Publications by authors named "Micah Piske"

12 Publications

  • Page 1 of 1

Preterm Birth and Antiretroviral Exposure in Infants HIV-exposed Uninfected.

Pediatr Infect Dis J 2021 Mar;40(3):245-250

From the Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.

Background: Infants HIV-exposed and uninfected (IHEU) who are born to women living with HIV are at an increased risk of preterm birth (PTB). Antenatal exposure to certain maternal antiretroviral therapy (ART) regimens has been associated with PTB, although existing studies in this domain are limited and report discordant findings. We determined odds of PTB among IHEU by antenatal ART regimens and timing of exposure, adjusting for maternal risk factors.

Methods: We retrospectively studied IHEU born in British Columbia (BC), Canada between 1990 and 2012 utilizing provincial health administrative databases. We included data from a control group of infants HIV-unexposed and uninfected (IHUU) matched ~3:1 for each IHEU on age, sex and geocode.

Results: A total of 411 IHEU and 1224 IHUU were included in univariable analysis. PTB was more frequent among IHEU (20%) compared with IHUU (7%). IHEU were more often antenatally exposed to alcohol, tobacco, as well as prescription, nonprescription, and illicit drugs (IHEU: 36%, 8% and 35%; vs. IHUU: 3%, 1% and 9%, respectively). After adjusting for maternal substance use and smoking exposure, IHEU remained at increased odds of PTB [adjusted odds ratio (aOR) (95% CI): 2.66; (1.73, 4.08)] compared with matched IHUU controls. ART-exposed IHEU (excluding those with NRTIs only ART) had lower adjusted odds of PTB compared with IHEU with no maternal ART exposure, regardless of regimen [aOR range: 0.16-0.29 (0.02-0.95)]. Odds of PTB between IHEU exposed to ART from conception compared with IHEU exposed to ART postconception did not differ [aOR: 0.91 (0.47, 1.76)]; however, both groups experienced lower odds of PTB compared with IHEU with no maternal ART [preconception: aOR: 0.28 (0.08, 0.89); postconception: aOR 0.30 (0.11, 0.83)].

Conclusions: BC IHEU were over twice as likely to be born preterm compared with demographically matched controls. Maternal substance use in pregnancy modulated this risk; however, we found no adverse associations of PTB with exposure to antenatal ART.
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March 2021

The potential epidemiological impact of COVID-19 on the HIV/AIDS epidemic and the cost-effectiveness of linked, opt-out HIV testing: A modeling study in six US cities.

Clin Infect Dis 2020 Oct 12. Epub 2020 Oct 12.

British Columbia Centre for Excellence in HIV/AIDS, Vancouver, BC, Canada.

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: Using a previously-calibrated dynamic HIV transmission model, we constructed three sets of scenarios for each city: (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 and incremental cost-effectiveness ratios of linked HIV testing over 20 years.

Results: In the absence of linked, opt-out HIV testing, we estimated a total of 16.5% decrease in HIV infections between 2020-2025 in the best-case scenario (50% reduction in risk behaviours and no service disruptions), and 9.0% increase in the worst-case scenario (no behavioural change and 50% reduction in service access). We estimated that HIV testing (offered at 10%-90% levels) could avert a total of 576-7,225 (1.6%-17.2%) new infections. The intervention would require an initial investment of $20.6M-$220.7M across cities; however, the intervention would ultimately result in savings in health care costs in each city.

Conclusions: 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.
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October 2020

Comparative effectiveness of buprenorphine-naloxone versus methadone for treatment of opioid use disorder: a population-based observational study protocol in British Columbia, Canada.

BMJ Open 2020 09 9;10(9):e036102. Epub 2020 Sep 9.

Epidemiology and Population Health Program, BC Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada

Introduction: Despite 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 Analysis: We 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 Dissemination: The 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.
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September 2020

"Ending the Epidemic" Will Not Happen Without Addressing Racial/Ethnic Disparities in the United States Human Immunodeficiency Virus Epidemic.

Clin Infect Dis 2020 Dec;71(11):2968-2971

School of Medicine, University of California, San Diego, La Jolla, California, USA.

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]).
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December 2020

Opioid agonist treatment and risk of mortality during opioid overdose public health emergency: population based retrospective cohort study.

BMJ 2020 03 31;368:m772. Epub 2020 Mar 31.

Health Economic Research Unit, British Columbia Centre for Excellence in HIV/AIDS, Vancouver, BC, V6Z 1Y6, Canada

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.
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March 2020

The cascade of care for opioid use disorder: a retrospective study in British Columbia, Canada.

Addiction 2020 08 6;115(8):1482-1493. Epub 2020 Feb 6.

BC Centre for Excellence in HIV/AIDS, Vancouver, BC, Canada.

Background And Aims: The 'cascade of care' framework, measuring attrition at various stages of care engagement, has been proposed to guide the public health response to the opioid overdose public health emergency in British Columbia, Canada. We estimated the cascade of care for opioid use disorder and identified factors associated with care engagement for people with opioid use disorder (PWOUD) provincially.

Design: Retrospective study using a provincial-level linkage of four health administrative databases.

Setting And Participants: All PWOUD in BC from 1 January 1996 to 30 November 2017.

Measurements: The eight-stage cascade of care included diagnosed PWOUD, ever on opioid agonist treatment (OAT), recently on OAT, currently on OAT and retained on OAT: ≥ 1, ≥ 3, ≥ 12 and ≥ 24 months). Health-care use, homelessness and other demographics were obtained from physician billing records, hospitalizations, and drug dispensation records. Receipt of income assistance was indicated by enrollment in Pharmacare Plan C.

