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Data from several modeling studies demonstrate that large-scale increases in human immunodeficiency virus (HIV) testing across settings with a high burden of HIV may produce the largest incidence reductions to support the US Ending the HIV Epidemic (EHE) initiative's goal of reducing new HIV infections 90% by 2030. Despite US Centers for Disease Control and Prevention's recommendations for routine HIV screening within clinical settings and at least yearly screening for individuals most at risk of acquiring HIV, fewer than half of US adults report ever receiving an HIV test. Furthermore, total domestic funding for HIV prevention has remained unchanged between 2013 and 2019. The authors describe the evidence supporting the value of expanded HIV testing, identify challenges in implementation, and present recommendations to address these barriers through approaches at local and federal levels to reach EHE targets.

IntroductionUrine drug tests (UDTs) are commonly used for monitoring opioid agonist treatment (OAT) responses, supporting the clinical decision for take-home doses and monitoring potential diversion. However, there is limited evidence supporting the utility of mandatory UDTs—particularly the impact of UDT frequency on OAT retention. Real-world evidence can inform patient-centred approaches to OAT and improve current strategies to address the ongoing opioid public health emergency. Our objective is to determine the safety and comparative effectiveness of alternative UDT monitoring strategies as observed in clinical practice among OAT clients in British Columbia, Canada from 2010 to 2020.Methods and analysisWe propose a population-level retrospective cohort study of all individuals 18 years of age or older who initiated OAT from 1 January 2010 to 17 March 2020. The study will draw on eight linked health administrative databases from British Columbia. Our primary outcomes include OAT discontinuation and all-cause mortality. To determine the effectiveness of the intervention, we will emulate a ‘per-protocol’ target trial using a clone censoring approach to compare fixed and dynamic UDT monitoring strategies. A range of sensitivity analyses will be executed to determine the robustness of our results.Ethics and disseminationThe protocol, cohort creation and analysis plan have been classified and approved as a quality improvement initiative by Providence Health Care Research Ethics Board and the Simon Fraser University Office of Research Ethics. Results will be disseminated to local advocacy groups and decision-makers, national and international clinical guideline developers, presented at international conferences and published in peer-reviewed journals electronically and in print.

We estimated human immunodeficiency virus incidence and incidence rate ratios (IRRs) for black and Hispanic vs white populations in 6 cities in the United States (2020–2030). Large reductions in incidence are possible, but without elimination of disparities in healthcare access, we found that wide disparities persisted for black compared with white populations in particular (lowest IRR, 1.69 [95% credible interval, 1.19–2.30]).

BACKGROUND Compared to children who are HIV-unexposed and uninfected (CHUU), children who are HIV-exposed and uninfected (CHEU) experience more clinical complications. We investigated hospitalizations among CHEU by antenatal antiretroviral therapy (ART) exposure, in British Columbia, Canada. METHODS This retrospective controlled cohort study used administrative health data from 1990 to 2012. CHEU and CHUU were matched 1:3 for age, sex and maternal geographical area of residence. We determined adjusted odds ratios (aORs) via conditional logistic regression, adjusting for maternal risk factors. RESULTS A total of 446 CHEU and 1333 CHUU were included. Compared with CHUU, more CHEU experienced one or more lifetime hospitalization (47.3% vs. 29.8%), one or more neonatal hospitalization (40.4% vs. 27.6%), and any intensive care unit admission (28.5% vs. 9.2%). In adjusted analyses, CHEU experienced higher odds of any lifetime hospitalization (aOR 2.30, 95% confidence interval 1.81-2.91) and neonatal hospitalization (aOR 2.14, 95% confidence interval 1.68-2.73), compared with CHUU. There was, however, no difference in infection-related hospitalizations (9.0% vs. 7.5%), which were primarily respiratory tract infections among both CHEU and CHUU. CHEU whose mothers-initiated ART preconception showed lower odds of infection-related hospitalizations than children whose mothers initiated ART during pregnancy or received no ART. CONCLUSIONS CHEU experienced increased odds of hospitalization relative to CHUU. A substantial number of CHEU hospitalizations occurred within the neonatal period and were ICU admissions. Initiating ART preconception may reduce the risk of infection-related hospitalizations. These findings reinforce the benefit of ART in pregnancy and the need for ongoing pediatric care to reduce hospitalizations.

