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OBJECTIVES: Both high and low levels of occupational physical activity are associated with back pain. Thus, there might be a “sweet- and sour-spot” of occupational physical activity for back pain. Our aim was to investigate if there exists an occupational physical activity “sweet- (lowest risk) and sour-spot” (highest risk) for back pain. METHODS: A total of 396 eldercare workers from 20 Danish nursing homes participated. Occupational physical activity was measured between 1–4 working days using thigh-worn accelerometry. Back pain intensity was reported monthly on a scale from 0–10 over 1-year. A zero-inflated mixed-effects model was developed regressing occupational physical activity against back pain, adjusted for confounders. The “sweet- and sour-spot” were defined as the occupational physical activity compositions (sitting, standing, light, and moderate-to-vigorous) associated with the 5% lowest and highest risk for back pain, respectively. RESULTS: The composition associated with the lowest risk of back pain – the “sweet-spot”– consisted of 71% worktime spent sitting, 18% spent standing, 5% spent on light physical activity and 6% spent on moderate-to-vigorous physical activity. The composition associated with highest risk for back pain –the “sour-spot”– consisted of 8% worktime spent sitting, 66% spent standing, 4% spent on light physical activity, and 21% spent on moderate-to-vigorous physical activity. CONCLUSIONS: The “sweet-spot” of occupational physical activity for back pain among eldercare workers involves more sitting and light physical activity time, while the “sour-spot” involves more standing and moderate-to-vigorous physical activity time. Research on the occupational physical activity “sweet- and sour-spot” is needed.

An outbreak of influenza A (H5N1) virus was detected in dairy cows in the United States. We detected influenza A virus sialic acid -α2,3/α2,6-galactose host receptors in bovine mammary glands by lectin histochemistry. Our results provide a rationale for the high levels of H5N1 virus in milk from infected cows.

Prader–Willi Syndrome (PWS) is a rare genetic disorder typically characterized by decreased social interaction, hyperphagia, poor behavioral control and temper tantrums, together with a high risk of morbid obesity unless food intake is controlled. The genetic defects that cause PWS include paternal 15q deletion (estimated in 60% of cases), chromosome 15 maternal uniparental disomy (UPD) (estimated in 35% of cases) and imprinting defects and translocations. Several studies indicate an oxytocin deficiency in PWS. Oxytocin is a hypothalamic nonapeptide with receptors located in the brain and in various other tissues in the body. It acts as a neuropeptide in several brain areas of great importance for behavioral and metabolic effects, as well as a neurohypophyseal hormone released into the circulation. Oxytocin in both rats and humans has strong and long-lasting behavioral and metabolic effects. Thus, an oxytocin deficiency might be involved in several of the behavioral and metabolic symptoms characterizing PWS. Treatment with oxytocin has, in some studies, shown improvement in psycho-social behavior and hyperphagia in individuals with PWS. This review focus on the behavioral and metabolic effects of oxytocin, the symptoms of a potential oxytocin deficiency in PWS and the effects of oxytocin treatment.

Abstract Background Seasonal malaria chemoprevention (SMC) is a World Health Organization-recommended intervention for the prevention of malaria among children at high risk in areas with seasonal transmission. During the coronavirus disease 2019 (COVID-19) pandemic, SMC drug distribution was rapidly adapted to reduce contact and mitigate the risk of transmission between communities and community distributors, with caregivers administering doses. To address the challenges and find local solutions to improve administration and adherence, the role model approach was designed, implemented and evaluated in selected communities of Burkina Faso, Chad and Togo. This paper describes the results of this evaluation. Methods Focus group discussions were held with primary caregivers in all three countries to understand their perceptions of the approach’s acceptability and feasibility. In Burkina Faso and Togo, household surveys assessed the characteristics of caregivers reached by role model activities. Key indicators on SMC coverage and adherence allowed for an assessment of caregiver engagement outcomes related to participation in activities. Statistical associations between participation in study’s activities and caregiver beliefs related to SMC had been tested. Results The majority of caregivers believed the approach to have a positive effect on drug administration, with most adopting the promoted strategies. Greater involvement of fathers in drug administration and acknowledgement of their joint responsibility was a notable positive outcome. However, several barriers to participation were noted and there was criticism of the group approach. In Burkina Faso and Togo, end-of-round survey results revealed that 98.4% of respondents agreed the approach improved their knowledge and skills in malaria prevention, while 100% expressed a desire to continue practicing the behaviours learned. However, there was a relatively low level of awareness of the approach among communities. Participation was strongly associated with participants’ self-reported belief in ease of remembering to administer, and ease of administering, SMC medicines. Conclusion Caregivers perceived the role model approach to be beneficial in aiding drug administration, with other positive impacts also reported. Replication and scale-up should utilize the most popular communication channels and existing community structures to ensure activities are promoted effectively. A mixture of group and one-on-one approaches should be used where appropriate and feasible.

Abstract Background Alzheimer’s disease (AD) is a common, complex and multifactorial disease that may require screening across multiple routes of referral to enable early detection and subsequent future implementation of tailored interventions. Blood- and eye-based biomarkers show promise as low-cost, scalable and patient-friendly tools for early AD detection given their ability to provide information on AD pathophysiological changes and manifestations in the retina, respectively. Eye clinics provide an intriguing real-world proof-of-concept setting to evaluate the performance of these potential AD screening tools given the intricate connections between the eye and brain, presumed enrichment for AD pathology in the aging population with eye disorders, and the potential for an accelerated diagnostic pathway for under-recognized patient groups. Methods The BeyeOMARKER study is a prospective, observational, longitudinal cohort study aiming to include individuals visiting an eye-clinic. Inclusion criteria entail being ≥ 50 years old and having no prior dementia diagnosis. Excluded eye-conditions include traumatic insults, superficial inflammation, and conditions in surrounding structures of the eye that are not engaged in vision. The BeyeOMARKER cohort (n = 700) will undergo blood collection to assess plasma p-tau217 levels and a brief cognitive screening at the eye clinic. All participants will subsequently be invited for annual longitudinal follow-up including remotely administered cognitive screening and questionnaires. The BeyeOMARKER + cohort (n = 150), consisting of 100 plasma p-tau217 positive participants and 50 matched negative controls selected from the BeyeOMARKER cohort, will additionally undergo Aβ-PET and tau-PET, MRI, retinal imaging including hyperspectral imaging (primary), widefield imaging, optical coherence tomography (OCT) and OCT-Angiography (secondary), and cognitive and cortical vision assessments. Results We aim to implement the current protocol between April 2024 until March 2027. Primary outcomes include the performance of plasma p-tau217 and hyperspectral retinal imaging to detect AD pathology (using Aβ- and tau-PET visual read as reference standard) and to detect cognitive decline. Initial follow-up is ~ 2 years but may be extended with additional funding. Conclusions We envision that the BeyeOMARKER study will demonstrate the feasibility of early AD detection based on blood- and eye-based biomarkers in alternative screening settings, and will improve our understanding of the eye-brain connection. Trial registration The BeyeOMARKER study (Eudamed CIV ID: CIV-NL-23–09-044086; registration date: 19th of March 2024) is approved by the ethical review board of the Amsterdam UMC.

