Multi-Omic characterization of the effects of Ocrelizumab in patients with relapsing-remitting multiple sclerosis.

The study examined changes in the plasma proteome, metabolome, and lipidome of N = 14 patients with relapsing-remitting multiple sclerosis (RRMS) initiating treatment with ocrelizumab, assayed at baseline, 6 months, and 12 months. Analyses of >4000 circulating biomarkers identified depletion of B-cell associated proteins as the early effect observed following ocrelizumab (OCR) initiation, accompanied by the reduction in plasma abundance of cytokines and cytotoxic proteins, markers of neuronaxonal damage, and biologically active lipids including ceramides and lysophospholipids, at 6 months. B-cell depletion was accompanied by decreases in B-cell receptor and cytokine signaling but a pronounced increase in circulating plasma B-cell activating factor (BAFF).

Heterogeneity in statin responses explained by variation in the human gut microbiome.

Background: Statins remain one of the most prescribed medications worldwide. While effective in decreasing atherosclerotic cardiovascular disease risk, statin use is associated with adverse effects for a subset of patients, including disrupted metabolic control and increased risk of type 2 diabetes.

Methods: We investigated the potential role of the gut microbiome in modifying patient responses to statin therapy across two independent cohorts (discovery n = 1,848, validation n = 991).

Manifestations of Alzheimer's disease genetic risk in the blood are evident in a multiomic analysis in healthy adults aged 18 to 90.

Genetics play an important role in late-onset Alzheimer's Disease (AD) etiology and dozens of genetic variants have been implicated in AD risk through large-scale GWAS meta-analyses. However, the precise mechanistic effects of most of these variants have yet to be determined. Deeply phenotyped cohort data can reveal physiological changes associated with genetic risk for AD across an age spectrum that may provide clues to the biology of the disease.

Multiple early factors anticipate post-acute COVID-19 sequelae.

Post-acute sequelae of COVID-19 (PASC) represent an emerging global crisis. However, quantifiable risk factors for PASC and their biological associations are poorly resolved. We executed a deep multi-omic, longitudinal investigation of 309 COVID-19 patients from initial diagnosis to convalescence (2-3 months later), integrated with clinical data and patient-reported symptoms.

Integrated analysis of plasma and single immune cells uncovers metabolic changes in individuals with COVID-19.

A better understanding of the metabolic alterations in immune cells during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may elucidate the wide diversity of clinical symptoms experienced by individuals with coronavirus disease 2019 (COVID-19). Here, we report the metabolic changes associated with the peripheral immune response of 198 individuals with COVID-19 through an integrated analysis of plasma metabolite and protein levels as well as single-cell multiomics analyses from serial blood draws collected during the first week after clinical diagnosis. We document the emergence of rare but metabolically dominant T cell subpopulations and find that increasing disease severity correlates with a bifurcation of monocytes into two metabolically distinct subsets.

Ambulatory Risk Models for the Long-Term Prevention of Sepsis: Retrospective Study.

Background: Sepsis is a life-threatening condition that can rapidly lead to organ damage and death. Existing risk scores predict outcomes for patients who have already become acutely ill.

Objective: We aimed to develop a model for identifying patients at risk of getting sepsis within 2 years in order to support the reduction of sepsis morbidity and mortality.

Multi-cohort analysis of host immune response identifies conserved protective and detrimental modules associated with severity across viruses.

Viral infections induce a conserved host response distinct from bacterial infections. We hypothesized that the conserved response is associated with disease severity and is distinct between patients with different outcomes. To test this, we integrated 4,780 blood transcriptome profiles from patients aged 0 to 90 years infected with one of 16 viruses, including SARS-CoV-2, Ebola, chikungunya, and influenza, across 34 cohorts from 18 countries, and single-cell RNA sequencing profiles of 702,970 immune cells from 289 samples across three cohorts.

Characteristics and Factors Associated With Coronavirus Disease 2019 Infection, Hospitalization, and Mortality Across Race and Ethnicity.

Background: Data on the characteristics of coronavirus disease 2019 (COVID-19) patients disaggregated by race/ethnicity remains limited. We evaluated the sociodemographic and clinical characteristics of patients across racial/ethnic groups and assessed their associations with COVID-19 outcomes.

