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Background Although global mortality rates in children under 5 years have decreased substantially in the last 30 years, there remain around 2.6 million stillbirths and 2.9 million neonatal deaths each year. The majority of these deaths occur in Africa and South Asia. To reduce perinatal deaths in East Africa, knowledge of the burden, but also the risk factors and causes of perinatal deaths are crucial. To the best of our knowledge, reviews have previously focused on the burden of perinatal deaths; here we aim to synthesize evidence on the burden, causes, and risk factors for perinatal mortality in East Africa. Methods We will conduct a systematic literature search in Medline, Web of Science, EMBASE, Global Health, SCOPUS, Cochrane Library, CINAHL, HINARI, African Index Medicus, African Journals Online (AJOL), and WHO African Regional Office (AFRO) Library. The study population includes all fetuses and newborns from ≥22 weeks of gestation (birth weight ≥500gm) to 7 days after birth, with reported causes or/and determinants as exposure, and perinatal mortality (stillbirths and/or early neonatal deaths) as an outcome. We will include studies from 2010 to 2022, and to facilitate the inclusion of up-to-date data, we will request recent data from ongoing surveillance in the region. To assess the quality of included studies, we will use the Joanna Briggs Institute quality assessment tool for observational and trial studies. We will analyze the data using STATA version 17 statistical software and assess heterogeneity and publication bias by Higgins’ I2 and funnel plot, respectively. Conclusions This systematic review will search for published studies, and seek unpublished data, on the burden, causes, and risk factors of perinatal mortality in East Africa. Findings will be reported, and gaps in the evidence base identified, with recommendations, with the ultimate aim of reducing perinatal deaths. Protocol registration PROSPERO-CRD42021291719.

Three-dimensional (3D) anatomical extraction techniques could help the forensic anthropologist in a precise and inclusive assessment of biological phenotypes for the development of facial reconstruction methods. In this research, the nose morphology and the underlying hard tissue of two South African populations were studied. To this end, a 3D computer-assisted approach based on an automated landmarking workflow was used to generate relevant 3D anatomical components, and shape discrepancies were investigated using a data set of 200 cone-beam computer tomography (CBCT) scans. The anatomical landmarks were placed on the external nose and the mid-facial skeleton (the nasal bones, the anterior nasal aperture, the zygoma, and the maxilla). Shape differences related to population affinity, sex, age, and size were statistically evaluated and visualised using geometric morphometric methods. Population affinity, sexual dimorphism, age, and size affect the nasal complex morphology. Shape variation in the mid-facial region was significantly influenced by population affinity, emphasising that shape variability was specific to the two population groups, along with the expression of sexual dimorphism and the effect of ageing. In addition, nasal complex shape and correlations vary greatly between white and black South Africans, highlighting a need for reliable population-specific 3D statistical nose prediction algorithms. Significance: • 3D anatomical structures were acquired and extracted from 200 CBCT scans of modern South Africans. • Geometric morphometric methods were applied. • Soft- and hard-tissue nasal complex morphology vary across South African groups.

ABSTRACTToday, more than 90% of people with cystic fibrosis (pwCF) are eligible for the highly effective cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy called elexacaftor/tezacaftor/ivacaftor (ETI) and its use is widespread. Given the drastic respiratory symptom improvement experienced by many post-ETI, clinical studies are already underway to reduce the number of respiratory therapies, including antibiotic regimens, that pwCF historically relied on to combat lung disease progression. Early studies suggest that bacterial burden in the lungs is reduced post-ETI, yet it is unknown how chronic Pseudomonas aeruginosa populations are impacted by ETI. We found that pwCF remain infected throughout their upper and lower respiratory tract with their same strain of P. aeruginosa post-ETI, and these strains continue to evolve in response to the newly CFTR-corrected airway. Our work underscores the continued importance of CF airway microbiology in the new era of highly effective CFTR modulator therapy.IMPORTANCEThe highly effective cystic fibrosis transmembrane conductance regulator modulator therapy Elexakaftor/Tezacaftor/Ivacaftor (ETI) has changed cystic fibrosis (CF) disease for many people with cystic fibrosis. While respiratory symptoms are improved by ETI, we found that people with CF remain infected with Pseudomonas aeruginosa. How these persistent and evolving bacterial populations will impact the clinical manifestations of CF in the coming years remains to be seen, but the role and potentially changing face of infection in CF should not be discounted in the era of highly effective modulator therapy.

Purpose: To evaluate rural community-based eye care models from the perspective of community ophthalmology experts and suggest sustainable technological solutions for enhancing rural eye care delivery. Methods: A semi-structured descriptive survey, using close-ended and open-ended questions, was administered to the experts in community ophthalmology sourced through purposive sampling. The survey was self-administered and was facilitated through online platforms or in-person meetings. Uniform questions were presented to all participants, irrespective of their roles. Results: Surveyed participants (n = 22 with 15 from India and 7 from Nepal) in high-volume tertiary eye hospitals faced challenges with resources and rural outreach. Participants had mixed satisfaction with pre-operative screening and theatre resources. Delayed presentations and inexperienced surgeons contributed to the surgery complications. Barriers to rural eye care included resource scarcity, funding disparities, and limited infrastructure. In rural/peri-urban areas 87% of participants agreed with providing primary eye care services, with more than 60% of the experts not in agreement with the makeshift center model of eye care delivery. Key components for an effective eye care model are sustainability, accessibility, affordability, and quality. These can be bolstered through a healthcare management platform and a human-chain supply distribution system. Conclusion: Tailored interventions are crucial for rural eye care, emphasizing the need for stronger human resources, optimized funding, and community awareness. Addressing challenges pertinent to delayed presentation and surgical training is vital to minimizing complications, especially with advanced cataracts. Enhancements in rural eye care demand a comprehensive approach prioritizing accessibility, affordability, and consistent quality.

Objectives: Primary healthcare providers have an important role in helping people manage their reproductive health and fertility by assessing pregnancy intentions to inform the provision of contraception and/or preconception care. This study explores how women navigating fertility decisions perceived and experienced interactions with their healthcare providers around their fertility. Methods: We conducted in-depth interviews (N = 17) and focus groups (N = 17 groups) with 65 women aged 18 to 35 years about fertility, infertility, and reproductive planning. Two researchers coded 2 transcripts using thematic and inductive methods and met to develop a structured codebook. We then applied the codebook to the remaining transcripts. Results: In all interviews and focus groups, participants discussed their interactions with healthcare providers around fertility. Three central themes emerged in the data, including a desire for more information from healthcare providers about fertility; experiences of having fertility concerns dismissed by healthcare providers (eg, ability to become pregnant when desired); and, feelings that healthcare providers lacked sensitivity in discussing fertility related issues. Notably, these themes were present, even among participants who were not trying to become pregnant or who did not wish to become pregnant. Conclusion: Participants wanted information about fertility from their primary healthcare providers that they felt was lacking. Moreover, participants wanted their healthcare providers to engage with them as multifaceted individuals with current needs as well as future plans regarding fertility. While healthcare providers regularly assess pregnancy intentions, they may need to make a concerted effort to address fertility concerns among both those who want to pursue pregnancy and those who do not wish to become pregnant immediately.

Recovery from respiratory pneumococcal infections generates lung-localized protection against heterotypic bacteria, mediated by resident memory lymphocytes. Optimal protection in mice requires re-exposure to pneumococcus within days of initial infection. Serial surface marker phenotyping of B cell populations in a model of pneumococcal heterotypic immunity revealed that bacterial re-exposure stimulates the immediate accumulation of dynamic and heterogeneous populations of B cells in the lung, and is essential for the establishment of lung resident memory B (BRM) cells. The B cells in the early wave were activated, proliferating locally, and associated with both CD4+ T cells and CXCL13. Antagonist- and antibody-mediated interventions were implemented during this early timeframe to demonstrate that lymphocyte recirculation, CD4+ cells, and CD40 ligand (CD40L) signaling were all needed for lung BRM cell establishment, whereas CXCL13 signaling was not. While most prominent as aggregates in the loose connective tissue of bronchovascular bundles, morphometry and live lung imaging analyses showed that lung BRM cells were equally numerous as single cells dispersed throughout the alveolar septae. We propose that CD40L signaling from antigen-stimulated CD4+ T cells in the infected lung is critical to establishment of local BRM cells, which subsequently protect the airways and parenchyma against future potential infections.

