Henry Lester Kirchner

BACKGROUND: While health systems have implemented resources to improve lipid management in people with atherosclerotic cardiovascular disease, the population-level effectiveness is unclear. METHODS: Electronic health record data from patients with atherosclerotic cardiovascular disease between January 1, 2021, and December 31, 2023, across 16 US academic health systems were analyzed. Atherosclerotic cardiovascular disease (defined by diagnosis and procedure codes) was established on or before the index date defined as the date of the most recent LDL-C (low-density lipoprotein-cholesterol) or the last day of the study period for those without an LDL-C available. Systems were surveyed to identify lipid management programs (eg, prevention/lipid clinic, electronic health record–based tools, and lipid management algorithms). Sequential multilevel multivariable logistic regression modeling was used to (1) assess the system-level association between an LDL-C <70 mg/dL and the presence of lipid management programs, adjusting for patient-level demographic and clinical characteristics, and (2) whether system-level uptake of statin or nonstatin lipid-lowering therapy was associated with an LDL-C <70 mg/dL. RESULTS: We included 1 738 042 patients with atherosclerotic cardiovascular disease (median, 88 365 per system; range, 17 086–2 48 371). About 81% of the health systems had prevention or lipid clinics. The proportion of those on statins ranged from 31.0% to 60.4% across health systems (median, 46.3%). Lower proportions were observed in the use of high-intensity statins (16.2%–33.1%), nonstatins (2.6%–8.1%), and combination lipid-lowering therapy (1.7%–6.3%). Among those with an LDL-C level available (n=890 521), 42.5% had an LDL-C <70 mg/dL, ranging 35.8% to 49.4% across systems. There was no association between the odds of achieving LDL-C <70 mg/dL and health system lipid management algorithm, prevention clinics/lipid clinics, or electronic health record–based tools. Neither system-level high-intensity statin utilization nor nonstatin use was associated with an LDL-C <70 mg/dL. CONCLUSIONS: Despite variability in lipid management resources and lipid-lowering therapy use across systems, many did not reach an LDL-C <70 mg/dL, and there was low uptake of lipid-lowering therapy. Innovative implementation strategies are needed for system-level lipid management.

Background: Obstructive sleep apnea (OSA) is associated with a wide range of comorbidities, but large-scale phenome-wide analyses in clinical biobanks remain under-reported. In this study, we identified common comorbidities enriched in patients with OSA, tested the temporality of these associations, and analyzed relevant associations with summary sleep recording data. Methods: 48,251 participants with OSA in the Mass General Brigham healthcare system were identified using a natural language processing phenotyping algorithm and/or evidence of an elevated apnea-hypopnea index (AHI). Controls were matched (2:1) on demographics, body mass index (BMI), and healthcare utilization. Associations with 358 incident and 563 cross-sectional diseases were tested using Modified Poisson regression, adjusting for covariates. Sensitivity analyses examined timing by binning data in years relative to the first OSA diagnosis. Selected laboratory results were obtained based on associated diseases. Associated diseases were tested with sleep recording statistics (n ≤18,348). Findings: 179 incident and 421 cross-sectional diseases were associated with OSA at Bonferroni significance. 37 diseases had Bonferroni-significant sex interactions. Several associations were significant years before the first recorded OSA diagnosis. Four red blood cell laboratory measures were significant ten years prior to the first diagnosis. One incident and 47 cross-sectional diseases were associated with the AHI and/or chronic hypoxemia. Interpretation: Obstructive sleep apnea is associated with enrichment of hundreds of diseases, several of which are supported by orthogonal polysomnographic evidence. Leveraging early signs of OSA in clinical data may help to identify at-risk patients. Funding: National Institutes of Health and the American Academy of Sleep Medicine Foundation.

