To achieve WHO targets for the elimination of hepatitis C virus (HCV) as a public threat, an increased uptake of HCV treatment among people who inject drugs (PWID) is urgently needed. Optimal HCV ...co-located treatment models for PWID have not yet been identified. We aimed to compare two patient-centred models of HCV care in PWID with active drug use.
We did a pragmatic randomised controlled trial at eight US cities in eight opioid treatment programmes and 15 community health centres. PWID actively injecting within 90 days of study entry were randomly assigned (1:1) to either patient navigation or modified directly observed therapy (mDOT) using computer-generated variable block sizes of 2-6 stratified by city, clinical settings, and cirrhosis status. The randomisation code was concealed, in a centralised REDCap database platform, from all investigators and research staff except for an authorised data manager at the data coordinating centre. All participants received a fixed-dose combination tablet (sofosbuvir 400 mg plus velpatasvir 100 mg) orally once daily for 12 weeks. The primary outcome was sustained virological response (SVR; determined by chart review between 70 days and 365 days after end of treatment and if unavailable, by study blood draws), and secondary outcomes were treatment initiation, adherence (measured by electronic blister packs), and treatment completion. Analyses were conducted within the modified intention-to-treat (mITT; all who initiated treatment), intention-to-treat (all who were randomised), and per-protocol populations. This trial is registered with ClinicalTrials.gov, NCT02824640.
Between Sept 15, 2016, and Aug 14, 2018, 1891 individuals were screened and 1136 were excluded (213 declined to participate and 923 did not meet the eligibility criteria). We randomly assigned 755 participants to patient navigation (n=379) or mDOT (n=376). In the mITT sample of participants who were randomised and initiated treatment (n=623), 226 (74% 95% CI 69-79) of 306 participants in the mDOT group and 236 (76% 69-79) of 317 in the patient navigation group had an SVR, with no significant difference between the groups (adjusted odds ratio AOR 0·97 95% CI 0·66-1·42; p=0·35). In the ITT sample (n=755), 226 (60% 95% CI 55-65) of 376 participants in the mDOT group and 236 (62% 57-67) of 379 in the patient navigation group had an SVR (AOR 0·92 0·68-1·25; p=0·61) and in the per-protocol sample (n=501), 226 (91% 87-94) of 248 participants in the mDOT group and 235 (93% 89-96) of 253 in the patient navigation group had an SVR (AOR 0·79 0·41-1·55; p=0·44). 306 (81%) of 376 participants in the mDOT group and 317 (84%) of 379 participants in the patient navigation group initiated treatment (AOR 0·86 0·58-1·26; p=0·44) and, among those, 251 (82%) participants in the mDOT group and 264 (83%) participants in the patient navigation group completed treatment (AOR 0·90 0·58-1·39; p=0·63). Mean daily adherence was higher in the mDOT group (78% 95% CI 75-81) versus the patient navigation group (73% 70-77), with a difference of 4·7% (1·9-7·4; p=0·0010). 421 serious adverse events were reported (217 in the mDOT group and 204 in the patient navigation group), with the most common being hospital admission (176 in the mDOT group vs 161 in the patient navigation group).
In this trial of active PWID, both models resulted in high SVR. Although adherence was significantly higher in the mDOT group versus the patient navigation group, there was no significant difference in SVR between the groups. Increases in adherence and treatment completion were associated with an increased likelihood of SVR. These results suggest that active PWID can reach high SVRs in diverse settings with either mDOT or patient navigation support.
Patient-Centered Outcomes Research Institute, Gilead Sciences, Quest Diagnostics, Monogram Biosciences, and OraSure Technologies.
