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PURPOSE: Clinically ascertained variants are under-utilized in neurodevelopmental disorder research. We established the Brain Gene Registry (BGR) to coregister clinically identified variants in putative brain genes with participant phenotypes. Here, we report 179 genetic variants in the first 179 BGR registrants and analyze the proportion that were novel to ClinVar at the time of entry and those that were absent in other disease databases. METHODS: From 10 academically affiliated institutions, 179 individuals with 179 variants were enrolled into the BGR. Variants were cross-referenced for previous presence in ClinVar and for presence in 6 other genetic databases. RESULTS: Of 179 variants in 76 genes, 76 (42.5%) were novel to ClinVar, and 62 (34.6%) were absent from all databases analyzed. Of the 103 variants present in ClinVar, 37 (35.9%) were uncertain (ClinVar aggregate classification of variant of uncertain significance or conflicting classifications). For 5 variants, the aggregate ClinVar classification was inconsistent with the interpretation from the BGR site-provided classification. CONCLUSION: A significant proportion of clinical variants that are novel or uncertain are not shared, limiting the evidence base for new gene-disease relationships. Registration of paired clinical genetic test results with phenotype has the potential to advance knowledge of the relationships between genes and neurodevelopmental disorders.

Spatially explicit prediction of soil organic carbon (SOC) serves as a crucial foundation for effective land management strategies aimed at mitigating soil degradation and assessing carbon sequestration potential. Here, using more than 1000 in situ observations, we trained two machine learning models (a random forest model and a k-means coupled with multiple linear regression model) and one process-based model (the vertically resolved MIcrobial-MIneral Carbon Stabilization, MIMICS, model) to predict the SOC stocks of the top 30 cm of soil in Australia. Parameters of MIMICS were optimised for different site groupings using two distinct approaches: plant functional types (MIMICS-PFT) and the most influential environmental factors (MIMICS-ENV). All models showed good performance with respect to SOC predictions, with an R2 value greater than 0.8 during out-of-sample validation, with random forest being the most accurate; moreover, it was found that SOC in forests is more predictable than that in non-forest soils excluding croplands. The performance of continental-scale SOC predictions by MIMICS-ENV is better than that by MIMICS-PFT especially in non-forest soils. Digital maps of terrestrial SOC stocks generated using all of the models showed a similar spatial distribution, with higher values in south-eastern and south-western Australia, but the magnitude of the estimated SOC stocks varied. The mean ensemble estimate of SOC stocks was 30.3 t ha−1, with k-means coupled with multiple linear regression generating the highest estimate (mean SOC stocks of 38.15 t ha−1) and MIMICS-PFT generating the lowest estimate (mean SOC stocks of 24.29 t ha−1). We suggest that enhancing process-based models to incorporate newly identified drivers that significantly influence SOC variation in different environments could be the key to reducing the discrepancies in these estimates. Our findings underscore the considerable uncertainty in SOC estimates derived from different modelling approaches and emphasise the importance of rigorous out-of-sample validation before applying any one approach in Australia.

Abstract The depths of the North Atlantic Ocean host a species-rich fauna providing heterogeneous habitats from thermal vent fields to cold-water coral reefs. With the increasing threat of destruction of deep-sea habitats due to human impacts, such as demersal fishing and the beginning of deep-sea mining, an analysis of the diversity and distribution of species is crucial for conservation efforts. Brittle stars occur in high biomasses, contributing to the biodiversity of the seafloor. Specimens were collected during several scientific expeditions to gain a more detailed insight into the brittle star diversity in the North Atlantic Ocean. An integrative approach to identify the species with DNA barcoding (mtCOI) in combination with morphological studies revealed 24 species. Most species have been previously identified in the North Atlantic, but sequences for 13 species are newly added to public repositories. Additionally, the MALDI-TOF-MS proteomic analysis was successfully applied for 197 specimens with known COI barcodes. Results are congruent with other molecular species delimitations demonstrating the functionality of proteomics for the identification of brittle stars. This dataset significantly expands our understanding of the taxonomic and genetic diversity of brittle stars and contributes to publicly available data. It emphasizes the importance of considering habitat heterogeneity for large scale patterns of biodiversity.

