Search

JAMA: Journal of the American Medical Association has published a Special Communication titled "The Integration of Clinical Trials With the Practice of Medicine: Repairing a House Divided," which discusses the need to integrate clinical trials with clinical practice. The authors highlight the separate missions and infrastructures of clinical trialists and clinicians, leading to inefficiencies and limitations in trials. They propose solutions such as implementation science, novel statistical analysis approaches, and integration of trials with electronic health records. JAMA is launching a new series called "Integrating Clinical Trials and Practice" to explore innovations in trial design, funding, regulation, education, and application. The goal is to align clinical trials with clinical practice and improve patient care. [Extracted from the article]

Context Not all research presented at scientific meetings is subsequently published and, even when it is, there may be inconsistencies between these results and what is ultimately printed. Although late-breaking trials sessions are now integrated into several major scientific meetings and the results are often promptly and prominently communicated, no studies have examined the publication fate and degree of consistency between meeting abstracts or presentations and subsequent full-length article publications for randomized controlled trials (RCTs) presented at these sessions. Objective To compare RCT abstracts presented in the late-breaking trials session vs other sessions at a major scientific meeting and subsequent full-length publications. Design RCTs were identified by hand searching abstract proceedings booklets and related Web sites for the American College of Cardiology scientific meetings (1999-2002). Subsequent full-length articles were identified via electronic databases. Main Outcome Measures Publication fate and degree of consistency between meeting abstract results and subsequent full-length publication results. Results The 86 late-breaking RCTs were significantly larger (median, 2737 patients vs 896; P<.001), were more likely to be preceded by a published design paper (27 [31%] vs 13 [13%]; P = .002), had higher quality scores when eventually published (mean Jadad score 2.69 vs 2.19; P = .01), and were less likely to report favorable results for the intervention than the 100 randomly chosen comparison RCTs presented in other sessions (50 [58%] vs 75 [75%]; P = .01; odds ratio 0.46; 95% confidence interval, 0.24-0.90). RCTs presented at the late-breaking trials sessions were significantly more likely to be published (79 [92%] vs 69 [69%]; P<.001) and appeared earlier after presentation (median 11.5 months vs 22.0 months; P<.001) than RCTs presented in other sessions, an association that persisted even after adjusting for sample size, conclusion of study, and RCT design: adjusted hazard ratio, 1.80 (95% confidence interval, 1.24-2.61). Sixty (41%) of the 148 RCTs that were subsequently published exhibited discrepancies between the efficacy estimate reported in the meeting abstract vs the one reported in the full-length article for the primary outcome. The mean change in effect was 0.44 SDs and in 20 cases (14%), the point estimate was statistically significant in only 1 member of the pair. The discrepancy rate was the same for late-breaking RCTs as for RCTs presented in other American College of Cardiology sessions (P = .92). Conclusions Late-breaking trials were larger, more likely to be preceded by a design paper, and less likely to report positive results than RCTs presented at other sessions, but discrepancies between the meeting abstract results and subsequent full-length publication results were common even for late-breaking trials. [ABSTRACT FROM AUTHOR]

The article presents a thank you to the 2005 "Journal of the American Medical Association" (JAMA) peer reviewers who completed manuscript reviews for JAMA and authors who submitted manuscripts for consideration for publication in JAMA. The article reflects on the peer reviewers' critiques and recommendations that help to ensure the scientific quality of articles published in JAMA. The reviewers alerted JAMA about ethical issues concerning some of the submitted papers, such as duplicate submissions, plagiarism, and concerns about data or research integrity. The authors submitted papers that cover a wide spectrum of medicine, including major medical trials and scientific discoveries.

Key Points: Question: Is stepped care, with palliative care visits occurring only at key points in patients' cancer trajectories and using a decrement in quality of life (QOL) to trigger more intensive palliative care, an effective model for delivering palliative care to patients with advanced cancer? Findings: In this randomized trial of 507 adults with advanced lung cancer, patients assigned to stepped palliative care had significantly fewer palliative care visits and reported QOL scores at week 24 that were noninferior (adjusted mean, 100.6 vs 97.8; P <.001) to the QOL scores of patients assigned to an early palliative care model with monthly visits after diagnosis. Meaning: Stepped palliative care is an effective and more scalable means to deliver palliative care to improve QOL for patients with advanced lung cancer. Importance: Despite the evidence for early palliative care improving outcomes, it has not been widely implemented in part due to palliative care workforce limitations. Objective: To evaluate a stepped-care model to deliver less resource-intensive and more patient-centered palliative care for patients with advanced cancer. Design, Setting, and Participants: Randomized, nonblinded, noninferiority trial of stepped vs early palliative care conducted between February 12, 2018, and December 15, 2022, at 3 academic medical centers in Boston, Massachusetts, Philadelphia, Pennsylvania, and Durham, North Carolina, among 507 patients who had been diagnosed with advanced lung cancer within the past 12 weeks. Intervention: Step 1 of the intervention was an initial palliative care visit within 4 weeks of enrollment and subsequent visits only at the time of a change in cancer treatment or after a hospitalization. During step 1, patients completed a measure of quality of life (QOL; Functional Assessment of Cancer Therapy–Lung [FACT-L]; range, 0-136, with higher scores indicating better QOL) every 6 weeks, and those with a 10-point or greater decrease from baseline were stepped up to meet with the palliative care clinician every 4 weeks (intervention step 2). Patients assigned to early palliative care had palliative care visits every 4 weeks after enrollment. Main Outcomes and Measures: Noninferiority (margin = −4.5) of the effect of stepped vs early palliative care on patient-reported QOL on the FACT-L at week 24. Results: The sample (n = 507) mostly included patients with advanced non–small cell lung cancer (78.3%; mean age, 66.5 years; 51.4% female; 84.6% White). The mean number of palliative care visits by week 24 was 2.4 for stepped palliative care and 4.7 for early palliative care (adjusted mean difference, −2.3; P <.001). FACT-L scores at week 24 for the stepped palliative care group were noninferior to scores among those receiving early palliative care (adjusted FACT-L mean score, 100.6 vs 97.8, respectively; difference, 2.9; lower 1-sided 95% confidence limit, −0.1; P <.001 for noninferiority). Although the rate of end-of-life care communication was also noninferior between groups, noninferiority was not demonstrated for days in hospice (adjusted mean, 19.5 with stepped palliative care vs 34.6 with early palliative care; P =.91). Conclusions and Relevance: A stepped-care model, with palliative care visits occurring only at key points in patients' cancer trajectories and using a decrement in QOL to trigger more intensive palliative care exposure, resulted in fewer palliative care visits without diminishing the benefits for patients' QOL. While stepped palliative care was associated with fewer days in hospice, it is a more scalable way to deliver early palliative care to enhance patient-reported outcomes. Trial Registration: ClinicalTrials.gov Identifier: NCT03337399 This randomized clinical trial assesses whether a stepped-care model of palliative care is noninferior to early integrated palliative care based on patient-reported quality of life among patients with advanced lung cancer. [ABSTRACT FROM AUTHOR]

Key Points: Question: For people with chronic obstructive pulmonary disease (COPD) at high risk of exacerbations, does bisoprolol reduce the number of exacerbations? Finding: In this randomized double-blind placebo-controlled trial of 515 people with COPD, the number of exacerbations requiring treatment with oral corticosteroids, antibiotics, or both did not differ significantly with use of bisoprolol (mean exacerbations, 2.03/y) vs placebo (mean exacerbations, 2.01/y). Meaning: Treatment with bisoprolol did not reduce COPD exacerbations requiring treatment with oral corticosteroids, antibiotics, or both. This randomized clinical trial examines whether the addition of bisoprolol to treatment of people with chronic obstructive pulmonary disease (COPD) at high risk of exacerbation reduces the rate of moderate to severe exacerbations. Importance: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Observational studies report that β-blocker use may be associated with reduced risk of COPD exacerbations. However, a recent trial reported that metoprolol did not reduce COPD exacerbations and increased COPD exacerbations requiring hospital admission. Objective: To test whether bisoprolol decreased COPD exacerbations in people with COPD at high risk of exacerbations. Design, Setting, and Participants: The Bisoprolol in COPD Study (BICS) was a double-blind placebo-controlled randomized clinical trial conducted in 76 UK sites (45 primary care clinics and 31 secondary clinics). Patients with COPD who had at least moderate airflow obstruction on spirometry (ratio of forced expiratory volume in the first second of expiration [FEV1] to forced vital capacity <0.7; FEV1 <80% predicted) and at least 2 COPD exacerbations treated with oral corticosteroids, antibiotics, or both in the prior 12 months were enrolled from October 17, 2018, to May 31, 2022. Follow-up concluded on April 18, 2023. Interventions: Patients were randomly assigned to bisoprolol (n = 261) or placebo (n = 258). Bisoprolol was started at 1.25 mg orally daily and was titrated as tolerated during 4 sessions to a maximum dose of 5 mg/d, using a standardized protocol. Main Outcomes and Measures: The primary clinical outcome was the number of patient-reported COPD exacerbations treated with oral corticosteroids, antibiotics, or both during the 1-year treatment period. Safety outcomes included serious adverse events and adverse reactions. Results: Although the trial planned to enroll 1574 patients, recruitment was suspended from March 16, 2020, to July 31, 2021, due to the COVID-19 pandemic. Two patients in each group were excluded postrandomization. Among the 515 patients (mean [SD] age, 68 [7.9] years; 274 men [53%]; mean FEV1, 50.1%), primary outcome data were available for 514 patients (99.8%) and 371 (72.0%) continued taking the study drug. The primary outcome of patient-reported COPD exacerbations treated with oral corticosteroids, antibiotics, or both was 526 in the bisoprolol group, with a mean exacerbation rate of 2.03/y, vs 513 exacerbations in the placebo group, with a mean exacerbation rate of 2.01/y. The adjusted incidence rate ratio was 0.97 (95% CI, 0.84-1.13; P =.72). Serious adverse events occurred in 37 of 255 patients in the bisoprolol group (14.5%) vs 36 of 251 in the placebo group (14.3%; relative risk, 1.01; 95% CI, 0.62-1.66; P =.96). Conclusions and Relevance: Among people with COPD at high risk of exacerbation, treatment with bisoprolol did not reduce the number of self-reported COPD exacerbations requiring treatment with oral corticosteroids, antibiotics, or both. Trial Registration: isrctn.org Identifier: ISRCTN10497306 [ABSTRACT FROM AUTHOR]

