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Abstract H5N1 high pathogenicity avian influenza virus has killed thousands of marine mammals in South America since 2022. Here we report epidemiological data and full genome characterization of clade 2.3.4.4b H5N1 HPAI viruses associated with a massive outbreak in southern elephant seals (Mirounga leonina) at Península Valdés, Argentina, in October 2023. We also report on H5N1 viruses in concurrently dead terns. Our genomic analysis shows that viruses from pinnipeds and terns in Argentina form a distinct clade with marine mammal viruses from Peru, Chile, Brazil and Uruguay. Additionally, these marine mammal clade viruses share an identical set of mammalian adaptation mutations which were also present in tern viruses. Our combined ecological and phylogenetic data support mammal-to-mammal transmission and occasional mammal-to-bird spillover and suggest multinational transmission of H5N1 viruses in mammals. We reflect that H5N1 viruses becoming more evolutionary flexible and adapting to mammals in new ways could have global consequences for wildlife, humans, and/or livestock.

Abstract Background The number of known inherited metabolic diseases (IMDs) has been expanding, and the rate of diagnosis is improving with the development of innovative approaches including next generation sequencing (NGS). However, a substantial proportion of IMDs remain undetected by traditional diagnostic approaches. We aim to highlight the spectrum of IMDs diagnosed by the Undiagnosed Diseases Network (UDN) and to learn from the UDN diagnostic processes that were able to detect IMDs. Methods We conducted a retrospective analysis of 757 UDN participants diagnosed from 2015 until 2023 using the cohort database, which were divided into a cohort with IMDs (n = 194; 27%) and a cohort whose phenotypes were not explained by an IMD (n = 563; 73%), based on the International Classification of Inherited Metabolic Disorders (ICIMD). Then, we divided the causes of the metabolic 194 diagnoses into seven groups that included all the ICIMD categories. We inspected which clinical and laboratory approaches contributed to a final UDN diagnosis. We also present a UDN case example from each group to highlight the diagnostic yields that resulted from combining newer diagnostic approaches in the UDN and illustrate potential pitfalls of current NGS methods. Results These 194 cases of IMDs included examples from 21/25 (84%) of the ICIMD categories. Of the UDN subjects 164/194 (85%) were diagnosed with IMDs through NGS. Conclusion The spectrum of IMDs detected in the UDN cohort is large and growing and appropriate use of newer multiple diagnostic approaches should further increase diagnosis of IMDs that are presently missed by the traditional laboratory screening methods.

ABSTRACT Measuring boundary layer stratification, wind shear, and turbulence remains challenging for wind resource assessment. In particular, larger eddy scales have the greatest impact on turbine load fluctuations, and there are few in situ methods to observe them adequately. Satellite remote sensing using synthetic aperture radar (SAR) is an alternative approach. In this study, eddy‐related signatures in 704 high‐resolution images are related to stratification through a bulk Richardson number ( Ri) measured by a buoy near Martha's Vineyard, the US epicenter of offshore wind. Variations in SAR‐observed atmospheric boundary layer eddies, or lack of them, correspond to specific Ri regimes. Accounting for strong vertical wind shear, typically under stable stratification, is critical for energy production and turbine loads, and SAR directly identifies these conditions by the absence of energetic eddies. SAR also provides a regional climatology of atmospheric stratification for offshore wind assessment, complementing other observations, and with potential application worldwide.

We used cross-sectional data from 226 patients with monkeypox virus to investigate the association between anatomic exposure site and lesion development. Penile, anorectal, and oral exposures predicted lesion presence at correlating anatomic sites. Exposure site also predicted the first lesion site of the penis and anus.

Abstract In wildlife populations, parasites often go unnoticed, as infected animals appear asymptomatic. However, these infections can subtly alter behaviour. Field evidence of how these subclinical infections induce changes in movement behaviour is scarce in free-ranging animals, yet it may be crucial for zoonotic disease surveillance. We used an ultra-high-resolution tracking system (ATLAS) to monitor the movements of 60 free-ranging swallows every 8 seconds across four breeding seasons, resulting in over 1 million localizations. About 40% of these swallows were naturally infected with haemosporidian parasites. Here, we show that infected individuals had reduced foraging ranges, foraged in lower quality habitats, and faced a lowered survival probability, with an average reduction of 7.4%, albeit with some variation between species and years. This study highlights the impact of subclinical infections on movement behaviour and survival, emphasizing the importance of considering infection status in movement ecology. Our findings provide insights into individual variations in behaviour and previously unobservable local parasite transmission dynamics.

Abstract We estimated the environmental impact and financial cost of two exemplar in-person academic events organised by the European academic society, the European Academy of Nursing Science, identified the main sources of these emissions, and then mapped them against the COM-B behaviour change framework of capability, opportunity, motivation to identify strategies that could be applied by organisers and participants to reduce this impact. These events contributed 41 tonnes and 99 tonnes of CO2e emissions per event, a per-participant mean of either 0.324 (SD 0.173) or 0.724, (SD 0.263) tonnes, representing 2 to 5.5 times the daily per-person European average. Distance from home was the largest contributor to emissions. Costs were similar for both events. Our multi-component behavioural change programme includes environmental change, enablement, education, incentivisation and persuasion, by which organisers provide participants with the opportunity for less-polluting behaviour, and enhance participants capabilities and motivation to act on the opportunities provided.

Objective We explored the relationship between achievement of clinical disease control and improvements in and normative values for patient‐reported outcomes (PROs), including quality of life (QoL) measures, in patients with psoriatic arthritis (PsA). Methods This was a post hoc analysis of 104‐week data from the SELECT‐PsA 1 and 2 trials in adults with PsA and inadequate response to one or more conventional synthetic (SELECT‐PsA 1) or biologic (SELECT‐PsA 2) disease‐modifying antirheumatic drug. Patients were initially randomized to upadacitinib 15 mg once daily (QD) to placebo switched to upadacitinib 15 mg QD at week 24 or to adalimumab 40 mg every other week (SELECT‐PsA 1 only), and data were pooled across treatments and analyzed. We evaluated several clinical disease control measures (minimal disease activity [MDA]; very low disease activity [VLDA]; and low disease activity [LDA] and/or remission by Disease Activity in Psoriatic Arthritis [DAPSA], Psoriatic Arthritis Disease Activity Score [PASDAS], and Routine Assessment of Patient Index Data 3 [RAPID3]) and examined their associations with improvements and normative values for various PROs. Results A total of 1,069 and 317 patients were analyzed for SELECT‐PsA 1 and 2, respectively. In both studies, responders (patients who achieved MDA or VLDA, and DAPSA, PASDAS, and RAPID3 LDA or remission) at week 104 achieved more marked changes from baseline, and more responders achieved normative values in PROs compared with nonresponders (most nominal P < 0.0001). Furthermore, numerically larger proportions of responders achieved minimal clinically important differences across PROs compared with nonresponders in both studies. In addition, patients who achieved MDA or VLDA were more likely to achieve DAPSA, PASDAS, and RAPID3 LDA or remission (all nominal P < 0.0001) for upadacitinib 15 mg QD and when treatment arms were pooled. Conclusion Patients with PsA who achieve clinical disease control are more likely to achieve improvements and normative values in PROs and QoL measures, which reinforces disease control as a treatment target.