ABSTRACTA comprehensive microbial surveillance was conducted at NASA’s Mars 2020 spacecraft assembly facility (SAF), where whole-genome sequencing (WGS) of 110 bacterial strains was performed. One isolate, designated 179-BFC-A-HST, exhibited less than 80% average nucleotide identity (ANI) to known species, suggesting a novel organism. This strain demonstrated high-level resistance [minimum inhibitory concentration (MIC) >256 mg/L] to third-generation cephalosporins, including ceftazidime, cefpodoxime, combination ceftazidime/avibactam, and the fourth-generation cephalosporin cefepime. The results of a comparative genomic analysis revealed that 179-BFC-A-HST is most closely related to Virgibacillus halophilus 5B73CT, sharing an ANI of 78.7% and a digital DNA-DNA hybridization (dDDH) value of 23.5%, while their 16S rRNA gene sequences shared 97.7% nucleotide identity. Based on these results and the recent recognition that the genus Virgibacillus is polyphyletic, strain 179-BFC-A-HST is proposed as a novel species of a novel genus, Tigheibacillus jepli gen. nov., sp. nov (type strain 179-BFC-A-HST = DSM 115946T = NRRL B-65666T), and its closest neighbor, V. halophilus, is proposed to be reassigned to this genus as Tigheibacillus halophilus comb. nov. (type strain 5B73CT = DSM 21623T = JCM 21758T = KCTC 13935T). It was also necessary to reclassify its second closest neighbor Virgibacillus soli, as a member of a novel genus Paracerasibacillus, reflecting its phylogenetic position relative to the genus Cerasibacillus, for which we propose Paracerasibacillus soli comb. nov. (type strain CC-YMP-6T = DSM 22952T = CCM 7714T). Within Amphibacillaceae (n = 64), P. soli exhibited 11 antibiotic resistance genes (ARG), while T. jepli encoded for 3, lacking any known β-lactamases, suggesting resistance from variant penicillin-binding proteins, disrupting cephalosporin efficacy. P. soli was highly resistant to azithromycin (MIC >64 mg/L) yet susceptible to cephalosporins and penicillins.IMPORTANCEThe significance of this research extends to understanding microbial survival and adaptation in oligotrophic environments, such as those found in SAF. Whole-genome sequencing of several strains isolated from Mars 2020 mission assembly cleanroom facilities, including the discovery of the novel species Tigheibacillus jepli, highlights the resilience and antimicrobial resistance (AMR) in clinically relevant antibiotic classes of microbes in nutrient-scarce settings. The study also redefines the taxonomic classifications within the Amphibacillaceae family, aligning genetic identities with phylogenetic data. Investigating ARG and virulence factors (VF) across these strains illuminates the microbial capability for resistance under resource-limited conditions while emphasizing the role of human-associated VF in microbial survival, informing sterilization practices and microbial management in similar oligotrophic settings beyond spacecraft assembly cleanrooms such as pharmaceutical and medical industry cleanrooms.

Background To study whether the use of TNF (tumor necrosis factor) inhibitors (TNFi) by pregnant women with rheumatoid arthritis affects sFlt‐1 (soluble Fms‐like tyrosine kinase‐1), PlGF (placental growth factor), or their impact on birthweight. Methods and Results sFlt‐1 and PlGF were measured in all trimesters of pregnancy in the Preconception Counseling in Active Rheumatoid Arthritis study and were compared according to the use of TNFi. The association of sFlt‐1 and PlGF with birthweight in relation to TNFi was determined. The study included 158 women, of whom 52.5% used TNFi during pregnancy. Both sFlt‐1 and PlGF increased during pregnancy, whereas their ratio declined. Taking into consideration the trimester‐related variation in levels of sFlt‐1 and PlGF, after correction for relevant confounders, the sFlt‐1/PlGF ratio was not significantly different between patients who did or did not use TNFi (sFlt‐1/PlGF ratio in the second trimester compared with the first trimester: estimated change 8.17 [95% CI, 2.54–26.29], P=0.79; sFlt‐1/PlGF ratio in the third trimester compared with the first trimester: estimated change 6.25 [95% CI, 1.73–22.50], P=0.25). In women who did not use TNFi, birthweight was significantly lower (3180 versus 3302 g; P=0.03), and sFlt‐1 displayed a negative correlation with birthweight (r=−0.462, P

Stable flies, Stomoxys calcitrans (L.), are important biting pests of dairy cattle and other livestock. These flies develop in decaying organic matter, such as soiled animal bedding. As part of a larger study of management options in organic dairy production, leftover debris from two winter housing systems, outdoor straw packs and indoor sawdust compost barns, were analyzed for the numbers and size of stable flies produced the following summer. The study was conducted at the University of Minnesota’s West Central Research and Outreach Center in Morris. During winter, independently managed groups of 20 cows were housed from November to May in replicate housing systems. After the cows were moved to summer pasture, fly traps were assembled in the leftover piles (n = 4): emergence traps to quantify stable fly emergence and Olson traps to study ambient adults. The size of the emerged flies and 30 ambient adult females were measured. The sampled females were also dissected to determine the gonotrophic age. During peak emergence in both years, straw piles produced significantly more stable flies than compost bedding, but the adults were equal in size. The Olson traps showed adults were equally abundant at both sources. Over 60% of the females dissected were previtellogenic, indicating local emergence. Compost bedding is useful in managing stable fly numbers, while straw presents a serious stable fly production liability if not disposed of properly.

Abstract Metabolic acidosis unfavourably influences the nutritional status of patients with non‐dialysis dependent chronic kidney disease (CKD) including the loss of muscle mass and functionality, but the benefits of correction are uncertain. We investigated the effects of correcting metabolic acidosis on nutritional status in patients with CKD in a systematic review and meta‐analysis. A search was conducted in MEDLINE and the Cochrane Library from inception to June 2023. Study selection, bias assessment, and data extraction were independently performed by two reviewers. The Cochrane risk of bias tool was used to assess the quality of individual studies. We applied random effects meta‐analysis to obtain pooled standardized mean difference (SMD) and 95% confidence intervals (CIs). We retrieved data from 12 intervention studies including 1995 patients, with a mean age of 63.7 ± 11.7 years, a mean estimated glomerular filtration rate of 29.8 ± 8.8 mL/min per 1.73 m2, and 58% were male. Eleven studies performed an intervention with oral sodium bicarbonate compared with either placebo or with standard care and one study compared veverimer, an oral HCl‐binding polymer, with placebo. The mean change in serum bicarbonate was +3.6 mEq/L in the intervention group and +0.4 mEq/L in the control group. Correcting metabolic acidosis significantly improved muscle mass assessed by mid‐arm muscle circumference (SMD 0.35 [95% CI 0.16 to 0.54], P

Abstract Nonreciprocity is a highly desirable feature in photonic media since it allows for control over the traveling electromagnetic waves, in a way that goes far beyond ordinary filtering. One of the most conventional ways to achieve nonreciprocity is via employing gyrotropic materials; however, their time-reversal-symmetry-breaking effects are very weak and, hence, large, bulky setups combined with very strong magnetic biases are required for technologically useful devices. In this work, artificial heterostructures are introduced to enhance the effective nonreciprocal behavior by reducing the contribution of the diagonal susceptibilities in the collective response; in this way, the off-diagonal ones, that are responsible for nonreciprocity, seem bigger. In particular, alternating gyrotropic and metallic or plasmonic films make an epsilon-near-zero (ENZ) effective-medium by averaging the diagonal permittivities of opposite sign, representing the consecutive layers. The homogenization process leaves unaltered the nonzero off-diagonal permittivities of the original gyrotropic substance, which become dominant and ignite strong nonreciprocal response. Realistic material examples that could be implemented experimentally in the mid-infrared spectrum are provided while the robustness of the enhanced nonreciprocity in the presence of actual media losses is discussed and bandwidth limitations due to the unavoidable frequency dispersion are elaborated. The proposed concept can be extensively utilized in designing optical devices that serve a wide range of applications from signal isolation and wave circulation to unidirectional propagation and asymmetric power amplification.