Abstract Background Whole-genome sequencing (WGS)-based prediction of drug resistance in Mycobacterium tuberculosis has the potential to guide clinical decisions in the design of optimal treatment regimens. Methods We utilized WGS to investigate drug resistance mutations in a 32-year-old Tanzanian male admitted to Kibong’oto Infectious Diseases Hospital with a history of interrupted multidrug-resistant tuberculosis treatment for more than three years. Before admission, he received various all-oral bedaquiline-based multidrug-resistant tuberculosis treatment regimens with unfavourable outcomes. Results Drug susceptibility testing of serial M. tuberculosis isolates using Mycobacterium Growth Incubator Tubes culture and WGS revealed resistance to first-line anti-TB drugs, bedaquiline, and fluoroquinolones but susceptibility to linezolid, clofazimine, and delamanid. WGS of serial cultured isolates revealed that the Beijing (Lineage 2.2.2) strain was resistant to bedaquiline, with mutations in the mmpR5 gene (Rv0678. This study also revealed the emergence of two distinct subpopulations of bedaquiline-resistant tuberculosis strains with Asp47f and Glu49fs frameshift mutations in the mmpR5 gene, which might be the underlying cause of prolonged resistance. An individualized regimen comprising bedaquiline, delamanid, pyrazinamide, ethionamide, and para-aminosalicylic acid was designed. The patient was discharged home at month 8 and is currently in the ninth month of treatment. He reported no cough, chest pain, fever, or chest tightness but still experienced numbness in his lower limbs. Conclusion We propose the incorporation of WGS in the diagnostic framework for the optimal management of patients with drug-resistant and extensively drug-resistant tuberculosis.

Abstract Background Posterior globe flattening (PGF) is a specific neuroimaging sign in patients with idiopathic intracranial hypertension (IIH), but its detection is based on subjective qualitative neuroradiological assessment. This study sought to evaluate the utility of transorbital ultrasound to detect and quantify PGF in IIH patients using the Posterior Globe Angle (PGA). Methods Consecutive IIH patients and healthy controls were enrolled in a prospective case-control study. Transorbital ultrasound was performed to assess the presence of PGF. For quantification of PGF, an angular measurement (PGA) was performed with the vertex centering the optic nerve at a predefined distance from the lamina cribrosa and angle legs tangentially aligned to the borders of the vitreous body. PGA measurements were compared between IIH patients and healthy controls. Additionally, the diagnostic accuracy of PGA measurements in detecting PGF was evaluated using ROC analysis. Results Thirty-one IIH patients (37.3 ± 12.3 years, 29 female) and 28 controls (33.3 ± 11.8 years, 21 female) were compared. PGF was present in 39% of IIH patients and absent in the control group. PGA3mm measurements significantly differed between IIH and controls (116.5° ± 5.5 vs. 111.7° ± 2.9; p

Abstract In 2020, Denmark buried approximately four million culled, farmed mink in mass graves treated with slaked lime due to widespread SARS-CoV-2 infections. After six months, environmental concerns prompted the exhumation of these cadavers. Our analysis encompassed visual inspections, soil pH measurements, and gas emission assessments of the grave environment. Additionally, we evaluated carcasses for decay status, cadaverine content, and the presence of various pathogens, including SARS-CoV-2 and mink coronavirus. Our findings revealed minimal microbial activity and limited carcass decomposition. Although viral RNA from SARS-CoV-2 and mink coronavirus, along with DNA from Aleutian mink disease virus, were detected, the absence of infectious SARS-CoV-2 in cell culture assays suggests slow natural degradation processes. This study provides critical insights for future considerations in managing mass burial scenarios during outbreaks of livestock-associated zoonotic pathogens.

Abstract Background Cervicitis, an infectious or noninfectious inflammation of the cervix, encompasses a wide range of clinical conditions, from asymptomatic infections to severe lesions, making its diagnosis difficult. Acute cervicitis may develop into pelvic inflammatory disease. In patients with cervicitis, current guidelines recommend testing for herpes simplex virus when external genital lesions are present. Here, we present the case of a patient with an atypical primary herpes simplex virus 2 infection manifesting as cervicitis without genital lesions. Case presentation A 29-year-old Caucasian woman was hospitalized for pelvic inflammatory disease. The patient complained of severe suprapubic pain, fever, and heavy vaginal discharge. The external genitalia were unremarkable, so empirical antibiotic treatment was initiated. Despite 48 hours of well-administered antibiotic therapy, her complaints persisted. Polymerase chain reaction for possible microbial causes was negative for Chlamydia trachomatis and Neisseria gonorrhoeae. There was no bacterial vaginosis. Repeat gynecological examinations with endovaginal ultrasound revealed an enlarged cervix, and pelvic magnetic resonance imaging supported a diagnosis of cervicitis. At this point, additional screening for other sexually transmitted infections and infectious disease-related etiologies of cervicitis was performed, and the polymerase chain reaction analysis of newly isolated samples was positive for herpes simplex virus 2. No antiviral treatment was initiated given the delay in diagnosing herpes simplex virus 2 infection and the slow but spontaneous abatement of symptoms. Conclusion Herpes simplex virus infection should be considered as a possible cause of cervicitis, even in the absence of typical genital lesions. Early detection of herpes simplex virus allows early treatment, helping to reduce the duration and severity of symptoms and therefore potentially reducing recurrences and improving disease control. These data and data from future cases might spur changes in the guidelines on cervicitis testing and treatment.

Abstract Asteroid (3200) Phaethon experiences extreme solar radiant heating ( ~ 750 °C) during perihelion (0.14 au), leading to comet-like activity. The regolith composition and mechanism of volatile emission are unknown but key to understanding JAXA’s DESTINY+ mission data (fly-by in 2029) and the fate of near-Sun asteroids more generally. By subjecting CM chondrite fragments to fast, open system, cyclic heating (2-20 °C/min), simulating conditions on Phaethon we demonstrate that rapid heating rates combine with the low permeability, resulting in reactions between volatile gases and decomposing minerals. The retention of S-bearing gas limits the thermal decomposition of Fe-sulphides, allowing these minerals to survive repeated heating cycles. Slow escape of S-bearing gases provides a mechanism for repeated gas release from a thermally processed surface and, therefore the comet-like activity without requiring surface renewal to expose fresh material each perihelion cycle. We predict Phaethon regolith is composed of olivine, Fe-sulphides, Ca-sulphates and hematite.

Abstract Malignant mesothelioma is a rare tumour caused by asbestos exposure that originates mainly from the pleural lining or the peritoneum. Treatment options are limited, and the prognosis is dismal. Although immune checkpoint blockade (ICB) can improve survival outcomes, the determinants of responsiveness remain elusive. Here, we report the outcomes of a multi-centre phase II clinical trial (MiST4, NCT03654833) evaluating atezolizumab and bevacizumab (AtzBev) in patients with relapsed mesothelioma. We also use tumour tissue and gut microbiome sequencing, as well as tumour spatial immunophenotyping to identify factors associated with treatment response. MIST4 met its primary endpoint with 50% 12-week disease control, and the treatment was tolerable. Aneuploidy, notably uniparental disomy (UPD), homologous recombination deficiency (HRD), epithelial-mesenchymal transition and inflammation with CD68+ monocytes were identified as tumour-intrinsic resistance factors. The log-ratio of gut-resident microbial genera positively correlated with radiological response to AtzBev and CD8+ T cell infiltration, but was inversely correlated with UPD, HRD and tumour infiltration by CD68+ monocytes. In summary, a model is proposed in which both intrinsic and extrinsic determinants in mesothelioma cooperate to modify the tumour microenvironment and confer clinical sensitivity to AtzBev. Gut microbiota represent a potentially modifiable factor with potential to improve immunotherapy outcomes for individuals with this cancer of unmet need.

