Spatial parasitology and the unmapped human helminthiases

Helminthiases are a class of neglected tropical diseases that affect at least 1 billion people worldwide, with a disproportionate impact on resource-poor areas with limited disease surveillance. Geospatial methods can offer valuable insights into the burden of these infections, particularly given that many are subject to strong ecological influences on the environmental, vector-borne or zoonotic stages of their life cycle. In this study, we screened 6829 abstracts and analysed 485 studies that use maps to document, infer or predict transmission patterns for over 200 species of parasitic worms. We found that quantitative mapping methods are increasingly used in medical parasitology, drawing on One Health surveillance data from the community scale to model geographic distributions and burdens up to the regional or global scale. However, we found that the vast majority of the human helminthiases may be entirely unmapped, with research effort focused disproportionately on a half-dozen infections that are targeted by mass drug administration programmes. Entire regions were also surprisingly under-represented in the literature, particularly southern Asia and the Neotropics. We conclude by proposing a shortlist of possible priorities for future research, including several neglected helminthiases with a burden that may be underestimated

Distal Xq duplication and functional Xq disomy

Distal Xq duplications refer to chromosomal disorders resulting from involvement of the long arm of the X chromosome (Xq). Clinical manifestations widely vary depending on the gender of the patient and on the gene content of the duplicated segment. Prevalence of Xq duplications remains unknown. About 40 cases of Xq28 functional disomy due to cytogenetically visible rearrangements, and about 50 cases of cryptic duplications encompassing the MECP2 gene have been reported. The most frequently reported distal duplications involve the Xq28 segment and yield a recognisable phenotype including distinctive facial features (premature closure of the fontanels or ridged metopic suture, broad face with full cheeks, epicanthal folds, large ears, small and open mouth, ear anomalies, pointed nose, abnormal palate and facial hypotonia), major axial hypotonia, severe developmental delay, severe feeding difficulties, abnormal genitalia and proneness to infections. Xq duplications may be caused either by an intrachromosomal duplication or an unbalanced X/Y or X/autosome translocation. In XY males, structural X disomy always results in functional disomy. In females, failure of X chromosome dosage compensation could result from a variety of mechanisms, including an unfavourable pattern of inactivation, a breakpoint separating an X segment from the X-inactivation centre in cis, or a small ring chromosome. The MECP2 gene in Xq28 is the most important dosage-sensitive gene responsible for the abnormal phenotype in duplications of distal Xq. Diagnosis is based on clinical features and is confirmed by CGH array techniques. Differential diagnoses include Prader-Willi syndrome and Alpha thalassaemia-mental retardation, X linked (ATR-X). The recurrence risk is significant if a structural rearrangement is present in one of the parent, the most frequent situation being that of an intrachromosomal duplication inherited from the mother. Prenatal diagnosis is performed by cytogenetic testing including FISH and/or DNA quantification methods. Management is multi-specialist and only symptomatic, with special attention to prevention of malnutrition and recurrent infections. Educational and rehabilitation support should be offered to all patients

Effects of eight neuropsychiatric copy number variants on human brain structure

Many copy number variants (CNVs) confer risk for the same range of neurodevelopmental symptoms and psychiatric conditions including autism and schizophrenia. Yet, to date neuroimaging studies have typically been carried out one mutation at a time, showing that CNVs have large effects on brain anatomy. Here, we aimed to characterize and quantify the distinct brain morphometry effects and latent dimensions across 8 neuropsychiatric CNVs. We analyzed T1-weighted MRI data from clinically and non-clinically ascertained CNV carriers (deletion/duplication) at the 1q21.1 (n = 39/28), 16p11.2 (n = 87/78), 22q11.2 (n = 75/30), and 15q11.2 (n = 72/76) loci as well as 1296 non-carriers (controls). Case-control contrasts of all examined genomic loci demonstrated effects on brain anatomy, with deletions and duplications showing mirror effects at the global and regional levels. Although CNVs mainly showed distinct brain patterns, principal component analysis (PCA) loaded subsets of CNVs on two latent brain dimensions, which explained 32 and 29% of the variance of the 8 Cohen’s d maps. The cingulate gyrus, insula, supplementary motor cortex, and cerebellum were identified by PCA and multi-view pattern learning as top regions contributing to latent dimension shared across subsets of CNVs. The large proportion of distinct CNV effects on brain morphology may explain the small neuroimaging effect sizes reported in polygenic psychiatric conditions. Nevertheless, latent gene brain morphology dimensions will help subgroup the rapidly expanding landscape of neuropsychiatric variants and dissect the heterogeneity of idiopathic conditions

