Community-Based Cluster-Randomized Trial to Reduce Opioid Overdose Deaths.

BACKGROUND: Evidence-based practices for reducing opioid-related overdose deaths include overdose education and naloxone distribution, the use of medications for the treatment of opioid use disorder, and prescription opioid safety. Data are needed on the effectiveness of a community-engaged intervention to reduce opioid-related overdose deaths through enhanced uptake of these practices. METHODS: In this community-level, cluster-randomized trial, we randomly assigned 67 communities in Kentucky, Massachusetts, New York, and Ohio to receive the intervention (34 communities) or a wait-list control (33 communities), stratified according to state. The trial was conducted within the context of both the coronavirus disease 2019 (Covid-19) pandemic and a national surge in the number of fentanyl-related overdose deaths. The trial groups were balanced within states according to urban or rural classification, previous overdose rate, and community population. The primary outcome was the number of opioid-related overdose deaths among community adults. RESULTS: During the comparison period from July 2021 through June 2022, the population-averaged rates of opioid-related overdose deaths were similar in the intervention group and the control group (47.2 deaths per 100,000 population vs. 51.7 per 100,000 population), for an adjusted rate ratio of 0.91 (95% confidence interval, 0.76 to 1.09; P = 0.30). The effect of the intervention on the rate of opioid-related overdose deaths did not differ appreciably according to state, urban or rural category, age, sex, or race or ethnic group. Intervention communities implemented 615 evidence-based practice strategies from the 806 strategies selected by communities (254 involving overdose education and naloxone distribution, 256 involving the use of medications for opioid use disorder, and 105 involving prescription opioid safety). Of these evidence-based practice strategies, only 235 (38%) had been initiated by the start of the comparison year. CONCLUSIONS: In this 12-month multimodal intervention trial involving community coalitions in the deployment of evidence-based practices to reduce opioid overdose deaths, death rates were similar in the intervention group and the control group in the context of the Covid-19 pandemic and the fentanyl-related overdose epidemic. (Funded by the National Institutes of Health; HCS ClinicalTrials.gov number, NCT04111939.).

Menthol and Other Flavor Chemicals in Cigarettes from Vietnam and the Philippines.

INTRODUCTION: Tobacco product flavors can increase product appeal, adolescent initiation and experimentation, and difficulty quitting. Flavored tobacco products are not restricted in Vietnam or the Philippines despite the high smoking prevalence among those 15 years of age and older (24% and 23%, respectively). There are no published reports to our knowledge on the levels of flavor chemicals in the cigarettes sold in these two countries. METHODS: Cigarettes were purchased in Vietnam (32 brand variants) and the Philippines (19 brand variants) during 2020. Chemical analyses gave the mg/filter, mg/rod, and mg/stick (= mg/(filter + rod)) values for 180 individual flavor chemicals. Values were calculated for menthol, clove-related compounds, and "other flavor chemicals" (OFCs). RESULTS: Five flavor groupings were found among the brand variants purchased in Vietnam: menthol + OFCs (n = 15), OFCs only (n = 8), nonflavored (n = 7), menthol + OFCs with a clove flavorant (n = 1) and menthol only (n = 1). Three flavor groupings were found among the brand variants purchased in the Philippines: menthol + OFCs (n = 10), nonflavored (n = 5), and menthol only (n = 4). CONCLUSIONS: A range of flavored cigarette products are being offered by tobacco companies in Vietnam and the Philippines, presumably to maximize cigarette sales. Regulation of flavor chemicals should be considered in these two countries. IMPLICATIONS: Article 9 of the WHO Framework Convention on Tobacco Control (FCTC), ratified by both Vietnam and the Philippines, states that "there is no justification for permitting the use of ingredients, such as flavoring agents, which help make tobacco products attractive." Flavors increase product appeal, adolescent initiation and experimentation, and difficulty quitting. These analyses found that cigarettes purchased in Vietnam and the Philippines contained menthol and other flavor chemicals. Tobacco companies are offering multiple flavor chemical profiles and nominally nonflavored versions in these countries; regulation of flavor chemicals should be considered in these two countries.

