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The spectral content of macroscopic neural activity evolves throughout development, yet how this maturation relates to underlying brain network formation and dynamics remains unknown. Here, we assess the developmental maturation of electroencephalogram spectra via Bayesian model inversion of the spectral graph model, a parsimonious whole-brain model of spatiospectral neural activity derived from linearized neural field models coupled by the structural connectome. Simulation-based inference was used to estimate age-varying spectral graph model parameter posterior distributions from electroencephalogram spectra spanning the developmental period. This model-fitting approach accurately captures observed developmental electroencephalogram spectral maturation via a neurobiologically consistent progression of key neural parameters: long-range coupling, axonal conduction speed, and excitatory:inhibitory balance. These results suggest that the spectral maturation of macroscopic neural activity observed during typical development is supported by age-dependent functional adaptations in localized neural dynamics and their long-range coupling across the macroscopic structural network.

BackgroundAlzheimer's disease (AD) is the most common form of dementia, progressively impairing cognitive abilities. While neuroimaging studies have revealed functional abnormalities in AD, how these relate to aberrant neuronal circuit mechanisms remains unclear. Using magnetoencephalography imaging we documented abnormal local neural synchrony patterns in patients with AD. To identify global abnormal biophysical mechanisms underlying the spatial and spectral electrophysiological patterns in AD, we estimated the parameters of a biophysical spectral graph model (SGM).MethodsSGM is an analytic neural mass model that describes how long-range fiber projections in the brain mediate the excitatory and inhibitory activity of local neuronal subpopulations. Unlike other coupled neuronal mass models, the SGM is linear, available in closed-form, and parameterized by a small set of biophysical interpretable global parameters. This facilitates their rapid and unambiguous inference which we performed here on a well-characterized clinical population of patients with AD (N = 88, age = 62.73 +/- 8.64 years) and a cohort of age-matched controls (N = 88, age = 65.07 +/- 9.92 years).ResultsPatients with AD showed significantly elevated long-range excitatory neuronal time scales, local excitatory neuronal time scales and local inhibitory neural synaptic strength. The long-range excitatory time scale had a larger effect size, compared to local excitatory time scale and inhibitory synaptic strength and contributed highest for the accurate classification of patients with AD from controls. Furthermore, increased long-range time scale was associated with greater deficits in global cognition.ConclusionsThese results demonstrate that long-range excitatory time scale of neuronal activity, despite being a global measure, is a key determinant in the local spectral signatures and cognition in the human brain, and how it might be a parsimonious factor underlying altered neuronal activity in AD. Our findings provide new insights into mechanistic links between abnormal local spectral signatures and global connectivity measures in AD.

Sleep is a highly stereotyped phenomenon, requiring robust spatiotemporal coordination of neural activity. Understanding how the brain coordinates neural activity with sleep onset can provide insights into the physiological functions subserved by sleep and the pathologic phenomena associated with sleep onset. We quantified whole-brain network changes in synchrony and information flow during the transition from wakefulness to light non-rapid eye movement (NREM) sleep, using MEG imaging in a convenient sample of 14 healthy human participants (11 female; mean 63.4 years [SD 11.8 years]). We furthermore performed computational modeling to infer excitatory and inhibitory properties of local neural activity. The transition from wakefulness to light NREM was identified to be encoded in spatially and temporally specific patterns of long-range synchrony. Within the delta band, there was a global increase in connectivity from wakefulness to light NREM, which was highest in frontoparietal regions. Within the theta band, there was an increase in connectivity in fronto-parieto-occipital regions and a decrease in temporal regions from wakefulness to Stage 1 sleep. Patterns of information flow revealed that mesial frontal regions receive hierarchically organized inputs from broad cortical regions upon sleep onset, including direct inflow from occipital regions and indirect inflow via parieto-temporal regions within the delta frequency band. Finally, biophysical neural mass modeling demonstrated changes in the anterior-to-posterior distribution of cortical excitation-to-inhibition with increased excitation-to-inhibition model parameters in anterior regions in light NREM compared with wakefulness. Together, these findings uncover whole-brain corticocortical structure and the orchestration of local and long-range, frequency-specific cortical interactions in the sleep-wake transition.SIGNIFICANCE STATEMENT Our work uncovers spatiotemporal cortical structure of neural synchrony and information flow upon the transition from wakefulness to light non-rapid eye movement sleep. Mesial frontal regions were identified to receive hierarchically organized inputs from broad cortical regions, including both direct inputs from occipital regions and indirect inputs via the parieto-temporal regions within the delta frequency range. Biophysical neural mass modeling revealed a spatially heterogeneous, anterior-posterior distribution of cortical excitation-to-inhibition. Our findings shed light on the orchestration of local and long-range cortical neural structure that is fundamental to sleep onset, and support an emerging view of cortically driven regulation of sleep homeostasis.

Pancreatic islets consist of multiple cell types that produce hormones required for glucose homeostasis, and islet dysfunction is a major factor in type 1 and type 2 diabetes. Numerous studies have assessed transcription across individual cell types using single-cell assays; however, there is no canonical reference of gene expression in islet cell types that is also easily accessible for researchers to query and use in bioinformatics pipelines. Here we present an integrated map of islet cell type-specific gene expression from 192,203 cells from single-cell RNA sequencing of 65 donors without diabetes, donors who were type 1 diabetes autoantibody positive, donors with type 1 diabetes, and donors with type 2 diabetes from the Human Pancreas Analysis Program. We identified 10 distinct cell types, annotated subpopulations of several cell types, and defined cell type-specific marker genes. We tested differential expression within each cell type across disease states and identified 1,701 genes with significant changes in expression, with most changes observed in β-cells from donors with type 1 diabetes. To facilitate user interaction, we provide several single-cell visualization and reference mapping tools, as well as the open-access analytical pipelines used to create this reference. The results will serve as a valuable resource to investigators studying islet biology.Article highlights

The relationship between brain functional connectivity and structural connectivity has caught extensive attention of the neuroscience community, commonly inferred using mathematical modeling. Among many modeling approaches, spectral graph model (SGM) is distinctive as it has a closed-form solution of the wide-band frequency spectra of brain oscillations, requiring only global biophysically interpretable parameters. While SGM is parsimonious in parameters, the determination of SGM parameters is non-trivial. Prior works on SGM determine the parameters through a computational intensive annealing algorithm, which only provides a point estimate with no confidence intervals for parameter estimates. To fill this gap, we incorporate the simulation-based inference (SBI) algorithm and develop a Bayesian procedure for inferring the posterior distribution of the SGM parameters. Furthermore, using SBI dramatically reduces the computational burden for inferring the SGM parameters. We evaluate the proposed SBI-SGM framework on the resting-state magnetoencephalography recordings from healthy subjects and show that the proposed procedure has similar performance to the annealing algorithm in recovering power spectra and the spatial distribution of the alpha frequency band. In addition, we also analyze the correlations among the parameters and their uncertainty with the posterior distribution which cannot be done with annealing inference. These analyses provide a richer understanding of the interactions among biophysical parameters of the SGM. In general, the use of simulation-based Bayesian inference enables robust and efficient computations of generative model parameter uncertainties and may pave the way for the use of generative models in clinical translation applications.

Growth faltering in children (low length for age or low weight for length) during the first 1,000 days of life (from conception to 2 years of age) influences short-term and long-term health and survival1,2. Interventions such as nutritional supplementation during pregnancy and the postnatal period could help prevent growth faltering, but programmatic action has been insufficient to eliminate the high burden of stunting and wasting in low- and middle-income countries. Identification of age windows and population subgroups on which to focus will benefit future preventive efforts. Here we use a population intervention effects analysis of 33 longitudinal cohorts (83,671 children, 662,763 measurements) and 30 separate exposures to show that improving maternal anthropometry and child condition at birth accounted for population increases in length-for-age z-scores of up to 0.40 and weight-for-length z-scores of up to 0.15 by 24 months of age. Boys had consistently higher risk of all forms of growth faltering than girls. Early postnatal growth faltering predisposed children to subsequent and persistent growth faltering. Children with multiple growth deficits exhibited higher mortality rates from birth to 2 years of age than children without growth deficits (hazard ratios 1.9 to 8.7). The importance of prenatal causes and severe consequences for children who experienced early growth faltering support a focus on pre-conception and pregnancy as a key opportunity for new preventive interventions.