Abstract Upon infecting its vertebrate host, the malaria parasite initially invades the liver where it undergoes massive replication, whilst remaining clinically silent. The coordination of host responses across the complex liver tissue during malaria infection remains unexplored. Here, we perform spatial transcriptomics in combination with single-nuclei RNA sequencing over multiple time points to delineate host-pathogen interactions across Plasmodium berghei-infected liver tissues. Our data reveals significant changes in spatial gene expression in the malaria-infected tissues. These include changes related to lipid metabolism in the proximity to sites of Plasmodium infection, distinct inflammation programs between lobular zones, and regions with enrichment of different inflammatory cells, which we term ‘inflammatory hotspots’. We also observe significant upregulation of genes involved in inflammation in the control liver tissues of mice injected with mosquito salivary gland components. However, this response is considerably delayed compared to that observed in P. berghei-infected mice. Our study establishes a benchmark for investigating transcriptome changes during host-parasite interactions in tissues, it provides informative insights regarding in vivo study design linked to infection and offers a useful tool for the discovery and validation of de novo intervention strategies aimed at malaria liver stage infection.

Abstract Background Shiga toxin-producing Escherichia coli (STEC) infections are a significant public health concern as they can cause serious illness and outbreaks. In England, STEC incidence is highest among children and guidance recommends that children under six diagnosed with STEC are excluded from childcare until two consecutive stool cultures are negative. We aimed to describe the barriers and facilitators to implementing exclusion and the impact of exclusion policies on young children and their families. Methods Individual level data was obtained from a wider study focusing on shedding duration among STEC cases aged

Abstract Caregivers play an essential role in the recovery of their adult loved ones with serious mental illness (SMI). Promoting caregiver empowerment and well-being is critical but has often been overlooked. Family peer interventions are well-suited to fill this need; however, research is limited supporting their use with caregivers of adults with SMI. Our team is currently engaged in a study evaluating an adapted version of the evidenced-based Parent Connectors program1,2, renamed Family Connectors (FC), for caregivers of young adults recently discharged from the First Episode Psychosis program in New York (OnTrackNY). This paper, written collaboratively with family peer professionals, describes the adaptation process we followed to systematically document the family peer professional experience one year into delivering the FC program to this novel population. Modifications made to improve intervention fit included tailoring the content of the intervention, incorporating an outside approach into the program, lengthening the service in some cases, and adding a weekly peer supervision meeting. We hope that these insights are used to inform future efforts to advance support for families of loved ones with SMI, and more broadly, that our approach serves as a model for effective collaboration to improve the application of peer support services for unique groups.

Abstract Background Individuals with higher weight (overweight or obesity) may experience social stigma due to their weight. Weight stigma can be internalized with adverse health effects. Internalized weight stigma is relevant across different weight categories, but no validated weight-neutral measure of internalized weight bias currently exists in Norway. The current study aimed to examine the validity of a Norwegian translation of the Modified Weight Bias Internalization Scale. Methods A Norwegian translation of the Modified Weight Bias Internalization Scale (WBIS-M) was administered in an adult Norwegian sample (N = 315, of which 251 women) ranging from self-reported “very underweight” to “very overweight”. Results A confirmatory factor analysis was conducted on 11 of the original 11 items in the WBIS-M. Based on previous factor analyses with this scale, we expected a one-factor model. One of the items related to competence showed poor model fit, and concern was raised around possible item ambiguity partway through the study. Two versions of this item were therefore tested, neither of which yielded an acceptable fit. After exclusion of this item, the results showed high loadings for the remaining 10 items on one factor with a high internal consistency (α = 0.94). Convergent validity was approached by looking at the relationship between answers on the WBIS-M, self-perceived weight, and items on overall health and psychological/emotional state. Conclusion The 10-item Norwegian version of the WBIS-M shows sound psychometric properties and can be used to measure internalized weight bias in a weight-neutral fashion in a Norwegian-speaking population. Internalized weight bias was correlated with psychological/emotional state and overall health, with those reporting more internalized weight bias also reporting that they felt worse. This relationship was stronger for women than men in our sample and was partially dependent on weight. The women also showed higher internalized weight bias than the men. Future studies should include more male participants and explore alternative versions of the missing item related to competence.

Abstract Measurement of overall survival (OS) remains the gold standard for interpreting the impact of new therapies for multiple myeloma in phase 3 trials. However, as outcomes have improved, it is increasingly challenging to use OS as the primary endpoint if timely approval of novel agents is to be ensured to enable maximum benefit for patients. Surrogate endpoints of OS, such as progression-free survival (PFS) and response to treatment, have contributed to approval decisions by the Food and Drug Administration (FDA) and European Medicines Agency as endpoints demonstrating clinical benefit, and the FDA has recently supported the use of minimal residual disease (MRD) as an accelerated approval endpoint in multiple myeloma. This review aims to address situations in which the use of PFS as a surrogate endpoint warrants careful interpretation especially for specific subgroups of patients and considers ways to ensure that studies can be designed to account for possible discordance between PFS and OS. The utility of subgroup analyses, including the potential for those not pre-specified, to identify target populations for new agents is also discussed.

Abstract Background Placement of peripheral intravenous catheters (PIVC) is a routine procedure in hospital settings. The primary objective is to explore the relationship between healthcare inequities and PIVC outcomes. Methods This study was a multicenter, observational analysis of adults with PIVC access established in the emergency department requiring inpatient admission between January 1st, 2021, and January 31st, 2023, in metro Detroit, Michigan, United States. Epidemiological, demographic, therapeutic, clinical, and outcomes data were collected. Health disparities were defined by the National Institute on Minority Health and Health Disparities. The primary outcome was the proportion of PIVC dwell time to hospitalization length of stay, expressed as the proportion of dwell time (hours) to hospital stay (hours) x 100%. Multivariable linear regression and a machine learning model were used for variable selection. Subsequently, a multivariate linear regression analysis was utilized to adjust for confounders and best estimate the true effect of each variable. Results Between January 1st, 2021, and January 31st, 2023, our study analyzed 144,524 ED encounters, with an average patient age of 65.7 years and 53.4% female. Racial demographics showed 67.2% White, and 27.0% Black, with the remaining identifying as Asian, American Indian Alaska Native, or other races. The median proportion of PIVC dwell time to hospital length of stay was 0.88, with individuals identifying as Asian having the highest ratio (0.94) and Black individuals the lowest (0.82). Black females had a median dwell time to stay ratio of 0.76, significantly lower than White males at 0.93 (p

Abstract Background It is uncertain what could be the best training methods for infection prevention and control when an infectious disease threat is active or imminent in especially vulnerable or resource-scarce settings. Methods A scoping review was undertaken to find and summarise relevant information about training modalities, replicability and effectiveness of IPC training programmes for clinical staff as reported in multiple study designs. Eligible settings were conflict-affected or in countries classified as low-income or lower-middle income (World Bank 2022 classifications). Search terms for LILACS and Scopus were developed with input of an expert working group. Initially found articles were dual-screened independently, data were extracted especially about infection threat, training outcomes, needs assessment and teaching modalities. Backwards and forwards citation searches were done to find additional studies. Narrative summary describes outcomes and aspects of the training programmes. A customised quality assessment tool was developed to describe whether each study could be informative for developing specific future training programmes in relevant vulnerable settings, based on six questions about replicability and eight questions about other biases. Findings Included studies numbered 29, almost all (n = 27) were pre-post design, two were trials. Information within the included studies to enable replicability was low (average score 3.7/6). Nearly all studies reported significant improvement in outcomes suggesting that the predominant study design (pre-post) is inadequate to assess improvement with low bias, that any and all such training is beneficial, or that publication bias prevented reporting of less successful interventions and thus a informative overview. Conclusion It seems likely that many possible training formats and methods can lead to improved worker knowledge, skills and / or practice in infection prevention and control. Definitive evidence in favour of any specific training format or method is hard to demonstrate due to incomplete descriptions, lack of documentation about unsuccessful training, and few least-biased study designs (experimental trials). Our results suggest that there is a significant opportunity to design experiments that could give insights in favour of or against specific training methods. “Sleeping” protocols for randomised controlled trials could be developed and then applied quickly when relevant future events arise, with evaluation for outcomes such as knowledge, practices, skills, confidence, and awareness.

