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.

Personal Actions to Create a Culture of Inclusion: Navigating Difficult Conversations With Medical Colleagues

Microaggressions between members of a team occur often in medicine, even despite good intentions. Such situations call for difficult conversations that restore inclusivity, diversity, and a healthy work culture. These conversations are often hard because of the unique background, experiences, and biases of each person. In medicine, skillful navigation of these interactions is paramount as it influences patient care and the workplace culture. Although much has been published about difficult interactions between providers and patients, significantly less information is available to help navigate provider-to-provider interactions, despite their critical role in improving multidisciplinary patient care teams and organizational environments. This article is intended to serve as a guide for medical professionals who are interested in taking personal responsibility for promoting a safe and inclusive culture by engaging in and modeling difficult conversations with colleagues. The article outlines important considerations to assist with intentional preparation and modulation of responses for all parties involved: conversation initiators, observers of the incident, and conversation receivers. Although these interactions are challenging, together as medical professionals we can approach each other with humility and compassion to achieve our ultimate goal of promoting humanity, not only for our patients but for ourselves and one another.

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.

Blood Pressure Effect of Traffic-Related Air Pollution: A Crossover Trial of In-Vehicle Filtration: Annals of Internal Medicine: Vol 176, No 12

Background: Ambient air pollution, including traffic-related air pollution (TRAP), increases cardiovascular disease risk, possibly through vascular alterations. Limited information exists about in-vehicle TRAP exposure and vascular changes. Objective: To determine via particle filtration the effect of on-roadway TRAP exposure on blood pressure and retinal vasculature. Design: Randomized crossover trial. (ClinicalTrials.gov: NCT05454930) Setting: In-vehicle scripted commutes driven through traffic in Seattle, Washington, during 2014 to 2016. Participants: Normotensive persons aged 22 to 45 years (n = 16). Intervention: On 2 days, on-road air was entrained into the vehicle. On another day, the vehicle was equipped with high-efficiency particulate air (HEPA) filtration. Participants were blinded to the exposure and were randomly assigned to the sequence. Measurements: Fourteen 3-minute periods of blood pressure were recorded before, during, and up to 24 hours after a drive. Image-based central retinal arteriolar equivalents (CRAEs) were measured before and after. Brachial artery diameter and gene expression were also measured and will be reported separately. Results: Mean age was 29.7 years, predrive systolic blood pressure was 122.7 mm Hg, predrive diastolic blood pressure was 70.8 mm Hg, and drive duration was 122.3 minutes (IQR, 4 minutes). Filtration reduced particle count by 86%. Among persons with complete data (n = 13), at 1 hour, mean diastolic blood pressure, adjusted for predrive levels, order, and carryover, was 4.7 mm Hg higher (95% CI, 0.9 to 8.4 mm Hg) for unfiltered drives compared with filtered drives, and mean adjusted systolic blood pressure was 4.5 mm Hg higher (CI, −1.2 to 10.2 mm Hg). At 24 hours, adjusted mean diastolic blood pressure (unfiltered) was 3.8 mm Hg higher (CI, 0.02 to 7.5 mm Hg) and adjusted mean systolic blood pressure was 1.1 mm Hg higher (CI, −4.6 to 6.8 mm Hg). Adjusted mean CRAE (unfiltered) was 2.7 μm wider (CI, −1.5 to 6.8 μm). Limitations: Imprecise estimates due to small sample size; seasonal imbalance by exposure order. Conclusion: Filtration of TRAP may mitigate its adverse effects on blood pressure rapidly and at 24 hours. Validation is required in larger samples and different settings. Primary Funding Source: U.S. Environmental Protection Agency and National Institutes of Health.

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.

Addressing Viral Medical Rumors and False or Misleading Information

The rapid spread of medical rumors and false or misleading information on social media during times of uncertainty is a vexing challenge that threatens public health. Understanding the information ecosystem, social media networks, and the scope of incentives that drive users and social media platforms can provide critical insights for strong coordination between stakeholders and funders to address this challenge. The COVID-19 pandemic created an opportunity to demonstrate the role of media monitoring and counter-messaging efforts in responding to dangerous medical rumors, misinformation, and disinformation. It also highlighted the challenges. The efforts of ThisIsOurShot and VacunateYa to spread accurate health information about COVID-19 and COVID-19 vaccines are described and lessons learned are discussed. These lessons include the need for substantial financial investments at the local and national levels to sustain and scale these types of programs. Examples in other fields that offer a path forward include Information Sharing and Analysis Centers and Public Health Emergency Operations Centers. Understanding the scale and scope of what it takes to address viral medical rumors, misinformation, and disinformation in a networked information environment should inspire elected leaders to consider policy and regulatory reforms. Our transformed information ecosystem requires new public health infrastructure to address information that threatens personal safety and population health.

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.

Suspected Bronchiectasis and Mortality in Adults With a History of Smoking Who Have Normal and Impaired Lung Function: A Cohort Study: Annals of Internal Medicine: Vol 176, No 10

Background: Bronchiectasis in adults with chronic obstructive pulmonary disease (COPD) is associated with greater mortality. However, whether suspected bronchiectasis—defined as incidental bronchiectasis on computed tomography (CT) images plus clinical manifestation—is associated with increased mortality in adults with a history of smoking with normal spirometry and preserved ratio impaired spirometry (PRISm) is unknown. Objective: To determine the association between suspected bronchiectasis and mortality in adults with normal spirometry, PRISm, and obstructive spirometry. Design: Prospective, observational cohort. Setting: The COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease) study. Participants: 7662 non-Hispanic Black or White adults, aged 45 to 80 years, with 10 or more pack-years of smoking history. Participants who were former and current smokers were stratified into normal spirometry (n = 3277), PRISm (n = 986), and obstructive spirometry (n = 3399). Measurements: Bronchiectasis identified by CT was ascertained using artificial intelligence–based measurements of an airway-to-artery ratio (AAR) greater than 1 (AAR >1), a measure of bronchial dilatation. The primary outcome of “suspected bronchiectasis” was defined as an AAR >1 of greater than 1% plus 2 of the following: cough, phlegm, dyspnea, and history of 2 or more exacerbations. Results: Among the 7662 participants (mean age, 60 years; 52% women), 1352 (17.6%) had suspected bronchiectasis. During a median follow-up of 11 years, 2095 (27.3%) died. Ten-year mortality risk was higher in participants with suspected bronchiectasis, compared with those without suspected bronchiectasis (normal spirometry: difference in mortality probability [Pr], 0.15 [95% CI, 0.09 to 0.21]; PRISm: Pr, 0.07 [CI, −0.003 to 0.15]; obstructive spirometry: Pr, 0.06 [CI, 0.03 to 0.09]). When only CT was used to identify bronchiectasis, the differences were attenuated in the normal spirometry (Pr, 0.04 [CI, −0.001 to 0.08]). Limitations: Only 2 racial groups were studied. Only 1 measurement was used to define bronchiectasis on CT. Symptoms of suspected bronchiectasis were nonspecific. Conclusion: Suspected bronchiectasis was associated with a heightened risk for mortality in adults with normal and obstructive spirometry. Primary Funding Source: National Heart, Lung, and Blood Institute.