Sustainable Development Goal 2.2-to end malnutrition by 2030-includes the elimination of child wasting, defined as a weight-for-length z-score that is more than two standard deviations below the median of the World Health Organization standards for child growth1. Prevailing methods to measure wasting rely on cross-sectional surveys that cannot measure onset, recovery and persistence-key features that inform preventive interventions and estimates of disease burden. Here we analyse 21 longitudinal cohorts and show that wasting is a highly dynamic process of onset and recovery, with incidence peaking between birth and 3 months. Many more children experience an episode of wasting at some point during their first 24 months than prevalent cases at a single point in time suggest. For example, at the age of 24 months, 5.6% of children were wasted, but by the same age (24 months), 29.2% of children had experienced at least one wasting episode and 10.0% had experienced two or more episodes. Children who were wasted before the age of 6 months had a faster recovery and shorter episodes than did children who were wasted at older ages; however, early wasting increased the risk of later growth faltering, including concurrent wasting and stunting (low length-for-age z-score), and thus increased the risk of mortality. In diverse populations with high seasonal rainfall, the population average weight-for-length z-score varied substantially (more than 0.5 z in some cohorts), with the lowest mean z-scores occurring during the rainiest months; this indicates that seasonally targeted interventions could be considered. Our results show the importance of establishing interventions to prevent wasting from birth to the age of 6 months, probably through improved maternal nutrition, to complement current programmes that focus on children aged 6-59 months.

Globally, 149 million children under 5 years of age are estimated to be stunted (length more than 2 standard deviations below international growth standards)1,2. Stunting, a form of linear growth faltering, increases the risk of illness, impaired cognitive development and mortality. Global stunting estimates rely on cross-sectional surveys, which cannot provide direct information about the timing of onset or persistence of growth faltering-a key consideration for defining critical windows to deliver preventive interventions. Here we completed a pooled analysis of longitudinal studies in low- and middle-income countries (n = 32 cohorts, 52,640 children, ages 0-24 months), allowing us to identify the typical age of onset of linear growth faltering and to investigate recurrent faltering in early life. The highest incidence of stunting onset occurred from birth to the age of 3 months, with substantially higher stunting at birth in South Asia. From 0 to 15 months, stunting reversal was rare; children who reversed their stunting status frequently relapsed, and relapse rates were substantially higher among children born stunted. Early onset and low reversal rates suggest that improving children's linear growth will require life course interventions for women of childbearing age and a greater emphasis on interventions for children under 6 months of age.

To address the challenge of translating genetic discoveries for type 1 diabetes (T1D) into mechanistic insight, we have developed the T1D Knowledge Portal (T1DKP), an open-access resource for hypothesis development and target discovery in T1D.

BACKGROUND: Many women experience suboptimal gestational weight gain (GWG) in low- and middle-income countries (LMICs), but our understanding of risk factors associated with GWG in these settings is limited. We investigated the relationships between demographic, anthropometric, lifestyle, and clinical factors and GWG in prospectively collected data from LMICs. METHODS AND FINDINGS: We conducted an individual participant-level meta-analysis of risk factors for GWG outcomes among 138,286 pregnant women with singleton pregnancies in 55 studies (27 randomized controlled trials and 28 prospective cohorts from 25 LMICs). Data sources were identified through PubMed, Embase, and Web of Science searches for articles published from January 2000 to March 2019. Titles and abstracts of articles identified in all databases were independently screened by 2 team members according to the following eligibility criteria: following inclusion criteria: (1) GWG data collection took place in an LMIC; (2) the study was a prospective cohort or randomized trial; (3) study participants were pregnant; and (4) the study was not conducted exclusively among human immunodeficiency virus (HIV)-infected women or women with other health conditions that could limit the generalizability of the results. The Institute of Medicine (IOM) body mass index (BMI)-specific guidelines were used to determine the adequacy of GWG, which we calculated as the ratio of the total observed weight gain over the mean recommended weight gain. Study outcomes included severely inadequate GWG (percent adequacy of GWG 125). Multivariable estimates from each study were pooled using fixed-effects meta-analysis. Study-specific regression models for each risk factor included all other demographic risk factors measured in a particular study as potential confounders, as well as BMI, maternal height, pre-pregnancy smoking, and chronic hypertension. Risk factors occurring during pregnancy were further adjusted for receipt of study intervention (if any) and 3-month calendar period. The INTERGROWTH-21st standard was used to define high and low GWG among normal weight women in a sensitivity analysis. The prevalence of inadequate GWG was 54%, while the prevalence of excessive weight gain was 22%. In multivariable models, factors that were associated with a higher risk of inadequate GWG included short maternal stature (

Meta-analyses consistently have found that antenatal multiple micronutrient supplementation (MMS) compared with iron and folic acid (IFA) alone reduce adverse birth outcomes. In 2020, the World Health Organization (WHO) placed a conditional recommendation for MMS and requested additional trials using ultrasounds to establish gestational age, because the evidence on low birthweight (LBW), preterm birth and small for gestational age (SGA) was considered inconsistent. We conducted meta-analyses to determine if the effects of MMS on LBW, preterm birth and SGA differed by gestational age assessment method. Using data from the 16 trials in the WHO analyses, we calculated the effect estimates of MMS versus IFA on birth outcomes (generic inverse variance method and random effects model) stratified by method of gestational age assessment: ultrasound, prospective collection of the date of last menstrual period (LMP) and confirmation of pregnancy by urine test and recall of LMP. The effects of MMS versus IFA on birthweight, preterm birth and SGA appeared consistent across subgroups with no evidence of subgroup differences (p > 0.05). When limited to the seven trials that used ultrasound, the beneficial effects of MMS were demonstrated: risk ratios of 0.87 (95% confidence interval [CI] 0.78-0.97) for LBW, 0.90 (95% CI, 0.79-1.03) for preterm birth and 0.9 (95% CI, 0.83-0.99) for SGA. Sensitivity analyses indicated consistency in the results. These results, together with recent analyses demonstrating comparable effects of MMS (vs. IFA) on maternal anaemia outcomes, strengthen the evidence to support a transition from IFA to MMS programmes in low- and middle-income countries.

The Gene Ontology (GO) knowledgebase (http://geneontology.org) is a comprehensive resource concerning the functions of genes and gene products (proteins and noncoding RNAs). GO annotations cover genes from organisms across the tree of life as well as viruses, though most gene function knowledge currently derives from experiments carried out in a relatively small number of model organisms. Here, we provide an updated overview of the GO knowledgebase, as well as the efforts of the broad, international consortium of scientists that develops, maintains, and updates the GO knowledgebase. The GO knowledgebase consists of three components: (1) the GO-a computational knowledge structure describing the functional characteristics of genes; (2) GO annotations-evidence-supported statements asserting that a specific gene product has a particular functional characteristic; and (3) GO Causal Activity Models (GO-CAMs)-mechanistic models of molecular "pathways" (GO biological processes) created by linking multiple GO annotations using defined relations. Each of these components is continually expanded, revised, and updated in response to newly published discoveries and receives extensive QA checks, reviews, and user feedback. For each of these components, we provide a description of the current contents, recent developments to keep the knowledgebase up to date with new discoveries, and guidance on how users can best make use of the data that we provide. We conclude with future directions for the project.

The lack of multi-omics cancer datasets with extensive follow-up information hinders the identification of accurate biomarkers of clinical outcome. In this cohort study, we performed comprehensive genomic analyses on fresh-frozen samples from 348 patients affected by primary colon cancer, encompassing RNA, whole-exome, deep T cell receptor and 16S bacterial rRNA gene sequencing on tumor and matched healthy colon tissue, complemented with tumor whole-genome sequencing for further microbiome characterization. A type 1 helper T cell, cytotoxic, gene expression signature, called Immunologic Constant of Rejection, captured the presence of clonally expanded, tumor-enriched T cell clones and outperformed conventional prognostic molecular biomarkers, such as the consensus molecular subtype and the microsatellite instability classifications. Quantification of genetic immunoediting, defined as a lower number of neoantigens than expected, further refined its prognostic value. We identified a microbiome signature, driven by Ruminococcus bromii, associated with a favorable outcome. By combining microbiome signature and Immunologic Constant of Rejection, we developed and validated a composite score (mICRoScore), which identifies a group of patients with excellent survival probability. The publicly available multi-omics dataset provides a resource for better understanding colon cancer biology that could facilitate the discovery of personalized therapeutic approaches.

