire-based studies conducted over 27 months in two tertiary paediatric emergency departments in Switzerland to compare caregiver perception of their child’s medical acuity and standard nurse triage. Furthermore, we examined socioeconomic factors associated with caregiver perception. Results Our study of 2,126 children seen in the two paediatric emergency departments showed that caregiver assessment aligned well with the acuity assigned by professional triage in 89% (1,901/2,126) of cases. In 142 cases (7%, 142/2,126), caregivers rating their child’s severity higher than nurse’s triage while in 83 cases (4%, 83/2,126), they rated it lower. In an univariable analysis, we found that family’s difficulties paying bills (20% vs. 12%) and low maternal education (19% vs. 10%) were associated with a higher percentage of caregiver rating their child’s severity higher than nurse’s triage. Fever as the main complaint was associated with caregiver rating their child’s severity lower than nurse’s triage. Conclusions This questionnaire-based study shows that caregiver’s assessment of the severity of the child and nurse triage are concordant in most situations. Our study sheds light on the association between caregiver assessment and professional triage in two paediatric emergency departments in Switzerland, revealing some of the factors leading to discordance. These factors most probably reflect health illiteracy. It is important that healthcare professionals recognize and address factors influencing caregiver assessments to facilitate accurate decision-making and enhanced paediatric emergency care outcomes.

Abstract The orbitofrontal cortex (OFC) is a large cortical structure, expansive across anterior-posterior axes. It is essential for flexibly updating learned behaviors, and paradoxically, also implicated in inflexible and compulsive-like behaviors. Here, we investigated mice bred to display inflexible reward-seeking behaviors that are insensitive to action consequences. We found that these mice also demonstrate insensitivity to Pavlovian-to-instrumental transfer, as well as compulsive-like grooming behavior that is ameliorated by fluoxetine and inhibitory, but not excitatory, chemogenetic modulation of excitatory OFC neurons. Thus, these mice offer the opportunity to identify neurobiological factors associated with inflexible and compulsive-like behavior. Experimentally bred mice suffer excitatory dendritic spine attrition, as well as changes in inhibitory synapse-associated proteins, GAD67/GAD1 and SLITRK3, largely in the anterior and not posterior OFC (or medial frontal cortex). They also display higher levels of the excitatory synaptic marker striatin in the nucleus accumbens and lower levels of the excitatory synaptic marker SAPAP3 in the dorsal striatum, striatal nuclei that receive input from the anterior OFC. Together, our findings point to the anterior OFC as a potential locus controlling action flexibility and compulsive-like behavior alike.

Abstract The faithful segregation of intact genetic material and the perpetuation of chromatin states through mitotic cell divisions are pivotal for maintaining cell function and identity across cell generations. However, most exogenous mutagens generate long-lasting DNA lesions that are segregated during mitosis. How this segregation is controlled is unknown. Here, we uncover a mitotic chromatin-marking pathway that governs the segregation of UV-induced damage in human cells. Our mechanistic analyses reveal two layers of control: histone ADP-ribosylation, and the incorporation of newly synthesized histones at UV damage sites, that both prevent local mitotic phosphorylations on histone H3 serine residues. Functionally, this chromatin-marking pathway controls the segregation of UV damage in the cell progeny with consequences on daughter cell fate. We propose that this mechanism may help preserve the integrity of stem cell compartments during asymmetric cell divisions.

Abstract Mice have evolved a new dental plan with two additional cusps on the upper molar, while hamsters were retaining the ancestral plan. By comparing the dynamics of molar development with transcriptome time series, we found at least three early changes in mouse upper molar development. Together, they redirect spatio-temporal dynamics to ultimately form two additional cusps. The mouse lower molar has undergone much more limited phenotypic evolution. Nevertheless, its developmental trajectory evolved as much as that of the upper molar and co-evolved with it. Among the coevolving changes, some are clearly involved in the new upper molar phenotype. We found a similar level of coevolution in bat limbs. In conclusion, our study reveals how serial organ morphology has adapted through organ-specific developmental changes, as expected, but also through shared changes that have organ-specific effects on the final phenotype. This highlights the important role of developmental system drift in one organ to accommodate adaptation in another.

