The Space Omics and Medical Atlas (SOMA) and international astronaut biobank.

Spaceflight induces molecular, cellular, and physiological shifts in astronauts and poses myriad biomedical challenges to the human body, which are becoming increasingly relevant as more humans venture into space1-6. Yet, current frameworks for aerospace medicine are nascent and lag far behind advancements in precision medicine on Earth, underscoring the need for rapid development of space medicine databases, tools, and protocols. Here, we present the Space Omics and Medical Atlas (SOMA), an integrated data and sample repository for clinical, cellular, and multi-omic research profiles from a diverse range of missions, including the NASA Twins Study7, JAXA CFE study8,9, SpaceX Inspiration4 crew10-12, plus Axiom and Polaris. The SOMA resource represents a >10-fold increase in publicly available human space omics data, with matched samples available from the Cornell Aerospace Medicine Biobank. The Atlas includes extensive molecular and physiological profiles encompassing genomics, epigenomics, transcriptomics, proteomics, metabolomics, and microbiome data sets, which reveal some consistent features across missions, including cytokine shifts, telomere elongation, and gene expression changes, as well as mission-specific molecular responses and links to orthologous, tissue-specific murine data sets. Leveraging the datasets, tools, and resources in SOMA can help accelerate precision aerospace medicine, bringing needed health monitoring, risk mitigation, and countermeasures data for upcoming lunar, Mars, and exploration-class missions.

Optimal hepatitis C treatment adherence patterns and sustained virologic response among people who inject drugs: The HERO study.

BACKGROUND & AIMS: Direct-acting antivirals (DAAs) are highly effective for treating HCV infection even among people who inject drugs (PWID). Yet, little is known about patients' adherence patterns and their association with sustained virologic response (SVR) rates. We aimed to summarize various adherence patterns and determine their associations with SVR. METHODS: Electronic blister packs were used to measure daily adherence to once-a-day sofosbuvir/velpatasvir during the 12-week treatment period among active PWIDs. Blister pack data were available for 496 participants who initiated DAAs for whom SVR status was known. Adherence was summarized in multiple patterns, such as total adherent days, consecutive missed days, and early discontinuations. Thresholds for adherence patterns associated with >90% SVR rates were also determined. RESULTS: The overall SVR rate was 92.7%, with a median adherence rate of 75%. All adherence patterns indicating greater adherence were significantly associated with achieving SVR. Participant groups with ≥50% (>42/84) adherent days or <26 consecutive missed days achieved an SVR rate of >90%. Greater total adherent days during 9-12 weeks and no early discontinuation were significantly associated with higher SVR rates only in those with <50% adherence. Participants with first month discontinuation and ≥2 weeks of treatment interruption had low SVR rates, 25% and 85%, respectively. However, greater adherent days were significantly associated with SVR (adjusted odds ratio 1.10; 95% CI 1.04-1.16; p <0.001) even among participants with ≥14 consecutive missed days. CONCLUSIONS: High SVR rates can be achieved in the PWID population despite suboptimal adherence. Encouraging patients to take as much medication as possible, with <2 weeks consecutive missed days and without early discontinuation, was found to be important for achieving SVR. IMPACT AND IMPLICATIONS: People who inject drugs can be cured of HCV in >90% of cases, even with relatively low adherence to direct-acting antivirals, but early discontinuations and long treatment interruptions can significantly reduce the likelihood of achieving cure. Clinicians should encourage people who inject drugs who are living with HCV to adhere daily to direct-acting antivirals as consistently as possible, but if any days are interrupted, to continue and complete treatment. These results from the HERO study are important for patients living with HCV, clinicians, experts writing clinical guidelines, and payers. CLINICAL TRIAL NUMBER: NCT02824640.

Haplotype diversity and sequence heterogeneity of human telomeres.