OBJECTIVES Evidence on the perinatal health of mother-infant dyads affected by opioids is limited. Elevated risks of opioid-related harms for people with opioid use disorder (OUD) increase the urgency to identify protective factors for mothers and infants. Our objectives were to determine perinatal outcomes after an OUD diagnosis and associations between opioid agonist treatment and birth outcomes. METHODS We conducted a population-based retrospective study among all women with diagnosed OUD before delivery and within the puerperium period in British Columbia, Canada, between 2000 and 2019 from provincial health administrative data. Controlling for demographic and clinical characteristics, we determined associations of opioid agonist treatment on birth weight, gestational age, infant disorders related to gestational age and birth weight, and neonatal abstinence syndrome via logistic regression. RESULTS The population included 4574 women and 6720 live births. Incidence of perinatal OUD increased from 166 in 2000 to 513 in 2019. Compared with discontinuing opioid agonist treatment during pregnancy, continuous opioid agonist treatment reduced odds of preterm birth (adjusted odds ratio: 0.6; 95% confidence interval: 0.4–0.8) and low birth weight (adjusted odds ratio: 0.4; 95% confidence interval: 0.2–0.7). Treatment with buprenorphine-naloxone (compared with methadone) reduced odds of each outcome including neonatal abstinence syndrome (adjusted odds ratio: 0.6; 95% confidence interval: 0.4–0.9). CONCLUSIONS Perinatal OUD in British Columbia tripled in incidence over a 20-year period. Sustained opioid agonist treatment during pregnancy reduced the risk of adverse birth outcomes, highlighting the need for expanded services, including opioid agonist treatment to support mothers and infants.

IntroductionOpioid agonist treatment (OAT) is a safe and effective treatment for opioid use disorder (OUD). However, people commonly stop and start OAT and their risk of death is high immediately after stopping. The prevalence of illicitly manufactured fentanyl and other highly potent synthetic opioids have increased in the illicit drug supply globally. Yet, there is limited evidence examining the relationship between OAT and mortality when these contaminants are widely available in the illicit drug supply. Objectives and ApproachWe aimed to compare the risk of mortality on and off OAT in a setting with a high prevalence of illicitly manufactured fentanyl and other potent synthetic opioids in the illicit drug supply. We linked five health administrative datasets in British Columbia, Canada, creating a cohort of 55,347 people with OUD who received OAT during a 23-year period (1996 to 2018). We compared the risk of mortality on and off treatment over time, and according to time since starting or stopping treatment and by medication type. Results7,030 of 55,347 (12.7%) OAT recipients died during follow-up. All-cause SMR was substantially lower on OAT (4.6 [4.4 to 4.8]) compared to off OAT (9.7 [9.5 to 10.0]). In a period of increasing prevalence of fentanyl, the relative risk of mortality off OAT was 2.1 [1.8 to 2.4] times higher than on OAT prior to the introduction of fentanyl, and increased to 3.4 [2.8 to 4.3] at the end of the study period (65% increase in relative risk). Conclusion / ImplicationsThe protective effect of OAT on mortality increased as fentanyl and other synthetic opioids became common in the illicit drug supply, while the risk of mortality remained high off OAT. As fentanyl becomes more widespread globally, these findings highlight the importance of interventions that improve retention on opioid agonist treatment and prevent recipients from stopping treatment.

IntroductionDespite a recent meta-analysis including 31 randomised controlled trials comparing methadone and buprenorphine for the treatment of opioid use disorder, important knowledge gaps remain regarding the long-term effectiveness of different treatment modalities across individuals, including rigorously collected data on retention rates and other treatment outcomes. Evidence from real-world data represents a valuable opportunity to improve personalised treatment and patient-centred guidelines for vulnerable populations and inform strategies to reduce opioid-related mortality. Our objective is to determine the comparative effectiveness of methadone versus buprenorphine/naloxone, both overall and within key populations, in a setting where both medications are simultaneously available in office-based practices and specialised clinics.Methods and analysisWe propose a retrospective cohort study of all adults living in British Columbia receiving opioid agonist treatment (OAT) with methadone or buprenorphine/naloxone between 1 January 2008 and 30 September 2018. The study will draw on seven linked population-level administrative databases. The primary outcomes include retention in OAT and all-cause mortality. We will determine the effectiveness of buprenorphine/naloxone vs methadone using intention-to-treat and per-protocol analyses—the former emulating flexible-dose trials and the latter focusing on the comparison of the two medication regimens offered at the optimal dose. Sensitivity analyses will be used to assess the robustness of results to heterogeneity in the patient population and threats to internal validity.Ethics and disseminationThe protocol, cohort creation and analysis plan have been approved and classified as a quality improvement initiative exempt from ethical review (Providence Health Care Research Institute and the Simon Fraser University Office of Research Ethics). Dissemination is planned via conferences and publications, and through direct engagement and collaboration with entities that issue clinical guidelines, such as professional medical societies and public health organisations.

