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People who inject drugs and have infective endocarditis have a high risk of recurrent infective endocarditis and death. We aimed to characterize clinical factors associated with mortality and assess the probability of infective endocarditis recurrence in the presence of death as a competing risk.A retrospective cohort study was conducted of people who inject drugs, identified between April 5, 2007 and March 15, 2018 with the Modified Duke Criteria for definite infective endocarditis. Fine-Gray sub-distribution and Cox proportional hazards modeling were conducted to determine variables associated with the rate of infective endocarditis recurrence and mortality, respectively.Of the 310 patients with infective endocarditis who inject drugs, 236 experienced a single episode and 74 experienced recurrent episodes. Peripherally inserted central catheter misuse was associated with an increased rate of infective endocarditis recurrence (sub-distribution hazard ratio 2.41; 95% confidence interval [CI], 1.17-4.98; P = .02) and mortality (hazard ratio [HR] 2.44; 95% CI, 1.15-5.17; P = .02). Non-right-sided infection, peripheral intravenous therapy, and intensive care unit admission were also associated with increased mortality. Oral therapy (HR 0.38; 95% CI, 0.16-0.91; P = .03), outpatient treatment (HR 0.39; 95% CI, 0.19-0.82; P = .01), and inpatient referral to addiction services (HR 0.39; 95% CI, 0.22-0.70; P = .002) were associated with a decrease in mortality.Patients who misuse their peripherally inserted central catheter are at higher risk of recurrent infective endocarditis and death. Avoidance of peripherally inserted central catheter lines and use of intravenous peripheral therapy did not reduce mortality, but oral therapy was associated with reduced risk. Inpatient addiction services referral is important.

BackgroundDetection of viral RNA by nucleic acid amplification testing (NAAT) remains the gold standard for diagnosis of SARS-CoV-2 infection but is limited by high cost and other factors. Whether serology-based assays can be effectively incorporated into a diagnostic algorithm remains to be determined. Herein we describe the development of a serology-based testing algorithm for SARS-CoV-2 infection.Patients and MethodsBetween July 2020 and February 2021, we included symptomatic unvaccinated patients evaluated in the Emergency Department of our institution for suspected SARS-CoV-2. All patients had testing by real-time Reverse Transcription Polymerase Chain Reaction. The performance characteristics of five commercial enzymatic serology assays testing for different antibody isotypes were evaluated in a derivation cohort and the assay with the best performance was further tested on a validation cohort. Optimal cut-off points were determined using receiver operating characteristic (ROC) curves and further tested using logistic regression.ResultsThe derivation and validations cohorts included 72 and 319 patients, respectively. Based on its initial performance, the Elecsys Anti-SARS-CoV-2 assay (Roche Diagnostics) was further tested in the validation cohort. Using ROC curve analysis, we estimated the diagnostic performance for different cut-off points assuming a prevalence of positive tests of 5%. At any given cut-off point the NPV was over 97%.DiscussionThis study suggests that an initial diagnostic strategy using the Elecsys Anti-SARS-CoV-2 serology test in symptomatic unvaccinated patients could help to rule out an acute SARS-CoV2 infection and potentially lead to appropriately tailored infection control measures or rational guidance for further testing with a potential cost reduction and increased availability.

IMPORTANCE: Antibiotic overuse contributes to adverse drug effects, increased costs, and antimicrobial resistance. OBJECTIVE: To evaluate peer-comparison audit and feedback to high-prescribing primary care physicians (PCPs) and assess the effect of targeted messaging on avoiding unnecessary antibiotic prescriptions and avoiding long-duration prescribing. DESIGN, SETTING, AND PARTICIPANTS: In this 3-arm randomized clinical trial, administrative data collected from IQVIA’s Xponent database were used to recruit the highest quartile of antibiotic-prescribing PCPs (n = 3500) in Ontario, Canada. INTERVENTIONS: Physicians were randomized 3:3:1 to receive a mailed letter sent in December 2018 addressing antibiotic treatment initiation (n = 1500), a letter addressing prescribing duration (n = 1500), or no letter (control; n = 500). Outliers at the 99th percentile at baseline for each arm were excluded from analysis. MAIN OUTCOMES AND MEASURES: The primary outcome was total number of antibiotic prescriptions over 12 months postintervention. Secondary outcomes were number of prolonged-duration prescriptions (>7 days) and antibiotic drug costs (in Canadian dollars). Robust Poisson regression controlling for baseline prescriptions was used for analysis. RESULTS: Of the 3465 PCPs included in analysis, 2405 (69.4%) were male, and 2116 (61.1%) were 25 or more years from their medical graduation. At baseline, PCPs receiving the antibiotic initiation letter and duration letter prescribed an average of 988 and 1000 antibiotic prescriptions, respectively; at 12 months postintervention, these PCPs prescribed an average of 849 and 851 antibiotic prescriptions, respectively. For the primary outcome of total antibiotic prescriptions 12 months postintervention, there was no statistically significant difference in total antibiotic use between PCPs who received the initiation letter compared with controls (relative risk [RR], 0.96; 97.5% CI, 0.92-1.01; P = .06) and a small statistically significant difference for the duration letter compared with controls (RR, 0.95; 97.5% CI, 0.91-1.00; P = .01). For PCPs receiving the duration letter, this corresponds to an average of 42 fewer antibiotic prescriptions over 12 months. There was no statistically significant difference between the letter arms. For the initiation letter, compared with controls there was an RR of 0.98 (97.5% CI, 0.93-1.03; P = .42) and 0.97 (97.5% CI, 0.92-1.02; P = .19) for the outcomes of prolonged-duration prescriptions and antibiotic drug costs, respectively. At baseline, PCPs who received the duration letter prescribed an average of 332 prolonged-duration prescriptions with $14 470 in drug costs. There was an 8.1% relative reduction (RR, 0.92; 97.5% CI, 0.87-0.97; P

