Search

IMPORTANCE: The prevalence estimates of physical activity, sedentary behavior, and sleep (collectively known as movement behaviors) in 3- and 4-year-old children worldwide remains uncertain. OBJECTIVE: To report the proportion of 3- and 4-year-old children who met the World Health Organization guidelines for physical activity, sedentary behavior, and sleep across 33 countries. DESIGN, SETTING, AND PARTICIPANTS: Pooled analysis of data from 14 cross-sectional studies (July 2008 to September 2022) identified through systematic reviews and personal networks. Thirty-three countries of varying income levels across 6 geographical regions. Each study site needed to have at least 40 children aged 3.0 to 4.9 years with valid accelerometry and parent-/caregiver-reported screen time and sleep duration data. Data were analyzed from October 2022 to February 2023. EXPOSURES: Time spent in physical activity was assessed by reanalyzing accelerometry data using a harmonized data-processing protocol. Screen time and sleep duration were proxy reported by parents or caregivers. MAIN OUTCOMES AND MEASURES: The proportion of children who met the World Health Organization guidelines for physical activity (≥180 min/d of total physical activity and ≥60 min/d of moderate- to vigorous-intensity physical activity), screen time (≤1 h/d), and sleep duration (10-13 h/d) was estimated across countries and by World Bank income group and geographical region using meta-analysis. RESULTS: Of the 7017 children (mean [SD] age, 4.1 [0.5] years; 3585 [51.1%] boys and 3432 [48.9%] girls) in this pooled analysis, 14.3% (95% CI, 9.7-20.7) met the overall guidelines for physical activity, screen time, and sleep duration. There was no clear pattern according to income group: the proportion meeting the guidelines was 16.6% (95% CI, 10.4-25.3) in low- and lower-middle–income countries, 11.9% (95% CI, 5.9-22.5) in upper-middle–income countries, and 14.4% (95% CI, 9.6-21.1) in high-income countries. The region with the highest proportion meeting the guidelines was Africa (23.9%; 95% CI, 11.6-43.0), while the lowest proportion was in North and South America (7.7%; 95% CI, 3.6-15.8). CONCLUSIONS AND RELEVANCE: Most 3- and 4-year-old children in this pooled analysis did not meet the current World Health Organization guidelines for physical activity, sedentary behavior, and sleep. Priority must be given to understanding factors that influence these behaviors in this age group and to implementing contextually appropriate programs and policies proven to be effective in promoting healthy levels of movement behaviors.

Single nucleotide polymorphisms (SNPs) in the cytotoxic T-lymphocyte–associated protein 4 (CTLA-4)gene, an inhibitor of T-cell priming, are associated with auto and alloimmunity. Studies implied a role for these SNPs as surrogate markers for immunotherapy-outcome in patients with melanoma. However, no predictive SNPs are defined to date. We analyzed different CTLA-4 SNPs in a large multicenter cohort of patients with ipilimumab-treated melanoma and investigated possible correlations with treatment-related outcomes. Archival blood and/or tumor tissue samples were collected from 361 patients with advanced-stage ipilimumab-treated (±nivolumab) in 6 Swiss and Dutch hospitals. Matrix-assisted laser desorption/ionization–time of flight mass spectrometry based DNA genotyping was performed for 10 different CTLA-4 SNPs: 49A>G, CT60G>A, Jo27T>C, Jo30G>A, Jo31G>T, −658C>T, −1722T>C, −1661A>G, 318C>T, and C>T rs1863800.Associations between different allele genotypes and occurrence of grade ≥3 adverse events (AEs) and survival were tested using univariable logistic regressions or Cox proportional hazard models. 262/361 (73%) patients could be analyzed; 65% of those were males, the median age was 58 years, 39% showed a partial or complete response, and 65% had ≥1 AEs. A TT-genotype of −1722T>C SNP was significantly associated with a lower incidence of grade ≥3 AEs (P= 0.049), whereas the GG-genotype of CT60G>A correlated with a higher incidence of grade ≥3 AEs (P= 0.026). The TT-genotype of Jo27T>C SNP (P= 0.056) and GG-genotype of Jo31G>T (P= 0.046) were associated with overall survival. CTLA-4 SNPs might predict treatment-related outcomes in patients with melanoma receiving ipilimumab. Confirmatory studies are needed to fully exploit those findings as predictive biomarkers for ipilimumab AEs.

Children with chronic neuromuscular conditions (CCNMC) have many coexisting conditions and often require musculoskeletal surgery for progressive neuromuscular scoliosis or hip dysplasia. Adequate perioperative optimization may decrease adverse perioperative outcomes. The purpose of this scoping review was to allow us to assess associations of perioperative health interventions (POHI) with perioperative outcomes in CCNMC.Eligible articles included those published from January 1, 2000 through March 1, 2022 in which the authors evaluated the impact of POHI on perioperative outcomes in CCNMC undergoing major musculoskeletal surgery. Multiple databases, including PubMed, Embase, Cumulative Index of Nursing and Allied Health Literature, Web of Science, the Cochrane Library, Google Scholar, and ClinicalTrials.gov, were searched by using controlled vocabulary terms and relevant natural language keywords. Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews guidelines were used to perform the review. A risk of bias assessment for included studies was performed by using the Risk of Bias in Non-randomized Studies of Interventions tool.A total of 7013 unique articles were initially identified, of which 6286 (89.6%) were excluded after abstract review. The remaining 727 articles’ full texts were then reviewed for eligibility, resulting in the exclusion of 709 (97.5%) articles. Ultimately, 18 articles were retained for final analysis. The authors of these studies reported various impacts of POHI on perioperative outcomes, including postoperative complications, hospital length of stay, and hospitalization costs. Because of the heterogeneity of interventions and outcome measures, meta-analyses with pooled data were not feasible.The findings reveal various impacts of POHI in CCNMC undergoing major musculoskeletal surgery. Multicenter prospective studies are needed to better address the overall impact of specific interventions on perioperative outcomes in CCNMC.

