Changes in alcohol use during hepatitis C treatment in persons who inject drugs.

People who inject drugs (PWID) are a vulnerable population at high risk for acquiring hepatitis C virus (HCV) and frequently suffer from comorbid alcohol use. This study examines the characteristics and correlates of alcohol use among study participants, the association between alcohol consumption and sustained virologic response (SVR) in patients receiving HCV treatment, changes in drinking behaviours during HCV treatment and associations of drinking over time with specific models of HCV treatment. Participants were 150 PWID with HCV who were receiving opioid agonist therapy (OAT) and enrolled in a randomized clinical trial exploring the effectiveness of three models of care for HCV treatment. The addiction severity index was the primary measure of alcohol consumption. Days of alcohol intake were evaluated longitudinally and across three treatment groups. At baseline, 31% (47/150) reported having at least one drink in the last 30 days including 24% (36/150) who reported drinking to intoxication in the last 30 days. There was no difference in SVR rates between groups. There was a significant decrease in overall days of drinking from baseline (7.78 ± 7.86) to follow-up at Week 24 (5.78 ± 8.83) (p = 0.041), but there were no significant changes among those who drank to intoxication; modified directly observed therapy (mDOT) was the only group with a significant decline in days of alcohol consumption (p = 0.041). In this cohort of PWID on OAT, baseline alcohol consumption did not affect SVR rates. HCV treatment was overall associated with decreased alcohol consumption. In particular, mDOT was associated with decreased alcohol consumption. Given the additive effect of alcohol and HCV on the development of cirrhosis, studies should be done to investigate the complimentary effects of the mDOT model of care on alcohol cessation.

Cinobufagin-induced DNA damage response activates G2/M checkpoint and apoptosis to cause selective cytotoxicity in cancer cells.

BACKGROUND: Processed extracts from toad skin and parotoid gland have long been used to treat various illnesses including cancer in many Asian countries. Recent studies have uncovered a family of bufadienolides as the responsible pharmacological compounds, and the two major molecules, cinobufagin and bufalin, have been shown to possess robust antitumor activity; however, the underlying mechanisms remain poorly understood. METHODS: Intracellular reactive oxygen species (ROS) were measured by DCFH-DA staining and flow cytometry, and DNA damage was analyzed by immunofluorescent staining and the alkaline comet assay. Cytotoxicity was measured by MTT as well as colony formation assays, and cell cycle and apoptosis were analyzed by flow cytometry. In addition, apoptosis was further characterized by TUNEL and mitochondrial membrane potential assays. RESULTS: Here we showed that sublethal doses of cinobufagin suppressed the viability of many cancer but not noncancerous cell lines. This tumor-selective cytotoxicity was preceded by a rapid, cancer-specific increase in cellular ROS and was significantly reduced by the ROS inhibitor N-acetyl cysteine (NAC), indicating oxidative stress as the primary source of cinobufagin-induced cancer cell toxicity. Sublethal cinobufagin-induced ROS overload resulted in oxidative DNA damage and intense replication stress in cancer cells, leading to strong DNA damage response (DDR) signaling. Subsequent phosphorylation of CDC25C and stabilization of p53 downstream of DDR resulted in activation of the G2/M checkpoint followed by induction of apoptosis. These data indicate that cinobufagin suppresses cancer cell viability via DDR-mediated G2 arrest and apoptosis. CONCLUSION: As elevated oxidative pressure is shared by most cancer cells that renders them sensitive to further oxidative insult, these studies suggest that nontoxic doses of cinobufagin can be used to exploit a cancer vulnerability for induction of cancer-specific cytotoxicity.

Factors and HCV treatment outcomes associated with smoking among people who inject drugs on opioid agonist treatment: secondary analysis of the PREVAIL randomized clinical trial.