Methods: This retrospective cohort study examined 629 953 patients tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a large health system spanning California, Oregon, and Washington between March 1 and December 31, 2020.

Characteristics and Factors Associated with COVID-19 Infection, Hospitalization, and Mortality Across Race and Ethnicity.

Background: Data on the characteristics of COVID-19 patients disaggregated by race/ethnicity remain limited. We evaluated the sociodemographic and clinical characteristics of patients across racial/ethnic groups and assessed their associations with COVID-19 outcomes.

Methods: This retrospective cohort study examined 629,953 patients tested for SARS-CoV-2 in a large health system spanning California, Oregon, and Washington between March 1 and December 31, 2020.

Multi-Omics Resolves a Sharp Disease-State Shift between Mild and Moderate COVID-19.

We present an integrated analysis of the clinical measurements, immune cells, and plasma multi-omics of 139 COVID-19 patients representing all levels of disease severity, from serial blood draws collected during the first week of infection following diagnosis. We identify a major shift between mild and moderate disease, at which point elevated inflammatory signaling is accompanied by the loss of specific classes of metabolites and metabolic processes. Within this stressed plasma environment at moderate disease, multiple unusual immune cell phenotypes emerge and amplify with increasing disease severity.

Health and disease markers correlate with gut microbiome composition across thousands of people.

Variation in the human gut microbiome can reflect host lifestyle and behaviors and influence disease biomarker levels in the blood. Understanding the relationships between gut microbes and host phenotypes are critical for understanding wellness and disease. Here, we examine associations between the gut microbiota and ~150 host phenotypic features across ~3,400 individuals.

Multiomic Immunophenotyping of COVID-19 Patients Reveals Early Infection Trajectories.

Host immune responses play central roles in controlling SARS-CoV2 infection, yet remain incompletely characterized and understood. Here, we present a comprehensive immune response map spanning 454 proteins and 847 metabolites in plasma integrated with single-cell multi-omic assays of PBMCs in which whole transcriptome, 192 surface proteins, and T and B cell receptor sequence were co-analyzed within the context of clinical measures from 50 COVID19 patient samples. Our study reveals novel cellular subpopulations, such as proliferative exhausted CD8 and CD4 T cells, and cytotoxic CD4 T cells, that may be features of severe COVID-19 infection.

Early lexical development of children raised in institutional care in Russia.

Children abandoned to institutions display a host of developmental delays, including those involving general cognition and language. The majority of published studies focus on children over 3 years of age; little is known about whether these delays may be detected earlier when children undergo rapid lexical development. To investigate the early language development of children raised in institutional settings in the Russian Federation, we compared a group of children in institutional care (n = 36; 8-35 months) to their age-matched peers raised in biological families, who have never been institutionalized (n = 72) using the Russian version of the CDI.

Genome-Wide Homozygosity Mapping Reveals Genes Associated With Cognitive Ability in Children From Saudi Arabia.

Recent studies of the genetic foundations of cognitive ability rely on large samples (in extreme, hundreds of thousands) of individuals from relatively outbred populations of mostly European ancestry. Hypothesizing that the genetic foundation of cognitive ability depends on the broader population-specific genetic context, we performed a genome-wide association study and homozygosity mapping of cognitive ability estimates obtained through latent variable modeling in a sample of 354 children from a consanguineous population of Saudi Arabia. Approximately half of the sample demonstrated significantly elevated homozygosity levels indicative of inbreeding, and among those with elevated levels, homozygosity was negatively associated with cognitive ability.

Effects of early social deprivation on epigenetic statuses and adaptive behavior of young children: A study based on a cohort of institutionalized infants and toddlers.

Early social deprivation (i.e., an insufficiency or lack of parental care) has been identified as a significant adverse early experience that may affect multiple facets of child development and cause long-term outcomes in physical and mental health, cognition and behavior.

Language Outcomes in Adults with a History of Institutionalization: Behavioral and Neurophysiological Characterization.

Impoverished early care environments are associated with developmental deficits in children raised in institutional settings. Despite the accumulation of evidence regarding deficits in general cognitive functioning in this population, less is known about the impact of institutionalization on language development at the level of brain and behavior. We examined language outcomes in young adults and adolescents raised in institutions (n = 23) as compared to their socioeconomic status and age peers raised in biological families (n = 24) using a behavioral language assessment and linguistic event-related potentials (ERPs).

