Marginal Structural Cox Proportional Hazards Research Articles

Virologically suppressed switch to Dolutegravir/Lamivudine 2-Drug regimen versus switch to commonly prescribed 3-Drug regimens in the United States

BackgroundTwo-drug regimens (2DRs) have been introduced in recent years to potentially reduce antiretroviral therapy (ART) toxicities and drug-drug interactions while demonstrating comparable efficacy to three-drug regimens (3DRs) for people with HIV (PWH). The objective of this study was to compare the real-world effectiveness and durability of a single-tablet 2DR of dolutegravir/lamivudine (DTG/3TC) with that of commonly prescribed 3DRs in ART-experienced, virologically suppressed PWH during the first 24 months of DTG/3TC availability in the United States.MethodsVirologically suppressed (viral load [VL] < 200 copies/mL) adult PWH initiating DTG/3TC 2DR, bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF), or a DTG-based 3DR between 01MAY2019 and 31OCT2020 were identified in the OPERA® cohort and followed through 30APR2021. Univariate Poisson regression (incidence rates) and marginal structural Cox proportional hazards models with inverse probability of treatment weights (hazard ratios) were used to quantify relationships between regimen type and confirmed virologic failure (2 consecutive VLs ≥ 200 copies/mL) or regimen discontinuation. Reasons for discontinuation were examined.ResultsA total of 8,037 ART-experienced, virologically suppressed PWH met the inclusion criteria and switched to DTG/3TC (n = 1,450), BIC/FTC/TAF (n = 5,691), or a DTG-based 3DR (n = 896). Incidence rates of confirmed virologic failure were low for all groups, at 0.66 (DTG/3TC), 0.84 (BIC/FTC/TAF), and 1.78 (DTG 3DR) per 100 person-years (py). Compared to DTG/3TC, only the DTG 3DRs were associated with a statistically significant increased hazard of confirmed virologic failure (hazard ratio: 5.21, 95% confidence interval: 1.85, 14.67). Discontinuation rates per 100 py were highest in the DTG 3DR group (24.90), followed by the DTG/3TC group (17.69) and the BIC/FTC/TAF group (8.30). Regardless of regimen, discontinuations were infrequently attributed to effectiveness (VL ≥ 200 copies/mL; 4%) or tolerability (adverse diagnoses, side effects, or lab abnormalities; 6%).ConclusionsAmong virologically suppressed PWH initiating a new regimen, few individuals experienced virologic failure in real-world clinical care. While rates of regimen discontinuation were high, most discontinuations could not be attributed to a lack of virologic control or poor tolerability. These findings suggest that DTG/3TC is an effective option for ART-experienced, virologically suppressed PWH.

Allopurinol, Febuxostat, and Nonuse of Xanthine Oxidoreductase Inhibitor Treatment in Patients Receiving Hemodialysis: A Longitudinal Analysis

Rationale & ObjectiveAllopurinol and febuxostat, which are xanthine oxidoreductase inhibitors, have been widely used as uric acid-lowering medications. However, evidence regarding their cardiovascular effects in hemodialysis is insufficient. This study compared the effects of allopurinol and febuxostat on mortality and cardiovascular outcomes in patients receiving hemodialysis. Study DesignRetrospective observational cohort study. Setting & ParticipantsData of 6,791 patients who had no history of topiroxostat usage and underwent maintenance hemodialysis between March 2016 and March 2019 at Yokohama Daiichi Hospital, Zenjinkai, and its affiliated dialysis clinics in Japan’s Kanagawa and Tokyo metropolitan areas were collected. ExposureAllopurinol, febuxostat, and non-treatment. OutcomesAll-cause mortality, cardiovascular disease (CVD) events, heart failure (HF), acute myocardial infarction (AMI), and stroke. Analytical ApproachFor the main analyses, marginal structural Cox proportional hazards models were used to estimate hazard ratios (HRs) adjusted for time-varying confounding and selection bias due to censoring. ResultsAllopurinol and febuxostat showed significantly better survival than non-treatment for all-cause mortality (HR: 0.40, 95% confidence interval [CI]: 0.30–0.54; HR: 0.49, 95% CI: 0.38–0.63, respectively), without significant difference between allopurinol and febuxostat. Allopurinol showed significantly better survival than non-treatment, whereas febuxostat did not for CVD events (HR: 0.89, 95% CI: 0.84–0.95; HR: 1.01, 95% CI: 0.96–1.07, respectively), HF (HR: 0.71, 95% CI: 0.56–0.90; HR: 1.03, 95% CI: 0.87–1.21, respectively), and AMI (HR: 0.48, 95% CI: 0.25–0.91; HR: 0.76, 95% CI: 0.49–1.19, respectively). No comparisons showed significant results for stroke. LimitationsThe ratio of renal or intestinal excretion of uric acid and uremic toxins could not be elucidated, and we could not investigate gene polymorphism because of the large number of cases. ConclusionsAllopurinol and febuxostat improved survival for all-cause mortality. Allopurinol, and not febuxostat, reduced the risk of CVD events, HF, and AMI.