Abstract Background The steep increase in knee arthroplasties in lower- and middle-income countries has increased demand for personalised rehabilitation care. Technology-based rehabilitation programs offer potential to replace or augment conventional face-to-face rehabilitation for providing continuum of care. We aimed to systematically develop a theory, evidence-driven, contextualised, and user-centred mobile health platform for people undergoing knee arthroplasty to facilitate monitoring progress during rehabilitation. Methods We followed the UK Medical Research Council’s framework and adopted a behaviour design thinking approach, consisting of five steps; (1) conduct multiple literature reviews and cross-sectional surveys to determine the needs and problems experienced during the rehabilitation phase by healthcare professionals and individuals with replaced knees, (2) identify target behaviours along with barriers and facilitators, integrated within the Capability, Opportunity, Motivation-Behaviour (COM-B) framework, (3) identify intervention functions and components, behaviour change techniques, and features for the mobile application, selected after discussions with orthopaedic surgeons, physiotherapists and behavioural experts, (4) develop a prototype application for end-users, and a web-based platform for healthcare professionals, and (5) pilot test the intervention for end-users’ feedback on usability of the application and to identify possible strategies for implementing the intervention package. Results Using the COM-B model, education, training, persuasion, enablement, and modelling were chosen as intervention functions for improving adherence to exercise protocol during early-phase of rehabilitation. The application featured five interlinked components; education, training, goal setting and self-management, communication, and a personalized therapy plan utilising 13 behaviour change techniques. An education booklet, exercise videos, text messaging, video consultation, and a digital tool for measuring range of motion were incorporated into the application. Feedback on the interactive prototype and education material was sought from ten patient volunteers and a physiotherapist. Pilot testing in a convenient sample with broad eligibility criteria (n = 30) indicated importance of digital literacy and dedicated time for remote consultation by healthcare provider within the existing clinical work. Overall, the intervention was well received and valued by the end users. Conclusion This paper demonstrates the development of a contextualised digital behavioural intervention grounded in behavioural theory and evidence from literature to improve end-user’s engagement with rehabilitation protocols after knee arthroplasty in lower- and middle-income country context. Trial registration Study registered prospectively (on 16 February 2023) at Clinical Trials Registry of India (CTRI/2023/02/049792).

Abstract Background Attitudes towards medication can affect treatment outcomes and adherence through mechanisms such as placebo and nocebo effects. Questionnaires assessing both negative and positive attitudes towards medication in general, which can be used across a variety of settings and in both patient and non-patient samples, are however lacking. To fill this gap, we developed and validated the General Attitude towards Medication Questionnaire (GAMQ). Methods Items were selected and adapted from existing questionnaires by a group of experts. Validation of the original Dutch version took place in 4 samples: 2 recruited from the general population (n = 508; n = 279) and 2 patient samples (patients with rheumatoid arthritis, n = 121; patients with atopic dermatitis, n = 70). We evaluated the psychometric properties of the GAMQ by determining the factor structure and its stability across samples, internal consistency, and convergent validity. Results The GAMQ contains 6 positive and 6 negatively worded items. A factor structure was observed with three subscales, representing ‘Trust in medication’, ‘Concerns about medication’, and ‘Reluctance to use medication’. The fit of the factor structure was satisfactory across samples, considering classic cut-offs, with an adequate or close to adequate fit. The total scale showed good internal consistency, good convergent validity with related scales (i.e., Beliefs about Medicines Questionnaire - General and a single medication attitude scale), and concurrent validity as reflected in associations with expectations about pain- and itch-relieving medication. It was not consistently or strongly associated with demographic or health-related characteristics. Conclusions The newly developed GAMQ showed satisfactory psychometric properties in a variety of populations, although limitations should be considered. The GAMQ is the first scale to assess both positive and negative attitudes towards medication in general, providing indicators of Trust, Concerns, and Reluctance regarding medication. The scale may be an informative measure for predicting treatment outcomes and adherence, as well as placebo and nocebo effects in diverse samples.

The design and first results of a high-transmission soft X-ray spectrometer operated at the X-SPEC double-undulator beamline of the KIT Light Source are presented. As a unique feature, particular emphasis was placed on optimizing the spectrometer transmission by maximizing the solid angle and the efficiencies of spectrometer gratings and detector. A CMOS detector, optimized for soft X-rays, allows for quantum efficiencies of 90% or above over the full energy range of the spectrometer, while simultaneously offering short readout times. Combining an optimized control system at the X-SPEC beamline with continuous energy scans (as opposed to step scans), the high transmission of the spectrometer, and the fast readout of the CMOS camera, enable the collection of entire rapid resonant inelastic soft X-ray scattering maps in less than 1 min. Series of spectra at a fixed energy can be taken with a frequency of up to 5 Hz. Furthermore, the use of higher-order reflections allows a very wide energy range (45 to 2000 eV) to be covered with only two blazed gratings, while keeping the efficiency high and the resolving power E/ΔE above 1500 and 3000 with low- and high-energy gratings, respectively.

Ageing is an inherent and intricate biological process that takes place in living organisms as time progresses. It involves the decline of multiple physiological functions, leading to body structure and overall performance modifications. The ageing process differs among individuals and is influenced by various factors, including lifestyle, environment and genetic makeup. Metabolic changes and reduced locomotor activity are common hallmarks of ageing. Our study focuses on exploring these phenomena in prematurely ageing PolgA(D257A/D257A) mice (also known as PolgA) aged 41–42 weeks, as they closely mimic human ageing. We assess parameters such as oxygen consumption (VO2), carbon dioxide production (VCO2), respiratory exchange ratio (RER) and locomotor activity using a metabolic cage for 4 days and comparing them with age‐matched wild‐type littermates (WT). Our findings revealed that VO2, VCO2, RER, locomotor activities, water intake and feeding behaviour show a daily rhythm, aligning with roughly a 24‐h cycle. We observed that the RER was significantly increased in PolgA mice compared to WT mice during the night‐time of the light–dark cycle, suggesting a shift towards a higher reliance on carbohydrate metabolism due to more food intake during the active phase. Additionally, female PolgA mice displayed a distinct phenotype with reduced walking speed, walking distance, body weight and grip strength in comparison to male PolgA and WT mice, indicating an early sign of ageing. Taken together, our research highlights the impact of sex‐specific patterns on ageing traits in PolgA mice aged 41–42 weeks, which may be attributable to human ageing phenotypes. The unique genetic composition and accelerated ageing characteristics of PolgA mice make them invaluable in ageing studies, facilitating the investigation of underlying biological mechanisms and the identification of potential therapeutic targets for age‐related diseases.

Abstract Nucleoside-modified mRNA-LNP vaccines have revolutionized vaccine development against infectious pathogens due to their ability to elicit potent humoral and cellular immune responses. In this article, we present the results of the first norovirus vaccine candidate employing mRNA-LNP platform technology. The mRNA-LNP bivalent vaccine encoding the major capsid protein VP1 from GI.1 and GII.4 of human norovirus, generated high levels of neutralizing antibodies, robust cellular responses, and effectively protected human enteroids from infection by the most prevalent genotype (GII.4). These results serve as a proof of concept, demonstrating that a modified-nucleoside mRNA-LNP vaccine based on norovirus VP1 sequences can stimulate an immunogenic response in vivo and generates neutralizing antibodies capable of preventing viral infection in models of human gastrointestinal tract infection.

Abstract Cyclic fluorescence microscopy enables multiple targets to be detected simultaneously. This, in turn, has deepened our understanding of tissue composition, cell-to-cell interactions, and cell signaling. Unfortunately, analysis of these datasets can be time-prohibitive due to the sheer volume of data. In this paper, we present CycloNET, a computational pipeline tailored for analyzing raw fluorescent images obtained through cyclic immunofluorescence. The automated pipeline pre-processes raw image files, quickly corrects for translation errors between imaging cycles, and leverages a pre-trained neural network to segment individual cells and generate single-cell molecular profiles. We applied CycloNET to a dataset of 22 human samples from head and neck squamous cell carcinoma patients and trained a neural network to segment immune cells. CycloNET efficiently processed a large-scale dataset (17 fields of view per cycle and 13 staining cycles per specimen) in 10 min, delivering insights at the single-cell resolution and facilitating the identification of rare immune cell clusters. We expect that this rapid pipeline will serve as a powerful tool to understand complex biological systems at the cellular level, with the potential to facilitate breakthroughs in areas such as developmental biology, disease pathology, and personalized medicine.

