Gabapentinoids and Risk for Severe Exacerbation in Chronic Obstructive Pulmonary Disease : A Population-Based Cohort Study.

BACKGROUND: North American and European health agencies recently warned of severe breathing problems associated with gabapentinoids, including in patients with chronic obstructive pulmonary disease (COPD), although supporting evidence is limited. OBJECTIVE: To assess whether gabapentinoid use is associated with severe exacerbation in patients with COPD. DESIGN: Time-conditional propensity score-matched, new-user cohort study. SETTING: Health insurance databases from the Régie de l'assurance maladie du Québec in Canada. PATIENTS: Within a base cohort of patients with COPD between 1994 and 2015, patients initiating gabapentinoid therapy with an indication (epilepsy, neuropathic pain, or other chronic pain) were matched 1:1 with nonusers on COPD duration, indication for gabapentinoids, age, sex, calendar year, and time-conditional propensity score. MEASUREMENTS: The primary outcome was severe COPD exacerbation requiring hospitalization. Hazard ratios (HRs) associated with gabapentinoid use were estimated in subcohorts according to gabapentinoid indication and in the overall cohort. RESULTS: The cohort included 356 gabapentinoid users with epilepsy, 9411 with neuropathic pain, and 3737 with other chronic pain, matched 1:1 to nonusers. Compared with nonuse, gabapentinoid use was associated with increased risk for severe COPD exacerbation across the indications of epilepsy (HR, 1.58 [95% CI, 1.08 to 2.30]), neuropathic pain (HR, 1.35 [CI, 1.24 to 1.48]), and other chronic pain (HR, 1.49 [CI, 1.27 to 1.73]) and overall (HR, 1.39 [CI, 1.29 to 1.50]). LIMITATION: Residual confounding, including from lack of smoking information. CONCLUSION: In patients with COPD, gabapentinoid use was associated with increased risk for severe exacerbation. This study supports the warnings from regulatory agencies and highlights the importance of considering this potential risk when prescribing gabapentin and pregabalin to patients with COPD. PRIMARY FUNDING SOURCE: Canadian Institutes of Health Research and Canadian Lung Association.

IL-32 Drives the Differentiation of Cardiotropic CD4+ T Cells Carrying HIV DNA in People With HIV.

Interleukin 32 (IL-32) is a potent multi-isoform proinflammatory cytokine, which is upregulated in people with HIV (PWH) and is associated with cardiovascular disease (CVD) risk. However, the impact of IL-32 isoforms on CD4 T-cell cardiotropism, a mechanism potentially contributing to heart inflammation, remains unknown. Here we show that IL-32 isoforms ß and γ induce the generation of CCR4+CXCR3+ double positive (DP) memory CD4 T-cell subpopulation expressing the tyrosine kinase receptor c-Met, a phenotype associated with heart-homing of T cells. Our ex vivo studies on PWH show that the frequency of DP CD4 T cells is significantly higher in individuals with, compared to individuals without, subclinical atherosclerosis and that DP cells from antiretroviral-naive and treated individuals are highly enriched with HIV DNA. Together, these data demonstrate that IL-32 isoforms have the potential to induce heart-homing of HIV-infected CD4 T cells, which may further aggravate heart inflammation and CVD in PWH.

Plasma Human Immunodeficiency Virus 1 Soluble Glycoprotein 120 Association With Correlates of Immune Dysfunction and Inflammation in Antiretroviral Therapy-Treated Individuals With Undetectable Viremia.

BACKGROUND: Chronic inflammation persists in some people living with human immunodeficiency virus (HIV) during antiretroviral therapy and is associated with premature aging. The glycoprotein 120 (gp120) subunit of HIV-1 envelope sheds and can be detected in plasma, showing immunomodulatory properties even in the absence of detectable viremia. We evaluated whether plasma soluble gp120 (sgp120) and a family of gp120-specific anti-cluster A antibodies, linked to CD4 depletion in vitro, contribute to chronic inflammation, immune dysfunction, and subclinical cardiovascular disease in participants of the Canadian HIV and Aging Cohort Study with undetectable viremia. METHODS: Cross-sectional assessment of sgp120 and anti-cluster A antibodies was performed in 386 individuals from the cohort. Their association with proinflammatory cytokines and subclinical coronary artery disease was assessed using linear regression models. RESULTS: High levels of sgp120 and anti-cluster A antibodies were inversely correlated with CD4+ T cell count and CD4/CD8 ratio. The presence of sgp120 was associated with increased levels of interleukin 6. In participants with detectable atherosclerotic plaque and detectable sgp120, anti-cluster A antibodies and their combination with sgp120 levels correlated positively with the total volume of atherosclerotic plaques. CONCLUSIONS: This study showed that sgp120 may act as a pan toxin causing immune dysfunction and sustained inflammation in a subset of people living with HIV, contributing to the development of premature comorbid conditions.

