An overall burden of rare structural genomic variants has not been reported in bipolar disorder (BD), although there have been reports of cases with microduplication and microdeletion. Here, we ...present a genome-wide copy number variant (CNV) survey of 1001 cases and 1034 controls using the Affymetrix single nucleotide polymorphism (SNP) 6.0 SNP and CNV platform. Singleton deletions (deletions that appear only once in the dataset) more than 100 kb in length are present in 16.2% of BD cases in contrast to 12.3% of controls (permutation P=0.007). This effect was more pronounced for age at onset of mania <or=18 years old. Our results strongly suggest that BD can result from the effects of multiple rare structural variants.
Abstract
Recognizing the importance of timely guidance regarding the rapidly evolving field of hepatitis C management, the American Association for the Study of Liver Diseases (AASLD) and the ...Infectious Diseases Society of America (IDSA) developed a web-based process for the expeditious formulation and dissemination of evidence-based recommendations. Launched in 2014, the hepatitis C virus (HCV) guidance website undergoes periodic updates as necessitated by availability of new therapeutic agents and/or research data. A major update was released electronically in September 2017, prompted primarily by approval of new direct-acting antiviral agents and expansion of the guidance's scope. This update summarizes the latest release of the HCV guidance and focuses on new or amended recommendations since the previous September 2015 print publication. The recommendations herein were developed by volunteer hepatology and infectious disease experts representing AASLD and IDSA and have been peer reviewed and approved by each society's governing board.
We conducted a systematic study of top susceptibility variants from a genome-wide association (GWA) study of bipolar disorder to gain insight into the functional consequences of genetic variation ...influencing disease risk. We report here the results of experiments to explore the effects of these susceptibility variants on DNA methylation and mRNA expression in human cerebellum samples. Among the top susceptibility variants, we identified an enrichment of cis regulatory loci on mRNA expression (eQTLs), and a significant excess of quantitative trait loci for DNA CpG methylation, hereafter referred to as methylation quantitative trait loci (mQTLs). Bipolar disorder susceptibility variants that cis regulate both cerebellar expression and methylation of the same gene are a very small proportion of bipolar disorder susceptibility variants. This finding suggests that mQTLs and eQTLs provide orthogonal ways of functionally annotating genetic variation within the context of studies of pathophysiology in brain. No lymphocyte mQTL enrichment was found, suggesting that mQTL enrichment was specific to the cerebellum, in contrast to eQTLs. Separately, we found that using mQTL information to restrict the number of single-nucleotide polymorphisms studied enhances our ability to detect a significant association. With this restriction a priori informed by the observed functional enrichment, we identified a significant association (rs12618769, P(bonferroni)<0.05) from two other GWA studies (TGen+GAIN; 2191 cases and 1434 controls) of bipolar disorder, which we replicated in an independent GWA study (WTCCC). Collectively, our findings highlight the importance of integrating functional annotation of genetic variants for gene expression and DNA methylation to advance the biological understanding of bipolar disorder.
To estimate the joint effects of substance use disorder (SUD) and recent substance use on human immunodeficiency virus (HIV) non-suppression.
Retrospective clinical cohort study with repeated ...observations within individuals.
Baltimore, Maryland, United States.
1881 patients contributed 10 794 observations.
The primary independent variable was the combination of history of SUD and recent substance use. History of SUD was defined as any prior International Classification of Diseases 9/10 code for cocaine or opioid disorder. Recent substance use was defined as the self-report of cocaine or non-prescribed opioid use on the National Institute of Drug Abuse-modified Alcohol, Smoking and Substance Involvement Screening Test or clinician-documented cocaine or opioid use abstracted from the medical record. The outcome was viral non-suppression, defined as HIV RNA >200 copies/mL on the first viral load measurement within 1 year subsequent to each observation of substance use. We adjusted for birth sex, Black race, age, HIV acquisition risk factors, years in care and CD4 cell count. In secondary analyses, we also adjusted for depressive, anxiety and panic symptoms, cannabis use and cannabis use disorder.
On their first observation, 31% of patients had a history of an SUD and 18% had recent substance use. Relative to no history of SUD and no recent substance use, the 1-year fully adjusted risk difference (RD) for viral non-suppression associated with cocaine and opioid use disorder and recent substance use was 7.7% (95% CI = 5.3%-10.0%), the RD was 5.5% (95% CI = 1.2%-9.7%) for history of cocaine use disorder without recent substance use, and the RD was 4.6% (95% CI = 2.7%-6.5%) for recent substance use without a SUD.