Abstract Ligation of the B cell antigen receptor (BCR) initiates humoral immunity. However, BCR signaling without appropriate co-stimulation commits B cells to death rather than to differentiation into immune effector cells. How BCR activation depletes potentially autoreactive B cells while simultaneously primes for receiving rescue and differentiation signals from cognate T lymphocytes remains unknown. Here, we use a mass spectrometry-based proteomic approach to identify cytosolic/nuclear shuttling elements and uncover transcription factor EB (TFEB) as a central BCR-controlled rheostat that drives activation-induced apoptosis, and concurrently promotes the reception of co-stimulatory rescue signals by supporting B cell migration and antigen presentation. CD40 co-stimulation prevents TFEB-driven cell death, while enhancing and prolonging TFEB’s nuclear residency, which hallmarks antigenic experience also of memory B cells. In mice, TFEB shapes the transcriptional landscape of germinal center B cells. Within the germinal center, TFEB facilitates the dark zone entry of light-zone-residing centrocytes through regulation of chemokine receptors and, by balancing the expression of Bcl-2/BH3-only family members, integrates antigen-induced apoptosis with T cell-provided CD40 survival signals. Thus, TFEB reprograms antigen-primed germinal center B cells for cell fate decisions.

Abstract High pathogenicity avian influenza viruses (HPAIVs) have caused major epizootics in recent years, with devastating consequences for poultry and wildlife worldwide. Domestic and wild ducks can be highly susceptible to HPAIVs, and infection leads to efficient viral replication and massive shedding (i.e., high titres for an extended time), contributing to widespread viral dissemination. Importantly, ducks are known to shed high amounts of virus in the earliest phase of infection, but the dynamics and impact of environmental contamination on the epidemiology of HPAIV outbreaks are poorly understood. In this study, we monitored mule ducks experimentally infected with two H5N8 clade 2.3.4.4b goose/Guangdong HPAIVs sampled in France in 2016–2017 and 2020–2021 epizootics. We investigated viral shedding dynamics in the oropharynx, cloaca, conjunctiva, and feathers; bird-to-bird viral transmission; and the role of the environment in viral spread and as a source of samples for early detection and surveillance. Our findings showed that viral shedding started before the onset of clinical signs, i.e., as early as 1 day post-inoculation (dpi) or post-contact exposure, peaked at 4 dpi, and lasted for up to 14 dpi. The detection of viral RNA in aerosols, dust, and water samples mirrored viral shedding dynamics, and viral isolation from these environmental samples was successful throughout the experiment. Our results confirm that mule ducks can shed high HPAIV titres through the four excretion routes tested (oropharyngeal, cloacal, conjunctival, and feather) while being asymptomatic and that environmental sampling could be a non-invasive tool for early viral RNA detection in HPAIV-infected farms.

Abstract In this work we continue the investigation of the extrapolate dictionary for celestial holography recently proposed in [1], at both the perturbative and non-perturbative level. Focusing on scalar field theories, we give a complete set of Feynman rules for extrapolate celestial correlation functions and their radial reduction in the hyperbolic slicing of Minkowski space. We prove to all orders in perturbation theory that celestial correlators can be rewritten in terms of corresponding Witten diagrams in EAdS which, in the hyperbolic slicing of Minkowski space, follows from the fact that the same is true in dS space. We then initiate the study of non-perturbative properties of celestial correlators, deriving the radial reduction of the Källén-Lehmann spectral representation of the exact Minkowski two-point function. We discuss the analytic properties of the radially reduced spectral function, which is a meromorphic function of the spectral parameter, and highlight a connection with the Watson-Sommerfeld transform.

Abstract Follicular lymphoma (FL) exhibits considerable variability in biological features and clinical trajectories across patients. To dissect the diversity of FL, we utilized a Bernoulli mixture model to identify genetic subtypes in 713 pre-treatment tumor tissue samples. Our analysis revealed the existence of five subtypes with unique genetic profiles that correlated with clinicopathological characteristics. The clusters were enriched in specific mutations as follows: CS (CREBBP and STAT6), TT (TNFAIP3 and TP53), GM (GNA13 and MEF2B), Q (quiescent, for low mutation burden), and AR (mutations of mTOR pathway-related genes). The subtype Q was enriched for patients with stage I disease and associated with a lower proliferative history than the other subtypes. The AR subtype was unique in its enrichment for IgM-expressing FL cases and was associated with advanced-stage and more than 4 nodal sites. The existence of subtypes was validated in an independent cohort of 418 samples from the GALLIUM trial. Notably, patients assigned to the TT subtype consistently experienced inferior progression-free survival when treated with immunochemotherapy. Our findings offer insight into core pathways distinctly linked with each FL cluster and are expected to be informative in the era of targeted therapies.

Abstract Background In the last decade, notable progress in mechatronics paved the way for a new generation of arm prostheses, expanding motor capabilities thanks to their multiple active joints. Yet, the design of control schemes for these advanced devices still poses a challenge, especially with the limited availability of command signals for higher levels of arm impairment. When addressing this challenge, current commercial devices lack versatility and customizing options to be employed as test-beds for developing novel control schemes. As a consequence, researchers resort to using lab-specific experimental apparatuses on which to deploy their innovations, such as virtual reality setups or mock prosthetic devices worn by unimpaired participants. Methods To meet this need for a test-bed, we developed the Smart Arm platform, a human-like, multi-articulated robotic arm that can be worn as a trans-humeral arm prosthesis. The design process followed three principles: provide a reprogrammable embedded system allowing in-depth customization of control schemes, favor easy-to-buy parts rather than custom-made components, and guarantee compatibility with industrial standards in prosthetics. Results The Smart ArM platform includes motorized elbow and wrist joints while being compatible with commercial prosthetic hands. Its software and electronic architecture can be easily adapted to build devices with a wide variety of sensors and actuators. This platform was employed in several experiments studying arm prosthesis control and sensory feedback. We also report our participation in Cybathlon, where our pilot with forearm agenesia successfully drives the Smart Arm prosthesis to perform activities of daily living requiring both strength and dexterity. Conclusion These application scenarios illustrate the versatility and adaptability of the proposed platform, for research purposes as well as outside the lab. The Smart Arm platform offers a test-bed for experimenting with prosthetic control laws and command signals, suitable for running tests in lifelike settings where impaired participants wear it as a prosthetic device. In this way, we aim at bridging a critical gap in the field of upper limb prosthetics: the need for realistic, ecological test conditions to assess the actual benefit of a technological innovation for the end-users.

Abstract Background Despite surgical and pharmacological interventions, endometriosis can recur. Reliable information regarding risk of recurrence following a first diagnosis is scant. The aim of this study was to examine clinical and survey data in the setting of disease recurrence to identify predictors of risk of endometriosis recurrence. Methods This observational study reviewed data from 794 patients having surgery for pelvic pain or endometriosis. Patients were stratified into two analytic groups based on self-reported or surgically confirmed recurrent endometriosis. Statistical analyses included univariate, followed by multivariate logistic regression to identify risk factors of recurrence, with least absolute shrinkage and selection operator (Lasso) regularisation. Risk-calibrated Supersparse Linear Integer Models (RiskSLIM) and survival analyses (with Lasso) were undertaken to identify predictive features of recurrence. Results Several significant features were repeatedly identified in association with recurrence, including adhesions, high rASRM score, deep disease, bowel lesions, adenomyosis, emergency room attendance for pelvic pain, younger age at menarche, higher gravidity, high blood pressure and older age. In the surgically confirmed group, with a score of 5, the RiskSLIM method was able to predict the risk of recurrence (compared to a single diagnosis) at 95.3% and included adenomyosis and adhesions in the model. Survival analysis further highlighted bowel lesions, adhesions and adenomyosis. Conclusions Following an initial diagnosis of endometriosis, clinical decision-making regarding disease management should take into consideration the presence of bowel lesions, adhesions and adenomyosis, which increase the risk of endometriosis recurrence.