Importance: Sodium-glucose cotransporter 2 (SGLT-2) inhibitors improve outcomes in patients with type 2 diabetes, heart failure, and chronic kidney disease, but their effect on outcomes of critically ill patients with organ failure is unknown. Objective: To determine whether the addition of dapagliflozin, an SGLT-2 inhibitor, to standard intensive care unit (ICU) care improves outcomes in a critically ill population with acute organ dysfunction. Design, Setting, and Participants: Multicenter, randomized, open-label, clinical trial conducted at 22 ICUs in Brazil. Participants with unplanned ICU admission and presenting with at least 1 organ dysfunction (respiratory, cardiovascular, or kidney) were enrolled between November 22, 2022, and August 30, 2023, with follow-up through September 27, 2023. Intervention: Participants were randomized to 10 mg of dapagliflozin (intervention, n = 248) plus standard care or to standard care alone (control, n = 259) for up to 14 days or until ICU discharge, whichever occurred first. Main Outcomes and Measures: The primary outcome was a hierarchical composite of hospital mortality, initiation of kidney replacement therapy, and ICU length of stay through 28 days, analyzed using the win ratio method. Secondary outcomes included the individual components of the hierarchical outcome, duration of organ support–free days, ICU, and hospital stay, assessed using bayesian regression models. Results: Among 507 randomized participants (mean age, 63.9 [SD, 15] years; 46.9%, women), 39.6% had an ICU admission due to suspected infection. The median time from ICU admission to randomization was 1 day (IQR, 0-1). The win ratio for dapagliflozin for the primary outcome was 1.01 (95% CI, 0.90 to 1.13; P =.89). Among all secondary outcomes, the highest probability of benefit found was 0.90 for dapagliflozin regarding use of kidney replacement therapy among 27 patients (10.9%) in the dapagliflozin group vs 39 (15.1%) in the control group. Conclusion and Relevance: The addition of dapagliflozin to standard care for critically ill patients and acute organ dysfunction did not improve clinical outcomes; however, confidence intervals were wide and could not exclude relevant benefits or harms for dapagliflozin. Trial Registration: ClinicalTrials.gov Identifier: NCT05558098 Key Points: Question: Does the addition of dapagliflozin to standard of care improve the hierarchical outcome of hospital mortality, initiation of kidney replacement therapy, and the length of stay in the intensive care unit (ICU) among critically ill patients with acute organ dysfunction? Findings: In this multicenter, open-label, randomized clinical trial that included 507 participants with at least 1 acute organ dysfunction (hypotension, kidney injury, or respiratory), the use of 10 mg of dapagliflozin for up to 14 days did not significantly reduce the combined outcome of hospital mortality, initiation of kidney replacement therapy, and ICU length of stay, assessed by the win ratio method (win ratio, 1.01, not significant) through 28 days after randomization. Meaning: The addition of dapagliflozin to standard care for individuals with critical illness and acute organ dysfunction did not improve clinical outcomes. This randomized clinical trial assessed whether adding dapagliflozin to standard care for patients with acute organ dysfunction could reduce the composite outcome of hospital mortality, initiation of kidney replacement therapy, and length of stay compared with standard care alone. [ABSTRACT FROM AUTHOR]

Key Points: Question: Do text messages with or without financial incentives promote weight loss in men with obesity? Findings: In this randomized trial that included 585 men with obesity, text messaging with behavioral messages combined with a financial incentive resulted in a 5% weight loss at 12 months, compared with weight loss of 3% for text messaging alone, and 1% for the control group. The difference in weight loss was statistically significant for the comparison between text messaging with financial incentives and the control group but not between the text messaging alone and the control group. Meaning: In men with obesity, a 12-month intervention consisting of text messaging with financial incentives resulted in modest but statistically significant weight loss compared with control. Importance: Effective weight loss interventions are needed for men with obesity. Objective: To determine whether an intervention that combined text messaging with financial incentives attained significant weight loss at the 12-month follow-up compared with the control group and whether an intervention of text messaging alone attained significant weight loss at the 12-month follow-up compared with the control group. Design, Setting, and Participants: An assessor-blinded randomized clinical trial conducted in Belfast, Bristol, and Glasgow areas in the UK. A total of 585 men with body mass index (BMI) of 30 or more were enrolled between July 2021 and May 2022. Final follow-up occurred June 2023. Interventions: Participants were randomly assigned to 12 months of behavioral focused text messages combined with financial incentives (n = 196), 12 months of behavioral focused text messages alone (n= 194), or a waiting list (control group; n= 195). The financial incentive consisted of a monetary reward that was lost if weight loss targets were not met. All participants received weight management information and a pedometer at baseline. Main Outcomes and Measures: The 2 primary comparisons were the 12-month comparison of within-participant weight change between the text messaging with financial incentive group and the control group and the comparison between the text messaging alone group and the control group (minimum clinically important difference, 3%). The P value defined for statistical significance was P <.025 for each comparison. Results: Of the 585 men (mean [SD] age, 50.7 [13.3] years; mean weight, 118.5 [19.9] kg; mean BMI, 37.7 [5.7]; 525 [90%] White), 227 (39%) lived in postal code areas with lower socioeconomic status, and 426 (73%) completed the 12-month follow-up. At the 12-month follow-up, compared with the control group, the mean percent weight change was significantly greater in the text messaging with financial incentive group (mean difference, −3.2%; 97.5% CI, −4.6% to −1.9%; P <.001) but was not significantly greater in the text messaging alone group (mean difference, −1.4%; 97.5% CI, −2.9% to 0.0, P =.05). The mean (SD) weight changes were −5.7 (7.4) kg for the text messaging with financial incentives group, −3.0 (7.5) kg for the text messaging alone group, and −1.5 (6.6) kg for the control group. The 12-month mean (SD) percentage weight changes from baseline were −4.8% (6.1%) for the text messaging with financial incentives group, −2.7% (6.3%) for text messaging alone group, and −1.3% (5.5%) for the control group. Of 366 adverse events reported, the most common were infections (83 [23%]). Of the 23 serious adverse events (6.3%), 12 (52%) occurred in the text messaging with financial incentives group, 5 (22%) in the texts messaging alone group, and 6 (26%) in the control group. None were considered related to participating in a trial group. Conclusion and Relevance: Among men with obesity, an intervention with text messaging with financial incentive significantly improved weight loss compared with a control group, whereas text messaging alone was not significantly better than the control condition. These findings support text messaging combined with financial incentives to attain weight loss in men with obesity. Trial Registration: isrctn.org Identifier: ISRCTN91974895 This randomized clinical trial assesses whether text messaging combined with financial incentives or text messages alone could help men with obesity lose weight at 12 months. [ABSTRACT FROM AUTHOR]

Key Points: Question: Does the benefit of renin-angiotensin system (RAS) blockers in patients with heart failure and reduced ejection fraction differ between Black and non-Black patients? Findings: In this meta-analysis involving more than 16 000 patients from 5 randomized trials, the mortality benefit from RAS blockade was similar in Black and non-Black patients. Although the relative risk reduction in hospitalizations for heart failure was smaller in Black patients, the absolute benefit was comparable in the 2 groups given the greater incidence of hospitalization in Black patients. Meaning: RAS blockers are effective at improving cardiovascular outcomes in Black and non-Black patients with heart failure. Importance: Concerns have arisen that renin-angiotensin system (RAS) blockers are less effective in Black patients than non-Black patients with heart failure and reduced ejection fraction (HFrEF). Objective: To determine whether the effects of RAS blockers on cardiovascular outcomes differ between Black patients and non-Black patients with HFrEF. Data Sources: MEDLINE and Embase databases through December 31, 2023. Study Selection: Randomized trials investigating the effect of RAS blockers on cardiovascular outcomes in adults with HFrEF that enrolled Black and non-Black patients. Data Extraction and Synthesis: Individual-participant data were extracted following Preferred Reporting Items for Systematic Reviews and Meta-analyses Independent Personal Data (PRISMA-IPD) reporting guidelines. Effects were estimated using a mixed-effects model using a 1-stage approach. Main Outcome and Measure: The primary outcome was first hospitalization for HF or cardiovascular death. Results: The primary analysis, based on the 3 placebo-controlled RAS inhibitor monotherapy trials, included 8825 patients (9.9% Black). Rates of death and hospitalization for HF were substantially higher in Black than non-Black patients. The hazard ratio (HR) for RAS blockade vs placebo for the primary composite was 0.84 (95% CI, 0.69-1.03) in Black patients and 0.73 (95% CI, 0.67-0.79) in non-Black patients (P for interaction =.14). The HR for first HF hospitalization was 0.89 (95% CI, 0.70-1.13) in Black patients and 0.62 (95% CI, 0.56-0.69) in non-Black patients (P for interaction =.006). Conversely, the corresponding HRs for cardiovascular death were 0.83 (95% CI, 0.65-1.07) and 0.84 (95% CI, 0.77-0.93), respectively (P for interaction =.99). For total hospitalizations for HF and cardiovascular deaths, the corresponding rate ratios were 0.82 (95% CI, 0.66-1.02) and 0.72 (95% CI, 0.66-0.80), respectively (P for interaction =.27). The supportive analyses including the 2 trials adding an angiotensin receptor blocker to background angiotensin-converting enzyme inhibitor treatment (n = 16 383) gave consistent findings. Conclusions and Relevance: The mortality benefit from RAS blockade was similar in Black and non-Black patients. Despite the smaller relative risk reduction in hospitalization for HF with RAS blockade in Black patients, the absolute benefit in Black patients was comparable with non-Black patients because of the greater incidence of this outcome in Black patients. This meta-analysis assesses whether Black patients with heart failure and reduced ejection fraction respond differently than patients of other races to renin-angiotensin system (RAS) blockade by examining individual patient data from randomized clinical trials. [ABSTRACT FROM AUTHOR]

Key Points: Question: Compared with the end point of cancer-specific mortality, is incidence of late-stage cancer a suitable alternative end point in randomized clinical trials of cancer screening? Findings: In this systematic review and meta-analysis that included 41 randomized clinical trials of cancer screening, correlation between the reduction in stage III and IV cancer and the reduction in cancer-specific mortality varied by cancer type. The correlation was high in trials that screened for ovarian (Pearson ρ = 0.99) and lung (Pearson ρ = 0.92) cancers, moderate for breast cancer (Pearson ρ = 0.70), and weak for colorectal (Pearson ρ = 0.39) and prostate (Pearson ρ = −0.69) cancers. Meaning: In randomized clinical trials of cancer screening, the correlation between reductions in late-stage cancer and cancer-specific mortality varied meaningfully by cancer type. The end point of late-stage cancer may be an appropriate alternative to cancer-specific mortality for randomized clinical trials of screening for some types of cancer, but not for others. Importance: Randomized clinical trials of cancer screening typically use cancer-specific mortality as the primary end point. The incidence of stage III-IV cancer is a potential alternative end point that may accelerate completion of randomized clinical trials of cancer screening. Objective: To compare cancer-specific mortality with stage III-IV cancer as end points in randomized clinical trials of cancer screening. Design, Setting, and Participants: This meta-analysis included 41 randomized clinical trials of cancer screening conducted in Europe, North America, and Asia published through February 19, 2024. Data extracted included numbers of participants, cancer diagnoses, and cancer deaths in the intervention and comparison groups. For each clinical trial, the effect of screening was calculated as the percentage reduction between the intervention and comparison groups in the incidence of participants with cancer-specific mortality and stage III-IV cancer. Exposures: Randomization to a cancer screening test or to a comparison group in a clinical trial of cancer screening. Main Outcomes and Measures: End points of cancer-specific mortality and incidence of stage III-IV cancer were compared using Pearson correlation coefficients with 95% CIs, linear regression, and fixed-effects meta-analysis. Results: The included randomized clinical trials tested benefits of screening for breast (n = 6), colorectal (n = 11), lung (n = 12), ovarian (n = 4), prostate (n = 4), and other cancers (n = 4). Correlation between reductions in cancer-specific mortality and stage III-IV cancer varied by cancer type (I2 = 65%; P =.02). Correlation was highest for trials that screened for ovarian (Pearson ρ = 0.99 [95% CI, 0.51-1.00]) and lung (Pearson ρ = 0.92 [95% CI, 0.72-0.98]) cancers, moderate for breast cancer (Pearson ρ = 0.70 [95% CI, −0.26 to 0.96]), and weak for colorectal (Pearson ρ = 0.39 [95% CI, −0.27 to 0.80]) and prostate (Pearson ρ = −0.69 [95% CI, −0.99 to 0.81]) cancers. Slopes from linear regression were estimated as 1.15 for ovarian cancer, 0.75 for lung cancer, 0.40 for colorectal cancer, 0.28 for breast cancer, and −3.58 for prostate cancer, suggesting that a given magnitude of reduction in incidence of stage III-IV cancer produced different magnitudes of change in incidence of cancer-specific mortality (P for heterogeneity =.004). Conclusions and Relevance: In randomized clinical trials of cancer screening, incidence of late-stage cancer may be a suitable alternative end point to cancer-specific mortality for some cancer types, but is not suitable for others. These results have implications for clinical trials of multicancer screening tests. This meta-analysis of 41 randomized clinical trials of cancer screening compares cancer-specific mortality with stage III-IV cancer as end points. [ABSTRACT FROM AUTHOR]