We performed whole-genome sequencing (WGS) in 327 children with cerebral palsy (CP) and their biological parents. We classified 37 of 327 (11.3%) children as having pathogenic/likely pathogenic (P/LP) variants and 58 of 327 (17.7%) as having variants of uncertain significance. Multiple classes of P/LP variants included single-nucleotide variants (SNVs)/indels (6.7%), copy number variations (3.4%) and mitochondrial mutations (1.5%). The COL4A1gene had the most P/LP SNVs. We also analyzed two pediatric control cohorts (n= 203 trios and n= 89 sib-pair families) to provide a baseline for de novo mutation rates and genetic burden analyses, the latter of which demonstrated associations between de novo deleterious variants and genes related to the nervous system. An enrichment analysis revealed previously undescribed plausible candidate CP genes (SMOC1, KDM5B, BCL11Aand CYP51A1). A multifactorial CP risk profile and substantial presence of P/LP variants combine to support WGS in the diagnostic work-up across all CP and related phenotypes.

Rapid growth in pediatric hospital medicine (PHM) fellowships has occurred, yielding many new program directors (PDs). Characteristics of PDs have potential implications on the field. To describe characteristics (demographic, educational) and scholarly interests of PHM fellowship PDs.We developed and distributed a 15-question, cross-sectional national survey to the PHM PDs listserv. Questions were pilot tested. The survey was open for 4 weeks with weekly reminders. Responses were summarized using descriptive statistics.Fifty-six current fellowship leaders (40 PDs, 16 associate PDs [APDs]) responded, including at least 1 from 43 of 59 active PHM fellowship programs (73%). Most respondents identified as female (71%) and ≤50 years old (80%). Four (7%, n = 2 PD, 2 APD) leaders identified as underrepresented in medicine. About half (n = 31, 55.4%) completed a fellowship themselves (APDs > PDs; 87.5% vs 42.5%), and 53.5% (n = 30) had advanced nonmedical degrees (eg, Master of Science, Doctor of Philosophy; APDs > PDs; 62% vs 45%). Most leaders (59%, n = 33) chose multiple domains when asked to select a “primary domain of personal scholarship.” Education was the most frequently selected (n = 37), followed by quality improvement (n = 29) and then clinical research (n = 19).This survey confirms a high percentage of women as PHM fellowship leaders and highlights the need to increase diversity. Less than half of senior PDs completed a fellowship in any specialty. Leaders report interest in multiple domains of scholarship; few focus solely on clinical research.

The expansion of the neocortex, a hallmark of mammalian evolution1,2, was accompanied by an increase in cerebellar neuron numbers3. However, little is known about the evolution of the cellular programmes underlying the development of the cerebellum in mammals. In this study we generated single-nucleus RNA-sequencing data for around 400,000 cells to trace the development of the cerebellum from early neurogenesis to adulthood in human, mouse and the marsupial opossum. We established a consensus classification of the cellular diversity in the developing mammalian cerebellum and validated it by spatial mapping in the fetal human cerebellum. Our cross-species analyses revealed largely conserved developmental dynamics of cell-type generation, except for Purkinje cells, for which we observed an expansion of early-born subtypes in the human lineage. Global transcriptome profiles, conserved cell-state markers and gene-expression trajectories across neuronal differentiation show that cerebellar cell-type-defining programmes have been overall preserved for at least 160 million years. However, we also identified many orthologous genes that gained or lost expression in cerebellar neural cell types in one of the species or evolved new expression trajectories during neuronal differentiation, indicating widespread gene repurposing at the cell-type level. In sum, our study unveils shared and lineage-specific gene-expression programmes governing the development of cerebellar cells and expands our understanding of mammalian brain evolution.

Pediatric obesity is a progressive, chronic disease that can lead to serious cardiometabolic complications. Here we investigated the peripheral lipidome in 958 children and adolescents with overweight or obesity and 373 with normal weight, in a cross-sectional study. We also implemented a family-based, personalized program to assess the effects of obesity management on 186 children and adolescents in a clinical setting. Using mass spectrometry-based lipidomics, we report an increase in ceramides, alongside a decrease in lysophospholipids and omega-3 fatty acids with obesity metabolism. Ceramides, phosphatidylethanolamines and phosphatidylinositols were associated with insulin resistance and cardiometabolic risk, whereas sphingomyelins showed inverse associations. Additionally, a panel of three lipids predicted hepatic steatosis as effectively as liver enzymes. Lipids partially mediated the association between obesity and cardiometabolic traits. The nonpharmacological management reduced levels of ceramides, phospholipids and triglycerides, indicating that lowering the degree of obesity could partially restore a healthy lipid profile in children and adolescents.

ObjectiveFat deposition is modulated by environmental factors and genetic predisposition. Genome-wide association studies identified PNPLA3p.I148M (rs738409) as a common variant that increases risk of developing liver steatosis. When and how this variant evolved in humans has not been studied to date.DesignHere we analyse ancient DNA to track the history of this allele throughout human history. In total, 6444 published ancient (modern humans, Neanderthal, Denisovan) and 3943 published present day genomes were used for analysis after extracting genotype calls for PNPLA3p.I148M. To quantify changes through time, logistic and, by grouping individuals according to geography and age, linear regression analyses were performed.ResultsWe find that archaic human individuals (Neanderthal, Denisovan) exclusively carried a fixed PNPLA3risk allele, whereas allele frequencies in modern human populations range from very low in Africa to >50% in Mesoamerica. Over the last 15 000 years, distributions of ancestral and derived alleles roughly match the present day distribution. Logistic regression analyses did not yield signals of natural selection during the last 10 000 years.ConclusionArchaic human individuals exclusively carried a fixed PNPLA3allele associated with fatty liver, whereas allele frequencies in modern human populations are variable even in the oldest samples. Our observation might underscore the advantage of fat storage in cold climate and particularly for Neanderthal under ice age conditions. The absent signals of natural selection during modern human history does not support the thrifty gene hypothesis in case of PNPLA3p.I148M.