Abstract The demographical history of France remains largely understudied despite its central role toward understanding modern population structure across Western Europe. Here, by exploring publicly available Europe-wide genotype datasets together with the genomes of 3234 present-day and six newly sequenced medieval individuals from Northern France, we found extensive fine-scale population structure across Brittany and the downstream Loire basin and increased population differentiation between the northern and southern sides of the river Loire, associated with higher proportions of steppe vs. Neolithic-related ancestry. We also found increased allele sharing between individuals from Western Brittany and those associated with the Bell Beaker complex. Our results emphasise the need for investigating local populations to better understand the distribution of rare (putatively deleterious) variants across space and the importance of common genetic legacy in understanding the sharing of disease-related alleles between Brittany and people from western Britain and Ireland.

Abstract Consciousness has been proposed to be supported by electrophysiological patterns poised at criticality, a dynamical regime which exhibits adaptive computational properties, maximally complex patterns and divergent sensitivity to perturbation. Here, we investigate dynamical properties of the resting-state electroencephalogram (EEG) of healthy subjects undergoing general anesthesia with propofol, xenon or ketamine. Importantly, all participants were unresponsive under anesthesia, while consciousness was retained only during ketamine anesthesia (in the form of vivid dreams), enabling an experimental dissociation between unresponsiveness and unconsciousness. For each condition, we measure (i) avalanche criticality, (ii) chaoticity, and (iii) criticality-related metrics, revealing that states of unconsciousness are characterized by a distancing from both avalanche criticality and the edge of chaos. We then ask whether these same dynamical properties are predictive of the perturbational complexity index (PCI), a TMS-based measure that has shown remarkably high sensitivity in detecting consciousness independently of behavior. We successfully predict individual subjects’ PCI values with considerably high accuracy from resting-state EEG dynamical properties alone. Our results establish a firm link between perturbational complexity and criticality, and provide further evidence that criticality is a necessary condition for the emergence of consciousness.

Abstract Background Addressing socioeconomic inequalities in health and healthcare, and reducing avoidable hospital admissions requires integrated strategy and complex intervention across health systems. However, the understanding of how to create effective systems to reduce socio-economic inequalities in health and healthcare is limited. The aim was to explore and develop a system’s level understanding of how local areas address health inequalities with a focus on avoidable emergency admissions. Methods In-depth case study using qualitative investigation (documentary analysis and key informant interviews) in an urban UK local authority. Interviewees were identified using snowball sampling. Documents were retrieved via key informants and web searches of relevant organisations. Interviews and documents were analysed independently based on a thematic analysis approach. Results Interviews (n = 14) with wide representation from local authority (n = 8), NHS (n = 5) and voluntary, community and social enterprise (VCSE) sector (n = 1) with 75 documents (including from NHS, local authority, VCSE) were included. Cross-referenced themes were understanding the local context, facilitators of how to tackle health inequalities: the assets, and emerging risks and concerns. Addressing health inequalities in avoidable admissions per se was not often explicitly linked by either the interviews or documents and is not yet embedded into practice. However, a strong coherent strategic integrated population health management plan with a system’s approach to reducing health inequalities was evident as was collective action and involving people, with links to a “strong third sector”. Challenges reported include structural barriers and threats, the analysis and accessibility of data as well as ongoing pressures on the health and care system. Conclusion We provide an in-depth exploration of how a local area is working to address health and care inequalities. Key elements of this system’s working include fostering strategic coherence, cross-agency working, and community-asset based approaches. Areas requiring action included data sharing challenges across organisations and analytical capacity to assist endeavours to reduce health and care inequalities. Other areas were around the resilience of the system including the recruitment and retention of the workforce. More action is required to embed reducing health inequalities in avoidable admissions explicitly in local areas with inaction risking widening the health gap.

Abstract Introduction Working on the frontline during the COVID-19 pandemic has been associated with increased risk to mental health and wellbeing in multiple occupations and contexts. The current study aimed to provide an insight into the rate of probable mental health problems amongst United Kingdom (UK) Government employees who contributed to the COVID-19 response whilst working from home, and to ascertain what factors and constructs, if any, influence mental health and wellbeing in the sample population. Method This paper reports on the findings from two studies completed by UK Government employees. Study 1: A cross-sectional online survey, containing standardised and validated measures of common mental health disorders of staff who actively contributed to the COVID-19 response from their own homes. Binary logistic regression was used to assess factors associated with mental health outcomes. Study 2: A secondary data analysis of cross-sectional survey data collected across three timepoints (May, June, and August) in 2020 focusing on the wellbeing of employees who worked from home during the COVID-19 pandemic. Results Study 1: 17.9% of participants met the threshold criteria for a probable moderate anxiety disorder, moderate depression, or post-traumatic stress disorder. Younger, less resilient, less productive individuals, with lower personal wellbeing and less enjoyment of working from home, were more likely to present with poorer mental health. Study 2: Found lower wellbeing was consistently associated with having less opportunities to look after one’s physical and mental health, and having unsupportive line managers and colleagues. Conclusion It is important to ensure UK Government employees’ psychological needs are met whilst working from home and responding to enhanced incidents. It is recommended that workplaces should be seeking to continually build and improve employee resilience (e.g., through opportunities to increase social ties and support networks), essentially ensuring employees have necessary resources and skills to support themselves and others.

Abstract In recent years, demographers have parsed variation in survivorship into two distinct components: the shape and the pace of ageing. The pace of ageing is defined by measures of longevity such as mean life expectancy or maximum longevity, whereas measures of the shape of ageing attempt to classify different shapes of the survivorship curve. We recently published a paper pointing out that a commonly used discretization of a shape measure, Keyfitz' entropy, does not correctly classify survivorship curves into negatively and positively senescing curves (de Vries et al., 2023). In that paper, we also suggested an alternative, accurate discrete‐time version of Keyfitz' entropy. de Vries et al. (2023) ended with two open questions, both of which have been answered by Giaimo (2024) now: (1) Can a discrete‐time entropy measure of survivorship be generalized beyond age‐based population models? Giaimo (2024) introduce a new formula that achieves this. (2) Will a discretization of Keyfitz' derivation of his measure as the elasticity of lifespan to a uniform change in mortality lead to the same formula as a discretization of Keyfitz' result? Giaimo (2024) answers: no. Here, we briefly discuss the implications of the results obtained by Giaimo (2024), and the implementation of his new formula into the Rpackage Rage, which is widely used for comparative demographic studies. We showcase the strength of the new method by reanalysing a comparison of Keyfitz' entropy to another shape measure. We find that the comparison is significantly altered by using Giaimo's new Keyfitz' formula. This example strengthens Giaimo's (2004) words of warning in approaching discretizations with attentiveness.

Abstract Adaptive nanopore sequencing as a diagnostic method for imprinting disorders and episignature analysis revealed an intragenic duplication of Exon 6 and 7 in UBE3A (NM_000462.5) in a patient with relatively mild Angelman-like syndrome. In an all-in-one nanopore sequencing analysis DNA hypomethylation of the SNURF:TSS-DMR, known contributing deletions on the maternal allele and point mutations in UBE3A could be ruled out as disease drivers. In contrast, breakpoints and orientation of the tandem duplication could clearly be defined. Segregation analysis in the family showed that the duplication derived de novo in the maternal grandfather. Our study shows the benefits of an all-in-one nanopore sequencing approach for the diagnostics of Angelman syndrome and other imprinting disorders.