Abstract Background Globally, detections of carbapenemase-producing Enterobacterales (CPE) colonisations and infections are increasing. The spread of these highly resistant bacteria poses a serious threat to public health. However, understanding of CPE transmission and evidence on effectiveness of control measures is severely lacking. This paper provides evidence to inform effective admission screening protocols, which could be important in controlling nosocomial CPE transmission. Methods CPE transmission within an English hospital setting was simulated with a data-driven individual-based mathematical model. This model was used to evaluate the ability of the 2016 England CPE screening recommendations, and of potential alternative protocols, to identify patients with CPE-colonisation on admission (including those colonised during previous stays or from elsewhere). The model included nosocomial transmission from colonised and infected patients, as well as environmental contamination. Model parameters were estimated using primary data where possible, including estimation of transmission using detailed epidemiological data within a Bayesian framework. Separate models were parameterised to represent hospitals in English areas with low and high CPE risk (based on prevalence). Results The proportion of truly colonised admissions which met the 2016 screening criteria was 43% in low-prevalence and 54% in high-prevalence areas respectively. Selection of CPE carriers for screening was improved in low-prevalence areas by adding readmission as a screening criterion, which doubled how many colonised admissions were selected. A minority of CPE carriers were confirmed as CPE positive during their hospital stay (10 and 14% in low- and high-prevalence areas); switching to a faster screening test pathway with a single-swab test (rather than three swab regimen) increased the overall positive predictive value with negligible reduction in negative predictive value. Conclusions Using a novel within-hospital CPE transmission model, this study assesses CPE admission screening protocols, across the range of CPE prevalence observed in England. It identifies protocol changes—adding readmissions to screening criteria and a single-swab test pathway—which could detect similar numbers of CPE carriers (or twice as many in low CPE prevalence areas), but faster, and hence with lower demand on pre-emptive infection-control resources. Study findings can inform interventions to control this emerging threat, although further work is required to understand within-hospital transmission sources.

Abstract Background Sexual health care, including assessment and patient teaching, is part of comprehensive patient care. Health professional (medical and nursing) students’ education in sexual health lacks uniformity in content and assessment skills. Objectives The current systematic review aimed to assess sexual health educational curriculum for health professional students regarding the educational content, duration, and evaluation of these educational interventions. Methods This systematic review followed the preferred reporting guidelines for systematic reviews. A comprehensive search was conducted between May–August, 2023 across four databases (PubMed, Scopus, CINAHL, EMBASE), outlining 614 sources. Following the screening process, 36 educational intervention studies were deemed eligible for inclusion. The quality assessment of these studies was conducted using The Effective Public Health Project tool, which was found appropriate for evaluating this type of research. Results The studies had a global representation, with most studies conducted in the US. Limited nursing educational interventions were found. Three main categories emerged from the analysis of the educational interventions: one-time interventions, workshops, and semester courses. These categories differed in terms of their duration. Upon evaluating the educational intervention programs, it was found that the majority relied on participant self-reporting, while only a few included objective evaluations. Conclusions This review revealed inconsistencies in educational content for healthcare professional students and may impact their clinical skills, particularly in sexual health. The variation in content, duration, and evaluation methods created challenges in assessing the interventions. The lack of standardized sexual health education highlighted a significant gap, raising concerns about students’ ultimate proficiency in this area. Bridging this divide is essential by integrating comprehensive sexual health content and assessment skills into the health professional curriculum.

Abstract Background Lifelong strength is fundamental to physical function, health, and quality of life. Reliable appropriate strength assessment measures for older adults play an important role in effective evaluation of baseline ability and exercise prescription to counter disease and disuse. This study aimed to investigate the within-session reliability of maximal isometric knee extension and flexion, hip abduction and adduction, and handgrip strength measures in frail and pre-frail older adults. Method The study was conducted at a residential care home in Birmingham, UK. All care home residents aged ≥ 65 years; pre-frail or frail according to the Fried Frailty phenotype criteria; able to speak and read English; not currently involved in any other clinical trial; without severe sensory impairments; and with a predicted life expectancy greater than the trial length were eligible. Maximal isometric lower limb testing was performed using specialised resistance training equipment and a portable measurement device, and grip strength was assessed using a portable dynamometer. All eligible participants attended a single testing session and performed three trials per measure. Peak force measures were obtained for analysis. Within-session reliability for each measure was calculated from repeated-measures analysis of variance, intraclass correlation coefficients (ICC), and coefficients of variation (CV) with 95% confidence intervals. Results Eleven frail and eleven pre-frail older adults participated in the study. Within-session absolute and relative measures were found to be reliable with the highest overall repeatability indicated between trial 2 and trial 3 for knee extension, hip abduction, and handgrip (CV ≤ 4.65%, ICC ≥ 0.96) with variation evident across all measures, except knee extension, from trial 1 to 2. Conclusions Overall, maximal isometric strength in frail and pre-frail older adults with no previous testing experience can be measured with good to high reliability within their first testing session. An initial two familiarisation trials followed by two measurement trials is recommended to achieve the highest level of overall repeatability. Trial registration The trial was registered with ClinicalTrials.gov: NCT03141879 on 05/05/2017.

Abstract With the advent of long-term human habitation in space and on the moon, understanding how the built environment microbiome of space habitats differs from Earth habitats, and how microbes survive, proliferate and spread in space conditions, is becoming more important. The microbial tracking mission series has been monitoring the microbiome of the International Space Station (ISS) for almost a decade. During this mission series, six unique strains of Gram-stain-positive bacteria, including two spore-forming and three non-spore-forming species, were isolated from the environmental surfaces of the ISS. The analysis of their 16S rRNA gene sequences revealed > 99% similarities with previously described bacterial species. To further explore their phylogenetic affiliation, whole genome sequencing was undertaken. For all strains, the gyrB gene exhibited

Abstract Previous studies on self-rated health and mortality have usually not differentiated between physical and mental health, respectively have not considered physical diseases. This study aims to determine self-rated physical and mental health from middle to old age, examine associations with mortality adjusted for objective risk factors and assess effect modification by gender. In a large population-based sample (N = 14,993 at baseline), self-rated physical and mental health were rated separately by a single-item. Associations to mortality were modelled by Cox regressions, adjusting for potential confounding variables. Most participants rated their physical (79.4%), resp. mental health (82.3%) as good. Poor self-rated physical health was lowest in the youngest group (19.6%, age 35–44), and highest in midlife (29.1%, age 55–64). Poor self-rated mental health was lowest among the oldest (18.5%), and highest from 45 to 54 years (29.3%). Poor self-rated physical, but not mental health was predictive of mortality when adjusting for objective risk factors. Male gender and poor self-rated physical health interacted (RERI 0.43 95%-CI 0.02–0.85). Self-rated physical health was best in the youngest and worst in the midlife group, this pattern was reversed regarding self-rated mental health. Poor self-rated physical, but not mental health was predictive of mortality, adjusting for objective risk factors. It was more strongly predictive of mortality in men than in women. Poor subjective physical health ratings, should be taken seriously as an unfavorable prognostic sign, particularly in men.

Abstract Fertiliser and pesticide application can cause extensive environmental damage. We use the water quality footprint to express nitrogen, phosphorus and glyphosate emissions from agriculture in volumes of water needed to virtually dilute pollution and apply the approach to agricultural imports for the German bioeconomy in 1995 and 2020. In total, the virtual German water quality footprint corresponds to 90 times the volume of Lake Constance. If water pollution had to be eliminated by dilution in export countries supplying Germany, volumes would be by a median of 300 times higher than the associated irrigation volumes there and could exceed natural water availability. Important and growing hotspots of clean water scarcity are China, Spain and India. The impact of German agricultural supply chains needs to be monitored with regard to the sustainability of national consumption and to the effectiveness of increasing fertiliser and pesticide use, especially in African, Asian and Pacific countries.

Abstract The atmosphere can transport large quantities of microplastics and disperse them throughout the globe to locations inaccessible by many other transport mechanisms. Meteorological events have been proven to pick up and transport particulate matter, however, how they influence the transport and deposition of atmospheric microplastics is still poorly understood. Here we present samples of atmospheric fallout collected during Hurricane Larry as it passed over Newfoundland, Canada in September 2021. During the storm peak, 1.13 × 105 particles m−2 day−1 were deposited, with a decline in deposition after the storm passed. Back-trajectory modelling and polymer type analysis indicate that those microplastics may have been ocean-sourced as the hurricane traversed the garbage patch of the North Atlantic Gyre. This study identifies the influence of North Atlantic hurricanes on the atmospheric transport and deposition of ocean-sourced microplastics and the possible consequences of increased exposure to microplastics in remote areas.

Abstract We present a comprehensive multi-omic analysis of the EPISTOP prospective clinical trial of early intervention with vigabatrin for pre-symptomatic epilepsy treatment in Tuberous Sclerosis Complex (TSC), in which 93 infants with TSC were followed from birth to age 2 years, seeking biomarkers of epilepsy development. Vigabatrin had profound effects on many metabolites, increasing serum deoxycytidine monophosphate (dCMP) levels 52-fold. Most serum proteins and metabolites, and blood RNA species showed significant change with age. Thirty-nine proteins, metabolites, and genes showed significant differences between age-matched control and TSC infants. Six also showed a progressive difference in expression between control, TSC without epilepsy, and TSC with epilepsy groups. A multivariate approach using enrollment samples identified multiple 3-variable predictors of epilepsy, with the best having a positive predictive value of 0.987. This rich dataset will enable further discovery and analysis of developmental effects, and associations with seizure development in TSC.

