Hydrochlorothiazide use and risk of keratinocyte carcinoma and melanoma: A multisite population-based cohort study.

BACKGROUND: The association between hydrochlorothiazide (HCTZ) and skin cancer remains controversial. OBJECTIVE: To determine whether HCTZ is associated with an increased risk of skin cancer compared with angiotensin-converting enzyme inhibitors and calcium channel blockers. METHODS: Two new-user, active comparator cohorts were assembled using 6 Canadian databases. Site-specific hazard ratios (HRs) with 95% CIs were estimated using standardized morbidity ratio weighted Cox proportional hazard models and pooled using random-effects meta-analysis. RESULTS: HCTZ was not associated with an overall increased risk of keratinocyte carcinoma compared with angiotensin-converting enzyme inhibitors or calcium channel blockers, although increased risks were observed with longer durations (≥10 years; HR: 1.12; 95% CI: 1.03-1.21) and higher cumulative doses (≥100,000 mg; HR: 1.49; 95% CI: 1.27-1.76). For melanoma, there was no association with angiotensin-converting enzyme inhibitors, but a 32% increased risk with calcium channel blockers (crude incidence rates: 64.2 vs 58.4 per 100,000 person-years; HR: 1.32; 95% CI: 1.19-1.46; estimated number needed to harm at 5 years of follow-up: 1627 patients), with increased risks with longer durations and cumulative doses. LIMITATIONS: Residual confounding due to the observational design. CONCLUSIONS: Increased risks of keratinocyte carcinoma and melanoma were observed with longer durations of use and higher cumulative doses of HCTZ.

Time-related biases in perinatal pharmacoepidemiology: A systematic review of observational studies.

BACKGROUND: Time-related biases, such as immortal time and time-window bias, frequently occur in pharmacoepidemiologic research. However, the prevalence of these biases in perinatal pharmacoepidemiology is not well understood. OBJECTIVE: To describe the frequency of time-related biases in observational studies of medications commonly used during pregnancy (antibiotic, antifungal, and antiemetic drugs) via systematic review. METHOD: We searched Medline and EMBASE for observational studies published between January 2013 and September 2020 and examining the association between antibiotic, antifungal, or antiemetic drugs and adverse pregnancy outcomes, including spontaneous abortion, stillbirth, preterm delivery, small-for-gestational age, pre-eclampsia, and gestational diabetes. The proportion of studies with time-related biases was estimated overall and by type (immortal time bias, time-window bias). RESULTS: Our systematic review included 20 studies (16 cohort studies, 3 nested case-control studies, and 1 case-control study), of which 12 examined antibiotic, 6 antiemetic, and 2 anti-fungal drugs. Eleven studies (55%) had immortal time bias due to the misclassification of unexposed, event-free person-time between cohort entry and exposure initiation as exposed. No included study had time-window bias. The direction of effect varied for both studies with and without time-related bias, with many studies reporting very wide confidence intervals around the effect estimates, thus making the direction of effect less interpretable. However, studies with time-related bias were more likely to show protective or null associations compared with studies without time-related bias. CONCLUSION: Time-related biases occur frequently in observational studies of drug effects during pregnancy. The use of appropriate study design and analytical approaches is needed to prevent time-related biases and ensure study validity.

The Mediating Role of Depressive Symptoms in the Association Between Food Insecurity and HIV Related Health Outcomes Among HIV-HCV Co-Infected People.

Food insecurity may lead to depressive symptoms, which are known to be associated with poor HIV related health outcomes. However, it is unclear to what extent food insecurity 'directly' affects these outcomes. We used data from the Food Security & HIV-HCV Sub-Study of the Canadian Co-Infection Cohort to assess the controlled direct effect. People experiencing severe food insecurity had 1.47 (95% CI 1.04-2.09) times the risk of having detectable HIV viral load and 0.94 (95% CI 0.87-1.02) fold change in CD4 count. After holding depressive symptoms constant, the association between severe food insecurity and HIV viral load was attenuated to a statistically non-significant level (RR 1.36, 95% CI: 0.95-1.96), whereas the association between severe food insecurity and CD4 count was unchanged. Depressive symptoms partially mediate the effect of severe food insecurity on HIV viral suppression; interventions focused on depressive symptoms alone may not be sufficient, however, to eliminate this effect.

Association between depressive symptoms, CD4 count and HIV viral suppression among HIV-HCV co-infected people.