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 Background In the hospital environment, carbapenemase-producing Pseudomonas aeruginosa (CPPA) may lead to fatal patient infections. However, the transmission routes of CPPA often remain unknown. Therefore, this case study aimed to trace the origin of CPPA ST357, which caused a hospital-acquired pneumonia in a repatriated critically ill patient suffering from Guillain-Barré Syndrome in 2023. Methods Antimicrobial susceptibility of the CPPA isolate for 30 single and combination therapies was determined by disk-diffusion, Etest or broth microdilution. Whole-genome sequencing was performed for three case CPPA isolates (one patient and two sinks) and four distinct CPPA ST357 patient isolates received in the Dutch CPPA surveillance program. Furthermore, 193 international P. aeruginosa ST357 assemblies were collected via three genome repositories and analyzed using whole-genome multi-locus sequence typing in combination with antimicrobial resistance gene (ARG) characterization. Results A Dutch patient who carried NDM-1-producing CPPA was transferred from Kenya to the Netherlands, with subsequent dissemination of CPPA isolates to the local sinks within a month after admission. The CPPA case isolates presented an extensively drug-resistant phenotype, with susceptibility only for colistin and cefiderocol-fosfomycin. Phylogenetic analysis showed considerable variation in allelic distances (mean = 150, max = 527 alleles) among the ST357 isolates from Asia (n = 92), Europe (n = 58), Africa (n = 21), America (n = 16), Oceania (n = 2) and unregistered regions (n = 4). However, the case isolates (n = 3) and additional Dutch patient surveillance program isolates (n = 2) were located in a sub-clade of isolates from Kenya (n = 17; varying 15–49 alleles), the United States (n = 7; 21–115 alleles) and other countries (n = 6; 14–121 alleles). This was consistent with previous hospitalization in Kenya of 2/3 Dutch patients. Additionally, over half of the isolates (20/35) in this sub-clade presented an identical resistome with 9/17 Kenyan, 5/5 Dutch, 4/7 United States and 2/6 other countries, which were characterized by the bla NDM-1, aph(3’)-VI, ARR-3 and cmlA1 ARGs. Conclusion This study presents an extensively-drug resistant subclone of NDM-producing P. aeruginosa ST357 with a unique resistome which was introduced to the Netherlands via repatriation of critically ill patients from Kenya. Therefore, the monitoring of repatriated patients for CPPA in conjunction with vigilance for the risk of environmental contamination is advisable to detect and prevent further dissemination.

Introduction: The Swiss Eosinophilic Esophagitis Cohort Study (SEECS) is a national cohort that was established in 2015 with the aim of improving quality of care of affected adults with eosinophilic esophagitis (EoE). Between 2020 and 2022, paper questionnaires were gradually replaced by fully electronic data capture using Research Electronic Data Capture (REDCap®) software. We aim to provide an update of the SEECS 8 years after its launch. Methods: The SEECS prospectively includes adults (≥18 years of age) with EoE as well as patients with gastroesophageal reflux disease (GERD) and healthy control subjects (HC). Upon inclusion and follow-up (typically once every 12–18 months), patients and physicians complete REDCap® questionnaires, which are available in German, French, and English. Patient-reported outcomes (PROs) and biologic findings are assessed on the same day using validated instruments (EEsAI PRO for symptoms; EoE-QoL-A for QoL; EREFS for endoscopic activity; modified EoE-HSS for histologic activity). The SEECS biobank includes biosamples from patients with EoE, GERD, and HC. Results: As of July 2023, the SEECS included 778 patients (716 [92%] with EoE, 29 [3.8%] with GERD, and 33 [4.2%] HC; 559/778 [71.9%] were male). Mean age ± SD (years) at enrollment according to diagnosis was as follows: EoE 41.9 ± 12.9, GERD 53.6 ± 16.4, HC 51.7 ± 17.2. Concomitant GERD was found in 200 patients (27.9%) of the EoE cohort. Concomitant allergic disorders (asthma, rhinoconjunctivitis, eczema) were present in 500 EoE patients (74.4%). At inclusion, 686 (95.8%) of EoE patients were on ongoing treatment (orodispersible budesonide tablet [Jorveza®] in 281 patients [41%]; budesonide or fluticasone syrup or swallowed powder in 290 patients [42.3%]; proton-pump inhibitors in 162 patients [23.6%]; elimination diets in 103 patients [15%]; and esophageal dilation at last visit in 166 patients [24.2%]). A total of 8,698 biosamples were collected, of which 1,395 (16%) were used in the framework of translational research projects. Conclusion: SEECS continuously grows and is operational using fully electronic data capture. SEECS offers up-to-date epidemiologic and real-world clinical efficacy data on EoE and promotes clinical and translational research.