Incidence and risk factors of chronic postoperative pain in same-day surgery: A prospective cohort study.

BACKGROUND: The amount of same-day surgery has increased markedly worldwide in recent decades, but there remains limited evidence on chronic postsurgical pain in this setting. METHODS: We assessed pain 90 days after ambulatory surgery in an international, multicentre prospective cohort study of patients ≥45 years old with comorbidities or ≥65 years old. Pain was assessed using the Brief Pain Inventory. Chronic postsurgical pain was defined as a change ≥1 in self-rated average pain at the surgical site between baseline and 90 days, and moderate to severe chronic postsurgical pain as a score ≥4 in self-rated average pain at the surgical site at 90 days. Risk factors for chronic postsurgical pain were identified using multivariable logistic regression. RESULTS: Between November 2021 and January 2023, a total of 2054 participants were included, and chronic postsurgical pain occurred in 12% of participants, of whom 93.1% had new chronic pain at the surgical site (i.e., participants without pain prior to surgery). Moderate to severe chronic postsurgical pain occurred in 9% of overall participants. Factors associated with chronic postsurgical pain were: active smoking (OR 1.82; 95% CI 1.20 to 2.76), orthopaedic surgery (OR 4.7; 95% CI 2.24 to 9.7), plastic surgery (OR 4.3; 95% CI 1.97 to 9.2), breast surgery (OR 2.74; 95% CI 1.29 to 5.8), vascular surgery (OR 2.71; 95% CI 1.09 to 6.7), and ethnicity (i.e., Hispanic/Latino ethnicity OR 3.41; 95% CI 1.68 to 6.9 and First Nations/Native persons OR 4.0; 95% CI 1.05 to 15.4). CONCLUSIONS: Persistent postsurgical pain after same-day surgery is common, usually moderate to severe in nature, and occurs mostly in patients without chronic pain prior to surgery.

Association Between the Development of Subclinical Cardiovascular Disease and Human Immunodeficiency Virus (HIV) Reservoir Markers in People With HIV on Suppressive Antiretroviral Therapy.

We report that people with human immunodeficiency virus (HIV) diagnosed with coronary artery atherosclerotic plaques display higher levels of HIV DNA compared with those without atherosclerotic plaques. In a multivariable prediction model that included 27 traditional and HIV-related risk factors, measures of HIV DNA were among the most important predictors of atherosclerotic plaque formation.

CD4/CD8 Ratio Outcome According to the Class of the Third Active Drug in Antiretroviral Therapy Regimens: Results From the Quebec Human Immunodeficiency Virus Cohort Study.

BACKGROUND: The impact of different therapeutic classes of drugs in antiretroviral therapy (ART) regimens on the CD4/CD8 ratio is not well documented in people treated for HIV. The objective of this study was to analyze the long-term effect of exposure to integrase strand transfer inhibitor (INSTI) on CD4/CD8 ratio compared with nonnucleoside reverse transcriptase inhibitor (NNRTI) or protease inhibitor (PI) among ART-treated persons with HIV (PWH). METHODS: Data from the Quebec HIV Cohort collected from 31 August 2017 were used. Our analysis included all patients in the cohort who received a first or subsequent ART regimen composed of 2 nucleoside reverse transcriptase inhibitors (NRTIs) and a third active drug of a different class (NNRTI, PI, or INSTI) for at least 16 weeks. Marginal structural Cox models were constructed to estimate the effect of different therapeutic classes on the CD4/CD8 ratio outcome. RESULTS: Among the 3907 eligible patients, 972 (24.9%), 1996 (51.1%), and 939 (24.0%) were exposed to an ART regimen whose third active agent was an NNRTI, PI, or INSTI, respectively. The total follow-up time was 13 640.24 person-years. The weighted hazard ratio for the association between the third active class and CD4/CD8 ratio ≥1 was .56 (95% confidence interval [CI]: .48-.65) for patients exposed to NNRTI + 2 NRTIs and .41 (95% CI: .35-.47) for those exposed to PI + 2 NRTIs, compared with those exposed INSTI + 2 NRTIs. CONCLUSIONS: For people treated for HIV, INSTI-based ART appears to be associated with a higher CD4/CD8 ratio than NNRTI and PI-based ART.