Translation elongation factor eEF1A2 constitutes the alpha subunit of the elongation factor-1 complex, responsible for the enzymatic binding of aminoacyl-tRNA to the ribosome. Since 2012, 21 pathogenic missense variants affecting EEF1A2have been described in 42 individuals with a severe neurodevelopmental phenotype including epileptic encephalopathy and moderate to profound intellectual disability (ID), with neurological regression in some patients. Through international collaborative call, we collected 26 patients with EEF1A2variants and compared them to the literature. Our cohort shows a significantly milder phenotype. 83% of the patients are walking (vs. 29% in the literature), and 84% of the patients have language skills (vs. 15%). Three of our patients do not have ID. Epilepsy is present in 63% (vs. 93%). Neurological examination shows a less severe phenotype with significantly less hypotonia (58% vs. 96%), and pyramidal signs (24% vs. 68%). Cognitive regression was noted in 4% (vs. 56% in the literature). Among individuals over 10 years, 56% disclosed neurocognitive regression, with a mean age of onset at 2 years. We describe 8 novel missense variants of EEF1A2. Modeling of the different amino-acid sites shows that the variants associated with a severe phenotype, and the majority of those associated with a moderate phenotype, cluster within the switch II region of the protein and thus may affect GTP exchange. In contrast, variants associated with milder phenotypes may impact secondary functions such as actin binding. We report the largest cohort of individuals with EEF1A2variants thus far, allowing us to expand the phenotype spectrum and reveal genotype-phenotype correlations.

In biological systems, the activities of macromolecular complexes must sometimes be turned off. Thus, a wide variety of protein inhibitors has evolved for this purpose. These inhibitors function through diverse mechanisms, including steric blocking of crucial interactions, enzymatic modification of key residues or substrates, and perturbation of post-translational modifications1. Anti-CRISPRs—proteins that block the activity of CRISPR–Cas systems—are one of the largest groups of inhibitors described, with more than 90 families that function through diverse mechanisms2–4. Here, we characterize the anti-CRISPR AcrIF25, and we show that it inhibits the type I-F CRISPR–Cas system by pulling apart the fully assembled effector complex. AcrIF25 binds to the predominant CRISPR RNA-binding components of this complex, comprising six Cas7 subunits, and strips them from the RNA. Structural and biochemical studies indicate that AcrIF25 removes one Cas7 subunit at a time, starting at one end of the complex. Notably, this feat is achieved with no apparent enzymatic activity. To our knowledge, AcrIF25 is the first example of a protein that disassembles a large and stable macromolecular complex in the absence of an external energy source. As such, AcrIF25 establishes a paradigm for macromolecular complex inhibitors that may be used for biotechnological applications.

Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental health disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium’s possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGSwas developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N= 2367) and replicated in the combined PsyCourse (N= 89) and BipoLife (N= 102) studies. The associations of Li+PGSand lithium treatment response —defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P< 0.05. Li+PGSwas positively associated with lithium treatment response in the ConLi+Gen cohort, in both the categorical (P= 9.8 × 10−12, R2= 1.9%) and continuous (P= 6.4 × 10−9, R2= 2.6%) outcomes. Compared to bipolar patients in the 1stdecile of the risk distribution, individuals in the 10thdecile had 3.47-fold (95%CI: 2.22–5.47) higher odds of responding favorably to lithium. The results were replicated in the independent cohorts for the categorical treatment outcome (P= 3.9 × 10−4, R2= 0.9%), but not for the continuous outcome (P= 0.13). Gene-based analyses revealed 36 candidate genes that are enriched in biological pathways controlled by glutamate and acetylcholine. Li+PGSmay be useful in the development of pharmacogenomic testing strategies by enabling a classification of bipolar patients according to their response to treatment.

Approximately 77% of NSW children aged 5 to 15 years do not meet physical activity guidelines and many spend a considerable amount of time sitting. Active breaks at primary school are feasible, may increase daily moderate to vigorous physical activity (MVPA) and decrease off‐task behaviour without adversely affecting cognitive function and learning. In this quasi‐experimental study, 101 primary school children in six intervention classrooms participated in three 10‐minute active breaks per day for six‐weeks during class time, while five control classrooms were run as usual (n = 89). Physical activity levels were measured using wrist‐worn Actigraph wGT3X‐BT accelerometers and analysed using a random forest model. Students' off‐task behaviour, wellbeing, cognitive function and maths performance were also measured. School staff completed a brief feedback survey. Children in the intervention group engaged in 15.4 and 10.9 minutes more MVPA per day at 3 and 6 weeks respectively (P< .001). Participation significantly increased the proportion of children who met the Australian 24‐Hour Movement Guidelines (P< .001). At pre, middle and end of intervention, 44.4%, 60.8% and 55.1% of intervention children and 46.5%, 45.9% and 45.8% of controls met the guidelines. Significantly fewer students engaged in off‐task behaviour in the intervention classes at mid and final weeks of intervention (−1.4 students, P= .003). No significant intervention effects were found for wellbeing, cognitive and maths performance. Active classroom breaks are an effective way to increase physical activity among primary school children while reducing off‐task classroom behaviour. Primary school students' health would benefit from active breaks with no detrimental effects on wellbeing, maths and cognitive performance.