Objective To compare the risk of mortality among people with opioid use disorder on and off opioid agonist treatment (OAT) in a setting with a high prevalence of illicitly manufactured fentanyl and other potent synthetic opioids in the illicit drug supply. Design Population based retrospective cohort study. Setting Individual level linkage of five health administrative datasets capturing drug dispensations, hospital admissions, physician billing records, ambulatory care reports, and deaths in British Columbia, Canada. Participants 55 347 people with opioid use disorder who received OAT between 1 January 1996 and 30 September 2018. Main outcome measures All cause and cause specific crude mortality rates (per 1000 person years) to determine absolute risk of mortality and all cause age and sex standardised mortality ratios to determine relative risk of mortality compared with the general population. Mortality risk was calculated according to treatment status (on OAT, off OAT), time since starting and stopping treatment (1, 2, 3-4, 5-12, >12 weeks), and medication type (methadone, buprenorphine/naloxone). Adjusted risk ratios compared the relative risk of mortality on and off OAT over time as fentanyl became more prevalent in the illicit drug supply. Results 7030 (12.7%) of 55 347 OAT recipients died during follow-up. The all cause standardised mortality ratio was substantially lower on OAT (4.6, 95% confidence interval 4.4 to 4.8) than off OAT (9.7, 9.5 to 10.0). In a period of increasing prevalence of fentanyl, the relative risk of mortality off OAT was 2.1 (95% confidence interval 1.8 to 2.4) times higher than on OAT before the introduction of fentanyl, increasing to 3.4 (2.8 to 4.3) at the end of the study period (65% increase in relative risk). Conclusions Retention on OAT is associated with substantial reductions in the risk of mortality for people with opioid use disorder. The protective effect of OAT on mortality increased as fentanyl and other synthetic opioids became common in the illicit drug supply, whereas the risk of mortality remained high off OAT. As fentanyl becomes more widespread globally, these findings highlight the importance of interventions that improve retention on opioid agonist treatment and prevent recipients from stopping treatment.

Background: Widespread viral and serological testing for SARS-CoV-2 may present a unique opportunity to also test for HIV infection. We estimated the potential impact of adding linked, opt-out HIV testing alongside SARS-CoV-2 testing on HIV incidence and the cost-effectiveness of this strategy in six US cities. Methods: We calibrated a dynamic compartmental HIV transmission model to match the epidemiological characteristics of six US cities (Atlanta, Baltimore, Los Angeles, Miami, New York City, Seattle). For each city, we constructed three sets of scenarios: (1) sustained current levels of HIV-related treatment and prevention services (status quo); (2) temporary disruptions in health services and changes in sexual and injection risk behaviours at discrete levels between 0%-50%; and (3) linked HIV and SARS-CoV-2 testing offered to 10%-90% of the adult population in addition to scenario (2). We estimated cumulative HIV infections between 2020-2025, as well as incremental costs, quality-adjusted life years, and incremental cost-effectiveness ratios of linked HIV testing over 20 years. Findings: In the absence of linked, opt-out HIV testing, we estimated a best-case scenario (50% reduction in risk behaviours and no service disruptions) of 6,733 fewer HIV infections between 2020-2025 (16.5% decrease), and a worst-case scenario (no behavioural change and 50% reduction in service access) of 3,669 additional HIV infections (9.0% increase) across cities. If HIV testing could be offered to 10%-90% of the adult population, we estimated that a total of 576-7,225 (1.6%-17.2%) new infections could be averted. The intervention would require an initial investment of $20M-$218M across cities; however, the intervention would ultimately result in savings in health care costs in each city. Interpretation: Although COVID-19-related disruptions in HIV-related services may increase or decrease HIV incidence, a campaign in which HIV testing is linked with SARS-CoV-2 testing could substantially reduce HIV incidence and reduce direct and indirect health care costs attributable to HIV. Funding Statement: US NIH-NIDA Grant No. R01-DA041747 Declaration of Interests: XZ, EK, SC, MP, WSA, CNB, CDR, DJF, BDLM, SHM, JM, LRM, BRS, SAS and BN declare no competing interests.