Abstract Shigellosis is an enteric infection that transmits through the faecal-oral route, which can occur during sex between men who have sex with men (MSM). Between 2009 and 2014, an epidemic of sexually transmissible Shigella flexneri 3a occurred in England that subsequently declined. However, from 2019 to 2021, despite SARS-CoV-2 restrictions, S. flexneri 3a continued to re-emerge. We explored possible drivers of re-emergence by comparing host demography and pathogen genomics. Cases were primarily among 35–64 year old men in London. Genomic analyses of 502 bacterial isolates showed that the majority (58%) of re-emerging MSM strains were a clonal replacement of the original, with reduced antimicrobial resistance, conservation of plasmid col156_1, and two SNPs with 19 predicted effects. The absence of major changes in the pathogen or host demographics suggest that other factors may have driven the re-emergence of S. flexneri 3a and highlight the need for further work in the area.

Abstract Background Traditionally managed semi-natural pastures are recognised for their high biodiversity. One drawback is that these pastures are often low in fodder production and hence rather unprofitable, which may lead to abandonment. Two ways to increase production and profitability and maintain grazing are to (i) offer the grazers supplementary feed, or (ii) co-enclose the semi-natural pasture with an improved pasture. Both practices may transfer nutrients to the semi-natural pasture, with potential negative effects on biodiversity. This systematic review aimed to analyse the available evidence concerning the following primary question: “What is the effect of giving grazers access to additional nutrient sources on biodiversity in semi-natural pastures?” (Q1). We also used two supporting questions: “What is the effect of giving grazers access to additional nutrient sources on nutrient status of the soils of semi-natural pastures?” (Q2) and “How do the grazers of semi-natural pastures behave while having access to additional nutrient sources?” (Q3). Methods Searches for peer-reviewed and grey literature were made using bibliographic databases, search engines, specialist websites, and stakeholder contacts. Literature was screened for relevance according to predefined eligibility criteria, and critical appraisal was performed using the tool CEECAT. A database of the relevant studies was compiled. Descriptive information about the evidence base is presented in tables and an interactive evidence atlas. Because of absent study setup replication, Q1 and Q2 were not analysed quantitatively. However, sample size allowed the use of mixed modelling to quantitatively analyse Q3 regarding the effects of (i) co-enclosing an improved pasture on grazers’ electivity for the improved area, and (ii) supplementary feed on the forage intake of grazers. Review findings A total of 12 articles on the effects of supplementary feeding and 19 on the effects of co-enclosing an improved pasture were included, of which some targeted multiple review questions. Because of the limited literature, it is not possible to draw any conclusions concerning the effects on biodiversity (Q1) or nutritional status (Q2) in semi-natural pastures. For Q3, 28 studies fulfilled our criteria, of which 18 investigated the behaviour of grazers related to co-enclosing an improved pasture, and 10 investigated their forage intake while having access to supplementary fodder. The results show that all grazer species except goats preferred grazing in the improved areas regardless of whether they were grazing together with other grazer species or not. We found no effect of supplementary feeding on forage intake of the grazers. Conclusions We detected a knowledge gap concerning the effects of the two additional nutrient sources on semi-natural pasture biodiversity (Q1) and nutrient status (Q2), which points toward further research needs. Analysis of Q3 showed that grazers prefer to graze improved compared to semi-natural pasture areas. However, how this behaviour subsequently affects nutrient transport and biodiversity is unclear and cannot be translated into management recommendations. To gain better knowledge about the primary question of our review, research focusing specifically on this question is needed. We provide suggestions for how such studies could be designed, including spatio-temporal setup, and key management and environmental conditions to consider.

Abstract The clinical course of COVID-19 is variable and often unpredictable. To test the hypothesis that disease progression and inflammatory responses associate with alterations in the microbiome and metabolome, we analyzed metagenome, metabolome, cytokine, and transcriptome profiles of repeated samples from hospitalized COVID-19 patients and uninfected controls, and leveraged clinical information and post-hoc confounder analysis. Severe COVID-19 was associated with a depletion of beneficial intestinal microbes, whereas oropharyngeal microbiota disturbance was mainly linked to antibiotic use. COVID-19 severity was also associated with enhanced plasma concentrations of kynurenine and reduced levels of several other tryptophan metabolites, lysophosphatidylcholines, and secondary bile acids. Moreover, reduced concentrations of various tryptophan metabolites were associated with depletion of Faecalibacterium, and tryptophan decrease and kynurenine increase were linked to enhanced production of inflammatory cytokines. Collectively, our study identifies correlated microbiome and metabolome alterations as a potential contributor to inflammatory dysregulation in severe COVID-19.

Abstract Background Digital speech assessment has potential relevance in the earliest, preclinical stages of Alzheimer’s disease (AD). We evaluated the feasibility, test-retest reliability, and association with AD-related amyloid-beta (Aβ) pathology of speech acoustics measured over multiple assessments in a remote setting. Methods Fifty cognitively unimpaired adults (Age 68 ± 6.2 years, 58% female, 46% Aβ-positive) completed remote, tablet-based speech assessments (i.e., picture description, journal-prompt storytelling, verbal fluency tasks) for five days. The testing paradigm was repeated after 2–3 weeks. Acoustic speech features were automatically extracted from the voice recordings, and mean scores were calculated over the 5-day period. We assessed feasibility by adherence rates and usability ratings on the System Usability Scale (SUS) questionnaire. Test-retest reliability was examined with intraclass correlation coefficients (ICCs). We investigated the associations between acoustic features and Aβ-pathology, using linear regression models, adjusted for age, sex and education. Results The speech assessment was feasible, indicated by 91.6% adherence and usability scores of 86.0 ± 9.9. High reliability (ICC ≥ 0.75) was found across averaged speech samples. Aβ-positive individuals displayed a higher pause-to-word ratio in picture description (B = -0.05, p = 0.040) and journal-prompt storytelling (B = -0.07, p = 0.032) than Aβ-negative individuals, although this effect lost significance after correction for multiple testing. Conclusion Our findings support the feasibility and reliability of multi-day remote assessment of speech acoustics in cognitively unimpaired individuals with and without Aβ-pathology, which lays the foundation for the use of speech biomarkers in the context of early AD.

Abstract Background Growth differentiation factor‐15 (GDF‐15) has been associated with senescence, lower muscle strength, and physical performance in healthy older people. Still, it is not clear whether GDF‐15 can be utilized as a biomarker of sarcopenia and frailty in the early stages of hospitalization. We investigated the association of plasma GDF‐15 with sarcopenia and frailty in older, acutely admitted medical patients. Methods The present study is based on secondary analyses of cross‐sectional data from the Copenhagen PROTECT study, a prospective cohort study including 1071 patients ≥65 years of age admitted to the acute medical ward at Copenhagen University Hospital, Bispebjerg, Denmark. Muscle strength was assessed using handgrip strength, and lean mass was assessed using direct segmental multifrequency bioelectrical impedance analyses and used to clarify the potential presence of sarcopenia defined according to guidelines from the European Working Group on Sarcopenia in Older People. Frailty was evaluated using the Clinical Frailty Scale. Plasma GDF‐15 was measured using electrochemiluminescence assays from Meso Scale Discovery (MSD, Rockville, MD, USA). Results We included 1036 patients with completed blood samples (mean age 78.9 ± 7.8 years, 53% female). The median concentration of GDF‐15 was 2669.3 pg/mL. Systemic GDF‐15 was significantly higher in patients with either sarcopenia (P