PURPOSE: Adults with high-grade glioma (HGG), WHO grade III or IV, have substantial palliative care needs. Our aim was to determine occurrence, timing, and factors associated with palliative care consultation (PCC) in HGG at one large academic institution. METHODS: HGG patients receiving care between 08/1/2011 and 01/23/2020 were identified retrospectively from a multi-center healthcare system cancer registry. Patients were stratified by any PCC (yes/no), and timing of initial PCC by disease phase: diagnosis (before radiation), during initial treatment (first-line chemotherapy/radiation), second-line treatment(s), or end-of-life (after last chemotherapy). RESULTS: Of 621 HGG patients, 134 (21.58%) received PCC with the vast majority occurring during hospital admission [111 (82.84%)]. Of the 134, 14 (10.45%) were referred during the diagnostic phase; 35 (26.12%) during initial treatment; 20 (14.93%) during second-line treatment; and 65 (48.51%) during end of life. In multivariable logistic regression, only higher Charlson Comorbidity Index was associated with greater odds of PCC [OR 1.3 (95% CI 1.2-1.4), p

With the increasing prevalence of Alzheimer's disease (AD) among aging populations and the limited therapeutic options available to slow or reverse its progression, the need has never been greater for improved diagnostic tools for identifying patients in the preclinical and prodomal phases of AD. Biophysics models of the connectome-based spread of amyloid-beta (Aβ) and microtubule-associated protein tau (τ) have enjoyed recent success as tools for predicting the time course of AD-related pathological changes. However, given the complex etiology of AD, which involves not only connectome-based spread of protein pathology but also the interactions of many molecular and cellular players over multiple spatiotemporal scales, more robust, complete biophysics models are needed to better understand AD pathophysiology and ultimately provide accurate patient-specific diagnoses and prognoses. Here we discuss several areas of active research in AD whose insights can be used to enhance the mathematical modeling of AD pathology as well as recent attempts at developing improved connectome-based biophysics models. These efforts toward a comprehensive yet parsimonious mathematical description of AD hold great promise for improving both the diagnosis of patients at risk for AD and our mechanistic understanding of how AD progresses.

Human milk is the ideal source of nutrition for most infants, but significant gaps remain in our understanding of human milk biology. As part of addressing these gaps, the Breastmilk Ecology: Genesis of Infant Nutrition (BEGIN) Project Working Groups 1-4 interrogated the state of knowledge regarding the infant-human milk-lactating parent triad. However, to optimize the impact of newly generated knowledge across all stages of human milk research, the need remained for a translational research framework specific to the field. Thus, with inspiration from the simplified environmental sciences framework of Kaufman and Curl, Working Group 5 of the BEGIN Project developed a translational framework for science in human lactation and infant feeding, which includes 5 nonlinear, interconnected translational stages, T1: Discovery; T2: Human health implications; T3: Clinical and public health implications; T4: Implementation; and T5: Impact. The framework is accompanied by 6 overarching principles: 1) Research spans the translational continuum in a nonlinear, nonhierarchical manner; 2) Projects engage interdisciplinary teams in continuous collaboration and cross talk; 3) Priorities and study designs incorporate a diverse range of contextual factors; 4) Research teams include community stakeholders from the outset through purposeful, ethical, and equitable engagement; 5) Research designs and conceptual models incorporate respectful care for the birthing parent and address implications for the lactating parent; 6) Research implications for real-world settings account for contextual factors surrounding the feeding of human milk, including exclusivity and mode of feeding. To demonstrate application of the presented translational research framework and its overarching principles, 6 case studies are included, each illustrating research gaps across all stages of the framework. Applying a translational framework approach to addressing gaps in the science of human milk feeding is an important step toward the aligned goals of optimizing infant feeding across diverse contexts as well as optimizing health for all.

Associations between human genetic variation and clinical phenotypes have become a foundation of biomedical research. Most repositories of these data seek to be disease-agnostic and therefore lack disease-focused views. The Type 2 Diabetes Knowledge Portal (T2DKP) is a public resource of genetic datasets and genomic annotations dedicated to type 2 diabetes (T2D) and related traits. Here, we seek to make the T2DKP more accessible to prospective users and more useful to existing users. First, we evaluate the T2DKP's comprehensiveness by comparing its datasets with those of other repositories. Second, we describe how researchers unfamiliar with human genetic data can begin using and correctly interpreting them via the T2DKP. Third, we describe how existing users can extend their current workflows to use the full suite of tools offered by the T2DKP. We finally discuss the lessons offered by the T2DKP toward the goal of democratizing access to complex disease genetic results.

We demonstrate the possibility to tune the saturation magnetization, coercivity, and uniaxial in-plane anisotropy constant in amorphous bilayers and multilayers of Co85 (Al70Zr30)15 and Sm11Co82Ti7 through the interface density. From magnetometry and x-ray circular dichroism (XMCD) measurements, we conclude that the easy-axis coercivity μ0 Hc increases four times when the number of bilayer repetitions, N, increases from 1 to 10 within a constant total sample thickness of 20 nm. At the same time, the anisotropy constant Ku also increases by a factor four, whereas the saturation magnetization Ms decreases slightly. The Co spin and orbital moments, ms and ml, are found to be approximately constant within the sample series. The average total Co moment is only 0.8-0.9 μB/atom, but the ml/ms ratio is strongly enhanced compared to pure Co. Magnetization curves extracted from XMCD measurements show that the Co and Sm moments are ferromagnetically coupled for all samples.

BackgroundChildren in rural communities often lack access to subspecialty medical care. Telemedicine has the potential to improve access to these services but its effectiveness has not been rigorously evaluated for paediatric patients with endocrine conditions besides diabetes.IntroductionThe purpose of this study was to assess the association between telemedicine and visit attendance among patients who received care from paediatric endocrinologists at an academic medical centre in northern California between 2009-2017.MethodsWe abstracted demographic data, encounter information and medical diagnoses from the electronic health record for patients ≤18 years of age who attended at least one in-person or telemedicine encounter with a paediatric endocrinologist during the study period. We used a mixed effects logistic regression model - adjusted for age, diagnosis and distance from subspecialty care - to explore the association between telemedicine and visit attendance.ResultsA total of 40,941 encounters from 5083 unique patients were included in the analysis. Patients who scheduled telemedicine visits were predominantly publicly insured (97%) and lived a mean distance of 161 miles from the children's hospital. Telemedicine was associated with a significantly higher odds of visit attendance (odds ratio 2.55, 95% confidence interval 2.15-3.02, p

ImportancePediatric referral centers are increasingly using telemedicine to provide consultations to help care for acutely ill children presenting to rural and community emergency departments (EDs). These pediatric telemedicine consultations may help improve physician decision-making and may reduce the frequency of overtriage and interfacility transfers.ObjectiveTo examine the use of pediatric critical care telemedicine vs telephone consultations associated with risk-adjusted transfer rates of acutely ill children from community and rural EDs.Design, setting, and participantsA cluster-randomized crossover trial was conducted between November 18, 2015, and March 26, 2018. Analyses were conducted from January 19, 2018, to July 23, 2022, 2022. Participants included acutely ill children aged 14 years and younger presenting to a participating ED in 15 rural and community EDs in northern California.InterventionsParticipating EDs were randomized to use telemedicine or telephone for consultations with pediatric critical care physicians according to 1 of 4 unbalanced (3 telemedicine:1 telephone) crossover treatment assignment sequences.Main outcomes and measuresIntention-to-treat, treatment-received, and per-protocol analyses were performed to determine the risk of transfer using mixed effects Poisson regression analyses with random intercepts for presenting EDs to account for hospital-level clustering.ResultsA total of 696 children (392 boys [56.3%]; mean [SD] age, 4.2 [4.6] years) were enrolled. Of the 537 children (77.2%) assigned to telemedicine, 251 (46.7%) received the intervention. In the intention-to-treat analysis, patients assigned to the telemedicine arm were less likely to be transferred compared with patients assigned to the telephone arm after adjusting for patient age, severity of illness, and hospital study period (risk rate [RR], 0.93; 95% CI, 0.88-0.99). The adjusted risk of transfer was significantly lower in the telemedicine arm compared with the telephone arm in both the treatment-received analysis (RR, 0.81; 95% CI, 0.71-0.94) and the per-protocol analysis (RR, 0.79; 95% CI, 0.68-0.92).Conclusions and relevanceIn this randomized trial, the use of telemedicine to conduct consultations for acutely ill children in rural and community EDs resulted in less frequent overall interfacility transfers than consultations done by telephone.Trial registrationClinicalTrials.gov Identifier: NCT02877810.