Abstract Background Hospital length of stay (LoS) after a hip fracture likely mirrors health status; however, a too short hospitalization might increase the risk of readmission. In this national register-based study, we investigated the association between LoS after a hip fracture and the risk of readmissions. Methods 73,551 patients with a first hip fracture between 2012 and 2019 were followed for 4 months after discharge. LoS was categorized by cubic splines and the association with readmissions was analyzed with Cox regression models. Results The mean LoS was 11 ± 6 days and 25% of the study population had at least one readmission. Compared to the mean LoS of 9–12 days, there was a 18% decreased risk of readmission for LoS of 2–4 days (HR 0.82 [95% CI 0.77–0.87]) and 13% decrease for 5–8 days (HR 0.87 [95% CI 0.83–0.91]), when adjusting for sex, age, walking ability, ASA score, CCI, complications during hospitalization and living arrangements. For longer LoS, risk of readmission increased (13–23 days: HR 1.09 [95% CI 1.05–1.13] and 24 + days: HR 1.19 [95% CI 1.11–1.28]). The results were robust across sex, age, and living arrangements. The most common specific reasons for readmission were trauma/injury, cardiovascular and complications, and the proportions did not differ considerably between short and long LoS-categories. Conclusions While a long LoS can be explained by the care need of the patient, a short LoS - compared to the average stay - does not increase the risk of readmission regardless of health status and hospital complications in a Swedish setting.

Abstract Biomolecular polyelectrolyte complexes can be formed between oppositely charged intrinsically disordered regions (IDRs) of proteins or between IDRs and nucleic acids. Highly charged IDRs are abundant in the nucleus, yet few have been functionally characterized. Here, we show that a positively charged IDR within the human ATP-dependent DNA helicase Q4 (RECQ4) forms coacervates with G-quadruplexes (G4s). We describe a three-step model of charge-driven coacervation by integrating equilibrium and kinetic binding data in a global numerical model. The oppositely charged IDR and G4 molecules form a complex in the solution that follows a rapid nucleation-growth mechanism leading to a dynamic equilibrium between dilute and condensed phases. We also discover a physical interaction with Replication Protein A (RPA) and demonstrate that the IDR can switch between the two extremes of the structural continuum of complexes. The structural, kinetic, and thermodynamic profile of its interactions revealed a dynamic disordered complex with nucleic acids and a static ordered complex with RPA protein. The two mutually exclusive binding modes suggest a regulatory role for the IDR in RECQ4 function by enabling molecular handoffs. Our study extends the functional repertoire of IDRs and demonstrates a role of polyelectrolyte complexes involved in G4 binding.

Abstract Despite a link between adverse childhood experiences (ACEs) and anxiety, the role of anxiety in the pathway to chronic pain is unclear. Potentially, inflammatory biomarkers such as C-reactive protein (CRP) are involved. Objectives were to (1) examine relationships between reported ACEs, anxiety, and chronic pain, and (2) assess associations between ACEs, anxiety, and CRP levels and between CRP and chronic pain. Data from 24,172 adults who participated in the UK Biobank were used to conduct Poisson regressions to assess relationships between ACEs, anxiety, and chronic pain. For participants with CRP data who met the inclusion criteria (n = 2007), similar models were run between ACEs, anxiety, and CRP, and CRP and chronic pain. For objective 1, three statistically significant interactions were found to predict pain: frequency of physical abuse x reported muscular symptoms during anxiety (p = 0.01); frequency in which they felt hated x having discussed anxiety with a professional (p = 0.03), and reported frequency of sexual abuse x difficulties relaxing during anxiety attacks (p = 0.03). For objective 2, frequency of sexual abuse and informing a professional about anxiety significantly interacted to predict elevated CRP. For correlations, the largest was between CRP and the number of times pain was reported over the years (p = 0.01). Finally, ACEs (physical abuse, sexual abuse, and whether taken to a doctor) significantly interacted with CRP to predict pain. This study suggests mechanisms of the impact of ACEs on chronic pain may include inflammation and anxiety, which warrants further study.

Abstract Background The gut microbiota is modulated by a combination of diet, host genetics, and sex effects. The magnitude of these effects and interactions among them is important to understanding inter-individual variability in gut microbiota. In a previous study, mouse strain-specific responses to American and ketogenic diets were observed along with several QTLs for metabolic traits. In the current study, we searched for genetic variants underlying differences in the gut microbiota in response to American and ketogenic diets, which are high in fat and vary in carbohydrate composition, between C57BL/6 J (B6) and FVB/NJ (FVB) mouse strains. Results Genetic mapping of microbial features revealed 18 loci under the QTL model (i.e., marginal effects that are not specific to diet or sex), 12 loci under the QTL by diet model, and 1 locus under the QTL by sex model. Multiple metabolic and microbial features map to the distal part of Chr 1 and Chr 16 along with eigenvectors extracted from principal coordinate analysis of measures of β-diversity. Bilophila, Ruminiclostridium 9, and Rikenella (Chr 1) were identified as sex- and diet-independent QTL candidate keystone organisms, and Parabacteroides (Chr 16) was identified as a diet-specific, candidate keystone organism in confirmatory factor analyses of traits mapping to these regions. For many microbial features, irrespective of which QTL model was used, diet or the interaction between diet and a genotype were the strongest predictors of the abundance of each microbial trait. Sex, while important to the analyses, was not as strong of a predictor for microbial abundances. Conclusions These results demonstrate that sex, diet, and genetic background have different magnitudes of effects on inter-individual differences in gut microbiota. Therefore, Precision Nutrition through the integration of genetic variation, microbiota, and sex affecting microbiota variation will be important to predict response to diets varying in carbohydrate composition. Video Abstract

Early detection of increased infections or new variants of SARS-CoV-2 is critical for public health response. To determine whether cycle threshold (Ct) data from PCR tests for SARS-CoV-2 could serve as an early indicator of epidemic growth, we analyzed daily mean Ct values in England, UK, by gene target and used iterative sequential regression to detect break points in mean Ct values (and positive test counts). To monitor the epidemic in England, we continued those analyses in real time. During September 2020–January 2022, a total of 7,611,153 positive SARS-CoV-2 PCR test results with Ct data were reported. Spike (S) gene target (S+/S−)–specific mean Ct values decreased 6–29 days before positive test counts increased, and S-gene Ct values provided early indication of increasing new variants (Delta and Omicron). Our approach was beneficial in the context of the first waves of the COVID-19 pandemic and can be used to support future infectious disease monitoring.

Mpox, also known as Monkeypox, is an infectious disease known to spread via direct contact and fomites, which poses a significant contagion risk in surgical settings and may increase the challenges already posed by COVID-19. Within the three years following the outbreak of Mpox, we conducted a review of the impact of Mpox on surgical practice. We searched Pubmed/Medline and Scopus, focusing on original studies and case reports in English or German. Our search terms included “Mpox”, “Monkeypox”, and “Surgery”. Out of 60 clinical or epidemiological studies, as well as expert opinions, brief reports, and pertinent literature reviews, eight were included after full-text assessment. We also incorporated two pertinent literature reviews, including a total of 10 papers, in this analysis. The main topics addressed by the literature are 1. manifestations of Mpox for surgical consideration or urgent management, for which it is important to consider whether a surgical approach is needed to address long-term Mpox-related lesions and 2. infection control in surgical settings, especially considering its impact on elective surgery and the well-being of healthcare workers. Mpox could affect surgical services and access to operating theaters. Unlike COVID-19, Mpox, compared to initial concerns, has not substantially compromised surgical delivery. However, limited reports exist on the surgical impact of Mpox. It is crucial to involve surgeons in Mpox diagnosis, educate surgical practitioners on its mimicry of common surgical conditions, enhance infection control during surgery, and ensure access to corrective surgery as a means of tackling the stigmatization associated with Mpox and sexually transmitted diseases in general.