BACKGROUND: Infective endocarditis is an increasingly common complication among people who inject drugs. We conducted this study to determine whether the removal of traditional controlled-release oxycodone from the Canadian market would be associated with an increase in the use of hydromorphone and an increased risk of infective endocarditis. METHODS: We conducted a retrospective, population-based time series analysis using the linked health administrative databases of Ontario, Canada. We measured the quarterly risk of admissions for infective endocarditis related to injection drug use and changes in opioid prescription rates from 2006 to 2015. We set the intervention point at the fourth quarter of 2011, when traditional controlled-release oxycodone was removed from the Canadian market. RESULTS: We observed an increase in the risk of admissions for infective endocarditis related to injection drug use during the study period. Before the intervention point, we observed a mean of 13.4 admissions per quarter, and after the intervention, we observed a mean of 35.1 admissions per quarter. However, no significant change in this risk occurred at the intervention point. Rather, the risk of infectious endocarditis appeared to have increased earlier and in parallel with the rise in hydromorphone prescriptions. Hydromorphone represented 16% of all opioid prescriptions at the start of the observation period and 53% by the end. INTERPRETATION: The risk of infective endocarditis related to injection drug use is increasing and is temporally associated with increasing prescriptions for hydromorphone. This relation warrants further exploration.

Because antiretroviral therapy (ART) is allowing people living with human immunodeficiency virus (PLWH) to survive longer, they are developing more age-related comorbidities. We evaluated the effects of age and gender on the burden of age-related comorbidities among PLWH. In this retrospective real-world study, de-identified data were extracted from the medical charts of 2000 HIV-positive adults on ART across 10 sites in Canada. The prevalence of age-related comorbidities was determined in 6 age subgroups (30, 30-39, 40-49, 50-59, 60-69, and ≥70 years). The effects of gender on these comorbidities were also examined. Risks of cardiovascular disease and chronic kidney disease (CKD) were calculated using the Framingham and D:A:D equations. Most persons were White (68%), male (87%), and virologically suppressed (94%). The mean age was 50.3 years (57% aged ≥50 years), and mean CD4+ T-cell count was 616 cells/mm3. The most common comorbidities were neuropsychiatric symptoms (61%), overweight/obesity (43%), liver disease (37%), and dyslipidemia (37%). The mean number of comorbidities increased across age subgroups (P.001). Across all age subgroups, the prevalence of hypertension (P = .04), dyslipidemia (P = .04), CKD (P = .03), bone fragility (P = .03), and depression (P = .02) differed between males and females. Both age (P.001) and gender (P.001) impacted cardiovascular disease and CKD risk. Age and gender influenced the burden, types, and risks of age-related comorbidities in PLWH in this Canadian cohort. These comorbidities should be diagnosed and treated in routine clinical practice.

ObjectivesMany studies suggest that infective endocarditis (IE) in people who inject drugs is predominantly right sided, while other studies suggest left sided disease; few have differentiated by class of drug used. We hypothesised that based on differing physiological mechanisms, opioids but not stimulants would be associated with right sided IE.MethodsA retrospective case series of 290 adult (age ≥18) patients with self-reported recent injection drug use, admitted for a first episode of IE to one of three hospitals in London Ontario between April 2007 and March 2018, stratified patients by drug class used (opioid, stimulant or both), and by site of endocarditis. Other outcomes captured included demographics, causative organisms, cardiac and non-cardiac complications, referral to addiction services, medical versus surgical management, and survival.ResultsOf those who injected only opioids, 47/71 (69%) developed right-sided IE, 17/71 (25%) developed left-sided IE and 4/71 (6%) had bilateral IE. Of those who injected only stimulants, 11/24 (46%) developed right-sided IE, 11/24 (46%) developed left-sided IE and 2/24 (8%) had bilateral IE. Relative to opioid-only users, stimulant-only users were 1.75 (95% CI 1.05 to 2.93; p=0.031) times more likely to have a left or bilateral IE versus right IE.ConclusionsWhile injection use of opioids is associated with a strong predisposition to right-sided IE, stimulants differ in producing a balanced ratio of right and left-sided disease. As the epidemic of crystal methamphetamine injection continues unabated, the rate of left-sided disease, with its attendant higher morbidity and mortality, may also grow.

4553 Background: The treatment landscape of metastatic renal cell carcinoma (mRCC) has evolved with the advent of either dual immune checkpoint inhibition (ICI) or in combination with Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor. Gut microbiota plays a central role in developing local and systemic immunity, with potential influence in controlling anti-tumor immune response in cancer patients treated with ICI. We hypothesize that FMT from healthy donors given before immunotherapy will establish a more resilient gut microbiota, reducing the treatment toxicity and improving response to therapy. PERFORM is an ongoing phase I study evaluating the safety of FMT and immunotherapy combination in first-line (1L) mRCC, and assessing whether FMT will prevent or mitigate immune-related adverse events (irAE). Methods: Eligible patients with untreated mRCC received a full dose and 2 supportive FMT procedures prior to the first 3 cycles of doublet ICI or in combination with VEGF-TKI. Primary endpoint is the feasibility and safety of combining FMT using intestinal bacteria existing in the stool of healthy donors with immunotherapy. Secondary endpoints include incidence of irAEs, objective response rate (ORR; RECIST v1.1), and changes in pts microbiome and immune profile post-FMT. We included a preliminary analysis of the first 10 patients. Results: 10 patients received FMT and doublet ICI therapy (10 ongoing). 8/10 (80%) patients were male. Median Age: 59.5 (53-71) years-old. Most common histology was clear cell RCC (90%) and all patients had an intermediate or poor-risk disease. 93.3% of planned FMT were administered. No dose-limiting toxicities due to FMT were observed. Median (range) follow-up was 5.5 (1–22) months. 4 patients (40%) discontinued treatment due to irAEs: colitis (n = 3), arthritis (n = 1). IrAEs were reported in 8 (80%) patients, including diarrhea (n = 6; 60%) and skin rash (n = 2, 20%). Grade 3/4 AEs were experienced by 6 (60%) patients, including colitis (n = 4, 40%). ORR was confirmed in 4/9 patients (44%; 95% CI, 30–60); 1 (11%) partial response. Microbiota and immune analysis data to be presented. Conclusions: The role of microbiome modification in preventing immune-related toxicities by adding FMT to ICI therapy was associated with a safety profile in unselected 1L mRCC and promising clinical efficacy data. Further prospective studies to examine the changes in the immune and microbiota profiles to determine biomarkers related to healthy outcomes/less frequent toxicities in patients receiving immunotherapy are warranted. Clinical trial information: NCT04163289.