Background & aimsSrc homology and collagen (Shc) proteins are major adapters to extracellular signals, however, the regulatory role of Shc isoforms in sterile inflammatory responses in alcoholic hepatitis (AH) has not been fully investigated. We hypothesized that in an isoform-specific manner Shc modulates pre-apoptotic signals, calreticulin (CRT) membrane exposure, and recruitment of inflammatory cells.MethodsLiver biopsy samples from patients with AH vs healthy subjects were studied for Shc expression using DNA microarray data and immunohistochemistry. Shc knockdown (hypomorph) and age-matched wild-type mice were pair-fed according to the chronic-plus-binge alcohol diet. To analyze hepatocyte-specific effects, adeno-associated virus 8-thyroxine binding globulin-Cre (hepatocyte-specific Shc knockout)-mediated deletion was performed in flox/flox Shc mice. Lipid peroxidation, proinflammatory signals, redox radicals, reduced nicotinamide adenine dinucleotide/oxidized nicotinamide adenine dinucleotide ratio, as well as cleaved caspase 8, B-cell-receptor-associated protein 31 (BAP31), Bcl-2-associated X protein (Bax), and Bcl-2 homologous antagonist killer (Bak), were assessed in vivo. CRT translocation was studied in ethanol-exposed p46ShcẟSH2-transfected hepatocytes by membrane biotinylation in conjunction with phosphorylated-eukaryotic initiation factor 2 alpha, BAP31, caspase 8, and Bax/Bak. The effects of idebenone, a novel Shc inhibitor, was studied in alcohol/pair-fed mice.ResultsShc was significantly induced in patients with AH (P < .01). Alanine aminotransferase, reduced nicotinamide adenine dinucleotide/oxidized nicotinamide adenine dinucleotide ratios, production of redox radicals, and lipid peroxidation improved (P < .05), and interleukin 1β, monocyte chemoattractant protein 1, and C-X-C chemokine ligand 10 were reduced in Shc knockdown and hepatocyte-specific Shc knockout mice. In vivo, Shc-dependent induction, and, in hepatocytes, a p46Shc-dependent increase in pre-apoptotic proteins Bax/Bak, caspase 8, BAP31 cleavage, and membrane translocation of CRT/endoplasmic reticulum-resident protein 57 were seen. Idebenone protected against alcohol-mediated liver injury.ConclusionsAlcohol induces p46Shc-dependent activation of pre-apoptotic pathways and translocation of CRT to the membrane, where it acts as a damage-associated molecular pattern, instigating immunogenicity. Shc inhibition could be a novel treatment strategy in AH.

We explore the stability and dynamic properties of a hierarchical, linearized, and analytic spectral graph model for neural oscillations that integrates the structural wiring of the brain. Previously, we have shown that this model can accurately capture the frequency spectra and the spatial patterns of the alpha and beta frequency bands obtained from magnetoencephalography recordings without regionally varying parameters. Here, we show that this macroscopic model based on long-range excitatory connections exhibits dynamic oscillations with a frequency in the alpha band even without any oscillations implemented at the mesoscopic level. We show that depending on the parameters, the model can exhibit combinations of damped oscillations, limit cycles, or unstable oscillations. We determined bounds on model parameters that ensure stability of the oscillations simulated by the model. Finally, we estimated time-varying model parameters to capture the temporal fluctuations in magnetoencephalography activity. We show that a dynamic spectral graph modeling framework with a parsimonious set of biophysically interpretable model parameters can thereby be employed to capture oscillatory fluctuations observed in electrophysiological data in various brain states and diseases.

BACKGROUND: Gestational weight gain (GWG) below or above the Institute of Medicine (IOM) recommendations has been associated with adverse perinatal outcomes. Few studies have examined the effect of prenatal nutrient supplementations on GWG in low- and middle-income countries (LMICs). OBJECTIVES: We aimed to investigate the effects of multiple micronutrient supplements (MMSs) and small-quantity lipid-based nutrient supplements (LNSs) on GWG in LMICs. METHODS: A 2-stage meta-analysis of individual participant data was conducted to examine the effects of MMSs (45,507 women from 14 trials) and small-quantity LNSs (6237 women from 4 trials) on GWG compared with iron and folic acid supplements only. Percentage adequacy of GWG and total weight gain at delivery were calculated according to the IOM 2009 guidelines. Binary outcomes included severely inadequate (percentage adequacy 125%) GWG. Results from individual trials were pooled using fixed-effects inverse-variance models. Heterogeneity was examined using I2, stratified analysis, and meta-regression. RESULTS: MMSs resulted in a greater percentage adequacy of GWG [weighted mean difference (WMD): 0.86%; 95% CI: 0.28%, 1.44%; P

BackgroundMeta-analyses show that small-quantity lipid-based nutrient supplements (SQ-LNSs) reduce child wasting and stunting. There is little information regarding effects on severe wasting or stunting.ObjectivesWe aimed to identify the effect of SQ-LNSs on prevalence of severe wasting (weight-for-length z score < -3) and severe stunting (length-for-age z score < -3).MethodsWe conducted a 2-stage meta-analysis of individual participant data from 14 randomized controlled trials of SQ-LNSs provided to children 6-24 mo of age. We generated study-specific and subgroup estimates of SQ-LNS compared with control and pooled the estimates using fixed-effects models. We used random-effects meta-regression to examine study-level effect modifiers. In sensitivity analyses, we examined whether results differed depending on study arm inclusion criteria and types of comparisons.ResultsSQ-LNS provision led to a relative reduction of 31% in severe wasting [prevalence ratio (PR): 0.69; 95% CI: 0.55, 0.86; n = 34,373] and 17% in severe stunting (PR: 0.83; 95% CI: 0.78, 0.90; n = 36,795) at endline. Results were similar in most of the sensitivity analyses but somewhat attenuated when comparisons using passive control arms were excluded (PR: 0.74; 95% CI: 0.57, 0.96; n = 26,327 for severe wasting and PR: 0.88; 95% CI: 0.81, 0.95; n = 28,742 for severe stunting). Study-level characteristics generally did not significantly modify the effects of SQ-LNSs, but results suggested greater effects of SQ-LNSs in sites with greater burdens of wasting or stunting, or with poorer water quality or sanitation.ConclusionsIncluding SQ-LNSs in preventive interventions to promote healthy child growth and development is likely to reduce rates of severe wasting and stunting. This meta-analysis was registered at www.crd.york.ac.uk/PROSPERO as CRD42019146592.

BackgroundPreventing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2_ infections in healthcare workers (HCWs) is critical for healthcare delivery. We aimed to estimate and characterize the prevalence and incidence of coronavirus disease 2019 (COVID-19) in a US HCW cohort and to identify risk factors associated with infection.MethodsWe conducted a longitudinal cohort study of HCWs at 3 Bay Area medical centers using serial surveys and SARS-CoV-2 viral and orthogonal serological testing, including measurement of neutralizing antibodies. We estimated baseline prevalence and cumulative incidence of COVID-19. We performed multivariable Cox proportional hazards models to estimate associations of baseline factors with incident infections and evaluated the impact of time-varying exposures on time to COVID-19 using marginal structural models.ResultsA total of 2435 HCWs contributed 768 person-years of follow-up time. We identified 21 of 2435 individuals with prevalent infection, resulting in a baseline prevalence of 0.86% (95% confidence interval [CI], .53%-1.32%). We identified 70 of 2414 incident infections (2.9%), yielding a cumulative incidence rate of 9.11 cases per 100 person-years (95% CI, 7.11-11.52). Community contact with a known COVID-19 case was most strongly correlated with increased hazard for infection (hazard ratio, 8.1 [95% CI, 3.8-17.5]). High-risk work-related exposures (ie, breach in protective measures) drove an association between work exposure and infection (hazard ratio, 2.5 [95% CI, 1.3-4.8). More cases were identified in HCWs when community case rates were high.ConclusionsWe observed modest COVID-19 incidence despite consistent exposure at work. Community contact was strongly associated with infections, but contact at work was not unless accompanied by high-risk exposure.