Substance use and substance use disorders appear to be highly prevalent among, and independently associated with, viral non-suppression among people with HIV.
To identify bipolar disorder (BD) genetic susceptibility factors, we conducted two genome-wide association (GWA) studies: one involving a sample of individuals of European ancestry (EA; n=1001 cases; ...n=1033 controls), and one involving a sample of individuals of African ancestry (AA; n=345 cases; n=670 controls). For the EA sample, single-nucleotide polymorphisms (SNPs) with the strongest statistical evidence for association included rs5907577 in an intergenic region at Xq27.1 (P=1.6 x 10(-6)) and rs10193871 in NAP5 at 2q21.2 (P=9.8 x 10(-6)). For the AA sample, SNPs with the strongest statistical evidence for association included rs2111504 in DPY19L3 at 19q13.11 (P=1.5 x 10(-6)) and rs2769605 in NTRK2 at 9q21.33 (P=4.5 x 10(-5)). We also investigated whether we could provide support for three regions previously associated with BD, and we showed that the ANK3 region replicates in our sample, along with some support for C15Orf53; other evidence implicates BD candidate genes such as SLITRK2. We also tested the hypothesis that BD susceptibility variants exhibit genetic background-dependent effects. SNPs with the strongest statistical evidence for genetic background effects included rs11208285 in ROR1 at 1p31.3 (P=1.4 x 10(-6)), rs4657247 in RGS5 at 1q23.3 (P=4.1 x 10(-6)), and rs7078071 in BTBD16 at 10q26.13 (P=4.5 x 10(-6)). This study is the first to conduct GWA of BD in individuals of AA and suggests that genetic variations that contribute to BD may vary as a function of ancestry.
Background and Aims
Direct‐acting antivirals (DAAs) are highly effective in treating hepatitis C. However, there is concern that cure rates may be lower, and reinfection rates higher, among people ...who inject drugs. We conducted a systematic review of treatment outcomes achieved with DAAs in people who inject drugs (PWID).
Methods
A search strategy was used to identify studies that reported sustained viral response (SVR), treatment discontinuation, adherence or reinfection in recent PWID and/or opioid substitution therapy (OST) recipients. Study quality was assessed using the Newcastle‐Ottawa Scale. Meta‐analysis of proportions was used to estimate pooled SVR and treatment discontinuation rates. The pooled relative risk of achieving SVR and pooled reinfection rate were calculated using generalized mixed effects linear models.
Results
The search identified 8075 references; 26 were eligible for inclusion. The pooled SVR for recent PWID was 88% (95% CI, 83%‐92%) and 91% (95% CI 88%‐95%) for OST recipients. The relative risk of achieving SVR for recent PWID compared to non‐recent PWID was 0.99 (95% CI, 0.94‐1.06). The pooled treatment discontinuation was 2% (95% CI, 1%‐4%) for both recent PWID and OST recipients. Amongst recent PWID, the pooled incidence of reinfection was 1.94 per 100 person years (95% CI, 0.87‐4.32). In OST recipients, the incidence of reinfection was 0.55 per 100 person years (95% CI, 0.17‐1.76).
Conclusions
Treatment outcomes were similar in recent PWID compared to non‐PWID treated with DAAs. People who report recent injecting or OST recipients should not be excluded from hepatitis C treatment.
See Editorial on Page 2238
Background
Increased uptake of hepatitis C virus (HCV) treatment among people who inject drugs (PWID) will be critical to achieve HCV elimination goals. There are limited data on HCV treatment uptake ...among PWID recruited from community‐based settings in the HCV direct‐acting antiviral (DAA) era.
Methods
We analysed data from PWID with HCV newly recruited into the Baltimore, Maryland‐based AIDS Linked to the IntraVenous Experience (ALIVE) cohort between 2015 and 2018. We characterized the HCV care continuum and evaluated factors associated with HCV treatment uptake.
Results
Of the 418 PWID with HCV, the median age was 49 years and most (88%) reported recent injection drug use (IDU). Overall, 23% had ever been evaluated by a provider for HCV treatment, 17% ever initiated DAA treatment and 13% were cured of HCV infection. Treatment uptake approximately doubled between 2015 and 2018 (13% to 26%, P = .01). In multivariable analyses, HIV infection (adjusted Odds Ratio aOR 2.5 95% Confidence Interval (CI) 1.3, 4.8), current employment (aOR 4.1 CI 1.2, 14.4), having a primary care provider (aOR 4.3 CI 1.2, 14.9) and longer duration of IDU (aOR 1.3 CI 1.1, 1.6) were positively associated with HCV treatment. PWID with a lower annual income (≤$5000) were less likely to have initiated HCV treatment (aOR 0.5 CI 0.3, 0.98).