Risk of stroke admission after long-term exposure to PM1: Evidence from a large cohort in South China

BackgroundLimited attention has been paid to the health effects of long-term PM1 exposure on stroke admission. Current investigations exploring the long-term PM exposure effect are largely based on observational studies, and PM generally is not allocated randomly to participants. Using traditional regression models might confuse messaging and hinder policy recommendations for pollution control and disease prevention policies. MethodsWe conducted a cohort study among 36,271 adults from one of the largest cities in China in 2015 and followed up through 2020. Hazard ratios of stroke admissions following long-term PM1 exposure were estimated via a causal inference approach, marginal structural time-varying Cox proportional hazard model, accounting for multiple confounders. Additionally, several sensitivity analyses and impact modification analyses were carried out. Results and discussionAssociations with 1 μg/m3 increase in long-term PM1 were identified for total (HR, 1.079; 95 %CI, 1.012–1.151) and ischemic stroke admissions (HR, 1.092; 95 %CI, 1.018–1.171). The harmful associations varied with exposure duration, initially increasing and then decreasing. The 2–3 years cumulative exposure was associated with a 3.3–5.4 % raised risk for total stroke. For every 1 μg/m³ increase in long-term PM1 exposure, females exhibited a higher risk of both total and ischemic stroke (13 % and 16 %) than men (4 % and 5 %). Low-exposure individuals (whose annual PM1 concentrations were under the third quartile among the annual concentrations for all the participants) exhibited greater sensitivity to PM1 effects (total stroke: 1.079 vs. 1.107; ischemic stroke: 1.092 vs. 1.116). The results underline the importance of safeguarding low-exposed people in highly polluted areas and suggest that long-term PM1 exposure may increase stroke admission risk, warranting attention to vulnerable groups.

Nephrotoxicity of Intravenous Ganciclovir in Pediatric Hematopoietic Cell Transplant Recipients.

Associations between ganciclovir and severe nephrotoxicity are incompletely defined. Studies incorporating the time-varying nature of medication exposures and those that address confounding by indication are particularly scarce in children undergoing hematopoietic cell transplantation. We identified children undergoing hematopoietic cell transplantation in the Pediatric Health Information System database and tracked them for 1 year following transplantation. The primary exposure of interest was the use of ganciclovir, which was treated as a time-varying variable. Secondary exposures of interest included cidofovir, foscarnet, amphotericin B, aminoglycosides, vancomycin and calcineurin inhibitors. The primary outcome of interest was renal replacement therapy, which was assessed using marginal structural Cox proportional hazards regression model incorporating time-varying variables and inverse-probability-of-treatment weight. Of 17,924 children who underwent hematopoietic cell transplantation during the study period, 3078 (17.2%) had exposure to ganciclovir. In marginal structural Cox proportional hazards regression model incorporating time-varying variables and inverse-probability-of-treatment weight, ganciclovir was associated with an increased hazard of renal replacement therapy (adjusted hazard ratio: 1.84, 95% confidence interval: 1.22-2.76). Some of secondary exposures of interest, including cidofovir, amphotericin B and vancomycin, also were associated with renal replacement therapy. Intravenously administered ganciclovir is associated with renal dysfunction severe enough to require renal replacement therapy in pediatric hematopoietic cell transplant recipients. Ganciclovir should be used with caution and close monitoring. Approaches to mitigate the risks of nephrotoxicity should be investigated.

Forced Expiratory Volume in 1 Second Variability Predicts Lung Transplant or Mortality in People with Cystic Fibrosis in the United States.

Rationale: Declines in percent predicted forced expiratory volume in 1 second (ppFEV1) are an important marker of clinical progression of cystic fibrosis (CF). Objectives: We examined ppFEV1 variability in relation to a combined outcome of lung transplant or death. Methods: We estimated the association between ppFEV1 variability and the combined outcome of lung transplant or death. We included children aged 8 years and older with CF and two prior years of ppFEV1 data before baseline between 2005 and 2021. We defined ppFEV1 increased variability as any relative increase or decrease of at least 10% in ppFEV1 from a 2-year averaged baseline. A marginal structural Cox proportional hazards model was used. We examined a cumulative measure of ppFEV1 variability, defined as the cumulative proportion of visits with ppFEV1 variability at each visit. Kaplan-Meier survival curves were generated on the basis of quartiles of the cumulative distribution of ppFEV1 variability. Results: We included 9,706 patients with CF in our cohort. The median age at cohort entry was 8.3 (interquartile range, 8.2-8.4) years; 50% of patients were female; 94% were White; and the median baseline ppFEV1 was 94.4 (interquartile range, 81.6-106.1). The unadjusted hazard ratio for increased ppFEV1 variability on lung transplant/mortality was 4.13 (95% confidence interval, 3.48-4.90), and the weighted hazard ratio was 1.49 (95% confidence interval, 1.19-1.86). Survival curves stratified by quartile of cumulative variability demonstrated an increased hazard of lung transplant/mortality as the proportion of cumulative ppFEV1 variability increased. Conclusions: We found a strong association between ppFEV1 variability and lung transplant or mortality in a cohort of people with CF in the United States.

Cumulative exposure to depressive symptoms and all-cause mortality among adults with HIV in Kenya, Nigeria, Tanzania, and Uganda.