Structural and social changes due to the COVID-19 pandemic and their impact on engagement in substance use disorder treatment services: a qualitative study among people with a recent history of injection drug use in Baltimore, Maryland

Abstract Background Substance use disorder treatment and recovery support services are critical for achieving and maintaining recovery. There are limited data on how structural and social changes due to the COVID-19 pandemic impacted individual-level experiences with substance use disorder treatment-related services among community-based samples of people who inject drugs. Methods People with a recent history of injection drug use who were enrolled in the community-based AIDS Linked to the IntraVenous Experience study in Baltimore, Maryland participated in a one-time, semi-structured interview between July 2021 and February 2022 about their experiences living through the COVID-19 pandemic (n = 28). An iterative inductive coding process was used to identify themes describing how structural and social changes due to the COVID-19 pandemic affected participants’ experiences with substance use disorder treatment-related services. Results The median age of participants was 54 years (range = 24–73); 10 (36%) participants were female, 16 (57%) were non-Hispanic Black, and 8 (29%) were living with HIV. We identified several structural and social changes due the pandemic that acted as barriers and facilitators to individual-level engagement in treatment with medications for opioid use disorder (MOUD) and recovery support services (e.g., support group meetings). New take-home methadone flexibility policies temporarily facilitated engagement in MOUD treatment, but other pre-existing rigid policies and practices (e.g., zero-tolerance) were counteracting barriers. Changes in the illicit drug market were both a facilitator and barrier to MOUD treatment. Decreased availability and pandemic-related adaptations to in-person services were a barrier to recovery support services. While telehealth expansion facilitated engagement in recovery support group meetings for some participants, other participants faced digital and technological barriers. These changes in service provision also led to diminished perceived quality of both virtual and in-person recovery support group meetings. However, a facilitator of recovery support was increased accessibility of individual service providers (e.g., counselors and Sponsors). Conclusions Structural and social changes across several socioecological levels created new barriers and facilitators of individual-level engagement in substance use disorder treatment-related services. Multilevel interventions are needed to improve access to and engagement in high-quality substance use disorder treatment and recovery support services among people who inject drugs

Prevalence and correlates of SARS-CoV-2 seropositivity among people who inject drugs in Baltimore, Maryland

Background: SARS-CoV-2 serosurveys can help characterize disparities in SARS-CoV-2 infection and identify gaps in population immunity. Data on SARS-CoV-2 seroprevalence among people who inject drugs (PWID) are limited. Methods: We conducted a cross-sectional study between December 2020 and July 2022 among 561 participants in the AIDS Linked to the IntraVenous Experience (ALIVE) study—a community-based cohort of current and former PWID in Baltimore, Maryland. Serum samples were assayed for infection-induced anti-nucleocapsid (anti-N) and infection and/or vaccination-induced anti-spike-1 (anti-S) SARS-CoV-2 IgG. We estimated adjusted prevalence ratios (aPR) via modified Poisson regression models. Results: The median age was 59 years, 35% were female, 84% were non-Hispanic Black, and 16% reported recent injection drug use. Anti-N antibody prevalence was 26% and anti-S antibody prevalence was 63%. Anti-N and anti-S antibody prevalence increased over time. Being employed (aPR=1.53 [95%CI=1.11–2.11]) was associated with higher anti-N prevalence, while a cancer history (aPR=0.40 [95%CI=0.17–0.90]) was associated with lower anti-N prevalence. HIV infection was associated with higher anti-S prevalence (aPR=1.13 [95%CI=1.02–1.27]), while younger age and experiencing homelessness (aPR=0.78 [95%CI=0.60–0.99]) were factors associated with lower anti-S prevalence. Substance use-related behaviors were not significantly associated with anti-N or anti-S prevalence. Conclusions: SARS-CoV-2 seroprevalence increased over time among current and former PWID, suggesting cumulative increases in the incidence of SARS-CoV-2 infection and vaccination; however, there were disparities in infection-induced seroprevalence and infection and/or vaccine-induced seroprevalence within this study sample. Dedicated prevention and vaccination programs are needed to prevent disparities in infection and gaps in population immunity among PWID during emerging epidemics

Factors associated with self-reported avoidance of harm reduction services during the COVID-19 pandemic by people who use drugs in five cities in the United States and Canada.