Abstract Background Postpartum depression (PPD) constitutes a significant mental health disorder affecting almost one fifth of pregnancies globally. Despite extensive research, the precise etiological mechanisms underlying PPD remain elusive. However, several risk factors like genetic predisposition, hormonal fluctuations, and stress-related environmental and psychosocial triggers have been found to be implicated in its development. Main Recently, an increased risk of PPD has been reported to be associated with gestational diabetes mellitus (GDM), which is characterized by the disruption of glucose metabolism, primarily attributed to the emergence of insulin resistance (IR). While IR during pregnancy seems to be an evolutionary adaptative mechanism to handle the profound metabolic alterations during pregnancy, its subsequent resolution following delivery necessitates a reconfiguration of the metabolic landscape in both peripheral tissues and the central nervous system (CNS). Considering the pivotal roles of energy metabolism, particularly glucose metabolism, in CNS functions, we propose a novel model that such pronounced changes in IR and the associated glucose metabolism seen postpartum might account for PPD development. This concept is based on the profound influences from insulin and glucose metabolism on brain functions, potentially via modulating neurotransmitter actions of dopamine and serotonin. Their sudden postpartum disruption is likely to be linked to mood changes, as observed in PPD. Conclusions The detailed pathogenesis of PPD might be multifactorial and still remains to be fully elucidated. Nevertheless, our hypothesis might account in part for an additional etiological factor to PPD development. If our concept is validated, it can provide guidance for future PPD prevention, diagnosis, and intervention.

Abstract Background Several surgical options for degenerative lumbar spinal stenosis (LSS) are available, but current guidelines do not recommend which one should be prioritized. Although previous network meta-analyses (NMAs) have been performed on this topic, they have major methodological problems and could not provide the convincing evidence and clinical practical information required. Methods Randomized controlled trials (RCTs) comparing at least two surgical interventions were included by searching AMED, CINAHL, EMBASE, the Cochrane Library, and MEDLINE (inception to August 2023). A frequentist random-effects NMA was performed for physical function and adverse events due to any reason. For physical function, three follow-up time points were included: short-term (

Abstract Aboveground biomass density (AGBD) estimates from Earth Observation (EO) can be presented with the consistency standards mandated by United Nations Framework Convention on Climate Change (UNFCCC). This article delivers AGBD estimates, in the format of Intergovernmental Panel on Climate Change (IPCC) Tier 1 values for natural forests, sourced from National Aeronautics and Space Administration’s (NASA’s) Global Ecosystem Dynamics Investigation (GEDI) and Ice, Cloud and land Elevation Satellite (ICESat-2), and European Space Agency’s (ESA’s) Climate Change Initiative (CCI). It also provides the underlying classification used by the IPCC as geospatial layers, delineating global forests by ecozones, continents and status (primary, young (≤20 years) and old secondary (>20 years)). The approaches leverage complementary strengths of various EO-derived datasets that are compiled in an open-science framework through the Multi-mission Algorithm and Analysis Platform (MAAP). This transparency and flexibility enables the adoption of any new incoming datasets in the framework in the future. The EO-based AGBD estimates are expected to be an independent contribution to the IPCC Emission Factors Database in support of UNFCCC processes, and the forest classification expected to support the generation of other policy-relevant datasets while reflecting ongoing shifts in global forests with climate change.

Abstract Background We explored vaccine motivation and preferences for tick-borne encephalitis (TBE) vaccine attributes among participants in TBE-endemic countries in Europe. Methods An online survey was conducted among the general public in Austria, Germany, Switzerland, and Sweden. Participants were ≥ 18 years old, open to receiving vaccines, and living in, or regularly traveling to, TBE-endemic regions in the aforementioned countries. Participants were asked about their general vaccine knowledge and motivations for vaccination, before rating the importance of TBE vaccine attributes, such as efficacy, safety, dosing schedule, and booster interval. Thereafter, participants were shown three hypothetical TBE vaccine profiles with different combinations of attributes. Assuming equal efficacy and safety, participants were asked to select their preferred profile from 12 screens as part of a discrete-choice conjoint analysis. Utility scores were calculated to show the importance of each attribute. Data are presented for the overall survey group and by age and gender, using t-tests to compare means. Results For 73% of participants (n = 1003/1379), self-protection was among the top three reasons to get vaccinated. Disease severity, protection of children or family, and advice or recommendation from a doctor/healthcare professional (HCP) were top three reasons for over half of participants. The majority (58–69%) agreed or strongly agreed that they trust their doctor/HCP on the subject of vaccines, they rely on their doctor/HCP’s vaccine knowledge, and they prefer their doctor/HCP to make recommendations on which vaccines they or their families should take. Efficacy and safety were the most important standalone TBE vaccine attributes; however, among TBE vaccine profiles including 3-, 5- and 10-year booster intervals, the 10-year booster interval was the most influential attribute level when choosing a preferred vaccine profile (utility score: 0.58 [standard error: 0.01]). Differences in motivators and preferences were observed between age and gender subgroups. Conclusion The high level of doctor/HCP reliance highlights the key role doctors/HCPs play in influencing vaccine decision-making. Booster interval was the biggest driver of choice when selecting a hypothetical TBE vaccine profile, with the strongest preference for a 10-year booster interval. These findings could be used to inform TBE vaccination recommendations and in the further development of TBE vaccines.

Abstract The ultrashort and intense pulses of X-rays produced at X-ray free electron lasers (XFELs) have enabled unique experiments on the atomic level structure and dynamics of matter, with time-resolved studies permitted in the femto- and attosecond regimes. To fully exploit them, it is paramount to obtain a comprehensive understanding of the complex nonlinear interactions that can occur at such extreme X-ray intensities. Herein, we report on the experimental observation of a resonant double-core excitation scheme in N2, where two 1σ core-level electrons are resonantly promoted to unoccupied $$1{\pi }_{g}^{* }$$ 1 π g * molecular orbitals by a single few-femtosecond broad-bandwidth XFEL pulse. The production of these neutral two-site double core hole states is evidenced through their characteristic decay channels, which are observed in good agreement with high-level theoretical calculations. Such multi-core excitation schemes, benefiting from the high interaction cross sections and state- and site-selective nature of resonant X-ray interactions, should be generally accessible in XFEL irradiated molecules, and provide interesting opportunities for chemical analysis and for monitoring ultrafast dynamic processes.

Abstract Background BI 836880 is a humanized bispecific nanobody® that binds to and blocks vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2). A comprehensive biomarker and modeling approach is presented here that supported dose finding for BI 836880. Methods Two Phase I dose-escalation studies (1336.1 [NCT02674152], 1336.6 [NCT02689505]) assessed BI 836880 in adults with confirmed locally advanced or metastatic solid tumors, refractory to standard therapy or for which standard therapy was not reliably effective. Two dosing schedules were investigated, 3 weeks (q3w) or once weekly (qw), starting at a dose of 40 mg. In a comprehensive biomarker approach, soluble pharmacodynamic markers (free and total plasma VEGF-A and Ang-2), as well as circulating angiogenic factors (soluble VEGF3, soluble Tie2 and placenta growth factor, amongst others) were analyzed to assess target engagement in peripheral blood for q3w doses. A Population based pharmacokinetics/pharmacodynamics (PopPK/PD) model was built using the limited Phase I dataset to support dose finding by simulations. In order to demonstrate drug activity in the tumor, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was applied. Results DCE-MRI scans supported target engagement in the tumor. Free VEGF-A was depleted at all doses, whereas free Ang-2 decreased dose-dependently, reaching depletion in most patients from 360 mg q3w onwards. While total VEGF-A levels increased in a dose-dependent manner, reaching saturation at 360 mg q3w, total Ang-2 levels increased, but did not plateau. Angiogenic biomarkers showed changes from doses ≥ 360 mg q3w. PopPK/PD modeling showed that doses ≥ 360 mg q3w led to > 90% inhibition of free Ang-2 at steady-state in most patients. By increasing the dose to ≥ 500 mg q3w, > 90% of patients are expected to achieve this level. Conclusions The comprehensive analyses of multiple target engagement markers support BI 836880 720 mg q3w as a biologically relevant monotherapy dose schedule. Trial registration: NCT02674152 and NCT02689505.