Common variation within the SETBP1 gene is associated with reading-related skills and patterns of functional neural activation.

Epidemiological population studies highlight the presence of substantial individual variability in reading skill, with approximately 5-10% of individuals characterized as having specific reading disability (SRD). Despite reported substantial heritability, typical for a complex trait, the specifics of the connections between reading and the genome are not understood. Recently, the SETBP1 gene has been implicated in several complex neurodevelopmental syndromes and disorders that impact language.

DNA methylation alterations in the genome of a toddler with cri-du-chat syndrome.

This manuscript reports on genomewide epigenetic alterations in cri-du-chat syndrome related to a partial aneusomy of chromosome 5. A systematic analysis of these alterations will open up new possibilities for the prognostic evaluation of CDCS patients and the development of new therapeutic interventions for reducing the severity of the disease.

What Reading Disability? Evidence for Multiple Latent Profiles of Struggling Readers in a Large Russian Sibpair Sample With at Least One Sibling at Risk for Reading Difficulties.

In this study, we performed a latent profile analysis of reading and related skills in a large ( n = 733) sibpair sample of Russian readers at risk for reading difficulties. The analysis suggested the presence of seven latent profiles, of which two were characterized by relatively high performance on measures of spelling and reading comprehension and the remaining five included severely as well as moderately affected readers with deficits in the domains of phonological, orthographic, and morphological processing. The results suggest that the development and manifestation of reading difficulties in Russian is mappable on a complex pattern of interactions between different types and severities of processing deficits.

The BDNF ValMet polymorphism is associated with structural neuroanatomical differences in young children.

The brain-derived neurotrophic factor (BDNF) ValMet single nucleotide polymorphism (SNP) has been associated with individual differences in brain structure and function, and cognition. Research on BDNF's influence on brain and cognition has largely been limited to adults, and little is known about the association of this gene, and specifically the ValMet polymorphism, with developing brain structure and emerging cognitive functions in children. We performed a targeted genetic association analysis on cortical thickness, surface area, and subcortical volume in 78 children (ages 6-10) who were Val homozygotes (homozygous Val/Val carriers) or Met carriers (Val/Met, Met/Met) for the ValMet locus using Atlas-based brain segmentation.

Epigenetic regulation of cognition: A circumscribed review of the field.

The last decade has been marked by an increased interest in relating epigenetic mechanisms to complex human behaviors, although this interest has not been balanced, accentuating various types of affective and primarily ignoring cognitive functioning. Recent animal model data support the view that epigenetic processes play a role in learning and memory consolidation and help transmit acquired memories even across generations. In this review, we provide an overview of various types of epigenetic mechanisms in the brain (DNA methylation, histone modification, and noncoding RNA action) and discuss their impact proximally on gene transcription, protein synthesis, and synaptic plasticity and distally on learning, memory, and other cognitive functions.

The BDNF Val66Met Polymorphism Influences Reading Ability and Patterns of Neural Activation in Children.

Understanding how genes impact the brain's functional activation for learning and cognition during development remains limited. We asked whether a common genetic variant in the BDNF gene (the Val66Met polymorphism) modulates neural activation in the young brain during a critical period for the emergence and maturation of the neural circuitry for reading. In animal models, the bdnf variation has been shown to be associated with the structure and function of the developing brain and in humans it has been associated with multiple aspects of cognition, particularly memory, which are relevant for the development of skilled reading.

Language development in rural and urban Russian-speaking children with and without developmental language disorder.

Using a newly developed Assessment of the Development of Russian Language (ORRIA), we investigated differences in language development between rural vs. urban Russian-speaking children (n = 100 with a mean age of 6.75) subdivided into groups with and without developmental language disorders.

Genome-Wide Association and Exome Sequencing Study of Language Disorder in an Isolated Population.

Background And Objective: Developmental language disorder (DLD) is a highly prevalent neurodevelopmental disorder associated with negative outcomes in different domains; the etiology of DLD is unknown. To investigate the genetic underpinnings of DLD, we performed genome-wide association and whole exome sequencing studies in a geographically isolated population with a substantially elevated prevalence of the disorder (ie, the AZ sample).

Methods: DNA samples were collected from 359 individuals for the genome-wide association study and from 12 severely affected individuals for whole exome sequencing.