We estimated the effects of cumulative exposure to depressive symptoms on risk of all-cause mortality among people with HIV (PWH) in four African countries. An analysis of prospective cohort data. The African Cohort Study (AFRICOS) is a prospective cohort of people receiving care at twelve clinics in Kenya, Nigeria, Tanzania, and Uganda. Every 6 months from January 2013 to May 2020, participants underwent laboratory monitoring, structured surveys, and assessment of depressive symptom severity using the Center for Epidemiologic Studies Depression Scale (CES-D). All-cause mortality was the outcome of interest. The predictor of interest was a time-updated measure of the percentage of days lived with depression (PDD). Marginal structural Cox proportional hazards regression models were used, adjusting for potential confounders including time-varying alcohol use, drug use, and viral load. Among 2520 enrolled participants, 1479 (59%) were women and the median age was 38 (interquartile range [IQR]: 32-46). At enrollment, 1438 (57%) were virally suppressed (<200 copies/ml) and 457 (18%) had CES-D at least 16, indicating possible depression. Across 9093 observed person-years, the median PDD was 0.7% (IQR: 0-5.9%) with 0.8 deaths per 100 person-years. Leading causes of death included cancer (18% of deaths) and accidents (14%). Models suggested that each 25% absolute increase in PDD was associated with a 69% increase in the risk of all-cause mortality (hazard ratio: 1.69; 95% confidence interval: 1.18-2.43). Cumulative exposure to depressive symptoms was substantially associated with the risk of mortality in this cohort of PWH in Africa.

Air pollution and serious bleeding events in high-risk older adults

ImportanceDespite biological plausibility, very few epidemiologic studies have investigated the risks of clinically significant bleeding events due to particulate air pollution. ObjectiveTo measure the independent and synergistic effects of PM2.5 exposure and anticoagulant use on serious bleeding events. DesignRetrospective cohort study (2008–2016). SettingNationwide Medicare population. ParticipantsA 50% random sample of Medicare Part D-eligible Fee-for-Service beneficiaries at high risk for cardiovascular and thromboembolic events. ExposuresFine particulate matter (PM2.5) and anticoagulant drugs (apixaban, dabigatran, edoxaban, rivaroxaban, or warfarin). Main outcomes and measuresThe outcomes were acute hospitalizations for gastrointestinal bleeding, intracranial bleeding, or epistaxis. Hazard ratios and 95% CIs for PM2.5 exposure were estimated by fitting inverse probability weighted marginal structural Cox proportional hazards models. The relative excess risk due to interaction was used to assess additive-scale interaction between PM2.5 exposure and anticoagulant use. ResultsThe study cohort included 1.86 million high-risk older adults (mean age 77, 60% male, 87% White, 8% Black, 30% anticoagulant users, mean PM2.5 exposure 8.81 μg/m3). A 10 μg/m3 increase in PM2.5 was associated with a 48% (95% CI: 45%–52%), 58% (95% CI: 49%–68%) and 55% (95% CI: 37%–76%) increased risk of gastrointestinal bleeding, intracranial bleeding, and epistaxis, respectively. Significant additive interaction between PM2.5 exposure and anticoagulant use was observed for gastrointestinal and intracranial bleeding. ConclusionsAmong older adults at high risk for cardiovascular and thromboembolic events, increasing PM2.5 exposure was significantly associated with increased risk of gastrointestinal bleeding, intracranial bleeding, and epistaxis. In addition, PM2.5 exposure and anticoagulant use may act together to increase risks of severe gastrointestinal and intracranial bleeding. Thus, clinicians may recommend that high-risk individuals limit their outdoor air pollution exposure during periods of increased PM2.5 concentrations. Our findings may inform environmental policies to protect the health of vulnerable populations.

Comparison of Different Modeling Approaches for Prescription Opioid Use and Its Association With Adverse Events.

Previous research linking opioid prescribing to adverse drug events has failed to properly account for the time-varying nature of opioid exposure. This study aimed to explore how the risk of opioid-related emergency department visits, readmissions, or deaths (composite outcome) varies with opioid dose and duration, comparing different novel modeling techniques. A prospective cohort of 1,511 hospitalized patients discharged from 2 McGill-affiliated hospitals in Montreal, 2014-2016, was followed from the first postdischarge opioid dispensation until 1 year after discharge. Marginal structural Cox proportional hazards models and their flexible extensions were used to explore the association between time-varying opioid use and the composite outcome. Weighted cumulative exposure models assessed cumulative effects of past use and explored how its impact depends on the recency of exposure. The patient mean age was 69.6 (standard deviation= 14.9) years; 57.7% were male. In marginal structural model analyses, current opioid use was associated with a 71% increase in the hazard of opioid-related adverse events (adjusted hazard ratio = 1.71, 95% confidence interval: 1.21, 2.43). The weighted cumulative exposure results suggested that the risk cumulates over the previous 50 days of opioid consumption. Flexible modeling techniques helped assess how the risk of opioid-related adverse events may be associated with time-varying opioid exposures while accounting for nonlinear relationships and the recency of past use.

Association between contact with mental health and substance use services and reincarceration after release from prison.