Abstract It has been challenging to test how proteins acquire specific metals in cells. The speciation of metalation is thought to depend on the preferences of proteins for different metals competing at intracellular metal-availabilities. This implies mis-metalation may occur if proteins become mis-matched to metal-availabilities in heterologous cells. Here we use a cyanobacterial MnII-cupin (MncA) as a metal trap, to test predictions of metalation. By re-folding MncA in buffered competing metals, metal-preferences are determined. Relating metal-preferences to metal-availabilities estimated using cellular metal sensors, predicts mis-metalation of MncA with FeII in E. coli. After expression in E. coli, predominantly FeII-bound MncA is isolated experimentally. It is predicted that in metal-supplemented viable cells metal-MncA speciation should switch. MnII-, CoII-, or NiII-MncA are recovered from the respective metal-supplemented cells. Differences between observed and predicted metal-MncA speciation are used to refine estimated metal availabilities. Values are provided as blueprints to guide engineering biological protein metalation.

Abstract Objectives Transcatheter edge-to-edge repair (TEER) is an alternative for patients with severe degenerative mitral regurgitation (MR). The objective of this study was to compare the outcomes of surgery and TEER in older patients with degenerative MR patients using real life data. Methods Consecutives older patients (≥ 65 years-old), with severe symptomatic, degenerative MR requiring surgery or TEER between 2013 and 2023 were included. Exclusion criteria were secondary MR, and active endocarditis. Primary outcome was a composite of all-cause death, hospitalization for heart failure or mitral valve intervention within one year. Results A total of 295 patients were included (203 underwent surgery and 92 underwent TEER). At 1 year, 26 (9%) patients had died, required reintervention or rehospitalization for heart failure: 8 patients in the surgery group (4%) and 18(20%) in the TEER group(p 2 (aHR 4.31 (95% CI: 1.51–12.25)), history of cardiac surgery (aHR 6.24 (95%CI: 2.16–18.05)), BMI (aHR 0.88 (95% CI: 0.77–0.98)), TR > 2 at baseline (aHR: 2.47 (95% CI: 1.03–5.91)). After adjustement on confounding factors, intervention type was not associated with the primary composite outcome (aHR: 3.41 (95% CI: 0.63–18.27)), p = 0.15). Conclusion Patients with severe primary MR treated with TEER experienced a higher rate of adverse events within one year compared to surgically managed patients. However, these differences were mainly associated to clinical characteristics and were no longer significant after adjustment on residual MR > 2. Graphical Abstract

Background/Objective: Although most gonadotroph cell–derived pituitary adenomas (PAs) give rise to nonfunctional PAs, hormonally active functional gonadotroph adenomas (FGAs) are exceedingly rare. We present a case of a giant and invasive functional gonadotropic pituitary macroadenoma treated with endoscopic transsphenoidal surgery and subsequent postoperative radiotherapy. Case Report: A 54-year-old man presented with gradually worsening vision over 1 year. Magnetic resonance imaging demonstrated a 5.2-cm sellar and suprasellar mass with cavernous sinus invasion, mass effect on the optic chiasm, and extension into the sphenoid sinus, nasal cavity, and clivus. Preoperative workup was remarkable for erythrocytosis without sleep apnea and increased levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin, and testosterone. Immunohistochemistry results following endoscopic transsphenoidal resection confirmed dominant staining for steroidogenic factor-1, FSH, and LH. Postoperatively, the patient’s FSH level decreased, whereas the LH level normalized within 1 week. The free testosterone level normalized at 9 months. The patient underwent radiotherapy for a small amount of residual tumor in the right cavernous sinus and has demonstrated no evidence of disease or hormonal progression. Discussion: There is no consensus on FGA-specific management that differs from the management of nonfunctional PAs; surgery is recommended when vision is impacted. The invasive nature of the tumor presented in this case is rare and limited safe gross total resection, requiring adjuvant radiotherapy. Conclusion: FGAs are rare, and those of similar size and extent of invasion as in our case are even more so. In addition to surgical resection, consideration of adjunct therapies including radiation and multidisciplinary physician involvement are vital in achieving clinical improvement and remission while preventing possible progression and recurrence.