Early detection of cancer will improve survival rates. The blood biomarker 5-hydroxymethylcytosine has been shown to discriminate cancer. In a large covariate-controlled study of over two thousand individual blood samples, we created, tested and explored the properties of a 5-hydroxymethylcytosine-based classifier to detect colorectal cancer (CRC). In an independent validation sample set, the classifier discriminated CRC samples from controls with an area under the receiver operating characteristic curve (AUC) of 90% (95% CI [87, 93]). Sensitivity was 55% at 95% specificity. Performance was similar for early stage 1 (AUC 89%; 95% CI [83, 94]) and late stage 4 CRC (AUC 94%; 95% CI [89, 98]). The classifier could detect CRC even when the proportion of tumor DNA in blood was undetectable by other methods. Expanding the classifier to include information about cell-free DNA fragment size and abundance across the genome led to gains in sensitivity (63% at 95% specificity), with similar overall performance (AUC 91%; 95% CI [89, 94]). We confirm that 5-hydroxymethylcytosine can be used to detect CRC, even in early-stage disease. Therefore, the inclusion of 5-hydroxymethylcytosine in multianalyte testing could improve sensitivity for the detection of early-stage cancer.

AimTo characterize cabotegravir population pharmacokinetics using data from phase 1, 2 and 3 studies and evaluate the association of intrinsic and extrinsic factors with pharmacokinetic variability.MethodsAnalyses were implemented in NONMEM and R. Concentrations below the quantitation limit were modelled with likelihood-based approaches. Covariate relationships were evaluated using forward addition (P

ObjectiveAntenatal multiple micronutrient supplements (MMS) are a cost-effective intervention to reduce adverse pregnancy and birth outcomes. However, the current WHO recommendation on the use of antenatal MMS is conditional, partly due to concerns about the effect on neonatal mortality in a subgroup of studies comparing MMS with iron and folic acid supplements (IFA) containing 60 mg of iron. We aimed to assess the effect of MMS vs IFA on neonatal mortality stratified by iron dose in each supplement.MethodsWe updated the neonatal mortality analysis of the 2020 WHO guidelines using the generic inverse variance method and applied the random effects model to calculate the effect estimates of MMS vs. IFA on neonatal mortality in subgroups of trials (n=13) providing the same or different amounts of iron, i.e. MMS with 60 mg of iron vs IFA with 60 mg of iron; MMS with 30 mg of iron vs IFA with 30 mg of iron; MMS with 30 mg of iron vs IFA with 60 mg of iron; and MMS with 20 mg of iron vs IFA with 60 mg of iron.ResultsThere were no statistically significant differences in neonatal mortality between MMS and IFA within any of the subgroups of trials. Analysis of MMS with 30 mg vs IFA with 60 mg of iron (7 trials, 14,114 participants), yielded a nonsignificant Risk Ratio (RR) of 1.12 (95% CI 0.83 to 1.50).ConclusionNeonatal mortality did not differ between MMS and IFA regardless of iron dose in either supplement.

Antenatal multiple micronutrient supplements (MMS) are more effective than iron and folic acid (IFA) supplements in reducing adverse pregnancy outcomes. Questions remain, however, about the ability of MMS to prevent anemia as effectively as IFA, especially at a lower dose of daily iron and in areas of high anemia prevalence. Analyzing data from 11 trials from a recent Cochrane review, we compared MMS to IFA, delivering either 30 or 60 mg of iron, in sustaining hemoglobin and preventing third trimester anemia and iron deficiency anemia (IDA), accounting for daily iron dose, total supplemental iron intake, and baseline prevalence of anemia. There were no differences between MMS and IFA in third trimester hemoglobin concentration or risks of anemia or IDA by iron dose or total supplemental iron consumed. MMS providing 30 mg of iron was comparable to IFA with 60 mg of iron: mean hemoglobin difference of -0.26 g/L (95% CI: -1.41 to 0.89), risk ratios of 0.99 (95% CI: 0.92-1.07) for anemia, and 1.31 (95% CI: 0.66-2.60) for IDA. Baseline prevalence of anemia did not explain heterogeneity in findings. Compared to IFA, MMS results in comparable hemoglobin concentration and protection against anemia during pregnancy, independently of iron dose.

Mathematical modeling of the relationship between the functional activity and the structural wiring of the brain has largely been undertaken using non-linear and biophysically detailed mathematical models with regionally varying parameters. While this approach provides us a rich repertoire of multistable dynamics that can be displayed by the brain, it is computationally demanding. Moreover, although neuronal dynamics at the microscopic level are nonlinear and chaotic, it is unclear if such detailed nonlinear models are required to capture the emergent meso-(regional population ensemble) and macro-scale (whole brain) behavior, which is largely deterministic and reproducible across individuals. Indeed, recent modeling effort based on spectral graph theory has shown that an analytical model without regionally varying parameters and without multistable dynamics can capture the empirical magnetoencephalography frequency spectra and the spatial patterns of the alpha and beta frequency bands accurately. In this work, we demonstrate an improved hierarchical, linearized, and analytic spectral graph theory-based model that can capture the frequency spectra obtained from magnetoencephalography recordings of resting healthy subjects. We reformulated the spectral graph theory model in line with classical neural mass models, therefore providing more biologically interpretable parameters, especially at the local scale. We demonstrated that this model performs better than the original model when comparing the spectral correlation of modeled frequency spectra and that obtained from the magnetoencephalography recordings. This model also performs equally well in predicting the spatial patterns of the empirical alpha and beta frequency bands.

Ralstonia solanacearum species complex (RSSC) strains are bacteria that colonize plant xylem tissue and cause vascular wilt diseases. However, individual strains vary in host range, optimal disease temperatures and physiological traits. To increase our understanding of the evolution, diversity and biology of the RSSC, we performed a meta-analysis of 100 representative RSSC genomes. These 100 RSSC genomes contain 4940 genes on average, and a pangenome analysis found that there are 3262 genes in the core genome (~60 % of the mean RSSC genome) with 13 128 genes in the extensive flexible genome. A core genome phylogenetic tree and a whole-genome similarity matrix aligned with the previously named species ( R. solanacearum , R. pseudosolanacearum , R. syzygii ) and phylotypes (I–IV). These analyses also highlighted a third unrecognized sub-clade of phylotype II. Additionally, we identified differences between phylotypes with respect to gene content and recombination rate, and we delineated population clusters based on the extent of horizontal gene transfer. Multiple analyses indicate that phylotype II is the most diverse phylotype, and it may thus represent the ancestral group of the RSSC. We also used our genome-based framework to test whether the RSSC sequence variant (sequevar) taxonomy is a robust method to define within-species relationships of strains. The sequevar taxonomy is based on alignments of a single conserved gene (egl). Although sequevars in phylotype II describe monophyletic groups, the sequevar system breaks down in the highly recombinogenic phylotype I, which highlights the need for an improved, cost-effective method for genotyping strains in phylotype I. Finally, we enabled quick and precise genome-based identification of newly sequenced RSSC strains by assigning Life Identification Numbers (LINs) to the 100 strains and by circumscribing the RSSC and its sub-groups in the LINbase Web service.

BackgroundAdolescence is a critical period of maturation when nutrient needs are high, especially among adolescents entering pregnancy. Using individual-level data from 140,000 participants, we examined socioeconomic, nutrition, and pregnancy and birth outcomes for adolescent mothers (10-19 years) compared to older mothers in low and middle-income countries.MethodsThis study was conducted between March 16, 2018 and May 25, 2021. Data were obtained from 20 randomised controlled trials of micronutrient supplementation in pregnancy. Stratified analyses were conducted by age (10-14 years, 15-17 years, 18-19 years, 20-29 years, 30-39 years, 40+ years) and geographical region (Africa, Asia). Crude and confounder-adjusted means, prevalence and relative risks of pregnancy, nutrition and birth outcomes were estimated using multivariable linear and log-binomial regression models with 95% confidence intervals.FindingsAdolescent mothers comprised 31.6% of our data. Preterm birth, small-for-gestational age (SGA), low birthweight (LBW) and newborn mortality followed a U-shaped trend in which prevalence was highest among the youngest mothers (10-14 years) and then reduced gradually, but increased again for older mothers (40+ years). When compared to mothers aged 20-29 years, there was a 23% increased risk of preterm birth, a 60% increased risk of perinatal mortality, a 63% increased risk of neonatal mortality, a 28% increased risk of LBW, and a 22% increased risk of SGA among mothers 10-14 years. Mothers 40+ years experienced a 22% increased risk of preterm birth and a 103% increased risk of stillbirth when compared to the 20-29 year group.InterpretationThe youngest and oldest mothers suffer most from adverse pregnancy and birth outcomes. Policy and programming agendas should consider both biological and socioeconomic/environmental factors when targeting these populations.FundingBill and Melinda Gates Foundation (Grant No: OP1137750).