BACKGROUND: Cigarette smoking has emerged as a leading cause of mortality among people with hepatitis C virus (HCV). People who inject drugs (PWID) represent the largest group of adults infected with HCV in the US. However, cigarette smoking remains virtually unexplored among this population. This study aimed at (1) determining prevalence and correlates of cigarette smoking among HCV-infected PWID enrolled in opiate agonist treatment programs; (2) exploring the association of smoking with HCV treatment outcomes including adherence, treatment completion and sustained virologic response (SVR); and 3) exploring whether cigarette smoking decreased after HCV treatment. METHODS: Participants were 150 HCV-infected PWID enrolled in a randomized clinical trial primarily designed to test three intensive models of HCV care. Assessments included sociodemographics, presence of chronic health and psychiatric comorbidities, prior and current drug use, quality of life, and HCV treatment outcomes. RESULTS: The majority of the patients (84%) were current cigarette smokers at baseline. There was a high prevalence of psychiatric and medical comorbidities in the overall sample of PWID. Alcohol and cocaine use were identified as correlates of cigarette smoking. Smoking status did not influence HCV treatment outcomes including adherence, treatment completion and SVR. HCV treatment was not associated with decreased cigarette smoking. CONCLUSIONS: The present study showed high prevalence of cigarette smoking among this population as well as identified correlates of smoking, namely alcohol and cocaine use. Cigarette smoking was not associated with HCV treatment outcomes. Given the detrimental effects that cigarette smoking and other co-occurring, substance use behaviors have on HCV-infected individuals' health, it is imperative that clinicians treating HCV also target smoking, especially among PWID. The high prevalence of cigarette smoking among PWID will contribute to growing morbidity and mortality among this population even if cured of HCV. Tailored smoking cessation interventions for PWID along with HCV treatment may need to be put into clinical practice. TRIAL REGISTRATION: NCT01857245 . Registered May 20, 2013.

Rapid detection of index for encoder in rotary inertial navigation system.

This paper presents an approach to detect the index of incremental photoelectric encoder with shorter time for rotary inertial navigation system. The order of index detection and coarse alignment is exchanged in this approach and information from coarse alignment is used to calculate the direction of index. Then two cases of azimuth axis and four cases of horizontal axes are analyzed and corresponding solutions are designed. The paper examines the solutions through two experiments in a tri-axis rotary inertial navigation system, and the results demonstrate that the system can capture index pulse in the application of the presupposes schemes with shorter time.

Induction of ROS Overload by Alantolactone Prompts Oxidative DNA Damage and Apoptosis in Colorectal Cancer Cells.

Cancer cells typically display higher than normal levels of reactive oxygen species (ROS), which may promote cancer development and progression but may also render the cancer cells more vulnerable to further ROS insult. Indeed, many of the current anticancer therapeutics kill cancer cells via induction of oxidative stress, though they target both cancer and normal cells. Recently, alantolactone (ATL), a natural sesquiterpene lactone, has been shown to induce apoptosis by increasing ROS levels specifically in cancer cells; however, the molecular mechanisms linking ROS overproduction to apoptosis remain unclear. Here we show that the ATL-induced ROS overload in human SW480 and SW1116 colorectal cancer cells was followed by a prominent accumulation of cellular oxidized guanine (8-oxoG) and immediate increase in the number of DNA strand breaks, indicating that increased ROS resulted in extensive oxidative DNA damage. Consequently, the G1/S-CDK suppresser CDKN1B (p21) and pro-apoptotic proteins Bax and activated caspase-3 were upregulated, while anti-apoptotic Bcl-2 was downregulated, which were followed by cell cycle arrest at G1 and marked apoptosis in ATL-treated cancer but not non-cancer cells. These results suggest that the ATL-induced ROS overload triggers cell death through induction of massive oxidative DNA damage and subsequent activation of the intrinsic apoptosis pathway.

Echinacoside Induces Apoptosis in Human SW480 Colorectal Cancer Cells by Induction of Oxidative DNA Damages.

Echinacoside is a natural compound with potent reactive oxygen species (ROS)-scavenging and anti-oxidative bioactivities, which protect cells from oxidative damages. As cancer cells are often under intense oxidative stress, we therefore tested if Echinacoside treatment would promote cancer development. Surprisingly, we found that Echinacoside significantly inhibited the growth and proliferation of a panel of cancer cell lines. Treatment of the human SW480 cancer cells with Echinacoside resulted in marked apoptosis and cell cycle arrest, together with a significant increase in active caspase 3 and cleaved PARP, and upregulation of the G1/S-CDK blocker CDKN1B (p21). Interestingly, immunocytochemistry examination of drug-treated cancer cells revealed that Echinacoside caused a significant increase of intracellular oxidized guanine, 8-oxoG, and dramatic upregulation of the double-strand DNA break (DSB)-binding protein 53BP1, suggesting that Echinacoside induced cell cycle arrest and apoptosis in SW480 cancer cells via induction of oxidative DNA damages. These results establish Echinacoside as a novel chemical scaffold for development of anticancer drugs.

