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.

Variability in changes in physician outpatient antibiotic prescribing from 2019 to 2021 during the COVID-19 pandemic in Ontario, Canada.

Objective: To evaluate inter-physician variability and predictors of changes in antibiotic prescribing before (2019) and during (2020/2021) the coronavirus disease 2019 (COVID-19) pandemic. Methods: We conducted a retrospective cohort analysis of physicians in Ontario, Canada prescribing oral antibiotics in the outpatient setting between January 1, 2019 and December 31, 2021 using the IQVIA Xponent data set. The primary outcome was the change in the number of antibiotic prescriptions between the prepandemic and pandemic period. Secondary outcomes were changes in the selection of broad-spectrum agents and long-duration (>7 d) antibiotic use. We used multivariable linear regression models to evaluate predictors of change. Results: There were 17,288 physicians included in the study with substantial inter-physician variability in changes in antibiotic prescribing (median change of -43.5 antibiotics per physician, interquartile range -136.5 to -5.0). In the multivariable model, later career stage (adjusted mean difference [aMD] -45.3, 95% confidence interval [CI] -52.9 to -37.8, p < .001), family medicine (aMD -46.0, 95% CI -62.5 to -29.4, p < .001), male patient sex (aMD -52.4, 95% CI -71.1 to -33.7, p < .001), low patient comorbidity (aMD -42.5, 95% CI -50.3 to -34.8, p < .001), and high prescribing to new patients (aMD -216.5, 95% CI -223.5 to -209.5, p < .001) were associated with decreases in antibiotic initiation. Family medicine and high prescribing to new patients were associated with a decrease in selection of broad-spectrum agents and prolonged antibiotic use. Conclusions: Antibiotic prescribing changed throughout the COVID-19 pandemic with overall decreases in antibiotic initiation, broad-spectrum agents, and prolonged antibiotic courses with inter-physician variability. These findings present opportunities for community antibiotic stewardship interventions.

Population-based evaluation of the effectiveness of nirmatrelvir-ritonavir for reducing hospital admissions and mortality from COVID-19.

BACKGROUND: A randomized controlled trial involving a high-risk, unvaccinated population that was conducted before the Omicron variant emerged found that nirmatrelvir-ritonavir was effective in preventing progression to severe COVID-19. Our objective was to evaluate the effectiveness of nirmatrelvir-ritonavir in preventing severe COVID-19 while Omicron and its subvariants predominate. METHODS: We conducted a population-based cohort study in Ontario that included all residents who were older than 17 years of age and had a positive polymerase chain reaction test for SARS-CoV-2 between Apr. 4 and Aug. 31, 2022. We compared patients treated with nirmatrelvir-ritonavir with patients who were not treated and measured the primary outcome of hospital admission from COVID-19 or all-cause death at 1-30 days, and a secondary outcome of all-cause death. We used weighted logistic regression to calculate weighted odds ratios (ORs) with confidence intervals (CIs) using inverse probability of treatment weighting (IPTW) to control for confounding. RESULTS: The final cohort included 177 545 patients, 8876 (5.0%) who were treated with nirmatrelvir-ritonavir and 168 669 (95.0%) who were not treated. The groups were well balanced with respect to demographic and clinical characteristics after applying stabilized IPTW. We found that the occurrence of hospital admission or death was lower in the group given nirmatrelvir-ritonavir than in those who were not (2.1% v. 3.7%; weighted OR 0.56, 95% CI 0.47-0.67). For death alone, the weighted OR was 0.49 (95% CI 0.39-0.62). Our findings were similar across strata of age, drug-drug interactions, vaccination status and comorbidities. The number needed to treat to prevent 1 case of severe COVID-19 was 62 (95% CI 43-80), which varied across strata. INTERPRETATION: Nirmatrelvir-ritonavir was associated with significantly reduced odds of hospital admission and death from COVID-19, which supports use to treat patients with mild COVID-19 who are at risk for severe disease.

In Elimination Settings, Measles Antibodies Wane After Vaccination but Not After Infection: A Systematic Review and Meta-Analysis.

BACKGROUND: We conducted a systematic review to assess whether measles humoral immunity wanes in previously infected or vaccinated populations in measles elimination settings. METHODS: After screening 16 822 citations, we identified 9 articles from populations exposed to wild-type measles and 16 articles from vaccinated populations that met our inclusion criteria. RESULTS: Using linear regression, we found that geometric mean titers (GMTs) decreased significantly in individuals who received 2 doses of measles-containing vaccine (MCV) by 121.8 mIU/mL (95% confidence interval [CI], -212.4 to -31.1) per year since vaccination over 1 to 5 years, 53.7 mIU/mL (95% CI, -95.3 to -12.2) 5 to 10 years, 33.2 mIU/mL (95% CI, -62.6 to -3.9), 10 to 15 years, and 24.1 mIU/mL (95% CI, -51.5 to 3.3) 15 to 20 years since vaccination. Decreases in GMT over time were not significant after 1 dose of MCV or after infection. Decreases in the proportion of seropositive individuals over time were not significant after 1 or 2 doses of MCV or after infection. CONCLUSIONS: Measles antibody waning in vaccinated populations should be considered in planning for measles elimination.