Background/Objective: Thyrotoxic periodic paralysis (TPP) is a rare condition causing weakness of the lower extremities associated with significant hypokalemia. Likewise, agranulocytosis due to methimazole use is a rare occurrence. We present the first documented case of concomitant TPP and agranulocytosis from methimazole use. Case Report: A 48-year-old woman presented with sore throat, fevers, odynophagia, and sudden-onset bilateral leg weakness. Methimazole had been started 10 weeks prior for a new diagnosis of Graves’ disease. On admission, the patient was febrile, tachycardic, thyrotoxic, and neutropenic. She also experienced near-paralysis of the lower extremities. She was diagnosed with TPP and treated with beta blockade. She was admitted to the intensive care unit and started on broad-spectrum antibiotics, lithium, and propranolol for treatment of septic shock and hyperthyroidism, respectively. Given persistent hypokalemia despite 2 days of therapy, she was also diagnosed with refeeding syndrome. Discussion: TPP is a rare entity, though it should be considered on the differential for any thyrotoxic patient presenting with sudden weakness. If the associated hypokalemia does not begin to normalize within 48 h of beta blockade, other etiologies should be investigated. Lastly, alternative treatments such as lithium may be used to control hyperthyroidism in patients with methimazole-induced agranulocytosis. Conclusion: While methimazole-induced agranulocytosis and thyrotoxic periodic paralysis are independently rare diagnoses, the combination of the 2 is exceedingly rare, and our case represents the first documented case in the literature reflecting a patient suffering from both syndromes.

Abstract: There is a scarcity of data on the tumor B-cell receptor (BCR) repertoire and lymphoid microenvironment in primary mediastinal B-cell lymphoma (PMBL). We applied 5ʹ rapid amplification of complimentary DNA ends (5′RACE) to tumor RNA samples from 137 patients with PMBL with available gene expression profiling and next-generation sequencing data. We obtained 5′RACE results for 75 of the 137 (54.7%) patients with the following clinical characteristics: median age (range), 33 years (18-64); female, 53.3%; performance status score 0 to 1, 86.7%; stage I to II, 57.3%; first-line treatment with anti-CD20 plus doxorubicin-based chemotherapy, 100%. Among the 60 biopsies that expressed a productive BCR, we highlighted a strong somatic hypermutation profile, defined as 81.1% and >78.6% of all complementarity-determining region 3 sequences for IgVH and IgVL, respectively. When compared with other patients, this subgroup had similar clinical characteristics but a greater median allele frequency for all somatic variants, a decreased BCR diversity, and greater expression of PDL1/PDL2 and MS4A1 genes, suggesting greater tumoral infiltration. We confirmed this poorer prognosis in a multivariate model and in an independent validation cohort in which 6 of 37 (16%) PMBL patients exhibited HCD (PFS: HR, 12; OS: HR, 17).

Background: Solubility is a common feature of allergens. However, the causative relationship between this protein-intrinsic feature and sensitization capacity of allergens is not fully understood. This study aimed to proof the concept of solubility as a protein intrinsic feature of allergens. Methods: The soluble birch pollen allergen Bet v 1 was covalently coupled to 1 μm silica particles. IgE-binding and -cross-linking capacity was assessed by inhibition ELISA and mediator release assay, respectively. Alterations in adjuvanticity by particle-loading were investigated by activation of dendritic cells, mast cells and the Toll-like receptor 4 pathway as well as by Th2 polarization in an IL-4 reporter mouse model. In BALB/c mice, particle-loaded and soluble Bet v 1 were compared in a model of allergic sensitization. Antigen uptake and presentation was analysed by restimulating human Bet v 1-specific T cell lines. Results: Covalent coupling of Bet v 1 to silica particles resulted in an insoluble antigen with retained IgE-binding and -cross-linking capacity and no increase in adjuvanticity. In vivo, particle-loaded Bet v 1 induced significantly lower Bet v 1-specific (s)IgE, whereas sIgG1 and sIgG2a levels remained unaffected. The ratio of Th2 to Th1 cells was significantly lower in mice sensitized with particle-loaded Bet v 1. Particle-loading of Bet v 1 resulted in a 24-fold higher T cell activation capacity in Bet v 1-specific T cell lines, indicating more efficient uptake and presentation than of soluble Bet v 1. Conclusions: Our results show that solubility is a decisive factor contributing to the sensitization capacity of allergens. The reduction in sensitization capacity of insoluble, particle-loaded antigens results from enhanced antigen uptake and presentation compared to soluble allergens.