Boreal and Arctic regions have warmed up to four times quicker than the rest of the planet since the 1970s. As a result, boreal and tundra ecosystems are experiencing more frequent and higher intensity extreme weather events and disturbances, such as wildfires. Yet limitations in ground and satellite data across the Arctic and boreal regions have challenged efforts to track these disturbances at regional scales. In order to effectively monitor the progression and extent of wildfires in the Arctic-boreal zone, it is essential to determine whether burned area (BA) products are accurate representations of BA. Here, we use 12 different datasets together with MODIS active fire data to determine the total yearly BA and seasonal patterns of fires in Arctic-boreal North America and Russia for the years 2001–2020. We found relatively little variability between the datasets in North America, both in terms of total BA and seasonality, with an average BA of 2.55 ± 1.24 (standard deviation) Mha/year for our analysis period, the majority (ca. 41%) of which occurs in July. In contrast, in Russia, there are large disparities between the products—GFED5 produces over four times more BA than GFED4s in southern Siberia. These disparities occur due to the different methodologies used; dNBR (differenced Normalized Burn Ratio) of short-term composites from Landsat images used alongside hotspot data was the most consistently successful in representing BA. We stress caution using GABAM in these regions, especially for the years 2001–2013, as Landsat-7 ETM+ scan lines are mistaken as burnt patches, increasing errors of commission. On the other hand, we highlight using regional products where possible, such as ABoVE-FED or ABBA in North America, and the Talucci et al. fire perimeter product in Russia, due to their detection of smaller fires which are often missed by global products.

Abstract Genetic variants in chromatin regulators are frequently found in neurodevelopmental disorders, but their effect in disease etiology is rarely determined. Here, we uncover and functionally define pathogenic variants in the chromatin modifier EZH1 as the cause of dominant and recessive neurodevelopmental disorders in 19 individuals. EZH1 encodes one of the two alternative histone H3 lysine 27 methyltransferases of the PRC2 complex. Unlike the other PRC2 subunits, which are involved in cancers and developmental syndromes, the implication of EZH1 in human development and disease is largely unknown. Using cellular and biochemical studies, we demonstrate that recessive variants impair EZH1 expression causing loss of function effects, while dominant variants are missense mutations that affect evolutionarily conserved aminoacids, likely impacting EZH1 structure or function. Accordingly, we found increased methyltransferase activity leading to gain of function of two EZH1 missense variants. Furthermore, we show that EZH1 is necessary and sufficient for differentiation of neural progenitor cells in the developing chick embryo neural tube. Finally, using human pluripotent stem cell-derived neural cultures and forebrain organoids, we demonstrate that EZH1 variants perturb cortical neuron differentiation. Overall, our work reveals a critical role of EZH1 in neurogenesis regulation and provides molecular diagnosis for previously undefined neurodevelopmental disorders.

The use of mathematical models to make predictions about tumor growth and response to treatment has become increasingly prevalent in the clinical setting. The level of complexity within these models ranges broadly, and the calibration of more complex models requires detailed clinical data. This raises questions about the type and quantity of data that should be collected and when, in order to maximize the information gain about the model behavior while still minimizing the total amount of data used and the time until a model can be calibrated accurately. To address these questions, we propose a Bayesian information-theoretic procedure, using an adaptive score function to determine the optimal data collection times and measurement types. The novel score function introduced in this work eliminates the need for a penalization parameter used in a previous study, while yielding model predictions that are superior to those obtained using two potential pre-determined data collection protocols for two different prostate cancer model scenarios: one in which we fit a simple ODE system to synthetic data generated from a cellular automaton model using radiotherapy as the imposed treatment, and a second scenario in which a more complex ODE system is fit to clinical patient data for patients undergoing intermittent androgen suppression therapy. We also conduct a robust analysis of the calibration results, using both error and uncertainty metrics in combination to determine when additional data acquisition may be terminated.

Abstract Background Tuberous sclerosis complex (TSC) is associated with a wide range of physical manifestations for which international clinical recommendations for diagnosis and management have been established. TSC is, however, also associated with a wide range of TSC-Associated Neuropsychiatric Disorders (TAND) that are typically under-identified and under-treated yet associated with a profound burden of disease. The contemporary evidence base for the identification and treatment of TAND is much more limited and, to date, consensus recommendations for the diagnosis and management of TAND have also been limited and non-specific. Methods The TANDem project was launched with an international, interdisciplinary, and participatory consortium of 24 individuals, including TSC family representatives, from all World Health Organization (WHO) regions but one. One of the aims of the TANDem project was to generate consensus recommendations for the identification and treatment of TAND. At the time of this project, no internationally adopted standard methodology and methodological checklists existed for the generation of clinical practice recommendations. We therefore developed our own systematic procedure for evidence review and consensus-building to generate evidence-informed consensus recommendations of relevance to the global TSC community. Results At the heart of the consensus recommendations are ten core principles surrounded by cluster-specific recommendations for each of the seven natural TAND clusters identified in the literature (autism-like, dysregulated behavior, eat/sleep, mood/anxiety, neuropsychological, overactive/impulsive, and scholastic) and a set of wraparound psychosocial cluster recommendations. The overarching recommendation is to “screen” for TAND at least annually, to “act” using appropriate next steps for evaluation and treatment, and to “repeat” the process to ensure early identification and early intervention with the most appropriate biological, psychological, and social evidence-informed approaches to support individuals with TSC and their families. Conclusions The consensus recommendations should provide a systematic framework to approach the identification and treatment of TAND for health, educational, social care teams and families who live with TSC. To ensure global dissemination and implementation of these recommendations, partnerships with the international TSC community will be important. One of these steps will include the generation of a “TAND toolkit” of “what to seek” and “what to do” when difficulties are identified in TAND clusters.

Abstract Raman scattering provides a convenient mechanism to generate or amplify light at wavelengths where gain is not otherwise available. When combined with recent advancements in high-power fiber lasers that operate at wavelengths ~2 μm, great opportunities exist for Raman systems that extend operation further into the mid-infrared regime for applications such as gas sensing, spectroscopy, and biomedical analyses. Here, a thulium-doped fiber laser is used to demonstrate Raman emission and amplification from a highly nonlinear silicon core fiber (SCF) platform at wavelengths beyond 2 μm. The SCF has been tapered to obtain a micrometer-sized core diameter (~1.6 μm) over a length of 6 cm, with losses as low as 0.2 dB cm−1. A maximum on-off peak gain of 30.4 dB was obtained using 10 W of peak pump power at 1.99 μm, with simulations indicating that the gain could be increased to up to ~50 dB by extending the SCF length. Simulations also show that by exploiting the large Raman gain and extended mid-infrared transparency of the SCF, cascaded Raman processes could yield tunable systems with practical output powers across the 2–5 μm range.

Abstract A perimetastatic capsule is a strong positive prognostic factor in liver metastases, but its origin remains unclear. Here, we systematically quantify the capsule’s extent and cellular composition in 263 patients with colorectal cancer liver metastases to investigate its clinical significance and origin. We show that survival improves proportionally with increasing encapsulation and decreasing tumor-hepatocyte contact. Immunostaining reveals the gradual zonation of the capsule, transitioning from benign-like NGFRhigh stroma at the liver edge to FAPhigh stroma towards the tumor. Encapsulation correlates with decreased tumor viability and preoperative chemotherapy. In mice, chemotherapy and tumor cell ablation induce capsule formation. Our results suggest that encapsulation develops where tumor invasion into the liver plates stalls, representing a reparative process rather than tumor-induced desmoplasia. We propose a model of metastases growth, where the efficient tumor colonization of the liver parenchyma and a reparative liver injury reaction are opposing determinants of metastasis aggressiveness.

Abstract Background Tuberous sclerosis complex (TSC) is a rare and complex genetic disorder, associated with tumor growth in various organ systems, epilepsy, and a range of neuropsychiatric manifestations including intellectual disability. With improving patient-centered care and targeted therapies, patient-reported outcome measures (PROMs) are needed to measure the impact of TSC manifestations on daily functioning. The aim of this study was to develop a TSC-specific PROM for adults that captures the impact of TSC on physical functions, mental functions, activity and participation, and the social support individuals with TSC receive, called the TSC-PROM. Methods COSMIN methodology was used to develop a self-reported and proxy-reported version. Development and validation consisted of the following studies: PROM development, content validity, structural validity, internal consistency, and construct validity. The International Classification of Functioning and Disability was used as a framework. Content validity was examined by a multidisciplinary expert group and cognitive interview study. Structural and construct validity, and internal consistency were examined in a large cohort, using confirmatory factor analysis, hypotheses testing, and Cronbach’s alpha. Results The study resulted in an 82-item self version and 75-item proxy version of the TSC-PROM with four subscales (physical functions 18 and 19 items, mental functions 37 and 28 items, activities and participation 13 and 14 items, social support 13 items, for self version and proxy version respectively). Sufficient results were found for structural validity with sufficient unidimensionality for each subscale. With regard to construct validity, 82% of the hypotheses were met for the self version and 59% for the proxy version. The PROM showed good internal consistency (Cronbach’s alpha 0.78–0.97). Conclusions We developed a PROM for adults with TSC, named TSC-PROM, showing sufficient evidence for reliability and validity that can be used in clinical and research settings to systematically gain insight into their experiences. It is the first PROM in TSC that addresses the impact of specific TSC manifestations on functioning, providing a valuable, patient-centered addition to the current clinical outcomes.