Baseline characteristics of a prospective cohort study of aging and cardiovascular diseases among people living with HIV.

OBJECTIVES: Our objective was to report the baseline characteristics of participants in the Canadian HIV and Aging Cohort Study (CHACS) and present amendments to the initial protocol. METHODS: CHACS is a multi-centred prospective cohort study that was initially set from 2011 to 2016 and will now continue recruitment until 2024. Four additional years of follow-up have been added, and additional outcomes and covariates will be prospectively collected. Frailty will be assessed using a modified version of the Fried's frailty phenotype. The four interrelated aspects of gender-gender roles, gender identity, gender relationships, and institutionalized gender-will be measured using the GENESIS-PRAXY questionnaire. Diet will be assessed using a validated, web-based, self-administered food frequency questionnaire. RESULTS: A total of 1049 participants (77% people living with HIV) were recruited between September 2011 and September 2019. Median age at baseline was 54 years (interquartile range 50-61). Most participants were male (84%) and white (83%). Compared with participants without HIV, those with HIV were more likely to be male; to report lower education levels and incomes; to be more sedentary; to use tobacco, recreational, and prescription drugs; to report a personal history of cardiovascular diseases; and to be frail. CONCLUSIONS: The new assessments added to the CHACS protocol will allow for an even more detailed portrait of the pathways leading to accentuated aging for people living with HIV. Participants in the CHACS cohort display important differences in socio-economic and cardiovascular risk factors according to HIV serostatus. These imbalances must be taken into account for all further inferential analyses.

Validation of ANG-1 and P-SEL as biomarkers of post-COVID-19 conditions using data from the Biobanque québécoise de la COVID-19 (BQC-19).

The quest for understanding and managing the long-term effects of COVID-19, often referred to as Long COVID or post-COVID-19 condition (PCC), remains an active research area. Recent findings highlighted angiopoietin-1 (ANG-1) and p-selectin (P-SEL) as potential diagnostic markers, but validation is essential, given the inconsistency in COVID-19 biomarker studies. Leveraging the biobanque québécoise de la COVID-19 (BQC19) biobank, we analyzed the data of 249 participants. Both ANG-1 and P-SEL levels were significantly higher in patients with PCC participants compared with control subjects at 3 months using the Mann-Whitney U test. We managed to reproduce and validate the findings, emphasizing the importance of collaborative biobanking efforts in enhancing the reproducibility and credibility of Long COVID research outcomes.

Peculiar Phenotypic and Cytotoxic Features of Pulmonary Mucosal CD8 T Cells in People Living with HIV Receiving Long-Term Antiretroviral Therapy.

People living with HIV have high burdens of chronic lung disease, lung cancers, and pulmonary infections despite antiretroviral therapy (ART). The rates of tobacco smoking by people living with HIV vastly exceed that of the general population. Furthermore, we showed that HIV can persist within the lung mucosa despite long-term ART. As CD8 T cell cytotoxicity is pivotal for controlling viral infections and eliminating defective cells, we explored the phenotypic and functional features of pulmonary versus peripheral blood CD8 T cells in ART-treated HIV+ and uninfected controls. Bronchoalveolar lavage fluid and matched blood were obtained from asymptomatic ART-treated HIV+ smokers (n = 11) and nonsmokers (n = 15) and uninfected smokers (n = 7) and nonsmokers (n = 10). CD8 T cell subsets and phenotypes were assessed by flow cytometry. Perforin/granzyme B content, degranulation (CD107a expression), and cytotoxicity against autologous Gag peptide-pulsed CD4 T cells (Annexin V+) following in vitro stimulation were assessed. In all groups, pulmonary CD8 T cells were enriched in effector memory subsets compared with blood and displayed higher levels of activation (HLA-DR+) and exhaustion (PD1+) markers. Significant reductions in proportions of senescent pulmonary CD28-CD57+ CD8 T cells were observed only in HIV+ smokers. Pulmonary CD8 T cells showed lower perforin expression ex vivo compared with blood CD8 T cells, with reduced granzyme B expression only in HIV+ nonsmokers. Bronchoalveolar lavage CD8 T cells showed significantly less in vitro degranulation and CD4 killing capacity than blood CD8 T cells. Therefore, pulmonary mucosal CD8 T cells are more differentiated, activated, and exhausted, with reduced killing capacity in vitro than blood CD8 T cells, potentially contributing to a suboptimal anti-HIV immune response within the lungs.