Abstract Purpose The management of soft tissue sarcoma (STS) at reference centers with specialized multidisciplinary tumor boards (MTB) improves patient survival. The German Cancer Society (DKG) certifies sarcoma centers in German-speaking countries, promoting high standards of care. This study investigated the variability in treatment recommendations for localized STS across different German-speaking tertiary sarcoma centers. Methods In this cross-sectional case-based survey study, 5 anonymized patient cases with imaging data of localized STS were presented to MTBs of 21 German-speaking tertiary referral hospitals. Centers provided recommendations on treatment sequence and modalities, along with the consensus level within their MTB. Agreement percentages were calculated, and consensus levels were rated on a scale of 1 to 10. Results Five patient cases were discussed resulting in 105 recommendations. Agreement percentages for case 1 to 5 were 14.3%, 61.9%, 33.3%, 52.4% and 9.3%, with a median agreement percentage of 33.3%. Grouping pre- and postoperative therapies as "perioperative" and including recommendations with and without regional hyperthermia raised the median agreement to 47.6%. The mean consensus level within each center across all 5 cases was 9.5. Conclusion This first case-based analysis of inter-center agreement for STS management in German-speaking countries reveals low inter-center agreement but high intra-center consensus. Our study includes nearly all tertiary sarcoma centers in German-speaking countries, affirming its strong external validity. These findings suggest potential and clinically very relevant differences in treatment standards among sarcoma centers. Enhanced case-based exchanges and collaborative efforts are needed to reduce discrepancies and standardize the management of STS patients.

Abstract Background Given the increasing recognition of the value of greater integration of physical and mental health services for children and young people, we aimed to evaluate preferences among parents for the characteristics associated with integrated health service provision for two conditions (eating disorders, functional symptom disorders). Methods Two discrete choice experiments (DCEs) were conducted, using electronic surveys. Participants were adult parents of children and young people. Choice scenarios were based on five attributes for the eating disorders study, and four attributes for the functional symptom disorders study. Results Two hundred parents participated in each DCE. For eating disorders, days missed from school in the last year was the attribute valued most highly, followed by days in hospital in the last year, costs to the NHS, functioning, and interaction with peers with eating disorders. Respondents were willing to trade £531 of costs to the NHS for one less day missed from school. For functional symptom disorders, time to diagnosis was valued most highly, followed by days missed from school while obtaining a diagnosis, reservations about seeing a mental health practitioner, and costs of diagnosis to the NHS. Respondents were willing to trade £4237 of costs to the NHS to wait one month less for a diagnosis. Conclusion Respondents’ preferences were largely consistent with the planned goals of integrating physical and mental health services. Our findings show the factors which ought to be considered when designing new integrated pathways and evaluating them.

Abstract Immune checkpoint inhibitors (ICI), i.e., anti-PD1/PDL1 and anti-CTLA-4, have reshaped the prognosis of many cancers. Increased use of ICI has led to the onset of new adverse events. Neurological immune-related adverse events are rare, heterogenous, and potentially life-threatening. Chronic intestinal pseudo-obstruction (CIPO) is an immune-related autonomic plexus neuropathy that may be caused by infiltration of the myenteric plexus by CD8 + T cells. It is a rare and potentially fatal side effect that can be difficult to diagnose early because of initial nonspecific clinical presentation including vomiting, nausea, diarrhea, and constipation. Some rare cases have been described in the literature reporting a frequent resistance to corticosteroids making it necessary to use other immunosuppressive therapy. Vedolizumab is an antibody (Ab) blocking integrin α4-β7 used to treat inflammatory bowel disease. We report the first three cases of ICI-induced CIPO-treated with vedolizumab after corticosteroid failure, with very limited benefits (only one patient with transitory improvement). Based on our results in three cases, vedolizumab does not currently appear to be a therapeutic option. Earlier administration with a standardized dose and frequency schedule may provide better outcomes.