Changes in Compliance with Bans on Tobacco Product Display and Advertising at Traditional and Modern Point-of-Sale Retailers in Depok, Indonesia, 2019-2021.

INTRODUCTION: Banning Point-of-Sale (POS) advertising and product display is an important tobacco control strategy. Depok, Indonesia enacted some regional tobacco control policies regulating the POS environment in 2021. This study examined changes in compliance before and after the implementation of these policies as of 2021. METHODS: Data collectors visited 180 modern retailers (hyper/supermarkets/convenience stores) and 147 traditional retailers (warungs) in 2019. The same retailers were re-visited in 2021. Data collectors assessed compliance with tobacco product display, and advertising regulations at POS, including if products were displayed in spaces to target minors (near candy or at a child's eye-level). Data were analyzed using McNemar and Mann-Whitney U tests. RESULTS: From 2019 to 2021, in modern retailers, tobacco product display (95.6% vs 52.2%) and product advertising (36.1% vs 3.9%) were significantly reduced (p<0.001). In traditional retailers, tobacco product display (94.6% in 2019, 91.2% in 2021, p>0.05) and product advertising (87.1% in 2019, 87.8% in 2021, p>0.05) remained common during both data collection periods. Tobacco products were commonly displayed in spaces to target minors in both modern retailers (43.3% in 2019, 34.4% in 2021, p>0.05) and traditional retailers (90.5% in 2019, 83.0% in 2021, p>0.05). CONCLUSIONS: Compliance with bans on tobacco product advertising and display at modern retailers improved significantly from 2019 to 2021; however, most modern retailers continue to display tobacco products in 2021. Traditional retailers remain largely non-compliant. Tobacco products are commonly displayed in areas that target minors. The enforcement of regional regulations should be strengthened, particularly among traditional retailers. IMPLICATIONS: In Depok, Indonesia, tobacco advertising and product display bans have been implemented; however, more work is needed to support compliance. Enforcement efforts, such as those carried out by civil police, can focus on tobacco product display bans in traditional and modern retailers, and traditional retailers need additional support to remove tobacco product advertising. Retailers may receive money from the tobacco industry for these advertisements. Creative solutions may include supporting retailers in finding alternative advertising revenue.

Pregnancy and STI/HIV prevention intervention preferences of South African adolescent girls: findings from a cultural consensus modelling qualitative study.

South African adolescent girls experience high rates of unintended pregnancy and sexually transmitted infections including HIV. To inform culturally-tailored dual protection interventions to prevent both unintended pregnancy and STIs/HIV, this study qualitatively examined girls' sexual health intervention preferences. Participants were aged 14-17 years old and Sesotho-speaking (N = 25). To elucidate shared cultural beliefs, individual interviews examined participants' perceptions about other adolescent girls' pregnancy and STI/HIV prevention intervention preferences. Interviews were conducted in Sesotho and translated into English. Two independent coders identified key themes in the data using a conventional content analysis approach with discrepancies resolved by a third coder. Participants indicated that intervention content should include efficacious pregnancy and STI/HIV prevention methods and ways to navigate peer pressure. Interventions should be accessible, avoid criticism and provide high-quality information. Preferred intervention formats included online, SMS/text, or delivery by social workers or older, knowledgeable peers, with mixed acceptability for delivery by parents or same-age peers. Schools, youth centres and sexual health clinics were preferred intervention settings. Results highlight the importance of cultural context in tailoring dual protection interventions to address the reproductive health disparities among adolescent girls in South Africa.

Attitudes and Intentions toward Use of HIV Pre-Exposure Prophylaxis (PrEP) among Adults Receiving Treatment for Opioid Use.