Importance: Many medical journals, including JAMA, restrict the use of causal language to the reporting of randomized clinical trials. Although well-conducted randomized clinical trials remain the preferred approach for answering causal questions, methods for observational studies have advanced such that causal interpretations of the results of well-conducted observational studies may be possible when strong assumptions hold. Furthermore, observational studies may be the only practical source of information for answering some questions about the causal effects of medical or policy interventions, can support the study of interventions in populations and settings that reflect practice, and can help identify interventions for further experimental investigation. Identifying opportunities for the appropriate use of causal language when describing observational studies is important for communication in medical journals. Observations: A structured approach to whether and how causal language may be used when describing observational studies would enhance the communication of research goals, support the assessment of assumptions and design and analytic choices, and allow for more clear and accurate interpretation of results. Building on the extensive literature on causal inference across diverse disciplines, we suggest a framework for observational studies that aim to provide evidence about the causal effects of interventions based on 6 core questions: what is the causal question; what quantity would, if known, answer the causal question; what is the study design; what causal assumptions are being made; how can the observed data be used to answer the causal question in principle and in practice; and is a causal interpretation of the analyses tenable? Conclusions and Relevance: Adoption of the proposed framework to identify when causal interpretation is appropriate in observational studies promises to facilitate better communication between authors, reviewers, editors, and readers. Practical implementation will require cooperation between editors, authors, and reviewers to operationalize the framework and evaluate its effect on the reporting of empirical research. This Special Communication examines drawing causal inferences about the effects of interventions from observational studies in medical journals. [ABSTRACT FROM AUTHOR]

Importance: Approximately 55 million people in the US and approximately 1.1 billion people worldwide are postmenopausal women. To inform clinical practice about the health effects of menopausal hormone therapy, calcium plus vitamin D supplementation, and a low-fat dietary pattern, the Women's Health Initiative (WHI) enrolled 161 808 postmenopausal US women (N = 68 132 in the clinical trials) aged 50 to 79 years at baseline from 1993 to 1998, and followed them up for up to 20 years. Observations: The WHI clinical trial results do not support hormone therapy with oral conjugated equine estrogens plus medroxyprogesterone acetate for postmenopausal women or conjugated equine estrogens alone for those with prior hysterectomy to prevent cardiovascular disease, dementia, or other chronic diseases. However, hormone therapy is effective for treating moderate to severe vasomotor and other menopausal symptoms. These benefits of hormone therapy in early menopause, combined with lower rates of adverse effects of hormone therapy in early compared with later menopause, support initiation of hormone therapy before age 60 years for women without contraindications to hormone therapy who have bothersome menopausal symptoms. The WHI results do not support routinely recommending calcium plus vitamin D supplementation for fracture prevention in all postmenopausal women. However, calcium and vitamin D are appropriate for women who do not meet national guidelines for recommended intakes of these nutrients through diet. A low-fat dietary pattern with increased fruit, vegetable, and grain consumption did not prevent the primary outcomes of breast or colorectal cancer but was associated with lower rates of the secondary outcome of breast cancer mortality during long-term follow-up. Conclusions and Relevance: For postmenopausal women, the WHI randomized clinical trials do not support menopausal hormone therapy to prevent cardiovascular disease or other chronic diseases. Menopausal hormone therapy is appropriate to treat bothersome vasomotor symptoms among women in early menopause, without contraindications, who are interested in taking hormone therapy. The WHI evidence does not support routine supplementation with calcium plus vitamin D for menopausal women to prevent fractures or a low-fat diet with increased fruits, vegetables, and grains to prevent breast or colorectal cancer. A potential role of a low-fat dietary pattern in reducing breast cancer mortality, a secondary outcome, warrants further study. This review of the Women's Health Initiative (WHI) summarizes the results of the 4 WHI clinical trials on menopausal hormone therapy, calcium plus vitamin D supplementation, and low-fat diet and their applications to current clinical practice. [ABSTRACT FROM AUTHOR]

This randomized clinical trial investigates the relative efficacy of Mindfulness-Oriented Recovery Enhancement in addition to methadone treatment as usual compared with usual care only. Key Points: Question: What is the relative efficacy of Mindfulness-Oriented Recovery Enhancement (MORE) as an adjunct to methadone treatment as usual (usual care) as compared with usual care only? Findings: In this randomized clinical trial of 154 individuals with chronic pain in methadone treatment for an opioid use disorder, relative to usual care, MORE plus usual care demonstrated efficacy for decreasing drug use, pain, and depression and increasing methadone treatment retention and adherence. Meaning: Phase 3 clinical trials of MORE and the development of strategies to train clinicians to integrate MORE into methadone treatment programs are warranted. Importance: Methadone treatment (MT) fails to address the emotion dysregulation, pain, and reward processing deficits that often drive opioid use disorder (OUD). New interventions are needed to address these factors. Objective: To evaluate the efficacy of MT as usual (usual care) vs telehealth Mindfulness-Oriented Recovery Enhancement (MORE) plus usual care among people with an OUD and pain. Design, Setting, and Participants: This study was a randomized clinical trial conducted from August 2020 to June 2022. Participants receiving MT for OUD and experiencing chronic pain were recruited at 5 clinics in New Jersey. Interventions: In usual care, participants received MT, including medication and counseling. Participants receiving MORE plus usual care attended 8 weekly, 2-hour telehealth groups that provided training in mindfulness, reappraisal, and savoring in addition to usual care. Main Outcomes and Measure: Primary outcomes were return to drug use and MT dropout over 16 weeks. Secondary outcomes were days of drug use, methadone adherence, pain, depression, and anxiety. Analyses were based on an intention-to-treat approach. Results: A total of 154 participants (mean [SD] age, 48.5 [11.8] years; 88 female [57%]) were included in the study. Participants receiving MORE plus usual care had significantly less return to drug use (hazard ratio [HR], 0.58; 95% CI, 0.37-0.90; P =.02) and MT dropout (HR, 0.41; 95% CI, 0.18-0.96; P =.04) than those receiving usual care only after adjusting for a priori–specified covariates (eg, methadone dose and recent drug use, at baseline). A total of 44 participants (57.1%) in usual care and 39 participants (50.6%) in MORE plus usual care returned to drug use. A total of 17 participants (22.1%) in usual care and 10 participants (13.0%) in MORE plus usual care dropped out of MT. In zero-inflated models, participants receiving MORE plus usual care had significantly fewer days of any drug use (ratio of means = 0.58; 95% CI, 0.53-0.63; P <.001) than those receiving usual care only through 16 weeks. A significantly greater percentage of participants receiving MORE plus usual care maintained methadone adherence (64 of 67 [95.5%]) at the 16-week follow-up than those receiving usual care only (56 of 67 [83.6%]; χ2 = 4.49; P =.04). MORE reduced depression scores and ecological momentary assessments of pain through the 16-week follow-up to a significantly greater extent than usual care (group × time F2,272 = 3.13; P =.05 and group × time F16,13000 = 6.44; P <.001, respectively). Within the MORE plus usual care group, EMA pain ratings decreased from a mean (SD) of 5.79 (0.29) at baseline to 5.17 (0.30) at week 16; for usual care only, pain decreased from 5.19 (0.28) at baseline to 4.96 (0.29) at week 16. Within the MORE plus usual care group, mean (SD) depression scores were 22.52 (1.32) at baseline and 18.98 (1.38) at 16 weeks. In the usual care–only group, mean (SD) depression scores were 22.65 (1.25) at baseline and 20.03 (1.27) at 16 weeks. Although anxiety scores increased in the usual care–only group and decreased in the MORE group, this difference between groups did not reach significance (group × time unadjusted F2,272 = 2.10; P=.12; Cohen d =.44; adjusted F2,268 = 2.33; P =.09). Within the MORE plus usual care group, mean (SD) anxiety scores were 25.5 (1.60) at baseline and 23.45 (1.73) at 16 weeks. In the usual care–only group, mean (SD) anxiety scores were 23.27 (1.75) at baseline and 24.07 (1.73) at 16 weeks. Conclusions and Relevance: This randomized clinical trial demonstrated that telehealth MORE was a feasible adjunct to MT with significant effects on drug use, pain, depression, treatment retention, and adherence. Trial Registration: ClinicalTrials.gov Identifier: NCT04491968 [ABSTRACT FROM AUTHOR]

Context The impact of clinical decision support systems (CDSS) on antimicrobial prescribing in ambulatory settings has not previously been evaluated. Objective To measure the added value of CDSS when coupled with a community intervention to reduce inappropriate prescribing of antimicrobial drugs for acute respiratory tract infections. Design, Participants and Setting Cluster randomized trial that included 407 460 inhabitants and 334 primary care clinicians in 12 rural communities in Utah and Idaho (6 with 1 shared characteristic and 6 with another), and a third group of 6 communities that served as nonstudy controls. The preintervention period was January to December 2001 and the postintervention period was January 2002 to September 2003. Acute respiratory tract infection diagnoses were classified into groups based on indication for antimicrobial use. Multilevel regression methods were applied to account for the clustered design. Intervention Six communities received a community intervention alone and 6 communities received community intervention plus CDSS that were targeted toward primary care clinicians. The CDSS comprised decision support tools on paper and a handheld computer to guide diagnosis and management of acute respiratory tract infection. Main Outcome Measure Community-wide antimicrobial usage was assessed using retail pharmacy data. Diagnosis-specific antimicrobial use was compared by chart review. Results Within CDSS communities, 71% of primary care clinicians participated in the use of CDSS. The prescribing rate decreased from 84.1 to 75.3 per 100 person-years in the CDSS arm vs 84.3 to 85.2 in community intervention alone, and remained stable in the other communities (P = .03). A total of 13 081 acute respiratory tract infection visits were abstracted. The relative decrease in antimicrobial prescribing for visits in the antibiotics “never-indicated” category during the post-intervention period was 32% in CDSS communities and 5% in community intervention-alone communities (P = .03). Use of macrolides decreased significantly in CDSS communities but not in community intervention–alone communities. Conclusion CDSS implemented in rural primary care settings reduced overall antimicrobial use and improved appropriateness of antimicrobial selection for acute respiratory tract infections. Trial Registration ClinicalTrials.gov Identifier: NCT00235703. [ABSTRACT FROM AUTHOR]

Presents the text of the speech by E. Patchen Dellinger, president of the Surgical Infection Society (SIS), presented at the 18th annual meeting of SIS on May 1, 1998, concerning the importance of clinical trials.