Abstract We evaluated the impacts of COVID‐19 on multi‐organ and metabolic function in patients following severe hospitalised infection compared to controls. Patients (n = 21) without previous diabetes, cardiovascular or cerebrovascular disease were recruited 5–7 months post‐discharge alongside controls (n = 10) with similar age, sex and body mass. Perceived fatigue was estimated (Fatigue Severity Scale) and the following were conducted: oral glucose tolerance (OGTT) alongside whole‐body fuel oxidation, validated magnetic resonance imaging and spectroscopy during resting and supine controlled exercise, dual‐energy X‐ray absorptiometry, short physical performance battery (SPPB), intra‐muscular electromyography, quadriceps strength and fatigability, and daily step‐count. There was a greater insulin response (incremental area under the curve, median (inter‐quartile range)) during the OGTT in patients [18,289 (12,497–27,448) mIU/min/L] versus controls [8655 (7948–11,040) mIU/min/L], P

This work explores the potential of a triple combination of meropenem (MEM), a novel metallo-β-lactamase (MBL) inhibitor (indole-2-carboxylate 58 (InC58)), and a serine-β-lactamase (SBL) inhibitor (avibactam (AVI)) for broad-spectrum activity against carbapenemase-producing bacteria. A diverse panel comprising MBL- and SBL-producing strains was used for susceptibility testing of the triple combination using the agar dilution method. The frequency of resistance (FoR) to MEM combined with InC58 was investigated. Mutants were sequenced and tested for cross resistance, fitness, and the stability of the resistance phenotype. Compared with the double combinations of MEM plus an SBL or MBL inhibitor, the triple combination extended the spectrum of activity to most of the isolates bearing SBLs (oxacillinase-48 (OXA-48) and Klebsiella pneumoniae carbapenemase-2 (KPC-2)) and MBLs (New Delhi metallo-β-lactamases (NDMs)), although it was not effective against Verona integron-encoded metallo-β-lactamase (VIM)-carrying Pseudomonas aeruginosa (P. aeruginosa) and OXA-23-carrying Acinetobacter baumannii (A. baumannii). The FoR to MEM plus InC58 ranged from 2.22 × 10−7 to 1.13 × 10−6. The resistance correlated with mutations to ompC and comR, affecting porin C and copper permeability, respectively. The mutants manifested a fitness cost, a decreased level of resistance during passage without antibiotic pressure, and cross resistance to another carbapenem (imipenem) and a β-lactamase inhibitor (taniborbactam). In conclusion, compared with the dual combinations, the triple combination of MEM with InC58 and AVI showed a much wider spectrum of activity against different carbapenemase-producing bacteria, revealing a new strategy to combat β-lactamase-mediated antimicrobial resistance.

Abstract Background The two major causes of cancer-related deaths among women in Ghana are breast cancer (BC) and cervical cancer (CC). These types of cancers typically do not show any symptoms until they have progressed. Therefore, it is important to screen for early detection. This research aimed to investigate the rate of breast cancer and cervical cancer screening, as well as the factors associated with it, among women of reproductive age in Ghana. Methods This study analysed data from the 2022 Ghana Demographic and Health Survey. A total of 15,014 women aged 15 to 49 years were included in the analysis. Descriptive statistics and binary logistic regression were employed to analyse the data with the aid of STATA/SE, version 17. Results It was found that 18.4% and 5.0% of the women had screened for BC and CC, respectively. Women aged 45–49 years were about three times more likely (aOR = 2.83, 95% CI: 1.88–4.24) to screen for BC compared to those aged 15–19 years. Women who had tested for HIV had increased odds (aOR = 1.88, 95% CI: 1.56–2.25) of screening for BC compared to their counterparts. Women within the richest wealth index (aOR = 1.95, 95% CI: 1.40–2.72) had increased odds of screening for BC compared to those in the poorest wealth index. Regarding CC screening, women with higher education (aOR = 2.56, 95% CI: 1.53–4.29) were two times more likely to screen for CC compared to those with no formal education. Women who did not use tobacco (aOR = 0.45, 95% CI: 0.21–0.96) had decreased odds of CC screening compared to their counterparts. Conclusions This study showed that the uptake of BC and CC screening services among women in Ghana was very low. The drivers of BC and CC screening included enabling, predisposing, and need factors. Stakeholders can leverage the mass media to raise awareness and educate women in reproductive age about the importance of BC and CC screening. This study provides relevant information that can inform BC and CC policies and programmes in Ghana.

Abstract The Maintenance of Lipid Asymmetry (Mla) pathway is a multicomponent system found in all gram-negative bacteria that contributes to virulence, vesicle blebbing and preservation of the outer membrane barrier function. It acts by removing ectopic lipids from the outer leaflet of the outer membrane and returning them to the inner membrane through three proteinaceous assemblies: the MlaA-OmpC complex, situated within the outer membrane; the periplasmic phospholipid shuttle protein, MlaC; and the inner membrane ABC transporter complex, MlaFEDB, proposed to be the founding member of a structurally distinct ABC superfamily. While the function of each component is well established, how phospholipids are exchanged between components remains unknown. This stands as a major roadblock in our understanding of the function of the pathway, and in particular, the role of ATPase activity of MlaFEDB is not clear. Here, we report the structure of E. coli MlaC in complex with the MlaD hexamer in two distinct stoichiometries. Utilising in vivo complementation assays, an in vitro fluorescence-based transport assay, and molecular dynamics simulations, we confirm key residues, identifying the MlaD β6-β7 loop as essential for MlaCD function. We also provide evidence that phospholipids pass between the C-terminal helices of the MlaD hexamer to reach the central pore, providing insight into the trajectory of GPL transfer between MlaC and MlaD.

Abstract Alcohol consumption in Tanzania exceeds the global average. While sociodemographic difference in alcohol consumption in Tanzania have been studied, the relationship between psycho-cognitive phenomena and alcohol consumption has garnered little attention. Our study examines how depressive symptoms and cognitive performance affect alcohol consumption, considering sociodemographic variations. We interviewed 2299 Tanzanian adults, with an average age of 53 years, to assess their alcohol consumption, depressive symptoms, cognitive performance, and sociodemographic characteristics using a zero-inflated negative binomial regression model. The logistic portion of our model revealed that the likelihood alcohol consumption increased by 8.4% (95% confidence interval [CI] 3.6%, 13.1%, p

Abstract National Swedish data shows substantial variation in the use of oxytocin for augmentation of spontaneous labour between obstetric units. This study aimed to investigate if variations in the use of oxytocin augmentation are associated with maternal and infant characteristics or clinical factors. We used a cohort design including women allocated to Robson group 1 (nulliparous women, gestational week ≥ 37 + 0, with singleton births in cephalic presentation and spontaneous onset of labour) and 3 (parous women, gestational week ≥ 37 + 0, with singleton births in cephalic presentation, spontaneous onset of labour, and no previous caesarean birth). Crude and adjusted logistic regression models with marginal standardisation were used to estimate risk ratios (RR) and risk differences (RD) with 95% confidence intervals (CI) for oxytocin use by obstetric unit. An interaction analysis was performed to investigate the potential modifying effect of epidural. The use of oxytocin varied between 47 and 73% in Robson group 1, and 10% and 33% in Robson group 3. Compared to the remainder of Sweden, the risk of oxytocin augmentation ranged from 13% lower (RD − 13.0, 95% CI − 15.5 to − 10.6) to 14% higher (RD 14.0, 95% CI 12.3–15.8) in Robson group 1, and from 6% lower (RD − 5.6, 95% CI − 6.8 to − 4.5) to 18% higher (RD 17.9, 95% CI 16.5–19.4) in Robson group 3. The most notable differences in risk estimates were observed among women in Robson group 3 with epidural. In conclusion, variations in oxytocin use remained despite adjusting for risk factors. This indicates unjustified differences in use of oxytocin in clinical practice.