Background: Although pre-exposure prophylaxis (PrEP) prevents HIV, little is known about PrEP awareness and factors associated with intention to take PrEP among people with opioid use disorder (OUD). Methods: HIV-negative adults recruited from an outpatient treatment program in Cincinnati, Ohio completed self-administered surveys. Items derived from literature and health behavioral theory included demographics, sexual and drug use behaviors, HIV prevention practices, PrEP knowledge, and attitudes toward PrEP. Primary outcomes were 1) intention to ask a clinician about PrEP and 2) intention to accept PrEP if recommended by a clinician. Outcomes were dichotomized into higher vs. lower intention for analyses in logistic regression models. Results: Among 198 participants, 60.3% reported past injection drug use. Among 58 participants (29.3%) meeting criteria for PrEP, 24% were aware of PrEP, 15.5% had discussed it with a clinician, and 5% had taken it. Factors associated with intention to ask a clinician about PrEP included being somewhat confident about consistent condom use (p < 0.01), motivation to comply with normative beliefs (p < 0.01), and reporting that PrEP fits very well (p < 0.01) and is easy to fit (p < 0.01) into current prevention practices. Factors associated with intention to accept PrEP if recommended by a clinician included motivation to comply with normative beliefs (p < 0.01) and PrEP being easy to fit into current prevention practices (p < 0.01). Conclusion: Among participants meeting indications for PrEP, only 24% were aware of it and few had taken it. Interventions that normalize PrEP and target incorporating PrEP into current prevention practices may improve uptake among individuals with OUD.

Temporary induction of hypoxic adaptations by preconditioning fails to enhance Schwann cell transplant survival after spinal cord injury.

Hypoxic preconditioning is protective in multiple models of injury and disease, but whether it is beneficial for cells transplanted into sites of spinal cord injury (SCI) is largely unexplored. In this study, we analyzed whether hypoxia-related preconditioning protected Schwann cells (SCs) transplanted into the contused thoracic rat spinal cord. Hypoxic preconditioning was induced in SCs prior to transplantation by exposure to either low oxygen (1% O2 ) or pharmacological agents (deferoxamine or adaptaquin). All preconditioning approaches induced hypoxic adaptations, including increased expression of HIF-1α and its target genes. These adaptations, however, were transient and resolved within 24 h of transplantation. Pharmacological preconditioning attenuated spinal cord oxidative stress and enhanced transplant vascularization, but it did not improve either transplanted cell survival or recovery of sensory or motor function. Together, these experiments show that hypoxia-related preconditioning is ineffective at augmenting either cell survival or the functional outcomes of SC-SCI transplants. They also reveal that the benefits of hypoxia-related adaptations induced by preconditioning for cell transplant therapies are not universal.

John squire and endothelial glycocalyx structure: an unfinished story.

John Squire did not only produce leading works in the muscle field, he also significantly contributed to the vascular permeability field by ultrastructural analysis of the endothelial glycocalyx. Presented here is a review of his involvement in the field by his main collaborator C.C. Michel and his last postdoctoral researcher KP Arkill. We end on a reinterpretation of his work that arguably links to our current understanding of endothelial glycocalyx structure and composition predicting 6 glycosaminoglycans fibres per syndecan core protein, only achieved in the endothelium by dimerization.

Concordance of Ethyl Glucuronide, Blood Alcohol Content, and Self-Reported Alcohol Use in Russian Women with HIV and Hepatitis C Virus Co-Infection.

Problematic alcohol use is prevalent in Russia and is deleterious for individuals with HIV and Hepatitis C Virus (HCV). Ethyl glucuronide (EtG) and blood alcohol content (BAC) provide objective biomarkers of drinking that can be compared to self-reported alcohol use. This paper describes patterns of alcohol use measured by biomarkers and self-report along with concordance across measures. Participants were Russian women with HIV and HCV co-infection (N = 200; Mean age = 34.9) from two Saint Petersburg comprehensive HIV care centers enrolled in an alcohol reduction intervention clinical trial. Measures were: (a) urine specimen analyzed for EtG; (b) breathalyzer reading of BAC; and (c) self-reported frequency of drinking, typical number of drinks consumed, and number of standard drinks consumed in the past month. At baseline, 64.0% (n = 128) had a positive EtG (> 500 ng/mL) and 76.5% (n = 153) had a positive breathalyzer reading (non-zero reading). There was agreement between EtG and BAC (kappa = 0.66, p < .001; Phi coefficient = 0.69, p < .001); self-reported alcohol measures were positively correlated with positive EtG and BAC (p's < 0.001). There was concordance between EtG and BAC measures, which have differing alcohol detection windows. Most participants endorsed frequent drinking at high quantities, with very few reporting no alcohol consumption in the past month. Concordance between biomarkers and self-reported alcohol use suggests that underreporting of alcohol use was minimal. Results highlight the need for alcohol screening within HIV care. Implications for alcohol assessment within research and clinical contexts are discussed.

