Real-World Effectiveness of BNT162b2 Against Infection and Severe Diseases in Children and Adolescents

Background: The efficacy of the BNT162b2 vaccine in pediatrics was assessed by randomized trials before the Omicron variant’s emergence. The long-term durability of vaccine protection in this population during the Omicron period remains limited. Objective: To assess the effectiveness of BNT162b2 in preventing infection and severe diseases with various strains of the SARS-CoV-2 virus in previously uninfected children and adolescents. Design: Comparative effectiveness research accounting for underreported vaccination in 3 study cohorts: adolescents (12 to 20 years) during the Delta phase and children (5 to 11 years) and adolescents (12 to 20 years) during the Omicron phase. Setting: A national collaboration of pediatric health systems (PEDSnet). Participants: 77 392 adolescents (45 007 vaccinated) during the Delta phase and 111 539 children (50 398 vaccinated) and 56 080 adolescents (21 180 vaccinated) during the Omicron phase. Intervention: First dose of the BNT162b2 vaccine versus no receipt of COVID-19 vaccine. Measurements: Outcomes of interest include documented infection, COVID-19 illness severity, admission to an intensive care unit (ICU), and cardiac complications. The effectiveness was reported as (1-relative risk)*100, with confounders balanced via propensity score stratification. Results: During the Delta period, the estimated effectiveness of the BNT162b2 vaccine was 98.4% (95% CI, 98.1% to 98.7%) against documented infection among adolescents, with no statistically significant waning after receipt of the first dose. An analysis of cardiac complications did not suggest a statistically significant difference between vaccinated and unvaccinated groups. During the Omicron period, the effectiveness against documented infection among children was estimated to be 74.3% (CI, 72.2% to 76.2%). Higher levels of effectiveness were seen against moderate or severe COVID-19 (75.5% [CI, 69.0% to 81.0%]) and ICU admission with COVID-19 (84.9% [CI, 64.8% to 93.5%]). Among adolescents, the effectiveness against documented Omicron infection was 85.5% (CI, 83.8% to 87.1%), with 84.8% (CI, 77.3% to 89.9%) against moderate or severe COVID-19, and 91.5% (CI, 69.5% to 97.6%) against ICU admission with COVID-19. The effectiveness of the BNT162b2 vaccine against the Omicron variant declined 4 months after the first dose and then stabilized. The analysis showed a lower risk for cardiac complications in the vaccinated group during the Omicron variant period. Limitation: Observational study design and potentially undocumented infection. Conclusion: This study suggests that BNT162b2 was effective for various COVID-19–related outcomes in children and adolescents during the Delta and Omicron periods, and there is some evidence of waning effectiveness over time. Primary Funding Source: National Institutes of Health.

Changes in Induced Medical and Procedural Abortion Rates in a Commercially Insured Population, 2018 to 2022: An Interrupted Time-Series Analysis: Annals of Internal Medicine: Vol 176, No 11

Background: During the COVID-19 pandemic, access to in-person care was limited, and regulations requiring in-person dispensing of mifepristone for medical abortions were relaxed. The effect of the pandemic and accompanying regulatory changes on abortion use is unknown. Objective: To estimate changes in the incidence rate of induced medical and procedural abortions. Design: Serial cross-sectional study with interrupted time-series analyses. Setting: Commercially insured persons in the United States. Participants: Reproductive-aged women. Intervention: Onset of the COVID-19 pandemic in March 2020 and subsequent regulatory changes affecting the in-person dispensing requirement for mifepristone. Measurements: Monthly age-adjusted incidence rates of medical and procedural abortions were measured among women aged 15 to 44 years from January 2018 to June 2022. Medical abortions were classified as in-person or telehealth. Linear segmented time-series regression was used to calculate changes in abortion rates after March 2020. Results: In January 2018, the estimated age-adjusted monthly incidence rate of abortions was 151 per million women (95% CI, 142 to 161 per million women), with equal rates of medical and procedural abortions. After March 2020, there was an immediate 14% decrease in the monthly incidence rate of abortions (21 per million women [CI, 7 to 35 per million women]; P = 0.004), driven by a 31% decline in procedural abortions (22 per million women [CI, 16 to 28 per million women]; P < 0.001). Fewer than 4% of medical abortions each month were administered via telehealth. Limitation: Only abortions reimbursed by commercial insurance were measured. Conclusion: The incidence rate of procedural abortions declined during the COVID-19 pandemic, and this lower rate persisted after other elective procedures rebounded to prepandemic rates. Despite removal of the in-person dispensing requirement for mifepristone, the use of telehealth for insurance-covered medical abortions remained rare. Amid increasing state restrictions, commercial insurers have the opportunity to increase access to abortion care, particularly via telehealth. Primary Funding Source: Health Resources and Services Administration.