Background: Tuberculosis treatment monitoring is hindered by the lack of a rapidly measured biomarker that accurately predicts clinically relevant outcomes. Symptom screening poorly correlates with bacillary burden. Although culture is a direct measure of viable bacillary burden, the long turnaround time makes it clinically irrelevant. Methods: The tuberculosis treatment monitoring potential of stool-based, quantitative PCR was prospectively assessed among 231 microbiologically confirmed tuberculosis participants of all ages from Eswatini, Tanzania, and Mozambique. Stool qPCR results were compared to sputum culture, persistent symptoms, drug resistance, and WHO tuberculosis outcomes. Results: Quantitative bacillary burden measured by stool qPCR strongly correlated with sputum culture at baseline (Spearman correlation rs = 0.79; p < 0.001). Stool was successfully collected at >90% of all timepoints, while sputum collection decreased to <50% at the end of therapy. Participants with isoniazid or rifampin resistance demonstrated decreased bacillary clearance by sputum culture and stool qPCR during the first two weeks of treatment. Participants who remained culture positive at 2 months had a slower decrease in bacillary burden measured by stool qPCR compared to those who were culture negative by 2 months. The odds of a participant being culture positive at two months was associated with i) a lower initial qPCR cycle threshold (Odds ratio (OR) = 0.792; p = 0.004), and ii) a smaller absolute difference between the qPCR cycle threshold measured at two weeks and baseline (OR = 0.72; p = 0.0006). Neither sputum culture, sputum Xpert Ultra, or stool qPCR were associated with resolution of symptoms or in-treatment death. Conclusions: Stool-based tuberculosis treatment monitoring correlates with sputum culture but provides results faster, leverages a more accessible specimen, and identifies patients with tuberculosis who are at risk for drug resistance and persistent 2-month culture positivity. None of the quantitative tests of bacillary burden singularly could predict symptom resolution or death.

Background: Lynch syndrome (LS) is a hereditary cancer predisposition that increases risk for colorectal, endometrial, and other cancers. Although population-based genomic screening programs identify individuals with LS, clinical presentation in such genomically ascertained populations is unknown. Methods: MyCode is a healthcare system-based biobank that returns clinically actionable genomic screening results to participants, including pathogenic/likely pathogenic (P/LP) variants in LS genes (MLH1, MSH2, MSH6, PMS2). Adult cases (participants with an LS result) and controls (participants without a cancer predisposition variant matched to cases) reported their personal and family cancer histories. Rates of meeting National Comprehensive Cancer Network (NCCN) genetic testing guidelines and rates of colorectal and endometrial cancers in cases, controls, and their family members were calculated and compared. Results: A total of 175 cases (10 MLH1, 7 MSH2, 83 MSH6, and 75 PMS2) and 169 controls were included. Of case pedigrees, 62/175 (35.4%) met NCCN criteria for LS evaluation. Case pedigrees were more likely (P < .001) to meet criteria than control pedigrees (4/169, 8.35%). Case probands had significantly higher rates of colorectal and endometrial cancer than controls (7.7% vs 2.4%, P = .03 colorectal; 11.5% vs 0%, P < .001 endometrial), as did their relatives (3.1% vs 0.9%, P < .001 colorectal; 2.2% vs 0.5%, P < .001 endometrial). Conclusions: NCCN guidelines missed 65% of cases with P/LP LS variants despite families having higher colorectal and endometrial cancer rates compared with controls. Genomic screening can assist in identifying individuals at risk for LS-related cancers, providing an opportunity to tailor risk management for cancer prevention and early detection.

Background: Despite robust evidence supporting an association with improved outcomes in eligible patients, cardiac rehabilitation (CR) remains underused, with a minority of eligible patients participating. Virtual cardiac rehabilitation (VCR) has been proposed as an alternative to traditional center‐based CR (CBCR) to improve usage rates. However, data supporting the efficacy and cost‐effectiveness of VCR are limited. In the present study, we compared the outcomes and cost of a VCR versus traditional CBCR program. Methods and Results: In a retrospective cohort study comparing VCR versus CBCR, CBCR data were collected from a period of January 2018 to September 2023. VCR data were collected from program initiation in July 2021 to September 2023. Primary health outcomes measured were 1‐year mortality rates, recurrent myocardial infarction, all‐cause hospital readmission, and emergency department visits. Primary cost outcomes were analyzed as cost ratios related to VCR versus CBCR assessing total medical costs allowed, pharmacy costs, and total costs of care over the 12 months post‐CR enrollment. VCR was associated with a significant reduction in 1‐year all‐cause hospital readmission (incident rate ratio [IRR], 0.616 [95% CI, 0.489–0.777], P P P =0.0144) and total costs allowed (cost ratio, 0.838 [95% CI, 0.725–0.970], P =0.0176). Conclusions: VCR is a viable alternative to CBCR with at least comparable efficacy and cost, and as such, represents a key mechanism for improving access to and participation in CR for eligible patients.