Distrust in the Health Care System and Adherence to Direct-Acting Antiviral Therapy among People with Hepatitis C Virus Who Inject Drugs.

This study is a secondary analysis of a randomized clinical trial (October 2013-April 2017) involving 150 People Who Inject Drugs (PWIDs) with hepatitis C virus (HCV) seen in opioid agonist treatment programs in the Bronx, New York, and investigates the impact of distrust in the healthcare system on adherence to Direct-Acting Antivirals (DAAs) HCV treatment therapy among PWIDs. The distrust was scaled on a 9-item instrument and the adherence to DAA medications was measured using electronic blister packs. This study demonstrated a significant inverse relationship between levels of distrust and medication adherence: 71.8 ± 2.2% (se) vs. 77.9 ± 1.8%, p = 0.024 between participants with higher and lower distrust levels. Despite the absence of significant association of distrust with sociodemographic or substance use characteristics, these findings suggest that building trust within the healthcare system is paramount for improving adherence to DAAs among PWIDs. The results call for a healthcare approach that emphasizes trust-building through patient-centered care, sensitivity training, peer support, and health system reform to effectively address the treatment needs of this marginalized population.

[Study on synergistic effect of bactericidal effect of chlorine dioxide solution by surfactant].

OBJECTIVE: To study the effect of gemini fluorocarbon, sodium p-perfluorous nonenoxybenzene sulfonate and sodium dodecyl sulfate on the chlorine dioxide solution sterilization to object surface. METHODS: Pure chlorine dioxide solution as the reference disinfectant, carrier quantitative bactericidal test and simulated test on-site were used to carry out laboratory observation according to The disinfection technical specifications (2002). RESULTS: Carrier quantitative bactericidal test showed that the addition dosage of gemini fluoronates, sodium dodecyl sulfate surfactant and perfluorinated the nonene oxy benzene sulfonate in disinfectant solution were 60, 60 and 40 mg/L respectively, the killing log value of Staphylococcus aureus exposed to the disinfectant solution containing chlorine dioxide 50 mg/L for 10 mm were all more than 3; and the addition dosage of gemini fluorinates, sodium dodecyl sulfate and perfluorinated the nonene oxy benzene sulfonate in disinfectant solution were 60 mg/L, the killing log value of Escherichia coli exposed to the disinfectant solution containing chlorine dixoxide 20 mg/L for 10 min were all more than 3. The bactericidal effect of the mixture use of surfactant and chlorine dioxide was better than the single use of chlorine dioxide. The simulated test on-site showed that the killing log value of Escherichia coli exposed to the disinfectant solution containing perfluorinated the nonene oxy benzene sulfonate 40 mg/L and chlorine dioxide 20 mg/L for 15 min was more than 3. CONCLUSION: Surface active agent on germicidal efficacy of chlorine dioxide solution had synergistic action.

Effects of short-term nicotine deprivation on delay discounting among young, experienced, exclusive ENDS users: An initial study.

Delay discounting describes how rapidly delayed rewards lose value as a function of delay and serves as one measure of impulsive decision-making. Nicotine deprivation among combustible cigarette smokers can increase delay discounting. We aimed to explore changes in discounting following nicotine deprivation among electronic nicotine delivery systems (ENDS) users. Thirty young adults (aged 18-24 years) that exclusively used ENDS participated in two laboratory sessions: one with vaping as usual and another after 16 hr of nicotine deprivation (biochemically assessed). At each session, participants completed a craving measure and three hypothetical delay discounting tasks presenting choices between small, immediate rewards and large, delayed ones (money-money; e-liquid-e-liquid; e-liquid-money). Craving for ENDS significantly increased during short-term nicotine deprivation relative to normal vaping. Delay discounting rates in the e-liquid now versus money later task increased (indicating a shift in preference for smaller, immediate rewards) following short-term nicotine deprivation relative to vaping as usual, but no changes were observed in the other two discounting tasks. Short-term nicotine deprivation increased the preference for smaller amounts of e-liquid delivered immediately over larger, monetary awards available after a delay in this first study of its kind. As similar preference shifts for drug now versus money later have been shown to be indicative of increased desire to use drug as well as relapse risk, the findings support the utility of the current model as a platform to explore interventions that can mitigate these preference shifts. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

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.

