Impacts of the COVID-19 pandemic on enrollment in medications for opioid use disorder (MOUD) in Vancouver, Canada: An interrupted time series analysis.

BACKGROUND: In anticipation of COVID-19 related disruptions to opioid use disorder (OUD) care, new provincial and federal guidance for the management of OUD and risk mitigation guidance (RMG) for prescription of pharmaceutical opioids were introduced in British Columbia, Canada, in March 2020. This study evaluated the combined impacts of the COVID-19 pandemic and counteracting OUD policies on enrollment in medications for OUD (MOUD). METHODS: Using data from three cohorts of people with presumed OUD in Vancouver, we conducted an interrupted time series analysis to estimate the combined effects impact of the COVID-19 pandemic and counteracting OUD policies on the prevalence of enrollment in MOUD overall, as well as in individual MOUDs (methadone, buprenorphine/naloxone, slow-release oral morphine) between November 2018 and November 2021, controlling for pre-existing trends. In sub-analysis we considered RMG opioids together with MOUD. RESULTS: We included 760 participants with presumed OUD. In the post-COVID-19 period, MOUD and slow-release oral morphine prevalence rates showed an estimated immediate increase in level (+7.6%, 95% CI: 0.6%, 14.6% and 1.8%, 95% CI: 0.3%, 3.3%, respectively), followed by a decline in the monthly trend (-0.8% per month, 95% CI: -1.4%, -0.2% and -0.2% per month, 95% CI: -0.4, -0.1, respectively). There were no significant changes in the prevalence trends of enrollment in methadone, buprenorphine/naloxone, or when RMG opioids were considered together with MOUD. CONCLUSIONS: Despite immediate improvements in MOUD enrollment in the post-COVID-19 period, this beneficial trend reversed over time. RMG opioids appeared to have provided additional benefits to sustain retention in OUD care.

Inability to contact opioid agonist therapy prescribers during the COVID-19 pandemic in a Canadian setting: a cross-sectional analysis among people on opioid agonist therapy.

BACKGROUND: The COVID-19 pandemic and consequent public health response may have undermined key responses to the protracted drug poisoning crisis, including reduced access to opioid agonist therapy (OAT) among people with opioid use disorder. Our study objectives were to estimate the prevalence of and identify factors associated with inability to contact OAT prescribers when in need among people on OAT in a Canadian setting during the dual public health crises. METHODS: Survey data were collected from three prospective cohort studies of community-recruited people who use drugs between July and November 2020, in Vancouver, Canada. A multivariable logistic regression analysis was used to identify potential factors associated with inability to contact OAT prescribers among patients who accessed OAT in the past 6 months. RESULTS: Among 448 respondents who reported accessing OAT in the past 6 months, including 231 (54.9%) men, 85 (19.0%) reported having been unable to contact OAT prescribers when needed, whereas 268 (59.8%) reported being able to talk to their prescriber when needed, and 95 (21.2%) reported that they did not want to talk to their medication prescriber in the previous 6 months. Among those who reported inability to contact prescribers, 45 (53.6%) reported that their overall ability to contact prescribers decreased since the start of the pandemic. In multivariable analyses, factors independently associated with inability to talk to OAT prescribers included: chronic pain (Adjusted Odds Ratio [AOR] = 1.82; 95% Confidence Interval [CI] 1.02, 3.27), moderate to severe symptoms of depression or anxiety (AOR = 4.74; 95% CI 2.30, 9.76), inability to access health/social services (AOR = 2.66; 95% CI 1.41, 5.02), and inability to self-isolate or socially distance most or all of the time (AOR = 2.13; 95% CI 1.10, 4.14). CONCLUSIONS: Overall, approximately one fifth of the sample reported inability to contact their OAT prescribers when needed, and those people were more likely to have co-occurring vulnerabilities (i.e., co-morbidities, inability to access health/social services) and higher vulnerability to COVID-19. Interventions are needed to ensure optimal access to OAT and mitigate the deepening health inequities resulting from the COVID-19 pandemic and the escalating drug poisoning crisis.

Low awareness of risk mitigation prescribing in response to dual crises of COVID-19 and overdose deaths among people who use unregulated drugs in Vancouver, Canada.