Viremic controllers and elite controllers/suppressors maintain control over HIV-1 replication. Some studies have suggested that control is a result of infection with a defective viral strain, while ...others suggested host immune factors have a key role. Here we document two HIV-1 transmission pairs: one consisting of a patient with progressive disease and an individual who became an elite suppressor, and the second consisting of a patient with progressive disease and a viremic controller. In contrast to another elite suppressor transmission pair, virus isolated from all patients was fully competent. These data suggest that some viremic controllers and elite suppressors are infected with HIV-1 isolates that replicate vigorously in vitro and are able to cause progressive disease in vivo. These data suggest that host factors have a dominant role in the control of HIV-1 infection, thus it may be possible to control fully pathogenic HIV-1 isolates with therapeutic vaccination.
Although people who inject drugs (PWID) having the highest incidence and prevalence of hepatitis C virus (HCV) in the US, HCV treatment is rarely provided to PWID due to assumptions about poor ...adherence and reinfection risk. As direct-acting antiviral agents (DAAs) have achieved sustained virologic response (SVR) rates of 95% or more, evidence-based strategies are urgently needed to demonstrate real-world effectiveness in marginalized patient populations such as PWID. The objectives of this study are: 1) to determine whether either of two patient-centered treatment models – patient navigation (PN) or modified directly observed therapy (mDOT) – results in more forward movement along the HCV care cascade including treatment initiation, adherence, and SVR; 2) using quantitative and qualitative methods, to understand factors associated with lack of treatment uptake, poor adherence (<80%), failure to achieve SVR, DAA resistance, and HCV reinfection.
The HERO study is a multi-site, pragmatic randomized clinical trial conducted in eight states where 754 HCV-infected PWID were randomly assigned to either PN or mDOT.
This study addresses an urgent need for timely and accurate information on optimal models of care to promote HCV treatment initiation, adherence, treatment completion and SVR among PWID, as well as rates and factors associated with reinfection and resistance after treatment. This clinical trial has the potential to provide valuable information on how to reduce the burden of the HCV epidemic in PWID.
Increasing research suggests that gait abnormalities can be a risk factor for Alzheimer's Disease (AD). Notably, there is growing evidence highlighting this risk factor in individuals with amnestic ...Mild Cognitive Impairment (aMCI), however further studies are needed. The aim of this study is to analyze cognitive tests results and brain-related measures over time in aMCI and examine how the presence of gait abnormalities (neurological or orthopedic) or normal gait affects these trends. Additionally, we sought to assess the significance of gait and gait-related measures as prognostic indicators for the progression from aMCI to AD dementia, comparing those who converted to AD with those who remained with a stable aMCI diagnosis during the follow-up.
Four hundred two individuals with aMCI from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database were included. Robust linear mixed-effects models were used to study the impact of gait abnormalities on a comprehensive neuropsychological battery over 36 months while controlling for relevant medical variables at baseline. The impact of gait on brain measures was also investigated. Lastly, the Cox proportional-hazards model was used to explore the prognostic relevance of abnormal gait and neuropsychological associated tests.
While controlling for relevant covariates, we found that gait abnormalities led to a greater decline over time in attention (DSST) and global cognition (MMSE). Intriguingly, psychomotor speed (TMT-A) and divided attention (TMT-B) declined uniquely in the abnormal gait group. Conversely, specific AD global cognition tests (ADAS-13) and auditory-verbal memory (RAVLT immediate recall) declined over time independently of gait profile. All the other cognitive tests were not significantly affected by time or by gait profile. In addition, we found that ventricles size increased faster in the abnormal gait group compared to the normal gait group. In terms of prognosis, abnormal gait (HR = 1.7), MMSE (HR = 1.09), and DSST (HR = 1.03) covariates showed a higher impact on AD dementia conversion.
The importance of the link between gait and related cognitive functions in terms of diagnosis, prognosis, and rehabilitation in aMCI is critical. We showed that in aMCI gait abnormalities lead to executive functions/attention deterioration and conversion to AD dementia.