Relationship between depressive symptoms and adherence to direct-acting antivirals: Implications for Hepatitis C treatment among people who inject drugs on medications for opioid use disorder.

BACKGROUND: Interferon-based regimens exacerbated depressive symptoms, which interfered with treating hepatitis C virus (HCV) among people who inject drugs (PWID). Direct-acting antivirals (DAA) are not associated with worsening depressive symptoms; however, the impact of depressive symptoms on adherence remains little known. We examined the association between depressive symptoms and adherence to DAA among HCV-infected PWID. A secondary aim was to identify the optimal cut-off for major depressive disorder for this population. METHODS: Participants were 150 HCV-infected PWID on maintenance treatment enrolled in a randomized clinical trial testing three HCV care models. Severity of depressive symptoms were assessed using the Beck Depression Inventory-II (BDI-II) at baseline and every 4 weeks during treatment. Current major depressive disorder at baseline was diagnosed by the Mini-International Neuropsychiatric Interview. Adherence was measured during treatment (weeks 1-12) using electronic blister packs RESULTS: BDI-II scores ≥ 18 were identified as the optimal threshold for diagnosing major depressive disorder. Participants with BDI scores ≥ 18 at baseline had significantly lower adherence rates at weeks 1-4 of treatment compared to those with BDI scores < 18 (b = -0.23, 95% CI: 0.45-0.01, p = 0.044), but not in any other time intervals (weeks 5-8, b = -0.03, 95% CI: -0.32, 0.26, p = 0.825; weeks 9-12, b = -0.33, 95% CI -0.70, 0.02, p = 0.066). CONCLUSIONS: Elevated depressive symptoms were associated with lower adherence to DAA only during the first 4 weeks of HCV treatment. Neither severe depressive symptoms nor major depressive disorder appears to be a barrier to DAA adherence among PWID.

Modeling the effect of stress on vaping behavior among young adults: A randomized cross-over pilot study.

BACKGROUND: Laboratory models have been useful in identifying the motivational processes underlying tobacco use. This pilot study aimed at (1)validating a human laboratory model initially developed for smokers to e-cigarette users; (2)applying this model to examine the effects of stress on the reinforcing value of nicotine among young adults. METHODS: Using a randomized cross-over design, young e-cigarette users (n = 30) who were nicotine deprived were exposed to a stress or a non-stress task, and then engaged in a laboratory task assessing vaping's reward value on two separate days. During the first part of the task, participants had the option of initiating an e-cigarette self-administration session or delaying initiation for up to 50 min in exchange for money. During the second part of the task, participants chose between vaping or receiving money. The length of the delay and the number of e-cigarette uses consumed were the primary outcomes. Craving and puff topography were secondary outcomes. RESULTS: There was no difference in the length of time that participants were able to refrain from vaping in the stress and control task (p = .90). Participants purchased and consumed more puffs after being exposed to the stress task compared to the control task (p<.001), puff topography and craving were unaffected. CONCLUSIONS: Exposure to a stressor did not undermine the ability to resist vaping among deprived e-cigarette users (first part), but it influenced the number of uses purchased once users decided to vape (second part). This study evidences that these two parts of the task for assessing reward value are differentially sensitive to the stress manipulation.

Alkannin-Induced Oxidative DNA Damage Synergizes With PARP Inhibition to Cause Cancer-Specific Cytotoxicity.