The dynamic changes and sex differences of 147 immune-related proteins during acute COVID-19 in 580 individuals.

INTRODUCTION: Severe COVID-19 leads to important changes in circulating immune-related proteins. To date it has been difficult to understand their temporal relationship and identify cytokines that are drivers of severe COVID-19 outcomes and underlie differences in outcomes between sexes. Here, we measured 147 immune-related proteins during acute COVID-19 to investigate these questions. METHODS: We measured circulating protein abundances using the SOMAscan nucleic acid aptamer panel in two large independent hospital-based COVID-19 cohorts in Canada and the United States. We fit generalized additive models with cubic splines from the start of symptom onset to identify protein levels over the first 14 days of infection which were different between severe cases and controls, adjusting for age and sex. Severe cases were defined as individuals with COVID-19 requiring invasive or non-invasive mechanical respiratory support. RESULTS: 580 individuals were included in the analysis. Mean subject age was 64.3 (sd 18.1), and 47% were male. Of the 147 proteins, 69 showed a significant difference between cases and controls (p < 3.4 × 10-4). Three clusters were formed by 108 highly correlated proteins that replicated in both cohorts, making it difficult to determine which proteins have a true causal effect on severe COVID-19. Six proteins showed sex differences in levels over time, of which 3 were also associated with severe COVID-19: CCL26, IL1RL2, and IL3RA, providing insights to better understand the marked differences in outcomes by sex. CONCLUSIONS: Severe COVID-19 is associated with large changes in 69 immune-related proteins. Further, five proteins were associated with sex differences in outcomes. These results provide direct insights into immune-related proteins that are strongly influenced by severe COVID-19 infection.

Remdesivir for the treatment of patients in hospital with COVID-19 in Canada: a randomized controlled trial.

BACKGROUND: The role of remdesivir in the treatment of patients in hospital with COVID-19 remains ill defined in a global context. The World Health Organization Solidarity randomized controlled trial (RCT) evaluated remdesivir in patients across many countries, with Canada enrolling patients using an expanded data collection format in the Canadian Treatments for COVID-19 (CATCO) trial. We report on the Canadian findings, with additional demographics, characteristics and clinical outcomes, to explore the potential for differential effects across different health care systems. METHODS: We performed an open-label, pragmatic RCT in Canadian hospitals, in conjunction with the Solidarity trial. We randomized patients to 10 days of remdesivir (200 mg intravenously [IV] on day 0, followed by 100 mg IV daily), plus standard care, or standard care alone. The primary outcome was in-hospital mortality. Secondary outcomes included changes in clinical severity, oxygen- and ventilator-free days (at 28 d), incidence of new oxygen or mechanical ventilation use, duration of hospital stay, and adverse event rates. We performed a priori subgroup analyses according to duration of symptoms before enrolment, age, sex and severity of symptoms on presentation. RESULTS: Across 52 Canadian hospitals, we randomized 1282 patients between Aug. 14, 2020, and Apr. 1, 2021, to remdesivir (n = 634) or standard of care (n = 648). Of these, 15 withdrew consent or were still in hospital, for a total sample of 1267 patients. Among patients assigned to receive remdesivir, in-hospital mortality was 18.7%, compared with 22.6% in the standard-of-care arm (relative risk [RR] 0.83 (95% confidence interval [CI] 0.67 to 1.03), and 60-day mortality was 24.8% and 28.2%, respectively (95% CI 0.72 to 1.07). For patients not mechanically ventilated at baseline, the need for mechanical ventilation was 8.0% in those assigned remdesivir, and 15.0% in those receiving standard of care (RR 0.53, 95% CI 0.38 to 0.75). Mean oxygen-free and ventilator-free days at day 28 were 15.9 (± standard deviation [SD] 10.5) and 21.4 (± SD 11.3) in those receiving remdesivir and 14.2 (± SD 11) and 19.5 (± SD 12.3) in those receiving standard of care (p = 0.006 and 0.007, respectively). There was no difference in safety events of new dialysis, change in creatinine, or new hepatic dysfunction between the 2 groups. INTERPRETATION: Remdesivir, when compared with standard of care, has a modest but significant effect on outcomes important to patients and health systems, such as the need for mechanical ventilation. Trial registration: ClinicalTrials.gov, no. NCT04330690.