Telomeres are regions of repetitive nucleotide sequences capping the ends of eukaryotic chromosomes that protect against deterioration, and whose lengths can be correlated with age and adverse health risk factors. Yet, given their length and repetitive nature, telomeric regions are not easily reconstructed from short-read sequencing, thus making telomere sequencing, mapping, and variant resolution challenging problems. Recently, long-read sequencing, with read lengths measuring in hundreds of kilobase pairs, has made it possible to routinely read into telomeric regions and inspect their sequence structure. Here, we describe a framework for extracting telomeric reads from whole-genome single-molecule sequencing experiments, including de novo identification of telomere repeat motifs and repeat types, and also describe their sequence variation. We find that long, complex telomeric stretches and repeats can be accurately captured with long-read sequencing, observe extensive sequence heterogeneity of human telomeres, discover and localize noncanonical telomere sequence motifs (both previously reported, as well as novel), and validate them in short-read sequence data. These data reveal extensive intra- and inter-population diversity of repeats in telomeric haplotypes, reveal higher paternal inheritance of telomeric variants, and represent the first motif composition maps of multi-kilobase-pair human telomeric haplotypes across three distinct ancestries (Ashkenazi, Chinese, and Utah), which can aid in future studies of genetic variation, aging, and genome biology.

Test characteristics for combining non-invasive liver fibrosis staging modalities in individuals with Hepatitis C virus.

Non-invasive methods have largely replaced biopsy to identify advanced fibrosis in hepatitis C virus (HCV). Guidelines vary regarding testing strategy to balance accuracy, costs and loss to follow-up. Although individual test characteristics are well-described, data comparing the accuracy of using two tests together are limited. We calculated combined test characteristics to determine the utility of combined strategies. This study synthesizes empirical data from fibrosis staging trials and the literature to estimate test characteristics for Fibrosis-4 (FIB4), APRI or a commercial serum panel (FibroSure®), followed by transient elastography (TE) or FibroSure®. We simulated two testing strategies: (1) second test only for those with intermediate first test results (staged approach), and (2) second test for all. We summarized empiric data with multinomial distributions and used this to estimate test characteristics of each strategy on a simulated population of 10,000 individuals with 4.2% cirrhosis prevalence. Negative predictive value (NPV) for cirrhosis from a single test ranged from 98.2% (95% CB 97.6-98.8%) for FIB-4 to 99.4% (95% CB 99.0-99.8%) for TE. Using a staged approach with TE second, sensitivity for cirrhosis rose to 93.3-96.9%, NPV to 99.7-99.8%, while PPV dropped to <32%. Using TE as a second test for all minimally changed estimated test characteristics compared with the staged approach. Combining two non-invasive fibrosis tests barely improves NPV and decreases or does not change PPV compared with a single test, challenging the utility of serial testing modalities. These calculated combined test characteristics can inform best methods to identify advanced fibrosis in various populations.

Overreporting of adherence to hepatitis C direct-acting antiviral therapy and sustained virologic response among people who inject drugs in the HERO study.

BACKGROUND: Self-reported adherence to direct-acting antivirals (DAAs) to treat hepatitis C virus (HCV) among persons who inject drugs (PWID) is often an overreport of objectively measured adherence. The association of such overreporting with sustained virologic response (SVR) is understudied. This study among PWID aimed to determine a threshold of overreporting adherence that optimally predicts lower SVR rates, and to explore correlates of the optimal overreporting threshold. METHODS: This study analyzed per-protocol data of participants with adherence data (N = 493) from the HERO (Hepatitis C Real Options) study. Self-reported and objective adherence to a 12-week DAA regimen were measured using visual analogue scales and electronic blister packs, respectively. The difference (Δ) between self-reported and objectively measured adherence was calculated. We used the Youden index based on receiver operating characteristic (ROC) curve analysis to identify an optimal threshold of overreporting for predicting lower SVR rates. Factors associated with the optimal threshold of overreporting were identified by comparing baseline characteristics between participants at/above versus those below the threshold. RESULTS: The self-reported, objective, and Δ adherence averages were 95.1% (SD = 8.9), 75.9% (SD = 16.3), and 19.2% (SD = 15.2), respectively. The ≥ 25% overreporting threshold was determined to be optimal. The SVR rate was lower for ≥ 25% vs. < 25% overreporting (86.7% vs. 95.8%, p <.001). The factors associated with ≥ 25% Δ adherence were unemployment; higher number of days and times/day of injecting drugs; higher proportion of positive urine drug screening for amphetamine, methamphetamine, and oxycodone, and negative urine screening for THC (tetrahydrocannabinol)/cannabis. CONCLUSIONS: Self-reported DAA adherence was significantly greater than objectively measured adherence among PWID by 19.2%. Having ≥ 25% overreported adherence was associated with optimal prediction of lower SVR rates. PWID with risk factors for high overreporting may need to be more intensively managed to promote actual adherence.