The 25th Annual Western Canadian Gastrointestinal Cancer Consensus Conference (WCGCCC) was held in Winnipeg, Manitoba, on 26–27 October 2023. The WCGCCC is an interactive multidisciplinary conference that was attended by healthcare professionals from across Western Canada (British Columbia, Alberta, and Manitoba) who are involved in the care of patients with gastrointestinal cancer. Surgical, medical, and radiation oncologists; pathologists; oncology nurses; pharmacists; and a family physician in oncology (FPO) participated in presentation and discussion sessions for the purpose of developing the recommendations presented here. This consensus statement addresses current issues in the management of gastroesophageal cancers.

Abstract This study investigates the prevalence and evaluates the prognostic implications of acute kidney injury (AKI) in COVID-19 patients, with a novel emphasis on the evaluation of serum uromodulin (sUmod) as a potential kidney-specific biomarker. A cohort of hospitalised COVID-19 patients (n = 378) was examined for AKI using standard criteria. In addition to traditional urinary biomarkers, sUmod levels were analysed. Univariable and multivariable regression models were employed to evaluate the association of sUmod and AKI and in-hospital mortality. Levels of sUmod were significantly lower in patients with CKD (91.8 ± 60.7 ng/ml) compared to patients with normal kidney function (204.7 ± 91.7 ng/ml; p

Abstract Background A heart positioned on the right side of the thorax can be more a complex situation than it seems, also the potentially associated congenital cardiopathies are variable. In this regard, patients with dextrocardia presenting with complete atrioventricular block require a thorough anatomical investigation to map the veno-arterial system and potential cardiovascular defects before proceeding with a permanent pacing procedure. Case presentation A 73-year-old Caucasian woman with no significant medical history presented with syncope. Physical examination showed regular heart sounds with an average heart rate of 35–40 beats per minute and no other relevant physical findings. Chest X-rays revealed a heart positioned in the right hemithorax. A standard electrocardiogram revealed complete atrioventricular block with junctional escape rhythm at nearly 35–40 beats per minute. A transthoracic echocardiogram showed a mirror image dextrocardia without any other remarkable abnormalities. Venogram performed using the left peripheral cephalic vein showed normal venous return into the right atrium positioned on the left side. Surgical intervention consisted of permanent dual chamber pacemaker implantation using the left subclavian vein. Discussion is provided based on the relevant medical literature outlining different potential scenarios with associated cardiac and major vessels abnormalities. Conclusion This case highlights an atypical presentation of atrioventricular block in a patient with dextrocardia and situs inversus, for whom a successful dual-pacemaker implantation procedure was performed.

Abstract Bile acids (BA) are supposed to cause metabolic alterations after bariatric surgery (BS). Here we report the longitudinal dynamics of the human BA metabolome by LC–MS/MS after BS versus low calory diet (LCD) in two obesity cohorts over 12 months. Rapid and persistent oscillations of 23 BA subspecies could be identified with highly specific patterns in BS vs. LCD. TCDCA, GLCA, and TLCA represent most promising candidates for drug development.

Background The 2013-2016 West African Ebola Virus Disease (EVD) outbreak resulted in 28,600 cases and 11,300 deaths officially reported to the World Health Organization. Previous studies investigating factors associated with death had conflicting findings, interventions showing promising outcomes had small sample sizes, studies were often single- or dual-country based and most focused on laboratory-confirmed EVD and not on clinically-suspected EVD. We used the Ebola data platform of the Infectious Disease Data Observatory (IDDO) to review individual patient records to assess factors associated with death, and particularly whether there were differences between laboratory-confirmed and clinically-suspected cases. Methods This was a cohort study involving analysis of secondary data in the IDDO database. The study population included all patients classified as having either clinically-suspected or laboratory-confirmed EVD, admitted to 22 Ebola Treatment Units (ETU) in Guinea, Liberia and Sierra Leone between December 2013 and March 2016. Baseline characteristics and treatments were documented along with ETU exit outcomes. Factors associated with death were investigated by multivariable modified Poisson regression. Results There were 14,163 patients, of whom 6,208 (43.8%) were laboratory-confirmed and 7,955 (56.2%) were clinically-suspected. Outcomes were not recorded in 2,889 (20.4%) patients. Of the 11,274 patients with known outcomes, 4,090 (36.3%) died: 2,956 (43.6%) with laboratory-confirmed EVD and 1,134 (18.8%) with clinically-suspected EVD. The strongest risk factor for death was confirmed disease status. Patients with laboratory-confirmed disease had 2.9 times higher risk of death compared to clinically-suspected patients, after adjusting for other co-variables. Other factors significantly associated with death included a higher risk for patients aged ≥60 years and a lower risk for patients in Sierra Leone. Conclusions Although laboratory-confirmed patients admitted to ETUs fared worse than clinically-suspected patients, the latter still had a substantial risk of death and more attention needs to be paid to this group in future EVD outbreaks.

VocQGen is an automated tool designed to generate multiple-choice cloze (MCC) questions for vocabulary assessment in second language learning contexts. It leverages several natural language processing (NLP) tools and OpenAI’s GPT-4 model to produce MCC items quickly from user-specified word lists. To evaluate its effectiveness, we used the first sublist in the Academic Word List (AWL) to generate 60 questions with VocQGen. Then we compared the quality of 60 autogenerated questions with 40 manually created ones through expert reviews and through pilot testing with 68 students. Expert review results indicate that automatically generated questions exhibit higher grammatical accuracy and clearer contexts in question stems. However, the tool occasionally produces distractors that are acceptable as correct responses. Pilot testing results show that in general the number of correct responses is higher in autogenerated questions, indicating the less challenging nature of these questions. The study concludes that manual check is still required for questions generated by VocQGen and future work should focus on improving distractor effectiveness.

Introduction Gestational diabetes mellitus (GDM) is increasingly becoming a serious public health challenge. Innovative, effective and scalable lifestyle interventions to support women with GDM to manage their condition and prevent adverse obstetric and neonatal outcomes as well as later morbidity are required. This study aims to evaluate whether a novel, multilingual and scalable mobile health (mHealth) intervention (SPARK; SmartPhone App for gestational diabetes patients suppoRting Key lifestyle behaviours and glucose control) can improve self-management and treatment of GDM and prevent adverse maternal and offspring outcomes.Methods/analyses SPARK is a multicentre two-arm randomised controlled trial recruiting women diagnosed with GDM in south-eastern Sweden. A total of 412 women will be randomised to either standard care (control) or the SPARK intervention. The SPARK online platform (accessed through a mobile app) provides a behaviour change programme for healthy eating, physical activity and glycaemic control. To increase reach, SPARK is available in Swedish, English, Arabic and Somali. SPARK also comes with a clinician portal where healthcare professionals monitor and intervene when glycaemic control is unsatisfactory (above certain cut-offs). Primary outcomes are glycaemic control that is, time in range and HbA1c, while diet, physical activity (ActiGraph), gestational weight gain, metabolic and inflammatory biomarkers in weeks 37–38, adherence to protocol for daily glucose sampling, as well as adverse obstetric and neonatal outcomes are secondary outcomes. Secondary outcomes also include cardiometabolic risk evaluation, physical activity and healthy eating behaviours 1 year postpartum. A health economic evaluation of SPARK vs standard care will also be conducted.Ethics and dissemination This study has been approved by the Swedish Ethical Review Authority (2021-06627-01; 2022-03842-02; 2023-05911-02). Results will be disseminated through scientific papers in peer-reviewed journals, posts in traditional and social media, and presentations at scientific and healthcare professionals’ conferences.Trial registration number This trial was registered at the ClinicalTrials.gov register platform (ID NCT05348863) 27 April 2022.