Abstract Caves are primary sites for studying human and animal subsistence patterns and genetic ancestry throughout the Palaeolithic. Iberia served as a critical human and animal refugium in Europe during the Last Glacial Maximum (LGM), 26.5 to 19 thousand years before the present (cal kya). Therefore, it is a key location for understanding human and animal population dynamics during this event. We recover and analyse sedimentary ancient DNA (sedaDNA) data from the lower archaeological stratigraphic sequence of El Mirón Cave (Cantabria, Spain), encompassing the (1) Late Mousterian period, associated with Neanderthals, and (2) the Gravettian (c. 31.5 cal kya), Solutrean (c. 24.5–22 cal kya), and Initial Magdalenian (d. 21–20.5 cal kya) periods, associated with anatomically modern humans. We identify 28 animal taxa including humans. Fifteen of these taxa had not been identified from the archaeozoological (i.e., faunal) record, including the presence of hyenas in the Magdalenian. Additionally, we provide phylogenetic analyses on 70 sedaDNA mtDNA genomes of fauna including the densest Iberian Pleistocene sampling of C. lupus. Finally, we recover three human mtDNA sequences from the Solutrean levels. These sequences, along with published data, suggest mtDNA haplogroup continuity in Iberia throughout the Solutrean/Last Glacial Maximum period.

Abstract Pyruvate metabolism defects lead to severe neuropathies such as the Leigh syndrome (LS) but the molecular mechanisms underlying neuronal cell death remain poorly understood. Here, we unravel a connection between pyruvate metabolism and the regulation of the epitranscriptome that plays an essential role during brain development. Using genetically engineered mouse model and primary neuronal cells, we identify the transcription factor E4F1 as a key coordinator of AcetylCoenzyme A (AcCoA) production by the pyruvate dehydrogenase complex (PDC) and its utilization as an essential co-factor by the Elongator complex to acetylate tRNAs at the wobble position uridine 34 (U34). E4F1-mediated direct transcriptional regulation of Dlat and Elp3, two genes encoding key subunits of the PDC and of the Elongator complex, respectively, ensures proper translation fidelity and cell survival in the central nervous system (CNS) during mouse embryonic development. Furthermore, analysis of PDH-deficient cells highlight a crosstalk linking the PDC to ELP3 expression that is perturbed in LS patients.

Abstract The archaeal ribosome is of the eukaryotic type. TACK and Asgard superphyla, the closest relatives of eukaryotes, have ribosomes containing eukaryotic ribosomal proteins not found in other archaea, eS25, eS26 and eS30. Here, we investigate the case of Saccharolobus solfataricus, a TACK crenarchaeon, using mainly leaderless mRNAs. We characterize the small ribosomal subunit of S. solfataricus bound to SD-leadered or leaderless mRNAs. Cryo-EM structures show eS25, eS26 and eS30 bound to the small subunit. We identify two ribosomal proteins, aS33 and aS34, and an additional domain of eS6. Leaderless mRNAs are bound to the small subunit with contribution of their 5’-triphosphate group. Archaeal eS26 binds to the mRNA exit channel wrapped around the 3’ end of rRNA, as in eukaryotes. Its position is not compatible with an SD:antiSD duplex. Our results suggest a positive role of eS26 in leaderless mRNAs translation and possible evolutionary routes from archaeal to eukaryotic translation.

Abstract Background Stigma significantly impacts individuals with Parkinson’s disease (PD) and their caregivers, exacerbating social isolation, psychological distress, and reducing quality of life (QoL). Although considerable research has been conducted on PD’s clinical aspects, the social and emotional challenges, like stigma, remain underexplored. Addressing stigma is crucial for enhancing well-being, fostering inclusivity and improving access to care and support. The review aims to fill this knowledge gap by synthesising existing literature on PD stigma, examining its effects on individuals and families affected, and identifying areas where interventions could reduce stigma’s impact. Methods This systematic review was conducted following Joanna Briggs Institute guidance. Studies were identified through searches in six databases, relevant websites, and reference lists. Covidence was used for duplicate removal, screening, and data extraction. Thematic analysis identified key themes from qualitative data, while narrative synthesis integrated findings from qualitative and quantitative studies. The review protocol was registered on PROSPERO (CRD42023399343). Results This review included 22 studies published between 2002 and 2024, using both qualitative and quantitative methodologies. Five key themes emerged. The first highlighted stereotypes in PD, such as misconceptions about symptoms, age stereotyping, and supernatural beliefs. The second explored drivers and facilitators of stigma, identifying factors like duration since diagnosis, disease severity, lack of public education, and media representation. The third theme revealed stigma’s impact on mental health and well-being, exacerbating feelings of shame, embarrassment, and social isolation. The fourth, responses and consequences of stigma, detailed strategies employed by individuals with PD to manage stigma, including seeking social support and adopting coping mechanisms. The fifth theme, beyond stigma, explored positive aspects of living with PD, highlighting resilience, positive interactions, and advocacy efforts. Conclusion This systematic review underscores the significant impact of stigma on individuals with PD and their caregivers, manifesting as social isolation, diminished QoL, and psychological distress. Key drivers include public misconceptions, cultural biases, and limited awareness and addressing these challenges requires targeted interventions. Recommendations include education to dispel myths, public awareness campaigns and advocacy efforts to reduce stigma, enhance support, and improve QoL.