The effect of antiretroviral therapy with high central nervous system penetration on HIV-related cognitive impairment: a systematic review and meta-analysis.

Chronic complications are a significant concern for people living with HIV/AIDS (PLWHA) infection. HIV-associated neurocognitive disorders (HAND) are prevalent in PLWHA. Yet, the efficacy of medications that penetrate the central nervous system (CNS) at preventing or slowing the progression of HAND remains largely unknown. The objective of this study was to determine whether high CNS penetration effectiveness (CPE) regimens improve neurocognitive test scores in PLWHA on combined antiretroviral therapy (cART). Primary literature evaluating cognitive outcomes based on CPE score of cART regimens in PLWHA was assembled from PubMed/Medline and EMBASE. Both randomized controlled trials and observational studies with at least 12 weeks of follow-up were included. A meta-analysis was conducted to calculate the standardized mean difference. Eight trials including a total of 3,303 patients with 13,103 person-years of follow-up were included in the systematic review. Four trials (n = 366 patients) met our inclusion criteria and were included in the meta-analysis. In the meta-analysis, HIV regimens with a high CPE score did not affect NPZ-4 or GDS scores (standardized mean difference (SMD) 0.10, 95% CI -0.19, 0.38; I2 = 26%). Future studies with larger sample sizes are warranted to prospectively evaluate the relationship between CPE and progression of HAND.

A Video-Observed Treatment Strategy to Improve Adherence to Treatment Among Persons Who Inject Drugs Infected With Hepatitis C Virus: Qualitative Study of Stakeholder Perceptions and Experiences.

BACKGROUND: Direct-acting antiviral medications have the potential to eliminate the hepatitis C virus (HCV) epidemic among people who inject drugs; yet, suboptimal adherence remains a barrier. Directly observed treatment (DOT), an effective strategy for optimizing adherence, has been frequently implemented in opioid treatment programs but less commonly in community health settings due to the heavy burden of daily visits. An alternative is video-observed therapy (VOT), which uses mobile health technology to monitor adherence. VOT has not been widely studied among people who inject drugs with HCV. OBJECTIVE: This qualitative study, part of a larger implementation evaluation, investigates stakeholder perceptions and experiences with VOT in Project HERO (Hepatitis C Real Outcomes), a multisite pragmatic trial testing treatment delivery models for people who inject drugs with HCV. Our goal was to understand the potential barriers and facilitators to the implementation of the VOT technology. METHODS: Qualitative interviews were conducted with 27 Project HERO study staff and 7 patients. Interviews focused on perceptions and experiences with the VOT app and barriers and facilitators to implementation. Team meeting minutes over the first 2 years of the project were transcribed. A coding system was developed and applied to the data. We summarized thematic data and compared participant perceptions to generate a close understanding of the data. RESULTS: Frequent barriers to VOT included mechanical failure, stolen or lost phones, and a steep learning curve for participants and study staff. In sites with older and less technically skilled participants, staff found it difficult to implement the VOT app. Research staff found that the routine monitoring of app use led to closer engagement with participants. This was both a benefit and a potential threat to the validity of this pragmatic trial. Patient participants reported mixed experiences. CONCLUSIONS: VOT may be a useful alternative to DOT for some patients, but it may not be feasible for all. Significant staff involvement may be required.

A Randomized Trial Comparing Brief Advice and Motivational Interviewing for Persons with HIV-HCV Co-infection Who Drink Alcohol.

Alcohol use contributes to the progression of liver disease in HIV-HCV co-infected persons, but alcohol interventions have never addressed low levels of alcohol use in this population. We enrolled 110 persons consuming at least 4 alcoholic drinks weekly in a clinical trial comparing two active 18-month long interventions, delivered every 3 months by phone, brief advice about drinking versus a motivational intervention. Final assessment was at 24 months. MI had larger reductions in alcohol use days than the BA arm at all follow-up assessments. The treatment by time effect was not significant for days of drinking (p = 0.470), mean drinks per day (p = 0.155), or for the continuous FIB-4 index (p = 0.175). Drinking declined in both conditions from baseline, but given the small sample, we do not have sufficient data to make any conclusion that one treatment is superior to the other.Trial Registry Trial registered at clinicaltrials.gov; Clinical Trial NCT02316184.