Depressive symptoms are associated with poor HIV viral control and immune recovery among people living with HIV. However, no prior studies assessed this association exclusively among people co-infected with HIV-hepatitis C virus (HCV). While people with HIV only and those with HIV-HCV co-infection share many characteristics, co-infected people may become more susceptible to the effects of depressive symptoms on health outcomes. We assessed this association exclusively among people co-infected with HIV-HCV in Canada using data from the Food Security & HIV-HCV Sub-Study (FS Sub-Study) of the Canadian Co-Infection Cohort (CCC). Stabilized inverse probability weighted marginal structural model was used to account for potential time-varying confounders. A total of 725 participants were enrolled between 2012 and 2015. At baseline, 52% of participants reported depressive symptoms, 75% had undetectable HIV viral load, and median CD4 count was 466 (IQR 300-665). People experiencing depressive symptoms had 1.32 times (95% CI: 1.07, 1.63) the risk of having detectable HIV viral load, but had comparable CD4 count to people who did not experience depressive symptoms (fold change of CD4 = 0.96, 95% CI: 0.91, 1.03). Presence of depressive symptoms is a risk factor for incomplete short-term HIV viral suppression among people co-infected with HIV-HCV. Therefore, depressive symptoms screening and related counseling may improve HIV related health outcomes and reduce HIV transmission.

Injection drug use, food insecurity, and HIV-HCV co-infection: a longitudinal cohort analysis.

Injection drug use (IDU) and food insecurity (FI) are highly prevalent among individuals living with HIV-hepatitis C virus (HCV) co-infection. We quantified the association between IDU and FI among co-infected individuals using biannual data from the Canadian Co-infection Cohort (N = 608, 2012-2015). IDU (in the past six months) and IDU frequency (non-weekly/weekly in the past month) were self-reported. FI (in the past six months) and FI severity (marginal FI, moderate FI, and severe FI) were measured using the Household Food Security Survey Module. Generalized estimating equations were used to estimate risk ratios (RR) quantifying the associations between IDU, IDU frequency, and FI with Poisson regression. The associations between IDU, IDU frequency, and FI severity were quantified by relative-risk ratios (RRR) estimated with multinomial regression. At the first time-point in the analytical sample, 54% of participants experienced FI in the past six months, 31% engaged in IDU in the six months preceding the FI measure, and 24% injected drugs in the past month. After adjustment for confounding, IDU in the past six months (RR = 1.15, 95% confidence interval [CI] = 1.04-1.28) as well as non-weekly (RR = 1.15, 95% CI = 1.02-1.29) and weekly IDU (RR = 1.21, 95% CI = 1.07-1.37) in the past month are associated with FI. Weekly IDU in the past month is also strongly associated with severe FI (RRR = 2.68, 95% CI = 1.47-4.91). Our findings indicate that there is an association between IDU and FI, particularly weekly IDU and severe FI. This suggests that reductions in IDU may mitigate FI, especially severe FI, in this vulnerable subset of the HIV-positive population.

Association Between Food Insecurity and HIV Viral Suppression: A Systematic Review and Meta-Analysis.

Although an increasing number of HIV infected people are accessing antiretroviral treatment, many do not achieve complete HIV viral suppression and remain at risk for AIDS and capable of HIV transmission. Food insecurity has been identified as a potential risk factor for poor virologic response, but the association between these factors has been inconsistently documented in the literature. We systematically searched five electronic databases and bibliographies of relevant studies through April 2015 and retrieved 11 studies that met our inclusion criteria, of which nine studies were conducted in North America and the remaining two studies were in Brazil and Uganda respectively. Meta-analyzed results indicated that experiencing food insecurity resulted in 29% lower odds of achieving complete HIV viral suppression (OR = 0.71, 95% CI 0.61-0.82) and this significant inverse association was consistently found regardless of study design, exposure measurement, and confounder adjustment methods. These findings suggest that food insecurity is a potential risk factor for incomplete HIV viral suppression in people living with HIV.

Impact of Food Insecurity on Depressive Symptoms Among HIV-HCV Co-infected People.

Food insecurity (FI) is associated with depressive symptoms among HIV mono-infected people. Our objective was to examine to what extent this association holds among HIV-hepatitis C virus (HCV) co-infected people. We used data from a prospective cohort study of HIV-HCV co-infected people in Canada. FI was measured using the ten-item adult scale of Health Canada's Household Food Security Survey Module and was classified into three categories: food secure, moderate FI, and severe FI. Depressive symptoms were measured using the Center for Epidemiologic Studies Depression Scale (CES-D-10) and was classified into absence or presence of depressive symptoms. FI, depressive symptoms, and other covariates were updated every 6 months. The association between FI and depressive symptoms was assessed using a stabilized inverse probability weighted marginal structural model. The study sample included 725 HIV-HCV co-infected people with 1973 person-visits over 3 years of follow up. At baseline, 23% of participants experienced moderate food insecurity, 34% experienced severe food insecurity and 52% had depressive symptoms. People experiencing moderate FI had 1.63 times (95% CI 1.44-1.86) the risk of having depressive symptoms and people experiencing severe FI had 2.01 times (95% CI 1.79-2.25) the risk of having depressive symptoms compared to people who were food secure. FI is a risk factor for developing depressive symptoms among HIV-HCV co-infected people. Food supplementation, psychosocial support and counseling may improve patient health outcomes.

