Miracle-dz/UniFAR-FTUs huggingface dataset:
Enhanced excitability of cortical neurons in low-divalent solutions is primarily mediated by altered voltage-dependence of voltage-gated sodium channels

Increasing extracellular [Ca2+] ([Ca2+]o) strongly decreases intrinsic excitability in neurons but the mechanism is unclear. By one hypothesis, [Ca2+]o screens surface charge, reducing voltage-gated sodium channel (VGSC) activation and by another [Ca2+]o activates Calcium-sensing receptor (CaSR) closing the sodium-leak channel (NALCN). Here we report that neocortical neurons from CaSR-deficient (Casr-/-) mice had more negative resting potentials and did not fire spontaneously in reduced divalent-containing solution (T0.2) in contrast with wild-type (WT). However, after setting membrane potential to −70 mV, T0.2 application similarly depolarized and increased action potential firing in Casr-/- and WT neurons. Enhanced activation of VGSCs was the dominant contributor to the depolarization and increase in excitability by T0.2 and occurred due to hyperpolarizing shifts in VGSC window currents. CaSR deletion depolarized VGSC window currents but did not affect NALCN activation. Regulation of VGSC gating by external divalents is the key mechanism mediating divalent-dependent changes in neocortical neuron excitability.
Cerebral oxygen saturation and cerebrovascular instability in newborn infants with congenital heart disease compared to healthy controls

Objective Infants with Congenital Heart Disease (CHD) are at risk for developmental delays, though the mechanisms of brain injury that impair development are unknown. Potential causes could include cerebral hypoxia and cerebrovascular instability. We hypothesized that we would detect significantly reduced cerebral oxygen saturation and greater cerebrovascular instability in CHD infants compared to the healthy controls. Methods We performed a secondary analysis on a sample of 43 term infants (28 CHD, 15 healthy controls) that assessed prospectively in temporal cross-section before or at 12 days of age. CHD infants were assessed prior to open-heart surgery. Cerebral oxygen saturation levels were estimated using Near-Infrared Spectroscopy, and cerebrovascular stability was assessed with the response of cerebral oxygen saturation after a postural change (supine to sitting). Results Cerebral oxygen saturation was 9 points lower in CHD than control infants in both postures (β = -9.3; 95%CI = -17.68, -1.00; p = 0.028), even after controlling for differences in peripheral oxygen saturation. Cerebrovascular stability was significantly impaired in CHD compared to healthy infants (β = -2.4; 95%CI = -4.12, -.61; p = 0.008), and in CHD infants with single ventricle compared with biventricular defects (β = -1.5; 95%CI = -2.95, -0.05; p = 0.04). Conclusion CHD infants had cerebral hypoxia and decreased cerebral oxygen saturation values following a postural change, suggesting cerebrovascular instability. Future longitudinal studies should assess the associations of cerebral hypoxia and cerebrovascular instability with long-term neurodevelopmental outcomes in CHD infants.
Risk of groundwater contamination widely underestimated because of fast flow into aquifers

Significance Clean groundwater is essential for water supply in many regions of the world. Fast flow to the groundwater through enlarged cracks and fissures, which is known to transmit short-lived pollutants into the groundwater, is often neglected in large-scale studies. We quantify the rapid transport of pollutants by fast flow into the carbonate rock groundwater storage in Europe, North Africa, and the Middle East. We show that, through rapid transport, up to 50% of infiltrating pollutants may still reach the groundwater table, which is substantially more than estimated when fast transport is neglected. These results imply that the contamination risk of usable groundwater storages is much larger than expected where fast flow to the groundwater occurs. Groundwater pollution threatens human and ecosystem health in many regions around the globe. Fast flow to the groundwater through focused recharge is known to transmit short-lived pollutants into carbonate aquifers, endangering the quality of groundwaters where one quarter of the world’s population lives. However, the large-scale impact of such focused recharge on groundwater quality remains poorly understood. Here, we apply a continental-scale model to quantify the risk of groundwater contamination by degradable pollutants through focused recharge in the carbonate rock regions of Europe, North Africa, and the Middle East. We show that focused recharge is the primary reason for widespread rapid transport of contaminants to the groundwater. Where it occurs, the concentration of pollutants in groundwater recharge that have not yet degraded increases from <1% to around 20 to 50% of their concentrations during infiltration. Assuming realistic application rates, our simulations show that degradable pollutants like glyphosate can exceed their permissible concentrations by 3 to 19 times when reaching the groundwater. Our results are supported by independent estimates of young water fractions at 78 carbonate rock springs over Europe and a dataset of observed glyphosate concentrations in the groundwater. They imply that in times of continuing and increasing industrial and agricultural productivity, focused recharge may result in an underestimated and widespread risk to usable groundwater volumes.
Cognitive performance and lifetime cannabis use in patients with first-episode schizophrenia spectrum disorder