Abstract During the construction and assembly of the Mars 2020 mission components at two different NASA cleanrooms, several fungal strains were isolated. Based on their colony morphology, two strains that showed yeast-like appearance were further characterized for their phylogenetic position. The species-level classification of these two novel strains, using traditional colony and cell morphology methods combined with the phylogenetic reconstructions using multi-locus sequence analysis (MLSA) based on several gene loci (ITS, LSU, SSU, RPB1, RPB2, CYTB and TEF1), and whole genome sequencing (WGS) was carried out. This polyphasic taxonomic approach supported the conclusion that the two basidiomycetous yeasts belong to hitherto undescribed species. The strain FJI-L2-BK-P3T, isolated from the Jet Propulsion Laboratory Spacecraft Assembly Facility, was placed in the Naganishia albida clade (Filobasidiales, Tremellomycetes), but is genetically and physiologically different from other members of the clade. Another yeast strain FKI-L6-BK-PAB1T, isolated from the Kennedy Space Center Payload Hazardous and Servicing Facility, was placed in the genus Cystobasidium (Cystobasidiales, Cystobasidiomycetes) and is distantly related to C. benthicum. Here we propose two novel species with the type strains, Naganishia kalamii sp. nov. (FJI-L2-BK-P3T = NRRL 64466 = DSM 115730) and Cystobasidium onofrii sp. nov. (FKI-L6-BK-PAB1T = NRRL 64426 = DSM 114625). The phylogenetic analyses revealed that single gene phylogenies (ITS or LSU) were not conclusive, and MLSA and WGS-based phylogenies were more advantageous for species discrimination in the two genera. The genomic analysis predicted proteins associated with dehydration and desiccation stress-response and the presence of genes that are directly related to osmotolerance and psychrotolerance in both novel yeasts described. Cells of these two newly-described yeasts were exposed to UV-C radiation and compared with N. onofrii, an extremophilic UV-C resistant cold-adapted Alpine yeast. Both novel species were UV resistant, emphasizing the need for collecting and characterizing extremotolerant microbes, including yeasts, to improve microbial reduction techniques used in NASA planetary protection programs.

Abstract Background Coronavirus disease 2019 (COVID-19) patients can develop pulmonary fibrosis (PF), which is associated with impaired outcome. We assessed specific leukocytic transcriptome profiles associated with PF and the influence of early dexamethasone (DEXA) treatment on the clinical course of PF in critically ill COVID-19 patients. Methods We performed a pre-post design study in 191 COVID-19 patients admitted to the Intensive Care Unit (ICU) spanning two treatment cohorts: the pre-DEXA- (n = 67) and the DEXA-cohort (n = 124). PF was identified based on radiological findings, worsening of ventilatory parameters and elevated circulating PIIINP levels. Longitudinal transcriptome profiles of 52 pre-DEXA patients were determined using RNA sequencing. Effects of prednisone treatment on clinical fibrosis parameters and outcomes were analyzed between PF- and no-PF-patients within both cohorts. Results Transcriptome analyses revealed upregulation of inflammatory, coagulation and neutrophil extracellular trap-related pathways in PF-patients compared to no-PF patients. Key genes involved included PADI4, PDE4D, MMP8, CRISP3, and BCL2L15. Enrichment of several identified pathways was associated with impaired survival in a external cohort of patients with idiopathic pulmonary fibrosis. Following prednisone treatment, PF-related profiles reverted towards those observed in the no-PF-group. Likewise, PIIINP levels decreased significantly following prednisone treatment. PF incidence was 28% and 25% in the pre-DEXA- and DEXA-cohort, respectively (p = 0.61). ICU length-of-stay (pre-DEXA: 42 [29–49] vs. 18 [13–27] days, p

Abstract Molecular biology aims to understand cellular responses and regulatory dynamics in complex biological systems. However, these studies remain challenging in non-model species due to poor functional annotation of regulatory proteins. To overcome this limitation, we develop a multi-layer neural network that determines protein functionality directly from the protein sequence. We annotate kinases and phosphatases in Glycine max. We use the functional annotations from our neural network, Bayesian inference principles, and high resolution phosphoproteomics to infer phosphorylation signaling cascades in soybean exposed to cold, and identify Glyma.10G173000 (TOI5) and Glyma.19G007300 (TOT3) as key temperature regulators. Importantly, the signaling cascade inference does not rely upon known kinase motifs or interaction data, enabling de novo identification of kinase-substrate interactions. Conclusively, our neural network shows generalization and scalability, as such we extend our predictions to Oryza sativa, Zea mays, Sorghum bicolor, and Triticum aestivum. Taken together, we develop a signaling inference approach for non-model species leveraging our predicted kinases and phosphatases.

Abstract Stage‐based demographic methods, such as matrix population models (MPMs), are powerful tools used to address a broad range of fundamental questions in ecology, evolutionary biology and conservation science. Accordingly, MPMs now exist for over 3000 species worldwide. These data are being digitised as an ongoing process and periodically released into two large open‐access online repositories: the COMPADRE Plant Matrix Database and the COMADRE Animal Matrix Database. During the last decade, data archiving and curation of COMPADRE and COMADRE, and subsequent comparative research, have revealed pronounced variation in how MPMs are parameterized and reported. Here, we summarise current issues related to the parameterisation and reporting of MPMs that arise most frequently and outline how they affect MPM construction, analysis, and interpretation. To quantify variation in how MPMs are reported, we present results from a survey identifying key aspects of MPMs that are frequently unreported in manuscripts. We then screen COMPADRE and COMADRE to quantify how often key pieces of information are omitted from manuscripts using MPMs. Over 80% of surveyed researchers (n = 60) state a clear benefit to adopting more standardised methodologies for reporting MPMs. Furthermore, over 85% of the 300 MPMs assessed from COMPADRE and COMADRE omitted one or more elements that are key to their accurate interpretation. Based on these insights, we identify fundamental issues that can arise from MPM construction and communication and provide suggestions to improve clarity, reproducibility and future research utilising MPMs and their required metadata. To fortify reproducibility and empower researchers to take full advantage of their demographic data, we introduce a standardised protocol to present MPMs in publications. This standard is linked to www.compadre‐db.org, so that authors wishing to archive their MPMs can do so prior to submission of publications, following examples from other open‐access repositories such as DRYAD, Figshare and Zenodo. Combining and standardising MPMs parameterized from populations around the globe and across the tree of life opens up powerful research opportunities in evolutionary biology, ecology and conservation research. However, this potential can only be fully realised by adopting standardised methods to ensure reproducibility.

Abstract Background The extent to which the recent global COVID-19 Pandemic has impacted young people with restrictive eating disorders [i.e., anorexia nervosa (AN) and atypical anorexia nervosa (AAN)] is unclear. We conducted a scoping review of the literature to identify how the pandemic has impacted this population and to identify gaps in the current literature to inform future research efforts. Main body We searched PubMed, EMBASE, the Web of Science, The Cochrane Library, PsycInfo, ProQuest Dissertations and Theses Global, LitCovid, Google Scholar, and relevant agency websites from 2019 to 2022. We included studies that focused on young people with AN/AAN globally. Of the 916 unduplicated articles screened, 17 articles met the inclusion criteria, reporting on 17 unique studies including 4,379 individuals. Three key findings were identified. First, an increase in hospitalizations related to eating disorders was found during COVID-19 among young people with AN and AAN. Multiple studies cited increased medical instability, even though the overall duration of disease was shorter compared to pre-pandemic levels. Second, changes in eating disorder-related symptomology during the pandemic were reported in this population, as well as poorer overall behavioral and mental health. Suggested reasons behind changes included boredom or minimal distraction from pathological thoughts, increased social isolation, increased social media and online use (e.g., reading blogs or watching YouTube), gym and school closures, changes in routines due to lockdowns and quarantines, and worries over gaining the “Quarantine 15”. Third, there was an increase in the use of telemedicine as a treatment modality for the treatment of AN. Challenges were reported by both clinicians and patients regardless of past experience using telemedicine. When compared to no treatment, telemedicine was recognized as the best option during COVID-19 lockdowns; however some individuals expressed the preference for in-person treatment and planned to return to it once it became available. Conclusion The pandemic significantly impacted young people with restrictive eating disorders as seen by increased hospitalizations and requests for outpatient care. A primary driver of the changes in eating disorder symptomatology may be lockdowns and quarantines. Further research investigating how the series of lockdowns and re-openings impacted individuals with AN/AAN is warranted.