Adoption of Internal Medicine Milestone Ratings and Changes in Bias Against Black, Latino, and Asian Internal Medicine Residents

Background: The 2014 adoption of the Milestone ratings system may have affected evaluation bias against minoritized groups. Objective: To assess bias in internal medicine (IM) residency knowledge ratings against Black or Latino residents—who are underrepresented in medicine (URiM)—and Asian residents before versus after Milestone adoption in 2014. Design: Cross-sectional and interrupted time-series comparisons. Setting: U.S. IM residencies. Participants: 59 835 IM residents completing residencies during 2008 to 2013 and 2015 to 2020. Intervention: Adoption of the Milestone ratings system. Measurements: Pre-Milestone (2008 to 2013) and post-Milestone (2015 to 2020) bias was estimated as differences in standardized knowledge ratings between U.S.-born and non–U.S.-born minoritized groups versus non-Latino U.S.-born White (NLW) residents, with adjustment for performance on the American Board of Internal Medicine IM certification examination and other physician characteristics. Interrupted time-series analysis measured deviations from pre-Milestone linear bias trends. Results: During the pre-Milestone period, ratings biases against minoritized groups were large (−0.40 SDs [95% CI, −0.48 to −0.31 SDs; P < 0.001] for URiM residents, −0.24 SDs [CI, −0.30 to −0.18 SDs; P < 0.001] for U.S.-born Asian residents, and −0.36 SDs [CI, −0.45 to −0.27 SDs; P < 0.001] for non–U.S.-born Asian residents). These estimates decreased to less than −0.15 SDs after adoption of Milestone ratings for all groups except U.S.-born Black residents, among whom substantial (though lower) bias persisted (−0.26 SDs [CI, −0.36 to −0.17 SDs; P < 0.001]). Substantial deviations from pre-Milestone linear bias trends coincident with adoption of Milestone ratings were also observed. Limitations: Unobserved variables correlated with ratings bias and Milestone ratings adoption, changes in identification of race/ethnicity, and generalizability to Milestones 2.0. Conclusion: Knowledge ratings bias against URiM and Asian residents was ameliorated with the adoption of the Milestone ratings system. However, substantial ratings bias against U.S.-born Black residents persisted. Primary Funding Source: None.

Surgery, Needle Fasciotomy, or Collagenase Injection for Dupuytren Contracture: A Randomized Controlled Trial: Annals of Internal Medicine: Vol 177, No 3