Insulin production is the central feature of functionally mature and differentiated pancreatic β -cells. Reduced insulin transcription and dedifferentiation have been implicated in type 2 diabetes, making drugs that could reverse these processes potentially useful. We have previously established ratiometric live-cell imaging tools to identify factors that increase insulin promoter activity and promote β -cell differentiation. Here, we present a single vector imaging tool with eGFP and mRFP, driven by the Pdx1 and Ins1 promoters, respectively, targeted to the nucleus to enhance identification of individual cells in a high-throughput manner. Using this new approach, we screened 1120 off-patent drugs for factors that regulate Ins1 and Pdx1 promoter activity in MIN6 β -cells. We identified a number of compounds that positively modulate Ins1 promoter activity, including several drugs known to modulate ion channels. Carbamazepine was selected for extended follow-up, as our previous screen also identified this use-dependent sodium channel inhibitor as a positive modulator of β -cell survival. Indeed, carbamazepine increased Ins1 and Ins2 mRNA in primary mouse islets at lower doses than were required to protect β -cells. We validated the role of sodium channels in insulin production by examining Nav1.7 ( Scn9a ) knockout mice and remarkably islets from these animals had dramatically elevated insulin content relative to wild-type controls. Collectively, our experiments provide a starting point for additional studies aimed to identify drugs and molecular pathways that control insulin production and β -cell differentiation status. In particular, our unbiased screen identified a novel role for a β -cell sodium channel gene in insulin production.

Objective The role and mechanisms of insulin receptor internalization remain incompletely understood. Previous trafficking studies of insulin receptors involved fluorescent protein tagging at their termini, manipulations that may be expected to result in dysfunctional receptors. Our objective was to determine the trafficking route and molecular mechanisms of functional tagged insulin receptors and endogenous insulin receptors in pancreatic beta-cells. Methods We generated functional insulin receptors tagged with pH-resistant fluorescent proteins between domains. Confocal, TIRF and STED imaging revealed a trafficking pattern of inter-domain tagged insulin receptors and endogenous insulin receptors detected with antibodies. Results Surprisingly, interdomain-tagged and endogenous insulin receptors in beta-cells bypassed classical Rab5a- or Rab7-mediated endocytic routes. Instead, we found that removal of insulin receptors from the plasma membrane involved tyrosine-phosphorylated caveolin-1, prior to trafficking within flotillin-1-positive structures to lysosomes. Multiple methods of inhibiting caveolin-1 significantly reduced Erk activation in vitro or in vivo, while leaving Akt signaling mostly intact. Conclusions We conclude that phosphorylated caveolin-1 plays a role in insulin receptor internalization towards lysosomes through flotillin-1-positive structures and that caveolin-1 helps bias physiological beta-cell insulin signaling towards Erk activation., Highlights • Insulin receptors are tagged between domains to maintain the functionality and endogenous intracellular trafficking patterns. • Insulin receptors have virtually no co-localization with classical endocytosis markers, but co-localize with Cav11. • Insulin receptor internalization and anti-apoptotic Erk signaling are modulated by phosphorylated Cav1.

Background Studies assessing the comparative effectiveness of methadone versus buprenorphine/naloxone for opioid use disorder in real-world settings are rare - challenged by structural differences in delivery across settings and factors influencing treatment selection. We identified determinants of selection into buprenorphine/naloxone and quantified contributions of individual and provider-level covariates in a setting delivering both medications within the same healthcare settings. Methods Utilizing linked health administrative datasets, we conducted a retrospective cohort study of people with opioid use disorder (PWOUD) receiving opioid agonist treatment (OAT) in British Columbia, Canada, from 2008-2017. Determinants of buprenorphine/naloxone selection were identified using a generalized linear mixed model with random intercept terms for providers and individuals. We determined the influence of individual demographics, clinical history, measures of provider experience and preference, and dates of key policy changes. Results A total of 39,605 individuals experienced 178,976 OAT episodes (methadone:139,439(77.9 %);buprenorphine/naloxone:39,537(22.1 %)). Male sex, less OAT experience, younger age, mental health conditions and chronic pain were associated with higher odds of buprenorphine/naloxone prescription. For providers, higher client-attachment, more complex OAT case-mixes, and higher buprenorphine/naloxone prescribing-preference were also associated with higher odds of buprenorphine/naloxone prescription. Observed individual-level covariates explained 9.7 % of variance in odds of buprenorphine/naloxone selection, while observed provider-level covariates explained 20.0 %. Controlling for covariates, residual unmeasured between-individual variance accounted for 18.5 % of the explained variation in the odds of buprenorphine/naloxone selection, while unmeasured between-provider variance accounted for 28.4 %. Conclusion Provider characteristics were more influential in selection of buprenorphine/naloxone over methadone informing subsequent analyses of comparative effectiveness of these regimens.