If You Can See It, You Can Be It: Perceptions of Diversity in Surgery Among Under-Represented Minority High School Students.

PURPOSE: Increasing racial and ethnic diversity in the surgical workforce is essential to improving outcomes for marginalized communities. To address the persistent shortage of under-represented minority (URM) surgeons, this study assessed the impact of providing early exposure to the field of surgery on URM high school students' perceptions of pursuing surgical careers. METHODS: The Association of Women Surgeons organized a pilot 3-hour "Day in the Life" virtual event geared toward URM high school students involving suturing/knot-tying, case conferences, and mentoring activities. RESULTS: Pre- and post-event survey results from 65 participants showed that students became more familiar with surgery (p < 0.001) and perceived the field as more diverse (p = 0.017). Over 70% felt capable of becoming surgeons themselves and over 80% were interested in learning more and gaining mentorship. CONCLUSIONS: Our programming provides a model for future initiatives aimed at strengthening the pipeline of URM surgeons.

Postoperative Mortality in Patients With Cirrhosis: Reconsidering Expectations.

BACKGROUND: A diagnosis of cirrhosis increases a patient's risk of postoperative mortality. Surgeons are reticent to operate when cirrhosis is known unless no option is available. This study aimed to identify the modern perioperative risk in cirrhotic patients undergoing intervention under general anesthesia for non-transplant operations. METHODS: A retrospective chart review was conducted utilizing the Rush Medical Center electronic medical record. All patients over 18 years of age with a diagnosis of cirrhosis undergoing intervention between 2009 and 2019 were reviewed. 90-day mortality rates in patients grouped by Child's score, Model for End-Stage Liver Disease (MELD), and Model for End-Stage Liver Disease with sodium incorporated (MELDNa) were compared to previously accepted rates. RESULTS: 93 patients (46% women) aged 22-72 years of all Child-Turcot-Pugh (CTP) (40% A, 36% B, and 25% C) classifications and MELD/MELDNa ranging 6-40 were analyzed. 90-day mortality of the entire population was 16%, significantly lower than expected based on CTP score (16% vs. 32%; P = .0005), MELD (16% vs. 41%; P < .0001), and MELDNa (16% vs. 46.8%; P < .0001). This was also true for CTP-B patients (12% vs. 30%; P = .025), CTP-C patients (35% vs. 70%; P = .0002), patients with MELD >14 (27% vs. 70%; P < .001), and patients with MELDNa >14 (23% vs. 70%; P < .0001). CONCLUSION: Data indicate that perioperative mortality is lower than widely accepted. This suggests the need for a national database study using a representative population to determine the risk of mortality for patients with cirrhosis having surgery in recent times. Accurate estimation of this risk allows for meaningful discussion between physicians and patients when deciding to proceed with elective, necessary operations.

The geographic distribution of un-immunized children in Ontario, Canada: Hotspot detection using Bayesian spatial analysis.

BACKGROUND: In Ontario, Canada, little is currently known about the extent to which un-immunized children may cluster geographically. Our objectives were to: describe the geographic distribution of fully un-immunized children; identify geographic clusters (hotspots) of un-immunized children; and to characterize the contribution of spatial effects and covariates on hotspots, where found. METHODS: Our analytic cohort consisted of Ontario students aged 7-17 years in the 2016-2017 school year. We defined students as un-immunized if they had zero doses of any vaccine and a non-medical exemption recorded in Ontario's registry. We calculated unadjusted proportions of un-immunized students by Census Subdivision (CSD) and then used a sequential approach to identify hotspots starting first with hotspot identification at the CSD level and then probed identified hotspots further by Dissemination Area (DA) and including covariates. Hotspots were identified using the Besag-York-Mollie Bayesian spatial model and were defined as areas with >95% probability of having two times the proportion of un-immunized students, relative to the province overall. RESULTS: We identified 15,208 (0.94%) un-immunized children within our cohort consisting of more than 1.61 million students. Unadjusted proportions of un-immunized students varied greatly by geography, ranging from 0% to 21.5% by CSD. We identified 16 hotspot CSDs which clustered in five distinct areas, all of which were located in southern Ontario. The contribution of covariates and spatial effects on the risk of having un-immunized students varied greatly across hotspot areas. CONCLUSIONS: Although the provincial proportion (0.94%) of un-immunized students is small, geographical clustering of such students is evident in Ontario and in some areas presents an important risk for future outbreaks. Further qualitative work within these hotspot areas would be a helpful next step to better characterize the factors associated with vaccine refusal in these communities.