Thermal proteome profiling (TPP) provides a powerful approach to studying proteome-wide interactions of small therapeutic molecules and their target and off-target proteins, complementing phenotypic-based drug screens. Detecting differences in thermal stability due to target engagement requires high quantitative accuracy and consistent detection. Isobaric tandem mass tags (TMTs) are used to multiplex samples and increase quantification precision in TPP analysis by data-dependent acquisition (DDA). However, advances in data-independent acquisition (DIA) can provide higher sensitivity and protein coverage with reduced costs and sample preparation steps. Herein, we explored the performance of different DIA-based label-free quantification approaches compared to TMT-DDA for thermal shift quantitation. Acute myeloid leukemia cells were treated with losmapimod, a known inhibitor of MAPK14 (p38α). Label-free DIA approaches, and particularly the library-free mode in DIA-NN, were comparable of TMT-DDA in their ability to detect target engagement of losmapimod with MAPK14 and one of its downstream targets, MAPKAPK3. Using DIA for thermal shift quantitation is a cost-effective alternative to labeled quantitation in the TPP pipeline.

In bipolar disorder (BD), the alternation of extreme mood states indicates deficits in emotion processing, accompanied by aberrant neural function of the emotion network. The present study investigated the effects of an emotion-centered psychotherapeutic intervention on amygdala responsivity and connectivity during emotional face processing in BD.

About 0.3% of all variants are due to de novo mobile element insertions (MEIs). The massive development of next-generation sequencing has made it possible to identify MEIs on a large scale. We analyzed exome sequencing (ES) data from 3232 individuals (2410 probands) with developmental and/or neurological abnormalities, with MELT, a tool designed to identify MEIs. The results were filtered by frequency, impacted region and gene function. Following phenotype comparison, two candidates were identified in two unrelated probands. The first mobile element (ME) was found in a patient referred for poikilodermia. A homozygous insertion was identified in the FERMT1gene involved in Kindler syndrome. RNA study confirmed its pathological impact on splicing. The second ME was a de novo Alu insertion in the GRIN2Bgene involved in intellectual disability, and detected in a patient with a developmental disorder. The frequency of de novo exonic MEIs in our study is concordant with previous studies on ES data. This project, which aimed to identify pathological MEIs in the coding sequence of genes, confirms that including detection of MEs in the ES pipeline can increase the diagnostic rate. This work provides additional evidence that ES could be used alone as a diagnostic exam.

In bipolar disorder, impaired affective theory of mind (aToM) performance and aberrant neural activation in the ToM brain network partly explain social functioning impairments. However, it is not yet known whether psychotherapy of bipolar disorder influences neuroimaging markers of aToM.

In the era of blood group genomics, reference collections of complete and fully resolved blood group gene alleles have gained high importance. For most blood groups, however, such collections are currently lacking, as resolving full-length gene sequences as haplotypes (ie, separated maternal/paternal origin) remains exceedingly difficult with both Sanger and short-read next-generation sequencing. Using the latest third-generation long-read sequencing, we generated a collection of fully resolved sequences for all 6 main ABO allele groups: ABO∗A1/A2/B/O.01.01/O.01.02/O.02. We selected 77 samples from an ABO genotype data set (n = 25 200) of serologically typed Swiss blood donors. The entire ABO gene was amplified in 2 overlapping long-range polymerase chain reactions (covering ∼23.6 kb) and sequenced by long-read Oxford Nanopore sequencing. For quality validation, 2 samples per ABO group were resequenced using Illumina and Pacific Biosciences technology. All 154 full-length ABO sequences were resolved as haplotypes. We observed novel, distinct sequence patterns for each ABO group. Most genetic diversity was found between, not within, ABO groups. Phylogenetic tree and haplotype network analyses highlighted distinct clades of each ABO group. Strikingly, our data uncovered 4 genetic variants putatively specific for ABO∗A1, for which direct diagnostic targets are currently lacking. We validated A1-diagnostic potential using whole-genome data (n = 4872) of a multiethnic cohort. Overall, our sequencing strategy proved powerful for producing high-quality ABO haplotypes and holds promise for generating similar collections for other blood groups. The publicly available collection of 154 haplotypes will serve as a valuable resource for molecular analyses of ABO, as well as studies about the function and evolutionary history of ABO.

•The first comprehensive collection of full-length haplotype sequences for all 6 main ABOallele groups will support ABOgenetic analyses.•ABOgenetic diversity patterns revealed putatively ABO∗A1-diagnostic variants, which could finally enable direct genetic typing of A1.

Introduction: Hydrocephalus after aneurysmal subarachnoid haemorrhage (aSAH) is a common complication which may lead to insertion of a ventriculoperitoneal shunt (VPS). Our aim is to evaluate a possible influence of specific clinical and biochemical factors on VPS dependency with special emphasis on hyperglycaemia on admission.Patients and methods: Retrospective analysis of a monocentric database of aSAH patients. Using univariable and multivariable logistic regression analysis we evaluated factors influencing VPS dependency, with a special focus on hyperglycaemia on blood sample within 24 h of admission, dichotomised at 126 mg/dl. Factors evaluated in the univariable analysis were age, sex, known diabetes, Hunt and Hess grade, Barrow Neurological Institute scale, treatment modality, extra-ventricular drain (EVD) insertion, complications (rebleeding, vasospasm, infarction, decompressive craniectomy, ventriculitis), outcome variables and laboratory parameters (glucose, C-reactive protein, procalcitonin).Results: We included 510 consecutive patients treated with acute aSAH requiring a VPS (mean age 58.2 years, 66% were female). An EVD was inserted in 387 (75.9%) patients. In the univariable analysis, VPS dependency was associated with hyperglycaemia on admission (OR 2.56, 95%CI 1.58–4.14, p< 0.001). In the multivariable regression analysis after stepwise backward regression, factors associated with VPS dependency were hyperglycaemia >126 mg/dl on admission (OR 1.93, 95%CI 1.13–3.30, p= 0.02), ventriculitis (OR 2.33, 95%CI 1.33–4.04, p= 0.003), Hunt and Hess grade (overall p-value 0.02) and decompressive craniectomy (OR 2.68, 95%CI 1.55–4.64, p< 0.001).Conclusion: Hyperglycaemia on admission was associated with an increased probability of VPS placement. If confirmed, this finding might facilitate treatment of these patients by accelerating insertion of a permanent draining system.