Key Points: Question: Is treatment with a coronary paclitaxel-coated balloon superior to an uncoated balloon for 1-year target lesion failure in patients undergoing percutaneous coronary intervention for in-stent restenosis? Findings: In a multicenter randomized trial of 600 patients designed to support US regulatory approval, target lesion failure was significantly lower in the paclitaxel-coated balloon group (17.9%) compared with the uncoated balloon group (28.6%) (P =.003). Ischemia-driven target lesion revascularization and target vessel myocardial infarction were also lower after treatment with a paclitaxel-coated balloon. Meaning: Treatment with a paclitaxel-coated balloon offers an effective treatment strategy for the management of coronary in-stent restenosis. Importance: Drug-coated balloons offer a potentially beneficial treatment strategy for the management of coronary in-stent restenosis. However, none have been previously evaluated or approved for use in coronary circulation in the United States. Objective: To evaluate whether a paclitaxel-coated balloon is superior to an uncoated balloon in patients with in-stent restenosis undergoing percutaneous coronary intervention. Design, Setting, and Participants: AGENT IDE, a multicenter randomized clinical trial, enrolled 600 patients with in-stent restenosis (lesion length <26 mm and reference vessel diameter >2.0 mm to ≤4.0 mm) at 40 centers across the United States between May 2021 and August 2022. One-year clinical follow-up was completed on October 2, 2023. Interventions: Participants were randomized in a 2:1 allocation to undergo treatment with a paclitaxel-coated (n = 406) or an uncoated (n = 194) balloon. Main Outcomes and Measures: The primary end point of 1-year target lesion failure—defined as the composite of ischemia-driven target lesion revascularization, target vessel–related myocardial infarction, or cardiac death—was tested for superiority. Results: Among 600 randomized patients (mean age, 68 years; 157 females [26.2%]; 42 Black [7%], 35 Hispanic [6%] individuals), 574 (95.7%) completed 1-year follow-up. The primary end point at 1 year occurred in 17.9% in the paclitaxel-coated balloon group vs 28.6% in the uncoated balloon group, meeting the criteria for superiority (hazard ratio [HR], 0.59 [95% CI, 0.42-0.84]; 2-sided P =.003). Target lesion revascularization (13.0% vs 24.7%; HR, 0.50 [95% CI, 0.34-0.74]; P =.001) and target vessel–related myocardial infarction (5.8% vs 11.1%; HR, 0.51 [95% CI, 0.28-0.92]; P =.02) occurred less frequently among patients treated with paclitaxel-coated balloon. The rate of cardiac death was 2.9% vs 1.6% (HR, 1.75 [95% CI, 0.49-6.28]; P =.38) in the coated vs uncoated balloon groups, respectively. Conclusions and Relevance: Among patients undergoing coronary angioplasty for in-stent restenosis, a paclitaxel-coated balloon was superior to an uncoated balloon with respect to the composite end point of target lesion failure. Paclitaxel-coated balloons are an effective treatment option for patients with coronary in-stent restenosis. Trial Registration: ClinicalTrials.gov Identifier: NCT04647253 This clinical trial compares a paclitaxel-coated balloon vs an uncoated balloon in patients with in-stent restenosis undergoing percutaneous coronary intervention. [ABSTRACT FROM AUTHOR]

This randomized clinical trial investigates the efficacy of a transdiagnostic ecological momentary intervention for improving self-esteem in youth with low self-esteem and exposure to childhood adversity. Key Points: Question: Can a transdiagnostic, blended ecological momentary intervention improve self-esteem in youth with low self-esteem and prior exposure to childhood adversity? Findings: This randomized clinical trial of 174 youth with low self-esteem and exposure to childhood adversity demonstrated that a novel transdiagnostic ecological momentary intervention improved the primary outcome of self-esteem at postintervention and 6-month follow-up. Small to moderate effect sizes signaled beneficial effects on general psychopathology, quality of life, and other secondary outcomes. Meaning: This trial demonstrated efficacy of a novel transdiagnostic ecological momentary intervention on self-esteem and signaled beneficial effects on secondary outcomes, which needs to be followed by investigating implementation in routine public mental health provision. Importance: Targeting low self-esteem in youth exposed to childhood adversity is a promising strategy for preventing adult mental disorders. Ecological momentary interventions (EMIs) allow for the delivery of youth-friendly, adaptive interventions for improving self-esteem, but robust trial-based evidence is pending. Objective: To examine the efficacy of SELFIE, a novel transdiagnostic, blended EMI for improving self-esteem plus care as usual (CAU) compared with CAU only. Design, Setting, and Participants: This was a 2-arm, parallel-group, assessor-blinded, randomized clinical trial conducted from December 2018 to December 2022. The study took place at Dutch secondary mental health services and within the general population and included youth (aged 12-26 years) with low self-esteem (Rosenberg Self-Esteem Scale [RSES] <26) exposed to childhood adversity. Interventions: A novel blended EMI (3 face-to-face sessions, email contacts, app-based, adaptive EMI) plus CAU or CAU only. Main Outcomes and Measures: The primary outcome was RSES self-esteem at postintervention and 6-month follow-up. Secondary outcomes included positive and negative self-esteem, schematic self-beliefs, momentary self-esteem and affect, general psychopathology, quality of life, observer-rated symptoms, and functioning. Results: A total of 174 participants (mean [SD] age, 20.7 [3.1] years; 154 female [89%]) were included in the intention-to-treat sample, who were primarily exposed to childhood emotional abuse or neglect, verbal or indirect bullying, and/or parental conflict. At postintervention, 153 participants (87.9%) and, at follow-up, 140 participants (80.5%), provided primary outcome data. RSES self-esteem was, on average, higher in the experimental condition (blended EMI + CAU) than in the control condition (CAU) across both postintervention and follow-up as a primary outcome (B = 2.32; 95% CI, 1.14-3.50; P <.001; Cohen d-type effect size [hereafter, Cohen d] = 0.54). Small to moderate effect sizes were observed suggestive of beneficial effects on positive (B = 3.85; 95% CI, 1.83-5.88; P <.001; Cohen d = 0.53) and negative (B = −3.78; 95% CI, −6.59 to −0.98; P =.008; Cohen d = −0.38) self-esteem, positive (B = 1.58; 95% CI, 0.41-2.75; P =.008; Cohen d = 0.38) and negative (B = −1.71; 95% CI, −2.93 to −0.48; P =.006; Cohen d = −0.39) schematic self-beliefs, momentary self-esteem (B = 0.29; 95% CI, 0.01-0.57; P =.04; Cohen d = 0.24), momentary positive affect (B = 0.23; 95% CI, 0.01-0.45; P =.04; Cohen d = 0.20), momentary negative affect (B = −0.33; 95% CI, −0.59 to −0.03, P =.01, Cohen d = −0.27), general psychopathology (B = −17.62; 95% CI, −33.03 to −2.21; P =.03; Cohen d = −0.34), and quality of life (B = 1.16; 95% CI, 0.18-2.13; P =.02; Cohen d = 0.33) across postintervention and follow-up. No beneficial effects on symptoms and functioning were observed. Conclusions and Relevance: A transdiagnostic, blended EMI demonstrated efficacy on the primary outcome of self-esteem and signaled beneficial effects on several secondary outcomes. Further work should focus on implementing this novel EMI in routine public mental health provision. Trial Registration: Dutch Trial Register Identifier:NL7129(NTR7475) [ABSTRACT FROM AUTHOR]

Key Points: Question: Among extremely preterm infants fed minimal maternal milk, does feeding of donor human milk compared with preterm formula during the birth hospitalization result in improved neurodevelopmental outcomes? Findings: In this randomized clinical trial, the Bayley Scales of Infant and Toddler Development adjusted mean cognitive score was 80.7 (measured at 22-26 months' corrected age) for infants fed donor human milk vs 81.1 for infants fed preterm formula (adjusted between-group mean difference, −0.77 [95% CI, −3.93 to 2.39]), which was not a significant difference. The adjusted mean language and motor scores also did not differ. Meaning: Among extremely preterm infants, donor milk feeding did not result in different 2-year neurodevelopmental outcomes compared with preterm formula feeding. Importance: Maternal milk feeding of extremely preterm infants during the birth hospitalization has been associated with better neurodevelopmental outcomes compared with preterm formula. For infants receiving no or minimal maternal milk, it is unknown whether donor human milk conveys similar neurodevelopmental advantages vs preterm formula. Objective: To determine if nutrient-fortified, pasteurized donor human milk improves neurodevelopmental outcomes at 22 to 26 months' corrected age compared with preterm infant formula among extremely preterm infants who received minimal maternal milk. Design, Setting, and Participants: Double-blind, randomized clinical trial conducted at 15 US academic medical centers within the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Infants younger than 29 weeks 0 days' gestation or with a birth weight of less than 1000 g were enrolled between September 2012 and March 2019. Intervention: Preterm formula or donor human milk feeding from randomization to 120 days of age, death, or hospital discharge. Main Outcomes and Measures: The primary outcome was the Bayley Scales of Infant and Toddler Development (BSID) cognitive score measured at 22 to 26 months' corrected age; a score of 54 (score range, 54-155; a score of ≥85 indicates no neurodevelopmental delay) was assigned to infants who died between randomization and 22 to 26 months' corrected age. The 24 secondary outcomes included BSID language and motor scores, in-hospital growth, necrotizing enterocolitis, and death. Results: Of 1965 eligible infants, 483 were randomized (239 in the donor milk group and 244 in the preterm formula group); the median gestational age was 26 weeks (IQR, 25-27 weeks), the median birth weight was 840 g (IQR, 676-986 g), and 52% were female. The birthing parent's race was self-reported as Black for 52% (247/478), White for 43% (206/478), and other for 5% (25/478). There were 54 infants who died prior to follow-up; 88% (376/429) of survivors were assessed at 22 to 26 months' corrected age. The adjusted mean BSID cognitive score was 80.7 (SD, 17.4) for the donor milk group vs 81.1 (SD, 16.7) for the preterm formula group (adjusted mean difference, −0.77 [95% CI, −3.93 to 2.39], which was not significant); the adjusted mean BSID language and motor scores also did not differ. Mortality (death prior to follow-up) was 13% (29/231) in the donor milk group vs 11% (25/233) in the preterm formula group (adjusted risk difference, −1% [95% CI, −4% to 2%]). Necrotizing enterocolitis occurred in 4.2% of infants (10/239) in the donor milk group vs 9.0% of infants (22/244) in the preterm formula group (adjusted risk difference, −5% [95% CI, −9% to −2%]). Weight gain was slower in the donor milk group (22.3 g/kg/d [95% CI, 21.3 to 23.3 g/kg/d]) compared with the preterm formula group (24.6 g/kg/d [95% CI, 23.6 to 25.6 g/kg/d]). Conclusions and Relevance: Among extremely preterm neonates fed minimal maternal milk, neurodevelopmental outcomes at 22 to 26 months' corrected age did not differ between infants fed donor milk or preterm formula. Trial Registration: ClinicalTrials.gov Identifier: NCT01534481 This randomized clinical trial compares the effect of donor human milk on neurodevelopmental outcomes at 22 to 26 months' corrected age compared with preterm infant formula among extremely preterm infants who received minimal maternal milk. [ABSTRACT FROM AUTHOR]