Defining the duration of the dispensation of oral anticoagulants in administrative healthcare databases.

PURPOSE: In clinical practice, warfarin therapy requires frequent dose adjustments. In pharmacy claims, the days supplied value may not reflect the true duration of warfarin dispensation. This may affect the measures of association comparing the safety of direct oral anticoagulants (DOACs) versus warfarin. METHODS: Using Quebec healthcare administrative databases, we formed a cohort of 55 230 patients newly treated with oral anticoagulants between 2010 and 2016. The duration of dispensations was defined using two approaches: the recorded days supplied value, and the longitudinal coverage approximation (data-driven) that may account for individual variation in drug usage patterns. Propensity scores adjusted Cox proportional hazards regression models were used to estimate the hazard ratio (HR) of major bleeding with dabigatran or rivaroxaban versus warfarin. RESULTS: Using the days supplied, the mean (and standard deviation) dispensation durations for dabigatran, rivaroxaban, and warfarin were 19 (15), 19 (14), and 13 (12) days, respectively. Using the data-driven approach, the durations were 20 (16), 19 (15), and 15 (16) days, respectively. The choice of the approach had no impact on the HR estimates. CONCLUSIONS: In our settings, the data-driven approach closely approximated the recorded days supplied value for the standard dose therapies such as dabigatran and rivaroxaban. For warfarin, the data-driven approach captured more variability in the duration of dispensations compared to the days supplied value, which may better reflect the true drug-taking behavior of warfarin. Both approaches may provide valid estimates when comparing the safety of DOACs versus warfarin.

A comparison of confounder selection and adjustment methods for estimating causal effects using large healthcare databases.

PURPOSE: Confounding adjustment is required to estimate the effect of an exposure on an outcome in observational studies. However, variable selection and unmeasured confounding are particularly challenging when analyzing large healthcare data. Machine learning methods may help address these challenges. The objective was to evaluate the capacity of such methods to select confounders and reduce unmeasured confounding bias. METHODS: A simulation study with known true effects was conducted. Completely synthetic and partially synthetic data incorporating real large healthcare data were generated. We compared Bayesian adjustment for confounding (BAC), generalized Bayesian causal effect estimation (GBCEE), Group Lasso and Doubly robust estimation, high-dimensional propensity score (hdPS), and scalable collaborative targeted maximum likelihood algorithms. For the hdPS, two adjustment approaches targeting the effect in the whole population were considered: Full matching and inverse probability weighting. RESULTS: In scenarios without hidden confounders, most methods were essentially unbiased. The bias and variance of the hdPS varied considerably according to the number of variables selected by the algorithm. In scenarios with hidden confounders, substantial bias reduction was achieved by using machine-learning methods to identify proxies as compared to adjusting only by observed confounders. hdPS and Group Lasso performed poorly in the partially synthetic simulation. BAC, GBCEE, and scalable collaborative-targeted maximum likelihood algorithms performed particularly well. CONCLUSIONS: Machine learning can help to identify measured confounders in large healthcare databases. They can also capitalize on proxies of unmeasured confounders to substantially reduce residual confounding bias.

Evidence of the Different Associations of Prognostic Factors With Censoring Across Treatment Groups and Impact on Censoring Weight Model Specification: The Example of Anticoagulation in Atrial Fibrillation.