ABSTRACT Introduction Cognitive impairment is among the core features of schizophrenia. In a healthy population, the cognitive deficit is often linked with cannabis abuse, and although the same would be expected in patients with schizophrenia, research has presented contradictory results. Methods Participants were patients with first-episode schizophrenia (FES) spectrum disorder who had been lifetime cannabis users (N = 30), FES non-users (N = 53) as well as healthy controls (HC) also divided into cannabis users (N = 20) and non-users (N = 49). All participants underwent an extensive neurocognitive assessment and filled in a cannabis questionnaire, which allowed for a comparison of the four groups on cognitive functioning. Results FES patients using cannabis showed less impaired cognitive functioning with the most prominent difference in visual memory compared to FES non-users. However, they differed neither in the clinical assessment of general psychopathology, positive and negative symptoms, nor in medication from the patient’s non-users. A comparison of the HC who used cannabis, and those who did not, revealed no sizeable differences in cognitive performance between the groups. Conclusions The results delivered supporting evidence for the trend of superior neurocognitive performance in FES patients with a lifetime history of cannabis use compared to non-using patients.
Adapting a Person’s Home in 3D Using a Mobile App (MapIt): Participatory Design Framework Investigating the App’s Acceptability

Background Home adaptation processes enhancing occupational engagement rely on identifying environmental barriers, generally during time-consuming home visits performed by occupational therapists (OTs). Relevance of a 3D model to the OT’s work has been attested, but a convenient and consumer-available technology to map the home environment in 3D is currently lacking. For instance, such a technology would support the exploration of home adaptations for a person with disability, with or without an OT visit. Objective The aim of this study was to document the development and acceptability of a 3D mapping eHealth technology, optimizing its contribution to the OT’s work when conducting assessments in which home representations are essential to fit a person’s needs. Methods A user-centered perspective, embedded in a participatory design framework where users are considered as research partners (not as just study participants), is reported. OTs, engineers, clinicians, researchers, and students, as well as the relatives of older adults contributed by providing ongoing feedback (eg, demonstrations, brainstorming, usability testing, questionnaires, prototyping). System acceptability, as per the Nielsen model, is documented by deductively integrating the data. Results A total of 24 stakeholders contributed significantly to MapIt technology’s co-design over a span of 4 years. Fueled by the objective to enhance MapIt’s acceptability, 11 iterations lead to a mobile app to scan a room and produce its 3D model in less than 5 minutes. The app is available for smartphones and paired with computer software. Scanning, visualization, and automatic measurements are done on a smartphone equipped with a motion sensor and a camera with depth perception, and the computer software facilitates visualization, while allowing custom measurement of architectural elements directly on the 3D model. Stakeholders’ perception was favorable regarding MapIt’s acceptability, testifying to its usefulness (ie, usability and utility). Residual usability issues as well as concerns about accessibility and scan rendering still need to be addressed to foster its integration to a clinical context. Conclusions MapIt allows to scan a room quickly and simply, providing a 3D model from images taken in real-world settings and to remotely but jointly explore home adaptations to enhance a person’s occupational engagement.
Risk of Ophthalmic Adverse Events in Patients Treated with Immune Checkpoint Inhibitor Regimens: A Systematic Review and Meta-analysis