ObjectivePeople released from prison who experience mental health and substance use problems are at high risk of reincarceration. This study aimed to examine the association between contact with mental health and substance use treatment services, and reincarceration, among adults released from prison.MethodsPre-release survey data from 1,115 adults released from prisons in Queensland, Australia were linked with administrative health and correctional records covering a median of 787 days post-release. We constructed marginal structural Cox proportional hazards models, adjusting for pre-release variables and time-varying indicators of emergent mental health and substance use problems, to examine the association between contact with mental health and substance use treatment services, and reincarceration.ResultsThe adjusted hazard ratio (AHR) for reincarceration associated with mental health service contact was 1.76 (95%CI 1.23,2.51). Among those not on parole following release, the AHR for reincarceration associated with substance use treatment service contact was 3.16 (95%CI 2.09,4.77); we found no evidence for an association among those who were released on parole (AHR = 1.07; 95%CI 0.80,1.43).ConclusionsAlthough we cannot eliminate the possibility of residual confounding, our findings suggest that infrequent or unsustained contact with community-based mental health and substance use treatment services is not protective against reincarceration, and may even be iatrogenic. Increased investment in high-quality and timely behavioural health services for people released from prison may simultaneously improve health outcomes, and reduce reincarceration.

The association of long-acting insulin analogue use versus neutral protamine Hagedorn insulin use and the risk of major adverse cardiovascular events among individuals with type 2 diabetes: A population-based cohort study.

To compare the risk of cardiovascular outcomes associated with long-acting insulin analogues versus neutral protamine Hagedorn (NPH) insulin among patients with type 2 diabetes. We conducted a population-based retrospective cohort study using the UK Clinical Practice Research Datalink Aurum, linked with hospitalization and vital statistics data. Patients with type 2 diabetes who initiated basal insulin treatment between 2002 and 2018 were included in the study. Exposure was defined as current use of long-acting insulin analogues or NPH insulin, defined using a time-varying approach. The primary outcome was major adverse cardiovascular events (MACE; a composite endpoint of myocardial infarction, ischaemic stroke and cardiovascular death). We used a marginal structural Cox proportional hazards model to estimate the hazard ratio (HR) and 95% confidence interval (CI) for MACE with current use of long-acting insulin analogues versus NPH insulin, and in secondary analyses, by long-acting insulin molecule. Our cohort included 57 334 patients. A total of 3494 MACE occurred over a mean follow-up of 1.6 years (incidence rate 37.4, 95% CI 36.2 to 38.7 per 1000 person-years). Long-acting insulin analogues were associated with a decreased risk of MACE compared to NPH insulin (HR 0.89, 95% CI 0.83 to 0.96). Current use of long-acting insulin analogues is associated with a modestly reduced risk of MACE compared to current use of NPH insulin among patients with type 2 diabetes. This study could have important implications for drug plan managers and guideline-writing committees for recommendations of insulin treatment for type 2 diabetes.

Risk of Recurrent Acute Arterial Events Associated With Thiopurines and Anti-Tumor Necrosis Factor in Inflammatory Bowel Diseases

Patients with inflammatory bowel disease (IBD) are at increased risk of acute arterial events. Treatment with anti-tumor necrosis factor (anti-TNF) agents has been associated with a protective effect against the first occurrence of acute arterial events, but the impact of treatment with anti-TNF in patients with a previous history of acute arterial events remains unclear. We assessed the effect of anti-TNF and thiopurines on the risk of recurrent acute arterial events in patients with IBD in a nationwide cohort. Based on the French nationwide health insurance database, patients with IBD and a previous history of an acute arterial event were followed up from January 1, 2009, until December 31, 2018. The risk of acute arterial event recurrence associated with anti-TNF and thiopurine exposure was assessed using marginal structural Cox proportional hazard models adjusted for baseline and time-varying covariates. A total of 27,185 patients were included. During 121,822 person-years (median follow-up period, 4.0 y), 6865 recurrent acute arterial events occurred (incidence rate per 1000 person-years, 56.4; 95% CI, 55.0-57.7). Exposure to both anti-TNF and thiopurines were associated with a decreased risk of recurrent acute arterial events compared with the absence of exposure to either treatment (hazard ratio, 0.75; 95% CI, 0.63-0.90 and hazard ratio, 0.76; 95% CI, 0.66-0.88, respectively). In a nationwide cohort study of patients with IBD and a previous history of an acute arterial event, exposure to both anti-TNF and thiopurines were associated with a decreased risk of recurrent acute arterial events.

Impact of thiopurines and tumour necrosis factor antagonists on primary sclerosing cholangitis outcomes in patients with inflammatory bowel disease.