Development of transcatheter mitral valve interventions has ushered a significant need for large animal models of secondary mitral regurgitation. Though currently used heart failure models that chronically develop secondary mitral regurgitation are viable, the severity is lower than patients, the incubation time is long, and mortality is high. We sought to develop a swine model of acute secondary mitral regurgitation that uses image-guided placement of snares around the mitral chordae. Twenty-seven adult swine (n = 27) were assigned to secondary mitral regurgitation induced by valve tethering with image-guided chordal encircling snares (group 1, n = 7, tether MR (tMR)); secondary mitral regurgitation by percutaneous posterolateral myocardial infarction causing ventricular dysfunction and regurgitation (group 2, n = 6, functional MR (fMR)); and control animals (group 3, n = 14). Regurgitant fraction in tMR was 42.1 ± 14.2%, in fMR was 22 ± 9.6%, and in controls was 5.3 ± 3.8%. Mitral tenting height was 9.6 ± 1.3 mm in tMR, 10.1 ± 1.5 mm in fMR, and 5.8 ± 1.2 mm in controls. Chordal encircling tethers reproducibly induce clinically relevant levels of secondary mitral regurgitation, providing a new animal model for use in translational research.

Objective: Postpartum depression (PPD) is a prevalent disorder that can result in negative child developmental outcomes. While a maternal history of unipolar depression is understood to be the larg...

Importance People who inject drugs (PWID) who are being treated for infective endocarditis remain at risk of new bloodstream infections (BSIs) due to ongoing intravenous drug use (IVDU). Objectives To characterize new BSIs in PWID receiving treatment for infective endocarditis, to determine the clinical factors associated with their development, and to determine whether new BSIs and treatment setting are associated with mortality. Design, Setting, and Participants This retrospective cohort study was performed at 3 tertiary care hospitals in London, Ontario, Canada, from April 1, 2007, to March 31, 2018. Participants included a consecutive sample of all PWID 18 years or older admitted with infective endocarditis. Data were analyzed from April 1, 2007, to June 29, 2018. Main Outcomes and Measures New BSIs and factors associated with their development, treatment setting of infective endocarditis episodes (ie, inpatient vs outpatient), and 90-day mortality. Results The analysis identified 420 unique episodes of infective endocarditis in 309 PWID (mean [SD] patient age, 35.7 [9.7] years; 213 episodes [50.7%] involving male patients), with 82 (19.5%) complicated by new BSIs. There were 138 independent new BSIs, of which 68 (49.3%) were polymicrobial and 266 were unique isolates. Aerobic gram-negative bacilli (143 of 266 [53.8%]) andCandidaspecies (75 of 266 [28.2%]) were the most common microorganisms. Ongoing inpatient IVDU was documented by a physician in 194 infective endocarditis episodes (46.2%), and 127 of these (65.5%) were confirmed by urine toxicology results. Multivariable time-dependent Cox regression demonstrated that previous infective endocarditis (hazard ratio [HR], 1.89; 95% CI, 1.20-2.98), inpatient treatment (HR, 4.49; 95% CI, 2.30-8.76), and physician-documented inpatient IVDU (HR, 5.07; 95% CI, 2.68-9.60) were associated with a significantly higher rate of new BSIs, whereas inpatient addiction treatment was associated with a significantly lower rate (HR, 0.53; 95% CI, 0.32-0.88). New BSIs were not significantly associated with 90-day mortality (HR, 1.76; 95% CI, 0.78-4.02); significant factors associated with mortality included inpatient infective endocarditis treatment (HR, 3.39; 95% CI, 1.53-7.53), intensive care unit admission (HR, 9.51; 95% CI, 4.91-18.42), and methicillin-resistantStaphylococcus aureusinfective endocarditis (HR, 1.77; 95% CI, 1.03-3.03), whereas right-sided infective endocarditis was associated with a significantly lower mortality rate (HR, 0.41; 95% CI, 0.25-0.67). Conclusions and Relevance In this study, new BSIs were common in PWID receiving parenteral treatment for infective endocarditis. Discharging patients to outpatient treatment was not associated with an increase in new BSI incidence or mortality; carefully selected PWID may therefore be considered for such treatment.

COVID-19 mitigation strategies have led to widespread school closures around the world. Initially, these were undertaken based on data from influenza outbreaks in which children were highly susceptible and important in community-wide transmission. An argument was made that school closures were necessary to prevent harm to vulnerable adults, especially the elderly. Although data are still accumulating, the recently described complication, pediatric multisystem inflammatory syndrome, is extremely rare and children remain remarkably unaffected by COVID-19. We also do not have evidence that children are epidemiologically important in community-wide viral spread. Previous studies have shown long-term educational, social, and medical harms from school exclusion, with very young children and those from marginalized groups such as immigrants and racialized minorities most affected. The policy and ethical implications of ongoing mandatory school closures, in order to protect others, need urgent reassessment in light of the very limited data of public health benefit.

Introduction Nonalcoholic fatty liver disease (NAFLD) is an obesity-related disorder that is rapidly increasing in incidence and is considered the hepatic manifestation of the metabolic syndrome. The gut microbiome plays a role in metabolism and maintaining gut barrier integrity. Studies have found differences in the microbiota between NAFLD and healthy patients and increased intestinal permeability in patients with NAFLD. Fecal microbiota transplantation (FMT) can be used to alter the gut microbiome. It was hypothesized that an FMT from a thin and healthy donor given to patients with NAFLD would improve insulin resistance (IR), hepatic proton density fat fraction (PDFF), and intestinal permeability. Methods Twenty-one patients with NAFLD were recruited and randomized in a ratio of 3:1 to either an allogenic (n = 15) or an autologous (n = 6) FMT delivered by using an endoscope to the distal duodenum. IR was calculated by HOMA-IR, hepatic PDFF was measured by MRI, and intestinal permeability was tested using the lactulose:mannitol urine test. Additional markers of metabolic syndrome and the gut microbiota were examined. Patient visits occurred at baseline, 2, 6 weeks, and 6 months post-FMT. Results There were no significant changes in HOMA-IR or hepatic PDFF in patients who received the allogenic or autologous FMT. Allogenic FMT patients with elevated small intestinal permeability (>0.025 lactulose:mannitol, n = 7) at baseline had a significant reduction 6 weeks after allogenic FMT. Discussion FMT did not improve IR as measured by HOMA-IR or hepatic PDFF but did have the potential to reduce small intestinal permeability in patients with NAFLD.