Key Points: In an unselected health system–based research study, we show that the phenotypic spectrum of X-linked Alport syndrome is wider than previously known. Kidney risks were lower for patients with p.Gly624Asp, a hypomorphic variant that is thought to have originated in Central and Eastern Europe. Many patients in this study had not been diagnosed with Alport syndrome, and consequently, many had not received appropriate testing and treatment. Background: Our knowledge of X-linked Alport syndrome comes mostly from selected cohorts with more severe disease. Methods: We examined the phenotypic spectrum of X-linked Alport syndrome in men and women with a genotype-based approach using data from the Geisinger MyCode DiscovEHR study, an unselected health system–based cohort with exome sequencing and electronic health records. Patients with COL4A5 variants reported as pathogenic or likely pathogenic in ClinVar, or protein-truncating variants, were each matched with up to five controls without COL4A3/4/5 variants by sociodemographics, diabetes diagnosis, and year of first outpatient encounter. Phenotypes examined included dipstick hematuria, bilateral sensorineural hearing loss, proteinuria, lower eGFR, and kidney failure. Results: Of 170,856 patients, there were 29 hemizygous men (mean age 52 years [SD 20]) and 55 heterozygous women (mean age 59 years [SD 19]) with a pathogenic/likely pathogenic COL4A5 variant, including 48 with the hypomorphic variant p.Gly624Asp. Overall, penetrance (having any Alport syndrome phenotypic feature) was the highest for non-p.Gly624Asp variants (men: 94%, women: 85%) and intermediate for p.Gly624Asp (men: 77%, women: 69%) compared with controls (men: 32%, women: 50%). The proportion with kidney failure was the highest for men with non-p.Gly624Asp variants (44%) and intermediate for men with p.Gly624Asp (15%) and women with non-p.Gly624Asp variants (10%) compared with controls (men: 3%, women: 2%). Only 47% of patients with COL4A5 had completed albuminuria screening, and a minority were taking renin-angiotensin-aldosterone system inhibitors. Only 38% of men and 16% of women had a known diagnosis of Alport syndrome or thin basement membrane disease. Conclusions: Using a genotype-first approach, we show that men and women with X-linked Alport syndrome are at higher risk of related phenotypic features with a wider spectrum of severity than has been described previously and variability by genotype.

The IMPACT-FH study implemented strategies (packet, chatbot, direct contact) to promote family member cascade testing for familial hypercholesterolemia (FH). We evaluated the impact of genetic counseling (GC) on medical outcomes, strategy selection, and cascade testing. Probands (i.e., patients with FH) were recommended to complete GC and select sharing strategies. Comparisons were performed for both medical outcomes and strategy selection between probands with or without GC. GEE models for Poisson regression were used to examine the relationship between proband GC completion and first-degree relative (FDR) cascade testing. Overall, 46.3% (81/175) of probands completed GC. Probands with GC had a median LDL-C reduction of −13.0 mg/dL (−61.0, 4.0) versus −1.0 mg/dL (−16.0, 17.0) in probands without GC (p = 0.0054). Probands with and without GC selected sharing strategies for 65.3% and 40.3% of FDRs, respectively (p < 0.0001). Similarly, 27.1% of FDRs of probands with GC completed cascade testing, while 12.0% of FDRs of probands without GC completed testing (p = 0.0043). Direct contact was selected for 47 relatives in total and completed for 39, leading to the detection of 18 relatives with FH. Proband GC was associated with improved medical outcomes and increased FDR cascade testing. Direct contact effectively identified FH cases for the subset who participated.