Spinning a global web: tactics used by Big Tobacco to attract children at tobacco points-of-sale.

Most of the published literature on cigarette advertising and promotion at points-of-sale is on research conducted in high-income countries. We report findings from monitoring cigarette advertising and promotion at points-of-sale near schools and playgrounds in 42 countries, the majority low-income and middle-income. Four strategies were detected across most of these countries: (1) display of cigarettes near snacks, sweets and sugary drinks, (2) placement of cigarette advertisements near the eye-level of children, (3) advertisements and display of flavoured cigarettes and (4) sale of single sticks of cigarettes. These advertising and promotional tactics target children and youth and demonstrate that multinational tobacco companies use similar strategies to promote cigarettes at points-of-sale. The widespread violations of existing laws and regulations, the exploitation of regulatory loopholes and lack of existing tobacco control policies that apply to points-of-sale call for adoption and enactment of provisions recommended by the WHO Framework Convention on Tobacco Control such as comprehensive bans on tobacco advertisement, promotion and sponsorship, bans on sale of single cigarette sticks and regulation of flavours. These strategies will help to protect children and youth from exposure to tobacco advertising.

Colours, capsules and concept flavour names on cigarette packs appeal to youth in Mexico.

BACKGROUND: Flavoured cigarettes are popular in Mexico. We examined how cigarette packaging design features used to communicate flavour influence perceptions of appeal, harm, perceived interest and pack preference among Mexico City residents. METHODS: We conducted an experimental survey. Participants aged 13-34 years were randomly assigned to one of three conditions, viewed packs with systematically manipulated design features (colour, capsule image and flavour name) and answered questions on appeal, perceived harm, perceived interest and pack preference. Data were analysed using mixed effects and conditional logistic regression. RESULTS: 1500 adolescents and 950 adults participated. Regardless of flavour, cigarette packs with a background colour and capsule image were more appealing to adolescents (OR=13.19, 95% CI 11.53 to 15.10; OR=1.68, 95% CI 1.45 to 1.88) and adults (OR=4.18, 95% CI 3.73 to 4.69; OR=1.66, 95% CI 1.49 to 1.85) than packs without. Among adolescents, 'Tropical Burst' named packs were more appealing (OR=1.43, 95% CI 1.20 to 1.72) than packs without a flavour name and among adults, 'Arctic Air' named packs were more appealing (OR=1.20, 95% CI 1.02 to 1.14). Adolescents and adults reported a preference for trying packs that displayed a flavour name, background colour or capsule image (b=0.104, b=0.702, b=1.316, p<0.001 and b=0.126, b=0.619, b=0.775, p<0.001). CONCLUSIONS: Colours and flavour capsule images appeal to adolescents and adults in Mexico. Mexico should consider adopting plain packaging to reduce appeal and interest.

Co­cultivation of anaerobic fungi with Clostridium acetobutylicum bolsters butyrate and butanol production from cellulose and lignocellulose.

A system for co-cultivation of anaerobic fungi with anaerobic bacteria was established based on lactate cross-feeding to produce butyrate and butanol from plant biomass. Several co-culture formulations were assembled that consisted of anaerobic fungi (Anaeromyces robustus, Neocallimastix californiae, or Caecomyces churrovis) with the bacterium Clostridium acetobutylicum. Co-cultures were grown simultaneously (e.g., 'one pot'), and compared to cultures where bacteria were cultured in fungal hydrolysate sequentially. Fungal hydrolysis of lignocellulose resulted in 7-11 mM amounts of glucose and xylose, as well as acetate, formate, ethanol, and lactate to support clostridial growth. Under these conditions, one-stage simultaneous co-culture of anaerobic fungi with C. acetobutylicum promoted the production of butyrate up to 30 mM. Alternatively, two-stage growth slightly promoted solventogenesis and elevated butanol levels (∼4-9 mM). Transcriptional regulation in the two-stage growth condition indicated that this cultivation method may decrease the time required to reach solventogenesis and induce the expression of cellulose-degrading genes in C. acetobutylicum due to relieved carbon-catabolite repression. Overall, this study demonstrates a proof of concept for biobutanol and bio-butyrate production from lignocellulose using an anaerobic fungal-bacterial co-culture system.