Deep learning has shown potential in various scientific domains but faces challenges when applied to complex, high-dimensional multi-omics data. Alzheimer's Disease (AD) is a neurodegenerative ...disorder that lacks targeted therapeutic options. This study introduces the Circular-Sliding Window Association Test (c-SWAT) to improve the classification accuracy in predicting AD using serum-based metabolomics data, specifically lipidomics.
The c-SWAT methodology builds upon the existing Sliding Window Association Test (SWAT) and utilizes a three-step approach: feature correlation analysis, feature selection, and classification. Data from 997 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) served as the basis for model training and validation. Feature correlations were analyzed using Weighted Gene Co-expression Network Analysis (WGCNA), and Convolutional Neural Networks (CNN) were employed for feature selection. Random Forest was used for the final classification.
The application of c-SWAT resulted in a classification accuracy of up to 80.8% and an AUC of 0.808 for distinguishing AD from cognitively normal older adults. This marks a 9.4% improvement in accuracy and a 0.169 increase in AUC compared to methods without c-SWAT. These results were statistically significant, with a p-value of 1.04 x 10ˆ-4. The approach also identified key lipids associated with AD, such as Cer(d16:1/22:0) and PI(37:6).
Our results indicate that c-SWAT is effective in improving classification accuracy and in identifying potential lipid biomarkers for AD. These identified lipids offer new avenues for understanding AD and warrant further investigation.
Identifying prediagnostic neurodegenerative disease is a critical issue in neurodegenerative disease research, and Alzheimer's disease (AD) in particular, to identify populations suitable for ...preventive and early disease-modifying trials. Evidence from genetic and other studies suggests the neurodegeneration of Alzheimer's disease measured by brain atrophy starts many years before diagnosis, but it is unclear whether these changes can be used to reliably detect prediagnostic sporadic disease.
We trained a Bayesian machine learning neural network model to generate a neuroimaging phenotype and AD score representing the probability of AD using structural MRI data in the Alzheimer's Disease Neuroimaging Initiative (ADNI) Cohort (cut-off 0.5, AUC 0.92, PPV 0.90, NPV 0.93). We go on to validate the model in an independent real-world dataset of the National Alzheimer's Coordinating Centre (AUC 0.74, PPV 0.65, NPV 0.80) and demonstrate the correlation of the AD-score with cognitive scores in those with an AD-score above 0.5. We then apply the model to a healthy population in the UK Biobank study to identify a cohort at risk for Alzheimer's disease.
We show that the cohort with a neuroimaging Alzheimer's phenotype has a cognitive profile in keeping with Alzheimer's disease, with strong evidence for poorer fluid intelligence, and some evidence of poorer numeric memory, reaction time, working memory, and prospective memory. We found some evidence in the AD-score positive cohort for modifiable risk factors of hypertension and smoking.
This approach demonstrates the feasibility of using AI methods to identify a potentially prediagnostic population at high risk for developing sporadic Alzheimer's disease.
The search to identify genes for the susceptibility to alcohol dependence (AD) is generating interest for genetic risk assessment. The purpose of this study is to examine the level of interest and ...concerns for genetic testing for susceptibility to AD.
Three hundred four African American adults were recruited through public advertisement. All participants were administered the Genetic Psycho-Social Implication (GPSI) questionnaire, which surveyed their interests in hypothetical genetic testing for AD, as well as their perception of ethical and legal concerns.
Over 85% of participants were interested in susceptibility genetic testing; however, persons with higher education (p=0.002) and income (p=0.008) were less willing to receive testing. Perception of AD as a deadly disease (48.60%) and wanting to know for their children (47.90%) were the strongest reasons for interest in testing. Among those not interested in testing, the belief that they were currently acting to lower their risk was the most prevalent. The most widely expressed concern in the entire sample was the accuracy of testing (35.50%). Other notable concerns, such as issues with the method of testing, side effects of venipuncture, falsely reassuring results, and lack of guidelines on "what to do next" following test results, were significantly associated with willingness to receive testing.