Background:Children from low-middle income countries (LMIC) are disproportionately affected by obesity, and low physical activity (PA) and high screen time (ST) are major contributors. Parents are key influencers on children's PA and ST, yet, no study has investigated relationships between parenting practices and children's PA and ST in LMIC families. This study examined parental influences on PA and ST among preschool-aged children from low-income families in Brazil.Methods:Parents completed a validated, culturally adapted interviewer-administered survey assessing child ST and parenting practices. Child sedentary time, total movement, and energetic play were measured by accelerometery.Results:Data were available on 77 parent-child dyads [mean age 4.6 years (standard deviation = 0.8), 53% male, and 41% mixed-race]. Parenting practices associated with greater PA were use of PA to reward/control behavior (rho = 0.34–0.49), limiting or monitoring ST (rho = 0.30), explicit modeling/enjoyment of PA (rho = 0.24), verbal encouragement for PA (rho = 0.30), and importance and value of PA (rho = 0.24–0.38; p< 0.05). Parenting practices associated with higher ST were rules around active play indoor (rho = 0.23), use of ST to reward/control behavior (rho = 0.30), exposure to screens (rho = 0.40), and explicit modeling/enjoyment of ST (rho = 0.50; p< 0.05).Conclusion:Recognized parenting practices such as explicit modeling of PA and ST, monitoring and limiting ST, and rules and restrictions about PA and ST are associated with young children's PA and ST in low-income Brazilian families. The findings identify potential targets for family-based interventions to promote healthy lifestyle behaviors and prevent childhood obesity.

BackgroundThe choroid is densely innervated by all parts of the autonomic nervous system and further harbours a network of local nerve cells, the intrinsic choroidal neurons (ICN). Their function in ocular control is currently unknown. While morphological data assume a role in intraocular pressure regulation, we here test if increased pressure on isolated choroids may activate ICN.MethodsDonor tissue was transferred into a pressurisable tissue culture chamber, and nasal and temporal choroid halves incubated for 1 or 4 hours, with pressures set to 15 or 50 mm Hg, followed by qRT-PCR expression analysis of the ICN-specific markers VIP, UCN, NOS1, UCH-L1. POL2-normalised data in the different pressure settings, incubation times and localisations were statistically analysed.ResultsThe presence of the ICN-specific markers VIP, UCN, NOS1, UCH-L1 was confirmed using immunohistochemistry, and mRNA of all markers was detected in all experimental conditions. Marker analysis revealed no significant changes of mRNA expression levels between 15 and 50 mm Hg in the different incubation times. When comparing all samples over all experimental conditions, a significant increase of VIP and NOS1 mRNA was detected in temporal versus nasal choroids.ConclusionIn this functional analysis of human ICN in vitro, higher amounts of VIP and NOS1 mRNA were detected in the temporal choroid, that is, the choroidal site with ICN accumulation. Further, our data indicate that elevated pressure is apparently not able to trigger ICN responses via the investigated markers. Alternative markers and stimuli need to be investigated in upcoming studies in order to unravel ICN function.

Bacteroidetes are abundant members of the human microbiota, utilizing a myriad of diet- and host-derived glycans in the distal gut1. Glycan uptake across the bacterial outer membrane of these bacteria is mediated by SusCD protein complexes, comprising a membrane-embedded barrel and a lipoprotein lid, which is thought to open and close to facilitate substrate binding and transport. However, surface-exposed glycan-binding proteins and glycoside hydrolases also play critical roles in the capture, processing and transport of large glycan chains. The interactions between these components in the outer membrane are poorly understood, despite being crucial for nutrient acquisition by our colonic microbiota. Here we show that for both the levan and dextran utilization systems of Bacteroides thetaiotaomicron, the additional outer membrane components assemble on the core SusCD transporter, forming stable glycan-utilizing machines that we term utilisomes. Single-particle cryogenic electron microscopy structures in the absence and presence of substrate reveal concerted conformational changes that demonstrate the mechanism of substrate capture, and rationalize the role of each component in the utilisome.

Background: The European Working Group on Sarcopenia in Older People (EWGSOP2) recently revised its definition and diagnostic criteria for sarcopenia, placing muscle strength at the forefront. The pathogenesis of dynapenia (or low muscle strength) is still not fully understood, but there is emerging evidence that central neural factors constitute critical determinants. Methods: Our cross-sectional study included 59 community-dwelling older women (mean age 73.1 ± 4.9 years). Participants underwent detailed skeletal muscle assessments for muscle strength defined by handgrip strength and chair rise time measurements using the recently published EWGSOP2 cut-off points. Functional magnetic resonance imaging (fMRI) was assessed during the performance of a cognitive dual-task paradigm, consisting of a baseline, two single-tasks (motor and arithmetic) and one dual-task (motor and arithmetic combined). Results: Forty-seven percent (28/59) of participants were classified as dynapenic. fMRI results revealed a differential recruitment of motor circuits in the brain during the dual-task condition in dynapenic as compared with non-dynapenic participants. In particular, while the brain activity during the single-tasks did not differ between the two groups, only during the dual-task non-dynapenic participants showed significant increased activation in dorsolateral prefrontal and premotor cortex, and in supplementary motor area as compared to dynapenic participants. Conclusion: Our results point to a dysfunctional involvement of brain networks associated with motor control in dynapenia in a multi-tasking paradigm. A better knowledge of the link between dynapenia and brain functions could provide new impulses in the diagnosis and interventions for sarcopenia.