Substance Use and Mental Health Screening Within an Emergency Department-Based HIV Screening Program: Outcomes From 1 Year of Implementation.

INTRODUCTION: The emergency department (ED) may be an optimal setting to screen for substance use disorders (SUDs) and co-occurring psychiatric disorders (CODs). We report on the frequency of problematic substance use and comorbid elevated mental health symptoms detected during a 1-year implementation period of an ED-based SUD/COD screening approach within an established ED HIV screening program. METHODS: Patients (N = 1,924) were approached by dedicated HIV screening staff in an urban, Midwestern ED. Patients first completed measures assessing problematic alcohol (Alcohol Use Disorder Identification Test-Concise [AUDIT-C]) and substance use across 10 categories of substances (National Institute on Drug Abuse-Modified Alcohol, Smoking, and Substance Involvement Screening Test [NIDA-Modified ASSIST]). Patients with positive alcohol and/or substance use screens completed measures assessing symptoms of depression (Patient Health Questionnaire-9 [PHQ-9]), anxiety (Generalized Anxiety Disorder-7 [GAD-7]), and post-traumatic stress disorder (PTSD) (PTSD Checklist-Civilian [PCL-C]). RESULTS: Patients were predominantly male (60.3%) with a mean age of 38.1 years (SD = 13.0); most identified as White (50.8%) or Black (44.8%). A majority (58.5%) had a positive screen for problematic alcohol and/or other substance use. Of those with a positive substance use screen (n = 1,126), 47.0% had a positive screen on one or more of the mental health measures with 32.1% endorsing elevated depressive symptoms, 29.6% endorsing elevated PTSD-related symptoms, and 28.5% endorsing elevated anxiety symptoms. CONCLUSIONS: Among those receiving ED HIV screening, a majority endorsed problematic alcohol and/or other substance use and co-occurring elevated mental health symptoms. Substance use and mental health screening programs that can be integrated within other ED preventive services may enhance the identification of individuals in need of further assessment, referral, or linkage to substance use treatment services.

Interpersonal abuse and alcohol use among African American young women: the mediating role of emotion dysregulation.

African American women experience a high prevalence of alcohol-related consequences, and no studies have explicitly examined the associations among lifetime interpersonal abuse, emotion dysregulation, and alcohol-related outcomes during the critical period of young adulthood within this population. This study used baseline data from a sample of African American young women (N = 560) who use alcohol, aged 18 to 24, enrolled in an HIV prevention intervention trial to examine whether emotion dysregulation mediated the relation between lifetime history of abuse and problematic alcohol use. Further, we sought to examine whether there were potential differential levels of problematic alcohol use based on the number of abuse types experienced. Multiple regression analyses showed that exposure to two or more forms of abuse was associated with problematic alcohol use, ß = .24, p < .001, and heavy alcohol consumption, ß = .23, p < .001, whereas history of a single form was not. Indirect effects of both single and multiple forms of abuse on problematic alcohol use (95% confidence interval [CI] [.16, 1.02]; [.46, 1.64]) and heavy alcohol consumption (95% CI [.02, .26]; [.05, .45]) via emotion dysregulation severity were found. Abuse and emotion dysregulation were associated with frequency of alcohol use and binge drinking, but not typical amount consumed. Hazardous alcohol consumption was prevalent among this sample of African American young women who use alcohol. This study provides preliminary evidence that emotion dysregulation may be an important mechanism buttressing the association between lifetime history of interpersonal abuse and problematic alcohol use among African American young women who use alcohol.