BackgroundIn utero or early-life exposure to aflatoxin, which contaminates staple crops in disadvantaged settings, may compromise pregnancy and infant outcomes, but investigations into the extent, persistence, and determinants of aflatoxin exposure at these life stages have lacked longitudinal data collection and broad geographic representation.ObjectivesAflatoxin exposure and selected determinants thereof were characterized in mother-child dyads with serial plasma/serum samples in prenatal, perinatal, and early life in Malawi and Bangladesh.MethodsCirculating aflatoxin B1 (AFB1)-lysine albumin adducts were measured in dyads from Bangladesh (n = 573; maternal first and third trimester, 3 mo postpartum, cord blood, infant 24 mo) and Malawi (n = 255; maternal second and third trimester, 6 mo postpartum, infant 6 and 18 mo) with isotope dilution mass spectrometry. We examined AFB1-lysine adduct magnitude, persistence, seasonality, and associations with infant feeding, and estimated daily AFB1 intake.ResultsMaternal AFB1-lysine was higher in Malawi (98% detectable; median: 0.469, IQR: 0.225-1.027 pg/µL) than in Bangladesh (59%; 0.030, nondetectable [nd]-0.077 pg/µL). Although estimated dietary exposure in Malawi was temporally stable (648 ng AFB1/day), estimated intake in Bangladesh was reduced by 94% between rainy and winter seasons (98 to 6 ng/day). AFB1-lysine was low in cord blood from Bangladesh (15% detectable; 0.045, 0.031-0.088 pg/µL among detectable) and in Malawian infants at 6 mo of age (0.072, nd-0.236 pg/µL), but reached maternal concentrations by 18 or 24 mo (Bangladesh: 0.034, nd-0.063 pg/µL; Malawi: 0.370, 0.195-0.964 pg/µL). In Malawian infants, exclusive breastfeeding at 3 mo was associated with 58% lower AFB1-lysine concentrations at 6 mo compared with other feeding modes (P = 0.010).ConclusionsAmong pregnant women, aflatoxin exposure was persistently high in Malawi, while lower and seasonal in Bangladesh. Infants were partially protected from exposure in utero and with exclusive breastfeeding, but exposures reached adult levels by 18-24 mo of age. The Bangladesh and Malawi trials are registered at clinicaltrials.gov as NCT00860470 and NCT01239693.

ContextApproximately 7.3 million births occur annually among adolescents in low- and middle-income countries. Pregnant adolescents constitute a nutritionally vulnerable group that could benefit from intervention to mitigate the mortality and adverse birth outcomes associated with adolescent pregnancy.ObjectiveThe aim of this systematic review and meta-analysis was to assess the following: (1) the effect of multiple-micronutrient (MMN) supplementation vs iron and folic acid (IFA) supplementation among adolescents on maternal morbidity, birth outcomes, and mortality outcomes, (2) the effects of MMN supplementation in adolescents compared with the effects in adult women, and (3) the effect modification, if any, of MMN supplementation by baseline and geographic characteristics of adolescents.Data sourcesMEDLINE and Cochrane databases were searched, along with the reference lists of relevant reviews.Study selectionMultiple-micronutrient supplementation trials in pregnancy that were conducted in a low- or middle-income country and had included at least 100 adolescents (10-19 years of age) were eligible for inclusion. Two independent reviewers assessed study eligibility.Data extractionThirteen randomized controlled trials conducted in Africa and Asia were identified from 1792 reviews and 1578 original trials. Individual-level data was shared by study collaborators and was checked for completeness and extreme values. One- and two-stage individual participant data meta-analyses were conducted using data from randomized controlled trials of MMN supplementation.ResultsA total of 15 283 adolescents and 44 499 adult women with singleton births were included in the individual participant data meta-analyses of MMN supplementation vs IFA supplementation. In adolescents, MMN supplementation reduced low birth weight (1-stage OR = 0.87, 95%CI 0.77-0.97; 2-stage OR = 0.81; 95%CI 0.74-0.88), preterm birth (1-stage OR = 0.88, 95%CI 0.80-0.98; 2-stage OR = 0.86, 95%CI 0.79-0.95), and small-for-gestational-age births (1-stage OR = 0.90, 95%CI 0.81-1.00; 2-stage OR = 0.86, 95%CI 0.79-0.95) when compared with IFA supplementation. The effects of MMN supplementation did not differ between adolescents and older women, although a potentially greater reduction in small-for-gestational-age births was observed among adolescents. Effect modification by baseline characteristics and geographic region was inconclusive.ConclusionsMultiple-micronutrient supplementation can improve birth outcomes among pregnant adolescents in low- and middle-income countries. Policy related to antenatal care in these settings should prioritize MMN supplementation over the currently recommended IFA supplementation for all pregnant women, especially adolescents.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) surveillance rates are suboptimal in clinical practice. We aimed to elicit providers opinions on the following aspects of HCC surveillance: preferred strategies, barriers and facilitators, and the impact of a patients HCC risk on the choice of surveillance modality. METHODS: We conducted a web-based survey among gastroenterology and hepatology providers (40% faculty physicians, 21% advanced practice providers, 39% fellow-trainees) from 26 US medical centers in 17 states. RESULTS: Of 654 eligible providers, 305 (47%) completed the survey. Nearly all (98.4%) of the providers endorsed semi-annual HCC surveillance in patients with cirrhosis, with 84.2% recommending ultrasound ± alpha fetoprotein (AFP) and 15.4% recommending computed tomography (CT) or magnetic resonance imaging (MRI). Barriers to surveillance included limited HCC treatment options, screening test effectiveness to reduce mortality, access to transportation, and high out-of-pocket costs. Facilitators of surveillance included professional society guidelines. Most providers (72.1%) would perform surveillance even if HCC risk was low (≤0.5% per year), while 98.7% would perform surveillance if HCC risk was ≥1% per year. As a patients HCC risk increased from 1% to 3% to 5% per year, providers reported they would be less likely to order ultrasound ± AFP (83.6% to 68.9% to 57.4%; P < .001) and more likely to order CT or MRI ± AFP (3.9% to 26.2% to 36.1%; P < .001). CONCLUSIONS: Providers recommend HCC surveillance even when HCC risk is much lower than the threshold suggested by professional societies. Many appear receptive to risk-based HCC surveillance strategies that depend on patients estimated HCC risk, instead of our current one-size-fits all strategy.

PurposePediatric readiness scores may be a useful measure of a hospital's preparedness to care for children. However, there is limited evidence linking these scores with patient outcomes or other metrics, including the need for interfacility transfer. This study aims to determine the association of pediatric readiness scores with the odds of interfacility transfer among a cohort of noninjured children (< 18 years old) presenting to emergency departments (EDs) in small rural hospitals in the state of California.MethodsData from the National Pediatric Readiness Project assessment were linked with the California Office of Statewide Health Planning and Development's ED and inpatient databases to conduct a cross-sectional study of pediatric interfacility transfers. Hospitals were manually matched between these data sets. Logistic regression was performed with random intercepts for hospital and adjustment for patient-level confounders.FindingsA total of 54 hospitals and 135,388 encounters met the inclusion criteria. EDs with a high pediatric readiness score (>70) had lower adjusted odds of transfer (aOR: 0.55, 95% CI: 0.33-0.93) than EDs with a low pediatric readiness score (≤ 70). The pediatric readiness section with strongest association with transfer was the "policies, procedures, and protocols" section; EDs in the highest quartile had lower odds of transfer than EDs in the lowest quartile (aOR: 0.54, 95% CI: 0.31-0.91).ConclusionsPediatric patients presenting to EDs at small rural hospitals with high pediatric readiness scores may be less likely to be transferred. Additional studies are recommended to investigate other pediatric outcomes in relation to hospital ED pediatric readiness.