Patients with primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) are at risk of biliary tract cancer and liver damage (possibly leading to liver transplantation), and are often treated for IBD with thiopurines and/or tumour necrosis factor antagonists (anti-TNF) on a long-term basis. To assess the risk of biliary tract cancer and liver transplantation in patients exposed to thiopurines and/or anti TNF agents in a French nationwide cohort. We performed a population-based study of patients aged 18 years or older with PSC and IBD in the French national health insurance database. Patients were followed from 1 January 2009 to 31 December 2018. The risks of biliary tract cancer and liver transplantation associated with thiopurines and anti-TNF exposure were assessed with marginal structural Cox proportional hazard models, adjusting for baseline demographics and comorbidities, and time-varying medications and PSC activity. Among the 1929 patients with PSC and IBD included, 37 biliary tract cancers and 83 liver transplantations occurred. Compared with patients not exposed to thiopurines or anti-TNF agents, patients exposed to thiopurines (hazard ratio [HR], 1.05; 95% confidence interval [CI], 0.39-2.82) or anti-TNF agents (HR, 0.59; 95% CI, 0.13-2.80) had no excess risk of biliary tract cancer. Similarly, patients exposed to thiopurines (HR, 0.67; 95% CI, 0.30-1.48) or anti-TNF agents (HR, 0.68; CI, 0.22-2.09) had no excess risk of liver transplantation. Patients with PSC and IBD who are exposed to thiopurines or anti-TNF agents are not at excess risk of biliary tract cancer or liver transplantation.

Survival benefit of remdesivir in hospitalized COVID-19 patients with high SARS-CoV-2 viral loads and low-grade systemic inflammation.

To assess the benefits of remdesivir in hospitalized COVID-19 patients receiving combined immunomodulatory therapy (CIT) with dexamethasone and tocilizumab. This was a cohort study of microbiologically confirmed COVID-19 hospitalized patients. The primary outcome was all-cause 28 day mortality. Secondary outcomes were need for invasive mechanical ventilation (IMV) and IMV/death. Subgroup analyses according to SARS-CoV-2 cycle threshold (Ct) values and inflammation biomarkers were performed. Multivariable marginal structural Cox proportional hazards regression models were used to analyse the association between remdesivir therapy and the risk of outcomes of interest. Of 1368 hospitalized patients treated with corticosteroids, 1014 (74%) also received tocilizumab, 866 (63%) remdesivir and 767 (56%) tocilizumab + remdesivir. The 28 day mortality was 9% in the overall cohort, with an adjusted HR (aHR) of 0.32 (95% CI = 0.17-0.59) for patients receiving CIT. In the latter group, the 28 day mortality was 6.5%, with an aHR of 1.11 (95% CI = 0.57-2.16) for remdesivir use and there were no differences in secondary outcomes. The risk of primary and secondary outcomes with remdesivir differed by Ct and C-reactive protein (CRP) levels in patients receiving CIT: for 28 day mortality, the aHR was 0.48 (95% CI = 0.21-1.11) for Ct <25, 0.12 (95% CI = 0.02-0.66) for Ct <25 and <5 day symptom duration and 0.13 (95% CI = 0.03-0.50) for CRP <38 mg/L; for IMV and IMV/death, the aHR was 0.32 (95% CI = 0.13-0.77) and 0.33 (95% CI = 0.17-0.63), respectively, in patients with Ct <25. The benefits of remdesivir administered with dexamethasone and tocilizumab in hospitalized COVID-19 patients differ depending on Ct and CRP. Remdesivir decreases the risk of mortality and need for IMV in patients with high viral loads and low-grade systemic inflammation.

Adherence to a priori-Defined Diet Quality Indices Throughout the Early Disease Course Is Associated With Survival in Head and Neck Cancer Survivors: An Application Involving Marginal Structural Models.

No studies, to date, have scrutinized the role of a priori dietary patterns on prognosis following a head and neck squamous cell carcinoma (HNSCC) diagnosis. The purpose of this analysis was to evaluate the associations between adherence to six a priori defined diet quality indices (including AHEI-2010, aMED, DASH, and three low-carbohydrate indices) throughout the first 3 years of observation and all-cause and cancer-specific mortalities in 468 newly diagnosed HNSCC patients from the University of Michigan Head and Neck Specialized Program of Research Excellence (UM-SPORE). The dietary intake data were measured using a food frequency questionnaire administered at three annual time points commencing at study entry. Deaths and their causes were documented throughout the study using various data sources. Marginal structural Cox proportional hazards models were used to evaluate the role of diet quality, as a time-varying covariate, on mortality. There were 93 deaths from all causes and 74 cancer-related deaths adjudicated throughout the observation period. There was a strong inverse association between adherence to the AHEI-2010, all-cause mortality (HRQ5–Q1:0.07, 95% CI:0.01–0.43, ptrend:0.04), and cancer-specific mortality (HRQ5–Q1:0.15, 95% CI:0.02–1.07, ptrend:0.04). Other more modest associations were noted for the low-carbohydrate indices. In sum, higher adherence to the AHEI-2010 and a plant-based low-carbohydrate index throughout the first 3 years since diagnosis may bolster survival and prognosis in newly diagnosed patients with HNSCC.