Key Points: Question: What is the safety and tolerability of lepodisiran, which is a short interfering RNA directed at hepatic production of apolipoprotein(a), and the effect on lipoprotein(a) serum concentrations at doses from 4 mg to 608 mg through 336 days (48 weeks) of follow-up? Findings: The trial enrolled 48 participants without cardiovascular disease and with lipoprotein(a) concentrations of 75 nmol/L or greater (or ≥30 mg/dL). A single serious adverse event occurred. The maximal median change from baseline in serum lipoprotein(a) concentrations was −5% in the placebo group, −41% in the 4 mg of lepodisiran group, −59% in the 12-mg dose group, −76% in the 32-mg dose group, −90% in the 96-mg dose group, −96% in the 304-mg dose group, and −97% in the 608-mg dose group. At day 337, the median change in lipoprotein(a) was −94% in the 608-mg dose group. Meaning: Lepodisiran was well tolerated and produced dose-dependent, long-duration reductions in serum lipoprotein(a) concentrations in this phase 1 trial; these findings support further study of lepodisiran. Importance: Epidemiological and genetic data have implicated lipoprotein(a) as a potentially modifiable risk factor for atherosclerotic disease and aortic stenosis, but there are no approved pharmacological treatments. Objectives: To assess the safety, tolerability, pharmacokinetics, and effects of lepodisiran on lipoprotein(a) concentrations after single doses of the drug; lepodisiran is a short interfering RNA directed at hepatic synthesis of apolipoprotein(a), an essential component necessary for assembly of lipoprotein(a) particles. Design, Setting, and Participants: A single ascending-dose trial conducted at 5 clinical research sites in the US and Singapore that enrolled 48 adults without cardiovascular disease and with lipoprotein(a) serum concentrations of 75 nmol/L or greater (or ≥30 mg/dL) between November 18, 2020, and December 7, 2021; the last follow-up visit occurred on November 9, 2022. Interventions: Participants were randomized to receive placebo or a single dose of lepodisiran (4 mg, 12 mg, 32 mg, 96 mg, 304 mg, or 608 mg) administered subcutaneously. Main Outcomes and Measures: The primary outcome was the safety and tolerability of the single ascending doses of lepodisiran. The secondary outcomes included plasma levels of lepodisiran for 168 days after dose administration and changes in fasting lipoprotein(a) serum concentrations through a maximum follow-up of 336 days (48 weeks). Results: Of the 48 participants enrolled (mean age, 46.8 [SD, 11.6] years; 35% were women), 1 serious adverse event occurred. The plasma concentrations of lepodisiran reached peak levels within 10.5 hours and were undetectable by 48 hours. The median baseline lipoprotein(a) concentration was 111 nmol/L (IQR, 78 to 134 nmol/L) in the placebo group, 78 nmol/L (IQR, 50 to 152 nmol/L) in the 4 mg of lepodisiran group, 97 nmol/L (IQR, 86 to 107 nmol/L) in the 12-mg dose group, 120 nmol/L (IQR, 110 to 188 nmol/L) in the 32-mg dose group, 167 nmol/L (IQR, 124 to 189 nmol/L) in the 96-mg dose group, 96 nmol/L (IQR, 72 to 132 nmol/L) in the 304-mg dose group, and 130 nmol/L (IQR, 87 to 151 nmol/L) in the 608-mg dose group. The maximal median change in lipoprotein(a) concentration was −5% (IQR, −16% to 11%) in the placebo group, −41% (IQR, −47% to −20%) in the 4 mg of lepodisiran group, −59% (IQR, −66% to −53%) in the 12-mg dose group, −76% (IQR, −76% to −75%) in the 32-mg dose group, −90% (IQR, −94% to −85%) in the 96-mg dose group, −96% (IQR, −98% to −95%) in the 304-mg dose group, and −97% (IQR, −98% to −96%) in the 608-mg dose group. At day 337, the median change in lipoprotein(a) concentration was −94% (IQR, −94% to −85%) in the 608 mg of lepodisiran group. Conclusions and Relevance: In this phase 1 study of 48 participants with elevated lipoprotein(a) levels, lepodisiran was well tolerated and produced dose-dependent, long-duration reductions in serum lipoprotein(a) concentrations. The findings support further study of lepodisiran. Trial Registration: ClinicalTrials.gov Identifier: NCT04914546 This randomized clinical trial compares a single dose of lepodisiran vs placebo to assess the safety, tolerability, pharmacokinetics, and effects on lipoprotein(a) concentrations in adults without cardiovascular disease and with lipoprotein(a) serum concentrations of 75 nmol/L or greater at baseline. [ABSTRACT FROM AUTHOR]

Key Points: Question: What is the performance of the novel multitarget stool RNA (mt-sRNA) test (ColoSense) for individuals 45 years and older undergoing colorectal cancer screening? Findings: A pivotal prospective, cross-sectional clinical trial comprising 8920 eligible participants was used to evaluate the sensitivity and specificity of the mt-sRNA test compared with a colonoscopy. The sensitivity of the mt-sRNA test for detecting colorectal cancer was 94%, the sensitivity for detecting advanced adenomas was 46%, and the specificity for no lesions on colonoscopy was 88%. Meaning: The mt-sRNA test exhibited strong performance across all age groups, including those aged 45 years and older. The mt-sRNA test demonstrated high sensitivity for detecting colorectal neoplasia and achieved a similar level of specificity compared with other molecular diagnostic tests. Importance: Noninvasive tests for colorectal cancer screening must include sensitive detection of colorectal cancer and precancerous lesions. These tests must be validated for the intended-use population, which includes average-risk individuals 45 years or older. Objective: To evaluate the sensitivity and specificity of a noninvasive, multitarget stool RNA (mt-sRNA) test (ColoSense) test compared with results from a colonoscopy. Design, Setting, and Participants: This phase 3 clinical trial (CRC-PREVENT) was a blinded, prospective, cross-sectional study to support a premarket approval application for a class III medical device. A total of 8920 participants were identified online using social media platforms and enrolled from June 2021 to June 2022 using a decentralized nurse call center. All participants completed the mt-sRNA test, which incorporated a commercially available fecal immunochemical test (FIT), concentration of 8 RNA transcripts, and participant-reported smoking status. Stool samples were collected prior to participants completing a colonoscopy at their local endoscopy center. The mt-sRNA test results (positive or negative) were compared with index lesions observed on colonoscopy. Over the course of 12 months, individuals 45 years and older were enrolled in the clinical trial using the decentralized recruitment strategy. Participants were enrolled from 49 US states and obtained colonoscopies at more than 3800 different endoscopy centers. Main Outcomes and Measures: The primary outcomes included the sensitivity of the mt-sRNA test for detecting colorectal cancer and advanced adenomas and the specificity for no lesions on colonoscopy. Results: The mean (range) age of participants was 55 (45-90) years, with 4% self-identified as Asian, 11% as Black, and 7% as Hispanic. Of the 8920 eligible participants, 36 (0.40%) had colorectal cancer and 606 (6.8%) had advanced adenomas. The mt-sRNA test sensitivity for detecting colorectal cancer was 94%, sensitivity for detecting advanced adenomas was 46%, and specificity for no lesions on colonoscopy was 88%. The mt-sRNA test showed significant improvement in sensitivity for colorectal cancer (94% vs 78%; McNemar P =.01) and advanced adenomas (46% vs 29%; McNemar P <.001) compared with results of the FIT. Conclusions and Relevance: In individuals 45 years and older, the mt-sRNA test showed high sensitivity for colorectal neoplasia (colorectal cancer and advanced adenoma) with significant improvement in sensitivity relative to the FIT. Specificity for no lesions on colonoscopy was comparable to existing molecular diagnostic tests. Trial Registration: ClinicalTrials.gov Identifier: NCT04739722 This article presents results from a prospective pivotal study in which individuals completed a multitarget stool RNA test prior to undergoing a colonoscopy to determine the sensitivity for detecting colorectal cancer and advanced ademonas. [ABSTRACT FROM AUTHOR]

Key Points: Question: Does β-blockade for up to 14 days with landiolol reduce organ failure as measured by the Sequential Organ Failure Assessment (SOFA) score for critically ill patients with tachycardia and septic shock treated with high-dose norepinephrine for more than 24 hours? Findings: In this randomized clinical trial enrolling 126 patients with tachycardia and established septic shock (treated with norepinephrine for >24 hours), the administration of landiolol intravenously to reduce heart rate to less than 95/min compared with standard care did not significantly decrease organ failure as measured by the mean SOFA score (8.8 vs 8.1, respectively) in the 14 days after randomization. Meaning: These results do not support the use of landiolol for managing patients with tachycardia treated with norepinephrine for established septic shock. Importance: Patients with septic shock undergo adrenergic stress, which affects cardiac, immune, inflammatory, and metabolic pathways. β-Blockade may attenuate the adverse effects of catecholamine exposure and has been associated with reduced mortality. Objectives: To assess the efficacy and safety of landiolol in patients with tachycardia and established septic shock requiring prolonged (>24 hours) vasopressor support. Design, Setting, and Participants: An open-label, multicenter, randomized trial involving 126 adults (≥18 years) with tachycardia (heart rate ≥95/min) and established septic shock treated for at least 24 hours with continuous norepinephrine (≥0.1 μg/kg/min) in 40 UK National Health Service intensive care units. The trial ran from April 2018 to December 2021, with early termination in December 2021 due to a signal of possible harm. Intervention: Sixty-three patients were randomized to receive standard care and 63 to receive landiolol infusion. Main Outcomes and Measures: The primary outcome was the mean Sequential Organ Failure Assessment (SOFA) score from randomization through 14 days. Secondary outcomes included mortality at days 28 and 90 and the number of adverse events in each group. Results: The trial was stopped prematurely on the advice of the independent data monitoring committee because it was unlikely to demonstrate benefit and because of possible harm. Of a planned 340 participants, 126 (37%) were enrolled (mean age, 55.6 years [95% CI, 52.7 to 58.5 years]; 58.7% male). The mean (SD) SOFA score in the landiolol group was 8.8 (3.9) compared with 8.1 (3.2) in the standard care group (mean difference [MD], 0.75 [95% CI, −0.49 to 2.0]; P =.24). Mortality at day 28 after randomization in the landiolol group was 37.1% (23 of 62) and 25.4% (16 of 63) in the standard care group (absolute difference, 11.7% [95% CI, −4.4% to 27.8%]; P =.16). Mortality at day 90 after randomization was 43.5% (27 of 62) in the landiolol group and 28.6% (18 of 63) in the standard care group (absolute difference, 15% [95% CI, −1.7% to 31.6%]; P =.08). There were no differences in the number of patients having at least one adverse event. Conclusion and Relevance: Among patients with septic shock with tachycardia and treated with norepinephrine for more than 24 hours, an infusion of landiolol did not reduce organ failure measured by the SOFA score over 14 days from randomization. These results do not support the use of landiolol for managing tachycardia among patients treated with norepinephrine for established septic shock. Trial Registration: EU Clinical Trials Register Eudra CT: 2017-001785-14; isrctn.org Identifier: ISRCTN12600919 This clinical trial assesses whether landiolol for patients with tachycardia and established septic shock requiring prolonged vasopressor support reduces the risk of organ failure. [ABSTRACT FROM AUTHOR]

Presents a study to identify deficiencies in the quality of reporting of placebo-controlled randomized trials published in German or English. Design; Main outcome measure; Results; Conclusion.