We review recent advances in using mathematical models of the relationship between the brain structure and function that capture features of brain dynamics. We argue the need for models that can jointly capture temporal, spatial, and spectral features of brain functional activity. We present recent work on spectral graph theory based models that can accurately capture spectral as well as spatial patterns across multiple frequencies in MEG reconstructions.

BackgroundNeuronal- and circuit-level abnormalities of excitation and inhibition are shown to be associated with tau and amyloid-beta (Aβ) in preclinical models of Alzheimer's disease (AD). These relationships remain poorly understood in patients with AD.MethodsUsing empirical spectra from magnetoencephalography and computational modeling (neural mass model), we examined excitatory and inhibitory parameters of neuronal subpopulations and investigated their specific associations to regional tau and Aβ, measured by positron emission tomography, in patients with AD.ResultsPatients with AD showed abnormal excitatory and inhibitory time-constants and neural gains compared to age-matched controls. Increased excitatory time-constants distinctly correlated with higher tau depositions while increased inhibitory time-constants distinctly correlated with higher Aβ depositions.ConclusionsOur results provide critical insights about potential mechanistic links between abnormal neural oscillations and cellular correlates of impaired excitatory and inhibitory synaptic functions associated with tau and Aβ in patients with AD.FundingThis study was supported by the National Institutes of Health grants: K08AG058749 (KGR), F32AG050434-01A1 (KGR), K23 AG038357 (KAV), P50 AG023501, P01 AG19724 (BLM), P50-AG023501 (BLM and GDR), R01 AG045611 (GDR); AG034570, AG062542 (WJ); NS100440 (SSN), DC176960 (SSN), DC017091 (SSN), AG062196 (SSN); a grant from John Douglas French Alzheimer's Foundation (KAV); grants from Larry L. Hillblom Foundation: 2015-A-034-FEL (KGR), 2019-A-013-SUP (KGR); grants from the Alzheimer's Association: AARG-21-849773 (KGR); PCTRB-13-288476 (KAV), and made possible by Part the CloudTM (ETAC-09-133596); a grant from Tau Consortium (GDR and WJJ), and a gift from the S. D. Bechtel Jr. Foundation.

BackgroundMeta-analyses show that small-quantity lipid-based nutrient supplements (SQ-LNSs) reduce child stunting and wasting. Identification of subgroups who benefit most from SQ-LNSs may facilitate program design.ObjectivesWe aimed to identify study-level and individual-level modifiers of the effect of SQ-LNSs on child growth outcomes.MethodsWe conducted a 2-stage meta-analysis of individual participant data from 14 randomized controlled trials of SQ-LNSs provided to children 6-24 mo of age (n = 37,066). We generated study-specific and subgroup estimates of SQ-LNS compared with control and pooled the estimates using fixed-effects models. We used random-effects meta-regression to examine study-level effect modifiers. In sensitivity analyses, we examined whether results differed depending on study arm inclusion criteria and types of comparisons.ResultsSQ-LNS provision decreased stunting (length-for-age z score < -2) by 12% (relative reduction), wasting [weight-for-length (WLZ) z score < -2] by 14%, low midupper arm circumference (MUAC) (

BackgroundSmall-quantity (SQ) lipid-based nutrient supplements (LNSs) provide many nutrients needed for brain development.ObjectivesWe aimed to generate pooled estimates of the effect of SQ-LNSs on developmental outcomes (language, social-emotional, motor, and executive function), and to identify study-level and individual-level modifiers of these effects.MethodsWe conducted a 2-stage meta-analysis of individual participant data from 14 intervention against control group comparisons in 13 randomized trials of SQ-LNSs provided to children age 6-24 mo (total n = 30,024).ResultsIn 11-13 intervention against control group comparisons (n = 23,588-24,561), SQ-LNSs increased mean language (mean difference: 0.07 SD; 95% CI: 0.04, 0.10 SD), social-emotional (0.08; 0.05, 0.11 SD), and motor scores (0.08; 95% CI: 0.05, 0.11 SD) and reduced the prevalence of children in the lowest decile of these scores by 16% (prevalence ratio: 0.84; 95% CI: 0.76, 0.92), 19% (0.81; 95% CI: 0.74, 0.89), and 16% (0.84; 95% CI: 0.76, 0.92), respectively. SQ-LNSs also increased the prevalence of children walking without support at 12 mo by 9% (1.09; 95% CI: 1.05, 1.14). Effects of SQ-LNSs on language, social-emotional, and motor outcomes were larger among study populations with a higher stunting burden (≥35%) (mean difference: 0.11-0.13 SD; 8-9 comparisons). At the individual level, greater effects of SQ-LNSs were found on language among children who were acutely malnourished (mean difference: 0.31) at baseline; on language (0.12), motor (0.11), and executive function (0.06) among children in households with lower socioeconomic status; and on motor development among later-born children (0.11), children of older mothers (0.10), and children of mothers with lower education (0.11).ConclusionsChild SQ-LNSs can be expected to result in modest developmental gains, which would be analogous to 1-1.5 IQ points on an IQ test, particularly in populations with a high child stunting burden. Certain groups of children who experience higher-risk environments have greater potential to benefit from SQ-LNSs in developmental outcomes.This trial was registered at www.crd.york.ac.uk/PROSPERO as CRD42020159971.

BackgroundSmall-quantity lipid-based nutrient supplements (SQ-LNSs) have been shown to reduce the prevalence of child anemia and iron deficiency, but effects on other micronutrients are less well known. Identifying subgroups who benefit most from SQ-LNSs could support improved program design.ObjectivesWe aimed to identify study-level and individual-level modifiers of the effect of SQ-LNSs on child hemoglobin (Hb), anemia, and inflammation-adjusted micronutrient status outcomes.MethodsWe conducted a 2-stage meta-analysis of individual participant data from 13 randomized controlled trials of SQ-LNSs provided to children 6-24 mo of age (n = 15,946). We generated study-specific and subgroup estimates of SQ-LNSs compared with control, and pooled the estimates using fixed-effects models. We used random-effects meta-regression to examine potential study-level effect modifiers.ResultsSQ-LNS provision decreased the prevalence of anemia (Hb < 110 g/L) by 16% (relative reduction), iron deficiency (plasma ferritin < 12 µg/L) by 56%, and iron deficiency anemia (IDA; Hb < 110 g/L and plasma ferritin 12 mo and provided 9 (as opposed to

BackgroundMeta-analyses show that small-quantity lipid-based nutrient supplements (SQ-LNSs) reduce child stunting and wasting. Identification of subgroups who benefit most from SQ-LNSs may facilitate program design.ObjectivesWe aimed to identify study-level and individual-level modifiers of the effect of SQ-LNSs on child growth outcomes.MethodsWe conducted a 2-stage meta-analysis of individual participant data from 14 randomized controlled trials of SQ-LNSs provided to children 6-24 mo of age (n = 37,066). We generated study-specific and subgroup estimates of SQ-LNS compared with control and pooled the estimates using fixed-effects models. We used random-effects meta-regression to examine study-level effect modifiers. In sensitivity analyses, we examined whether results differed depending on study arm inclusion criteria and types of comparisons.ResultsSQ-LNS provision decreased stunting (length-for-age z score < -2) by 12% (relative reduction), wasting [weight-for-length (WLZ) z score < -2] by 14%, low midupper arm circumference (MUAC) (

BackgroundSmall-quantity lipid-based nutrient supplements (SQ-LNSs) have been shown to reduce the prevalence of child anemia and iron deficiency, but effects on other micronutrients are less well known. Identifying subgroups who benefit most from SQ-LNSs could support improved program design.ObjectivesWe aimed to identify study-level and individual-level modifiers of the effect of SQ-LNSs on child hemoglobin (Hb), anemia, and inflammation-adjusted micronutrient status outcomes.MethodsWe conducted a 2-stage meta-analysis of individual participant data from 13 randomized controlled trials of SQ-LNSs provided to children 6-24 mo of age (n = 15,946). We generated study-specific and subgroup estimates of SQ-LNSs compared with control, and pooled the estimates using fixed-effects models. We used random-effects meta-regression to examine potential study-level effect modifiers.ResultsSQ-LNS provision decreased the prevalence of anemia (Hb < 110 g/L) by 16% (relative reduction), iron deficiency (plasma ferritin < 12 µg/L) by 56%, and iron deficiency anemia (IDA; Hb < 110 g/L and plasma ferritin 12 mo and provided 9 (as opposed to

