Clinical Effectiveness of Cognitively Enhanced Tai Ji Quan Training on Global Cognition and Dual-Task Performance During Walking in Older Adults With Mild Cognitive Impairment or Self-Reported Memory Concerns: A Randomized Controlled Trial: Annals of Internal Medicine: Vol 176, No 11

Background: Mild cognitive impairment (MCI) negatively impacts cognition and dual-task abilities. A physical–cognitive integrated treatment approach could mitigate this risk for dementia. Objective: To compare the effectiveness of cognitively enhanced tai ji quan versus standard tai ji quan or stretching exercise in improving global cognition and reducing dual-task walking costs in older adults with MCI or self-reported memory concerns. Design: 3-group, randomized (1:1:1), superiority trial. (ClinicalTrials.gov: NCT04070703) Setting: Community residential homes. Participants: 318 older adults with self-reported memory decline or concern and a Clinical Dementia Rating (CDR) global score of 0.5 or lower at baseline. Intervention: Cognitively enhanced tai ji quan (n = 105), standard tai ji quan (n = 107), or stretching (n = 106). All groups exercised at home via real-time videoconferencing, 1 hour semiweekly for 24 weeks. Measurements: The co–primary endpoints were change in Montreal Cognitive Assessment (MoCA; range, 0 to 30) and dual-task walking costs (difference between single- and dual-task gait speed, expressed in percentage) from baseline to 24 weeks. Secondary outcomes included CDR–Sum of Boxes (CDR-SB), Trail Making Test B, Digit Span Backward (DSB), and physical performance tests. Outcomes were assessed at 16, 24 (primary endpoint), and 48 weeks (6 months after intervention). Results: A total of 304 participants (96%) completed the 24-week assessment. Cognitively enhanced tai ji quan outperformed standard tai ji quan and stretching with a greater improvement in MoCA score (mean difference, 1.5 points [98.75% CI, 0.7 to 2.2 points] and 2.8 points [CI, 2.1 to 3.6 points], respectively) and in dual-task walking (mean difference, 9.9% [CI, 2.8% to 16.6%] and 22% [CI, 13% to 31%], respectively). The intervention effects persisted at 48-week follow-up. Limitation: There was no nonexercise control group; participants had subjective or mild cognitive impairment. Conclusion: Among community-dwelling older adults with MCI, cognitively enriched tai ji quan therapy was superior to standard tai ji quan and stretching exercise in improving global cognition and reducing dual-task gait interference, with outcomes sustained at 48 weeks. Primary Funding Source: National Institute on Aging.

Gene Therapy Versus Common Care for Eligible Individuals With Sickle Cell Disease in the United States: A Cost-Effectiveness Analysis: Annals of Internal Medicine: Vol 177, No 2

Background: Sickle cell disease (SCD) and its complications contribute to high rates of morbidity and early mortality and high cost in the United States and African heritage community. Objective: To evaluate the cost-effectiveness of gene therapy for SCD and its value-based prices (VBPs). Design: Comparative modeling analysis across 2 independently developed simulation models (University of Washington Model for Economic Analysis of Sickle Cell Cure [UW-MEASURE] and Fred Hutchinson Institute Sickle Cell Disease Outcomes Research and Economics Model [FH-HISCORE]) using the same databases. Data Sources: Centers for Medicare & Medicaid Services claims data, 2008 to 2016; published literature. Target Population: Persons eligible for gene therapy. Time Horizon: Lifetime. Perspective: U.S. health care sector and societal. Intervention: Gene therapy versus common care. Outcome Measures: Incremental cost-effectiveness ratios (ICERs), equity-informed VBPs, and price acceptability curves. Results of Base-Case Analysis: At an assumed $2 million price for gene therapy, UW-MEASURE and FH-HISCORE estimated ICERs of $193 000 per QALY and $427 000 per QALY, respectively, under the health care sector perspective. Corresponding estimates from the societal perspective were $126 000 per QALY and $281 000 per QALY. The difference in results between models stemmed primarily from considering a slightly different target population and incorporating the quality-of-life (QOL) effects of splenic sequestration, priapism, and acute chest syndrome in the UW model. From a societal perspective, acceptable (>90% confidence) VBPs ranged from $1 million to $2.5 million depending on the use of alternative effective metrics or equity-informed threshold values. Results of Sensitivity Analysis: Results were sensitive to the costs of myeloablative conditioning before gene therapy, effect on caregiver QOL, and effect of gene therapy on long-term survival. Limitation: The short-term effects of gene therapy on vaso-occlusive events were extrapolated from 1 study. Conclusion: Gene therapy for SCD below a $2 million price tag is likely to be cost-effective when applying a societal perspective at an equity-informed threshold for cost-effectiveness analysis. Primary Funding Source: National Heart, Lung, and Blood Institute.

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.