Injection Drug Use, Unemployment, and Severe Food Insecurity Among HIV-HCV Co-Infected Individuals: A Mediation Analysis.

Severe food insecurity (FI), which indicates reduced food intake, is common among HIV-hepatitis C virus (HCV) co-infected individuals. Given the importance of unemployment as a proximal risk factor for FI, this mediation analysis examines a potential mechanism through which injection drug use (IDU) is associated with severe FI. We used biannual data from the Canadian Co-infection Cohort (N = 429 with 3 study visits, 2012-2015). IDU in the past 6 months (exposure) and current unemployment (mediator) were self-reported. Severe FI in the following 6 months (outcome) was measured using the Household Food Security Survey Module. An overall association and a controlled direct effect were estimated using marginal structural models. Among participants, 32% engaged in IDU, 78% were unemployed, and 29% experienced severe FI. After adjustment for confounding and addressing censoring through weighting, the overall association (through all potential pathways) between IDU and severe FI was: risk ratio (RR) = 1.69 (95% confidence interval [CI] = 1.15-2.48). The controlled direct effect (the association through all potential pathways except that of unemployment) was: RR = 1.65 (95% CI = 1.08-2.53). We found evidence of an overall association between IDU and severe FI and estimated a controlled direct effect that is suggestive of pathways from IDU to severe FI that are not mediated by unemployment. Specifically, an overall association and a controlled direct effect that are similar in magnitude suggests that the potential impact of IDU on unemployment is not the primary mechanism through which IDU is associated with severe FI. Therefore, while further research is required to understand the mechanisms linking IDU and severe FI, the strong overall association suggests that reductions in IDU may mitigate severe FI in this vulnerable subset of the HIV-positive population.

Food insecurity and low CD4 count among HIV-infected people: a systematic review and meta-analysis.

Food insecurity is defined as a limited or uncertain ability to acquire acceptable foods in socially acceptable ways, or limited or uncertain availability of nutritionally adequate and safe foods. While effective antiretroviral treatment can significantly increase CD4 counts in the majority of patients, there are certain populations who remain at relatively low CD4 count levels. Factors possibly associated with poor CD4 recovery have been extensively studied, but the association between food insecurity and low CD4 count is inconsistent in the literature. The objective is to systematically review published literature to determine the association between food insecurity and CD4 count among HIV-infected people. PubMed, Web of Science, ProQuest ABI/INFORM Complete, Ovid Medline and EMBASE Classic, plus bibliographies of relevant studies were systematically searched up to May 2015, where the earliest database coverage started from 1900. Studies that quantitatively assessed the association between food insecurity and CD4 count among HIV-infected people were eligible for inclusion. Study results were summarized using random effects model. A total of 2093 articles were identified through electronic database search and manual bibliographic search, of which 8 studies included in this meta-analysis. Food insecure people had 1.32 times greater odds of having lower CD4 counts compared to food secure people (OR = 1.32, 95% CI: 1.15-1.53) and food insecure people had on average 91 fewer CD4 cells/µl compared to their food secure counterparts (mean difference = -91.09, 95% CI: -156.16, -26.02). Food insecurity could be a potential barrier to immune recovery as measured by CD4 counts among HIV-infected people.

Step down to 6 months of prophylactic-dose low molecular weight heparin after initial full-dose anticoagulation for the treatment of cancer-associated thrombosis (STEP-CAT): A pilot study.

BACKGROUND: Patients with cancer-associated thrombosis (CAT) are treated with full-dose anticoagulation for at least 3 months, but optimal dosing thereafter is unknown. AIM: We explored the feasibility of extended prophylactic-dose low molecular weight heparin (LMWH) treatment following a minimum of 3 months of full-dose LMWH. METHODS: We conducted a multicenter prospective pilot study of patients with CAT who completed at least 3 months of therapeutic-dose LMWH. Patients received 6 months of prophylactic-dose subcutaneous enoxaparin (40 mg once daily). The primary outcome was recurrence of deep vein thrombosis (DVT) or pulmonary embolism (PE), and secondary outcomes included major, clinically relevant non-major (CRNM), and minor bleeding. RESULTS: From August 2016 to May 2019, 52 patients with a mean age of 64.1 years were included. The study was stopped early because of poor recruitment. Breast (23.1%) and colorectal (19.2%) were the most common cancers, and 61.0% had stage IV malignancy. Index CAT consisted of DVT alone in 57.7% of patients and pulmonary embolism (PE) with or without DVT in 42.3%. Patients received a mean of 7.6 months of weight-adjusted LMWH before enrollment. During a mean follow-up of 5.6 months, one patient was diagnosed with recurrent incidental PE (0.0035 events/subject-month). There were no major bleeding events, one CRNM, and one minor bleeding event. Eight (15.4%) patients died; six from cancer and two from respiratory disease unrelated to PE. CONCLUSIONS: These results, in part, provide support for trials of extended reduced-dose anticoagulation for the secondary prevention of CAT. (ClinicalTrials.gov: NCT02752607).

