The impact of benzodiazepine exposure on treatment retention in an open-access methadone program: A retrospective cohort study.

BACKGROUND: Open-access opioid treatment programs (OTP) offer same-day access to methadone without an appointment and aim to minimize treatment barriers that often reduce admission and/or retention. We explored whether patients with benzodiazepine exposure at treatment entry would have similar 12-month retention compared to those without benzodiazepine exposure. METHODS: We conducted a retrospective cohort study of 2968 patients consecutively initiated on methadone between January 2015 and February 2017 at an open-access OTP. The sample was stratified into benzodiazepine-exposed and nonexposed groups based on intake urine toxicology. Group comparison of 12-month retention was conducted. Kaplan Meier analysis compared time to methadone treatment discontinuation between groups with a log-rank test. Multivariable Cox regression was performed to compare retention by baseline benzodiazepine exposure with adjustment for confounders. RESULTS: Overall, 31% of patients with benzodiazepine exposure (n = 171) and 31% without exposure (n = 2423) were retained at 12 months (p = 0.95). Median treatment duration was 182 days (95% CI, 152-239) and 175 days (95% CI, 156-196) for patients with and without benzodiazepine exposure, respectively. Kaplan-Meier analysis showed no significant difference in treatment duration between groups (log-rank test p = 0.73). Cox regression found no difference in treatment retention between groups (adjusted Hazard Ratio= 1.03, 95% CI, 0.91-1.16). CONCLUSIONS: In this cohort of patients receiving methadone at an open-access OTP, benzodiazepine exposure at intake was not observed to impact 12-month treatment retention or duration. These findings support U.S. Food and Drug Administration (FDA) recommendations to not withhold medications for opioid use disorder from patients taking benzodiazepines.

Bma-LAD-2, an Intestinal Cell Adhesion Protein, as a Potential Therapeutic Target for Lymphatic Filariasis.

Lymphatic filariasis is a debilitating disease that afflicts over 70 million people worldwide. It is caused by the parasitic nematodes Wuchereria bancrofti, Brugia malayi, and Brugia timori. Despite substantial success, efforts to eliminate LF will likely require more time and resources than predicted. Identifying new drug and vaccine targets in adult filariae could help elimination efforts. This study's aim was to evaluate intestinal proteins in adult Brugia malayi worms as possible therapeutic targets. Using short interfering RNA (siRNA), we successfully targeted four candidate gene transcripts: Bma-Serpin, Bma-ShTK, Bma-Reprolysin, and Bma-LAD-2. Of those, Bma-LAD-2, an immunoglobulin superfamily cell adhesion molecule (IgSF CAM), was determined to be essential for adult worm survival. We observed a 70.42% knockdown in Bma-LAD-2 transcript levels 1 day post-siRNA incubation and an 87.02% reduction in protein expression 2 days post-siRNA incubation. This inhibition of Bma-LAD-2 expression resulted in an 80% decrease in worm motility over 6 days, a 93.43% reduction in microfilaria release (Mf) by day 6 post-siRNA incubation, and a dramatic decrease in (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction. Transmission electron microscopy revealed the loss of microvilli and unraveling of mitochondrial cristae in the intestinal epithelium of Bma-LAD-2 siRNA-treated worms. Strikingly, Bma-LAD-2 siRNA-treated worms exhibited an almost complete loss of pseudocoelomic fluid. A luciferase immunoprecipitation system assay did not detect anti-Bma-LAD-2 IgE in the serum of 30 LF patients, indicating that LF exposure does not result in IgE sensitization to this antigen. These results indicate that Bma-LAD-2 is an essential protein for adult Brugia malayi and may be an effective therapeutic target. IMPORTANCE Brugia malayi is a parasitic nematode that can cause lymphatic filariasis, a debilitating disease prevalent in tropical and subtropical countries. Significant progress has been made toward eliminating the disease. However, complete eradication may require new therapeutics such as drugs or a vaccine that kill adult filariae. In this study, we identified an immunoglobulin superfamily cell adhesion molecule (Bma-LAD-2) as a potential drug and vaccine candidate. When we knocked down Bma-LAD-2 expression, we observed a decrease in worm motility, fecundity, and metabolism. We also visualized the loss of microvilli, destruction of the mitochondria in the intestinal epithelium, and loss of pseudocoelomic fluid contents after Bma-LAD-2 siRNA treatment. Finally, we demonstrated that serum from filaria-infected patients does not contain preexisting IgE to Bma-LAD-2, which indicates that this antigen would be safe to administer as a vaccine in populations where the disease is endemic.

Methadone Access for Opioid Use Disorder During the COVID-19 Pandemic Within the United States and Canada.

Importance: Methadone access may be uniquely vulnerable to disruption during COVID-19, and even short delays in access are associated with decreased medication initiation and increased illicit opioid use and overdose death. Relative to Canada, US methadone provision is more restricted and limited to specialized opioid treatment programs. Objective: To compare timely access to methadone initiation in the US and Canada during COVID-19. Design, Setting, and Participants: This cross-sectional study was conducted from May to June 2020. Participating clinics provided methadone for opioid use disorder in 14 US states and territories and 3 Canadian provinces with the highest opioid overdose death rates. Statistical analysis was performed from July 2020 to January 2021. Exposures: Nation and type of health insurance (US Medicaid and US self-pay vs Canadian provincial). Main Outcomes and Measures: Proportion of clinics accepting new patients and days to first appointment. Results: Among 268 of 298 US clinics contacted as a patient with Medicaid (90%), 271 of 301 US clinics contacted as a self-pay patient (90%), and 237 of 288 Canadian clinics contacted as a patient with provincial insurance (82%), new patients were accepted for methadone at 231 clinics (86%) during US Medicaid contacts, 230 clinics (85%) during US self-pay contacts, and at 210 clinics (89%) during Canadian contacts. Among clinics not accepting new patients, at least 44% of 27 clinics reported that the COVID-19 pandemic was the reason. The mean wait for first appointment was greater among US Medicaid contacts (3.5 days [95% CI, 2.9-4.2 days]) and US self-pay contacts (4.1 days [95% CI, 3.4-4.8 days]) than Canadian contacts (1.9 days [95% CI, 1.7-2.1 days]) (P < .001). Open-access model (walk-in hours for new patients without an appointment) utilization was reported by 57 Medicaid (30%), 57 self-pay (30%), and 115 Canadian (59%) contacts offering an appointment. Conclusions and Relevance: In this cross-sectional study of 2 nations, more than 1 in 10 methadone clinics were not accepting new patients. Canadian clinics offered more timely methadone access than US opioid treatment programs. These results suggest that the methadone access shortage was exacerbated by COVID-19 and that changes to the US opioid treatment program model are needed to improve the timeliness of access. Increased open-access model adoption may increase timely access.