Abstract P3-12-34: Antibiotic use and mortality from triple-negative breast cancer

Abstract Background: Gut-associated lymphoid tissue is the largest component of the body's immune system, as it influences both local and systemic immune responses. Gut microbiome dysbiosis related to antimicrobial exposure may be associated with decreased circulating and tumor-infiltrating lymphocytes and decreased immune repertoire, which may adversely impact survival in patients with triple-negative breast cancer (TNBC). We hypothesized that increasing antimicrobial exposure may lead to higher overall mortality (OM) and BC-specific mortality (BCM) in the presence of time-varying absolute lymphocyte count (ALC). Methods: Women with TNBC were identified in the Oncoshare database, a breast cancer registry that integrates data from the population-based SEER Registry and electronic medical records from two California healthcare systems (Stanford University and Sutter Health). We defined antibiotic use in three ways at each time point: (1) current use (“Antibiotic Use”), (2) total number of prescriptions (“Total Antibiotics”), and (3) total number of unique antibiotics prescribed (“Unique Antibiotics”) to study overall OM and BCM. We used marginal structural Cox proportional hazards multivariate models, with time-varying covariates (antibiotic use and ALC) to avoid immortal time bias. Results: 772 women were diagnosed with TNBC and treated from 2000-2014. The median overall follow-up time (including time to death) was 104 (IQR [61.66, 147.03]) months; the median follow-up time among those who were alive through the observation period was 121 (IQR [86.89, 160.93]) months. There were 654 (85%) patients who ever used antibiotics after TNBC diagnosis. There were 24/118 (20%) deaths among patients who never took antibiotics and 153/654 (23%) deaths in patients who ever took antibiotics during the study period. We previously showed that higher minimum ALC was associated with lower OM (HR 0.23, 95%CI (0.16, 0.35)) and BCM (HR 0.19, 95%CI (0.11, 0.34)) in TNBC patients from this cohort, with a significant association between higher peripheral lymphocyte count and tumor-infiltrating lymphocytes. Here, we found antibiotic use was associated with higher OM and BCM using definitions (2) and (3), but not definition (1). Model results are shown in the table and individual covariates are included for all definitions of antibiotic use. Conclusion: Higher number of antibiotic prescriptions and of unique antibiotics prescribed was associated with overall and breast cancer-specific mortality among women with TNBC. Future research on the role of the microbiome in mediating ALC and immune response may inform interventions to reduce TNBC mortality. Table. Overall and breast cancer-specific mortality among women with TNBC, Cox proportional hazards modelsOverall MortalityAntibiotic UseTotal AntibioticsUnique AntibioticsAntibiotic use1.54 (0.99, 2.39)Total number of antibiotics1.07* (1.04, 1.09)Number of unique antibiotics1.17* (1.12, 1.23)Age at diagnosis1.01* (1.00, 1.03)†1.01 (1.00, 1.02)1.01 (1.00, 1.03)Race/ethnicity (reference=White)Hispanic1.25 (0.70, 2.24)1.26 (0.70, 2.26)1.23 (0.69, 2.22)Non-Hispanic Asian Pacific Islander1.01 (0.64, 1.61)1.16 (0.74, 1.80)1.10 (0.69, 1.73)Non-Hispanic Black2.07* (1.12, 3.82)2.01* (1.10, 3.68)1.87* (1.03, 3.38)Neighborhood socioeconomic status quintile (reference=lowest)Second-lowest1.15 (0.49, 2.73)1.08 (0.47, 2.51)1.10 (0.49, 2.47)Middle1.22 (0.53, 2.81)1.05 (0.46, 2.40)1.06 (0.48, 2.35)Second-highest0.78 (0.34, 1.83)0.69 (0.30, 1.59)0.70 (0.31, 1.56)Highest0.96 (0.44, 2.11)0.82 (0.37, 1.78)0.80 (0.38, 1.70)Stage (reference=I)II1.72* (1.14, 2.59)1.61* (1.05, 2.45)1.71* (1.13, 2.57)III4.93* (3.08, 7.89)4.99* (3.10, 8.04)5.15* (3.20, 8.29)Grade (reference= 1)21.84 (0.66, 5.12)1.70 (0.61, 4.73)1.61 (0.57, 4.59)32.56 (0.95, 6.89)2.37 (0.88, 6.38)2.24 (0.82, 6.13)Received chemotherapy0.72 (0.45, 1.17)0.61 (0.37, 0.99)0.66 (0.41, 1.08)Received radiotherapy0.97 (0.70, 1.35)0.96 (0.69, 1.35)0.99 (0.71, 1.36)Used growth factors (e.g., filgrastim)1.38 (0.97, 1.97)1.31 (0.90, 1.93)1.15 (0.79, 1.67)† 95% CI lower bound is rounded from 1.001. * p &amp;lt; 0.05 Breast Cancer-Specific MortalityAntibiotic UseTotal AntibioticsUnique AntibioticsAntibiotic use1.50 (0.90, 2.47)Total number of antibiotics1.07* (1.04, 1.10)Number of unique antibiotics1.18* (1.12, 1.25)Age at diagnosis1.00 (0.98, 1.01)1.00 (0.98, 1.01)1.00 (0.98, 1.01)Race/ethnicity (reference=White)Hispanic1.36 (0.71, 2.61)1.36 (0.71, 2.60)1.34 (0.69, 2.58)Non-Hispanic Asian Pacific Islander1.41 (0.86, 2.31)1.48 (0.91, 2.40)1.47 (0.90, 2.40)Non-Hispanic Black1.69 (0.76, 3.76)1.66 (0.76, 3.60)1.55 (0.70, 3.43)Neighborhood socioeconomic status quintile (reference=lowest)Second-lowest1.54 (0.52, 4.52)1.71 (0.57, 5.17)1.59 (0.53, 4.79)Middle1.50 (0.53, 4.26)1.61 (0.55, 4.71)1.48 (0.51, 4.31)Second-highest1.15 (0.41, 3.27)1.17 (0.40, 3.41)1.12 (0.39, 3.26)Highest1.14 (0.42, 3.06)1.19 (0.43, 3.30)1.05 (0.38, 2.92)Stage (reference=I)II2.39* (1.37, 4.17)2.43* (1.39, 4.27)2.45* (1.40, 4.28)III7.96* (4.31, 14.70)8.35* (4.49, 15.53)8.48* (4.55, 15.80)Grade (reference= 1)21.12 (0.37, 3.36)1.01 (0.33, 3.05)0.91 (0.30, 2.81)31.67 (0.60, 4.68)1.52 (0.54, 4.26)1.42 (0.50, 4.04)Received chemotherapy0.64 (0.36, 1.14)0.61 (0.34, 1.10)0.60 (0.33, 1.09)Received radiotherapy0.95 (0.64, 1.39)0.91 (0.62, 1.33)0.95 (0.65, 1.38)Used growth factors (e.g., filgrastim)1.05 (0.70, 1.57)0.94 (0.63, 1.41)0.88 (0.58, 1.33)NOTE: * denotes p&amp;lt;0.05 Citation Format: Julia D Ransohoff, Karen Andrade, Natasha Purington, Vidhya Balasubramanian, Summer Han, Mina Liu, Jennifer Caswell-Jin, George Sledge, Ami Bhatt, Allison Kurian. Antibiotic use and mortality from triple-negative breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-12-34.