The association between glycaemic control during hospitalization and risk of adverse events: A retrospective cohort study.

INTRODUCTION: Hyperglycaemia is common during hospitalization; glycaemic targets in non-critical care settings have not been well studied. We assessed associations between inpatient glycaemic control and adverse events. METHODS: We conducted a retrospective cohort study on non-critically ill medical patients hospitalized in a tertiary care hospital between 2015 and 2018. Mean glycaemia during the first four days of hospitalization was categorized as 4.0-7.0 mmol/L, 7.1-10.0 mmol/L and >10.0 mmol/L. The primary outcome was a composite of adverse events including mortality, infections, acute kidney injury, thromboembolic and cardiovascular events. The secondary outcome was hypoglycaemia, defined as any glycaemia <4.0 mmol/L. Logistic regression was used to assess adverse events, and a Cox proportional hazards model was used to estimate hypoglycaemia risk. RESULTS: Our cohort included 1,368 patients, of whom 407 (29.8%) experienced an adverse event. We did not find associations between glycaemia of 4.0-7.0 mmol/L (adjusted odds ratio [OR]: 0.88, 95% confidence interval [CI]: 0.63-1.23) or glycaemia of >10.0 mmol/L (adjusted OR: 0.98, 95% CI: 0.75-1.28) and the occurrence of adverse events, compared to a glycaemia of 7.1-10.0 mmol/L. Glycaemia of >10.0 mmol/L was associated with an increased risk of hypoglycaemia (adjusted hazard ratio [HR]: 1.72, 95% CI: 1.21-2.45). Hypoglycaemia was associated with adverse events (adjusted OR 1.85, 95% CI 1.31-2.60). CONCLUSIONS: Neither glycaemia of 4.0-7.0 mmol/L nor glycaemia of >10.0mmol/L during non-critical care hospitalization was associated with increased adverse events. Glycaemia of >10.0 mmol/L was associated with increased hypoglycaemia, likely due to aggressive glucose lowering. These findings highlight the need for further studies to discern optimal inpatient glycaemic targets.

Off-label postpartum use of domperidone in Canada: a multidatabase cohort study.

BACKGROUND: Trends in off-label postpartum use of domperidone and the impact of safety advisories on its use remain unknown. Our objectives were to describe postpartum use of domperidone in Canada, to evaluate the impact of Health Canada advisories on prescribing patterns, and to describe the association between domperidone use and a composite end point of sudden cardiac death or ventricular tachycardia (VT) among postpartum patients. METHODS: We conducted a multidatabase cohort study involving pregnant patients with live births between 2004 and 2017 using administrative health databases from 5 Canadian provinces (British Columbia, Alberta, Saskatchewan, Manitoba and Ontario). We excluded patients with less than 1 year of prepregnancy database history and with approved indications for domperidone. We assessed domperidone use in the 6 months postpartum and the impact of the 2012 and 2015 Health Canada advisories on prescribing via interrupted time series analysis. We estimated crude rates of VT and sudden cardiac death. RESULTS: We included 1 190 987 live births. Mean maternal age was 28.6 (standard error 0.6) years. Domperidone use increased over time, from 7% in 2003-2005 to 12% in 2009-2011, when it plateaued. The 2012 advisory was followed by a drop in use and a reduction in slope, and the 2015 advisory had a more modest impact. Crude analysis suggests that domperidone may be associated with increased VT or sudden cardiac death (0.74 v. 0.37 per 10 000 person-years; difference per 10 000 person-years: 0.37, 95% confidence interval -0.67 to 1.41). INTERPRETATION: Postpartum domperidone use increased between 2004 and 2017, with prescribing attenuated after Health Canada advisories and a very low absolute rate of VT or sudden cardiac death. These findings suggest that Health Canada advisories affected prescribing; any potential increase in VT or sudden cardiac death with use of domperidone is small and could not be confirmed in this large study STUDY REGISTRATION: ClinicalTrials.gov, no. NCT04024865.