BackgroundChoroidal vascular regulation is mediated by the autonomic nervous system in order to gain proper blood flow control. While the mechanisms behind this control are unknown, neuroregulatory peptides are involved in this process. To better understand choroidal function, we investigate the presence of urocortin-1 (UCN), a neuroregulatory peptide with vascular effects, in the human choroid and its possible intrinsic and extrinsic origin.MethodsHuman choroid and eye-related cranial ganglia (superior cervical ganglion- SCG, ciliary ganglion-CIL, pterygopalatine ganglion-PPG, trigeminal ganglion-TRI) were prepared for immunohistochemistry against UCN, protein–gene product 9.5 (PGP9.5), substance P (SP), tyrosine hydroxylase (TH) and vesicular acetylcholine transporter (VAChT). For documentation, confocal laser scanning microscopy was used.ResultsIn choroidal stroma, UCN-immunoreactivity was present in nerve fibres, small cells and intrinsic choroidal neurons (ICN). Some UCN+ nerve fibres colocalised for VAChT, while others were VAChT. A similar situation was found with SP: some UCN+ nerve fibres showed colocalisation for SP, while others lacked SP. Colocalisation for UCN and TH was not observed. In eye-related cranial ganglia, only few cells in the SCG, PPG and TRI were UCN+, while many cells of the CIL displayed weak UCN immunoreactivity.ConclusionUCN is part of the choroidal innervation. UCN+/VAChT+ fibres could derive from the few cells of the PPG or cells of the CIL, if these indeed supply the choroid. UCN+/SP+ fibres might originate from ICN, or the few UCN+ cells detected in the TRI. Further studies are necessary to establish UCN function in the choroid and its implication for choroidal autonomic control.

BackgroundWe present genomic and phenotypic findings of a transgenerational family consisting of three male offspring, each with a maternally inherited distal 220 kb deletion at locus 16p11.2 (BP2–BP3). Genomic analysis of all family members was prompted by a diagnosis of autism spectrum disorder (ASD) in the eldest child, who also presented with a low body mass index.MethodsAll male offspring underwent extensive neuropsychiatric evaluation. Both parents were also assessed for social functioning and cognition. The family underwent whole-genome sequencing. Further data curation was undertaken from samples ascertained for neurodevelopmental disorders and congenital abnormalities.ResultsOn medical examination, both the second and third-born male offspring presented with obesity. The second-born male offspring met research diagnostic criteria for ASD at 8 years of age and presented with mild attention deficits. The third-born male offspring was only noted as having motor deficits and received a diagnosis of developmental coordination disorder. Other than the 16p11.2 distal deletion, no additional contributing variants of clinical significance were observed. The mother was clinically evaluated and noted as having a broader autism phenotype.ConclusionIn this family, the phenotypes observed are most likely caused by the 16p11.2 distal deletion. The lack of other overt pathogenic mutations identified by genomic sequencing reinforces the variable expressivity that should be heeded in a clinical setting. Importantly, distal 16p11.2 deletions can present with a highly variable phenotype even within a single family. Our additional data curation provides further evidence on the variable clinical presentation among those with pathogenetic 16p11.2 (BP2–BP3) mutations.

MALDI-TOF MS is a powerful analytical technique that provides a fast and label-free readout for in vitroassays in the high-throughput screening (HTS) environment. Here, we describe the development of a novel, HTS compatible, MALDI-TOF MS-based drug discovery assay for the endoplasmic reticulum aminopeptidase 1 (ERAP1), an important target in immuno-oncology and auto-immune diseases. A MALDI-TOF MS assay was developed beginning with an already established ERAP1 RapidFire MS (RF MS) assay, where the peptide YTAFTIPSI is trimmed into the product TAFTIPSI. We noted low ionisation efficiency of these peptides in MALDI-TOF MS and hence incorporated arginine residues into the peptide sequences to improve ionisation. The optimal assay conditions were established with these new basic assay peptides on the MALDI-TOF MS platform and validated with known ERAP1 inhibitors. Assay stability, reproducibility and robustness was demonstrated on the MALDI-TOF MS platform. From a set of 699 confirmed ERAP1 binders, identified in a prior affinity selection mass spectrometry (ASMS) screen, active compounds were determined at single concentration and in a dose-response format with the new MALDI-TOF MS setup. Furthermore, to allow for platform performance comparison, the same compound set was tested on the established RF MS setup, as the new basic peptides showed fragmentation in ESI-MS. The two platforms showed a comparable performance, but the MALDI-TOF MS platform had several advantages, such as shorter sample cycle times, reduced reagent consumption, and a lower tight-binding limit.

Purpose: Adequate bone mineral density (BMD) is necessary for success in spine surgery. Dual-energy X-ray absorptiometry (DXA) is the gold standard in determining BMD but may give spuriously high values. Hounsfield units (HU) from computed tomography (CT) may provide a more accurate depiction of the focal BMD encountered during spine surgery. Our objective is to determine the discrepancy rate between DXA and CT BMD determinations and how often DXA overestimates BMD compared to CT. Methods: We retrospectively reviewed 93 patients with both DXA and CT within 6 months. DXA lumbar spine and overall Tscores were classified as osteoporotic (TScore  ≤ − 2.5) or non-osteoporotic (TScore > −2.5). L1 vertebral body HU were classified as osteoporotic or non-osteoporotic using cutoff thresholds of either ≤ 135 HU or ≤ 110 HU. Corresponding DXA and HU classifications were compared to determine disagreement and overestimation rates. Results: Using lumbar Tscores, the CT vs DXA disagreement rate was 40–54% depending on the HU threshold. DXA overestimated BMD 97–100% of the time compared to CT. Using overall DXA Tscores, the disagreement rate was 33–47% with DXA greater than CT 74–87% of the time. In the sub-cohort of 10 patients with very low HU (HU &lt; 80), DXA overestimated BMD compared to CT in every instance. Conclusions: There is a large discrepancy between DXA and CT BMD determinations. DXA frequently overestimates regional BMD encountered during spine surgery compared with CT. While DXA remains the gold standard in determining BMD, CT may play an important role in defining the focal BMD pertinent to spine surgery.