Chronic opioid use in women following hysterectomy: Patterns and predictors.

BACKGROUND: Most women are prescribed an opioid after hysterectomy. The goal of this study was to determine the association between initial opioid prescribing characteristics and chronic opioid use after hysterectomy. METHODS: This study included women enrolled in a commercial health plan who had a hysterectomy between 1 July 2010 and 31 March 2015. We used trajectory models to define chronic opioid use as patients with the highest probability of having an opioid prescription filled during the 6 months post-surgery. A multivariable logistic regression was applied to examine the association between initial opioid dispensing (amount prescribed and duration of treatment) and chronic opioid use after adjusting for potential confounders. RESULTS: A total of 693 of 50 127 (1.38%) opioid-naïve women met the criteria for chronic opioid use following hysterectomy. The baseline variables and initial opioid prescription characteristics predicted the pattern of long-term opioid use with moderate discrimination (c statistic = 0.70). Significant predictors of chronic opioid use included initial opioid daily dose (≥60 MME vs <40 MME, aOR: 1.43, 95% CI: 1.14-1.79) and days' supply (4-7 days vs 1-3 days, aOR: 1.28, 95% CI: 1.06-1.54; ≥8 days vs 1-3 days, aOR: 1.41, 95% CI: 1.05-1.89). Other significant baseline predictors included older age, abdominal or laparoscopic/robotic hysterectomy, tobacco use, psychiatric medication use, back pain, and headache. CONCLUSION: Initial opioid prescribing characteristics are associated with the risk of chronic opioid use after hysterectomy. Prescribing lower daily doses and shorter days' supply of opioids to women after hysterectomy may result in lower risk of chronic opioid use.

Cytokine/chemokine expression associated with Human Pegivirus (HPgV) infection in women with HIV.

A beneficial impact of the Human Pegivirus (HPgV)-formerly called GB virus C (GBV-C)-on HIV disease progression has been reported previously. One possible mechanism by which HPgV inhibits HIV replication is an alteration of the cytokine/chemokine milieu. Their expression has not been specifically evaluated in women despite their influence on disease progression and the possibility of gender-based differences in expression. Moreover, the impact of HPgV genotype on cytokine/chemokine expression is unknown. Sera levels of IL-2, IL-4, IL-7, IL-8, IL-10, IL-12p70, IL-13, IFNγ, TNFα, IP-10, MIP-1α, MIP-1ß, and TGF-ß1 were quantified in 150 HIV-positive women based on HPgV RNA status. Cytokines/chemokines with detection rates of at least 50% included IL-2, IL-4, IL-8, IL-10, IL-12p70, IFNγ, TNFα, IP-10, MIP-1α, MIP-1ß, and TGF-ß1 . Absolute values were significantly higher for HPgV positive compared to HPgV negative women for IL-7, IL-13, IL-12p70, and IFNγ. Absolute values were significantly lower for HPgV positive women for IL-4, IL-8, TGF-ß1 , and IP-10. IFNγ values were higher for HPgV genotype 2 than for genotype 1 (P = 0.036). Further study of cytokine/chemokine regulation by HPgV may ultimately lead to the development of novel therapeutic agents to treat HIV infection and/or the design of vaccine strategies that mimic the "protective" effects of HPgV replication.

The challenges and opportunities of translating best practice immunisation strategies among low performing general practices to reduce equity gaps in childhood immunisation coverage in New Zealand.

BACKGROUND: Immunisation coverage rates vary considerably at the local level across New Zealand and challenges remain with effectively translating best available research evidence into public health practice. This study aimed to translate best practices from high performing general practices into strategies to improve childhood immunisation coverage among low performing practices. METHODS: An intervention study was undertaken of general practices with low immunisation coverage rates and a high percentage of the enrolled population being of Maori ethnicity. Intervention groups received customised action plans and support for a 12 month period while control groups received 'business as usual' support. Structured interviews were conducted with key informants from all participating practices to understand current aspects related to childhood immunisation delivery and surveys were conducted to understand how the intervention worked. Collected data were thematically analysed. RESULTS: Ten sites were randomised to either intervention (n = 6) or control group (n = 4). Positive aspects of childhood immunisation delivery included high prioritisation at the practice and staff being pro-immunisation and knowledgeable. Key challenges experienced included inaccurate family contact information and discrepancies with referral processes to other providers. Other challenges noted were building rapport with families and vaccine hesitancy. The action plans included various strategies aimed to improve processes at the practice, contact and engagement with parents, and partnership development with local service providers. CONCLUSIONS: Creating customised action plans and providing support to providers were considered as helpful approaches when attempting to improve childhood immunisation coverage rates. Our study supports the notion that one strategy will not solely by itself improve childhood immunisation rates and highlights the importance of having a toolkit of strategies from which to draw from.