ABSTRACT Background Immune checkpoint inhibitors (ICIs) -induced adverse events (AEs) have been reported affecting almost all human organs. However, studies about ocular AEs are few. A meta-analysis was performed to evaluate the risks of ICI-related ophthalmic AEs compare to chemotherapy. Methods: Eligible studies were selected from phase II/III randomized controlled trials investigating ICIs. The data were analyzed by R software and Stata. Results Odds ratio of treatment-related AE (trAEs) and nonspecific ophthalmic trAEs (NS-trAEs) were lower for PD-1/PD-L1 inhibitors than chemotherapy (OR 0.44, p < .05; OR 0.28, p < .001; OR 0.18, p < . 05; OR: 0.18, p < .001respectively). Compared with monotherapy, PD-1 plus CTLA-4 inhibitors increased the risks of immune-related AEs (irAEs) (OR 4.52, p < .01); ICIs plus chemotherapy increased the risks of trAEs and irAEs (OR 2.82, p < .001; OR 3.63, p < .05 respectively). Conclusions PD-L1/PD-1 inhibitors had lower risks of trAEs and NS-trAEs than chemotherapy; Compared with monotherapy, combination therapy had higher risks of ophthalmic trAEs and irAEs. Abbreviation PD-1: programmed cell death protein 1; PD-L1: programmed cell death protein ligand 1; CTLA-4: cytotoxic T-lymphocyte-associated protein 4; ICI: immune checkpoint inhibitor; AE: adverse event; trAE: treatment-related adverse event;irAE: immune-related adverse events; NS-trAE: nonspecific ophthalmic treatment-related adverse event; RCT: randomized controlled trials; PFS: progression-free survival; OS: overall survival; ORR: objective response rate; MM: melanoma; NSCLC: non-small cell lung cancer; SCLC: small cell lung cancer; HNSCC: head-neck squamous cell carcinoma; PICOL: patient, intervention, comparison, and outcome; Versus: VS; Chem: chemotherapy; 95%CI: 95% confidence interval; FEM: fixed-effects model; REM: random-effects model; NA: not applicable; MeSH: medical subject heading
Tolerability, Safety, Pharmacokinetics, and Immunogenicity of a Novel SARS-CoV-2 Neutralizing Antibody, Etesevimab, in Chinese Healthy Adults: a Randomized, Double-Blind, Placebo-Controlled, First-in-Human Phase 1 Study

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread rapidly worldwide. This study is the first to report the tolerability, safety, pharmacokinetics (PK), and immunogenicity of a recombinant human anti-SARS-CoV-2 monoclonal antibody, etesevimab (CB6, JS016, LY3832479, or LY-CoV016), in healthy adults. ABSTRACT Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread rapidly worldwide. This study is the first to report the tolerability, safety, pharmacokinetics (PK), and immunogenicity of a recombinant human anti-SARS-CoV-2 monoclonal antibody, etesevimab (CB6, JS016, LY3832479, or LY-CoV016), in healthy adults. This paper describes a randomized, double-blind, placebo-controlled, phase 1 study. A total of 40 participants were enrolled to receive a single intravenous dose of either etesevimab or placebo in one of four sequential ascending intravenous dose cohorts. All 40 participants completed the study. Seventeen (42.5%) participants experienced 22 treatment emergent adverse events (TEAEs) that were drug-related, and the rates of these TEAEs among different dose cohorts were numerically comparable. No difference was observed between the combined etesevimab group and the placebo group. The exposure after etesevimab infusion increased in an approximately proportional manner as the dose increased from 2.5 to 50 mg/kg. The elimination half-life (t1/2) value did not differ among different dose cohorts and was estimated to be around 4 weeks. Etesevimab was well tolerated after administration of a single dose at a range of 2.5 mg/kg to 50 mg/kg in healthy Chinese adults. The PK profiles of etesevimab in healthy volunteers showed typical monoclonal antibody distribution and elimination characteristics. (This study has been registered at ClinicalTrials.gov under identifier NCT04441918.)
Efficacy of sacral neuromodulation and percutaneous tibial nerve stimulation in the treatment of chronic nonobstructive urinary retention: A systematic review