For patients hospitalized with severe influenza A virus infection, morbidity and mortality remain high. MHAA4549A, a human monoclonal antibody targeting the influenza A virus hemagglutinin stalk, has demonstrated pharmacological activity in animal studies and in a human influenza A challenge study. We evaluated the safety and efficacy of MHAA4549A plus oseltamivir against influenza A virus infection in hospitalized patients. The CRANE trial was a phase 2b randomized, double-blind, placebo-controlled study of single intravenous (i., For patients hospitalized with severe influenza A virus infection, morbidity and mortality remain high. MHAA4549A, a human monoclonal antibody targeting the influenza A virus hemagglutinin stalk, has demonstrated pharmacological activity in animal studies and in a human influenza A challenge study. We evaluated the safety and efficacy of MHAA4549A plus oseltamivir against influenza A virus infection in hospitalized patients. The CRANE trial was a phase 2b randomized, double-blind, placebo-controlled study of single intravenous (i.v.) doses of placebo, 3,600 mg MHAA4549A, or 8,400 mg MHAA4549A each combined with oral oseltamivir (+OTV) in patients hospitalized with severe influenza A virus infection. Patients, enrolled across 68 clinical sites in 18 countries, were randomized 1:1:1. The primary outcome was the median time to normalization of respiratory function, defined as the time to removal of supplemental oxygen support to maintain a stable oxygen saturation (SpO2) of ≥95%. Safety, pharmacokinetics, and effects on influenza viral load were also assessed. One hundred sixty-six patients were randomized and analyzed during a preplanned interim analysis. Compared to placebo+OTV, MHAA4549A+OTV did not significantly reduce the time to normalization of respiratory function (placebo+OTV, 4.28 days; 3,600 mg MHAA4549A+OTV, 2.78 days; 8,400 mg MHAA4549A+OTV, 2.65 days), nor did it improve other secondary clinical outcomes. Adverse event frequency was balanced across cohorts. MHAA4549A+OTV did not further reduce viral load versus placebo+OTV. In hospitalized patients with influenza A virus infection, MHAA4549A did not improve clinical outcomes over OTV alone. Variability in patient removal from oxygen supplementation limited the utility of the primary endpoint. Validated endpoints are needed to assess novel treatments for severe influenza A virus infection. (This study has been registered at ClinicalTrials.gov under registration no. NCT02293863.)

BackgroundCombination antiretroviral therapy (cART) during pregnancy prevents vertical transmission, but many antiretrovirals cross the placenta and several can affect mitochondria. Exposure to maternal human immunodeficiency virus (HIV) and/or cART could have long-term effects on children who are HIV exposed and uninfected (CHEU). Our objective was to compare blood mitochondrial DNA (mtDNA) content in CHEU and children who are HIV unexposed and uninfected (CHUU), at birth and in early life.MethodsWhole-blood mtDNA content at birth and in early life (age 0–3 years) was compared cross-sectionally between CHEU and CHUU. Longitudinal changes in mtDNA content among CHEU was also evaluated.ResultsAt birth, CHEU status and younger gestational age were associated with higher mtDNA content. These remained independently associated with mtDNA content in multivariable analyses, whether considering all infants, or only those born at term. Longitudinally, CHEU mtDNA levels remained unchanged during the first 6 months of life, and gradually declined thereafter. A separate age- and sex-matched cross-sectional analysis (in 214 CHEU and 214 CHUU) illustrates that the difference in mtDNA between the groups remains detectable throughout the first 3 years of life.ConclusionThe persistently elevated blood mtDNA content observed among CHEU represents a long-term effect, possibly resulting from in utero stresses related to maternal HIV and/or cART. The clinical impact of altered mtDNA levels is unclear.

Background Approximately 25% of outpatient antibiotic prescriptions are unnecessary among family physicians in Canada. Minimizing unnecessary antibiotics is key for community antibiotic stewardship. However, unnecessary antibiotic prescribing is much harder to measure than total antibiotic prescribing. We investigated the association between total and unnecessary antibiotic use by family physicians and evaluated inter-physician variability in unnecessary antibiotic prescribing. Methods This was a cohort study based on electronic medical records of family physicians in Ontario, Canada, between April 2011 and March 2016. We used predefined expected antibiotic prescribing rates for 23 common primary care conditions to calculate unnecessary antibiotic prescribing rates. We used multilevel Poisson regression models to evaluate the association between total antibiotic volume (number of antibiotic prescriptions per patient visit), adjusted for multiple practice- and physician-level covariates, and unnecessary antibiotic prescribing. Results There were 499 570 physician–patient encounters resulting in 152 853 antibiotic prescriptions from 341 physicians. Substantial inter-physician variability was observed. In the fully adjusted model, we observed a significant association between total antibiotic volume and unnecessary prescribing rate (adjusted rate ratio 2.11 per 10% increase in total use; 95% CI 2.05–2.17), and none of the practice- and physician-level variables were associated with unnecessary prescribing rate. Conclusions We demonstrated substantial inter-physician variability in unnecessary antibiotic prescribing in this cohort of family physicians. Total antibiotic use was strongly correlated with unnecessary antibiotic prescribing. Total antibiotic volume is a reasonable surrogate for unnecessary antibiotic use. These results can inform community antimicrobial stewardship efforts.