Review of sexualized drug use associated with sexually transmitted and blood-borne infections in gay, bisexual and other men who have sex with men.

PURPOSE: The aim of the present study was to quantify associations between sexualized drug use (SDU) and sexually-transmitted and blood-borne infection (STBBI) diagnoses in gay, bisexual and other men who have sex with men (GBMSM) with defined temporal proximity between SDU exposure and STBBI diagnoses. METHODS: In May 2018 and June 2019, we searched the literature for primary studies that quantified the association between STBBI and SDU among GBMSM. A random-effects model was used to meta-analyze the data and estimate the association between SDU and STBBIs. RESULTS: Nineteen studies met the inclusion criteria and fourteen studies were included in the meta-analyses. SDU was associated with higher odds of bacterial STI diagnoses, higher odds of HCV diagnoses, and higher odds of HIV diagnoses. Associations between SDU and diagnoses of bacterial STIs or HCV remained after adjustment for behavioral and sociodemographic factors. CONCLUSIONS: Robust and consistent associations between SDU and STBBI identified in this review add to the evidence suggesting SDU is a potential contributor to bacterial STIs and HCV or a proxy indicator for other risk factors.

Asymptomatic Infection and Transmission of Pertussis in Households: A Systematic Review.

We conducted a systematic review to describe the frequency of mild, atypical, and asymptomatic infection among household contacts of pertussis cases and to explore the published literature for evidence of asymptomatic transmission. We included studies that obtained and tested laboratory specimens from household contacts regardless of symptom presentation and reported the proportion of cases with typical, mild/atypical, or asymptomatic infection. After screening 6789 articles, we included 26 studies. Fourteen studies reported household contacts with mild/atypical pertussis. These comprised up to 46.2% of all contacts tested. Twenty-four studies reported asymptomatic contacts with laboratory-confirmed pertussis, comprising up to 55.6% of those tested. Seven studies presented evidence consistent with asymptomatic pertussis transmission between household contacts. Our results demonstrate a high prevalence of subclinical infection in household contacts of pertussis cases, which may play a substantial role in the ongoing transmission of disease. Our review reveals a gap in our understanding of pertussis transmission.

The effect of time since measles vaccination and age at first dose on measles vaccine effectiveness - A systematic review.

BACKGROUND: In settings where measles has been eliminated, vaccine-derived immunity may in theory wane more rapidly due to a lack of immune boosting by circulating measles virus. We aimed to assess whether measles vaccine effectiveness (VE) waned over time, and if so, whether differentially in measles-eliminated and measles-endemic settings. METHODS: We performed a systematic literature review of studies that reported VE and time since vaccination with measles-containing vaccine (MCV). We extracted information on case definition (clinical symptoms and/or laboratory diagnosis), method of vaccination status ascertainment (medical record or vaccine registry), as well as any biases which may have arisen from cold chain issues and a lack of an age at first dose of MCV. We then used linear regression to evaluate VE as a function of age at first dose of MCV and time since MCV. RESULTS: After screening 14,782 citations, we identified three full-text articles from measles-eliminated settings and 33 articles from measles-endemic settings. In elimination settings, two-dose VE estimates increased as age at first dose of MCV increased and decreased as time since MCV increased; however, the small number of studies available limited interpretation. In measles-endemic settings, one-dose VE increased by 1.5% (95% CI 0.5, 2.5) for every month increase in age at first dose of MCV. We found no evidence of waning VE in endemic settings. CONCLUSIONS: The paucity of data from measles-eliminated settings indicates that additional studies and approaches (such as studies using proxies including laboratory correlates of protection) are needed to answer the question of whether VE in measles-eliminated settings wanes. Age at first dose of MCV was the most important factor in determining VE. More VE studies need to be conducted in elimination settings, and standards should be developed for information collected and reported in such studies.

Exploring indirect protection associated with influenza immunization - A systematic review of the literature.

