Genome and clonal hematopoiesis stability contrasts with immune, cfDNA, mitochondrial, and telomere length changes during short duration spaceflight.

Background: The Inspiration4 (I4) mission, the first all-civilian orbital flight mission, investigated the physiological effects of short-duration spaceflight through a multi-omic approach. Despite advances, there remains much to learn about human adaptation to spaceflight's unique challenges, including microgravity, immune system perturbations, and radiation exposure. Methods: To provide a detailed genetics analysis of the mission, we collected dried blood spots pre-, during, and post-flight for DNA extraction. Telomere length was measured by quantitative PCR, while whole genome and cfDNA sequencing provided insight into genomic stability and immune adaptations. A robust bioinformatic pipeline was used for data analysis, including variant calling to assess mutational burden. Result: Telomere elongation occurred during spaceflight and shortened after return to Earth. Cell-free DNA analysis revealed increased immune cell signatures post-flight. No significant clonal hematopoiesis of indeterminate potential (CHIP) or whole-genome instability was observed. The long-term gene expression changes across immune cells suggested cellular adaptations to the space environment persisting months post-flight. Conclusion: Our findings provide valuable insights into the physiological consequences of short-duration spaceflight, with telomere dynamics and immune cell gene expression adapting to spaceflight and persisting after return to Earth. CHIP sequencing data will serve as a reference point for studying the early development of CHIP in astronauts, an understudied phenomenon as previous studies have focused on career astronauts. This study will serve as a reference point for future commercial and non-commercial spaceflight, low Earth orbit (LEO) missions, and deep-space exploration.

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.

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.

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).

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.

Reduction in Depressive Symptoms in People who Inject Drugs who Are Cured of Hepatitis C Virus Infection: The HERO Study.

Background: Depressive symptoms are prevalent among people who inject drugs (PWID) and people with hepatitis C virus (HCV). We examined changes in depressive symptoms among HCV-infected PWID following direct-acting antiviral treatments to evaluate whether these changes differed by history of depressive symptoms, substance use, or HCV treatment outcome. Methods: We conducted a secondary analysis of the HERO Study (NCT02824640), a pragmatic randomized clinical trial among PWID, to test the effectiveness of HCV care models. Depressive symptoms (primary outcome) were measured using the Patient Health Questionnaire (PHQ-9) at baseline, end of treatment (EOT), and at follow-up 12 and 24 weeks after EOT. Sustained virologic response (SVR) was defined as undetectable HCV RNA at ≥12 weeks following EOT. Baseline drug use was defined as having a positive urine screening test for amphetamine, methamphetamine, benzodiazepine, cocaine, cannabis, opiate, or oxycodone. Results: The sample (n = 498) was 72.3% male, 64.2% White, and on average 43.9 years old. In patients who achieved SVR (F(3432) = 4.58; P = .004) and those with drug use at baseline (F(3478) = 5.11; P < .01), PHQ-9 scores significantly declined over time, with scores lower at EOT and both follow-ups as compared with baseline. Mean PHQ-9 scores at EOT and follow-ups were significantly lower than at baseline, except for those with no depression or mild depression at baseline. Conclusions: This study showed that HCV treatment in PWID is associated with sustained declines in depression up to 24 weeks post-treatment among those who achieve SVR and that drug use does not interfere with improvement in depressive symptoms.

Shame and stigma in association with the HCV cascade to cure among people who inject drugs.

BACKGROUND: Psycho-social experiences including shame and experienced and internalized stigma have been associated with substance use, HCV infection, and reluctance to disclose HCV status and pursue treatment. These psycho-social barriers have been examined independently for many chronic diseases, including HCV, but to our knowledge have not been quantitatively explored in a large multi-site US-based sample of people who inject drugs (PWID) in HCV treatment. METHODS: We examine baseline relationships with HCV-stigma and engagement across the HCV treatment cascade as well as baseline and longitudinal relationships between shame and engagement across the HCV treatment cascade including treatment initiation, adherence, completion, and sustained virologic response (SVR) among a multi-site sample of PWID with HCV, where N=755 were randomized to the pragmatic trial comparing HCV treatment outcomes in modified directly observed treatment (mDOT) or patient navigation, and N=623 initiated treatment. RESULTS: While cross-sectional assessments of shame and HCV-stigma were not associated with engagement across the HCV treatment cascade, those whose shame scores decreased compared to those who reported consistently high and increasing levels of shame were significantly more likely to complete HCV treatment (aOR=5.29; 95%CI: 1.56,18.00) and achieve SVR (aOR=6.32; 95%CI: 1.61, 24.87). CONCLUSION: Results underscore the relationships between lower levels of shame and health-related behavior and treatment outcomes among PWID and suggest SVR achievement may contribute to reductions in shame or that reductions in shame may contribute to continued treatment and thus SVR.