•Quantitative assessment of residents’ perceptions after the implementation of a cycling-friendly infrastructure intervention.•Pre- and post-survey results show improvements in residents’ quality of life.•Socio-demographics and daily mode use affect the residents’ perceptions.•Cycling infrastructure contributes not only to transport but also to urban development policies.

Inflammatory responses are important in cancer, particularly in the context of monocyte-rich aggressive myeloid neoplasm. We developed a label-free cellular phenotypic drug discovery assay to identify anti-inflammatory drugs in human monocytes derived from acute myeloid leukemia (AML), by tracking several features ionizing from only 2500 cells using matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry. A proof-of-concept screen showed that the BCR-ABL inhibitor nilotinib, but not the structurally similar imatinib, blocks inflammatory responses. In order to identify the cellular (off-)targets of nilotinib, we performed thermal proteome profiling (TPP). Unlike imatinib, nilotinib and other later-generation BCR-ABL inhibitors bind to p38α and inhibit the p38α-MK2/3 signaling axis, which suppressed pro-inflammatory cytokine expression, cell adhesion, and innate immunity markers in activated monocytes derived from AML. Thus, our study provides a tool for the discovery of new anti-inflammatory drugs, which could contribute to the treatment of inflammation in myeloid neoplasms and other diseases.

Constructs such as pain intensity, pain catastrophizing, pain-related injustice appraisal, and mood are comprised of stable and time-varying variance. Recent research indicates that pain-related injustice appraisals also show variability at the daily level; however, daily interrelationships between injustice appraisals and other pain-related constructs have not been examined in prior research. The current study is a secondary data analysis of an Internet-based 10-day daily diary dataset from 200 adults with chronic low back pain. A two-level multilevel model was estimated examining daily pain intensity, pain catastrophizing, and injustice appraisal as predictors of daily pain-related activity and social interference, with daily levels of depressed mood and anger as potential mediating variables. Results indicated differences between study variables when examining daily (level-1) and individual mean (level-2) variance. When examined at the daily level, all exogenous variables (pain, catastrophizing and injustice perception) showed significant direct relationships with activity and social interference; depressed mood but not anger mediated the effects of all 3 exogenous variables on social interference. Level-2 analyses indicated different mediated effects, including an indirect of pain intensity on activity interference through depressed mood and indirect effect of injustice perception on social interference through daily anger. Study results indicate that individuals with chronic pain show different cognitive/affective responses to days of greater pain than to having consistently higher or lower levels of average pain and highlight the need to consider the complexity and dynamic nature of the interrelationships between pain, cognitive and affective states, and pain-related functional interference in future research.

Objectives The current study investigated the role of maternal child- and self-oriented injustice appraisals about child pain in understanding maternal attention for child pain and adult anger cues and pain-attending behavior.Methods Forty-four children underwent a painful cold pressor task (CPT) while their mother observed. Eye tracking was used to measure maternal attention to child pain and adult anger cues. Initial attention allocation and attentional maintenance were indexed by probability of first fixation and gaze duration, respectively. Maternal pain-attending behaviors toward the child were videotaped and coded after CPT completion. Mothers also rated the intensity of pain and anger cues used in the free-viewing tasks. All analyses controlled for maternal catastrophizing about child pain.Results Neither child-oriented nor self-oriented injustice was associated with maternal attentional bias toward child pain. Regarding attention toward self-relevant anger cues, differential associations were observed for self- and child-oriented injustice appraisals, with maternal self-oriented injustice being associated with a greater probability of first fixating on anger and with higher anger ratings, whereas maternal child-oriented injustice was associated with enhanced attentional maintenance toward anger. Neither type of maternal injustice appraisals was associated with maternal pain-attending behavior, which was only associated with maternal catastrophizing.Conclusions The current study sheds light on potential differential mechanisms through which maternal self- vs. child-oriented injustice appraisals may exert their impact on parent and child pain-related outcomes. Theoretical implications and future directions are discussed.

This study investigated the neurodevelopmental impact of pathogenic adenomatous polyposis coli (APC) gene variants in patients with familial adenomatous polyposis (FAP), a cancer predisposition syndrome. We hypothesized that certain pathogenic APC variants result in behavioral–cognitive challenges. We compared 66 FAP patients (cases) and 34 unaffected siblings (controls) to explore associations between APC variants and behavioral and cognitive challenges. Our findings indicate that FAP patients exhibited higher Social Responsiveness Scale (SRS) scores, suggesting a greater prevalence of autistic traits when compared to unaffected siblings (mean 53.8 vs. 47.4, Wilcoxon p= 0.018). The distribution of SRS scores in cases suggested a bimodal pattern, potentially linked to the location of the APC variant, with scores increasing from the 5′ to 3′ end of the gene (Pearson's r= 0.33, p= 0.022). While we observed a trend toward lower educational attainment in cases, this difference was not statistically significant. This study is the first to explore the connection between APC variant location and neurodevelopmental traits in FAP, expanding our understanding of the genotype–phenotype correlation. Our results emphasize the importance of clinical assessment for autistic traits in FAP patients, shedding light on the potential role of APCgene variants in these behavioral and cognitive challenges.