Objective To assess the effect of goal-directed mobilisation (GDM) on physical functioning in medical inpatients.Design Randomised, controlled, single-centre, parallel, superiority trial with a 3-month follow-up and blinded outcome assessment.Setting General internal medicine wards of a Swiss tertiary acute hospital, September 2021 to April 2023.Participants Adults with expected hospitalisation of ≥5 days, physiotherapy prescription and ability to follow study procedures.Intervention GDM during hospitalisation, which includes personal goal setting and a short session of patient education through a physiotherapist (experimental group), versus standard care (control group).Outcome measures The primary outcome was the change in physical activity between baseline and day 5 (De Morton Mobility Index (DEMMI)). Secondary outcomes included in-hospital accelerometer-measured mobilisation time; in-hospital falls; delirium; length of stay; change in independence in activities of daily living, concerns of falling and quality of life; falls, readmission and mortality within 3 months.Results The study was completed by 123 of 162 (76%) patients enrolled, with the primary outcome collected at day 5 in 126 (78%) participants. DEMMI Score improved by 8.2 (SD 15.1) points in the control group and 9.4 (SD 14.2) in the intervention group, with a mean difference of 0.3 (adjusted for the stratification factors age and initial DEMMI Score, 95% CI −4.1 to 4.8, p=0.88). We did not observe a statistically significant difference in effects of the interventions on any secondary outcome.Conclusions The patient’s physical functioning improved during hospitalisation, but the improvement was similar for GDM and standard of care. Improving physical activity during an acute medical hospitalisation remains challenging. Future interventions should target additional barriers that can be implemented without augmenting resources.Trial registration number NCT04760392.

BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is linked to high mortality, primarily through an intense inflammatory response. Diacerein has emerged as a potential therapy for COVID-19 due to its potential impact in decreasing the inflammasome activation and coronavirus replication. This study aims to explore diacerein’s influence in inhibiting both viral replication and the inflammatory response after SARS-CoV-2 infection.MethodsHuman peripheral blood mononuclear cells (PBMCs) were obtained from healthy volunteers and infected in vitro with SARS-CoV-2. Additionally, we carried out a pilot randomized, double-blind, placebo-controlled study with 14 participants allocated to diacerein (n = 7) or placebo (n = 7) therapies every 12 h for 10 days. The primary endpoint was change in plasma markers of inflammasome activation (NLRP3, caspase-1, and gasdermin-D).ResultsIn vitro protocols have shown that rhein, diacerein’s primary metabolite, decreased IL-1β secretion caused by SARS-CoV-2 infection in human PBMCs (p < 0.05), and suppressed viral replication when administered either before or after the virus incubation (p < 0.05). This later effect was, at least partially, attributed to its inhibitory effect on 3-chymotrypsin-like protease (SARS-CoV-2 3CLpro) and papain-like protease in the SARS-CoV-2 (SARS-CoV-2 PLpro) virus and in the phosphorylation of proteins related cytoskeleton network (p < 0.05). Diacerein-treated COVID-19 patients presented a smaller area under the curve for NLRP3, caspase-1 and GSDM-D measured on days 2, 5, and 10 after hospitalization compared to those receiving a placebo (p < 0.05).ConclusionThe indicated mechanisms of action of diacerein/rhein can reduce viral replication and mitigate the inflammatory response related to SARS-CoV-2. These findings are preliminary and require confirmation in clinical trials.

El complejo del Leopardus colocolo, según una reciente actualización taxonómica, ha sido dividido en cinco especies. Una de estas es el Leopardus braccatus conocida como gato del pantanal, distribuido en Bolivia, Brasil y Paraguay. A pesar de su distribución, esta es una especie poco estudiada. Presentamos aquí un nuevo registro de esta especie, siendo el primero en el bosque seco chiquitano, un ecosistema amenazado que previamente no se consideraba su hábitat. Este hallazgo se llevó a cabo como parte de un programa de monitoreo de felinos con cámaras trampa, donde adicionalmente seis especies de félidos fueron detectadas en un área de 41km2, lo que indica una alta diversidad de felinos en esta ecorregión. Además, se identificaron amenazas directas para el gato del pantanal, como la actividad agrícola y ganadera, los perros domésticos y la cacería ilegal. La relevancia de este nuevo registro radica en su ubicación en el límite occidental-sur de la distribución conocida para Bolivia, así también como sus características morfológicas similares a la especie L. munoai. Esto subraya la necesidad de realizar investigaciones adicionales para comprender mejor su distribución y conservación. Estudios futuros podrían explorar también las similitudes morfológicas y de distribución entre L. braccatus y L. munoai.