Background Checkpoint inhibitors have changed the outcomes for patients with advanced melanoma. However, many patients still show primary resistance to single-agent therapy. Recently, the role of the gut microbiome in influencing antitumor immunity has been established. Currently, various methods of modifying the gut microbiome of cancer patients are being explored. We report the initial safety results of the first two patients treated on a phase I study combining Fecal Microbiota Transplantation (FMT) with single-agent anti-PD1 in treatment-naive patients with advanced melanoma. Methods Two healthy donors were selected through our screening process and approximately 100 grams of fresh stool was processed and prepared for FMT as per our standardized protocol. FMT recipients were melanoma patients with unresectable or metastatic disease who were treatment naive for their advanced disease. Bowel preparation was completed the day prior and FMT was performed using oral administration of approximately 40 capsules. Anti-PD1 was started at least 1 week after FMT to allow for microbiome engraftment. Blood and stool were analyzed at baseline (pre-FMT), before immunotherapy, and three weeks after it. Results Patient 1 was diagnosed with recurrent melanoma of the lower limb with multiple in-transit lesions refractory to control with surgery and a single intralesional injection of IL-2. Patient received stool from Donor 1 and did not experience any adverse effects from FMT. At the time of treatment #4, a solitary large cutaneous lesion stabilized but the patient experienced grade 1 diarrhoea, grade 2 nausea, and grade 2 fatigue, and grade 2 depression (NCI-CTCAE v5.0). Patient 2 was diagnosed with recurrent melanoma of the parotid gland with metastatic lesions in the lungs. Patient 2 received stool from Donor 2 and experienced only grade 1 flatus from FMT. At the time of treatment #3, the patient experienced grade 1 constipation. Both patients had a vigorous immune response to FMT measured by changes in the immune subpopulations in peripheral blood one week after FMT, including an increase in CD28+ CD8+ T cells and a decrease in PDL1+ CD3- cells. Following anti-PD1 therapy, both patients had an increase in CD39+ CD8+ T cell population. The PD1+ CD38+ CD8+ dysfunctional T cell levels decreased in both patients post-FMT and anti-PD1 therapy. Conclusions FMT combined with anti-PD1 therapy in patients with advanced melanoma appears to be safe. A measurable immune response was observed one week after FMT in both patients. One patient experienced several grade 2 toxicities with stabilization of a large cutaneous lesion. Acknowledgements This study is funded by a grant from The Lotte & John Hecht Memorial Foundation and a grant from The Medical Oncology Research Funds (MORF) from Western University. Trial Registration NCT03772899 Ethics Approval The study was approved by Western University Institutution‘s Ethics Board, approval number 113131, date of approval March 15, 2019.

Background Ibezapolstat, a DNA polymerase IIIC inhibitor, currently in Phase 2 clinical development for treatment of C. difficile infection (CDI). Its unique mechanism of action targets low G+C content Gram-positive bacteria primarily Firmicutes including C. difficile. Phase I healthy volunteer results demonstrated a favorable microbiome profile suggestive of an anti-recurrence effect. The purpose of this study was to report clinical outcomes, pharmacokinetics, and microbiome changes from this Phase 2a clinical study and to continue to test for anti-recurrence microbiome properties. Methods Ibezapolstat 450 mg was given twice daily for 10 days to patients with mild-moderate CDI defined as diarrhea plus a positive C. difficile toxin test. Test of cure was evaluated at day 12 and sustained clinical cure at day 38. Stool samples were evaluated for C. difficile cultures and microbiome changes. Results Ten subjects (female: 50%) aged 50 ±15 years were enrolled. All ten subjects experienced a clinical cure by the test of cure visit at day 12 and all 10 subjects experienced a sustained clinical cure at the day 38 visit. Ibezapolstat was well tolerated with 1 adverse event (nausea) probably related to drug. Ibezapolstat systemic exposure was minimal with no plasma level reaching 1 ug/mL any time during therapy. Ibezapolstat colonic concentrations averaged 400 ug/g stool at day 3 and greater than 1,000 ug/g by day 10 of dosing. Six of the seven available baseline stool samples grew toxigenic C. difficile of various ribotypes including RT078-226 and RT014-020 (Ibezapolstat MIC range: 0.25-1 ug/mL). Follow-up cultures were no growth starting from day 3 stool cultures. Microbiome changes included overgrowth of Actinobacteria and/or Firmicute phylum species while on therapy. Conclusion Favorable clinical efficacy and safety results were observed in ibezapolstat patients with CDI including 100% clinical cure and sustained clinical cure. These results begin to validate our approach to ibezapolstat development in that the favorable microbiome effects seen in healthy Phase 1 volunteers may be predictive of beneficial patient outcomes, including low rates of recurrence. These results support the continued clinical development of ibezapolstat. Disclosures Kevin W. Garey, Pharm.D., M.S., FASHP, Summit Therapeutics (Research Grant or Support) Michael Silverman, MD, Acurx Pharmaceuticals (Consultant)

The COVID-19 pandemic has led to an exponential increase in SARS-CoV-2 infections and associated deaths, and represents a significant challenge to healthcare professionals and facilities. Individual countries have taken several prevention and containment actions to control the spread of infection, including measures to guarantee safety of both healthcare professionals and patients who are at increased risk of infection from COVID-19. Faecal microbiota transplantation (FMT) has a well-established role in the treatment of Clostridioides difficile infection. In the time of the pandemic, FMT centres and stool banks are required to adopt a workflow that continues to ensure reliable patient access to FMT while maintaining safety and quality of procedures. In this position paper, based on the best available evidence, worldwide FMT experts provide guidance on issues relating to the impact of COVID-19 on FMT, including patient selection, donor recruitment and selection, stool manufacturing, FMT procedures, patient follow-up and research activities.

Background Antimicrobials remain among the most prescribed medications in Canada, with over 90% prescribed in outpatient settings. Older adults (aged ≥65 years) prescribed antimicrobials are particularly vulnerable to adverse drug events and antimicrobial resistance. This study compared annual rates of indication-associated, outpatient prescribing to seniors across two Canadian provinces. Methods All outpatient, oral antimicrobials dispensed to older adults (≥65 years) were identified from administrative health databases, from 2000 to 2018. Antimicrobials were limited to outpatient use only and linked to an indication using a 3-tiered diagnostic hierarchy. When possible, a record of dispensation was matched to a tier 1 indication (always require antibiotics) first. In the absence of a tier 1 indication, priority was given to tier 2 (sometimes require antibiotics), then 3 (never require antibiotics). Prescription rates were calculated per 1000 population, and trends were examined overall, by drug class, and patient demographics. Results Our study included over 18 million individuals (aged ≥65 years) with a total of 23,773,552 antibiotic prescriptions issued to seniors, for common infections. In both provinces, prescribing for tier 1 diagnoses increased over the study period (BC: 44%; ON: 28%). Urinary tract infections accounted for most prescriptions within this tier (ON: 89 prescriptions/1000, BC: 129 prescriptions/1000 population by 2018). Pneumonia-associated prescribing increased by roughly 10% in both provinces. In any given study year, for both provinces, tier 3 diagnosis was the most common reason for antibiotic use, accounting for 50% of all indication-associated antibiotic prescribing. As diagnoses within this tier do not warrant prescribing all antibiotics issued are therefore inappropriate prescriptions. Figure 1. Rates of indication-associated antibiotic use in Canadian seniors, from 2000 to 2018. Conclusion Elevated prescribing to seniors continues across Canadian outpatient settings. Antibiotic prescribing remains an issue of high concern with 50% of all antimicrobials prescribed to seniors, for common infections, used inappropriately. Disclosures All Authors: No reported disclosures

Jeffrey Man Hay Wong,1 Neha Kanga,1 Nupur Dogra,1 Mary Shilalukey Ngoma,2 Lena Serghides,3 Michael Silverman4 1Faculty of Medicine, University of Toronto, Toronto, ON, Canada; 2Department of Pediatrics, University of Zambia, Lusaka, Zambia; 3Toronto General Research Institute, University Health Network, Toronto, ON, Canada; 4Department of Infectious Diseases, Western University, London, ON, Canada Introduction: Intramuscular and vaginal progesterone are recommended for prevention of preterm labor (PTL) in women with risk factors. Studies are emerging to indicate that HIV-infected women on combination antiretroviral therapy (cART) are at risk of PTL and low birth weight (LBW), and may benefit from supplemental progesterone. This study aims to determine the perceived acceptability of various modes of progesterone supplementation to prevent PTL and LBW in HIV-infected and HIV-uninfected women.Methods: HIV-infected and HIV-uninfected women were recruited in Lusaka, Zambia. The participants completed a questionnaire to assess their willingness to take oral, vaginal, or intramuscular progesterone supplementation for preventing PTL and LBW, preferred modes of supplementation, and concern for PTL and LBW.Results: The study questionnaire was completed by 147 participants. Of the participants, 98.6% would consider using a medication to help prevent PTL and LBW, of whom 97.9% would consider using an oral form of progesterone.In addition, 83.3% and 84.0% of women would consider intramuscular and vaginal (gel or tablet) administration of progesterone respectively. Between intramuscular and vaginal modes of progesterone, 60.5% of participants (n=147) preferred intramuscular progesterone, while 39.5% preferred vaginal progesterone. There was no difference in preference between HIV-infected (n=70) and HIV-uninfected (n=77) women.Conclusions/implications: Pregnant Zambian women demonstrated a high degree of acceptance for all modes of progesterone supplementation for the prevention of PTL and LBW. Women preferred intramuscular over vaginal supplementation. Progesterone supplementation can be considered a feasible intervention for preventing PTL and LBW in both HIV-infected and HIV-uninfected pregnant Zambian women. Keywords: HIV/AIDS, progesterone, preterm labor, low birth weight, global health

KEY POINTS A 52-year-old man in a long-term, same-gender sexual relationship presented with agitation, confusion and problems speaking for about two weeks. On assessment, his vital signs were normal, but he was agitated and had global aphasia. No other focal deficits were identified on a screening

The purpose of this exploratory study was to examine the effects of legal name change on socioeconomic factors, general and transgender-related healthcare access and utilization, and transgender-related victimization in a sample of young transgender women (transwomen) of color. A cross-sectional group comparison approach was used to assess the potential effects of legal name change. A convenience sample of young transwomen enrolled in a no-cost legal name change clinic were recruited to complete a 30-minute interviewer-guided telephone survey including sociodemographic and socioeconomic factors, health and well-being, health care utilization, transgender transition-related health care, and transgender-related victimization. Sixty-five transgender women of color (37 = pre-name change group; 28 = post-name change group) completed the survey. Results indicated that the transwomen in the post-name change group were significantly older than the pre-name change group. In age-adjusted analyses, the post-name change group was significantly more likely to have a higher monthly income and stable housing than the pre-name change group. No significant differences were observed for general healthcare utilization; however, a significantly greater percentage of transwomen in the pre-name change group reported postponing medical care due to their gender identity. In addition, a significantly larger proportion of transwomen in the pre-name change group reported using non-prescribed hormones injected by friends and experiencing verbal harassment by family and friends compared to transwomen in the post-name change group. Findings suggest that legal name change may be an important structural intervention for low-income transwomen of color, providing increased socioeconomic stability and improved access to primary and transition-related health care.

Three hospital emergency rooms (ERs) routinely referred all cases of cellulitis requiring outpatient intravenous antibiotics, to a central ER-staffed cellulitis clinic. We performed a retrospective cohort study of all patients seen by the ER clinic in the last 4months preceding a policy change (ER management cohort [ERMC]) (n=149) and all those seen in the first 3months of a new policy of automatic referral to an infectious disease (ID) specialist-supervised cellulitis clinic (ID management cohort [IDMC]) (n=136). Fifty-four (40%) of 136 patients in the IDMC were given an alternative diagnosis (noncellulitis), compared to 16 (11%) of 149 in the ERMC (P0.0001). Logistic regression-demonstrated rates of disease recurrence were lower in the IDMC than the ERMC (hazard ratio [HR], 0.06; P=0.003), as were rates of hospitalization (HR, 0.11; P=0.01). There was no significant difference in mortality. Automatic ID consultation for cellulitis was beneficial in differentiating mimickers from true cellulitis, reducing recurrence, and preventing hospital admissions.

Purpose: The purpose of this study was to explore individual and structural factors associated with employment among young transgender women (TW) of color. Methods: Sixty-five trans women of color were recruited from the Transgender Legal Defense and Education Fund to complete a 30-min interviewer-assisted survey assessing sociodemographics, housing, workplace discrimination, job-seeking self-efficacy, self-esteem, perceived public passability, and transactional sex work. Results: Logistic regression models revealed that stable housing (structural factor) and job-seeking self-efficacy (individual factor) were significantly associated with currently being employed. Conclusion: Our findings underscore the need for multilevel approaches to assist TW of color gain employment.

Background Postpartum depression (PPD) can result in negative personal and child developmental outcomes. Only a few large population-based studies of PPD have used clinical diagnoses of depression and no study has examined how a maternal depression history interacts with known risk factors. The objective of this study was to examine the impact of a depression history on PPD and pre- and perinatal risk factors. Methods A nationwide prospective cohort study of all women with live singleton births in Sweden from 1997 through 2008 was conducted. Relative risk (RR) of clinical depression within the first year postpartum and two-sided 95% confidence intervals were estimated. Results The RR of PPD in women with a history of depression was estimated at 21.03 (confidence interval: 19.72–22.42), compared to those without. Among all women, PPD risk increased with advanced age (1.25 (1.13–1.37)) and gestational diabetes (1.70 (1.36–2.13)). Among women with a history of depression, pregestational diabetes (1.49 (1.01–2.21)) and mild preterm delivery also increased risk (1.20 (1.06–1.36)). Among women with no depression history, young age (2.14 (1.79–2.57)), undergoing instrument-assisted (1.23 (1.09–1.38)) or cesarean (1.64(1.07–2.50)) delivery, and moderate preterm delivery increased risk (1.36 (1.05–1.75)). Rates of PPD decreased considerably after the first postpartum month (RR = 0.27). Conclusion In the largest population-based study to date, the risk of PPD was more than 20 times higher for women with a depression history, compared to women without. Gestational diabetes was independently associated with a modestly increased PPD risk. Maternal depression history also had a modifying effect on pre- and perinatal PPD risk factors.

Data are lacking on factors that may impact conception-related decision-making among individuals living with HIV. This study’s aim was to shed light on these considerations. Participants were invited to complete a survey on preconception considerations. A rank-ordered logit model was fit to estimate the relative importance of listed consideration factors; the interaction of HIV status and the factors was assessed. Fifty-nine participants living with HIV and 18 partners (11 HIV-negative participants and 7 living with HIV) were included. Risk of vertical and horizontal HIV transmission and the effect of antiretroviral therapy on the fetus were the top considerations. However, individuals living with HIV prioritized vertical transmission, whereas HIV-negative participants prioritized horizontal transmission. Other factors of importance were probability of conception, stress of trying to conceive, cost associated with fertility clinics, and stigma associated with certain conception methods. This study builds our understanding of the preconception considerations for people living with HIV.

Background: The gut microbiome, which consists of a highly diverse ecologic community of micro-organisms, has increasingly been studied regarding its role in multiple sclerosis (MS) immunopathogenesis. This review critically examines the literature investigating the gut microbiome in MS. Methods: A comprehensive search was performed of PubMed databases and ECTRIMS meeting abstracts for literature relating to the gut microbiome in MS. Controlled studies examining the gut microbiome in patients with MS were included for review. Results: Identified studies were predominantly case-control in their design and consistently found differences in the gut microbiome of MS patients compared to controls. We examine plausible mechanistic links between these differences and MS immunopathogenesis, and discuss the therapeutic implications of these findings. Conclusions: Review of the available literature reveals potential immunopathogenic links between the gut microbiome and MS, identifies avenues for therapeutic advancement, and emphasizes the need for further systematic study in this emerging field.

In Reconstructing Jerusalem Ristau provides a thesis for the development of the centrality of Jerusalem while Yehud was within the Persian Empire. He constructs this picture on the basis of a revie...

Background Infective endocarditis (IE) is increasing among persons who inject drugs (PWID) and has high morbidity and mortality. Recurrent IE in PWID is not well described. Methods This was a retrospective cohort study conducted between February 2007 and March 2016. It included adult inpatients (≥18) at any of 3 tertiary care centers in London, Ontario, with definite IE based on the Modified Duke's Criteria. The objectives were to characterize recurrent IE in PWID, identify risk factors for recurrent IE, identify the frequency of fungal endocarditis, and establish whether fungal infection was associated with higher mortality. Results Three hundred ninety patients had endocarditis, with 212/390 in PWID. Sixty-eight of 212 (32%) PWID had a second episode, with 28/212 (12%) having additional recurrences. Second-episode IE was more common in PWID (11/178 [6.2%] vs 68/212 [32.1%]; P < .001). Peripherally inserted central catheter (PICC) line abuse was associated with increased risk of recurrent endocarditis (odds ratio [OR], 1.97; 95% confidence interval [CI], 1.01–3.87; P = .04). In PWID, fungal IE was more common in second episodes than first episodes (1/212 [0.5%] vs 5/68 [7.4%]; P = .004). Additionally, fungal infections were associated with mortality in second-episode IE in PWID with an adjusted OR of 16.49 (95% CI, 1.12–243.17; P = .041). Despite recurrent infection, likely due to continued drug use, there was a low rate of referral to addiction treatment (14/68 [20.6%]). Conclusions PWID have a high risk of recurrent endocarditis, particularly in patients who abuse PICC lines. Fungal endocarditis is more common in second-episode endocarditis and is associated with increased mortality. Consideration of empiric antifungal therapy in PWID with IE history and suspected IE should be considered.