BackgroundThe COVID-19 pandemic had serious impact on the well-being of health care workers and highlighted the need for resources to help hospital staff to cope with psychologically negative consequences. The purpose of this study was to investigate the potentially protective effect of spirituality, as measured by the construct of transpersonal trust, against anxiety in physicians and in hospital pastoral care workers. In addition, transpersonal trust was compared to the effects of other potential resources, namely sense of coherence, optimism, and resilience. We also explored the relationship between transpersonal trust and anxiety and how it was moderated by sense of coherence and expected a significant effect.MethodThe sample included N = 405 participants (n = 151 pastoral care workers and n = 254 physicians) who completed an online survey during the first wave of the COVID-19 pandemic between 20th April and 05th July, 2020, that comprised established questionnaires assessing anxiety, transpersonal trust, sense of coherence, and resilience.ResultsThere was no statistically significant negative relationship between transpersonal trust and anxiety in either profession or broken down by occupational group. Multiple regression analysis revealed that sense of coherence inversely predicted generalized anxiety, while transpersonal trust, resilience, and optimism did not. As hypothesized, the association between transpersonal trust and anxiety was moderated by sense of coherence. However, we could not confirm our hypothesis of a protective effect of transpersonal trust against anxiety.ConclusionOur results point to the significant role of sense of coherence as a protective factor against anxiety and highlight the complexity of the relationship among spirituality, transpersonal trust, and anxiety.

Parkinson's disease (PD) pathology is characterized by alpha-synuclein (α-syn) aggregates, degeneration of dopamine neurons in the substantia nigra pars compacta (SNpc), and neuroinflammation. The presence of reactive glia correlates with deposition of pathological α-syn in early-stage PD. Thus, understanding the neuroinflammatory response of microglia and astrocytes to synucleinopathy may identify therapeutic targets. Here we characterized the neuroinflammatory gene expression profile of reactive microglia and astrocytes in the SNpc during early synucleinopathy in the rat α-syn pre-formed fibril (PFF) model. Rats received intrastriatal injection of α-syn PFFs and expression of immune genes was quantified with droplet digital PCR (ddPCR), after which fluorescent in situ hybridization (FISH) was used to localize gene expression to microglia or astrocytes in the SNpc. Genes previously associated with reactive microglia (Cd74, C1qa, Stat1, Axl, Casp1, Il18, Lyz2) and reactive astrocytes (C3, Gbp2, Serping1) were significantly upregulated in the SN of PFF injected rats. Localization of gene expression to SNpc microglia near α-syn aggregates identified a unique α-syn aggregate microglial gene expression profile characterized by upregulation of Cd74, Cxcl10, Rt-1a2, Grn, Csf1r, Tyrobp, C3, C1qa, Serping1 and Fcer1g. Importantly, significant microglial upregulation of Cd74 and C3 were only observed following injection of α-syn PFFs, not α-syn monomer, confirming specificity to α-syn aggregation. Serping1 expression also localized to astrocytes in the SNpc. Interestingly, C3 expression in the SNpc localized to microglia at 2- and 4-months post-PFF, but to astrocytes at 6-months post-PFF. We also observed expression of Rt1-a2 and Cxcl10 in SNpc dopamine neurons. Cumulatively our results identify a dynamic, yet reproducible gene expression profile of reactive microglia and astrocytes associated with early synucleinopathy in the rat SNpc.

Background Inhibition of prostaglandin synthesis by nonsteroidal anti‐inflammatory drugs is associated with cardiovascular mortality and kidney disease. This study hypothesizes that urinary prostaglandin E2 (PGE2) and PGE2 metabolite (PGEM) excretions are markers of cardiovascular and kidney health, because they reflect both systemic and kidney‐derived PGE2 production. Methods and Results PGE2 and PGEM were measured in spot urine samples from 2291 participants (≥55 years old) of the population‐based Rotterdam Study. Urinary PGE2 and PGEM excretions were analyzed using linear regression analyses to identify cross‐sectional associations with cardiovascular risk factors and baseline estimated glomerular filtration rate (eGFR). Longitudinal associations with cardiovascular mortality and kidney outcomes (eGFR

BackgroundHepatitis C virus (HCV) infections are more prevalent in people who inject drugs (PWID) who often experience additional health risks. HCV induces inflammation and immune alterations that contribute to hepatic and non-hepatic morbidities. It remains unclear whether curative direct acting antiviral (DAA) therapy completely reverses immune alterations in PWID.MethodsPlasma biomarkers of immune activation associated with chronic disease risk were measured in HCV-seronegative (n=24) and HCV RNA+ (n=32) PWID at baseline and longitudinally after DAA therapy. Adjusted generalised estimating equations were used to assess longitudinal changes in biomarker levels. Comparisons between community controls (n=29) and HCV-seronegative PWID were made using adjusted multiple regression modelling.ResultsHCV-seronegative PWID exhibited significantly increased levels of inflammatory biomarkers including soluble (s) TNF-RII, IL-6, sCD14 and sCD163 and the diabetes index HbA1c as compared to community controls. CXCL10, sTNF-RII, vascular cell adhesion molecule-1 and lipopolysaccharide binding protein (LBP) were additionally elevated in PWID with viremic HCV infection as compared to HCV- PWID. Whilst curative DAA therapy reversed some biomarkers, others including LBP and sTNF-RII remained elevated 48 weeks after HCV cure.ConclusionElevated levels of inflammatory and chronic disease biomarkers in PWID suggest an increased risk of chronic morbidities such as diabetes and cardiovascular disease. HCV infection in PWID poses an additional disease burden, amplified by the incomplete reversal of immune dysfunction following DAA therapy. These findings highlight the need for heightened clinical surveillance of PWID for chronic inflammatory diseases, particularly those with a history of HCV infection.

BackgroundThe COVID-19 pandemic presents a significant challenge to professional responders in healthcare settings. This is reflected in the language used to describe the pandemic in the professional literature of the respective professions. The aim of this multidisciplinary study was to analyze the linguistic imagery in the relevant professional literature and to determine the identification of different professional groups with it and its emotional effects.MethodA list of 14 typical, widespread and differing imageries for COVID-19 in form of single sentences (e.g., “Until the pandemic is over, we can only run on sight.”) were presented to 1,795 healthcare professionals in an online survey. The imageries had been extracted from a qualitative search in more than 3,500 international professional journals in medicine, psychology and theology. Ratings of agreement with these imageries and feelings about them were subjected to factor analysis.ResultsBased on the list of imageries presented, it was possible to identify three factors for high/low agreement by experiences, and two factors for high/low induced feelings. Broad agreement emerged for imageries on “fight against the crisis” and “lessons learned from the crisis”, while imageries on “acceptance of uncontrollability” tended to be rejected. Imageries of “challenges” tended to lead to a sense of empowerment among subjects, while imageries of “humility” tended to lead to a sense of helplessness.ConclusionBased on the qualitative and subsequential quantitative analysis, several factors for imageries for the COVID-19 pandemic were identified that have been used in the literature. Agreement with imageries is mixed, as is the assessment of how helpful they are.

During visual search, we quickly learn to attend to an object's likely location. Research has shown that this process can be guided by learning target locations based on consistent spatial contextual associations or other statistical regularities. Here, we tested how different types of associations guide learning and the utilisation of established memories for different purposes. Participants learned contextual associations or rule-like statistical regularities that predicted target locations within different scenes. The consequences of this learning for subsequent performance were then evaluated on attention-orienting and memory-recall tasks. Participants demonstrated facilitated attention-orienting and recall performance based on both contextual associations and statistical regularities. Contextual associations facilitated attention orienting with a different time course compared to statistical regularities. Benefits to memory-recall performance depended on the alignment between the learned association or regularity and the recall demands. The distinct patterns of behavioural facilitation by contextual associations and statistical regularities show how different forms of long-term memory may influence neural information processing through different modulatory mechanisms.