An expanded safety/feasibility study of the EMulate Therapeutics Voyager™ System in patients with recurrent glioblastoma.

Aim: The EMulate Therapeutics Voyager™ is a simple, wearable, home-use device that uses an alternating electromagnetic field to alter biologic signaling within cells. Objective: To assess the safety/feasibility of the Voyager in the treatment of recurrent glioblastoma (rGBM). Methods: In this study, patients with rGBM were treated with Voyager as monotherapy or in combination with standard chemotherapy at the Investigator's discretion. Safety was assessed by incidence of adverse events associated with the Voyager. Patients were followed until death. Results: A total of 75 patients were enrolled and treated for at least one day with the Voyager (safety population). Device-related adverse events were uncommon and generally did not result in interruption or withdrawal from treatment. There were no serious adverse events associated with Voyager. A total of 60 patients were treated for at least one month (clinical utility population). The median progression-free survival (PFS) was 17 weeks (4.3 months) in the Voyager only group (n = 24) and 21 weeks (5.3 months) in the Voyager + concurrent therapy group (n = 36). The median overall survival (OS) was 7 months in the Voyager only group and 9 months in the Voyager + concurrent therapy group. In patients treated with Voyager + concurrent therapy, the median OS for patients enrolled with their 1st or 2nd recurrence (n = 26) was 10 months, while in patients enrolled with their 3rd or 4th recurrence (n = 10) OS was 7 months. Conclusion: The data support the safety and feasibility of the Voyager for the treatment of rGBM. Further prospective study of the device is warranted. Trial Registration Number: NCT02296580 (ClinicalTrials.gov).

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.

Injecting practices during and after hepatitis C treatment and associations with not achieving cure among persons who inject drugs.

BACKGROUND: Persons who inject drugs (PWID) are a key population for hepatitis C virus (HCV) treatment. Study aims were to describe injection practices of PWID during HCV treatment with direct-acting antivirals (DAAs) and assess whether injection practices were associated with not achieving a sustained virologic response (SVR). METHODS: Secondary analysis of the HERO Study (ClinicalTrials.gov, NCT02824640), a pragmatic randomized trial in 8 U.S. states to evaluate the effectiveness of HCV care models among active PWID seen in opioid treatment programs and community clinics. Frequency, sharing and reuse of injecting equipment were assessed at baseline, end-of-treatment (EOT) and quarterly visits up to 60 weeks post-treatment. Generalized Estimating Equations logistic regression models with linear spline were used to compare trends in injecting behaviors during vs. post-treatment. Multivariable logistic regression models explored associations between injecting behaviors during treatment and lack of SVR. RESULTS: Among 501 participants, 27% were female, 35% were non-white, mean age was 44 (SD 11.5) years and nearly half (49%) were unhoused. At baseline, 41% reported receptive sharing of injecting equipment, declining to 16% at EOT visit. Receptive sharing of cookers, rinses, or needles/syringes during treatment was associated with a nearly 5-fold increase in not achieving SVR (adjusted odds ratio (aOR)=4.83; 95% CI: 2.26, 10.28) as was reuse of one's own needles/syringes (aOR=2.37; 95% CI: 1.11, 4.92). CONCLUSIONS: PWID in the HERO study adopted safer injecting behaviors during DAA treatment; receptive sharing of injecting equipment and reuse of one's own equipment during treatment were associated with not achieving cure.

The experience of re-infection among people who inject drugs successfully treated for hepatitis C.