BACKGROUND: When the novel coronavirus pandemic emerged in March 2020, many settings across Canada and the USA were already contending with an existing crisis of drug overdoses due to the toxic unregulated drug supply. In response, the Canadian province of British Columbia (BC) released innovative risk mitigation prescribing (RMP) guidelines for medical professionals to prescribe pharmaceutical alternatives to unregulated drugs in an effort to support the self-isolation of people who use unregulated drugs (PWUD) in preventing both SARS-CoV-2 virus infection and overdoses. We sought to assess the level of awareness of RMP and identify factors associated with this awareness among PWUD in Vancouver, BC. METHODS: Cross-sectional data were derived from participants enrolled in three community-recruited prospective cohort studies of PWUD in Vancouver, interviewed between July and November 2020. Multivariable logistic regression analysis was used to identify factors associated with awareness of RMP. RESULTS: Among 633 participants, 302 (47.7%) had heard of RMP. Of those 302 participants, 199 (65.9%) had never tried to access RMP services, ten (3.3%) made an unsuccessful attempt to access RMP, and 93 (30.8%) received RMP. In the multivariable analysis, participants who had awareness of RMP guidelines were more likely to self-identify as white (adjusted odds ratio [AOR] = 1.47; 95% confidence interval [CI]: 1.01, 2.13), to have completed secondary school education or higher (AOR = 1.67; 95% CI: 1.16, 2.39), to have used drugs at a supervised consumption or overdose prevention site in the past six months (AOR = 1.66; 95% CI: 1.10, 2.52), and to have received opioid agonist therapy as treatment for opioid use disorder in the past six months (AOR = 1.51; 95% CI: 1.02, 2.24). CONCLUSION: At least four months after the release of the guidelines, RMP was known to less than half of our study participants, warranting urgent educational efforts for PWUD, particularly among racialized groups and those who were not accessing other harm reduction services. Furthermore, the majority of participants who were aware of RMP guidelines had never tried to access the service, suggesting the need to improve perceived accessibility and knowledge of eligibility criteria.

Factors associated with perceived decline in the quality of drugs during the COVID-19 pandemic: Evidence from community-recruited cohorts of people who use drugs in Vancouver, Canada.

OBJECTIVES: Driven by an increasingly toxic drug supply, drug toxicity deaths in the United States and Canada have risen to unprecedented levels during the COVID-19 pandemic. This study aimed to characterize the prevalence of and the factors associated with a perceived decline in the quality of drugs during the COVID-19 pandemic among community-recruited cohorts of PWUD in Vancouver, Canada. METHODS: Data collection took place between July and November 2020. In adherence with COVID-19 safety protocols, questionnaires were administered by interviewers through remote means (e.g., phone or videoconference). Using multivariable logistic regression, we characterized the prevalence of and factors associated with a perceived decline in drug quality during the start of the COVID-19 pandemic in Vancouver, Canada. RESULTS: Of the 738 individuals included in this analysis, 272 (36.9%) reported that the quality of drugs declined during the COVID-19 pandemic. In multivariable analysis, perceived decline in the quality of drugs was significantly associated with: recent non-fatal overdose (adjusted odds ratio [AOR]=2.01, 95% Confidence Interval [CI]: 1.29-3.15), at least weekly injection drug use (AOR=1.94, 95% CI: 1.40-2.71), at least weekly crack use (AOR=1.61, 95%CI: 1.10-2.36), and at least weekly crystal methamphetamine use (AOR=1.46, 95%CI: 1.03-2.08). DISCUSSION: Over a third of PWUD perceived that the quality of drugs declined during the COVID-19 pandemic and these individuals were significantly more likely to report experiencing a recent non-fatal overdose, engaging in frequent injection drug and stimulant use. Study findings indicate the need for interventions to address the toxic drug supply, including providing a regulated supply.

The utility of visual appearance in predicting the composition of street opioids.