Conclusions
Although HCV treatment uptake among PWID in this community‐based setting in the DAA era remains suboptimal, it is encouraging that treatment uptake has increased in recent years. Innovative strategies are needed to reach all PWID infected with HCV.
Background and aims
People who inject drugs (PWID) are at risk for adverse outcomes across multiple dimensions. While evidence‐based interventions are available, services are often fragmented and ...difficult to access. We measured the effectiveness of an integrated care van (ICV) that offered services for PWID.
Design, setting and participants
This was a cluster‐randomized trial, which took place in Baltimore, MD, USA. Prior to randomization, we used a research van to recruit PWID cohorts from 12 Baltimore neighborhoods (sites), currently served by the city's mobile needle exchange program.
Intervention and comparator
We randomized sites to receive weekly visits from the ICV (n = 6) or to usual services (n = 6) for 14 months. The ICV offered case management; buprenorphine/naloxone; screening for HIV, hepatitis C virus and sexually transmitted infections; HIV pre‐exposure prophylaxis; and wound care.
Measurements
The primary outcome was a composite harm mitigation score that captured access to evidence‐based services, risk behaviors and adverse health events (range = 0−15, with higher numbers indicating worse status). We evaluated effectiveness by comparing changes in the composite score at 7 months versus baseline in the two study arms.
Findings
We enrolled 720 cohort participants across the study sites (60 per site) between June 2018 and August 2019: 38.3% women, 72.6% black and 85.1% urine drug test positive for fentanyl. Over a median of 10.4 months, the ICV provided services to 734 unique clients (who may or may not have been cohort participants) across the six intervention sites, including HIV/hepatitis C virus testing in 577 (78.6%) and buprenorphine/naloxone initiation in 540 (74%). However, only 52 (7.2%) of cohort participants received services on the ICV. The average composite score decreased at 7 months relative to baseline, with no significant difference in the change between ICV and usual services (difference in differences: −0.31; 95% confidence interval: −0.70, 0.08; P = 0.13).
Conclusions
This cluster‐randomized trial in Baltimore, MD, USA, found no evidence that weekly neighborhood visits from a mobile health van providing injection‐drug‐focused services improved access to services and outcomes among people who injected drugs in the neighborhood, relative to usual services. The van successfully served large numbers of clients but unexpectedly low use of the van by cohort participants limited the ability to detect meaningful differences.
Fatal opioid overdose is a pressing public health concern in the United States. Addressing barriers and augmenting facilitators to take-home naloxone (THN) access and administration could expand ...program reach in preventing fatal overdoses.
THN access (i.e., being prescribed or receiving THN) was assessed in a Baltimore, Maryland-based sample of 577 people who use opioids (PWUO) and had a history of injecting drugs. A sub-analysis examined correlates of THN administration among those with THN access and who witnessed an overdose (N = 345). Logistic generalized estimating equations with robust standard errors were used to identify facilitators and barriers to accessing and using THN.
The majority of PWUO (66%) reported THN access. In the multivariable model, decreased THN access was associated with the fear that a person may become aggressive after being revived with THN (aOR: 0.55, 95% CI: 0.35-0.85), police threaten people at an overdose event (aOR: 0.68, 95% CI: 0.36-1.00), and insufficient overdose training (aOR: 0.43, 95% CI: 0.28-0.68). Enrollment in medication-assisted treatment, personally experiencing an overdose, and graduating from high school were associated with higher access. About half (49%) of PWUO with THN access and who had witnessed an overdose reported having administered THN. THN use was positively associated with "often" or "always" carrying THN (aOR: 3.47, 95% CI: 1.99-6.06), witnessing more overdoses (aOR:5.18, 95% CI: 2.22-12.07), experiencing recent homelessness, and injecting in the past year. THN use was reduced among participants who did not feel that they had sufficient overdose training (aOR: 0.56, 95% CI: 0.32-0.96).
THN programs must bolster confidence in administering THN and address barriers to use, such as fear of a THN recipient becoming aggressive. Normative change around carrying THN is an important component in an overdose prevention strategy.
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