Ciclosporin A Proof of Concept Study in Patients with Active, Progressive HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis

HTLV-1 is a retrovirus transmitted through body fluids that is commonly seen in the West Indies, South America and Southern Japan but rarely in the UK. Although most patients remain healthy carriers, HTLV-1 causes serious conditions such as adult T cell leukaemia/lymphoma (ATLL) and HTLV-1-associated myelopathy/Tropical Spastic Paraparesis (HAM/TSP). The infection which is life-long cannot be eradicated and treatments for the associated diseases are limited. We report the encouraging findings of the first UK Medical Research Council funded treatment study for patients with early and/or deteriorating HAM/TSP. Treatment with ciclosporin A, a drug commonly used to dampen the immune system in transplant patients, was investigated. Symptoms and signs of disease, particularly low back pain and muscle stiffness, improved by week 24 and in some patients this improvement persisted after the 48 weeks of treatment, at least to the end of the study at week 72. Most striking was the finding that the amount of HTLV-1 in the fluid around the spinal cord, called cerebrospinal fluid, was reduced during treatment. These findings justify the further study of ciclosporin A in patients with HAM/TSP

Single-nucleotide polymorphisms in the beta-tubulin gene and its relationship with treatment response to albendazole in human soil-transmitted helminths in southern Mozambique

9 páginas, 2 tablas, 3 figuras.Soil-transmitted helminth (STH) cornerstone control strategy is mass drug administration (MDA) with benzimidazoles. However, MDA might contribute to selection pressure for anthelmintic resistance, as occurred in livestock. The aim of this study is to evaluate the treatment response to albendazole and the relationship with the presence of putative benzimidazole resistance single-nucleotide polymorphisms (SNPs) in the b-tubulin gene of STH in Southern Mozambique. After screening 819 participants, we conducted a cohort study with 184 participants infected with STH in Manhic¸ a district, Southern Mozambique. A pretreatment and a posttreatment stool samples were collected and the STH infection was identified by duplicate Kato-Katz and quantitative polymerase chain reaction (qPCR). Cure rate and egg reduction rates were calculated. Putative benzimidazole resistance SNPs (F167Y, F200T, and E198A) in Trichuris trichiura and Necator americanus were assessed by pyrosequencing. Cure rates by duplicate Kato-Katz and by qPCR were 95.8% and 93.6% for Ascaris lumbricoides, 28% and 7.8% for T. trichiura, and 88.9% and 56.7% for N. americanus. Egg reduction rate by duplicate Kato-Katz was 85.4% for A. lumbricoides, 34.9% for T. trichiura, and 40.5% for N. americanus. Putative benzimidazole resistance SNPs in the b-tubulin gene were detected in T. trichiura (23%) and N. americanus (21%) infected participants at pretreatment. No statistical difference was observed between pretreatment and posttreatment frequencies for none of the SNPs. Although treatment response to albendazole was low, particularly in T. trichiura, the putative benzimidazole resistance SNPs were not higher after treatment in the population studied. New insights are needed for a better understanding and monitoring of human anthelmintic resistance.This work was supported by the British Society for Antimicrobial Chemotherapy (Bsac-2018-0018) and Mundo Sano Foundation (www.mundosano.org). We acknowledge support from the Spanish Ministry of Science and Innovation through the “Centro de Excelencia Severo Ochoa 2019–2023” Program (CEX2018- 000806-S), and support from the “Generalitat de Catalunya” through the CERCA Program. CISM is supported by the Government of Mozambique and the Spanish Agency for International Development (AECID). M. C. P. was funded by Junta de Castilla y Leon and Fondo Social Europeo (LE-135-19). J. G. was personally supported at the beginning of the work by the Ramon Areces Foundation and is now funded by the Spanish “Juan de la Cierva” Programme, Ministry of Economy and Competitiveness (FJC-2018-38305). M. M. V. by the “Ramon y Cajal ” Programme (RYC-2015-18368), Spanish Ministry of Economy, Industry and Competitiveness (MINECO). This project was in part funded by the EDCTP2 program supported by the European Union (Grant no. RIA2017NCT-1845-STOP; www.stoptheworm.org) Horizon 2020 European Union Funding for Research and Innovation.Peer reviewe

Replication Study and Meta-Analysis in European Samples Supports Association of the 3p21.1 Locus with Bipolar Disorder

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Novel variation and <i>de novo </i>mutation rates in population-wide <i>de novo</i> assembled Danish trios

Building a population-specific catalogue of single nucleotide variants (SNVs), indels and structural variants (SVs) with frequencies, termed a national pan-genome, is critical for further advancing clinical and public health genetics in large cohorts. Here we report a Danish pan-genome obtained from sequencing 10 trios to high depth (50 × ). We report 536k novel SNVs and 283k novel short indels from mapping approaches and develop a population-wide de novo assembly approach to identify 132k novel indels larger than 10 nucleotides with low false discovery rates. We identify a higher proportion of indels and SVs than previous efforts showing the merits of high coverage and de novo assembly approaches. In addition, we use trio information to identify de novo mutations and use a probabilistic method to provide direct estimates of 1.27e−8 and 1.5e−9 per nucleotide per generation for SNVs and indels, respectively

GWAS of Suicide Attempt in Psychiatric Disorders Identifies Association With Major Depression Polygenic Risk Scores

Objective: Over 90% of suicide attempters have a psychiatric diagnosis, however twin and family studies suggest that the genetic etiology of suicide attempt (SA) is partially distinct from that of the psychiatric disorders themselves. Here, we present the largest genome-wide association study (GWAS) on suicide attempt using major depressive disorder (MDD), bipolar disorder (BIP) and schizophrenia (SCZ) cohorts from the Psychiatric Genomics Consortium. Method: Samples comprise 1622 suicide attempters and 8786 non-attempters with MDD, 3264 attempters and 5500 non-attempters with BIP and 1683 attempters and 2946 non-attempters with SCZ. SA GWAS were performed by comparing attempters to non-attempters in each disorder followed by meta-analyses across disorders. Polygenic risk scoring was used to investigate the genetic relationship between SA and the psychiatric disorders. Results: Three genome-wide significant loci for SA were found: one associated with SA in MDD, one in BIP, and one in the meta-analysis of SA in mood disorders. These associations were not replicated in independent mood disorder cohorts from the UK Biobank and iPSYCH. No significant associations were found in the meta-analysis of all three disorders. Polygenic risk scores for major depression were significantly associated with SA in MDD (R2=0.25%, P=0.0006), BIP (R2=0.24%, P=0.0002) and SCZ (R2=0.40%, P=0.0006). Conclusions: This study provides new information on genetic associations and demonstrates that genetic liability for major depression increases risk for suicide attempt across psychiatric disorders. Further collaborative efforts to increase sample size hold potential to robustly identify genetic associations and gain biological insights into the etiology of suicide attempt

Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe