Mailed feedback to primary care physicians on antibiotic prescribing for patients aged 65 years and older: pragmatic, factorial randomised controlled trial.

OBJECTIVES: To evaluate whether providing family physicians with feedback on their antibiotic prescribing compared with that of their peers reduces antibiotic prescriptions. To also identify effects on antibiotic prescribing from case-mix adjusted feedback reports and messages emphasising antibiotic associated harms. DESIGN: Pragmatic, factorial randomised controlled trial. SETTING: Primary care physicians in Ontario, Canada PARTICIPANTS: All primary care physicians were randomly assigned a group if they were eligible and actively prescribing antibiotics to patients 65 years or older. Physicians were excluded if had already volunteered to receive antibiotic prescribing feedback from another agency, or had opted out of the trial. INTERVENTION: A letter was mailed in January 2022 to physicians with peer comparison antibiotic prescribing feedback compared with the control group who did not receive a letter (4:1 allocation). The intervention group was further randomised in a 2x2 factorial trial to evaluate case-mix adjusted versus unadjusted comparators, and emphasis, or not, on harms of antibiotics. MAIN OUTCOME MEASURES: Antibiotic prescribing rate per 1000 patient visits for patients 65 years or older six months after intervention. Analysis was in the modified intention-to-treat population using Poisson regression. RESULTS: 5046 physicians were included and analysed: 1005 in control group and 4041 in intervention group (1016 case-mix adjusted data and harms messaging, 1006 with case-mix adjusted data and no harms messaging, 1006 unadjusted data and harms messaging, and 1013 unadjusted data and no harms messaging). At six months, mean antibiotic prescribing rate was 59.4 (standard deviation 42.0) in the control group and 56.0 (39.2) in the intervention group (relative rate 0.95 (95% confidence interval 0.94 to 0.96). Unnecessary antibiotic prescribing (0.89 (0.86 to 0.92)), prolonged duration prescriptions defined as more than seven days (0.85 (0.83 to 0.87)), and broad spectrum prescribing (0.94 (0.92 to 0.95)) were also significantly lower in the intervention group compared with the control group. Results were consistent at 12 months post intervention. No significant effect was seen for including emphasis on harms messaging. A small increase in antibiotic prescribing with case-mix adjusted reports was noted (1.01 (1.00 to 1.03)). CONCLUSIONS: Peer comparison audit and feedback letters significantly reduced overall antibiotic prescribing with no benefit of case-mix adjustment or harms messaging. Antibiotic prescribing audit and feedback is a scalable and effective intervention and should be a routine quality improvement initiative in primary care. TRIAL REGISTRATION: ClinicalTrials.gov NCT04594200.

Dissecting mechanisms of fecal microbiota transplantation efficacy in disease.

Fecal microbiota transplantation (FMT) has emerged as an alternative or adjunct experimental therapy for microbiome-associated diseases following its success in the treatment of recurrent Clostridioides difficile infections (rCDIs). However, the mechanisms of action involved remain relatively unknown. The term 'dysbiosis' has been used to describe microbial imbalances in relation to disease, but this traditional definition fails to consider the complex cross-feeding networks that define the stability of the microbiome. Emerging research transitions toward the targeted restoration of microbial functional networks in treating different diseases. In this review, we explore potential mechanisms responsible for the efficacy of FMT and future therapeutic applications, while revisiting definitions of 'dysbiosis' in favor of functional network restoration in rCDI, inflammatory bowel diseases (IBDs), metabolic diseases, and cancer.

Adjunctive glucocorticoid therapy for Pneumocystis jirovecii pneumonia in solid organ transplant recipients: A multicenter cohort, 2015-2020.

Solid organ transplant recipients (SOTRs) frequently receive adjunctive glucocorticoid therapy (AGT) for Pneumocystis jirovecii pneumonia (PJP). This multicenter cohort of SOTRs with PJP admitted to 20 transplant centers in Canada, the United States, Europe, and Australia, was examined for whether AGT was associated with a lower rate of all-cause intensive care unit (ICU) admission, 90-day death, or a composite outcome (ICU admission or death). Of 172 SOTRs with PJP (median [IQR] age: 60 (51.5-67.0) years; 58 female [33.7%]), the ICU admission and death rates were 43.4%, and 20.8%, respectively. AGT was not associated with a reduced risk of ICU admission (adjusted odds ratio [aOR] [95% CI]: 0.49 [0.21-1.12]), death (aOR [95% CI]: 0.80 [0.30-2.17]), or the composite outcome (aOR [95% CI]: 0.97 [0.71-1.31]) in the propensity score-adjusted analysis. AGT was not significantly associated with at least 1 unit of the respiratory portion of the Sequential Organ Failure Assessment score improvement by day 5 (12/37 [32.4%] vs 39/111 [35.1%]; P = .78). We did not observe significant associations between AGT and ICU admission or death in SOTRs with PJP. Our findings should prompt a reevaluation of routine AGT administration in posttransplant PJP treatment and highlight the need for interventional studies.

Fecal microbiota transplantation plus anti-PD-1 immunotherapy in advanced melanoma: a phase I trial.

Fecal microbiota transplantation (FMT) represents a potential strategy to overcome resistance to immune checkpoint inhibitors in patients with refractory melanoma; however, the role of FMT in first-line treatment settings has not been evaluated. We conducted a multicenter phase I trial combining healthy donor FMT with the PD-1 inhibitors nivolumab or pembrolizumab in 20 previously untreated patients with advanced melanoma. The primary end point was safety. No grade 3 adverse events were reported from FMT alone. Five patients (25%) experienced grade 3 immune-related adverse events from combination therapy. Key secondary end points were objective response rate, changes in gut microbiome composition and systemic immune and metabolomics analyses. The objective response rate was 65% (13 of 20), including four (20%) complete responses. Longitudinal microbiome profiling revealed that all patients engrafted strains from their respective donors; however, the acquired similarity between donor and patient microbiomes only increased over time in responders. Responders experienced an enrichment of immunogenic and a loss of deleterious bacteria following FMT. Avatar mouse models confirmed the role of healthy donor feces in increasing anti-PD-1 efficacy. Our results show that FMT from healthy donors is safe in the first-line setting and warrants further investigation in combination with immune checkpoint inhibitors. ClinicalTrials.gov identifier NCT03772899 .

The effect of late-onset CMV infection on the outcome of renal allograft considering initial graft function.

BACKGROUND: Delayed graft function (DGF) increases the renal allograft failure risk. Late-onset Cytomegalovirus (CMV) infection's effect on the association between DGF and allograft failure has not been determined. METHODS: In this retrospective cohort, we included all renal allograft recipients at London Health Sciences Centre from January 1, 2014 to December 30, 2017, and continued clinical follow-up until February 28, 2020. We determined whether late-onset CMV infection affects the association between DGF and allograft failure in stratified and Cox proportional hazard analyses. RESULTS: Of 384 patients (median age [interquartile range]: 55 [43.3-63]; 38.7% female), 57 recipients (14.8%) were diagnosed with DGF. Patients with DGF were at a greater risk of CMV infection than patients without DGF (22.8% vs. 11.3%, p = .017). Late-onset CMV infection (odds ratio [OR]: 4.7, 95% CI: 2.07-10.68) and rejection (OR: 9.59, 95% CI: 4.15-22.16) significantly increased the risk of allograft failure in recipients with DGF. Patients with DGF had a significantly greater risk of graft failure than those without DGF (17.5% vs. 6.1%, p = .007). In the adjusted Cox hazard model, CMV infection significantly increased the risk of allograft failure (aHR: 3.19, 95% CI: 1.49-6.84). CONCLUSION: Late-onset CMV infection considerably increased the risk of graft failure in patients with DGF. A hybrid preventive model including prophylaxis followed by CMV-specific cell-mediated immunity monitoring may decrease the risk of allograft failure in recipients with DGF.

Improved MAIT cell functions following fecal microbiota transplantation for metastatic renal cell carcinoma.

Strategies to modify the gut microbiome in cancer patients using fecal microbiota transplantation (FMT) have gained momentum as a therapeutic intervention. However, how FMT impacts innate-like, antimicrobial T lymphocytes is unclear. In this study, we assessed peripheral blood (PB) mucosa-associated invariant T (MAIT) cell frequencies and functions in patients with metastatic renal cell carcinoma (mRCC) before and seven days after they received FMT as part of a clinical trial. We found comparable MAIT cell frequencies in healthy controls and mRCC patients. In contrast, γδ T cells exhibited a numerical decline in mRCC, which was partially reversed by FMT. We also found a significant increase in the PB CD4+ MAIT cell compartment of mRCC patients with or without FMT. Paired sample analyses revealed CD69 upregulation on MAIT cells accompanied by decreased PD-1 levels post-FMT. These changes were unique to MAIT cells as non-MAIT T lymphocytes showed either no trend or a trend in the opposite direction. Importantly, FMT did not render MAIT cells exhausted as also judged by their stable expression of TIM-3, LAG-3, BTLA, CTLA-4, TIGIT and VISTA. These findings were corroborated in functional assays in which MAIT cells were stimulated with MR1 ligands or with a combination of IL-12 and IL-18 to produce inflammatory cytokines and granzyme B. Indeed, when stimulated ex vivo with IL-12 and IL-18, MAIT cells mounted a more rigorous TNF-α response post-FMT. In conclusion, FMT improves MAIT cell functions, which should serve patients well in subsequent microbial challenges in the face of cancer-elicited immunosuppression. Trial Registration: https://clinicaltrials.gov/ Identifier: NCT04163289 (registration date: November 14, 2019).

Association of Higher-Dose Fluoroquinolone Therapy With Serious Adverse Events in Older Adults With Advanced Chronic Kidney Disease.

Importance: Population-based data are needed to inform the safe prescribing of fluoroquinolone antibiotics to patients with advanced chronic kidney disease (CKD). Objective: To quantify the 14-day risk of a hospital visit with nervous system and/or psychiatric disorders, hypoglycemia, or a collagen-associated event in patients with advanced CKD newly prescribed a fluoroquinolone at a higher vs a lower dose. Design, Setting, and Participants: This population-based cohort study in Ontario, Canada (January 1, 2008, to March 17, 2020) used linked health care data to identify new users of fluoroquinolone antibiotics. Participants included adults 66 years or older with advanced CKD (an estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m2 but not receiving dialysis). Data analysis was performed from January 1 to April 30, 2021. Exposures: A new prescription for a higher-dose fluoroquinolone (ciprofloxacin, 501-1000 mg/d; levofloxacin, 501-750 mg/d; or norfloxacin, 401-800 mg/d) vs a lower-dose fluoroquinolone (ciprofloxacin, 500 mg/d; levofloxacin, 250-500 mg/d; or norfloxacin, 400 mg/d). Main Outcomes and Measure: The primary outcome was the 14-day risk of a hospital visit with nervous system and/or psychiatric disorders, hypoglycemia, or a collagen-associated event. Secondary outcomes included a hospital visit with sepsis, retinal detachment or other tendinopathies, all-cause hospitalization, all-cause mortality, and sudden cardiac death. Inverse probability of treatment weighting on the propensity score was used to balance comparison groups on baseline health. Weighted risk ratios and risk differences were obtained using modified Poisson regression and binomial regression, respectively. Results: Of 11 917 patients (median age, 83 years [IQR, 77-89 years]; 7438 women [62.4%]; median eGFR, 25 [IQR, 21-28] mL/min/1.73 m2) included in the analysis, 5482 (46.0%) received a higher-dose and 6435 (54.0%) received a lower-dose fluoroquinolone. After weighting, the primary composite outcome-a hospital visit with nervous system and/or psychiatric disorders, hypoglycemia, or a collagen-associated event-occurred in 68 of 5482 patients (1.2%) treated with a higher-dose fluoroquinolone and in 47 of 5516 (0.9%) treated with a lower-dose fluoroquinolone (weighted risk ratio, 1.45 [95% CI, 1.01-2.08]; weighted risk difference, 0.39% [95% CI, 0.01%-0.76%]). The risk of sepsis, retinal detachment, all-cause hospitalization, all-cause mortality, and sudden cardiac death did not differ significantly between groups. Conclusions and Relevance: These findings suggest that older patients with advanced CKD who were prescribed a fluoroquinolone at a higher-than-recommended dose were significantly more likely to experience the composite outcome of a hospital visit with nervous system and/or psychiatric disorders, hypoglycemia, or a collagen-associated event, although the absolute risk of these events was less than 2%.

Fecal microbiota transplantation is safe and tolerable in patients with multiple sclerosis: A pilot randomized controlled trial.

Background: Patients with MS have an altered gut microbiota compared to healthy individuals, as well as elevated small intestinal permeability, which may be contributing to the development and progression of the disease. Objective: We sought to investigate if fecal microbiota transplantation was safe and tolerable in MS patients and if it could improve abnormal intestinal permeability. Methods: Nine patients with MS were recruited and provided monthly FMTs for up to six months. The primary outcome investigated was change in peripheral blood cytokine concentrations. The secondary outcomes were gut microbiota composition, intestinal permeability, and safety (assessed with EDSS and MRI). Results: The study was terminated early and was subsequently underpowered to assess whether peripheral blood cytokines were altered following FMTs. FMTs were safe in this group of patients. Two of five patients had elevated small intestinal permeability at baseline that improved to normal values following FMTs. Significant, donor-specific, beneficial alterations to the MS patient gut microbiota were observed following FMT. Conclusion: FMT was safe and tolerable in this cohort of RRMS patients, may improve elevated small intestinal permeability, and has the potential to enrich for an MS-protective microbiota. Further studies with longer follow-up and larger sample sizes are required to determine if FMT is a suitable therapy for MS.

Incidence and Outcomes Associated With Clostridioides difficile Infection in Solid Organ Transplant Recipients.

Importance: Little is known about the incidence and outcomes of Clostridioides difficile infection (CDI) in solid organ transplant (SOT) recipients. Objective: To estimate the CDI incidence and outcomes in SOT recipients. Design, Setting, and Participants: A population-based cohort study was conducted using administrative health care data for all Ontario, Canada, residents who received organ allografts from April 1, 2003, to December 31, 2017; March 31, 2020, was the end of the study period. Main Outcomes and Measures: The primary outcome was hospital admission with CDI diagnosis. The secondary outcomes included all-cause death, intensive care unit admission, acute kidney injury requiring dialysis, and fulminant CDI comprising any of the following: toxic megacolon, ileus, perforation, or colectomy. The association between short- vs long-term mortality (ie, death occurring within or after 90 days post-CDI) and the following variables was evaluated: age, sex, Deyo-Charlson Comorbidity Index, SOT type, early- vs late-onset CDI, fulminant CDI, intensive care unit admission, and acute kidney injury requiring acute dialysis. Results: Overall, 10 724 SOT recipients (6901 [64.4%] men; median age, 54 [IQR, 44-62] years) were eligible. Kidney transplant was the most common SOT type (6453 [60.2%]). The median follow-up time was 5.0 (IQR, 2.3-8.8) years, resulting in 61 987 person-years of follow-up. A total of 726 patients (6.8%) were hospitalized with CDI. The 1-year CDI incidence significantly increased in annual cohorts (ie, from 23.1; 95% CI, 12.8-41.8 per 1000 person-years in 2004 to 46.7; 95% CI, 35.0-62.3 per 1000 person-years in 2017; P = .001). Clostridioides difficile was associated with a 16.8% rate (n = 122) of 90-day mortality. In patients who underwent kidney transplant, CDI was typically late-onset (median interval, 2.2; IQR, 0.4-6.0 years) compared with recipients of other organs. Acute kidney injury requiring dialysis was significantly associated with short-term (adjusted odds ratio [aOR], 1.86; 95% CI, 1.07-3.26) and long-term (adjusted hazard ratio [aHR], 1.89; 95% CI, 1.29-2.78) mortality, and late-onset CDI was also significantly associated with a greater risk of short-term (aOR, 4.26; 95% CI, 2.51-7.22) and long-term (aHR, 2.49; 95% CI, 1.78-3.49) mortality. Conclusions and Relevance: In this study, increasing CDI trends in annual cohorts of SOT recipients were observed. Posttransplant CDI was associated with mortality, and late-onset CDI was associated with a greater risk of death than early-onset CDI. These findings suggest that preventive strategies should not be limited to the initial months following transplantation. Comprehensive therapeutic approaches targeting acute kidney injury risk factors in SOT recipients may reduce short- and long-term post-CDI mortality.

Evaluating the safety and effectiveness of a nurse-led outpatient virtual IV vancomycin monitoring clinic: a retrospective cohort study.

BACKGROUND: Outpatient parenteral antimicrobial therapy (OPAT) with vancomycin is a common treatment modality for certain Gram-positive infections. Data regarding the safety of various models of delivery are limited. OBJECTIVES: To review outcomes of a nurse-led OPAT vancomycin monitoring service. METHODS: This was a retrospective cohort study of consecutive patients referred to a nurse-led OPAT vancomycin clinic from December 2015 to March 2018. Patients were administered IV vancomycin in the home with active laboratory monitoring of vancomycin trough levels, renal function and complete blood count using an integrated electronic database linked with community laboratories (virtual vancomycin clinic, VVC). Monitoring was coordinated by nurses with physician approval of recommended dosing changes. Data were extracted from the electronic medical record. Demographics; clinical indication; microbial aetiology; culture source; antimicrobial regimen(s); serum creatinine and vancomycin trough values; initiation, discharge and completion dates; hospitalizations; adverse events; and outcomes were all evaluated. RESULTS: Two hundred and seventy-five patients underwent a total of 301 courses of OPAT with vancomycin; 285 courses were completed. The rate of treatment discontinuation due to adverse effects was 33/301 (11.0%), with 15/33 (45.5%) being due to renal adverse effects (15/301 [5.0%] of episodes). Two of 15 (18.2%) patients developed stage 2 acute kidney injury (AKI), and no patients had stage 3 AKI or required haemodialysis. Nine of 301 (3.0%) required readmission for treatment failure. Nursing costs associated with monitoring were $63.93 CAD/patient ($48.43 USD). CONCLUSIONS: A nurse-led VVC was a safe, effective and inexpensive modality for administering outpatient vancomycin.

Gastrointestinal Histoplasmosis Mimicking Crohn's Disease.

Disseminated histoplasmosis is a life-threatening disease usually seen in immunocompromised patients living in endemic areas. We present an apparently immunocompetent patient with gastrointestinal histoplasmosis who was initially diagnosed with biopsy-proven Crohn's disease. Following discontinuation of anti-inflammatory drugs and institution of antifungal therapy, his gastrointestinal illness completely improved. Specific fungal staining should be routinely included in histopathologic assessment of tissue specimens diagnosed as Crohn's disease.

Late-onset allograft rejection, cytomegalovirus infection, and renal allograft loss: Is anti-CMV prophylaxis required following late-onset allograft rejection?

Renal transplant recipients remain at risk of delayed-onset cytomegalovirus (CMV) infection occurring beyond a complete course of prophylaxis. In this retrospective cohort, all 278 patients who received renal allografts from deceased donors from 2014 to 2016 were followed until September 1, 2019. We determined the effect of early-vs late-onset acute rejection (EAR vs LAR [ie, occurring beyond 12 months after transplantation]) on CMV infection and subsequently long-term allograft outcome. Median (IQR) duration of follow-up was 1186.0 (904.7-1531.2) days. Seventy patients including 49 patients with EAR and 21 with LAR received augmented immunosuppression. In the same interval, 40 patients developed CMV infection (36 patients beyond 90 days after transplantation [90%]). In logistic regression analysis, D+/R- CMV serostatus (OR: 5.5, 95% CI: 2.5-12.2) and LAR (OR: 7.9, 95% CI: 2.8-22.2) significantly increased the risk of CMV infection. In Cox proportional hazard model, delayed-onset CMV infection (HR: 2.51, 95% CI: 1.08-5.86) and LAR (HR: 5.46, 95% CI: 2.26-13.14) significantly increased the risk of allograft loss. Patients with LAR are at risk of late-onset CMV infection. Post-LAR, targeted prophylaxis may reduce the risk of CMV infection and subsequently allograft loss. Further studies are required to demonstrate the effect of targeted prophylaxis following LAR.

Should We Delay the Second COVID-19 Vaccine Dose in Order to Optimize Rollout? A Mathematical Perspective.

Objectives: With vaccination shortage persisting in many countries, adopting an optimal vaccination program is of crucial importance. Given the slow pace of vaccination campaigns globally, a very relevant and burning public health question is whether it is better to delay the second COVID-19 vaccine shot until all priority group people have received at least one shot. Currently, many countries are looking to administer a third dose (booster shot), which raises the question of how to distribute the available daily doses to maximize the effectively vaccinated population. Methods: We formulate a generalized optimization problem with a total of u T = ∑ i = 1 n u i vaccine doses, that have to be optimally distributed between n different sub-populations, where sub-population u i represents people receiving the ith dose of the vaccine with efficacy α i . The particular case where n = 2 is solved first, followed by the general case of n dose regimen. Results: In the case of a two dose regimen, if the efficacy of the second dose is less than (or equal to) twice the efficacy of the first dose, the optimal strategy to maximize the number of effectively vaccinated people is to delay the second vaccine as much as possible. Otherwise, the optimal strategy would consist of administering the second dose as quickly as possible. In the general case, the optimal vaccination strategy would be to administer the k - th dose corresponding to the index providing the maximum inter-dose efficacy difference (α i - α i-1) for all possible values of i ∈ {1, … , n}, with α 0 = 0. Conclusion: Our results suggest that although extending the interval between doses beyond 12 weeks was likely optimal earlier in the pandemic, the reduced single dose efficacy of vaccines against the delta variant make this approach no longer viable.

Treating From the Inside Out: Relevance of Fecal Microbiota Transplantation to Counteract Gut Damage in GVHD and HIV Infection.

The gastrointestinal (GI) tract is a complex and well-balanced milieu of anatomic and immunological barriers. The epithelial surface of the GI tract is colonized by trillions of microorganisms, known as the gut microbiota, which is considered an "organ" with distinctive endocrine and immunoregulatory functions. Dysregulation of the gut microbiota composition, termed dysbiosis, has been associated with epithelial damage and translocation of microbial products into the circulating blood. Dysbiosis, increased gut permeability and chronic inflammation play a major role on the clinical outcome of inflammatory bowel diseases, graft-vs.-host disease (GVHD) and HIV infection. In this review, we focus on GVHD and HIV infection, conditions sharing gut immune damage leading to dysbiosis. The degree of dysbiosis and level of epithelial gut damage predict poor clinical outcome in both conditions. Emerging interventions are therefore warranted to promote gut microbiota homeostasis and improve intestinal barrier function. Interventions such as anti-inflammatory medications, and probiotics have toxicity and/or limited transitory effects, justifying innovative approaches. Fecal microbiota transplantation (FMT) is one such approach where fecal microorganisms are transferred from healthy donors into the GI tract of the recipient to restore microbiota composition in patients with Clostridium difficile-induced colitis or inflammatory bowel diseases. Preliminary findings point toward a beneficial effect of FMT to improve GVHD and HIV-related outcomes through the engraftment of beneficial donor bacteria, notably those producing anti-inflammatory metabolites. Herein, we critically review the potential for FMT in alleviating dysbiosis and gut damage in patients with GVHD or HIV-infection. Understanding the underlying mechanism by which FMT restores gut function will pave the way toward novel scalable and targeted interventions.

Case report - Primary renal echinococcal infection.

Renal echinococcal infection is an uncommonly encountered infection in North America but is endemic in many parts of the world. With increasing migration, it is conceivable that practicing Canadian physicians will see more patients presenting at various stages of infection. Herein, we describe an unusual presentation of primary renal echinococcal infection and describe current diagnostic, as well as medical and surgical management strategies.

New hepatitis C diagnoses in Ontario, Canada are associated with the local prescription patterns of a controlled-release opioid.

Increases in acute hepatitis C virus (HCV) incidence may be a result of the rising prevalence of injection drug use and the opioid epidemic. Among persons who inject drugs, sharing of needles/syringes is less common and leads to a smaller proportion of incident cases than does sharing of injection drug preparation equipment. In Canada and Europe, hydromorphone controlled release has been associated with frequent reuse and sharing of IDPE. Drug excipients within HCR have been shown to preserve virus survival within IDPE. We hypothesized that regional differences in HCV incidence would mirror regional differences in HCR prescribing. We reviewed HCV incidence data across Ontario, Canada for 2016. Opioid prescribing patterns in each Health Unit were reviewed. Multivariable Poisson regression analyses were performed to test the strength of hydromorphone controlled release dispensing patterns in explaining HCV incidence compared to all opioids. Less vehicle access, lack of education, lower income, less population density, higher white race/ethnicity and more opioid substitution therapy recipients remained significant positive predictors of hepatitis C incidence in the Ontario model. Higher hydromorphone controlled release dispensing rate was a stronger predictor of HCV incidence than all opioid prescriptions (standardized risk ratio = 1.17, P < .0001 vs sRR = 1.11, P = .02). When hydromorphone controlled release was excluded from the opioid prescription variable, dispensing patterns of all other opioids no longer remained a significant predictor (sRR = 1.042, P = .34). The observed relationship between HCV incidence and hydromorphone controlled release dispensing suggests that the type of opioid prescribed locally may contribute to variations in HCV incidence. These data add support to evidence that hydromorphone controlled release use is contributing to HCV spread in Ontario.

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.

Correction: A controlled-release oral opioid supports S. aureus survival in injection drug preparation equipment and may increase bacteremia and endocarditis risk.

[This corrects the article DOI: 10.1371/journal.pone.0219777.].