Land management by seasonal migratory herding, traditionally implemented by pastoralists, has allowed semi-arid rangeland ecosystems to remain productive and resilient to highly erratic, seasonal rainfall patterns. Changing pastoralist practices and rainfall patterns due to climate change have the potential to negatively influence the resilience of rangelands. To test the impact of different communal rangeland practices and increasing frequency of disturbance on the rangelands' vegetation, we established a clipping experiment in three rangeland management types: rainy season rangeland, dry season rangeland and seasonal exclosures, in the Maasai Steppe, northern Tanzania. Across these rangeland management types, we tested two clipping frequencies monthly vs. once per growing period and either fenced or open to grazing (herbivory) over two consecutive growing periods. We found that rainy season rangeland exhibited lowest regrowth rates and highest proportion of bare ground across herbivory, clipping frequency and growing period. When rainfall was low, seasonal exclosures showed lowest proportion of bare ground across herbivory and clipping frequency and plots that were seasonally clipped and excluded herbivores generated significantly more grass biomass, higher grass regrowth rates and lowest proportion of bare ground compared to all other treatments. Excluding herbivores had little impact on the vegetation biomass and cover but had a positive impact on grass regrowth rates when rainfall was high. Seasonal clipping allowed for lower proportion of bare ground, and in most cases higher regrowth rates and higher biomass compared to monthly clipping. We conclude that traditional seasonal migratory herding is a relevant concept to sustain rangeland productivity and resilience under increasing intensity of disturbance if grazing pressure on rainy season rangelands is adapted to rainfall conditions and sufficient resting time after heavy defoliation is granted. Dry season grazing (including rainy season resting) proved to be the most sustainable concept to maintain regrowth and control erosion.

Abstract Non-technical summary Brazil – one of the world's largest biocultural diversities – faces high rates of habitat loss, social inequality, and land conflicts impacting indigenous and local peoples. To challenge that, Brazilian sustainability science and education needs to be strengthened. We searched for elements in ongoing bottom-up sustainability social movements that can help serve that purpose. We found values, contents, and attitudes that, if incorporated into Brazilian sustainability science and education, can assist its transformative potential by reflecting local voices and critically engaging with (often-hegemonic) northern concepts. Technical summary In Brazil, a strong sustainability science and education is required to confront ‘glocal’ issues such as zoonotic pandemics and climate change, which are worsened by rampant ecosystem loss and social vulnerability. However, a largely disciplinary university system has been slow to meet these urgent needs. To address if and how dialogical processes with non-academics can prompt integration between distinct types of knowledge, we analyze four bottom-up sustainability initiatives that promote dialogues between science, the arts, religion, youth, and indigenous and local knowledge, and reflect on lessons learnt with movement organizers, scientists, and educators – the authors of this paper. Although sustainability science produced in dialogue with other forms of knowledge is still emerging in Brazil, we find that bottom-up initiatives outside academia can inspire science and education to approach sustainability as wholeness – a state of balance to be fulfilled when reached individually, collectively, and cosmically. We discuss how to approach a transdisciplinary and reflexive attitude in Brazilian sustainability science and education, and highlight its unique contribution to frontier topics in global sustainability debates. Social media summary Social movements’ values, contents, and attitudes can inspire transformative Brazilian sustainability science and education.

The general public and scientific community alike are abuzz over the release of ChatGPT and GPT-4. Among many concerns being raised about the emergence and widespread use of tools based on large language models (LLMs) is the potential for them to propagate biases and inequities. We hope to open a conversation within the environmental data science community to encourage the circumspect and responsible use of LLMs. Here, we pose a series of questions aimed at fostering discussion and initiating a larger dialogue. To improve literacy on these tools, we provide background information on the LLMs that underpin tools like ChatGPT. We identify key areas in research and teaching in environmental data science where these tools may be applied, and discuss limitations to their use and points of concern. We also discuss ethical considerations surrounding the use of LLMs to ensure that as environmental data scientists, researchers, and instructors, we can make well-considered and informed choices about engagement with these tools. Our goal is to spark forward-looking discussion and research on how as a community we can responsibly integrate generative AI technologies into our work.

PurposeTo describe the early experiences of patients with neovascular age-related macular degeneration (nAMD) and polypoidal choroidal vasculopathy (PCV) whose treatment was switched to faricimab from other anti-vascular endothelial growth factor (VEGF) agents.MethodsThis is a prospective cohort of eyes with nAMD and PCV that were previously treated with anti-VEGF agents other than faricimab. We evaluated visual acuity (VA), central subfield thickness (CST), macular volume (MV), pigment epithelial detachment (PED) height, and choroidal thickness (CT) after one administration of faricimab. Where present, fluid was further evaluated according to intraretinal fluid (IRF), subretinal fluid (SRF), or within PED.ResultsSeventy-one eyes from 71 patients were included (45.07% PCV and 54.93% typical nAMD). The mean [standard deviation (± SD)] VA, CST, and MV improved from 0.50 logMAR (± 0.27 logMAR) to 0.46 logMAR (± 0.27 logMAR) (p = 0.20), 383.35 µm (± 111.24 µm) to 322.46 µm (± 103.89 µm (p < 0.01), and 9.40 mm3 (± 1.52 mm3) to 8.75 mm3 (± 1.17 mm3) (p < 0.01) from switch to post switch visit, respectively. The CT reduced from 167 µm (± 151 µm) to 149 µm (± 113 µm) (p < 0.01). There was also a significant reduction in the maximum PED height between visits [302.66 µm (± 217.97 µm)] and the post switch visit [236.66 µm (± 189.05 µm); p < 0.01]. This difference was greater in PEDs that were predominantly serous in nature. In the eyes with typical nAMD (n = 39), improvements were significant for CST, MV, CT, and PED. In the eyes with PCV (n = 32), only reductions in CT were statistically significant, while VA, CST, MV, and PED only showed numerically smaller improvements. One patient developed mild vitritis without vasculitis, which resolved with topical steroids with no sequelae.ConclusionsIn our case series of Asian nAMD patients, switching to faricimab was associated with a stable VA and meaningful anatomical improvements, particularly with typical nAMD subtypes.

Introduction: Technical advances and the increasing role of interdisciplinary decision-making may warrant formal definitions of expertise in surgical neuro-oncology. Research question: The EANS Neuro-oncology Section felt that a survey detailing the European neurosurgical perspective on the concept of expertise in surgical neuro-oncology might be helpful. Material and methods: The EANS Neuro-oncology Section panel developed an online survey asking questions regarding criteria for expertise in neuro-oncological surgery and sent it to all individual EANS members. Results: Our questionnaire was completed by 251 respondents (consultants: 80.1%) from 42 countries. 67.7% would accept a lifetime caseload of >200 cases and 86.7% an annual caseload of >50 as evidence of neuro-oncological surgical expertise. A majority felt that surgeons who do not treat children (56.2%), do not have experience with spinal fusion (78.1%) or peripheral nerve tumors (71.7%) may still be considered experts. Majorities believed that expertise requires the use of skull-base approaches (85.8%), intraoperative monitoring (83.4%), awake craniotomies (77.3%), and neuro-endoscopy (75.5%) as well as continuing education of at least 1/year (100.0%), a research background (80.0%) and teaching activities (78.7%), and formal interdisciplinary collaborations (e.g., tumor board: 93.0%). Academic vs. non-academic affiliation, career position, years of neurosurgical experience, country of practice, and primary clinical interest had a minor influence on the respondents’ opinions. Discussion and conclusion: Opinions among neurosurgeons regarding the characteristics and features of expertise in neuro-oncology vary surprisingly little. Large majorities favoring certain thresholds and qualitative criteria suggest a consensus definition might be possible.

Background The COVID-19 pandemic both relied and placed significant burdens on the experts involved from research and public health sectors. The sustained high pressure of a pandemic on responders, such as healthcare workers, can lead to lasting psychological impacts including acute stress disorder, post-traumatic stress disorder, burnout, and moral injury, which can impact individual wellbeing and productivity. Methods As members of the infectious disease modelling community, we convened a reflective workshop to understand the professional and personal impacts of response work on our community and to propose recommendations for future epidemic responses. The attendees represented a range of career stages, institutions, and disciplines. This piece was collectively produced by those present at the session based on our collective experiences. Results Key issues we identified at the workshop were lack of institutional support, insecure contracts, unequal credit and recognition, and mental health impacts. Our recommendations include rewarding impactful work, fostering academia-public health collaboration, decreasing dependence on key individuals by developing teams, increasing transparency in decision-making, and implementing sustainable work practices. Conclusions Despite limitations in representation, this workshop provided valuable insights into the UK COVID-19 modelling experience and guidance for future public health crises. Recognising and addressing the issues highlighted is crucial, in our view, for ensuring the effectiveness of epidemic response work in the future.