BACKGROUND: Influenza causes significant annual morbidity and mortality, particularly in older adults, for whom influenza vaccine effectiveness (VE) is also lower. Immunizing one group (e.g., children) against influenza may indirectly protect another group (e.g., older adults) against influenza and its complications. METHODS: We updated previous systematic reviews on indirect protection against influenza by searching MEDLINE and EMBASE for relevant human studies published until January 4, 2017. We abstracted and critically appraised English language publications that reported or provided information to calculate indirect VE against influenza, as a percentage, in non-institutional settings. We developed a term called 'estimated actual protection' to explore the relationship between indirect protection and the product of direct VE and relative vaccine coverage. We calculated estimated actual protection for a subset of studies that reported coverage and indirect VE for: laboratory-confirmed influenza; outpatient care for respiratory illness; influenza-associated emergency visits; or influenza-associated hospitalizations. We ran linear mixed models to compare estimated actual protection against indirect VE for the four outcomes, and graphed the data. RESULTS: Of 2320 unique records identified, we abstracted and appraised 26 articles describing 24 studies. The majority of included studies reported at least one outcome suggesting that immunizing one group reduced influenza-related outcomes in another group. Critical appraisal of the abstracted studies identified recurring methodological weaknesses, such as lack of laboratory-confirmed influenza. Our exploratory analyses of 18 studies indicated a positive but not statistically significant relationship between estimated actual protection and indirect protection for each of the four outcomes. CONCLUSIONS: Our systematic review and exploratory analyses suggest influenza immunization provides some level of indirect protection. However, our critical appraisal highlights the need for a standardized and consistently applied approach to measuring indirect protection against influenza to fill existing knowledge gaps. Additionally, the concept of estimated actual protection requires validation.

Fast Generation of Functional Subtype Astrocytes from Human Pluripotent Stem Cells.

Differentiation of astrocytes from human pluripotent stem cells (hPSCs) is a tedious and variable process. This hampers the study of hPSC-generated astrocytes in disease processes and drug development. By using CRISPR/Cas9-mediated inducible expression of NFIA or NFIA plus SOX9 in hPSCs, we developed a method to efficiently generate astrocytes in 4-7 weeks. The astrocytic identity of the induced cells was verified by their characteristic molecular and functional properties as well as after transplantation. Furthermore, we developed a strategy to generate region-specific astrocyte subtypes by combining differentiation of regional progenitors and transgenic induction of astrocytes. This simple and efficient method offers a new opportunity to study the fundamental biology of human astrocytes and their roles in disease processes.

Waning of measles maternal antibody in infants in measles elimination settings - A systematic literature review.

INTRODUCTION: Most infants are born with immunity to measles through maternal antibodies transferred in pregnancy, which decay over time. However, in measles elimination settings, where measles does not circulate endemically and most immunity is from immunization rather than infection, maternal antibody levels are lower. This results in infant immunity that wanes earlier, and a wider susceptibility gap between maternal antibody decay and infant immunization than in non-eliminated settings. We aimed to systematically quantify the extent and duration of protection from measles in infants in settings that have sustained measles elimination. METHODS: We conducted a systematic review of studies of measles maternal antibody waning in infants in measles elimination settings. We searched MEDLINE, Embase, CINAHL, Scopus, BIOSIS Previews, and Global Health databases for relevant studies. Studies were included if they were set in countries that had eliminated measles for ≥3 years, and if the study cohort included healthy, full-term, unvaccinated infants ≤12 months, born to healthy mothers, and reported a relevant measure of measles maternal antibody in infants. We assessed study quality using the MetaQAT tool. RESULTS: We identified 4692 unique citations, eight of which met inclusion criteria. One study reported anti-measles antibody in cord blood, six reported antibody in infant sera, and one reported both. Two studies reported that 80 and 100% of infants were protected from measles at birth. One study reported no protection amongst 3-7 month old infants, and another reported limited protection in infants >4 months. The remaining studies reported the proportion of infants with detected antibody, but not the proportion immune. CONCLUSION: Although limited, these data suggest that in settings that have sustained measles elimination, some infants are susceptible to measles well before the age of routine measles immunization. Setting-specific seroprevalence and vaccine effectiveness studies are required to evaluate this in different jurisdictions.

Role of smoking in the recurrence of atrial arrhythmias after cardioversion.

We aimed to determine whether smoking status affects the recurrence of atrial fibrillation or atrial flutter in patients after cardioversion. The clinical data of patients undergoing cardioversion for atrial flutter from January 1, 2000 to December 31, 2005 were prospectively collected. Arrhythmia recurrences were detected by retrospective review of comprehensive medical records and were determined using electrocardiography. The smoking history was prospectively collected through a standardized clinical form and subsequently categorized as lifetime nonsmoker, exsmoker, or current smoker. Univariate and multivariate associations with end points for clinical and lifestyle variables were assessed with Cox proportional hazards models. Women who were current smokers at cardioversion had a greater risk of atrial arrhythmia recurrence than did nonsmokers (hazard ratio 1.71, 95% confidence interval 1.10 to 2.67, p = 0.02). The increased risk of arrhythmia recurrence in female smokers was not seen in male smokers. Compared to lifetime nonsmokers, the mortality hazard ratio among men was 1.18 (95% confidence interval 0.88 to 1.58; p = 0.28) in exsmokers and 1.93 (95% confidence interval 1.20 to 3.11; p = 0.007) in current smokers. The risk of death after cardioversion was not increased in women. In conclusion, smoking is an independent predictor of atrial arrhythmia recurrence after cardioversion in women; however, an increased mortality risk, but not arrhythmia recurrence risk, was seen in men.