INTRODUCTION: Highly effective direct-acting antiviral (DAA) agents have changed the landscape of hepatitis C virus infection (HCV) treatment and have become more available to people who inject drugs (PWID) over the past several years. Although many achieve a sustained virologic response (SVR), a small proportion will become re-infected. This study examined experiences of re-infection among participants in Project HERO, a large multi-site treatment trial designed to test alternative treatment delivery models for DAAs. METHODS: Study staff conducted qualitative interviews with twenty-three HERO participants who experienced reinfection following successful treatment for HCV. Interviews focused on life circumstances and experiences with treatment/re-infection. We conducted a thematic analysis, followed by a narrative analysis. RESULTS: Participants described challenging life circumstances. The initial experience of cure was joyful, leading participants to feel that they had escaped a defiled, stigmatized identity. Re-infection was very painful. Feelings of shame were common. Participants with fully developed narratives of re-infection described both a strong emotional response as well as a plan for avoiding re-infection during retreatment. Participants who lack such stories showed signs of hopelessness and apathy. CONCLUSION: Though the promise of personal transformation through SVR may be motivating for patients, clinicians should be cautious about how they describe the "cure" when educating patients about HCV treatment. Patients should be encouraged to avoid stigmatizing, dichotomizing language of the self, including terms such as "dirty" and "clean." In acknowledging the benefits of HCV cure, clinicians should emphasize that re-infection does not mean failed treatment; and that current treatment guidelines support retreatment of re-infected PWID.

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.

Roles of homologous recombination in response to ionizing radiation-induced DNA damage.

PURPOSE: Ionizing radiation induces a vast array of DNA lesions including base damage, and single- and double-strand breaks (SSB, DSB). DSBs are among the most cytotoxic lesions, and mis-repair causes small- and large-scale genome alterations that can contribute to carcinogenesis. Indeed, ionizing radiation is a 'complete' carcinogen. DSBs arise immediately after irradiation, termed 'frank DSBs,' as well as several hours later in a replication-dependent manner, termed 'secondary' or 'replication-dependent DSBs. DSBs resulting from replication fork collapse are single-ended and thus pose a distinct problem from two-ended, frank DSBs. DSBs are repaired by error-prone nonhomologous end-joining (NHEJ), or generally error-free homologous recombination (HR), each with sub-pathways. Clarifying how these pathways operate in normal and tumor cells is critical to increasing tumor control and minimizing side effects during radiotherapy. CONCLUSIONS: The choice between NHEJ and HR is regulated during the cell cycle and by other factors. DSB repair pathways are major contributors to cell survival after ionizing radiation, including tumor-resistance to radiotherapy. Several nucleases are important for HR-mediated repair of replication-dependent DSBs and thus replication fork restart. These include three structure-specific nucleases, the 3' MUS81 nuclease, and two 5' nucleases, EEPD1 and Metnase, as well as three end-resection nucleases, MRE11, EXO1, and DNA2. The three structure-specific nucleases evolved at very different times, suggesting incremental acceleration of replication fork restart to limit toxic HR intermediates and genome instability as genomes increased in size during evolution, including the gain of large numbers of HR-prone repetitive elements. Ionizing radiation also induces delayed effects, observed days to weeks after exposure, including delayed cell death and delayed HR. In this review we highlight the roles of HR in cellular responses to ionizing radiation, and discuss the importance of HR as an exploitable target for cancer radiotherapy.

Patient-centred models of hepatitis C treatment for people who inject drugs: a multicentre, pragmatic randomised trial.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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). INTERPRETATION: 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. FUNDING: Patient-Centered Outcomes Research Institute, Gilead Sciences, Quest Diagnostics, Monogram Biosciences, and OraSure Technologies.

Nucleases and Co-Factors in DNA Replication Stress Responses.