# Introduction Cystic fibrosis (CF) is a severe autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. This condition disrupts chloride channels and leads to the production of thick, sticky mucus, affecting the respiratory and gastrointestinal systems. CF's prevalence is particularly high in Saudi Arabia, where the incidence has increased from 1 in 2,000 to 1 in 1,000 births. Effective management of CF is essential for improving patient outcomes, yet there is a notable lack of understanding regarding respiratory therapists' (RTs) adherence to established CF management protocols. # Methods This descriptive quantitative study aimed to assess RTs' adherence to the Cystic Fibrosis Foundation's guidelines. Using a convenience sampling technique, a self-report survey was distributed to 750 members of the Saudi Society for Respiratory Care (SSRC), resulting in 351 responses, of which 166 were fully completed and met the inclusion criteria. The survey focused on RTs' knowledge and management practices related to CF. Data analysis was conducted using SPSS version 25, with descriptive statistics (mean, standard deviation, frequency, percentage, and mode) and non-parametric tests. The Kruskal-Wallis Test was employed to evaluate differences in adherence scores across demographic groups (e.g., education level, years of experience). Chi-square analysis was applied to examine relationships between categorical demographic variables (e.g., region of practice) and adherence to guidelines. # Results The analysis revealed significant gaps in RTs' adherence to CF guidelines, with only 42.8% accurately identifying the sweat chloride threshold for CF diagnosis and a limited 36.1% recognizing Pseudomonas aeruginosa as a common CF pathogen. Additionally, just 56.6% correctly identified the gold-standard airway clearance therapy. The Wilcoxon signed-ranks test further highlighted a statistically significant disparity (p = 0.00) between RTs' theoretical knowledge and practical application of CF management techniques, emphasizing the need for improved training. # Discussion The findings suggest a need for enhanced training and resources to bridge the gap between theoretical knowledge and practical management of CF. The lack of adherence to clinical guidelines could impact patient outcomes and survival rates. # Conclusion Improving RTs' adherence to CF management guidelines through ongoing education and updated clinical standards is essential. Addressing these gaps could elevate the standard of care and contribute to better patient outcomes and survival rates in Saudi Arabia.

The adenosine triphosphate–binding cassette transporter A7 (ABCA7) gene is ranked as one of the top susceptibility loci for Alzheimer's disease (AD). While ABCA7 mediates lipid transport across cellular membranes, ABCA7 loss of function has been shown to exacerbate amyloid-β (Aβ) pathology and compromise microglial function. Our family-based study uncovered an extremely rare ABCA7 p.A696S variant that was substantially segregated with the development of AD in 3 African American families. Using the knockin mouse model, we investigated the effects of ABCA7-A696S substitution on amyloid pathology and brain immune response in 5xFAD transgenic mice. Importantly, our study demonstrated that ABCA7-A696S substitution reduces amyloid plaque–associated microgliosis and increases dystrophic neurites around amyloid deposits compared to control mice. We also found increased X-34–positive amyloid plaque burden in 5xFAD mice with ABCA7-A696S substitution, while there was no evident difference in insoluble Aβ levels between mouse groups. Thus, ABCA7-A696S substitution may disrupt amyloid compaction resulting in aggravated neuritic dystrophy due to insufficient microglia barrier function. In addition, we observed that ABCA7-A696S substitution disturbs the induction of proinflammatory cytokines interleukin 1β and interferon γ in the brains of 5xFAD mice, although some disease-associated microglia gene expression, including Trem2 and Tyrobp, are upregulated. Lipidomics also detected higher total lysophosphatidylethanolamine levels in the brains of 5xFAD mice with ABCA7-A696S substitution than controls. These results suggest that ABCA7-A696S substitution might compromise the adequate innate immune response to amyloid pathology in AD by modulating brain lipid metabolism, providing novel insight into the pathogenic mechanisms mediated by ABCA7. One sentence summary: A rare Alzheimer's disease risk ABCA7 p.A696S variant compromises microglial response to amyloid pathology.

Background: Medication for Opioid Use Disorder (MOUD) reduces morbidity and mortality for patients with opioid use disorder (OUD). Emergency department-initiated buprenorphine (EDIB) doubles retention in treatment at 30 days compared to outpatient referral alone. Little is known about acceptance rates of EDIB and reasons why patients decline this life-saving intervention. Objectives: The aim of this study was to quantify the number of patients who initiate and decline buprenorphine in the ED and determine reasons for declination. Methods: Seven SC EDs implemented EDIB programs that included ED-based peer recovery specialists (PRSs) to provide a brief intervention and assist with referral to outpatient treatment. The PRSs recorded patient interactions in a database including medical eligibility, if EDIB was provided, and the reason(s) why eligible patients declined EDIB. All eligible EDIB patients were entered in the PRS database and included in the study. Reasons for declining buprenorphine in eligible patients were analyzed with both fixed and free-text response options. Results: A total of 2205 patients were eligible for EDIB. Of those, 963 (43.6 %) patients accepted buprenorphine and 1242 (56.3 %) declined. The most common reasons for declination were 1) the “patient preferring non-MOUD treatment” (53.4 %), 2) “Not ready/would like to think about it and/or check with other treatment providers or case workers” (16.7 %). Conclusions: Over half of patients with OUD who were eligible for EDIB declined treatment, with the most common reason being preference for non-MOUD treatment. Given the success of MOUD for treatment of OUD, this topic requires further exploration.

Essential oils (EOs) are aromatic compounds known for their potent anti-inflammatory and antibacterial properties. However, these molecules are susceptible to degradation when exposed to external conditions, such as light and oxygen. Numerous studies have reported the protective effects of encapsulation on sensitive bioactive, such as EOs, for improved or preserved stability and shelf life. The aim of this study was to investigate the antibacterial activity of different formulations of carvacrol, the most important and used component of EOs. We comparatively evaluated the activity of free, protein-complexed and nano-emulsified carvacrol against two selected pathogenic bacteria: Staphylococcus aureus (a Gram+ strain) and Escherichia coli (a Gram- strain). Free carvacrol exhibited antibacterial activity against both tested bacteria, with comparable minimum inhibitory concentrations of 380 µg/mL for S. aureus and 370 µg/mL for E. coli. Indeed, carvacrol interact strongly with lactoferrin and β-lactoglobulin, two model carrier proteins, with preserved antibacterial activity. Unexpectedly, nano-emulsification of carvacrol, resulting in nano-droplets of 100 to 240 nm, decreased its antibacterial effect. Therefore, complexation with food proteins is a viable option to formulate a carrier with preserved carvacrol bioactivity. Ongoing studies aim to understand the reasons behind the recovered low activity of nano-emulsified carvacrol on the two pathogen species and under used experimental set-up.

Summary: The plastid-encoded RNA polymerase (PEP) plays an essential role in the transcription of the chloroplast genome. Here, we present a strategy to purify the transcriptionally active protein complex from transplastomic tobacco (Nicotiana tabacum) lines in which one of the PEP core subunits is fused to an epitope tag. We describe experimental procedures for designing transformation constructs for PEP purification, selection, and analysis of transplastomic tobacco plants. We then detail the steps for purifying PEP from the transplastomic tobacco leaves.For complete details on the use and execution of this protocol, please refer to Wu et al.1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