Inverse probability of censoring weights (IPCWs) may reduce selection bias due to informative censoring in longitudinal studies. However, in studies with an active comparator, the associations between predictors and censoring may differ across treatment groups. We used the clinical example of anticoagulation treatment with warfarin or a direct oral anticoagulant (DOAC) in atrial fibrillation to illustrate this. The cohort of individuals initiating an oral anticoagulant during 2010-2016 was identified from the Régie de l'assurance maladie du Québec (RAMQ) databases. The parameter of interest was the hazard ratio (HR) of the composite of stroke, major bleeding, myocardial infarction, or death associated with continuous use of warfarin versus DOACs. Two strategies for the specification of the model for estimation of censoring weights were explored: exposure-unstratified and exposure-stratified. The HR associated with continuous treatment with warfarin versus DOACs adjusted with exposure-stratified IPCWs was 1.26 (95% confidence interval: 1.20, 1.33). Using exposure-unstratified IPCWs, the HR differed by 15% in favor of DOACs (1.41, 95% confidence interval: 1.34, 1.48). Not accounting for the different associations between the predictors and informative censoring across exposure groups may lead to misspecification of censoring weights and biased estimate on comparative effectiveness and safety.

Rates of Incomplete Resection of 1- to 20-mm Colorectal Polyps: A Systematic Review and Meta-Analysis.

BACKGROUND & AIMS: Incomplete resection of neoplastic colorectal polyps can result in postcolonoscopy colorectal cancer. We performed a systematic review and meta-analysis to determine the incomplete resection rate (IRR) of colorectal polyps and associated factors. METHODS: We searched MEDLINE, EMBASE, EBM Reviews, and CINAHL to identify full-text articles that reported IRRs of polyps 1 to 20 mm, published until March 2019. Exclusion criteria were studies of inflammatory bowel disease cohorts, referrals for difficult polypectomy, polyp sizes larger than 20 mm, and endoscopic submucosal resection and/or dissection as polypectomy approaches. IRRs were calculated based on findings from biopsies taken at polypectomy sites or assessments of margins of resected polyps. The primary outcome was IRR for snare removal of polyps 1 to 20 mm. Secondary outcomes included IRR for polyps 1 to 10 mm and 10 to 20 mm, IRR for hot and cold snare removal of polyps 1 to 10 mm and 10 to 20 mm, IRR of snare removal with or without submucosal injection, and IRR for forceps and cold snare removal of polyps 1 to 5 mm. RESULTS: We identified 6148 reports and used 32 studies, with a total of 9282 polyps, in our quantitative analysis. The IRR for snare removal of polyps 1 to 20 mm was 13.8% (95% confidence interval [CI] 10.3-17.3; 13 studies, 5128 polypectomies). IRRs were 15.9% for snare removal of polyps 1 to 10 mm (95% CI 9.6-22.1; 9 studies, 2531 polypectomies) and 20.8% for snare removal of polyps 10 to 20 mm (95% CI 12.9-28.8; 6 studies, 412 polypectomies). The IRR for hot snare removal of polyps 1 to 10 mm was 14.2% (95% CI 5.2-23.2) vs 17.3% for cold snare polypectomy (95% CI 14.3‒20.3). The IRR for forceps removal of polyps 1 to 5 mm was 9.9% (95% CI 7.1-13.0) vs 4.4% for snare polypectomy (95% CI 2.9-6.1). CONCLUSIONS: In a systematic review and meta-analysis, we found that colorectal polyps 1 to 20 mm are frequently incompletely resected, and that risk increases for polyps 10 mm or larger. There is no difference in IRRs of cold vs hot snares for polyps 1 to 10 mm. Snare polypectomy should be used over forceps for polyps 1 to 5 mm.

Prevalence and Characterization of Subclinical Coronary Atherosclerotic Plaque with CT among Individuals with HIV: Results from the Canadian HIV and Aging Cohort Study.