Background: Surgery, needle fasciotomy, and collagenase injection are used to treat Dupuytren contracture. The treatment decision requires balancing initial morbidity and costs of surgery against its potential long-term benefits over needle fasciotomy and collagenase. Objective: To compare the effectiveness of surgery, needle fasciotomy, and collagenase injection at 3 months and 2 years (secondary time points of the trial). Design: A multicenter, randomized, outcome assessor–blinded, superiority trial. (ClinicalTrials.gov: NCT03192020) Setting: 6 public hospitals in Finland. Participants: 302 persons with treatment-naive Dupuytren contracture (contracture angle <135°). Intervention: Surgery (n = 101), needle fasciotomy (n = 101), or collagenase (n = 100). Measurements: The primary outcome was the success rate, defined as greater than 50% contracture release and patients reaching the patient acceptable symptom state. Secondary outcomes included hand function, pain, quality of life, patient satisfaction, residual contracture angle, finger flexion, risk for retreatment, and serious adverse events. Results: A total of 292 (97%) and 284 (94%) participants completed the 3-month and 2-year follow-ups. Success rates were similar at 3 months: 71% (95% CI, 62% to 80%) for surgery, 73% (CI, 64% to 82%) for needle fasciotomy, and 73% (CI, 64% to 82%) for collagenase. At 2 years, surgery had superior success rates compared with both needle fasciotomy (78% vs. 50%; adjusted risk difference [aRD], 0.30 [CI, 0.17 to 0.43]) and collagenase (78% vs. 65%; aRD, 0.13 [CI, 0.01 to 0.26]). Secondary analyses paralleled with the primary analysis. Limitation: Participants were not blinded. Conclusion: Initial outcomes are similar between the treatments, but at 2 years success rates were maintained in the surgery group but were lower with both needle fasciotomy and collagenase despite retreatments. Primary Funding Source: Research Council of Finland.

Paternal Use of Metformin During the Sperm Development Period Preceding Conception and Risk for Major Congenital Malformations in Newborns

Background: Metformin is the most used oral antidiabetic medication. Despite its established safety profile, it has known antiandrogenic and epigenetic modifying effects. This raised concerns about possible adverse developmental effects caused by genomic alterations related to paternal use of metformin during the spermatogenesis period preceding conception. Objective: To assess the potential adverse intergenerational effect of metformin by examining the association between paternal metformin use during spermatogenesis and major congenital malformations (MCMs) in newborns. Design: Nationally representative cohort study. Setting: A large Israeli health fund. Participants: 383 851 live births linked to fathers and mothers that occurred in 1999 to 2020. Measurements: MCMs and parental cardiometabolic conditions were ascertained using clinical diagnoses, medication dispensing information, and laboratory test results. The effect of metformin use on MCMs was estimated using general estimating equations, accounting for concurrent use of other antidiabetic medications and parental cardiometabolic morbidity. Results: Compared with unexposed fathers, the prevalence of cardiometabolic morbidity was substantially higher among fathers who used metformin during spermatogenesis, and their spouses. Whereas the crude odds ratio (OR) for paternal metformin exposure in all formulations and MCMs was 1.28 (95% CI, 1.01 to 1.64), the adjusted OR was 1.00 (CI, 0.76 to 1.31). Within specific treatment regimens, the adjusted OR was 0.86 (CI, 0.60 to 1.23) for metformin in monotherapy and 1.36 (CI, 1.00 to 1.85) for metformin in polytherapy, a treatment that was more common in patients with more poorly controlled diabetes. Limitation: Laboratory test results for hemoglobin A1c to assess underlying diabetes severity were available only for a subset of the cohort. Conclusion: Paternal use of metformin in monotherapy does not increase the risk for MCMs. Association for metformin in polytherapy could potentially be explained by worse underlying parental cardiometabolic risk profile. Primary Funding Source: None.

Development and Validation of the CANHEART Population-Based Laboratory Prediction Models for Atherosclerotic Cardiovascular Disease