Abstract Background Maternal agonistic autoantibodies against the angiotensin II type 1 receptor (AT1-AAs) have been implicated in the pathophysiology of preeclampsia, but their presence in their offsprings and their possible neonatal effects have not been specifically explored. This prospective study aimed to evaluate the presence of AT1-AAs and their potential clinical effects in neonates of AT1-AAs positive mothers. Methods Women with preeclampsia and their neonates were included. Blood samples were collected in order to search for AT1-AAs. Results AT1-AA determination was positive in 35 out of 64 of the studied women (54.7%). Thirty one newborns from the group of AT1-AA positive women were included and 22 (71%) were AT1-AA positive. The mothers’ and children’s AT1-AAs titers were significantly correlated. The 33 newborns from the group of AT1-AA negative women were all negative for AT1-AAs. Regarding the clinical data of newborns (birth weight, percentile of weight, gestational age, Apgar score at five minutes, mechanical or noninvasive ventilation), no significant difference was observed between the children with or without detected AT1-AAs. Conclusion Even though AT1-AAs are detected in newborns of positive mothers during the first days of life, no specific clinical signs seem to be associated with the presence of these antibodies.

Abstract Background Seasonal vaccination is the mainstay of human influenza prevention. Licensed influenza vaccines are regularly updated to account for viral mutations and antigenic drift and are standardised for their haemagglutinin content. However, vaccine effectiveness remains suboptimal. Neuraminidase (NA) evolves more gradually than hemagglutinin and has been demonstrated to provide added clinical benefits. However, NA is not currently a mandated or standardised component of influenza vaccines. Methods Here, we collated expert opinions on the importance of NA in influenza vaccines in a two-stage Delphi survey. Nine statements about NA were formulated by a steering committee based on a targeted literature review. In the survey’s first round, panellists recruited from three continents were requested to report on their agreement with each statement and estimate the strength of evidence for each statement. Panellists were also requested to explain their choice of answer and suggest revisions to the statements. Consensus was considered reached if ≥ 75% of panellists agreed with a statement. If consensus was not reached for a statement, this statement was revised and included in the survey’s second round. Results Nine panellists with a broad range of NA-related expertise, including clinical, research, and public health experience, completed the survey. They agreed that anti-NA responses acquired via natural infection or vaccination are associated with protective immunity independently of haemagglutinin and that NA provided additional advantages including improving disease severity metrics. The experts identified several knowledge gaps concerning heterologous cross-reactivity of vaccine-induced anti-NA antibodies, correlations between anti-NA titres and reduced transmission or infection risks, and differences in anti-NA responses to seasonal influenza vaccines. Conclusions NA is an important influenza vaccine component and is associated with specific benefits. These benefits would likely be greater if NA content were standardised. Additional research is needed to optimise vaccines for anti-NA effects.