Abstract Hydrogen sulfide (H2S) in environments with temperatures below 100 °C is generally assumed to be of microbial origin, while abiotic H2S production is typically restricted to higher temperatures (T). In this study, we report an abiotic process for sulfidogenesis through the reduction of elemental sulfur (S0) by hydrogen (H2), mediated by pyrite (FeS2). The process was investigated in detail at pH 4 and 80 °C, but experimental conditions ranged between 40 and 80 °C and pH 4–6. The experiments were conducted with H2 as reducing molecule, and µm-sized spherical (but not framboidal) pyrite particles that formed in situ from the H2S, S0 and Fe2+ present in the experiments. Fe monosulfides, likely mackinawite, were identified as potential pyrite precursors. The absence of H2 production in controls, combined with geochemical modelling, suggests that pyrite formation occurred through the polysulfide pathway, which is unexpected under acidic conditions. Most spherical aggregates of authigenic pyrite were composed of nanometric, acicular crystals oriented in diverse directions, displaying varying degrees of organization. Although it was initially hypothesized that the catalytic properties were related to the surface structure, commercially sourced, milled pyrite particles (

Abstract Williams syndrome (WS) is associated with atypical social communication and cognition reminiscent of the behaviours observed in autism. Nonetheless, WS also differs significantly from autism, such as regarding social motivation, which is typically enhanced in WS and reduced in autism. This study sought to examine the conditions’ transdiagnostic similarities and differences for autistic symptoms and social functioning, and their developmental trajectories, by comparing individuals with WS (n = 24) and those diagnosed with idiopathic autism (n = 24) and attention deficit hyperactivity disorder (ADHD; n = 24), aged 9 to 53 years, on measures of autism, social functioning, IQ and cooccurring psychiatric conditions. Although only 12.5% in the WS group met the criteria for an autism diagnosis, a majority exhibited distinct difficulties within social communication, social cognition, repetitive behaviours, and atypical sensory reactivity resembling autism. Conversely, elevated social motivation and a high number of social initiatives accompany these characteristics. No group differences in the developmental trajectories of autism symptoms were found. Our results demonstrate that autistic behaviours are more frequent in individuals with WS, than in individuals with idiopathic ADHD, and emphasize the need for clinical management of these behaviours.

Abstract Light-driven rotary molecular motors are among the most promising classes of responsive molecular machines and take advantage of their intrinsic chirality which governs unidirectional rotation. As a consequence of their dynamic function, they receive considerable interest in the areas of supramolecular chemistry, asymmetric catalysis and responsive materials. Among the emerging classes of responsive photochromic molecules, multistate first-generation molecular motors driven by benign visible light remain unexplored, which limits the exploitation of the full potential of these mechanical light-powered systems. Herein, we describe a series of all-visible-light-driven first-generation molecular motors based on the salicylidene Schiff base functionality. Remarkable redshifts up to 100 nm in absorption are achieved compared to conventional first-generation motor structures. Taking advantage of all-visible-light-driven multistate motor scaffolds, adaptive behaviour is found as well, and potential application in multistate photoluminescence is demonstrated. These functional visible-light-responsive motors will likely stimulate the design and synthesis of more sophisticated nanomachinery with a myriad of future applications in powering dynamic systems.

Abstract Background Haemophilia A (HA; Factor VIII deficiency) is a congenital X-linked bleeding disorder characterized by trauma-related or spontaneous bleeding events, most notably arising within the intraarticular space and resulting in chronic inflammation and degeneration of affected joints. Endogenous clotting factor activity relative to normal levels determines the severity of HA symptoms, as mild (> 5–40%), moderate (1–5%), or severe (

Abstract Background Families and carers are pivotal in supporting loved ones experiencing eating disorders. This role can bring immense distress and burden, yet the experience of caring for someone with an enduring eating disorder has had minimal research focus. Thus, the purpose of this study is to give voice to carers empowering their stories to increase awareness and understanding, which could inform support to carers and consequently people with a lived and/or living experience of eating disorders. Methods Semi-structured interviews were conducted with 9 carers supporting individuals who had been experiencing an eating disorder for 7 or more years. Data were collected and analysed using narrative inquiry approach. Results Carers’ narratives revealed feelings of guilt and personal failure; a profound sense of disillusion with current treatment approaches; and immense grief and anguish. As they negotiated a tenuous relationship with hope and the uncertainty of their loved one’s future, carers spoke to a complex myriad of feelings of acceptance, letting go, and forging on. Conclusion Carers deserve to have their voices heard where they are too often silenced. Their narratives provide an urgent call for transformation in our treatments for eating disorders and further involvement of carers within the treatment journey, and their lived experience perspectives have great potential to guide this endeavour. Level of Evidence Level V, qualitative interviews.

Abstract PRMT5 is a widely expressed arginine methyltransferase that regulates processes involved in tumor cell proliferation and survival. In the study described here, we investigated whether PRMT5 provides a target for tumor radiosensitization. Knockdown of PRMT5 using siRNA enhanced the radiosensitivity of a panel of cell lines corresponding to tumor types typically treated with radiotherapy. To extend these studies to an experimental therapeutic setting, the PRMT5 inhibitor LLY-283 was used. Exposure of the tumor cell lines to LLY-283 decreased PRMT5 activity and enhanced their radiosensitivity. This increase in radiosensitivity was accompanied by an inhibition of DNA double-strand break repair as determined by γH2AX foci and neutral comet analyses. For a normal fibroblast cell line, although LLY-283 reduced PRMT5 activity, it had no effect on their radiosensitivity. Transcriptome analysis of U251 cells showed that LLY-283 treatment reduced the expression of genes and altered the mRNA splicing pattern of genes involved in the DNA damage response. Subcutaneous xenografts were then used to evaluate the in vivo response to LLY-283 and radiation. Treatment of mice with LLY-283 decreased tumor PRMT5 activity and significantly enhanced the radiation-induced growth delay. These results suggest that PRMT5 is a tumor selective target for radiosensitization.

Abstract No reviews so far have been conducted to define the constructs of patient-experienced quality in healthcare transitions or to identify existing generic measures of patients’ experience of the quality within healthcare transitions. Our aim was to identify domains relevant for people experiencing healthcare transitions when evaluating the quality of care they have received, map the comprehensiveness of existing patient-reported experience measures (PREM), and evaluate the PREMs’ content validity. The method was guided by the Joanna Briggs Institutes’ guidance for scoping reviews. The search was performed on 07 December 2021 and updated 27 May 2024, in the electronic databases Medline (Ovid), Embase (Ovid), and Cinahl (EBSCO). The search identified 20,422 publications, and 190 studies were included for review. We identified 30 PREMs assessing at least one aspect of adults’ experience of transitions in healthcare. Summarising the content, we consider a model with two domains, organisational and human-relational, likely to be adequate. However, a more comprehensive analysis and adequate definition of the construct is needed. None of the PREMs were considered content valid.

Abstract Antarctic krill (Euphausia superba, hereafter krill) is a pelagic living crustacean and a key species in the Southern Ocean ecosystem. Krill builds up a huge biomass and its synchronized behavioral patterns, such as diel vertical migration (DVM), substantially impact ecosystem structure and carbon sequestration. However, the mechanistic basis of krill DVM is unknown and previous studies of krill behavior in the laboratory were challenged by complex behavior and large variability. Using a new experimental set-up, we recorded the swimming activity of individual wild-caught krill under light–dark cycles. Krill individuals exhibited differential phototactic responses to the light regime provided. However, using a new activity metric, we showed for the first time a consistent nocturnal increase in krill swimming activity in a controlled environment. Krill swimming activity in the new set-up was strongly synchronized with the light–dark cycle, similar to the diel vertical migration pattern of krill in the field when the krill were sampled for the experiment, demonstrated by hydroacoustic recordings. The new set-up presents a promising tool for investigating the mechanisms underlying krill behavioral patterns, which will increase our understanding of ecological interactions, the spatial distribution of populations, and their effects on biogeochemical cycles in the future.