Depressive symptoms are no longer a barrier to HCV treatment initiation in the HIV–HCV co-infected population in Canada

Background Psychiatric illness was a major barrier for HCV treatment during the Interferon (IFN) treatment era due to neuropsychiatric side effects. While direct acting antivirals (DAA) are better tolerated, patient-level barriers persist. We aimed to assess the effect of depressive symptoms on time to HCV treatment initiation among HIV–HCV co-infected persons during the IFN (2003–2011) and second-generation DAA (2013–2020) eras. Methods We used data from the Canadian Co-infection Cohort, a multicentre prospective cohort, and its associated sub-study on Food Security (FS). We predicted Center for Epidemiologic Studies Depression Scale-10 (CES-D-10) classes for depressive symptoms indicative of a depression risk using a random forest classifier and corrected for misclassification using predictive value-based record-level correction. We used marginal structural Cox proportional hazards models with inverse weighting for competing risks (death) to assess the effect of depressive symptoms on treatment initiation among HCV RNA-positive participants. Results We included 590 and 1127 participants in the IFN and DAA eras. The treatment initiation rate increased from 9 (95% confidence interval (CI): 7–10) to 21 (95% CI: 19–22) per 100 person-years from the IFN to DAA era. Treatment initiation was lower among those with depressive symptoms compared to those without in the IFN era (hazard ratio: 0.81 (95% CI: 0.69–0.95)) and was higher in the DAA era (1.19 (95% CI: 1.10–1.27)). Conclusion Depressive symptoms no longer appear to be a barrier to HCV treatment initiation in the co-infected population in the DAA era. The higher rate of treatment initiation in individuals with depressive symptoms suggests those previously unable to tolerate IFN are now accessing treatment.

Impact of Anti-tumour Necrosis Factor Agents on the Risk of Colorectal Cancer in Patients with Ulcerative Colitis: Nationwide French Cohort Study.

Patients with ulcerative colitis [UC] are at increased risk of colorectal cancer. Anti-tumour necrosis factor agents [anti-TNF] aim to reduce chronic colonic inflammation and may lower the risk of colorectal cancer [CRC], but the impact of anti-TNF exposure has not yet been assessed in population-based cohort studies. The aim of this nationwide study was to assess the risk of CRC in patients with UC exposed to anti-TNF. Based on the French health insurance database, patients aged 18 years or older with a diagnosis of UC, previously exposed to or initiating immunosuppressive treatment, were followed from January 1, 2009, until December 31, 2018. The risk of CRC associated with anti-TNF exposure was assessed using marginal structural Cox proportional hazard models adjusting for baseline and time-varying comorbidities including primary sclerosing cholangitis, UC disease activity, colonoscopic surveillance, and other medications. Among 32 403 patients with UC, 15 542 [48.0%] were exposed to anti-TNF. During a median follow-up of 6.1 years [198 249 person-years], 246 incident CRC occurred (incidence rate per 1000 person-years, 1.24; 95% confidence intrval [CI], 1.10-1.41). Whereas the risk of CRC associated with anti-TNF exposure was not decreased in the overall group of patients with UC (hazard ratio [HR], 0.85; 95% CI, 0.58-1.26), anti-TNF exposure was associated with a decreased risk of CRC in patients with long-standing colitis [disease duration ≥10 years] [HR, 0.41; 95% CI, 0.20-0.86]. In a nationwide cohort of patients with UC, anti-TNF exposure was associated with a decreased risk of CRC in patients with long-standing colitis.