Background People living with HIV (PLWH) have a higher risk of myocardial infarction. Coronary atherosclerotic plaque CT characterization helps to predict cardiovascular risk. Purpose To measure CT characteristics of coronary plaque in PLWH without known cardiovascular disease and healthy volunteers without HIV. Materials and Methods In this prospective study, noncontrast CT (all participants, n = 265) was used for coronary artery calcium (CAC) scoring in asymptomatic PLWH and healthy volunteers without HIV, without known cardiovascular disease, from 2012 to 2019. At coronary CT angiography (n = 233), prevalence, frequency, and volume of calcified, mixed, and noncalcified plaque were measured. Poisson regressions were used with adjustment for cardiovascular risk factors. Results There were 181 PLWH (mean age, 56 years ± 7; 167 men) and 84 healthy volunteers (mean age, 57 years ± 8; 65 men) evaluated by using noncontrast CT. CT angiography was performed in 155 PLWH and 78 healthy volunteers. Median 10-year Framingham risk score was not different between PLWH and healthy volunteers (10% vs 9%, respectively; P = .45), as were CAC score (odds ratio [OR], 1.06; 95% CI: 0.58, 1.94; P = .85) and overall plaque prevalence (prevalence ratio, 1.07; 95% CI: 0.86, 1.32; P = .55) after adjustment for cardiovascular risk. Noncalcified plaque prevalence (prevalence ratio, 2.5; 95% CI: 1.07, 5.67; P = .03) and volume (OR, 2.8; 95% CI: 1.05, 7.40; P = .04) were higher in PLWH. Calcified plaque frequency was reduced in PLWH (OR, 0.6; 95% CI: 0.40, 0.91; P = .02). Treatment with protease inhibitors was associated with higher volume of overall (OR, 1.8; 95% CI: 1.09, 2.85; P = .02) and mixed plaque (OR, 1.6; 95% CI: 1.04, 2.45; P = .03). Conclusion Noncalcified coronary plaque burden at coronary CT angiography was two- to threefold higher in asymptomatic people living with HIV without known cardiovascular disease compared with healthy volunteers without HIV. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Lai in this issue.

Effectiveness and safety among direct oral anticoagulants in nonvalvular atrial fibrillation: A multi-database cohort study with meta-analysis.

AIMS: There are conflicting signals in the literature about comparative safety and effectiveness of direct oral anticoagulants (DOACs) for nonvalvular atrial fibrillation (NVAF). METHODS: We conducted multicentre matched cohort studies with secondary meta-analysis to assess safety and effectiveness of dabigatran, rivaroxaban and apixaban across 9 administrative healthcare databases. We included adults with NVAF initiating anticoagulation therapy (dabigatran, rivaroxaban or apixaban), and constructed 3 cohorts to compare DOACs pairwise. The primary outcome was pooled hazard ratio (pHR) of ischaemic stroke or systemic thromboembolism. Secondary outcomes included pHR of major bleeding, and a composite of stroke, major bleeding, or all-cause mortality. We used proportional hazard Cox regressions models, and pooled estimates were obtained with random effect meta-analyses. RESULTS: The cohorts included 73 414 new users of dabigatran, 92 881 of rivaroxaban, and 61 284 of apixaban. After matching, the pHRs (95% confidence intervals) comparing rivaroxaban initiation to dabigatran were: 1.11 (0.93, 1.32) for ischaemic stroke or systemic thromboembolism, 1.26 (1.09, 1.46) for major bleeding, and 1.17 (1.05, 1.30) for the composite endpoint. For apixaban vs dabigatran, they were: 0.91 (0.74, 1.12) for ischaemic stroke or systemic thromboembolism, 0.89 (0.75, 1.05) for major bleeding, and 0.94 (0.78 to 1.14) for the composite endpoint. For apixaban vs rivaroxaban, they were: 0.85 (0.74, 0.99) for ischaemic stroke or systemic thromboembolism, 0.61 (0.53, 0.70) for major bleeding, and 0.82 (0.76, 0.88) for the composite endpoint. CONCLUSION: We found that apixaban use is associated with lower risks of stroke and bleeding compared with rivaroxaban, and similar risks compared with dabigatran.

Plasma Levels of C-Type Lectin REG3α and Gut Damage in People With Human Immunodeficiency Virus.

BACKGROUND: Regenerating islet-derived protein 3α (REG3α) is an antimicrobial peptide secreted by intestinal Paneth cells. Circulating REG3α has been identified as a gut damage marker in inflammatory bowel diseases. People living with human immunodeficiency virus (PWH) on antiretroviral therapy (ART) present with an abnormal intestinal landscape leading to microbial translocation, persistent inflammation, and development of non-AIDS comorbidities. Herein, we assessed REG3α as a marker of gut damage in PWH. METHODS: Plasma from 169 adult PWH, including 30 elite controllers (ECs), and 30 human immunodeficiency virus (HIV)-uninfected controls were assessed. REG3α plasma levels were compared with HIV disease progression, epithelial gut damage, microbial translocation, and immune activation markers. RESULTS: Cross-sectionally, REG3α levels were elevated in untreated and ART-treated PWH compared with controls. ECs also had elevated REG3α levels compared to controls. Longitudinally, REG3α levels increased in PWH without ART and decreased in those who initiated ART. REG3α levels were inversely associated with CD4 T-cell count and CD4:CD8 ratio, while positively correlated with HIV viral load in untreated participants, and with fungal product translocation and inflammatory markers in all PWH. CONCLUSIONS: Plasma REG3α levels were elevated in PWH, including ECs. The gut inflammatory marker REG3α may be used to evaluate therapeutic interventions and predict non-AIDS comorbidity risks in PWH.