The synthetic opioid fentanyl increases HIV replication and chemokine co-receptor expression in vitro.

The US is experiencing a major public health crisis that is fueled by the illicit use of synthetic opioids including fentanyl. While several drugs of abuse can enhance viral replication and/or antagonize immune responses, the impact of specific synthetic opioids on HIV pathogenesis is poorly understood. Thus, we evaluated the effects of fentanyl on HIV replication in vitro. HIV-susceptible or HIV-expressing cell lines were incubated with fentanyl. HIV p24 synthesis and chemokine receptor levels were quantified by ELISA in culture supernatants and cell lysates, respectively. Addition of fentanyl resulted in a dose-dependent increase in HIV replication. Fentanyl enhanced expression of the HIV chemokine co-receptors CXCR4 and CCR5 and caused a dose-dependent decrease in cell viability. The opioid antagonist naltrexone blocked the effect of fentanyl on HIV replication and CCR5 receptor levels but not CXCR4 receptor levels. TLR9 expression was induced by HIV; however, fentanyl inhibited TLR9 expression in a dose-dependent manner. These data demonstrate that the synthetic opioid fentanyl can promote HIV replication in vitro. As increased HIV levels are associated with accelerated disease progression and higher likelihood of transmission, additional research is required to enhance the understanding of opioid-virus interactions and to develop new and/or optimized treatment strategies for persons with HIV and opioid use disorder.

Patient Pain Experiences and the Emergency Department Encounter: A Qualitative Analysis.

BACKGROUND: Legislation, practice recommendations, and the likely link between therapeutic opioid exposure and iatrogenic opioid use disorder (OUD) have led to reduced opioid prescribing. The effects of this change on unrelieved pain and the overdose crisis are not well-characterized. AIM: We explored emergency department (ED) patients' beliefs and experiences involving pain and emergency care to inform the development of future psychosocial interventions that balance the need for acute pain management with risks from opioid exposure. METHODS: Qualitative, semi-structured interviews were conducted after discharge from an urban, academic Level 1 trauma center ED from September 2020 to May 2021 with 18 adult patients presenting with acute pain. After transcription of audio recording, common themes were identified using framework analysis. Thematic hierarchy was validated with Pearson correlation coefficients for cluster analysis of word similarity. RESULTS: Of the 18 participants, most were Black (n = 11, 61%) and male (n = 12, 66.7%). Analysis identified one overarching theme: locus of control with an emergency pain encounter. Four themes were identified surrounding internal and external influences on pain management: (1) accessing healthcare for acute pain; (2) managing the pain after discharge; (3) seeking opioids: self-medicating and misuse; and (4) opioid crisis makes people in pain suffer. CONCLUSIONS: Patients discharged from the ED reported unrelieved pain, factors that influence their pain management, and an ability to seek opioids from non-medical sources. There is a significant disconnect between patients and providers in terms of priorities in pain management and the importance of individualized care.

Associations between elevated depressive symptoms and substance use, prescription opioid misuse, overdose history, pain, and general health among community pharmacy patients prescribed opioids.

Background: Individuals with pain prescribed opioids experience high rates of comorbid depression. The aim of this study was to characterize pain, substance use, and health status as a function of depressive symptom level in individuals filling an opioid prescription at a community pharmacy. Methods: Participants (N = 1268) filling an opioid prescription enrolled in a study validating a prescription drug monitoring metric completed an online survey assessing sociodemographics, depressive symptoms, substance use, prescription opioid misuse, overdose history, general health, and pain severity and interference. Results: Approximately one-fifth (19.3%) had a positive depression screen result. In covariate-adjusted logistic regression analyses, individuals with a positive depression screen result were more likely to have moderate/high substance use risk scores for prescription opioids (adjusted odds ratio [AOR] = 2.06; 95% confidence interval [CI], 1.51-2.79); street opioids (AOR = 7.18; 95% CI, 2.57-20.01); cannabis (AOR = 2.00; 95% CI, 1.34-3.00); cocaine (AOR = 3.46; 95% CI, 1.46-8.22); tobacco (AOR = 1.59; 95% CI, 1.18-2.15); methamphetamine (AOR = 7.59; 95% CI, 2.58-22.35); prescription stimulants (AOR = 2.95; 95% CI, 1.59-5.49); and sedatives (AOR = 3.41; 95% CI, 2.43-4.79). Individuals with a positive depression screen were more likely to misuse prescription opioids (AOR = 3.46; 95% CI, 2.33-5.15), experience a prior overdose (AOR = 2.69; 95% CI, 1.76-4.11), report poorer general health (AOR = 0.25, 95% CI, 0.18-0.35), and report moderate/severe pain severity (AOR = 4.36, 95% CI, 2.80-6.77) and interference (AOR = 6.47, 95% CI, 4.08-10.26). Conclusions: Individuals prescribed opioids with heightened depression were more likely to report other substance use, prescription opioid misuse, prior overdose, greater pain, and poorer health.