A Randomized Controlled Trial to Increase Navy Bean or Rice Bran Consumption in Colorectal Cancer Survivors.

Consumption of navy beans (NB) and rice bran (RB) have been shown to inhibit colon carcinogenesis. Given the overall poor diet quality in colorectal cancer (CRC) survivors and low reported intake of whole grains and legumes, practical strategies to increase consumption merit attention. This study determined feasibility of increasing NB or RB intake in CRC survivors to increase dietary fiber and examined serum inflammatory biomarkers and telomere lengths. Twenty-nine subjects completed a randomized controlled trial with foods that included cooked NB powder (35 g/day), heat-stabilized RB (30 g/day), or no additional ingredient. Fasting blood, food logs, and gastrointestinal health questionnaires were collected. The amount of NB or RB consumed equated to 4-9% of subjects' daily caloric intake and no major gastrointestinal issues were reported with increased consumption. Dietary fiber amounts increased in NB and RB groups at Weeks 2 and 4 compared to baseline and to control (P ≤ 0.01). Telomere length correlated with age and HDL cholesterol at baseline, and with improved serum amyloid A (SAA) levels at Week 4 (P ≤ 0.05). This study concludes feasibility of increased dietary NB and RB consumption to levels associated with CRC chemoprevention and warrants longer-term investigations with both foods in high-risk populations that include cancer prevention and control outcomes.

Restrictions for Medicaid Reimbursement of Sofosbuvir for the Treatment of Hepatitis C Virus Infection in the United States.

The aim of this study was to systematically evaluate state Medicaid policies for the treatment of hepatitis C virus (HCV) infection with sofosbuvir in the United States. Medicaid reimbursement criteria for sofosbuvir were evaluated in all 50 states and the District of Columbia. The authors searched state Medicaid Web sites between 23 June and 7 December 2014 and extracted data in duplicate. Any differences were resolved by consensus. Data were extracted on whether sofosbuvir was covered and the criteria for coverage based on the following categories: liver disease stage, HIV co-infection, prescriber type, and drug or alcohol use. Of the 42 states with known Medicaid reimbursement criteria for sofosbuvir, 74% limit sofosbuvir access to persons with advanced fibrosis (Meta-Analysis of Histologic Data in Viral Hepatitis [METAVIR] fibrosis stage F3) or cirrhosis (F4). One quarter of states require persons co-infected with HCV and HIV to be receiving antiretroviral therapy or to have suppressed HIV RNA levels. Two thirds of states have restrictions based on prescriber type, and 88% include drug or alcohol use in their sofosbuvir eligibility criteria, with 50% requiring a period of abstinence and 64% requiring urine drug screening. Heterogeneity is present in Medicaid reimbursement criteria for sofosbuvir with respect to liver disease staging, HIV co-infection, prescriber type, and drug or alcohol use across the United States. Restrictions do not seem to conform with recommendations from professional organizations, such as the Infectious Diseases Society of America and the American Association for the Study of Liver Diseases. Current restrictions seem to violate federal Medicaid law, which requires states to cover drugs consistent with their U.S. Food and Drug Administration labels.

Current practices of screening for incident hepatitis C virus (HCV) infection among HIV-infected, HCV-uninfected individuals in primary care.