ABSTRACT Cellular adaptations to change often involve post-translational modifications of nuclear and cytoplasmic proteins. An example found in protists and plants is the modification of serine and threonine residues of dozens to hundreds of nucleocytoplasmic proteins with a single fucose (O-fucose). A nucleocytoplasmic O-fucosyltransferase occurs in the pathogen Toxoplasma gondii, the social amoeba Dictyostelium, and higher plants, where it is called Spy because mutants have a spindly appearance. O-fucosylation, which is required for optimal proliferation of Toxoplasma and Dictyostelium, is paralogous to the O-GlcNAcylation of nucleocytoplasmic proteins of plants and animals that are involved in stress and nutritional responses. O-fucose was first discovered in Toxoplasma using Aleuria aurantia lectin, but its broad specificity for terminal fucose residues on N- and O-linked glycans in the secretory pathway limits its use. Here we present affinity-purified rabbit antisera that are selective for the detection and enrichment of proteins bearing fucose-O-Ser or fucose-O-Thr. These antibodies detect numerous nucleocytoplasmic proteins in Toxoplasma, Dictyostelium, and Arabidopsis, as well as O-fucose occurring on secretory proteins of Dictyostelium and mammalian cells except when blocked by further glycosylation. The antibodies label Toxoplasma, Acanthamoeba, and Dictyostelium in a pattern reminiscent of O-GlcNAc in animal cells including nuclear pores. The O-fucome of Dictyostelium is partially conserved with that of Toxoplasma and is highly induced during starvation-induced development. These antisera demonstrate the unique antigenicity of O-fucose, document the conservation of the O-fucome among unrelated protists, and enable the study of the O-fucomes of other organisms possessing O-fucosyltransferase-like genes.IMPORTANCEO-fucose (O-Fuc), a form of mono-glycosylation on serine and threonine residues of nuclear and cytoplasmic proteins of some parasites, other unicellular eukaryotes, and plants, is understudied because it is difficult to detect owing to its neutral charge and lability during mass spectrometry. Yet, the O-fucosyltransferase enzyme (OFT) is required for optimal growth of the agent for toxoplasmosis, Toxoplasma gondii, and an unrelated protist, the social amoeba Dictyostelium discoideum. Furthermore, O-fucosylation is closely related to the analogous process of O-GlcNAcylation of thousands of proteins of animal cells, where it plays a central role in stress and nutritional responses. O-Fuc is currently best detected using Aleuria aurantia lectin (AAL), but in most organisms, AAL also recognizes a multitude of proteins in the secretory pathway that are modified with fucose in different ways. By establishing the potential to induce highly specific rabbit antisera that discriminate O-Fuc from all other forms of protein fucosylation, this study expands knowledge about the protist O-fucome and opens a gateway to explore the potential occurrence and roles of this intriguing posttranslational modification in bacteria and other protist pathogens such as Acanthamoeba castellanii.

ABSTRACT Coronaviruses (CoV) emerge suddenly from animal reservoirs to cause novel diseases in new hosts. Discovered in 2012, the Middle East respiratory syndrome coronavirus (MERS-CoV) is endemic in camels in the Middle East and is continually causing local outbreaks and epidemics. While all three newly emerging human CoVs from the past 20 years (SARS-CoV, SARS-CoV-2, and MERS-CoV) cause respiratory disease, each CoV has unique host interactions that drive differential pathogeneses. To better understand the virus and host interactions driving lethal MERS-CoV infection, we performed a longitudinal multi-omics analysis of sublethal and lethal MERS-CoV infection in mice. Significant differences were observed in body weight loss, virus titers, and acute lung injury among lethal and sub-lethal virus doses. Virus-induced apoptosis of type I and II alveolar epithelial cells suggests that loss or dysregulation of these key cell populations was a major driver of severe disease. Omics analysis suggested differential pathogenesis was multi-factorial with clear differences among innate and adaptive immune pathways as well as those that regulate lung epithelial homeostasis. Infection of mice lacking functional T and B cells showed that adaptive immunity was important in controlling viral replication but also increased pathogenesis. In summary, we provide a high-resolution host response atlas for MERS-CoV infection and disease severity. Multi-omics studies of viral pathogenesis offer a unique opportunity to not only better understand the molecular mechanisms of disease but also to identify genes and pathways that can be exploited for therapeutic intervention all of which is important for our future pandemic preparedness.IMPORTANCEEmerging coronaviruses like SARS-CoV, SARS-CoV-2, and MERS-CoV cause a range of disease outcomes in humans from an asymptomatic, moderate, and severe respiratory disease that can progress to death but the factors causing these disparate outcomes remain unclear. Understanding host responses to mild and life-threatening infections provides insight into virus-host networks within and across organ systems that contribute to disease outcomes. We used multi-omics approaches to comprehensively define the host response to moderate and severe MERS-CoV infection. Severe respiratory disease was associated with dysregulation of the immune response. Key lung epithelial cell populations that are essential for lung function get infected and die. Mice lacking key immune cell populations experienced greater virus replication but decreased disease severity implicating the immune system in both protective and pathogenic roles in response to MERS-CoV. These data could be utilized to design new therapeutic strategies targeting specific pathways that contribute to severe disease.

The G protein-coupled receptor (GPCR) melanocortin receptor 4 (MC4R) is an essential regulator of body weight homeostasis. MC4R is unusual among GPCRs in that its activity is regulated by 2 opposing physiological ligands, the agonist ⍺-MSH and the antagonist/inverse agonist AgRP. Paradoxically, while MC4R localizes and functions at the cilium of hypothalamic neurons, the ciliary levels of MC4R are very low under unrestricted feeding conditions. Here, we find that the constitutive activity of MC4R is responsible for the continuous depletion of MC4R from cilia and that inhibition of MC4R's activity via AgRP leads to a robust accumulation of MC4R in cilia. Ciliary targeting of MC4R is mediated by its partner MRAP2 and the constitutive exit of MC4R from cilia relies on the sensor of activation β-arrestin, on ubiquitination, and on the BBSome ciliary trafficking complex. Thus, while MC4R exits cilia via conventional mechanisms, it only accumulates in cilia when its activity is suppressed by AgRP.

Abstract Introduction The Prince of Wales Hospital's Emergency Ambulatory Care (EAC) service, initiated in August 2021, exemplifies an innovative approach to the emergency department (ED) to address the increasing demands on healthcare systems. This study evaluates the impact of EAC service on hospital admissions, focusing on patients with ambulatory care‐sensitive conditions over the initial 5 months. Methods A retrospective cohort study was conducted to evaluate the EAC service from 1 August 2021 to 31 December 2021. The service integrated the ED's workflow and operated 171 eight‐hour sessions. Descriptive statistics and the Spearman correlation test were used in the analysis. Results A total of 408 patients were recruited and the service achieved a high discharge rate of 89.5%, contributing to a 7.5% reduction in hospital admissions for medical conditions. These results were supported by a significant negative correlation (r = −1.000, p

Abstract Disease freedom surveillance is challenging in settings where environmental conditions and population health can change abruptly. We propose a novel approach to freedom evaluation that is specifically suited to open environments. The approach merges information about pathogen introduction risk with information from pathogen surveillance to estimate assurance of freedom. While the logic is not new, the approach uses a generalizable model designed by an expert panel to estimate introduction probability, easing the need for costly, site‐specific risk assessment. This introduction probability is then used to inform the time‐adjusted value of historical surveillance data and adapt the consequent requirements (sampling volume and frequency) of future surveys. We apply the approach to an open water region on the Pacific Coast of the United States known for its mollusk production. Results support absence of the target pathogens—Marteilia refringens, Marteilioides chungmuensis, Ostreid herpesvirus 1, Perkinsus marinus, and Perkinsus olseni—for the host species, region, and time‐period under investigation. Findings demonstrate (1) the ability to retain assurance in pathogen freedom through time in open systems, (2) the limitations of sample volume, and importance of sampling frequency, for pathogens with higher introduction risk, and (3) expert elicitation as a generalizable alternative to formal risk assessment.

ABSTRACT Identifying the most important variables that determine patterns and processes is one of the main goals in many scientific fields, including ecological and evolutionary studies. Variable or relative importance is generally seen as the proportion of the variation in a response variable explained directly and indirectly by a specific predictor. Although partial regression coefficients are perhaps the most frequently used, ‘standard’, statistical technique in ecological and evolutionary studies, they are inadequate indices of variable importance when predictors are intercorrelated, which tends to be the rule in most observational data sets. Among other statistical techniques, random forests and hierarchical partitioning are designed to cope with collinearity but are still much less used than beta weights to measure variable importance. Here, we compared random forests and hierarchical partitioning with linear mixed models to attempt to unravel the individual and shared variation of environmental, economic, and human population factors with success of alien species richness in eight taxonomic groups at a global scale. Results showed that random forests and hierarchical partitioning generally agreed in ranking variable importance but showed considerably different conclusions to the standard statistical approach. Specifically, random forests and hierarchical partitioning attached more importance to economic and human population variables in explaining spatial patterns of alien species richness than did region area and mean air temperature, which were emphasized more by the standard approach. Beta weights also tended to highlight less correlated predictors, such as sampling effort and precipitation. Variable importance in random forests attached more importance to economic than population variables and to absolute rather than relative predictors. In conclusion, using variable importance measures enable to better identify the most significant drivers of biological invasions but it can also be applied to other biological and scientific questions, leading to tackle more efficient management and conservation decisions in global change research.