Background: People living with HIV treated with antiretroviral therapy (ART) are now living longer and thus many are requiring surgical procedures. For healthcare resource planning, it would be helpful to better understand the prevalence of HIV in surgical patients, the types of surgery HIV-positive patients are undergoing and whether HIV status impacts mortality. Objective: The goal of this study was to determine the prevalence of HIV in surgical inpatients and the extent of ART coverage, as well as to assess any differences between HIV-positive and HIV-negative patients in type of surgery undergone and in-hospital mortality at Karanda Mission Hospital, Mount Darwin, Zimbabwe. Method: A 1-year retrospective chart review was undertaken to collect clinical and demographic data for adult (excluding maternity cases) and paediatric surgical inpatients including age, sex, type of surgery, HIV status, CD4+ counts and, if patient was HIV-positive, whether he or she was taking ART. Results and conclusion : Charts for 1510 surgical inpatient stays were reviewed. HIV prevalence among the adults was higher than that in the general population in Zimbabwe in 2016 (23.2% vs. 14.7%). There was no significant difference in inpatient mortality between the HIV-negative group and the HIV-positive group. Within the group of patients with malignancies, people living with HIV were significantly younger than uninfected patients (mean age 50.5 vs. 64.4 years; p < 0.01). There were correlations between HIV and certain malignancies. Thus, in addition to AIDS-defining illnesses, clinicians must be alert to squamous cell carcinoma and oesophageal, anal and penile cancers in HIV-positive patients.

BACKGROUND Colon ischaemia is a common disease which has been associated with various medications and comorbidities. AIM To test the hypothesis that there are differences in the frequencies of these associations in older compared with younger patients. METHODS A retrospective cohort study was performed of patients hospitalized with colon ischaemia at two major medical centres from 2005-2017. Clinical, colonoscopic and pathologic criteria were used to identify patients admitted with colon ischaemia; patients with other types of colitis were excluded. Demographic and medical data were extracted. Two cohorts were created: patients aged 18-64 years and patients > 65 years. These were compared using SAS 14.3. RESULTS A total of 788 patients were included, of which 271 (34.4%) were of ages 18-64 years, and 517 (66.6%) were 65 years old or older. In the older cohort, constipation-inducing medications (83.8% vs 64.1%; P =

Background: For patients hospitalized with severe influenza A, morbidity and mortality remain high. MHAA4549A, a human monoclonal antibody targeting the influenza A hemagglutinin stalk, has demonstrated pharmacological activity in animal studies and in a human influenza A challenge study. We evaluated the safety and efficacy of MHAA4549A plus oseltamivir (OS) against influenza A infection in hospitalized patients. Methods: The CRANE trial was a phase 2b, randomized, double-blind, placebocontrolled study of single intravenous (IV) doses of placebo, 3600-mg, or 8400-mg MHAA4549A, all in combination with oral oseltamivir (+OS) in patients hospitalized with severe influenza A. Patients were enrolled across 68 clinical sites in 18 countries and randomized 1:1:1 into the three cohorts. The primary endpoint was the median time to normalization of respiratory function defined as the time to removal of supplemental oxygen support to maintain a stable SpO2 ≥ 95%. Findings: 166 patients were randomized and analyzed during a preplanned interim analysis (placebo+OS: 56; 3600-mg MHAA4549A+OS: 55; 8400-mg MHAA4549A+OS: 47). Compared to placebo+OS, MHAA4549A+OS did not significantly affect the time to normalization of respiratory function (placebo+OS: 4·28 days (80% CI: 3·06, 6·60); 3600-mg MHAA4549A+OS: 2·78 days (80% CI: 2·52, 4·20); 8400-mg MHAA4549A+OS: 2·65 days (80% CI: 1·58, 4·52). Patient deaths comprised 4 of 9, 6 of 13, and 4 of 9 study discontinuations in each of those treatment arms, respectively. Frequency of adverse events between treatment arms was not significantly different (placebo+OS: 45 (80·4%); 3600-mg MHAA4549A+OS: 37 (67·3%); 8400-mg MHAA4549A+OS: 35 (74·5%)). Interpretation: In hospitalized patients with influenza A, MHAA4549A did not improve clinical outcomes over oseltamivir alone. Variability in patient removal from oxygen supplementation limited the utility of the primary endpoint. Validated endpoints are needed to assess novel treatments for severe influenza A. Trial Registration: This completed trial was registered under ClinicalTrials.gov #NCT02293863 and EudraCT #2014- 000461-43. Funding Statement: Genentech, Inc. provided funding for this study. Declaration of Interests: JJL, PK, JMM, RD, CL, XY, AN, PH, MM, AC, MCP, JG, TC, EMN, and JAT were employees of Genentech, Inc., a member of the Roche group, and own/owned Roche stock and/or options at the time this study was performed. Genentech, Inc. provided research funding to the institutions of ACN, MS, and NA for the conduct of this study. AC is currently an employee of Calico Life Sciences, LLC. Ethics Approval Statement: The CRANE trial was conducted in full conformance with the International Council for Harmonisation (ICH) E6 guideline for Good Clinical Practice (GCP) and the principles of the Declaration of Helsinki, or the laws and regulations of the country in which the research is conducted, whichever afforded the greater protection to the individual. The study complied with the requirements of the ICH E2A guideline (Clinical Safety Data Management: Definitions and Standards for Expedited Reporting). Studies conducted in the European Union (EU) or European Economic Area complied with the EU Clinical Trial Directive (2001/20/EC). All patients or their legally authorized representative provided written, informed consent.

Recurring themes and traditions within the biblical corpus have attracted much scholarship. This article uses P. T. Anderson’s Magnolia (1999) as a test case for the ways traditions may or may not interact, and what that means for ‘tradition history.’ While the film has many features which strike many viewers as biblical, the author-director denies prior knowledge of these connections. The film is analyzed in terms of structure, Anderson’s claimed sources, the American cultural context of the 1990s, and its biblical resonances. After assessing the import of these observations, the tradition history of Magnolia is compared to the tradition history of the exodus in the Hebrew Bible. Within the framework of attention to media contexts, the article concludes by noting the importance of authority, canon, and multiple lines of transmission. In so doing, our understanding of the transmission of traditions is problematized, and a broader, less text-centric paradigm is called for.