Context: Previous studies indicate that industry-sponsored trials tend to draw proindustry conclusions. Objective: To explore whether the association between funding and conclusions in randomized drug trials reflects treatment effects or adverse events. Design: Observational study of 370 randomized drug trials included in meta-analyses from Cochrane reviews selected from the Cochrane Library, May 2001. From a random sample of 167 Cochrane reviews, 25 contained eligible meta-analyses (assessed a binary outcome; pooled at least 5 full-paper trials of which at least 1 reported adequate and 1 reported inadequate allocation concealment). The primary binary outcome from each meta-analysis was considered the primary outcome for all trials included in each meta-analysis. The association between funding and conclusions was analyzed by logistic regression with adjustment for treatment effect, adverse events, and additional confounding factors (methodological quality, control intervention, sample size, publication year, and place of publication). Main Outcome Measure: Conclusions in trials, classified into whether the experimental drug was recommended as the treatment of choice or not. Results: The experimental drug was recommended as treatment of choice in 16% of trials funded by nonprofit organizations, 30% of trials not reporting funding, 35% of trials funded by both nonprofit and for-profit organizations, and 51% of trials funded by for-profit organizations (P<.001; χ[sup 2] test). Logistic regression analyses indicated that funding, treatment effect, and double blinding were the only significant predictors of conclusions. Adjusted analyses showed that trials funded by for-profit organizations were significantly more likely to recommend the experimental drug as treatment of choice (odds ratio, 5.3; 95% confidence interval, 2.0-14.4) compared with trials funded by nonprofit organizations. This association did not appear to reflect treatment effect or adverse events... INSET: Box. Scale Used to Grade Conclusions in Trials. [ABSTRACT FROM AUTHOR]

This randomized clinical trial assesses the efficacy of cognitive behavioral therapy for insomnia in veterans receiving treatment for alcohol use disorder. Key Points: Question: Is cognitive behavioral therapy for insomnia (CBT-I) feasible and efficacious early in treatment for alcohol use disorder, and if so, does it affect alcohol use? Findings: In this randomized clinical trial involving veterans with insomnia who were in treatment for alcohol use disorder, CBT-I was associated with greater reductions in insomnia symptoms and alcohol-related problems over time than a single session of instruction about sleep hygiene. No group differences emerged for abstinence or heavy-drinking frequency. Meaning: Long-term abstinence may not be required to derive benefit from CBT-I, which is feasible early in alcohol use disorder treatment and may reduce alcohol-related harm. Importance: Three of 4 adults in treatment for alcohol use disorder (AUD) report symptoms of insomnia. Yet the first-line treatment for insomnia (cognitive behavioral therapy for insomnia, CBT-I) is often delayed until abstinence is established. Objective: To test the feasibility, acceptability, and preliminary efficacy of CBT-I among veterans early in their AUD treatment and to examine improvement in insomnia as a mechanism for improvement in alcohol use outcomes. Design, Setting, and Participants: For this randomized clinical trial, participants were recruited through the Addictions Treatment Program at a Veterans Health Administration hospital between 2019 and 2022. Patients in treatment for AUD were eligible if they met criteria for insomnia disorder and reported alcohol use in the past 2 months at baseline. Follow-up visits occurred posttreatment and at 6 weeks. Interventions: Participants were randomly assigned to receive 5 weekly sessions of CBT-I or a single session about sleep hygiene (control). Participants were asked to complete sleep diaries for 7 days at each assessment. Main Outcomes and Measures: Primary outcomes included posttreatment insomnia severity (assessed using the Insomnia Severity Index) and follow-up frequency of any drinking and heavy drinking (4 drinks for women, ≥5 drinks for men; number of days via Timeline Followback) and alcohol-related problems (Short Inventory of Problems). Posttreatment insomnia severity was tested as a mediator of CBT-I effects on alcohol use outcomes at the 6-week follow-up. Results: The study cohort included 67 veterans with a mean (SD) age of 46.3 years (11.8); 61 (91%) were male and 6 (9%) female. The CBT-I group included 32 participants, and the sleep hygiene control group 35 participants. Of those randomized, 59 (88%) provided posttreatment or follow-up data (31 CBT-I, 28 sleep hygiene). Relative to sleep hygiene, CBT-I participants reported greater decreases in insomnia severity at posttreatment (group × time interaction: −3.70; 95% CI, −6.79 to −0.61) and follow-up (−3.34; 95% CI, −6.46 to −0.23) and greater improvements in sleep efficiency (posttreatment, 8.31; 95% CI, 1.35 to 15.26; follow-up, 18.03; 95% CI, 10.46 to 25.60). They also reported greater decreases in alcohol problems at follow-up (group × time interaction: −0.84; 95% CI, −1.66 to −0.02), and this effect was mediated by posttreatment change in insomnia severity. No group differences emerged for abstinence or heavy-drinking frequency. Conclusions and Relevance: In this randomized clinical trial, CBT-I outperformed sleep hygiene in reducing insomnia symptoms and alcohol-related problems over time but had no effect on frequency of heavy drinking. CBT-I should be considered a first-line treatment for insomnia, regardless of abstinence. Trial Registration: ClinicalTrials.gov Identifier: NCT03806491 [ABSTRACT FROM AUTHOR]

This randomized clinical trial investigates the accuracy of field sobriety tests administered by law enforcement officers to assess functional impairment and driving performance among individuals who have smoked cannabis. Key Points: Question: How accurate are field sobriety tests (FSTs) in identifying acute Δ9-tetrahydrocannabinol (THC) impairment? Findings: In this randomized clinical trial of 184 cannabis users randomized to THC or placebo, law enforcement officers classified 81.0% and 49.2%, respectively, as FST impaired, and officers suspected that 99.2% of FST-impaired participants received THC. Driving simulator performance was associated with select FSTs. Meaning: In this study, FSTs differentiated between THC- and placebo-exposed participants; however, the substantial overlap of FST impairment between groups and the high frequency at which FST impairment was suspected to be due to THC suggest that absent other indicators, FSTs alone may be insufficient to identify THC-specific driving impairment. Importance: With increasing medicinal and recreational cannabis legalization, there is a public health need for effective and unbiased evaluations for determining whether a driver is impaired due to Δ9-tetrahydrocannabinol (THC) exposure. Field sobriety tests (FSTs) are a key component of the gold standard law enforcement officer–based evaluations, yet controlled studies are inconclusive regarding their efficacy in detecting whether a person is under the influence of THC. Objective: To examine the classification accuracy of FSTs with respect to cannabis exposure and driving impairment (as determined via a driving simulation). Design, Setting, and Participants: This double-blind, placebo-controlled parallel randomized clinical trial was conducted from February 2017 to June 2019 at the Center for Medicinal Cannabis Research, University of California, San Diego. Participants were aged 21 to 55 years and had used cannabis in the past month. Data were analyzed from August 2021 to April 2023. Intervention: Participants were randomized 1:1:1 to placebo (0.02% THC), 5.9% THC cannabis, or 13.4% THC cannabis smoked ad libitum. Main Outcome and Measures: The primary end point was law enforcement officer determination of FST impairment at 4 time points after smoking. Additional measures included officer estimation as to whether participants were in the THC or placebo group as well as driving simulator data. Officers did not observe driving performance. Results: The study included 184 participants (117 [63.6%] male; mean [SD] age, 30 [8.3] years) who had used cannabis a mean (SD) of 16.7 (9.8) days in the past 30 days; 121 received THC and 63, placebo. Officers classified 98 participants (81.0%) in the THC group and 31 (49.2%) in the placebo group as FST impaired (difference, 31.8 percentage points; 95% CI, 16.4-47.2 percentage points; P <.001) at 70 minutes after smoking. The THC group performed significantly worse than the placebo group on 8 of 27 individual FST components (29.6%) and all FST summary scores. However, the placebo group did not complete a median of 8 (IQR, 5-11) FST components as instructed. Of 128 participants classified as FST impaired, officers suspected 127 (99.2%) as having received THC. Driving simulator performance was significantly associated with results of select FSTs (eg, ≥2 clues on One Leg Stand was associated with impairment on the simulator: odds ratio, 3.09; 95% CI, 1.63-5.88; P <.001). Conclusions and Relevance: This randomized clinical trial found that when administered by highly trained officers, FSTs differentiated between individuals receiving THC vs placebo and driving abilities were associated with results of some FSTs. However, the high rate at which the participants receiving placebo failed to adequately perform FSTs and the high frequency that poor FST performance was suspected to be due to THC-related impairment suggest that FSTs, absent other indicators, may be insufficient to denote THC-specific impairment in drivers. Trial Registration: ClinicalTrials.gov Identifier: NCT02849587 [ABSTRACT FROM AUTHOR]