BackgroundSmall-quantity (SQ) lipid-based nutrient supplements (LNSs) provide many nutrients needed for brain development.ObjectivesWe aimed to generate pooled estimates of the effect of SQ-LNSs on developmental outcomes (language, social-emotional, motor, and executive function), and to identify study-level and individual-level modifiers of these effects.MethodsWe conducted a 2-stage meta-analysis of individual participant data from 14 intervention against control group comparisons in 13 randomized trials of SQ-LNSs provided to children age 6-24 mo (total n = 30,024).ResultsIn 11-13 intervention against control group comparisons (n = 23,588-24,561), SQ-LNSs increased mean language (mean difference: 0.07 SD; 95% CI: 0.04, 0.10 SD), social-emotional (0.08; 0.05, 0.11 SD), and motor scores (0.08; 95% CI: 0.05, 0.11 SD) and reduced the prevalence of children in the lowest decile of these scores by 16% (prevalence ratio: 0.84; 95% CI: 0.76, 0.92), 19% (0.81; 95% CI: 0.74, 0.89), and 16% (0.84; 95% CI: 0.76, 0.92), respectively. SQ-LNSs also increased the prevalence of children walking without support at 12 mo by 9% (1.09; 95% CI: 1.05, 1.14). Effects of SQ-LNSs on language, social-emotional, and motor outcomes were larger among study populations with a higher stunting burden (≥35%) (mean difference: 0.11-0.13 SD; 8-9 comparisons). At the individual level, greater effects of SQ-LNSs were found on language among children who were acutely malnourished (mean difference: 0.31) at baseline; on language (0.12), motor (0.11), and executive function (0.06) among children in households with lower socioeconomic status; and on motor development among later-born children (0.11), children of older mothers (0.10), and children of mothers with lower education (0.11).ConclusionsChild SQ-LNSs can be expected to result in modest developmental gains, which would be analogous to 1-1.5 IQ points on an IQ test, particularly in populations with a high child stunting burden. Certain groups of children who experience higher-risk environments have greater potential to benefit from SQ-LNSs in developmental outcomes.This trial was registered at www.crd.york.ac.uk/PROSPERO as CRD42020159971.

ObjectiveTo determine the association between potentially avoidable transfers (PATs) and emergency department (ED) pediatric readiness scores and the score's associated components.Study designThis cross-sectional study linked the 2012 National Pediatric Readiness Project assessment with individual encounter data from California's statewide ED and inpatient databases during the years 2011-2013. A probabilistic linkage, followed by deterministic heuristics, linked pretransfer, and post-transfer encounters. Applying previously published definitions, a transferred child was considered a PAT if they were discharged within 1 day from the ED or inpatient care and had no specialized procedures. Analyses were stratified by injured and noninjured children. We compared PATs with necessary transfers using mixed-effects logistic regression models with random intercepts for hospital and adjustment for patient and hospital covariates.ResultsAfter linkage, there were 6765 injured children (27% PATs) and 18 836 noninjured children (14% PATs) who presented to 283 hospitals. In unadjusted analyses, a 10-point increase in pediatric readiness was associated with lower odds of PATs in both injured (OR 0.93, 95% CI 0.90-0.96) and noninjured children (OR 0.90, 95% CI 0.88-0.93). In adjusted analyses, a similar association was detected in injured patients (aOR 0.92, 95% CI 0.86-0.98) and was not detected in noninjured patients (aOR 0.94, 95% CI 0.88-1.00). Components associated with decreased PATs included having a nurse pediatric emergency care coordinator and a quality improvement plan.ConclusionsHospital ED pediatric readiness is associated with lower odds of a PAT. Certain pediatric readiness components are modifiable risk factors that EDs could target to reduce PATs.

Defects in axonal transport may partly underpin the differences between the observed pathophysiology of Alzheimer's disease (AD) and that of other non-amyloidogenic tauopathies. Particularly, pathological tau variants may have molecular properties that dysregulate motor proteins responsible for the anterograde-directed transport of tau in a disease-specific fashion. Here we develop the first computational model of tau-modified axonal transport that produces directional biases in the spread of tau pathology. We simulated the spatiotemporal profiles of soluble and insoluble tau species in a multicompartment, two-neuron system using biologically plausible parameters and time scales. Changes in the balance of tau transport feedback parameters can elicit anterograde and retrograde biases in the distributions of soluble and insoluble tau between compartments in the system. Aggregation and fragmentation parameters can also perturb this balance, suggesting a complex interplay between these distinct molecular processes. Critically, we show that the model faithfully recreates the characteristic network spread biases in both AD-like and non-AD-like mouse tauopathy models. Tau transport feedback may therefore help link microscopic differences in tau conformational states and the resulting variety in clinical presentations.

Single-nucleus assay for transposase-accessible chromatin using sequencing (snATAC-seq) creates new opportunities to dissect cell type-specific mechanisms of complex diseases. Since pancreatic islets are central to type 2 diabetes (T2D), we profiled 15,298 islet cells by using combinatorial barcoding snATAC-seq and identified 12 clusters, including multiple alpha, beta and delta cell states. We cataloged 228,873 accessible chromatin sites and identified transcription factors underlying lineage- and state-specific regulation. We observed state-specific enrichment of fasting glucose and T2D genome-wide association studies for beta cells and enrichment for other endocrine cell types. At T2D signals localized to islet-accessible chromatin, we prioritized variants with predicted regulatory function and co-accessibility with target genes. A causal T2D variant rs231361 at the KCNQ1 locus had predicted effects on a beta cell enhancer co-accessible with INS and genome editing in embryonic stem cell-derived beta cells affected INS levels. Together our findings demonstrate the power of single-cell epigenomics for interpreting complex disease genetics.

ABSTRACTBackgroundSmall-quantity lipid-based nutrient supplements (SQ-LNS) have been shown to reduce the prevalence of anemia and iron deficiency among infants and young children, but effects on other micronutrients are less well known. Identifying subgroups who may experience greater benefits from SQ-LNS, or who are more likely to respond to the intervention, may facilitate the development of public health policies and programs.ObjectiveOur objective was to identify study-level and individual-level modifiers of the effect of SQ-LNS on child hematological and micronutrient status outcomes.MethodsWe conducted a two-stage meta-analysis of individual participant data from 13 randomized controlled trials of SQ-LNS provided to children 6 to 24 months of age in low- and middle-income countries (n = 15,946). Outcomes were hemoglobin (Hb), inflammation-adjusted plasma ferritin, soluble transferrin receptor, zinc, retinol and retinol binding protein (RBP), and erythrocyte zinc protoporphyrin, and respective dichotomous outcomes indicative of anemia and micronutrient deficiency. We generated study-specific estimates of SQ-LNS vs. control, including main effects and subgroup estimates for individual-level effect modifiers, and pooled the estimates using fixed-effects models. We used random effects meta-regression to examine potential study-level effect modifiers.ResultsProvision of SQ-LNS decreased the prevalence of anemia (Hb < 110 g/L) by 16% (relative reduction), iron deficiency (plasma ferritin < 12 µg/L) by 56% and iron deficiency anemia (IDA; Hb < 110 g/L and plasma ferritin < 12 µg/L) by 64%. We observed positive effects of SQ-LNS on hematological and iron status outcomes within all subgroups of the study-level and individual-level effect modifiers, but effects were larger in certain subgroups. For example, effects of SQ-LNS on anemia and iron status were greater in trials that provided SQ-LNS for > 12 months and provided 9 mg/d vs. < 9 mg iron/d, and among later-born (vs. first-born) children. There was no effect of SQ-LNS on plasma zinc or retinol, but there was a 7% increase in plasma RBP and a 56% reduction in vitamin A deficiency (RBP < 0.70 µmol/L), with little evidence of effect modification by individual-level characteristics.ConclusionsSQ-LNS provided to infants and young children 6-24 months of age can substantially reduce the prevalence of anemia, iron deficiency, and IDA across a range of individual, population and study design characteristics. Policy-makers and program planners should consider SQ-LNS within intervention packages to prevent anemia and iron deficiency. This study was registered at www.crd.york.ac.uk/PROSPERO as CRD42020156663.