BackgroundThe lack of osteoporosis treatment initiation after fragility fractures is a significant gap, especially in primary care. It is unclear whether barriers for primary care physicians (PCPs) arise from uncertainty about investigations, treatment initiation, or medication side effects. Key questions remain about whether active learning platforms improve treatment initiation rates better than passive methods and how PCP demographics affect learning outcomes. With PCPs increasingly using web-based platforms for continuing professional development due to time constraints and heavy workloads, an interactive community fracture capture (CFC) tool may serve as an effective alternative to in-person learning. Our CFC pilot study tested this new program’s design and content, showing promising potential. ObjectiveWe aim to evaluate the interactive, case-based, web-based CFC Learning Hub, examining user acceptance and engagement with the platform, focusing on participants’ interactions, satisfaction levels, and overall experience. MethodsParticipating PCPs are recruited through Praxhub, a web-based medical education platform, and provide electronic consent for data use after deidentification. They have been allocated into small groups (12-20 members) and join the CFC Learning Hub, a secure web-based community. This hub includes a web-based discussion forum with participant-contributed case studies and a knowledge repository. Over the 6-week program, participants will receive weekly modules with instructions, resources, discussion threads, and quizzes, along with interactive discussions moderated by experienced PCPs and physicians. The platform also hosts web-based surveys that, in combination with platform analytics, allow assessment of baseline knowledge gaps, level of activity or engagement, and improvements following the course completion. This study protocol demonstrates the creation and proposed evaluation of the CFC Learning Hub, featuring an interactive, case-based, small-group web-based learning platform equipped with flexibly scheduled, tailored modules to address the fracture treatment gap within the community. Both qualitative (via thematic analysis) and quantitative (by using 2-tailed paired t tests, Wilcoxon signed rank tests, and multivariable regression analysis) analyses will be used to assess levels of engagement and acceptance and changes in PCPs’ knowledge and confidence after engagement with the CFC Learning Hub. ResultsRecruitment of participants started in May 2022. Data collection, analysis, and reporting will be completed following the completion of four 6-week cycles of the program. ConclusionsThe study described in this protocol will provide important insights into the function and effectiveness of the CFC Learning Hub. This information will guide the expansion of the program. This initiative offers a simple digital solution for promoting current bone health practices tailored to PCPs’ needs and thereafter to expand the rollout of the e-learning hub and implementation of fracture liaison models at a primary care level in Australia and elsewhere. Future applications may extend to other clinical areas and professions. International Registered Report Identifier (IRRID)DERR1-10.2196/57511

ABSTRACT Introduction Hearing and vision impairments are prevalent among residents in long‐term care settings. Hearing and vision impairments frequently go unsupported, affecting residents' quality of life and healthcare costs. This paper describes the protocol for a pre−post evaluation and process evaluation of a pragmatic sensory support intervention (SSI) that was developed with residents, informal caregivers and long‐term care workers. Methods and Analysis A prospective pre−post‐intervention trial within long‐term care will be conducted, including three groups: residents (n = 87), informal caregivers (n = 87) and long‐term care workers (n = 40). Outcome measures include health‐related quality of life and well‐being measures relevant to each group measured at baseline, 3‐ and 6‐months post‐intervention. Health resource and sensory device utilisation will be captured from routine data and by direct observation. Qualitative interviews, including a representative sample of residents and informal caregivers, will be conducted as part of a simultaneous process evaluation. Generalised linear models and paired t‐tests will be used to evaluate the effects on residents' and caregivers' quality of life and sensory device use. The cost‐effectiveness of the intervention will be examined using within‐trial analysis, economic modelling and budget impact assessment. A process evaluation will use descriptive statistics and thematic analysis to assess the intervention's reach, adoption, implementation, acceptability, mechanisms of change and contextual influences. Conclusion Hearing and vision impairments are common but under‐supported in older adults in long‐term care. This protocol involves a systematic evaluation of the effectiveness and implementation challenges of a pragmatic SSI to optimise hearing and vision function and improve the quality of life for long‐term care residents and their caregivers.

BackgroundSwimming is widely acknowledged for its safety and health benefits. Across the world children are receiving swimming lessons in which a variety of learning methods are employed. However, little is known about the effectiveness of those methods, and a comprehensive overview of pertinent research is lacking. Such an overview is needed for both researchers and instructors seeking to improve swimming skill acquisition in children.ObjectiveThis scoping review aims to provide an overview of studies examining the effectiveness of motor learning methods for the acquisition of swimming skills by 5- to 12-year-old children, including an evaluation of their theoretical underpinnings, methodological quality, and core findings.MethodsThis scoping review adhered to the PRISMA guidelines and followed Tricco et al.'s framework for conducting and reporting scoping reviews. Five bibliographic databases were systematically searched. Peer-reviewed studies in all languages published before 2025 were considered. Studies focusing on children with water-related fear were included. Gray literature, non-peer-reviewed studies and studies on specific groups (e.g., young, competitive swimmers or children with disabilities), or cognitive/motivational outcomes were excluded. Review selection and characterization were performed by three independent reviewers using pretested forms.ResultsA total of 23 studies were included, which were classified into three main categories: traditional motor learning methods (n = 4), contemporary methods (n = 1), and atheoretical methods (n = 18). Traditional methods focused on video-based instruction and feedback (n = 4). Contemporary methods involved a single study on a non-linear swimming program (n = 1). Atheoretical methods were further classified into learn-to-swim programs (n = 12), learning environments (n = 3), and assistive devices (n = 3). Most studies (87%) reported a positive effect of the motor learning method under investigation during practice. However, significant methodological limitations were identified. Specifically, 87% of studies did not incorporate retention or transfer tests, 35% lacked control or comparison groups, and 48% did not provide detailed descriptions of the investigated intervention(s). Additionally, 83% of studies were not explicitly grounded in theoretical frameworks, except for the video-based studies and the study on a non-linear swimming program.ConclusionThe literature on this topic is scarce, generally atheoretical and of questionable methodological quality. Addressing these shortcomings in future research will improve the evidence-base for the effectiveness of theoretically inspired learning methods for the acquisition of swimming skills in children, and their long-term retention and transfer, which in turn might result in evidence-based innovations in swimming lessons.Systematic Review RegistrationPRISMA (RRID:SCR_018721).

IntroductionCurrently available dietary recommendations for fluoride provided as “adequate intake” (AI) and “tolerable upper intake level” (UL) assume 100% fluoride availability for utilization by the body, which is often not the case. To prevent the development of dental fluorosis, AI and UL values must include fluoride bioavailability. However, the lack of data on fluoride bioavailability/bio-accessibility has hindered progress so far. This study aimed to measure fluoride bio-accessibility of the dietary sources commonly consumed by children below four years of age.MethodsA total of 103 food and meal samples were purchased, prepared, and analyzed for fluoride content, subjected to a standardized static in vitro digestion procedure and subsequent determination of fluoride concentration of resultant mixtures necessary for the final fluoride bio-accessibility calculation. Fluoride concentrations before and after in vitro digestion were determined directly using a fluoride-ion-selective electrode after addition of TISAB III, or indirectly by an acid diffusion method. Additionally, fluoride concentration of milk samples was determined using a combination of microwave-assisted acid digestion and the direct method of fluoride analysis.ResultsMean (SD) fluoride bio-accessibility for individual food samples was 44.7% (37.5%). The mean (SD) fluoride bio-accessibilities for meals created with juice, carbonated drinks, tap water, and milk were 79.0% (21.9%), 64.3% (20.7%), 40.2% (20.9%), and 71.5% (17.1%), respectively. For the rest of the meals with no common mixing agent, the mean (SD) fluoride bio-accessibility was 50.8% (55.9%).ConclusionThe majority of dietary sources analyzed in this project resulted in fluoride bio-accessibilities below 100%, indicating incomplete utilization of consumed fluoride. As the first study of its kind, these findings represent a critical initial step for future research and provide valuable insights to inform policymakers and health authorities in revising fluoride intake guidelines.