Background: Prediction of atherosclerotic cardiovascular disease (ASCVD) in primary prevention assessments exclusively with laboratory results may facilitate automated risk reporting and improve uptake of preventive therapies. Objective: To develop and validate sex-specific prediction models for ASCVD using age and routine laboratory tests and compare their performance with that of the pooled cohort equations (PCEs). Design: Derivation and validation of the CANHEART (Cardiovascular Health in Ambulatory Care Research Team) Lab Models. Setting: Population-based cohort study in Ontario, Canada. Participants: A derivation and internal validation cohort of adults aged 40 to 75 years without cardiovascular disease from April 2009 to December 2015; an external validation cohort of primary care patients from January 2010 to December 2014. Measurements: Age and laboratory predictors measured in the outpatient setting included serum total cholesterol, high-density lipoprotein cholesterol, triglycerides, hemoglobin, mean corpuscular volume, platelets, leukocytes, estimated glomerular filtration rate, and glucose. The ASCVD outcomes were defined as myocardial infarction, stroke, and death from ischemic heart or cerebrovascular disease within 5 years. Results: Sex-specific models were developed and internally validated in 2 160 497 women and 1 833 147 men. They were well calibrated, with relative differences less than 1% between mean predicted and observed risk for both sexes. The c-statistic was 0.77 in women and 0.71 in men. External validation in 31 697 primary care patients showed a relative difference less than 14% and an absolute difference less than 0.3 percentage points in mean predicted and observed risks for both sexes. The c-statistics for the laboratory models were 0.72 for both sexes and were not statistically significantly different from those for the PCEs in women (change in c-statistic, −0.01 [95% CI, −0.03 to 0.01]) or men (change in c-statistic, −0.01 [CI, −0.04 to 0.02]). Limitation: Medication use was not available at the population level. Conclusion: The CANHEART Lab Models predict ASCVD with similar accuracy to more complex models, such as the PCEs. Primary Funding Source: Canadian Institutes of Health Research.

Receipt of Clinician Recommendation for Colorectal Cancer Screening Among Underscreened U.S. Adults

Telemedicine Versus In-Person Primary Care: Treatment and Follow-up Visits

Background: Beyond initial COVID-19 pandemic emergency expansions of telemedicine use, it is unclear how well primary care telemedicine addresses patients’ needs. Objective: To compare treatment and follow-up visits (office, emergency department, hospitalization) between primary care video or telephone telemedicine and in-person office visits. Design: Retrospective design based on administrative and electronic health record (EHR) data. Setting: Large, integrated health care delivery system with more than 1300 primary care providers, between April 2021 and December 2021 (including the COVID-19 pandemic Delta wave). Patients: 1 589 014 adult patients; 26.5% were aged 65 years or older, 54.9% were female, 22.2% were Asian, 7.4% were Black, 22.3% were Hispanic, 46.5% were White, 21.5% lived in neighborhoods with lower socioeconomic status, and 31.8% had a chronic health condition. Measurements: Treatment outcomes included medication or antibiotic prescribing and laboratory or imaging ordering. Follow-up visits included in-person visits to the primary care office or emergency department or hospitalization within 7 days. Outcomes were adjusted for sociodemographic and clinical characteristics overall and stratified by clinical area (abdominal pain, gastrointestinal concerns, back pain, dermatologic concerns, musculoskeletal pain, routine care, hypertension or diabetes, and mental health). Results: Of 2 357 598 primary care visits, 50.8% used telemedicine (19.5% video and 31.3% telephone). After adjustment, medications were prescribed in 46.8% of office visits, 38.4% of video visits, and 34.6% of telephone visits. After the visit, 1.3% of in-person visits, 6.2% of video visits, and 7.6% of telephone visits had a 7-day return in-person primary care visit; 1.6% of in-person visits, 1.8% of video visits, and 2.1% of telephone visits were followed by an emergency department visit. Differences in follow-up office visits were largest after index office versus telephone visits for acute pain conditions and smallest for mental health. Limitations: In the study setting, telemedicine is fully integrated with ongoing EHRs and with clinicians, and the study examines an insured population during the late COVID-19 pandemic period. Observational comparison lacks detailed severity or symptom measures. Follow-up was limited to 7 days. Clinical area categorization uses diagnosis code rather than symptom. Conclusion: In-person return visits were somewhat higher after telemedicine compared with in-person primary care visits but varied by specific clinical condition. Primary Funding Source: Agency for Healthcare Research and Quality.