Although an overwhelming majority of participants expressed an interest in genetic testing for AD, there is an understandable high level of methodological and ethical concerns. Such information should form the basis of policies to guide future genetic testing of AD.
Abstract Background Migraine is a common comorbidity among individuals with bipolar disorder, but the underlying mechanisms for this co-occurrence are poorly understood. The aim of this study was to ...investigate the genetic background of bipolar patients with and without migraine. Methods We performed a genome-wide association analysis contrasting 460 bipolar migraneurs with 914 bipolar patients without migraine from the Bipolar Genome Study (BiGS). Results We identified one genome-wide significant association between migraine in bipolar disorder patients and rs1160720, an intronic single nucleotide polymorphism (SNP) in the NBEA gene ( P =2.97×10−8 , OR: 1.82, 95% CI: 1.47–2.25), although this was not replicated in a smaller sample of 289 migraine cases. Limitations Our study is based on self-reported migraine. Conclusions NBEA encodes neurobeachin, a scaffolding protein primarily expressed in the brain and involved in trafficking of vesicles containing neurotransmitter receptors. This locus has not previously been implicated in migraine per se. We found no evidence of association in data from the GWAS migraine meta-analysis consortium ( n =118,710 participants) suggesting that the association might be specific to migraine co-morbid with bipolar disorder.
Baltimore is an urban center that has been highly impacted by human immunodeficiency virus (HIV) and hepatitis C virus (HCV); however, many individuals are unaware of their HIV and/or HCV status. In ...2013, the Johns Hopkins Center for AIDS Research (CFAR) developed Generation Tomorrow, an HIV and HCV education, testing, and counseling program with community input and collaboration.
The aims of Generation Tomorrow are to increase HIV and HCV awareness and detection in Baltimore and engage the next generation of health professionals (students) and community members (peers) in HIV and HCV outreach services.
The Generation Tomorrow educational component includes formal HIV and HCV testing and counselling training, and a lecture series for students and peers. The participants then engage in field assignments and outreach events with Johns Hopkins associated programs or community-based organizations.
Generation Tomorrow trained 71 students and peers in three cohorts, 70% of whom reported that they planned to stay in HIV- and/or HCV-related work. From October 2014 to May 2015, which represents the first year that Generation Tomorrow ran with the full academic calendar, Generation Tomorrow students and peers worked with partner organizations to conduct 1,104 HIV rapid antibody tests and found 19 individuals (1.72%) to be HIV positive. Additionally, 778 HCV rapid antibody tests were conducted and 175 individuals (22.5%) were HCV antibody positive.
Generation Tomorrow has been successful in engaging students and community peers in HIV and HCV education, testing, and counseling, and has documented HIV and HCV positivity rates well above general community prevalence.
Research suggests that clinical symptom dimensions may be more useful in delineating the genetics of bipolar disorder (BD) than standard diagnostic models. To date, no study has applied this concept ...to data from genome-wide association studies (GWAS). We performed a GWAS of factor dimensions in 927 clinically well-characterized BD patients of German ancestry. Rs9875793, which is located in an intergenic region of 3q26.1 and in the vicinity of the solute carrier family 2 (facilitated glucose transporter), member 2 gene (SLC2A2), was significantly associated with the factor analysis-derived dimension 'negative mood delusions' (n=927; P=4.65 × 10(-8), odds ratio (OR)=2.66). This dimension was comprised of the symptoms delusions of poverty, delusions of guilt and nihilistic delusions. In case-control analyses, significant association with the G allele of rs9875793 was only observed in the subgroup of BD patients who displayed symptoms of 'negative mood delusions' (allelic χ(2) model: P(G)=0.0001, OR=1.92; item present, n=89). Further support for the hypothesis that rs9875793 is associated with BD in patients displaying 'negative mood delusions' symptom, such as delusions of guilt, was obtained from an European American sample (GAIN/TGEN), which included 1247 BD patients and 1434 controls (P(EA)=0.028, OR=1.27).
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