OBJECTIVES To assess and compare neurodevelopmental disorders in HIV-exposed uninfected (HEU) and HIV-unexposed uninfected (HUU) children in British Columbia, Canada. To determine associations between these outcomes and in-utero exposure to antiretroviral drugs. DESIGN Retrospective controlled cohort study. METHODS Data were collected on 446 HEU children and 1323 HUU children (matched ∼1 : 3 for age, sex, and geocode) born between 1990 and 2012. Multivariable logistic regressions determined odds ratios of neurodevelopmental disorder diagnoses. RESULTS HEUs had three times higher odds of being born preterm (P

Objective To evaluate the birth rates of women living with HIV (WLWH) compared to the general population in British Columbia (BC), Canada. Methods We retrospectively reviewed clinical and population level surveillance data from 1997 to 2015. Live birth rates from 1997 to 2015 among WLWH aged 15–49 years were compared with those of all BC women. Next, the number of live births among WLWH with a live birth between 1997–2012 and HIV-negative controls matched 1:3 by geocode were compared. Results WLWH had a lower birth rate compared to all BC women [31.4 (95%CI, 28.6–34.3) vs. 40.0 (39.3–40.1)/1000 person years]. Stratified by age, WLWH aged 15–24 years had a higher birth rate while WLWH aged 25–49 years had a lower birth rate than BC women (p

Multiple signaling pathways mediate the actions of metabolic hormones to control glucose homeostasis, but the proteins that coordinate such networks are poorly understood. We previously identified the molecular scaffold protein, 14-3-3 zeta, as a critical regulator of in vitro beta-cell survival and adipogenesis, but its metabolic roles in glucose homeostasis have not been studied in depth. Herein, we report that Ywhaz gene knockout mice (14-3-3 zeta KO) exhibited elevated fasting insulin levels while maintaining normal beta-cell responsiveness to glucose when compared with wild-type littermate controls. In contrast with our observations after an ip glucose bolus, glucose tolerance was significantly improved in 14-3-3 zeta KO mice after an oral glucose gavage. This improvement in glucose tolerance was associated with significantly elevated fasting glucagon-like peptide-1 (GLP-1) levels. 14-3-3 zeta knockdown in GLUTag L cells elevated GLP-1 synthesis and increased GLP-1 release. Systemic inhibition of the GLP-1 receptor attenuated the improvement in oral glucose tolerance that was seen in 14-3-3 zeta KO mice. When taken together these findings demonstrate novel roles of 14-3-3 zeta in the regulation of glucose homeostasis and suggest that modulating 14-3-3 zeta levels in intestinal L cells may have beneficial metabolic effects through GLP-1-dependent mechanisms. Refereed/Peer-reviewed

The proteins that coordinate complex adipogenic transcriptional networks are poorly understood. 14-3-3ζ is a molecular adaptor protein that regulates insulin signalling and transcription factor networks. Here we report that 14-3-3ζ-knockout mice are strikingly lean from birth with specific reductions in visceral fat depots. Conversely, transgenic 14-3-3ζ overexpression potentiates obesity, without exacerbating metabolic complications. Only the 14-3-3ζ isoform is essential for adipogenesis based on isoform-specific RNAi. Mechanistic studies show that 14-3-3ζ depletion promotes autophagy-dependent degradation of C/EBP-δ, preventing induction of the master adipogenic factors, Pparγ and C/EBP-α. Transcriptomic data indicate that 14-3-3ζ acts upstream of hedgehog signalling-dependent upregulation of Cdkn1b/p27Kip1. Indeed, concomitant knockdown of p27Kip1 or Gli3 rescues the early block in adipogenesis induced by 14-3-3ζ knockdown in vitro. Adipocyte precursors in 14-3-3ζKO embryos also appear to have greater Gli3 and p27Kip1 abundance. Together, our in vivo and in vitro findings demonstrate that 14-3-3ζ is a critical upstream driver of adipogenesis., 14-3-3 family proteins are adaptor proteins involved in various cellular functions. Here Lim et al. show that 14-3-3ζ regulates adipogenesis in vitro, and the formation of visceral fat in mice, by reducing autophagic degradation of the adipogenic master transcription factor C/EBP-δ.

s / Can J Diabetes 36 (2012) S2eS22 S18 plasticity of adult pancreatic b-cells. Efforts to harness these immature cells and manipulate their maturation might be one avenue for replacing or repopulating lost/nonfunctional b-cells in the diabetic pancreas.