Sunscreens With High Versus Low Sun Protection Factor and Cutaneous Squamous Cell Carcinoma Risk: A Population-Based Cohort Study.

Evidence on sunscreen use and cutaneous squamous cell carcinoma (cSCC) risk is limited. Most studies have not taken sun protection factor (SPF) into consideration and used nonusers of sunscreen as the reference group. Nonusers are likely a priori at lower cSCC risk than users. No study has investigated the effect of high- versus low-SPF sunscreens on cSCC, appropriately adjusting for time-varying confounding. Using data from the Norwegian Women and Cancer Study (1991–2016), we investigated whether use of SPF ≥15 versus SPF <15 sunscreens reduces cSCC risk. We used a marginal structural Cox proportional hazards model with inverse probability of treatment and censoring weights to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). During follow-up of 148,781 women (mean follow-up, 14.3 years), 653 women were diagnosed with cSCC. The effect on cSCC risk of sunscreens with SPF ≥15 versus SPF <15 was close to the null when used at any latitudes (HR = 1.02, 95% CI: 0.82, 1.27) and when used in lower-latitude settings (HR = 1.05, 95% CI: 0.84, 1.32). In conclusion, we found no indication that sunscreens with SPF ≥15 reduced Norwegian women’s cSCC risk more than sunscreens with SPF <15, suggesting that either there is no difference in their effects long-term or the difference is diluted by incorrect application.

Immunosuppression does not prevent severe gastrointestinal tract involvement in systemic sclerosis.

We aimed to test the hypothesis that exposure to immunosuppression in early systemic sclerosis (SSc) could modify the risk of developing new onset severe gastrointestinal (GIT) involvement. A total of 762 subjects with <3 years of disease duration and without severe GIT disease at baseline study visit were identified from combined longitudinal cohort data from the Canadian Scleroderma Research Group (CSRG) and Australian Scleroderma Interest Group (ASIG). The primary exposure was ever use of methotrexate, cyclophosphamide, mycophenolate mofetil and/or azathioprine during the study period. Severe GIT disease was defined as: 1-malabsorption, 2-hyperalimentation, 3-pseudo-obstruction, and/or 4-≥10% weight loss in association with the use of antibiotics for bacterial overgrowth or oesophageal stricture. The change in the hazard of severe GIT disease due to exposure was estimated using a marginal structural Cox proportional hazards model fit by inverse probability of treatment weights (IPTW) to address potential confounding. Study subjects were 81.5% female, had a mean age of 53.7±13.0 years and mean disease duration at baseline of 1.4±0.8 years. During a mean follow-up of 4.0±2.6 years, severe GIT involvement developed in 11.6% of the 319 subjects exposed to immunosuppression and in 6.8% of the 443 unexposed subjects. In an IPTW-adjusted analysis, exposure to immunosuppression was not associated with severe GIT disease (weighted hazard ratio 0.91, 95% confidence interval 0.52-1.58). In this large inception SSc cohort, the risk of severe GIT involvement was not modified by exposure to immunosuppression.

Association of Opioid Consumption Profiles After Hospitalization With Risk of Adverse Health Care Events

Although better pain management has guided policies for opioid use over the past few decades, evidence is limited regarding how patterns of use are associated with the risk of potentially avoidable opioid-related adverse events. To estimate the risk of harms associated with opioid dose and duration of use, and to ascertain whether the risk is modified by treatment indication and age. This ad hoc cohort study followed up patients who were enrolled in a cluster randomized trial of medication reconciliation between October 1, 2014, and November 30, 2016, 12 months after they were discharged from the McGill University Health Centre in Montreal, Quebec, Canada. To be eligible for this study, patients needed to have filled at least 1 opioid prescription 3 months after discharge. Patients with a history of using methadone or buprenorphine were excluded. Data analyses were performed between February 1, 2019, and February 28, 2020. Time-varying measures of opioid use included current use, daily morphine milligram equivalent (MME) dose, cumulative and continuous use duration, and type of ingredients in prescription opioids used. Hospitalization records, dispensed prescriptions records, and postdischarge interviews were used to evaluate adherence to the opioid prescriptions after discharge. Opioid-related emergency department visits, hospital readmissions, or all-cause death. Outcomes were ascertained using provincial medical services claims and hospitalization databases. Of 3486 participants in the cluster randomized trial (mean [SD] age of 69.6 [14.9] years; 2010 men [57.7%]), 1511 patients were included in this ad hoc cohort study. Among those with at least 1 opioid dispensation, 241 patients (15.9%) experienced an opioid-related emergency department visit, hospital readmission, or death. Results from marginal structural Cox proportional hazards regression models showed more than a 2-fold increase in the risk of opioid-related adverse events associated with a cumulative use duration of more than 90 days (adjusted hazard ratio, 2.56; 95% CI, 1.25-5.27) compared with 1 to 30 days. A 3-fold risk increase was found with a mean daily dose higher than 90 MME (adjusted hazard ratio, 3.51; 95% CI, 1.58-7.82) compared with 90 MME or lower. This study found an association between risk of adverse health care events and higher opioid doses and longer treatment duration. This finding can inform policies for limiting opioid duration and dose to attenuate the risk of avoidable morbidity.