BackgroundThis study examines individual-level factors associated with avoiding two important health services for people who use drugs-medications for treatment of opioid use disorder and syringe service programs-during the first year of the COVID-19 pandemic.MethodsData come from two subsamples of people who use drugs who were active participants in one of nine cohort studies in Vancouver, British Columbia; Baltimore, Maryland; Los Angeles, California; Chicago, Illinois; and Miami, Florida. Participants were interviewed remotely about COVID-19-associated disruptions to healthcare. We estimated the association of demographic, social, and health factors with each outcome using logistic regression among 702 participants (medication analysis) and 304 participants (syringe service analysis.) Analyses were repeated, stratified by city of residence, to examine geographic variation in risk.ResultsThere were large differences between cities in the prevalence of avoiding picking up medications for opioid use disorder, with almost no avoidance in Vancouver (3%) and nearly universal avoidance in Los Angeles, Chicago, and Miami (>90%). After accounting for between-city differences, no individual factors were associated with avoiding picking up medications. The only factor significantly associated with avoiding syringe service programs was higher levels of self-reported worry about COVID-19.ConclusionDuring the first year of the COVID-19 pandemic, geographic differences in service and policy contexts likely influenced avoidance of health and harm reduction services by people who use drugs in the United States and Canada more than individual differences between people

Clinical and functional heterogeneity associated with the disruption of retinoic acid receptor beta

PurposeDominant variants in the retinoic acid receptor beta (RARB) gene underlie a syndromic form of microphthalmia, known as MCOPS12, which is associated with other birth anomalies and global developmental delay with spasticity and/or dystonia. Here, we report 25 affected individuals with 17 novel pathogenic or likely pathogenic variants in RARB. This study aims to characterize the functional impact of these variants and describe the clinical spectrum of MCOPS12.MethodsWe used in vitro transcriptional assays and in silico structural analysis to assess the functional relevance of RARB variants in affecting the normal response to retinoids.ResultsWe found that all RARB variants tested in our assays exhibited either a gain-of-function or a loss-of-function activity. Loss-of-function variants disrupted RARB function through a dominant-negative effect, possibly by disrupting ligand binding and/or coactivators' recruitment. By reviewing clinical data from 52 affected individuals, we found that disruption of RARB is associated with a more variable phenotype than initially suspected, with the absence in some individuals of cardinal features of MCOPS12, such as developmental eye anomaly or motor impairment.ConclusionOur study indicates that pathogenic variants in RARB are functionally heterogeneous and associated with extensive clinical heterogeneity

Widening of the genetic and clinical spectrum of Lamb–Shaffer syndrome, a neurodevelopmental disorder due to SOX5 haploinsufficiency

International audiencePURPOSE: Lamb-Shaffer syndrome (LAMSHF) is a neurodevelopmental disorder described in just over two dozen patients with heterozygous genetic alterations involving SOX5, a gene encoding a transcription factor regulating cell fate and differentiation in neurogenesis and other discrete developmental processes. The genetic alterations described so far are mainly microdeletions. The present study was aimed at increasing our understanding of LAMSHF, its clinical and genetic spectrum, and the pathophysiological mechanisms involved.METHODS: Clinical and genetic data were collected through GeneMatcher and clinical or genetic networks for 41 novel patients harboring various types of SOX5 alterations. Functional consequences of selected substitutions were investigated.RESULTS: Microdeletions and truncating variants occurred throughout SOX5. In contrast, most missense variants clustered in the pivotal SOX-specific high-mobility-group domain. The latter variants prevented SOX5 from binding DNA and promoting transactivation in vitro, whereas missense variants located outside the high-mobility-group domain did not. Clinical manifestations and severity varied among patients. No clear genotype-phenotype correlations were found, except that missense variants outside the high-mobility-group domain were generally better tolerated.CONCLUSIONS:This study extends the clinical and genetic spectrum associated with LAMSHF and consolidates evidence that SOX5 haploinsufficiency leads to variable degrees of intellectual disability, language delay, and other clinical features