Background: With the emergence of unregulated fentanyl, people who use unregulated opioids are increasingly relying on appearance in an effort to ascertain the presence of fentanyl and level of drug potency. However, the utility of visual inspection to identify drug composition in the fentanyl era has not been assessed. Methods: We assessed client expectation, appearance, and composition of street drug samples being presented for drug checking. Results of a visual screening test were compared to fentanyl immunoassay strip testing. We calculated sensitivity, specificity and likelihood ratios (LR) to assess the accuracy of the common assumption that samples with a "pebbles" appearance contain fentanyl. Results: In total, of the 2502 unregulated opioid samples tested, 1820 (73.5%) appeared as "pebbles", of which 1729 (95.0%) tested positive for fentanyl for a sensitivity of 75.9% (95% Confidence Interval [CI]: 74.2-77.6) and specificity of 59.4% (95%CI: 57.5-61.3). Although, the odds of samples containing fentanyl was 4.60 (95%CI: 3.47-6.11) times higher among pebbles samples compared to non-pebble samples, the positive LR for pebbles to contain fentanyl was only 1.87 (CI: 1.59-2.19). The negative LR was more useful at 0.41 (95% CI: 0.36-0.46). Conclusions: A positive screening test for pebbles is not strongly enough associated to be used as a proxy for detecting fentanyl. While the absence of the appearance of pebbles does somewhat reduce the likelihood of fentanyl being present in a given sample, the high prevalence of fentanyl and fentanyl analogues in the drug supply and the risks of consumption are such that public health providers should routinely advise people who use unregulated opioids against solely relying on visual characteristics of drugs as a harm reduction strategy.

Fragment-Based Discovery of Dual JC Virus and BK Virus Helicase Inhibitors.

There are currently no treatments for life-threatening infections caused by human polyomaviruses JCV and BKV. We therefore report herein the first crystal structure of the hexameric helicase of JCV large T antigen (apo) and its use to drive the structure-based design of dual JCV and BKV ATP-competitive inhibitors. The crystal structures obtained by soaking our early inhibitors into the JCV helicase allowed us to rapidly improve the biochemical activity of our inhibitors from 18 µM for the early 6-(2-methoxyphenyl)- and the 6-(2-ethoxyphenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole hits 1a and 1b to 0.6 µM for triazolopyridine 12i. In addition, we were able to demonstrate measurable antiviral activity in Vero cells for our thiazolopyridine series in the absence of marked cytotoxicity, thus confirming the usefulness of this approach.

Clinical and radiographic outcomes after spinous process fixation and posterior fusion in an elderly cohort.

Spinous process fixation (SPF) has gained attention as a less invasive option for lumbar fusion surgery. Minimally invasive techniques are of interest in an elderly population due to decreased surgical time and post-operative complications. Clinical outcomes and fusion rates have not been determined in a large cohort. Our objective was to describe significant predictors of visual analog scale (VAS), length of stay, blood loss, fusion rates, and complication rates for patients treated for degenerative lumbar spondolysis with ISP fixation with and without supplemental instrumentation. Charts were assessed for post-operative VAS vs. pre-operative VAS at: 1-3, >3-6, and >6-12 months. To control confounding variables, VAS scores were modeled as a repeated-measures linear-mixed-model. In a sub-cohort CT images were assessed for interspinous and interbody (IB) fusion. The images were reviewed by an independent radiologist to evaluate fusion status. Eighty-six SPF patients (91 levels, mean age 67 years) were identified. After determining the model, age and sex remained predictors of VAS. Adjusting for age and sex, patients saw a decrease of 3.6 VAS points from baseline to three months (95% CI: 2.9-4.4, p<0.0001) that was maintained over the six to 12 month follow-up period. A sub-cohort of 50 patients with CT scans were identified and assessed for ISP and IB fusion at a mean of 181 days postoperatively. Ninety-four percent of levels demonstrated ISP fusion. Sixty-one percent of solid ISP fusion patients also had an interbody cage, but this did not impact fusion rates. Eighty-six percent of these levels showed solid IB fusion (BSF-3). Of the four pseudoarthrosed levels, two had pedicle screw fixation, and two were IB and ISP fixation. Only two patients went on to re-exploration and explantation due to pain secondary to spinous process and/or lamina fracture. This elderly cohort treated with SPF demonstrated significant improvement in VAS with reliable fusion rates.

[C+NC+CC] coupling-enabled synthesis of influenza neuramidase inhibitor A-315675.

An efficient synthesis of the neuramidase inhibitor A-315675 is reported. The fully functionalized pyrrolidine core of the target is assembled in one pot via an exo-selective asymmetric [C+NC+CC] coupling reaction.

Recurrent die-offs of adult coho salmon returning to spawn in Puget Sound lowland urban streams.