Abstract Background Type 1 diabetes is a serious, chronic disorder with an increasing incidence among children and adolescents. Glycemic control in individuals with type 1 diabetes is better managed through a basal-bolus regimen with either regular human or rapid-acting insulin analogues administered as a bolus at mealtimes. Rapid-acting insulin analogues have been hypothesized to cause optimal glycemic control and less risk of hypoglycemic episodes compared to regular human insulins. However, this has never been systematically assessed in children and adolescents with type 1 diabetes. Therefore, this systematic review aims to assess the beneficial and harmful effects of regular human insulins versus rapid-acting insulin analogues in children and adolescents. Methods This is a protocol for a systematic review. A search in major medical databases (e.g., MEDLINE, EMBASE, CENTRAL) and clinical trial registries will be performed by a search specialist. We will include published and unpublished randomized clinical trials comparing regular human insulins versus rapid-acting insulin analogues (lispro, aspart, or glulisine). Two review authors will independently extract data and conduct risk of bias assessments. Primary outcomes will be severe hypoglycemia, ketoacidosis, and serious adverse events. Secondary outcomes will be quality of life, HbA1c, and non-serious adverse events. Data will be analyzed using fixed-effect meta-analyses, random-effects meta-analyses, and Trial Sequential Analysis. Several subgroup analyses are planned. Risk of bias will be assessed with the Cochrane Risk of Bias tool—version 2, an eight-step procedure will be used to assess if the thresholds for clinical significance are crossed, and the certainty of the evidence will be assessed by Grading of Recommendations, Assessment, Development and Evaluations (GRADE). Discussion The beneficial and adverse effects of regular human insulins versus rapid-acting insulin analogues have not been systematically assessed in children and adolescents. There is a need for a comprehensive systematic review of the current evidence. Systematic review registration PROSPERO: CRD42024508625.

Abstract In critically ill patients with atrial fibrillation (AF), standard treatment algorithms might not be applicable. Emergency departments (ED) play a crucial role in implementing individualized treatment approaches. The aim of this study was to assess the association of lactate and cardioversion success rates in AF patients presenting to an ED. This was a retrospective single-center study analyzing 3535 AF episodes between 2012 and 2022. The main outcome was cardioversion (CV) to sinus rhythm (SR) depending on serum lactate levels (mmol/L). Lactate levels were divided into quintiles (lac 2.3 mmol/L). Overall CV success declined with rising lactate levels (SR: lac 2.3 mmol/L 61% (n = 393); p 2.3 mmol/L 95% (n = 106); p = 0.716). However, for mCV, conversion success decreased with increasing lactate levels (SR: lac 2.3 mmol/L 59% (n = 97); p

Abstract Background Study aims were to assess the current state and needs of faculty to inform the design of a formal mentorship program in a large academic Department of Psychiatry. Methods A 57- item self-administered online survey questionnaire was distributed to all faculty members. Results 225 faculty members completed the survey (24%). 68% of respondents had a mentor and reported high satisfaction (mean = 4.3, SD = 1.05) (range 1 to 5). Among those respondents lacking access to mentorship, 65% expressed interest. Open-ended questions indicated that international medical graduates, faculty identifying as minority, women and clinician teachers may lack access to mentorship. PhD faculty felt disadvantaged compared to MD faculty in gaining first authorship (M Non−MD=1.64 ± 0.79 vs. MMD=1.36 ± 0.67; t = 2.51, p = .013); reported more authorship disputes (M Non−MD =1.99 ± 0.91 vs. MMD =1.66 ± 0.76; t = 2.63 p = .009) and experienced questionable scientific integrity concerning colleagues (M Non−MD =2.01 ± 0.92 vs. MMD =1.70 ± 0.81; t = 2.42 p = .017). For both MD and PhD faculty, women were significantly more likely to experience authorship disputes (χ2(2) = 8.67, p = .013). The department was perceived as treating faculty with respect (72% agreed) with 54% agreeing that it embraces diversity (54%). Identified benefits to mentorship included receiving advice about academic promotion, opportunities for career advancement, advocacy, and advice as a researcher, teacher or clinician. Only 26% of mentors received formal training to support their role; 59% expressed interest in education. Respondents supported a more formal, accessible, inclusive program, with training, tools, and a matching strategy based on mentee preferences. Conclusions Challenges and inequities were identified with the department’s current ad hoc approach to mentorship. A limitation of the study was the response rate, while similar to response rates of other physician surveys, raises the potential for response bias. In comparing study participants to the department, the sample appeared to provide a fair representation. The study has implications for identifying the need and design of more formal mentorship programs in academic medicine.