BACKGROUND: Human immunodeficiency virus (HIV)-infected, hepatitis C virus (HCV)-uninfected patients are at risk for incident HCV infection, but little is known about screening practices for incident HCV among HIV-infected individuals in HIV primary care clinics. METHODS: We used data from the Center for AIDS Research Network of Integrated Clinical Systems (CNICS) to investigate historical trends in screening for incident HCV infection among HIV-infected patients who were HCV-uninfected at enrollment in care. We used descriptive measures and Poisson regression to identify factors associated with screening for HCV infection (using HCV antibody or RNA), performed temporal analyses to assess changes in screening over time, and investigated the frequency with which elevated alanine aminotransferase (ALT) levels were followed by diagnostic HCV testing. RESULTS: Among 17 090 patients registered at CNICS sites between 2000 and 2011, 14 534 (85%) received HCV antibody screening within 3 months of enrolling in care, and 9077 met all of the inclusion criteria. Only 55.6% ever received additional HCV screening. HCV screening increased over time, but not uniformly at all sites. Only 26.7% of first-time ALT elevations to >100 IU/L were followed up within 12 months by HCV antibody or RNA testing. CONCLUSIONS: Although most HIV-infected patients were screened for prevalent HCV infection at enrollment in care, only half who were HCV uninfected were screened again. Screening varied between sites, even when controlling for demographics and risk behaviors. Patients with new ALT elevations to >100 IU/L were seldom assessed for incident HCV infection. Guidelines are needed to help HIV providers know whom to screen, how frequently to screen, and which screening test to use.

Breaking down the barriers to hepatitis C virus (HCV) treatment among individuals with HCV/HIV coinfection: action required at the system, provider, and patient levels.

The majority of hepatitis C virus (HCV) and human immunodeficiency virus (HIV) coinfection occurs among persons who inject drugs. Rapid improvements in responses to HCV therapy have been observed, but liver-related morbidity rates remain high, given notoriously low uptake of HCV treatment. Advances in HCV therapy will have a limited impact on the burden of HCV-related disease at the population-level unless barriers to HCV education, screening, evaluation, and treatment are addressed and treatment uptake increases. This review will outline barriers to HCV care in HCV/HIV coinfection, with a particular emphasis on persons who inject drugs, proposing strategies to enhance HCV treatment uptake and outcomes.

Evaluation of intervention components to maximize yoga practice among people with chronic pain taking opioid agonist therapy: A factorial experiment using the multiphase optimization strategy framework.

BACKGROUND: Chronic pain affects up to half of individuals taking opioid agonist therapy (OAT; i.e., methadone and buprenorphine) for opioid use disorder (OUD), and yoga-based interventions may be useful for decreasing pain-related disability. Whereas more yoga practice (i.e., higher "dosage") may improve pain-related outcomes, it can be challenging for people with chronic pain taking OAT to attend class regularly and sustain a regular personal yoga practice. Therefore, we plan to optimize a yoga-based intervention (YBI) package in order to support class attendance and personal practice, thus maximizing the yoga dose received. STUDY DESIGN: Using the Multiphase Optimization Strategy (MOST) framework, we will conduct a factorial experiment to examine four intervention components that may be added to a weekly yoga class as part of a YBI. Components include: 1) personal practice videos featuring study yoga teachers, 2) two private sessions with a yoga teacher, 3) daily text messages to inspire personal practice, and 4) monetary incentives for class attendance. The primary outcome will be minutes per week engaged in yoga (including class attendance and personal practice). We plan to enroll 192 adults with chronic pain who are taking OAT for OUD in this 2x2x2x2 factorial experiment. CONCLUSION: Results of the study will guide development of an optimized yoga-based intervention package that maximizes dosage of yoga received. The final treatment package can be tested in a multisite efficacy trial of yoga to reduce pain interference in daily functioning in people with chronic pain who are taking OAT. TRIAL REGISTRATION: Pre-registration of the study was completed on ClinicalTrials.gov (identifier: NCT04641221).

Telomeric RNA (TERRA) increases in response to spaceflight and high-altitude climbing.

Telomeres are repetitive nucleoprotein complexes at chromosomal termini essential for maintaining genome stability. Telomeric RNA, or TERRA, is a previously presumed long noncoding RNA of heterogeneous lengths that contributes to end-capping structure and function, and facilitates telomeric recombination in tumors that maintain telomere length via the telomerase-independent Alternative Lengthening of Telomeres (ALT) pathway. Here, we investigated TERRA in the radiation-induced DNA damage response (DDR) across astronauts, high-altitude climbers, healthy donors, and cellular models. Similar to astronauts in the space radiation environment and climbers of Mt. Everest, in vitro radiation exposure prompted increased transcription of TERRA, while simulated microgravity did not. Data suggest a specific TERRA DDR to telomeric double-strand breaks (DSBs), and provide direct demonstration of hybridized TERRA at telomere-specific DSB sites, indicative of protective TERRA:telomeric DNA hybrid formation. Targeted telomeric DSBs also resulted in accumulation of TERRA foci in G2-phase, supportive of TERRA's role in facilitating recombination-mediated telomere elongation. Results have important implications for scenarios involving persistent telomeric DNA damage, such as those associated with chronic oxidative stress (e.g., aging, systemic inflammation, environmental and occupational radiation exposures), which can trigger transient ALT in normal human cells, as well as for targeting TERRA as a therapeutic strategy against ALT-positive tumors.