Several Seattle-area streams in Puget Sound were the focus of habitat restoration projects in the 1990s. Post-project effectiveness monitoring surveys revealed anomalous behaviors among adult coho salmon returning to spawn in restored reaches. These included erratic surface swimming, gaping, fin splaying, and loss of orientation and equilibrium. Affected fish died within hours, and female carcasses generally showed high rates (>90%) of egg retention. Beginning in the fall of 2002, systematic spawner surveys were conducted to 1) assess the severity of the adult die-offs, 2) compare spawner mortality in urban vs. non-urban streams, and 3) identify water quality and spawner condition factors that might be associated with the recurrent fish kills. The forensic investigation focused on conventional water quality parameters (e.g., dissolved oxygen, temperature, ammonia), fish condition, pathogen exposure and disease status, and exposures to metals, polycyclic aromatic hydrocarbons, and current use pesticides. Daily surveys of a representative urban stream (Longfellow Creek) from 2002-2009 revealed premature spawner mortality rates that ranged from 60-100% of each fall run. The comparable rate in a non-urban stream was <1% (Fortson Creek, surveyed in 2002). Conventional water quality, pesticide exposure, disease, and spawner condition showed no relationship to the syndrome. Coho salmon did show evidence of exposure to metals and petroleum hydrocarbons, both of which commonly originate from motor vehicles in urban landscapes. The weight of evidence suggests that freshwater-transitional coho are particularly vulnerable to an as-yet unidentified toxic contaminant (or contaminant mixture) in urban runoff. Stormwater may therefore place important constraints on efforts to conserve and recover coho populations in urban and urbanizing watersheds throughout the western United States.

N-phenylphenylglycines as novel corticotropin releasing factor receptor antagonists.

Screening of a computationally designed synthetic library led to the discovery of the N-phenylphenylglycines (NPPGs) as a novel class of human corticotropin releasing factor (h-CRF(1)) antagonists. Several NPPGs with greater potency than the original hit 1 were rapidly identified, and resolution of the racemate demonstrated that only the R-enantiomer displays activity. This structural class represents the first example of a non-peptide CRF(1) antagonist with a stereochemically distinct receptor binding affinity.

Galactolipids rather than phlorotannins as herbivore deterrents in the brown seaweed Fucus vesiculosus.

The first investigation of seaweed chemical defense against herbivores involved the brown seaweed Fucus vesiculosus and suggested defense via phlorotannins. The first demonstration of seaweed induction of secondary metabolites in response to herbivory also involved the genus Fucus and assumed a defensive function for phlorotannins. Many other investigations correlate herbivore feeding preference with changing levels of phlorotannins in this genus and others, but few directly test the effects of phlorotannins. No studies have assessed Fucus chemical defenses using bioassay-guided separation to investigate the complete complement of compounds deterring herbivores. We investigated the deterrence of F. vesiculosus chemical extracts using herbivore bioassays to guide our chemical investigations. Although crude extracts from F. vesiculosus strongly deterred feeding by the sea urchin Arbacia punctulata, phlorotannins from this extract did not deter feeding at 2x or 4x natural concentration by dry mass. Feeding deterrence was due to: (1) a polar galactolipid in the ethyl acetate-soluble extract, and (2) a non-phenolic compound, or compounds, in the water-soluble extract. Although this is the first evidence of galactolipids deterring herbivores, such defenses could be geographically and taxonomically widespread. The galactolipid we discovered in Fucus occurs in marine dinoflagellates, and a related metabolite that deters herbivory has recently been discovered in a tropical green seaweed. We were unable to identify the second deterrent compound, but deterrence occurred in a fraction containing carbohydrates, including sulfated sugars, but no phlorotannins. Given the polarity of these chemical deterrents, they could co-occur with and confound bioassays of phlorotannins if investigators test phlorotannin-containing algal extracts without further purification.

Arylamidrazones as novel corticotropin releasing factor receptor antagonists.

The arylamidrazones have been found to be potent corticotropin releasing factor (CRF) receptor antagonists structurally distinct from previously reported CRF1 antagonists. Attempts to modify the arylamidrazone core suggested an important role for the anilino NH moiety. The right-hand-side 2-nitro feature in lead 1 could be replaced with substituents methyl, chloro, cyano, or trifluoromethyl with a 4- to 10-fold reduction in receptor binding. With appropriate left-hand-side modifications, this potency loss could be recovered.