The aim of this systematic review is to provide an updated report on the efficacy and complications of sacral neuromodulation (SNM) and percutaneous tibial nerve stimulation (PTNS) in the treatment of chronic nonobstructive urinary retention (CNOUR), with a focus on the contemporary technique of SNM utilizing the percutaneous placement of tined leads.
RENEB Inter-Laboratory comparison 2017: limits and pitfalls of ILCs

Abstract Purpose In case of a mass-casualty radiological event, there would be a need for networking to overcome surge limitations and to quickly obtain homogeneous results (reported aberration frequencies or estimated doses) among biodosimetry laboratories. These results must be consistent within such network. Inter-laboratory comparisons (ILCs) are widely accepted to achieve this homogeneity. At the European level, a great effort has been made to harmonize biological dosimetry laboratories, notably during the MULTIBIODOSE and RENEB projects. In order to continue the harmonization efforts, the RENEB consortium launched this intercomparison which is larger than the RENEB network, as it involves 38 laboratories from 21 countries. In this ILC all steps of the process were monitored, from blood shipment to dose estimation. This exercise also aimed to evaluate the statistical tools used to compare laboratory performance. Materials and methods Blood samples were irradiated at three different doses, 1.8, 0.4 and 0 Gy (samples A, C and B) with 4-MV X-rays at 0.5 Gy min−1, and sent to the participant laboratories. Each laboratory was requested to blindly analyze 500 cells per sample and to report the observed frequency of dicentric chromosomes per metaphase and the corresponding estimated dose. Results This ILC demonstrates that blood samples can be successfully distributed among laboratories worldwide to perform biological dosimetry in case of a mass casualty event. Having achieved a substantial harmonization in multiple areas among the RENEB laboratories issues were identified with the available statistical tools, which are not capable to advantageously exploit the richness of results of a large ILCs. Even though Z- and U-tests are accepted methods for biodosimetry ILCs, setting the number of analyzed metaphases to 500 and establishing a tests’ common threshold for all studied doses is inappropriate for evaluating laboratory performance. Another problem highlighted by this ILC is the issue of the dose-effect curve diversity. It clearly appears that, despite the initial advantage of including the scoring specificities of each laboratory, the lack of defined criteria for assessing the robustness of each laboratory’s curve is a disadvantage for the ‘one curve per laboratory’ model. Conclusions Based on our study, it seems relevant to develop tools better adapted to the collection and processing of results produced by the participant laboratories. We are confident that, after an initial harmonization phase reached by the RENEB laboratories, a new step toward a better optimization of the laboratory networks in biological dosimetry and associated ILC is on the way.
Psychiatric understanding and treatment of patients with amputations

Amputation changes the lives of patients and their families. Consequently, the patient must adapt to altered body function and image. During this adaptation process, psychological problems, such as depression, anxiety, and posttraumatic stress disorder, can occur. The psychological difficulties of patients with amputation are often accepted as normal responses that are often poorly recognized by patients, family members, and their primary physicians. Psychological problems can interfere with rehabilitation and cause additional psychosocial problems. Therefore, their early detection and treatment are important. A multidisciplinary team approach, including mental health professionals, is ideal for comprehensive and biopsychosocial management. Mental health professionals could help patients set realistic goals and use adaptive coping styles. Psychiatric approaches should consider the physical, cognitive, psychological, social, and spiritual functions and social support systems before and after amputation. The abilities and limitations of physical, cognitive, psychological, and social functions should also be considered. To improve the patient’s adaptation, psychological interventions such as short-term psychotherapy, cognitive behavioral therapy, mindfulness meditation, biofeedback, and group psychotherapy can be helpful.
Shifting access to pools of shoot water sustains gas exchange and increases stem hydraulic safety during seasonal atmospheric drought.