Key Points: Question: Can an individualized treatment rule identify patients who benefit as much or more from self-guided internet-delivered cognitive behavioral therapy (i-CBT) as from guided i-CBT? Findings: In this secondary analysis of a randomized clinical trial of 1319 university students with anxiety and/or depression, guided i-CBT optimized the probability of (1) joint remission of anxiety and depression for 91.7% of participants, (2) remission of anxiety for 100% of participants, and (3) remission of depression for 71.5% of participants. Self-guided i-CBT, in comparison, optimized the probability of remission of depression for the remaining 28.5% of participants. Meaning: Self-guided i-CBT is sometimes equally or more effective than guided i-CBT for depression but not anxiety. Importance: Guided internet-delivered cognitive behavioral therapy (i-CBT) is a low-cost way to address high unmet need for anxiety and depression treatment. Scalability could be increased if some patients were helped as much by self-guided i-CBT as guided i-CBT. Objective: To develop an individualized treatment rule using machine learning methods for guided i-CBT vs self-guided i-CBT based on a rich set of baseline predictors. Design, Setting, and Participants: This prespecified secondary analysis of an assessor-blinded, multisite randomized clinical trial of guided i-CBT, self-guided i-CBT, and treatment as usual included students in Colombia and Mexico who were seeking treatment for anxiety (defined as a 7-item Generalized Anxiety Disorder [GAD-7] score of ≥10) and/or depression (defined as a 9-item Patient Health Questionnaire [PHQ-9] score of ≥10). Study recruitment was from March 1 to October 26, 2021. Initial data analysis was conducted from May 23 to October 26, 2022. Interventions: Participants were randomized to a culturally adapted transdiagnostic i-CBT that was guided (n = 445), self-guided (n = 439), or treatment as usual (n = 435). Main Outcomes and Measures: Remission of anxiety (GAD-7 scores of ≤4) and depression (PHQ-9 scores of ≤4) 3 months after baseline. Results: The study included 1319 participants (mean [SD] age, 21.4 [3.2] years; 1038 women [78.7%]; 725 participants [55.0%] came from Mexico). A total of 1210 participants (91.7%) had significantly higher mean (SE) probabilities of joint remission of anxiety and depression with guided i-CBT (51.8% [3.0%]) than with self-guided i-CBT (37.8% [3.0%]; P =.003) or treatment as usual (40.0% [2.7%]; P =.001). The remaining 109 participants (8.3%) had low mean (SE) probabilities of joint remission of anxiety and depression across all groups (guided i-CBT: 24.5% [9.1%]; P =.007; self-guided i-CBT: 25.4% [8.8%]; P =.004; treatment as usual: 31.0% [9.4%]; P =.001). All participants with baseline anxiety had nonsignificantly higher mean (SE) probabilities of anxiety remission with guided i-CBT (62.7% [5.9%]) than the other 2 groups (self-guided i-CBT: 50.2% [6.2%]; P =.14; treatment as usual: 53.0% [6.0%]; P =.25). A total of 841 of 1177 participants (71.5%) with baseline depression had significantly higher mean (SE) probabilities of depression remission with guided i-CBT (61.5% [3.6%]) than the other 2 groups (self-guided i-CBT: 44.3% [3.7%]; P =.001; treatment as usual: 41.8% [3.2%]; P <.001). The other 336 participants (28.5%) with baseline depression had nonsignificantly higher mean (SE) probabilities of depression remission with self-guided i-CBT (54.4% [6.0%]) than guided i-CBT (39.8% [5.4%]; P =.07). Conclusions and Relevance: Guided i-CBT yielded the highest probabilities of remission of anxiety and depression for most participants; however, these differences were nonsignificant for anxiety. Some participants had the highest probabilities of remission of depression with self-guided i-CBT. Information about this variation could be used to optimize allocation of guided and self-guided i-CBT in resource-constrained settings. Trial Registration: ClinicalTrials.gov Identifier: NCT04780542 This prespecified secondary analysis of a randomized clinical trial discusses the development of an individualized treatment rule using machine learning methods for guided vs self-guided internet-delivered cognitive behavioral therapy based on a rich set of baseline predictors. [ABSTRACT FROM AUTHOR]

Key Points: Question: In children aged 2 to 11 years with acute sinusitis, does the efficacy of antibiotic treatment differ based on nasopharyngeal colonization with a bacterial pathogen or by the color of the nasal discharge? Findings: Children without nasopharyngeal bacterial colonization (28% of all enrolled) benefited significantly less from antibiotic treatment than children colonized with pathogens. The effect of antibiotics did not differ based on the color of the nasal discharge. Meaning: In children with acute sinusitis, antibiotic treatment had minimal benefit for those without nasopharyngeal bacterial pathogens. The antibiotic effect did not depend on the color of nasal discharge. Importance: The large overlap between symptoms of acute sinusitis and viral upper respiratory tract infection suggests that certain subgroups of children being diagnosed with acute sinusitis, and subsequently treated with antibiotics, derive little benefit from antibiotic use. Objective: To assess if antibiotic therapy could be appropriately withheld in prespecified subgroups. Design, Setting, and Participants: Randomized clinical trial including 515 children aged 2 to 11 years diagnosed with acute sinusitis based on clinical criteria. The trial was conducted between February 2016 and April 2022 at primary care offices affiliated with 6 US institutions and was designed to evaluate whether symptom burden differed in subgroups defined by nasopharyngeal Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis on bacterial culture and by the presence of colored nasal discharge. Interventions: Oral amoxicillin (90 mg/kg/d) and clavulanate (6.4 mg/kg/d) (n = 254) or placebo (n = 256) for 10 days. Main Outcomes and Measures: The primary outcome was symptom burden based on daily symptom scores on a validated scale (range, 0-40) during the 10 days after diagnosis. Secondary outcomes included treatment failure, adverse events including clinically significant diarrhea, and resource use by families. Results: Most of the 510 included children were aged 2 to 5 years (64%), male (54%), White (52%), and not Hispanic (89%). The mean symptom scores were significantly lower in children in the amoxicillin and clavulanate group (9.04 [95% CI, 8.71 to 9.37]) compared with those in the placebo group (10.60 [95% CI, 10.27 to 10.93]) (between-group difference, −1.69 [95% CI, −2.07 to −1.31]). The length of time to symptom resolution was significantly lower for children in the antibiotic group (7.0 days) than in the placebo group (9.0 days) (P =.003). Children without nasopharyngeal pathogens detected did not benefit from antibiotic treatment as much as those with pathogens detected; the between-group difference in mean symptom scores was −0.88 (95% CI, −1.63 to −0.12) in those without pathogens detected compared with −1.95 (95% CI, −2.40 to −1.51) in those with pathogens detected. Efficacy did not differ significantly according to whether colored nasal discharge was present (the between-group difference was −1.62 [95% CI, −2.09 to −1.16] for colored nasal discharge vs −1.70 [95% CI, −2.38 to −1.03] for clear nasal discharge; P =.52 for the interaction between treatment group and the presence of colored nasal discharge). Conclusions: In children with acute sinusitis, antibiotic treatment had minimal benefit for those without nasopharyngeal bacterial pathogens on presentation, and its effects did not depend on the color of nasal discharge. Testing for specific bacteria on presentation may represent a strategy to reduce antibiotic use in this condition. Trial Registration: ClinicalTrials.gov Identifier: NCT02554383 This randomized clinical trial compares the effect of amoxicillin and clavulanate vs placebo on symptom burden in children diagnosed with acute sinusitis. [ABSTRACT FROM AUTHOR]

Key Points: Question: Does continuous administration of meropenem reduce a composite of mortality and emergence of drug-resistant bacteria among critically ill patients with sepsis compared with intermittent administration? Findings: In this randomized clinical trial enrolling 607 critically ill patients with sepsis or septic shock, continuous administration of meropenem, compared with intermittent administration, did not significantly decrease the composite of all-cause mortality and emergence of pandrug-resistant or extensively drug-resistant bacteria at day 28 (47% vs 49%, respectively). Meaning: Continuous administration of meropenem, compared with intermittent administration, does not improve clinically relevant outcomes in critically ill patients with sepsis. Importance: Meropenem is a widely prescribed β-lactam antibiotic. Meropenem exhibits maximum pharmacodynamic efficacy when given by continuous infusion to deliver constant drug levels above the minimal inhibitory concentration. Compared with intermittent administration, continuous administration of meropenem may improve clinical outcomes. Objective: To determine whether continuous administration of meropenem reduces a composite of mortality and emergence of pandrug-resistant or extensively drug-resistant bacteria compared with intermittent administration in critically ill patients with sepsis. Design, Setting, and Participants: A double-blind, randomized clinical trial enrolling critically ill patients with sepsis or septic shock who had been prescribed meropenem by their treating clinicians at 31 intensive care units of 26 hospitals in 4 countries (Croatia, Italy, Kazakhstan, and Russia). Patients were enrolled between June 5, 2018, and August 9, 2022, and the final 90-day follow-up was completed in November 2022. Interventions: Patients were randomized to receive an equal dose of the antibiotic meropenem by either continuous administration (n = 303) or intermittent administration (n = 304). Main Outcomes and Measures: The primary outcome was a composite of all-cause mortality and emergence of pandrug-resistant or extensively drug-resistant bacteria at day 28. There were 4 secondary outcomes, including days alive and free from antibiotics at day 28, days alive and free from the intensive care unit at day 28, and all-cause mortality at day 90. Seizures, allergic reactions, and mortality were recorded as adverse events. Results: All 607 patients (mean age, 64 [SD, 15] years; 203 were women [33%]) were included in the measurement of the 28-day primary outcome and completed the 90-day mortality follow-up. The majority (369 patients, 61%) had septic shock. The median time from hospital admission to randomization was 9 days (IQR, 3-17 days) and the median duration of meropenem therapy was 11 days (IQR, 6-17 days). Only 1 crossover event was recorded. The primary outcome occurred in 142 patients (47%) in the continuous administration group and in 149 patients (49%) in the intermittent administration group (relative risk, 0.96 [95% CI, 0.81-1.13], P =.60). Of the 4 secondary outcomes, none was statistically significant. No adverse events of seizures or allergic reactions related to the study drug were reported. At 90 days, mortality was 42% both in the continuous administration group (127 of 303 patients) and in the intermittent administration group (127 of 304 patients). Conclusions and Relevance: In critically ill patients with sepsis, compared with intermittent administration, the continuous administration of meropenem did not improve the composite outcome of mortality and emergence of pandrug-resistant or extensively drug-resistant bacteria at day 28. Trial Registration: ClinicalTrials.gov Identifier: NCT03452839 This randomized clinical trial compares the effect of continuous administration of meropenem vs intermittent administration on a composite outcome of mortality and emergence of pandrug-resistant or extensively drug-resistant bacteria in critically ill patients with sepsis. [ABSTRACT FROM AUTHOR]