Circulating (1→3)-ß-D-glucan Is Associated With Immune Activation During Human Immunodeficiency Virus Infection.

BACKGROUND: Microbial translocation from the gut to systemic circulation contributes to immune activation during human immunodeficiency virus (HIV) infection and is usually assessed by measuring plasma levels of bacterial lipopolysaccharide (LPS). Fungal colonization in the gut increases during HIV-infection and people living with HIV (PLWH) have increased plasma levels of fungal polysaccharide (1→3)-ß-D-Glucan (ßDG). We assessed the contribution of circulating DG to systemic immune activation in PLWH. METHODS: Cross-sectional and longitudinal assessments of plasma ßDG levels were conducted along with markers of HIV disease progression, epithelial gut damage, bacterial translocation, proinflammatory cytokines, and ßDG-specific receptor expression on monocytes and natural killer (NK) cells. RESULTS: Plasma ßDG levels were elevated during early and chronic HIV infection and persisted despite long-term antiretroviral therapy (ART). ßDG increased over 24 months without ART but remained unchanged after 24 months of treatment. ßDG correlated negatively with CD4 T-cell count and positively with time to ART initiation, viral load, intestinal fatty acid-binding protein, LPS, and soluble LPS receptor soluble CD14 (sCD14). Elevated ßDG correlated positively with indoleamine-2,3-dioxygenase-1 enzyme activity, regulatory T-cell frequency, activated CD38+Human Leukocyte Antigen - DR isotype (HLA-DR)+ CD4 and CD8 T cells and negatively with Dectin-1 and NKp30 expression on monocytes and NK cells, respectively. CONCLUSIONS: PLWH have elevated plasma ßDG in correlation with markers of disease progression, gut damage, bacterial translocation, and inflammation. Early ART initiation prevents further ßDG increase. This fungal antigen contributes to immune activation and represents a potential therapeutic target to prevent non-acquired immunodeficiency syndrome events.

Cytomegalovirus Seropositivity Is Associated With Increased Microbial Translocation in People Living With Human Immunodeficiency Virus and Uninfected Controls.

BACKGROUND: Cytomegalovirus (CMV) seropositivity and anti-CMV immunoglobulin G (IgG) levels are associated with adverse health outcomes in elderly populations. Among people living with human immunodeficiency virus (PLWH), CMV seropositivity has been associated with persistent CD8 T-cell elevation and increased risk of developing non-AIDS comorbidities despite long-term antiretroviral therapy (ART). Herein, we investigated whether CMV seropositivity and elevation of anti-CMV IgG levels were associated with increased epithelial gut damage, microbial translocation, and systemic inflammation. METHODS: A total of 150 PLWH (79 ART-naive and 71 ART-treated) were compared to 26 without human immunodeficiency virus (HIV) infection (uninfected controls). Plasma markers of HIV disease progression, epithelial gut damage, microbial translocation, nonspecific B-cell activation, anti-CMV and anti-Epstein-Barr virus (EBV) IgG levels, and proinflammatory cytokines were measured. RESULTS: CMV seropositivity and elevated anti-CMV IgG levels were associated with markers of epithelial gut damage, microbial translocation, and inflammation in PLWH and participants without HIV infection. In contrast, total nonspecific IgG, immunoglobulin M, immunoglobulin A, and anti-EBV IgG levels were not associated with these markers. CMV seropositivity was associated with markers of epithelial gut damage, microbial translocation, and inflammation independent of sociodemographic and behavioral characteristics of the study population. CONCLUSIONS: CMV-seropositive people with and without HIV had increased epithelial gut damage, microbial translocation, and inflammation. Furthermore, anti-CMV IgG levels were independently associated with increased epithelial gut damage and microbial translocation. CMV coinfection may partially explain persistent gut damage, microbial translocation, and inflammation in ART-treated PLWH.