Treatment with hypoxia-mimetics protects cultured rat Schwann cells against oxidative stress-induced cell death.

Schwann cell (SC) grafts promote axon regeneration in the injured spinal cord, but transplant efficacy is diminished by a high death rate in the first 2-3 days postimplantation. Both hypoxic preconditioning and pharmacological induction of the cellular hypoxic response can drive cellular adaptations and improve transplant survival in a number of disease/injury models. Hypoxia-inducible factor 1 alpha (HIF-1α), a regulator of the cellular response to hypoxia, is implicated in preconditioning-associated protection. HIF-1α cellular levels are regulated by the HIF-prolyl hydroxylases (HIF-PHDs). Pharmacological inhibition of the HIF-PHDs mimics hypoxic preconditioning and provides a method to induce adaptive hypoxic responses without direct exposure to hypoxia. In this study, we show that hypoxia-mimetics, deferoxamine (DFO) and adaptaquin (AQ), enhance HIF-1α stability and HIF-1α target gene expression. Expression profiling of hypoxia-related genes demonstrates that HIF-dependent and HIF-independent expression changes occur. Analyses of transcription factor binding sites identify several candidate transcriptional co-regulators that vary in SCs along with HIF-1α. Using an in vitro model system, we show that hypoxia-mimetics are potent blockers of oxidative stress-induced death in SCs. In contrast, traditional hypoxic preconditioning was not protective. The robust protection induced by pharmacological preconditioning, particularly with DFO, indicates that pharmacological induction of hypoxic adaptations could be useful for promoting transplanted SC survival. These agents may also be more broadly useful for protecting SCs, as oxidative stress is a major pathway that drives cellular damage in the context of neurological injury and disease, including demyelinating diseases and peripheral neuropathies.

Factors associated with phosphatidylethanol (PEth) sensitivity for detecting unhealthy alcohol use: An individual patient data meta-analysis.

BACKGROUND: Objective measurement of alcohol consumption is important for clinical care and research. Adjusting for self-reported alcohol use, we conducted an individual participant data (IPD) meta-analysis to examine factors associated with the sensitivity of phosphatidylethanol (PEth), an alcohol metabolite, among persons self-reporting unhealthy alcohol consumption. METHODS: We identified 21 eligible studies and obtained 4073 observations from 3085 participants with Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) positive scores (≥3 for women and ≥4 for men) and PEth measurements. We conducted 1-step IPD meta-analysis using mixed effects models with random intercepts for study site. We examined the associations between demographic (sex, race/ethnicity, and age) and biologic (body mass index-BMI, hemoglobin, HIV status, liver fibrosis, and venous versus finger-prick blood collection) variables with PEth sensitivity (PEth≥8 ng/ml), adjusting for the level of self-reported alcohol use using the AUDIT-C score. RESULTS: One third (31%) of participants were women, 32% were African, 28% African American, 28% White, and 12% other race/ethnicity. PEth sensitivity (i.e., ≥8 ng/ml) was 81.8%. After adjusting for AUDIT-C, we found no associations of sex, age, race/ethnicity, or method of blood collection with PEth sensitivity. In models that additionally included biologic variables, those with higher hemoglobin and indeterminate and advanced liver fibrosis had significantly higher odds of PEth sensitivity; those with higher BMI and those living with HIV had significantly lower odds of PEth sensitivity. African Americans and Africans had higher odds of PEth sensitivity than whites in models that included biologic variables. CONCLUSIONS: Among people reporting unhealthy alcohol use, several biological factors (hemoglobin, BMI, liver fibrosis, and HIV status) were associated with PEth sensitivity. Race/ethnicity was associated with PEth sensitivity in some models but age, sex, and method of blood collection were not. Clinicians should be aware of these factors, and researchers should consider adjusting analyses for these characteristics where possible.