Effect of Health Service Area on Primary Care Physician Provision of Low-Value Cancer Screening

Background: Using a health systems approach to investigate low-value care (LVC) may provide insights into structural drivers of this pervasive problem. Objective: To evaluate the influence of service area practice patterns on low-value mammography and prostate-specific antigen (PSA) testing. Design: Retrospective study analyzing LVC rates between 2008 and 2018, leveraging physician relocation in 3-year intervals of matched physician and patient groups. Setting: U.S. Medicare claims data. Participants: 8254 physicians and 56 467 patients aged 75 years or older. Measurements: LVC rates for physicians staying in their original service area and those relocating to new areas. Results: Physicians relocating from higher-LVC areas to low-LVC areas were more likely to provide lower rates of LVC. For mammography, physicians staying in high-LVC areas (LVC rate, 10.1% [95% CI, 8.8% to 12.2%]) or medium-LVC areas (LVC rate, 10.3% [CI, 9.0% to 12.4%]) provided LVC at a higher rate than physicians relocating from those areas to low-LVC areas (LVC rates, 6.0% [CI, 4.4% to 7.5%] [difference, −4.1 percentage points {CI, −6.7 to −2.3 percentage points}] and 5.9% [CI, 4.6% to 7.8%] [difference, −4.4 percentage points {CI, −6.7 to −2.4 percentage points}], respectively). For PSA testing, physicians staying in high- or moderate-LVC service areas provided LVC at a rate of 17.5% (CI, 14.9% to 20.7%) or 10.6% (CI, 9.6% to 13.2%), respectively, compared with those relocating from those areas to low-LVC areas (LVC rates, 9.9% [CI, 7.5% to 13.2%] [difference, −7.6 percentage points {CI, −10.9 to −3.8 percentage points}] and 6.2% [CI, 3.5% to 9.8%] [difference, −4.4 percentage points {CI, −7.6 to −2.2 percentage points}], respectively). Physicians relocating from lower- to higher-LVC service areas were not more likely to provide LVC at a higher rate. Limitation: Use of retrospective observational data, possible unmeasured confounding, and potential for relocating physicians to practice differently from those who stay. Conclusion: Physicians relocating to service areas with lower rates of LVC provided less LVC than physicians who stayed in areas with higher rates of LVC. Systemic structures may contribute to LVC. Understanding which factors are contributing may present opportunities for policy and interventions to broadly improve care. Primary Funding Source: National Cancer Institute of the National Institutes of Health.

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.

Time-Restricted Eating for Treatment of Obesity? The Devil Is in the (Counseling) Details

Effectiveness of Nirmatrelvir–Ritonavir Against the Development of Post–COVID-19 Conditions Among U.S. Veterans: A Target Trial Emulation: Annals of Internal Medicine: Vol 176, No 11

Background: COVID-19 has been linked to the development of many post–COVID-19 conditions (PCCs) after acute infection. Limited information is available on the effectiveness of oral antivirals used to treat acute COVID-19 in preventing the development of PCCs. Objective: To measure the effectiveness of outpatient treatment of COVID-19 with nirmatrelvir–ritonavir in preventing PCCs. Design: Retrospective target trial emulation study comparing matched cohorts receiving nirmatrelvir–ritonavir versus no treatment. Setting: Veterans Health Administration (VHA). Participants: Nonhospitalized veterans in VHA care who were at risk for severe COVID-19 and tested positive for SARS-CoV-2 during January through July 2022. Intervention: Nirmatrelvir–ritonavir treatment for acute COVID-19. Measurements: Cumulative incidence of 31 potential PCCs at 31 to 180 days after treatment or a matched index date, including cardiac, pulmonary, renal, thromboembolic, gastrointestinal, neurologic, mental health, musculoskeletal, endocrine, and general conditions and symptoms. Results: Eighty-six percent of the participants were male, with a median age of 66 years, and 17.5% were unvaccinated. Baseline characteristics were well balanced between participants treated with nirmatrelvir–ritonavir and matched untreated comparators. No differences were observed between participants treated with nirmatrelvir–ritonavir (n = 9593) and their matched untreated comparators in the incidence of most PCCs examined individually or grouped by organ system, except for lower combined risk for venous thromboembolism and pulmonary embolism (subhazard ratio, 0.65 [95% CI, 0.44 to 0.97]; cumulative incidence difference, −0.29 percentage points [CI, −0.52 to −0.05 percentage points]). Limitations: Ascertainment of PCCs using International Classification of Diseases, 10th Revision, codes may be inaccurate. Evaluation of many outcomes could have resulted in spurious associations with combined thromboembolic events by chance. Conclusion: Out of 31 potential PCCs, only combined thromboembolic events seemed to be reduced by nirmatrelvir–ritonavir. Primary Funding Source: U.S. Department of Veterans Affairs.

Colonoscopy-Ascertained Prevalence of Advanced Neoplasia According to Fecal Hemoglobin Concentration in a Large Cohort of Fecal Immunochemical Test–Negative Screening Participants

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