This document is a collection of letters from readers of High Country News, a publication dedicated to independent journalism and informed debate. The letters cover a range of topics, including the Goldendale pumped storage project in Washington, the importance of protecting shorebirds and the Great Salt Lake, praise for an essay about prairie dogs, concerns about data centers and their impact on local employment, admiration for an article about an all-female seal-hunting crew, questions about fencing around solar installations, and gratitude for an article that led to the repatriation of Native American remains and funeral objects. The letters provide diverse perspectives and opinions on various issues, offering valuable insights for library patrons conducting research. [Extracted from the article]

•A sample of Arab-Americans reflected on injustice appraisal concerning their chronic low back pain.•Interviews were with respect to the existing Injustice Experience Questionnaire (IEQ).•Arabic culture and Islamic beliefs influenced participants’ interpretation.•Many “universal” concepts in the IEQ may not be interpreted similarly across groups.

Graphical abstract:

To determine if a school‐based physical activity (PA) intervention that supported primary school teachers to schedule PA during school hours impacted their own PA. A 2x2 factorial group cluster‐randomised controlled trial was undertaken in 12 Australian primary schools. The nine‐month intervention supported classroom teachers to increase scheduled weekly PA for their class via physical education, sport, Energisers and integrated lessons. Teachers’ PA (n = 76) was measured at follow‐up only using accelerometers (Actigraph GT3X or GT9X). Linear mixed models were used to estimate between‐group differences in teachers’ mean minutes of sedentary, light, moderate‐to‐vigorous‐intensity physical activity (MVPA) across the school day and during class‐time. At follow‐up, there were non‐significant between‐group differences favouring intervention teachers, compared to controls, for light PA (4.9 minutes, 95% CI: −6.3, 16.0; P= .33) and MVPA (0.4 minutes, 95% CI: −10.9, 11.6; P= .94) across the school day; although not favouring the intervention for sedentary behaviour (5.1 minutes, 95% CI: −11.4, 21.7; P= .48). Similar patterns were seen during class‐time for light PA and sedentary time, but not for MVPA. Supporting teachers with the scheduling of PA for their class may impact on their own PA. Fully powered studies are needed to better understand the impact of the intervention on teachers’ PA. Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12616001228471 (http://www.anzctr.org.au/).

PAN2encodes a subunit of a deadenylation complex with important functions in mRNA stability and post-transcriptional regulation of gene expression. A homozygous frameshift deletion in PAN2was reported in a single affected individual with developmental delay and multiple congenital anomalies. Here, we describe five additional individuals from three unrelated families with homozygous predicted loss-of-function variants in PAN2. The affected individuals presented with significant overlap in their clinical features, including mild-moderate intellectual disability, hypotonia, sensorineural hearing loss, EEG abnormalities, congenital heart defects (tetralogy of Fallot, septal defects, dilated aortic root), urinary tract malformations, ophthalmological anomalies, short stature with other skeletal anomalies, and craniofacial features including flat occiput, ptosis, long philtrum, and short neck. Our data confirm that biallelic predicted loss-of-function variants in PAN2cause a syndrome with multiple congenital anomalies, and suggest an important role of mRNA polyA tail length for proper organ formation.

The optimal management of suspected penile fractures post collagenase clostridium histolyticum (CCH) remains indeterminate, with some advocating for observation and others surgical repair. To address this issue, the current study sent surveys to 158 men with Peyronie’s Disease (PD) who completed four CCH injection series. The survey included the Erectile Function Domain from the International Index of Erectile Function (IIEF-EFD) and questions regarding potential symptoms of corporal rupture (hematoma, popping, and detumescence). Men were categorized as having a suspected fracture (SF+) if they reported a popping sensation or rapid detumescence. All SF(+) men were managed conservatively without surgical intervention. Results were compared statistically against baseline IIEF-EFD values and between SF(+) and SF(−) groups. The key study objective was to determine whether erectile function was negatively impacted by conservative management of suspected fractures. Of the 53 returned surveys, 45 had complete data for review. The sample was statistically representative of the broader cohort of 158 men, except being older (60.0 vs 57.1 [SD 6.0 vs 9.0], p= 0.01) with shorter durations of PD (median 9 [IQR 5, 19] mo vs 13 [IQR 8, 24], p= 0.01). Overall, 7/45 (16%) of men were defined as SF(+), with all fractures occurring within 6 weeks of CCH administration. No demographic or pathophysiologic characteristics predicted SF(+). Importantly, SF(+) men did not experience worsened erectile function compared to SF(−), with a median IIEF-EFD change of +2 vs +1, p= 0.16, respectively. Curvatures were improved to a greater degree among SF(+) men (primary: median −30 [IQR −20, −32.5] vs −15 [−5, −26], p= 0.04; composite: −35 [−25, −40] vs −25 [−7, −30], p= 0.15). We concluded that suspected penile fractures in PD men undergoing CCH may be reasonably managed without surgical intervention and portend greater improvements in curvature correction.

Tandem repeat expansions (TREs) are associated with over 60 monogenic disorders and have recently been implicated in complex disorders such as cancer and autism spectrum disorder. The role of TREs in schizophrenia is now emerging. In this study, we have performed a genome-wide investigation of TREs in schizophrenia. Using genome sequence data from 1154 Swedish schizophrenia cases and 934 ancestry-matched population controls, we have detected genome-wide rare (<0.1% population frequency) TREs that have motifs with a length of 2–20 base pairs. We find that the proportion of individuals carrying rare TREs is significantly higher in the schizophrenia group. There is a significantly higher burden of rare TREs in schizophrenia cases than in controls in genic regions, particularly in postsynaptic genes, in genes overlapping brain expression quantitative trait loci, and in brain-expressed genes that are differentially expressed between schizophrenia cases and controls. We demonstrate that TRE-associated genes are more constrained and primarily impact synaptic and neuronal signaling functions. These results have been replicated in an independent Canadian sample that consisted of 252 schizophrenia cases of European ancestry and 222 ancestry-matched controls. Our results support the involvement of rare TREs in schizophrenia etiology.