Heavy Alcohol Use is Associated with Lower CD4 Counts among Russian Women Living with HIV: A Multilevel Analysis.

Alcohol use remains prevalent among Russian women with HIV infection. Multilevel mixed effects models were used to estimate the association of heavy drinking and HIV outcomes among women (N = 250 at baseline; N = 207 at follow-up), aged 18-35, engaged in HIV care in Saint Petersburg. Alcohol use was assessed at baseline and 3 months by self-report and by the biomarker phosphatidylethanol (PEth). Overall, 35% of women were heavy drinkers, defined as women reporting ≥ 1 past-30-day heavy drinking episode (≥ 4 standard drinks on one occasion) or with PEth blood levels ≥ 80 ng/mL. Women who engaged in heavy drinking had an average 41 CD4 cells/mm3 (95% CI = - 81, - 2; z = - 2.04; P = 0.042) fewer than those who did not. Heavy drinking was associated with higher HIV symptom burden (IRR = 1.20; 95% CI = 1.05, 1.36; z = 2.73; P = 0.006) and suboptimal antiretroviral adherence (OR = 3.04; 95% CI = 1.27, 7.28; χ2 = 2.50; P = 0.013), but not with viral load. Findings support the integration of alcohol treatment interventions as part of routine HIV care in Russia.

RESUMEN: El consumo de alcohol es común en las mujeres rusas con VIH. Utilizamos modelos multinivel de efectos mixtos para estimar la asociación entre el consumo de alcohol excesivo y los resultados adversos de VIH en un grupo de mujeres (N = 250 al inicio del estudio; N = 207 en el seguimiento), de 18 a 35 años de edad, que recibían atención médica para el VIH en San Petersburgo. El consumo de alcohol excesivo, definido como el consumo de ≥ 4 bebidas alcohólicas en una ocasión en base a autoinforme o a niveles de fosfatidiletanol ≥ 80 ng/mL, se evaluó al inicio del estudio y a los 3 meses. Las mujeres que bebían en exceso, el 35% de la muestra, tenían un promedio de 41 células CD4/mm3 (IC del 95% = − 81, − 2; z = − 2,04; P = 0,042) menos que las que no lo hacían. El consumo excesivo de alcohol se asoció con una mayor carga de síntomas de VIH (TIR = 1,20; IC del 95% = 1,05, 1,36; z = 2,73; P = 0,006) y una adherencia al tratamiento antirretroviral subóptima (OR = 3,04; IC del 95% = 1,27, 7,28; χ2 = 2,50; P = 0,013), pero no con carga viral. Los hallazgos respaldan la integración de la atención para el tratamiento del alcoholismo en los servicios de atención rutinaria del VIH en Rusia.

Reevaluating tear gas toxicity and safety.

Tear gases, or chemical demonstration control agents (DCA), were originally created as weapons that could severely disable or kill enemy troops. Though banned in war, these chemicals are still used in domestic policing. Here we review the available scientific literature on tear gas, summarizing findings from animal and environmental studies as well describing data from new human studies. We find a lack of scientific evidence supporting the safety of tear gas, especially regarding its long-term impacts on human health and the environment. Many of the available studies were published decades ago, and do not parse data by variables such as chemical type and exposure time, nor do they account for the diversity of individuals who are exposed to tear gas in real-life situations. Due to the dearth of scientific research and the misinterpretation of some of the available studies, we conclude that a serious reevaluation of chemical DCA safety and more comprehensive exposure follow-up studies are necessary.