Although various options are available to treat injured organs and peripheral nerves, none is without limitations. Auto- and allografts are the first choice of treatment, but tissue survival or functionality is not guaranteed due to often limited vascular and neural networks. In response, tissue-engineered solutions have been developed, yet clinical translations is rare. In this study, a systematic review was performed on tissue-engineered advancements for peripheral nerves and tissues, to aid future developments in bridging the gap toward the clinic by identifying high-potential solutions and unexplored areas. A systematic search was performed in PubMed, Embase, Web of Science, and Scopus until November 9, 2023. Search terms involved “tissue engineering,” “guided,” “tissue scaffold,” and “tissue graft,” together with “innervation” and “reinnervation.” Original in vivo or in vitro studies meeting the inclusion criteria (tissue-engineered peripheral nerve/innervation of tissue) and no exclusion criteria (no full text available; written in foreign language; nonoriginal article; tissue-engineering of central nervous system; publication before 2012; insufficient study quality or reproducibility) were assessed. A total of 68 out of 3626 original studies were included. Data extraction was based on disease model, cell origin and host species, biomaterial nature and composition, and external stimuli of biological, chemical or physical origin. Although tissue engineering is still in its infancy, explored innervation strategies of today were highlighted with respect to biomaterials, cell types, and external stimuli. The findings emphasize that natural biomaterials, pre-seeding with autologous cell sources, and solutions for reproductive organs are beneficial for future research. Natural biomaterials possess important cues required for cell-material interaction and closely resemble native tissue in terms of biomechanical, geometrical and chemical composition. Autologous cells induce biomaterial functionalization. As these solutions pose no risk of immunorejection and have demonstrated good outcomes, they are most likely to fulfill the clinical demands.

IntroductionFor years, the Lichtenstein technique was the gold standard for open repair, but several open pre-peritoneal techniques have developed since the fifties of the 20th century that offer some benefits over the Lichtenstein technique in terms of post-surgical incidence of pain. Since the 2023 update of the International HerniaSurge Guidelines, open preperitoneal mesh techniques have been an acceptable alternative, providing available expertise and competence with at least equal results as Lichtenstein repair.AimThe aim of this project is to understand the views of surgeons regarding the approach to inguinal hernia repair and determine best practice principles for optimal surgical outcomes.MethodsUsing a modified Delphi method, a panel of experts developed 43 Likert scale statements across six key domains. These statements were used to develop an online survey distributed to surgeons in Europe involved in inguinal hernia repair. The threshold for consensus was set a priori at 75%.ResultsA total of 202 responses were received from surgeons involved in inguinal hernia repair over three rounds of survey. After the initial survey round, seven statements were revised and reissued for a further round. At the conclusion of the survey phase, 31 of the 38 remaining statements achieved consensus (of which 13 achieved ≥90% agreement). From these results, the panellists developed a set of 3 recommendations to help define principles for optimal approach to inguinal hernia repair. Accordingly Open preperitoneal techniques seems to be an alternative to Lichtenstein technique if expertise is available and should be included in a tailored concept. Knowledge of anatomy, Education and Training in open preperitoneal techniques is crucial for the acceptance of these techniques.ConclusionThe proposed set of recommendations provides some principles for surgeons to consider when selecting an approach to inguinal hernia repair, ensuring good patient outcomes in a practical and cost-effective manner.

Introduction As a result of improving survival rates, the adverse consequences of rectal cancer surgery are becoming increasingly recognised. Low anterior resection syndrome (LARS) is one such consequence and describes a constellation of bowel symptoms after rectal cancer surgery which includes urgency, faecal incontinence, stool clustering and incomplete evacuation. LARS has a significant adverse impact on quality of life (QoL) and symptoms are present in up to 75% of patients in the first year after surgery. Despite this, little is known about the natural history and there is poor evidence to support current treatment options.Methods and analysis The objectives of POLARiS are to explore the natural history of LARS and to evaluate the clinical and cost-effectiveness of transanal irrigation (TAI) or sacral neuromodulation (SNM) compared with optimised conservative management (OCM) for people with major LARS.POLARiS is a prospective, international, open-label, multi-arm, phase 3 randomised superiority trial within a cohort design, with internal pilot phase, qualitative sub-study, process evaluation and economic evaluation. Approximately 1500 adult participants from UK hospitals and 500 from Australian hospitals who have undergone a high or low anterior resection for colorectal cancer in the last 10 years will be recruited into the cohort. Six-hundred participants from the UK and 200 participants from Australia, with major LARS symptoms, defined as a LARS score of ≥30, will be recruited to the randomised controlled trial (RCT) element. Participants entering the RCT will be randomised between OCM, TAI or SNM, all with equal allocation ratios.Cohort and RCT participants will be followed up for a 24-month period, completing a series of questionnaires measuring LARS symptoms and QoL, as well as clinical review for those in the RCT. A process evaluation, qualitative sub-study and economic evaluation will also be conducted.The primary outcome measure of the POLARiS cohort and RCT is the LARS score up to 24 months post-registration/randomisation. Analyses of the RCT will be conducted on an intention-to-treat basis. Comparative effectiveness analyses for each endpoint will consist of two pairwise treatment comparisons: TAI versus OCM and SNM versus OCM. Secondary outcomes include health-related QoL, adverse events, treatment compliance and cost-effectiveness (up to 24 months post-registration/randomisation).Ethics and dissemination Ethical approval has been granted by Wales REC 4 (reference: 23/WA/0171) in the UK and Sydney Local Health District HREC (reference: 2023/ETH00749) in Australia. The results of this trial will be disseminated to participants on request and published on completion of the trial in a peer-reviewed journal and at international conferences.Trial registration number ISRCTN12834598; ACTRN12623001166662.

Aim: Diabetes mellitus (DM) represents a notable risk factor within surgical and interventional procedures. Data on its influence on survival after Transcatheter Edge-to-Edge Repair (TEER) of Mitral valve Regurgitation (MR) are sparse. Methods: In a retrospective monocentric assessment after successful treatment of MR using TEER from 06/2010 to 03/2018 patients were stratified for DM. Mortality was analyzed during follow-up using Cox regression analyses. Results: Of 627 patients (47.0 % females, 88.2 % aged ≥ 70 years, median follow-up 486 days) consecutively included, subjects with DM (N = 174, 27.8 %) had a higher prevalence of comorbidities like obesity (27.3 % vs. 9.2 %, p

Summary: The COVID-19 pandemic underscores the need to prepare for future emerging coronavriuses (CoVs) by understanding the principles behind effective CoV vaccine design such as protective immunity and antibody responses. To study which epitopes and subdomains contribute to in vivo protection, we utilized the prefusion-stabilized spike protein of MERS-CoV, MERS S-2P, as a vaccine immunogen. Vaccination with MERS S-2P elicited both receptor-binding domain (RBD)- and non-RBD-specific antibodies, including N-terminal domain (NTD)-specific G2-and CDC2-A2-like antibodies. Intriguingly, the immunogen MERS S-2P_ΔRBD, MERS S-2P with the RBDs removed, protects comparably to S1 and S-2P immunogens against MERS-CoV challenge. Moreover, passive transfer studies of polyclonal IgG from MERS S-2P immunized mice depleted of subdomain-specific antibodies demonstrated that non-RBD antibodies protected more than non-NTD antibodies. Altogether, these findings illustrate that in-vivo protection is not solely driven by RBD-specific antibodies and highlights the importance of targeting non-RBD sites in future CoV vaccine designs.

Background A common cause of preventable harm is the failure to detect and appropriately respond to clinical deterioration. Timely intervention is needed, particularly in medically complex patients, to mitigate the effects of adverse events, disease progression, and medical error. This challenging problem requires clinical surveillance, early recognition, timely notification of the appropriate clinicians, and effective intervention.