Effect of self-efficacy among persons who inject drugs treated with direct-acting antivirals on Hepatitis C treatment initiation, duration, completion, adherence, and cure.

BACKGROUND: Self-efficacy, a patient-level factor, has been shown to facilitate patient engagement in treatment and optimize treatment-related outcomes in various health contexts. Research on interventions supporting hepatitis C virus (HCV) direct-acting antiviral (DAA) treatment uptake and adherence among persons who inject drugs (PWID) is needed, but whether self-efficacy factors influence DAA treatment cascade outcomes in this population has been less studied. METHODS: Using the HERO study data, we analyzed a subset of participants with any general health self-efficacy data (n=708) measured at baseline and end-of-treatment time points using a 5-items instrument (facets: 'goal setting', 'goal attainment', 'having a positive effect', 'being in control', and 'working to improve'). The cascade outcomes included DAA treatment initiation, duration, adherence, completion, and sustained virologic response (SVR). The effect of baseline and change (Δ) scores for composite and item-level self-efficacy on the cascade outcomes was assessed using logistic regression and generalized linear models. RESULTS: Higher baseline composite self-efficacy [adjusted odds ratio (95 % confidence interval) =1.57 (1.07, 2.29)], 'goal attainment' [1.31 (1.03, 1.67)] and 'having a positive effect' [1.33 (1.03, 1.74)] were associated with greater likelihood of treatment initiation. 'Δ Goal attainment' was significantly associated with SVR [1.63 (1.04, 2.53)]. 'Δ Being in control' and 'Δ working to improve' were associated with treatment adherence and duration, respectively. CONCLUSIONS: General health self-efficacy positively influences DAA treatment initiation among PWID. 'Goal attainment' facilitates the achievement of DAA treatment-related outcomes. Further studies should assess the effect of self-efficacy related to performing healthcare tasks specific to DAAs on the treatment-related outcomes.

Self-reported and measured adherence to hepatitis C direct-acting antiviral therapy and sustained virologic response among people who inject drugs: The HERO study.

BACKGROUND: Objective adherence measures, such as electronic blister pack (BP), for direct-acting antivirals (DAAs) for hepatitis C virus (HCV) treatment have high accuracy, but their use is limited in real practice settings. We examined the association of self-reported adherence using a visual analogue scale (VAS) with objective BP adherence and sustained virologic response (SVR) among people who inject drugs. METHODS: We conducted secondary analyses using a subset of participants (N = 493) from the per-protocol sample of the HERO study, a pragmatic randomized trial of HCV treatment interventions that used both VAS and BP to measure adherence to a 12-week sofosbuvir/velpatasvir DAA regimen. Multivariable mixed-effects regression models tested the association of self-report adherence level with longitudinal weekly objective adherence. Multivariable logistic regression tested the association of self-report adherence with SVR. RESULTS: The average VAS and BP adherences were 95.1 % (SD = 8.9 %) and 76.0 % (16.0 %), respectively, and the proportion of the participants achieving SVR was 92.9 %. The estimated adjusted mean objective adherence was significantly different (-16 %; 95 % CI: -22 %, -11 %, p < .001) between participants with 100 % and <80 % VAS adherence. The likelihood of SVR was significantly lower for those with <80 % VAS adherence [adjusted OR = 0.07; 95 % CI: 0.02, 0.24; p < .001] compared to those with 100 %. CONCLUSION: Self-reported adherence overestimated objective adherence. However, higher self-report adherence was significantly associated with higher objective adherence. Also, self-reported adherence ≥80 % was significantly associated with SVR. Thus, the self-report measure has utility as a monitoring tool for adherence during DAA treatment.