Understanding how plants acclimate to drought is crucial for predicting future vulnerability, yet seasonal acclimation of traits that improve drought tolerance in trees remains poorly resolved. We hypothesized that dry season acclimation of leaf and stem traits influencing shoot water storage and hydraulic capacitance would mitigate the drought-associated risks of reduced gas exchange and hydraulic failure in the mangrove Sonneratia alba. By late dry season, availability of stored water had shifted within leaves and between leaves and stems. While whole shoot capacitance remained stable, the symplastic fraction of leaf water increased 86%, leaf capacitance increased 104% and stem capacitance declined 80%. Despite declining plant water potentials, leaf and whole plant hydraulic conductance remained unchanged, and midday assimilation rates increased. Further, the available leaf water between the minimum water potential observed and that corresponding to 50% loss of stem conductance increased 111%. Shifting availability of pools of water, within and between organs, maintained leaf water available to buffer periods of increased photosynthesis and losses in stem hydraulic conductivity, mitigating risks of carbon depletion and hydraulic failure during atmospheric drought. Seasonal changes in access to tissue and organ water may have an important role in drought acclimation and avoidance. This article is protected by copyright. All rights reserved.
Compound heterozygous KCTD7 variants in progressive myoclonus epilepsy

Abstract KCTD7 is a member of the potassium channel tetramerization domain-containing protein family and has been associated with progressive myoclonic epilepsy (PME), characterized by myoclonus, epilepsy, and neurological deterioration. Here we report four affected individuals from two unrelated families in which we identified KCTD7 compound heterozygous single nucleotide variants through exome sequencing. RNAseq was used to detect a non-annotated splicing junction created by a synonymous variant in the second family. Whole-cell patch-clamp analysis of neuroblastoma cells overexpressing the patients’ variant alleles demonstrated aberrant potassium regulation. While all four patients experienced many of the common clinical features of PME, they also showed variable phenotypes not previously reported, including dysautonomia, brain pathology findings including a significantly reduced thalamus, and the lack of myoclonic seizures. To gain further insight into the pathogenesis of the disorder, zinc finger nucleases were used to generate kctd7 knockout zebrafish. Kctd7 homozygous mutants showed global dysregulation of gene expression and increased transcription of c-fos, which has previously been correlated with seizure activity in animal models. Together these findings expand the known phenotypic spectrum of KCTD7-associated PME, report a new animal model for future studies, and contribute valuable insights into the disease.
Impacts of an egg intervention on nutrient adequacy among young Malawian children

Abstract Eggs are a rich source of multiple nutrients that support child growth and development. Provision of eggs as a complementary food may improve dietary adequacy among young children at risk for undernutrition. Our objective was to test the impact of an egg intervention on the adequacy of total nutrient intakes and micronutrient density among 6‐ to 15‐month‐old Malawian children. Children 6 to 9 months old, living in Mangochi District, Malawi, were randomly assigned to the intervention group (n = 331) receiving an egg per day or a control group (n = 329) consuming their usual diet. Dietary intakes of macronutrients, vitamins and minerals were assessed using 24‐h recalls at baseline, 3‐month midline and 6‐month endline, with repeat recalls in a subsample. Usual nutrient intake and micronutrient density distributions were modelled to estimate group means and prevalence of inadequacy. Group differences at midline and endline were tested using unequal variance t tests with bootstrapped standard errors. The egg intervention resulted in higher intakes of fat and protein and lower intakes of carbohydrates. The egg group had lower prevalence of inadequacy for selenium, vitamin A, riboflavin, vitamin B5, vitamin B12 and choline. Micronutrient density inadequacy was lower in the egg group for vitamin A and choline at midline and endline, riboflavin at midline and vitamin B5 at endline. Inadequacy of nutrient intakes or density remained highly prevalent in both groups for multiple micronutrients. Though the egg intervention increased intakes of protein and several micronutrients, total intakes and micronutrient density of multiple micronutrients remained far below recommendations.