DNA replication stress is a constant threat that cells must manage to proliferate and maintain genome integrity. DNA replication stress responses, a subset of the broader DNA damage response (DDR), operate when the DNA replication machinery (replisome) is blocked or replication forks collapse during S phase. There are many sources of replication stress, such as DNA lesions caused by endogenous and exogenous agents including commonly used cancer therapeutics, and difficult-to-replicate DNA sequences comprising fragile sites, G-quadraplex DNA, hairpins at trinucleotide repeats, and telomeres. Replication stress is also a consequence of conflicts between opposing transcription and replication, and oncogenic stress which dysregulates replication origin firing and fork progression. Cells initially respond to replication stress by protecting blocked replisomes, but if the offending problem (e.g., DNA damage) is not bypassed or resolved in a timely manner, forks may be cleaved by nucleases, inducing a DNA double-strand break (DSB) and providing a means to accurately restart stalled forks via homologous recombination. However, DSBs pose their own risks to genome stability if left unrepaired or misrepaired. Here we focus on replication stress response systems, comprising DDR signaling, fork protection, and fork processing by nucleases that promote fork repair and restart. Replication stress nucleases include MUS81, EEPD1, Metnase, CtIP, MRE11, EXO1, DNA2-BLM, SLX1-SLX4, XPF-ERCC1-SLX4, Artemis, XPG, and FEN1. Replication stress factors are important in cancer etiology as suppressors of genome instability associated with oncogenic mutations, and as potential cancer therapy targets to enhance the efficacy of chemo- and radiotherapeutics.

Treatment for hepatitis C virus with direct acting antiviral agents: Perspectives and treatment experiences of people who inject drugs.

INTRODUCTION: Increasingly, people who inject drugs (PWID) infected with hepatitis C virus (HCV) are gaining access to highly effective direct-acting antiviral agents (DAAs). Although past studies examined patient experiences with interferon-based treatments, few have explored patient experiences with these new generation therapeutics. Research and real world experience indicate that many PWID can be successfully treated with the new DAAs. Yet a substantial minority fail to complete treatment or achieve only suboptimal adherence. This qualitative study examines experiences with treatment among participants in Project HERO, a large multisite trial designed to compare treatment delivery methods for DAAs. We explored treatment experiences among HERO participants, with the goal of understanding potential barriers to treatment engagement and completion. METHODS: We conducted qualitative interviews with a sample of 21 participants, including 14 who completed HCV treatment and 7 participants who discontinued treatment before the end of the 12-week medication course. The first phase of the analysis was descriptive, examining participants' life experiences, histories of disease and treatment seeking, experiences with the program, and barriers to treatment completion. The second phase of the analysis examined differences between completers and noncompleters. RESULTS: Participants offered a variety of reasons for seeking treatment. Both groups of participants reported highly positive experiences of the HERO trial. Participants described research staff as caring, respectful, and nonjudgmental. Substance use was reported by both groups, yet completers described "manageable" substance use, while noncompleters described substance use that sapped their energy and motivation. Shame over drug use was a barrier to treatment completion. Homelessness and a reported lack of social support were much more common in the noncompleter group. CONCLUSIONS: Reasons for noncompletion were not related to features of the clinical trial or treatment program. Our results indicate the importance of: 1) recognizing and addressing severe social and economic challenges such as homelessness; and 2) building a program culture of respect and compassion in treatment programs for PWID infected with HCV.

Metnase and EEPD1: DNA Repair Functions and Potential Targets in Cancer Therapy.

Cells respond to DNA damage by activating signaling and DNA repair systems, described as the DNA damage response (DDR). Clarifying DDR pathways and their dysregulation in cancer are important for understanding cancer etiology, how cancer cells exploit the DDR to survive endogenous and treatment-related stress, and to identify DDR targets as therapeutic targets. Cancer is often treated with genotoxic chemicals and/or ionizing radiation. These agents are cytotoxic because they induce DNA double-strand breaks (DSBs) directly, or indirectly by inducing replication stress which causes replication fork collapse to DSBs. EEPD1 and Metnase are structure-specific nucleases, and Metnase is also a protein methyl transferase that methylates histone H3 and itself. EEPD1 and Metnase promote repair of frank, two-ended DSBs, and both promote the timely and accurate restart of replication forks that have collapsed to single-ended DSBs. In addition to its roles in HR, Metnase also promotes DSB repair by classical non-homologous recombination, and chromosome decatenation mediated by TopoIIα. Although mutations in Metnase and EEPD1 are not common in cancer, both proteins are frequently overexpressed, which may help tumor cells manage oncogenic stress or confer resistance to therapeutics. Here we focus on Metnase and EEPD1 DNA repair pathways, and discuss opportunities for targeting these pathways to enhance cancer therapy.