Abstract Understanding the change in soil organic carbon (C) stock in a warmer climate and the effect of current land management on that stock is critical for soil and environmental conservation and climate policy. By simulation modeling, we predicted changes in Australia’s soil organic C stock from 2010 to 2100. These vary from losses of 0.014–0.077 t C ha−1 year−1 between 2020 and 2045 and 0.013–0.047 t C ha−1 year−1 between 2070 and 2100, under increasing emissions of greenhouse gases and temperature. Thus, Australian soil will be a net emitter of CO2. Depending on the future socio-economic conditions, we predict that croplands will accrue as much as 0.19 t C ha−1 year−1 between 2020 and 2045 due to their management, but accrual will decrease with warming and increased emissions by 2070–2100. The gains will be too small to counteract the losses of C from the larger areas of rangelands and coastal regions that are more sensitive to a warmer climate. In principle, prudent management of the rangelands, for example, improving grazing management and regenerating biodiverse, endemic native plant communities, could sequester more C and mitigate the loss; in practice, it may be more difficult, requiring innovation, interdisciplinary science, cultural awareness and effective policies.

Healthy sleep is defined by the combination of adequate duration, good quality, and regular timing. In children, sleep thus depends on the interplay of individual, parental, organizational, community, and social variables, but only a few studies have addressed this issue in a comprehensive way nationwide. Using the Uruguayan nationally representative survey (Nutrition, Child Development, and Health Survey, Encuesta de Nutrición, Desarrollo Infantil y Salud, ENDIS), we present the first epidemiological characterization of chronobiological and sleep parameters in Latin American children. On average, Uruguayan urban children (n = 2437; 5−10-years old) showed quite late chronotypes (MSFsc = 03:53 ± 1:07), moderate misalignment (SJL = 1.0 ± 0.9 h), and adequate sleep duration (SDweek = 9.9 ± 1.0 h). Further, we show the substantial influence of school shift schedules on children's circadian typology and sleep patterns. Our results show that children attending the morning school shift have a higher risk of sleep problems than afternoon-school shift ones. The chronotype and sleep were earlier in morning-school shift children than in children attending the afternoon school shift. However, morning-school shift children had stronger misalignment, shorter sleep on school days, and a higher risk of chronic sleep deficit and non-healthy circadian misalignment (even worse in late chronotypes) than afternoon-shift children. This evidence points to the need of evaluating policies to reorganize school start times to prevent the negative effects that early schooling seems to have on children's sleep health, which has been neglected so far.

IntroductionMuscle activity patterns in the residual arm are systematically present during phantom hand movements (PHM) in transhumeral amputees. However, their characteristics have not been directly investigated yet, leaving their neurophysiological origin poorly understood. This study pioneers a neurophysiological perspective in examining PHM-related muscle activity patterns by characterizing and comparing them with those in the arm, forearm, and hand muscles of control participants executing intact hand movements (IHM) of similar types.MethodsTo enable rigorous comparison, we developed meta-variables independent of electrode placement, quantifying the phasic profile of recorded surface EMG signals and the specificity of their patterns across electrode sites and movement types.ResultsSimilar to the forearm and hand muscles during IHM, each signal recorded from the residual upper arm during PHM displays a phasic profile, synchronized with the onset and offset of each movement repetition. Furthermore, the PHM-related patterns of phasic muscle activity are specific not only to the type of movement but also to the electrode site, even within the same upper arm muscle, while these muscles exhibit homogeneous activities in intact arms.DiscussionOur results suggest the existence of peripheral reorganization, eventually leading to the emergence of independently controlled muscular sub-volumes. This reorganization potentially occurs through the sprouting of severed axons and the recapture of muscle fibers in the residual limb. Further research is imperative to comprehend this mechanism and its relationship with PHM, holding significant implications for the rehabilitation process and myoelectric prosthesis control.