Findings: A total of 55 470 diagnosed PWOUD were alive at end of follow-up. As of 2017, a majority of the population (n = 39 456; 71%) received OAT during follow-up; however, only 33% (n = 18 519) were currently engaged in treatment and 16% (n = 8960) had been retained for at least 1 year. Compared with those never on OAT, those currently engaged in OAT were more likely to be aged under 45 years [adjusted odds ratio (aOR) = 1.75, 95% confidence interval (CI) = 1.64, 1.89], male (aOR = 1.72, 95% CI = 1.64, 1.82), with concurrent substance use disorders (aOR = 2.56, 95% CI = 2.44, 2.70), hepatitis C virus (HCV) (aOR = 1.22, 95% CI = 1.14, 1.33) and either homeless or receiving income-assistance (aOR = 4.35, 95% CI = 4.17, 4.55). Regular contact with the health-care system-either in out-patient or acute care settings-was common among PWOUD not engaged in OAT, regardless of time since diagnosis or treatment discontinuation.

Conclusions: People with opioid use disorder in British Columbia, Canada show high levels of out-patient care prior to diagnosis. Younger age, male sex, urban residence, lower income level and homelessness appear to be independently associated with increased opioid agonist treatment engagement.
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August 2020

Exploring the live birth rates of women living with HIV in British Columbia, Canada.

PLoS One 2019 6;14(2):e0211434. Epub 2019 Feb 6.

Women's Health Research Institute, British Columbia Women's Hospital, Vancouver, British Columbia, Canada.

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<0.01). Between 1997 and 2015, birth rates for both populations decreased among women aged 15-24 years, and increased among women aged 25-49 years, most strikingly among WLWH 35-49 years (p<0.01). When comparing WLWH with a live birth to HIV-negative geocode matched controls, WLWH aged 15-24 years (p = 0.03) and aged 25-34 years (p<0.01) had more live births than controls while WLWH aged 35-49 years did not (p = 0.06).

Conclusions: On a population level, WLWH have lower birth rates than the general population. However, this is not observed among WLWH who have ever given birth compared with matched controls, suggesting that sociodemographic factors may play an important role. WLWH are increasingly giving birth in their later reproductive years. Taken together, our data supports the integration of reproductive health and HIV care.
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November 2019

Neurodevelopmental outcomes and in-utero antiretroviral exposure in HIV-exposed uninfected children.

AIDS 2018 11;32(17):2583-2592

Department of Pathology & Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.

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 < 0.0001), and a more than two-fold increase in odds for autism, disturbance of emotions, hyperkinetic syndrome, and developmental delay compared with matched HUUs (P < 0.02) in unadjusted analysis. This association was reduced [adjusted neurodevelopmental disorder odds ratio (AOR) = 1.67; 95% confidence interval: 1.12-2.48; P = 0.011] after adjusting for maternal substance use and/or smoking (children born after April 2000). Regardless of antiretroviral exposure type (i.e. none, treatment with one or multiple drug classes), HEUs had higher odds of any neurodevelopmental disorders compared with matched HUUs; however, there was no evidence suggesting any specific classes of antiretroviral drugs or exposure durations increased their likelihood of neurodevelopmental disorders.

Conclusion: The results suggest no adverse associations between antiretroviral drugs and neurodevelopmental disorders within antiretroviral-exposed HEU children in our cohort. Prevalence of neurodevelopmental disorders is higher in HEUs; however, maternal substance use plays a role, as could other environmental factors not captured. These findings highlight a need for holistic support for pregnant women as well as careful developmental monitoring of HEUs past infancy, and access to early interventions, particularly among those born preterm and those exposed to addictive substances.
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November 2018

Ywhaz/14-3-3ζ Deletion Improves Glucose Tolerance Through a GLP-1-Dependent Mechanism.

Endocrinology 2016 07 11;157(7):2649-59. Epub 2016 May 11.

Department of Cellular and Physiological Sciences (G.E.L., M.P., J.D.J.), University of British Columbia, Vancouver, BC, Canada; ALPCO (J.E.L.), Salem, New Hampshire; and The Centre for Cancer Biology (H.S.R., A.F.L.), South Australia Pathology and University of South Australia, Adelaide, Australia.

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, 14-3-3ζ, as a critical regulator of in vitro β-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 (14-3-3ζKO) exhibited elevated fasting insulin levels while maintaining normal β-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 14-3-3ζKO mice after an oral glucose gavage. This improvement in glucose tolerance was associated with significantly elevated fasting glucagon-like peptide-1 (GLP-1) levels. 14-3-3ζ 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 14-3-3ζKO mice. When taken together these findings demonstrate novel roles of 14-3-3ζ in the regulation of glucose homeostasis and suggest that modulating 14-3-3ζ levels in intestinal L cells may have beneficial metabolic effects through GLP-1-dependent mechanisms.
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July 2016

Inter-domain tagging implicates caveolin-1 in insulin receptor trafficking and Erk signaling bias in pancreatic beta-cells.

Mol Metab 2016 May 10;5(5):366-378. Epub 2016 Feb 10.

Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada. Electronic address:

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.
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May 2016

High-content screening identifies a role for Na(+) channels in insulin production.

R Soc Open Sci 2015 Dec 2;2(12):150306. Epub 2015 Dec 2.

Department of Cellular and Physiological Sciences University of British Columbia Life Sciences Centre, 2350 Health Sciences Mall, Vancouver, British Columbia, Canada V6T 1Z3.

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.
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December 2015

14-3-3ζ coordinates adipogenesis of visceral fat.

Nat Commun 2015 Jul 29;6:7671. Epub 2015 Jul 29.

Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.

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/p27(Kip1). Indeed, concomitant knockdown of p27(Kip1) 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 p27(Kip1) abundance. Together, our in vivo and in vitro findings demonstrate that 14-3-3ζ is a critical upstream driver of adipogenesis.
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July 2015