Once-Weekly Insulin Icodec With Dosing Guide App Versus Once-Daily Basal Insulin Analogues in Insulin-Naive Type 2 Diabetes (ONWARDS 5): A Randomized Trial: Annals of Internal Medicine: Vol 176, No 11

Background: Inadequate dose titration and poor adherence to basal insulin can lead to suboptimal glycemic control in persons with type 2 diabetes (T2D). Once-weekly insulin icodec (icodec) is a basal insulin analogue that is in development and is aimed at reducing treatment burden. Objective: To compare the effectiveness and safety of icodec titrated with a dosing guide app (icodec with app) versus once-daily basal insulin analogues (OD analogues) dosed per standard practice. Design: 52-week, randomized, open-label, parallel-group, phase 3a trial with real-world elements. (ClinicalTrials.gov: NCT04760626) Setting: 176 sites in 7 countries. Participants: 1085 insulin-naive adults with T2D. Intervention: Icodec with app or OD analogue (insulin degludec, insulin glargine U100, or insulin glargine U300). Measurements: The primary outcome was change in glycated hemoglobin (HbA1c) level from baseline to week 52. Secondary outcomes included patient-reported outcomes (Treatment Related Impact Measure for Diabetes [TRIM-D] compliance domain score and change in Diabetes Treatment Satisfaction Questionnaire [DTSQ] total treatment satisfaction score). Results: The estimated mean change in HbA1c level from baseline to week 52 was greater with icodec with app than with OD analogues, with noninferiority (P < 0.001) and superiority (P = 0.009) confirmed in prespecified hierarchical testing (estimated treatment difference [ETD], −0.38 percentage points [95% CI, −0.66 to −0.09 percentage points]). At week 52, patient-reported outcomes were more favorable with icodec with app than with OD analogues (ETDs, 3.04 [CI, 1.28 to 4.81] for TRIM-D and 0.78 [CI, 0.10 to 1.47] for DTSQ). Rates of clinically significant or severe hypoglycemia were low and similar with both treatments. Limitation: Inability to differentiate the effects of icodec and the dosing guide app. Conclusion: Compared with OD analogues, icodec with app showed superior HbA1c reduction and improved treatment satisfaction and compliance with similarly low hypoglycemia rates. Primary Funding Source: Novo Nordisk A/S.

Association of Low Glomerular Filtration Rate With Adverse Outcomes at Older Age in a Large Population With Routinely Measured Cystatin C

Background: The commonly accepted threshold of glomerular filtration rate (GFR) to define chronic kidney disease (CKD) is less than 60 mL/min/1.73 m2. This threshold is based partly on associations between estimated GFR (eGFR) and the frequency of adverse outcomes. The association is weaker in older adults, which has created disagreement about the appropriateness of the threshold for these persons. In addition, the studies measuring these associations included relatively few outcomes and estimated GFR on the basis of creatinine level (eGFRcr), which may be less accurate in older adults. Objective: To evaluate associations in older adults between eGFRcr versus eGFR based on creatinine and cystatin C levels (eGFRcr-cys) and 8 outcomes. Design: Population-based cohort study. Setting: Stockholm, Sweden, 2010 to 2019. Participants: 82 154 participants aged 65 years or older with outpatient creatinine and cystatin C testing. Measurements: Hazard ratios for all-cause mortality, cardiovascular mortality, and kidney failure with replacement therapy (KFRT); incidence rate ratios for recurrent hospitalizations, infection, myocardial infarction or stroke, heart failure, and acute kidney injury. Results: The associations between eGFRcr-cys and outcomes were monotonic, but most associations for eGFRcr were U-shaped. In addition, eGFRcr-cys was more strongly associated with outcomes than eGFRcr. For example, the adjusted hazard ratios for 60 versus 80 mL/min/1.73 m2 for all-cause mortality were 1.2 (95% CI, 1.1 to 1.3) for eGFRcr-cys and 1.0 (CI, 0.9 to 1.0) for eGFRcr, and for KFRT they were 2.6 (CI, 1.2 to 5.8) and 1.4 (CI, 0.7 to 2.8), respectively. Similar findings were observed in subgroups, including those with a urinary albumin–creatinine ratio below 30 mg/g. Limitation: No GFR measurements. Conclusion: Compared with low eGFRcr in older patients, low eGFRcr-cys was more strongly associated with adverse outcomes and the associations were more uniform. Primary Funding Source: Swedish Research Council, National Institutes of Health, and Dutch Kidney Foundation.