Abstract Homozygous MTAP deletion occurs in ~15% of cancers, making them vulnerable to decreases in the concentration of S-adenosylmethionine (SAM). AG-270/S095033 is an oral, potent, reversible inhibitor of methionine adenosyltransferase 2 A (MAT2A), the enzyme primarily responsible for the synthesis of SAM. We report results from the first-in-human, phase 1 trial of AG-270/S095033 as monotherapy in patients with advanced malignancies (ClinicalTrials.gov Identifier: NCT03435250). Eligible patients had tumors with homozygous deletion of CDKN2A/MTAP and/or loss of MTAP protein by immunohistochemistry. Patients received AG-270/S095033 once daily (QD) or twice daily (BID) in 28-day cycles. The primary objective was to assess the maximum tolerated dose (MTD) of AG-270/S095033. Secondary objectives included safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy. Forty patients were treated with AG-270/S095033. Plasma concentrations of AG-270/S095033 increased with dose. Maximal reductions in plasma SAM concentrations ranged from 54% to 70%. Analysis of paired tumor biopsies showed decreases in levels of symmetrically di-methylated arginine (SDMA) residues. Reversible increases in liver function tests, thrombocytopenia, anemia and fatigue were common treatment-related toxicities. Two partial responses were observed; five additional patients achieved radiographically confirmed stable disease for ≥16 weeks. AG-270/S095033 has a manageable safety profile. Our data provide preliminary evidence of clinical activity and proof-of-mechanism for MAT2A inhibition.

Abstract Background Moral distress is reported to be a critical force contributing to intensifying rates of anxiety, depression and burnout experienced by healthcare workers. In this paper, we examine the moral dilemmas and ensuing distress personally and collectively experienced by healthcare workers while caring for patients during the pandemic. Methods Data are drawn from free-text responses from a cross-sectional national online survey of Australian healthcare workers about the patient care challenges they faced. Results Three themes were derived from qualitative content analysis that illuminated the ways in which moral dilemmas and distress were relationally experienced by healthcare workers: (1) the moral ambiguity of how to care well for patients amid a rapidly changing work environment; (2) the distress of witnessing suffering shared between healthcare workers and patients; and (3) the distress of performing new forms of invisible work in the absence of institutional recognition. These findings reveal that moral distress was a strongly shared experience. Conclusions Findings advance understandings of moral distress as a relational experience, collectively felt, constituted, and experienced by healthcare workers. Considering how to harness collective solidarity in effectively responding to moral distress experienced across the frontline healthcare workforce is critical.

Aims: Lower limb reconstruction (LLR) has a profound impact on patients, affecting multiple areas of their lives. Many patient-reported outcome measures (PROMs) are employed to assess these impacts; however, there are concerns that they do not adequately capture all outcomes important to patients, and may lack content validity in this context. This review explored whether PROMs used with adults requiring, undergoing, or after undergoing LLR exhibited content validity and adequately captured outcomes considered relevant and important to patients. Methods: A total of 37 PROMs were identified. Systematic searches were performed to retrieve content validity studies in the adult LLR population, and hand-searches used to find PROM development studies. Content validity assessments for each measure were performed following Consensus-based Standards for the selection of health measurement Instruments (COSMIN) guidelines. A mapping exercise compared all PROMs to a conceptual framework previously developed by the study team (‘the PROLLIT framework’) to explore whether each PROM covered important and relevant concepts. Results: The systematic searches found 13 studies, while hand searches found 50 PROM development studies, and copies of all 37 measures. Although several studies discussed content validity, none were found which formally assessed this measurement property in the adult LLR population. Development of many PROMs was rated as inadequate, no PROM had sufficient content validity in the study population, and none covered all areas of the PROLLIT framework. The LIMB-Q was the most promising and comprehensive measure assessed, although further validation in a wider sample of LLR patients was recommended. Conclusion: Current PROMs used in adults requiring, undergoing, or after undergoing LLR lack content validity and do not assess all important and relevant outcomes. There is an urgent need for improved outcome measurement in this population. This can be achieved through development of a new PROM, or through validation of existing measures in representative samples. Cite this article: Bone Jt Open 2024;5(12):1049–1066.

Notre article propose d’analyser le rôle des compétences listées dans le Référentiel de métier de 2013 à destination des futurs enseignants du second degré dans le système éducatif français. Il explore les liens entre le document, la formation initiale des étudiants et le développement de leurs gestes professionnels mais aussi de leur évaluation. Note étude se situe à l’Inspé de Limoges.