Objective To test the effect of a complex, interdisciplinary, lifestyle and psychosocial intervention on metabolic and mental health outcomes in women with gestational diabetes mellitus during pregnancy and in the post partum.Design Single centred, single blinded, randomised, controlled trial (the MySweetheart trial).Setting Lausanne University Hospital, Switzerland, from 2 September 2016 to 25 October 2021.Participants 211 women aged at least 18 years with a diagnosis of gestational diabetes mellitus at 24-32 gestational weeks were randomly assigned (1:1) to the intervention (n=105) or to usual care (n=106).Interventions In addition to a comparator based on active guidelines for prepartum and postpartum usual care, the intervention consisted of four individual lifestyle visits during pregnancy and four interdisciplinary visits in the postpartum group, a peer support group workshop in pregnancy and post partum, and a bimonthly lifestyle coach support through telemedicine. The intervention focused on tailored behavioural and psychosocial strategies to improve diet, physical activity, mental health, social support, and adherence to gestational weight gain during pregnancy and weight retention recommendations.Main outcome measures Primary outcomes were between-group differences in the decrease in maternal weight and depression symptom scores between baseline and one year post partum. Secondary outcomes included changes in total and central body fat, anxiety, wellbeing, glycaemic parameters (homeostatic model assessment for insulin resistance (known as HOMA-IR) and Matsuda indices), aerobic fitness (maximal oxygen uptake), gestational weight gain, and weight retention. Assessors were blinded to primary and secondary outcomes.Results 84 (80%) of 105 women in the intervention and 95 (90%) of 106 in the usual care completed the study. There was not enough evidence of a difference in the decrease in weight (mean difference –0.38 kg (95% confidence interval –2.08 to 1.30)) or depression scores (–0.67 (–1.84 to 0.49)). The intervention led to an increase in fat-free mass (0.02 kg (0.01 to 0.03)). The intervention also decreased gestational weight gain since the first gestational diabetes mellitus visit (–1.20 kg (–2.14 to –0.26)) and weekly weight gain throughout the entire pregnancy (–0.14 kg (–0.25 to –0.03)), and led to a higher proportion of women without weight retention at one year post partum (34.1% (28/82) v 20.8% (20/96), P=0.034).Conclusions Compared with active usual care based on guidelines, there was not enough evidence to conclude that the intervention led to decrease in weight or depression symptoms. However, the intervention decreased gestational weight gain and increased the proportion of women without weight retention.Trial registration Clinicaltrials.gov NCT02890693.

Soil organic carbon (SOC) is crucial for soil health and quality, and its sequestration has been suggested as a natural solution to climate change. Accurate and cost-efficient determination of SOC and its functional fractions is essential for effective SOC management. Visible near-infrared spectroscopy (vis-NIR) has emerged as a cost-efficient approach. However, its ability to predict whole-profile SOC content and its fractions has rarely been assessed. Here, we measured SOC and its two functional fractions, particulate (POC) and mineral-associated organic carbon (MAOC), down to a depth of 200 ​cm in seven sequential layers across 183 dryland cropping fields in northwest, southwest, and south China. Then, vis-NIR spectra of the soil samples were collected to train a machine learning model (partial least squares regression) to predict SOC, POC, MAOC, and the ratio of MAOC to SOC (MAOC/SOC – an index of carbon vulnerability). We found that the accuracy of the model indicated by the determination coefficient of validation (Rval2) is 0.39, 0.30, 0.49, and 0.48 for SOC, POC, MAOC, and MAOC/SOC, respectively. Incorporating mean annual temperature improved model performance, and Rval2 was increased to 0.64, 0.31, 0.63, and 0.51 for the four carbon variables, respectively. Further incorporating SOC into the model increased Rval2 to 0.82, 0.64, and 0.59, respectively. These results suggest that combining vis-NIR spectroscopy with readily-available climate data and total SOC measurements enables fast and accurate estimation of whole-profile POC and MAOC across diverse environmental conditions, facilitating reliable prediction of whole-profile SOC dynamics over large spatial extents.

Abstract Proteomic fingerprinting using MALDI-TOF mass spectrometry is a well-established tool for identifying microorganisms and has shown promising results for identification of animal species, particularly disease vectors and marine organisms. And thus can be a vital tool for biodiversity assessments in ecological studies. However, few studies have tested species identification across different orders and classes. In this study, we collected data from 1246 specimens and 198 species to test species identification in a diverse dataset. We also evaluated different specimen preparation and data processing approaches for machine learning and developed a workflow to optimize classification using random forest. Our results showed high success rates of over 90%, but we also found that the size of the reference library affects classification error. Additionally, we demonstrated the ability of the method to differentiate marine cryptic-species complexes and to distinguish sexes within species.

Los pacientes con tumores de la vía aérea (VA) superior y aquellos que previamente han recibido radioterapia son un grupo cuyo manejo siempre supone un desafío. La progresión de la enfermedad, infección y la radioterapia tienen como consecuencia un incremento de edema, que hace que estos pacientes sean más complicados, con un manejo anestésico de predecible dificultad, en la que todo el equipo médico debe estar involucrado. Para estos casos, existen varios dispositivos utilizables para el manejo de la vía aérea. La intubación del paciente despierto con fibroscopio (FBO) probablemente sea la técnica más segura, pero es también la más estresante, se precisa de experiencia, disponer del equipo necesario y de unos asistentes entrenados y conocedores de la misma, según explican las recomendaciones de NAP4. En este caso presentamos un paciente con predictores de vía aérea difícil (VAD) que fue intubado despierto con Glidescope en el primer intento.