Background: Oncogenic transformation is associated with elevated oxidative stress that promotes tumor progression but also renders cancer cells vulnerable to further oxidative insult. Agents that stimulate ROS generation or suppress antioxidant systems can drive oxidative pressure to toxic levels selectively in tumor cells, resulting in oxidative DNA damage to endanger cancer cell survival. However, DNA damage response signaling protects cancer cells by activating DNA repair and genome maintenance mechanisms. In this study, we investigated the synergistic effects of combining the pro-oxidative natural naphthoquinone alkannin with inhibition of DNA repair by PARP inhibitors. Methods and Results: The results showed that sublethal doses of alkannin induced ROS elevation and oxidative DNA damage in colorectal cancer but not normal colon epithelial cells. Blocking DNA repair with the PARP inhibitor olaparib markedly synergized with alkannin to yield synergistic cytotoxicity in colorectal cancer cells at nontoxic doses of both drugs. Synergy between alkannin and olaparib resulted from interrupted repair of alkannin-induced oxidative DNA damage and PARP-trapping, as it was significantly attenuated by NAC or by OGG1 inhibition and the non-trapping PARP inhibitor veliparib did not yield synergism. Mechanistically, the combination of alkannin and olaparib caused intense replication stress and DNA strand breaks in colorectal cancer cells, leading to apoptotic cancer cell death after G2 arrest. Consequently, coadministration of alkannin and olaparib induced significant regression of tumor xenografts in vivo, while each agent alone had no effect. Conclusion: These studies clearly show that combining alkannin and olaparib can result in synergistic cancer cell lethality at nontoxic doses of the drugs. The combination exploits a cancer vulnerability driven by the intrinsic oxidative pressure in most cancer cells and hence provides a promising strategy to develop broad-spectrum anticancer therapeutics.

Declines in Depressive Symptoms Among People who Inject Drugs Treated With Direct-Acting Antivirals While on Opioid Agonist Therapy.

BACKGROUND: Hepatitis C virus (HCV) frequently co-occurs with symptoms of depression, which are aggravated on interferon-based regimens. However, it is unknown whether HCV treatment with direct-acting antivirals (DAAs) has effects on depressive symptoms among people who inject drugs (PWID). In this study, we examined changes in depressive symptoms during and after HCV treatment among PWID on opioid agonist therapies (OATs). METHODS: Participants were 141 PWID who achieved sustained viral response after on-site HCV treatment at 3 OAT programs.Depressive symptoms were assessed using the Beck Depression Inventory-II (BDI-II) at baseline, every 4 weeks during treatment, and 12 and 24 weeks after treatment completion. Current diagnosis of depression or other psychiatric diagnoses were obtained through chart review. Use of illicit drugs was measured by urine toxicology screening. Alcohol use was measured using the Addiction Severity Index-Lite. RESULTS: Of the 141 PWID infected with HCV, 24.1% had severe, 9.9% had moderate, 15.6% had mild, and 50.4% had minimal levels of depression as per BDI-II scores at baseline. HCV treatment was significantly associated with reductions in depressive symptoms that persisted long term, regardless of symptom severity (P < .001) or presence of depression (P ≤ .01) or other psychiatric diagnoses (P ≤ .01) at baseline. Concurrent drug use (P ≤ .001) or hazardous alcohol drinking (P ≤ .001) did not interfere with reductions in depressive symptoms. CONCLUSIONS: Depressive symptoms are highly prevalent among HCV-infected PWID. HCV treatment was associated with sustained reductions in depressive symptoms. HCV therapy with DAAs may have important implications for PWID that go beyond HCV cure.

Echinacoside induces apoptotic cancer cell death by inhibiting the nucleotide pool sanitizing enzyme MTH1.

Inhibition of the nucleotide pool sanitizing enzyme MTH1 causes extensive oxidative DNA damages and apoptosis in cancer cells and hence may be used as an anticancer strategy. As natural products have been a rich source of medicinal chemicals, in the present study, we used the MTH1-catalyzed enzymatic reaction as a high-throughput in vitro screening assay to search for natural compounds capable of inhibiting MTH1. Echinacoside, a compound derived from the medicinal plants Cistanche and Echinacea, effectively inhibited the catalytic activity of MTH1 in an in vitro assay. Treatment of various human cancer cell lines with Echinacoside resulted in a significant increase in the cellular level of oxidized guanine (8-oxoguanine), while cellular reactive oxygen species level remained unchanged, indicating that Echinacoside also inhibited the activity of cellular MTH1. Consequently, Echinacoside treatment induced an immediate and dramatic increase in DNA damage markers and upregulation of the G1/S-CDK inhibitor p21, which were followed by marked apoptotic cell death and cell cycle arrest in cancer but not in noncancer cells. Taken together, these studies identified a natural compound as an MTH1 inhibitor and suggest that natural products can be an important source of anticancer agents.