Importance: Approximately 18.6 million people worldwide are affected by a diabetic foot ulcer each year, including 1.6 million people in the United States. These ulcers precede 80% of lower extremity amputations among people diagnosed with diabetes and are associated with an increased risk of death. Observations: Neurological, vascular, and biomechanical factors contribute to diabetic foot ulceration. Approximately 50% to 60% of ulcers become infected, and about 20% of moderate to severe infections lead to lower extremity amputations. The 5-year mortality rate for individuals with a diabetic foot ulcer is approximately 30%, exceeding 70% for those with a major amputation. The mortality rate for people with diabetic foot ulcers is 231 deaths per 1000 person-years, compared with 182 deaths per 1000 person-years in people with diabetes without foot ulcers. People who are Black, Hispanic, or Native American and people with low socioeconomic status have higher rates of diabetic foot ulcer and subsequent amputation compared with White people. Classifying ulcers based on the degree of tissue loss, ischemia, and infection can help identify risk of limb-threatening disease. Several interventions reduce risk of ulcers compared with usual care, such as pressure-relieving footwear (13.3% vs 25.4%; relative risk, 0.49; 95% CI, 0.28-0.84), foot skin measurements with off-loading when hot spots (ie, greater than 2 °C difference between the affected foot and the unaffected foot) are found (18.7% vs 30.8%; relative risk, 0.51; 95% CI, 0.31-0.84), and treatment of preulcer signs. Surgical debridement, reducing pressure from weight bearing on the ulcer, and treating lower extremity ischemia and foot infection are first-line therapies for diabetic foot ulcers. Randomized clinical trials support treatments to accelerate wound healing and culture-directed oral antibiotics for localized osteomyelitis. Multidisciplinary care, typically consisting of podiatrists, infectious disease specialists, and vascular surgeons, in close collaboration with primary care clinicians, is associated with lower major amputation rates relative to usual care (3.2% vs 4.4%; odds ratio, 0.40; 95% CI, 0.32-0.51). Approximately 30% to 40% of diabetic foot ulcers heal at 12 weeks, and recurrence after healing is estimated to be 42% at 1 year and 65% at 5 years. Conclusions and Relevance: Diabetic foot ulcers affect approximately 18.6 million people worldwide each year and are associated with increased rates of amputation and death. Surgical debridement, reducing pressure from weight bearing, treating lower extremity ischemia and foot infection, and early referral for multidisciplinary care are first-line therapies for diabetic foot ulcers. This Review summarizes current evidence regarding the epidemiology, pathophysiology, diagnosis, treatment, and prevention of diabetic foot ulcers. [ABSTRACT FROM AUTHOR]

Regulatory and ethical considerations mandate that minorities affected by health disparities be included in research. Despite concerns about clinical outcomes for patients with obesity, clinical trials have reported few data about participation of and outcomes for such patients. This article examines the lack of body size diversity in clinical research participants and reviews the evidence and ethical arguments for including larger-bodied patients. Drawing on examples of improved gender diversification of trial participants, this article suggests that similar benefits would be likely from inclusion of body diversity. [ABSTRACT FROM AUTHOR]

Key Points: Question: How effective is family-based behavioral treatment for childhood overweight and obesity when implemented in pediatric primary care settings? Finding: In this randomized trial with follow-up over 24 months, children, parents, and siblings with overweight or obesity assigned to undergo family-based treatment had significantly better weight loss outcomes, measured by percentage above the median body mass index for their age and sex, than those assigned to undergo usual care. Meaning: Family-based treatment can be successfully implemented in pediatric primary care settings and leads to improved weight loss outcomes among participating children and their parents and siblings. Importance: Intensive behavioral interventions for childhood overweight and obesity are recommended by national guidelines, but are currently offered primarily in specialty clinics. Evidence is lacking on their effectiveness in pediatric primary care settings. Objective: To evaluate the effects of family-based treatment for overweight or obesity implemented in pediatric primary care on children and their parents and siblings. Design, Setting, and Participants: This randomized clinical trial in 4 US settings enrolled 452 children aged 6 to 12 years with overweight or obesity, their parents, and 106 siblings. Participants were assigned to undergo family-based treatment or usual care and were followed up for 24 months. The trial was conducted from November 2017 through August 2021. Interventions: Family-based treatment used a variety of behavioral techniques to develop healthy eating, physical activity, and parenting behaviors within families. The treatment goal was 26 sessions over a 24-month period with a coach trained in behavior change methods; the number of sessions was individualized based on family progress. Main Outcomes and Measures: The primary outcome was the child's change from baseline to 24 months in the percentage above the median body mass index (BMI) in the general US population normalized for age and sex. Secondary outcomes were the changes in this measure for siblings and in BMI for parents. Results: Among 452 enrolled child-parent dyads, 226 were randomized to undergo family-based treatment and 226 to undergo usual care (child mean [SD] age, 9.8 [1.9] years; 53% female; mean percentage above median BMI, 59.4% [n = 27.0]; 153 [27.2%] were Black and 258 [57.1%] were White); 106 siblings were included. At 24 months, children receiving family-based treatment had better weight outcomes than those receiving usual care based on the difference in change in percentage above median BMI (−6.21% [95% CI, −10.14% to −2.29%]). Longitudinal growth models found that children, parents, and siblings undergoing family-based treatment all had outcomes superior to usual care that were evident at 6 months and maintained through 24 months (0- to 24-month changes in percentage above median BMI for family-based treatment and usual care were 0.00% [95% CI, −2.20% to 2.20%] vs 6.48% [95% CI, 4.35%-8.61%] for children; −1.05% [95% CI, −3.79% to 1.69%] vs 2.92% [95% CI, 0.58%-5.26%] for parents; and 0.03% [95% CI, −3.03% to 3.10%] vs 5.35% [95% CI, 2.70%-8.00%] for siblings). Conclusions and Relevance: Family-based treatment for childhood overweight and obesity was successfully implemented in pediatric primary care settings and led to improved weight outcomes over 24 months for children and parents. Siblings who were not directly treated also had improved weight outcomes, suggesting that this treatment may offer a novel approach for families with multiple children. Trial Registration: ClinicalTrials.gov Identifier: NCT02873715 This randomized clinical trial evaluates the effects of family-based treatment implemented in primary care pediatric settings on weight change for children with overweight or obesity. [ABSTRACT FROM AUTHOR]

Key Points: Question: Is minimally invasive mitral valve repair better at improving physical function at 12 weeks than conventional sternotomy mitral valve repair for degenerative mitral regurgitation? Findings: In this randomized clinical trial involving 330 patients, minimally invasive repair was not superior to sternotomy as determined by recovery of physical function at 12 weeks. Both techniques achieved high-quality and durable valve repair at 1 year with similar postoperative complications. Meaning: Minimally invasive mitral valve repair does not improve physical function at 12 weeks compared with sternotomy, but outcomes at 1 year show minimally invasive repair is as safe and effective as sternotomy for degenerative mitral regurgitation. These findings can inform shared decision-making and treatment guidelines. Importance: The safety and effectiveness of mitral valve repair via thoracoscopically-guided minithoracotomy (minithoracotomy) compared with median sternotomy (sternotomy) in patients with degenerative mitral valve regurgitation is uncertain. Objective: To compare the safety and effectiveness of minithoracotomy vs sternotomy mitral valve repair in a randomized trial. Design, Setting, and Participants: A pragmatic, multicenter, superiority, randomized clinical trial in 10 tertiary care institutions in the UK. Participants were adults with degenerative mitral regurgitation undergoing mitral valve repair surgery. Interventions: Participants were randomized 1:1 with concealed allocation to receive either minithoracotomy or sternotomy mitral valve repair performed by an expert surgeon. Main Outcomes and Measures: The primary outcome was physical functioning and associated return to usual activities measured by change from baseline in the 36-Item Short Form Health Survey (SF-36) version 2 physical functioning scale 12 weeks after the index surgery, assessed by an independent researcher masked to the intervention. Secondary outcomes included recurrent mitral regurgitation grade, physical activity, and quality of life. The prespecified safety outcomes included death, repeat mitral valve surgery, or heart failure hospitalization up to 1 year. Results: Between November 2016 and January 2021, 330 participants were randomized (mean age, 67 years, 100 female [30%]); 166 were allocated to minithoracotomy and 164 allocated to sternotomy, of whom 309 underwent surgery and 294 reported the primary outcome. At 12 weeks, the mean between-group difference in the change in the SF-36 physical function T score was 0.68 (95% CI, −1.89 to 3.26). Valve repair rates (≈ 96%) were similar in both groups. Echocardiography demonstrated mitral regurgitation severity as none or mild for 92% of participants at 1 year with no difference between groups. The composite safety outcome occurred in 5.4% (9 of 166) of patients undergoing minithoracotomy and 6.1% (10 of 163) undergoing sternotomy at 1 year. Conclusions and relevance: Minithoracotomy is not superior to sternotomy in recovery of physical function at 12 weeks. Minithoracotomy achieves high rates and quality of valve repair and has similar safety outcomes at 1 year to sternotomy. The results provide evidence to inform shared decision-making and treatment guidelines. Trial Registration: isrctn.org Identifier: ISRCTN13930454 This randomized clinical trial compares the effectiveness and safety of minithoracotomy vs sternotomy mitral valve repair. [ABSTRACT FROM AUTHOR]

Key Points: Question: Is treatment to a goal low-density lipoprotein cholesterol (LDL-C) level between 50 and 70 mg/dL noninferior to a strategy using high-intensity statin therapy among patients with coronary artery disease? Findings: In this randomized noninferiority trial that included 4400 patients with coronary artery disease, the rate of the 3-year composite of all-cause death, myocardial infarction, stroke, or any coronary revascularization was 8.1% in the treat-to-target strategy group compared with 8.7% in the high-intensity statin therapy group, a difference that met the prespecified noninferiority margin of 3.0 percentage points. Meaning: Among patients with coronary artery disease, the treat-to-target LDL-C strategy was noninferior to the high-intensity statin strategy for major clinical outcomes. Importance: In patients with coronary artery disease, some guidelines recommend initial statin treatment with high-intensity statins to achieve at least a 50% reduction in low-density lipoprotein cholesterol (LDL-C). An alternative approach is to begin with moderate-intensity statins and titrate to a specific LDL-C goal. These alternatives have not been compared head-to-head in a clinical trial involving patients with known coronary artery disease. Objective: To assess whether a treat-to-target strategy is noninferior to a strategy of high-intensity statins for long-term clinical outcomes in patients with coronary artery disease. Design, Setting, and Participants: A randomized, multicenter, noninferiority trial in patients with a coronary disease diagnosis treated at 12 centers in South Korea (enrollment: September 9, 2016, through November 27, 2019; final follow-up: October 26, 2022). Interventions: Patients were randomly assigned to receive either the LDL-C target strategy, with an LDL-C level between 50 and 70 mg/dL as the target, or high-intensity statin treatment, which consisted of rosuvastatin, 20 mg, or atorvastatin, 40 mg. Main Outcomes and Measures: Primary end point was a 3-year composite of death, myocardial infarction, stroke, or coronary revascularization with a noninferiority margin of 3.0 percentage points. Results: Among 4400 patients, 4341 patients (98.7%) completed the trial (mean [SD] age, 65.1 [9.9] years; 1228 females [27.9%]). In the treat-to-target group (n = 2200), which had 6449 person-years of follow-up, moderate-intensity and high-intensity dosing were used in 43% and 54%, respectively. The mean (SD) LDL-C level for 3 years was 69.1 (17.8) mg/dL in the treat-to-target group and 68.4 (20.1) mg/dL in the high-intensity statin group (n = 2200) (P =.21, compared with the treat-to-target group). The primary end point occurred in 177 patients (8.1%) in the treat-to-target group and 190 patients (8.7%) in the high-intensity statin group (absolute difference, –0.6 percentage points [upper boundary of the 1-sided 97.5% CI, 1.1 percentage points]; P <.001 for noninferiority). Conclusions and Relevance: Among patients with coronary artery disease, a treat-to-target LDL-C strategy of 50 to 70 mg/dL as the goal was noninferior to a high-intensity statin therapy for the 3-year composite of death, myocardial infarction, stroke, or coronary revascularization. These findings provide additional evidence supporting the suitability of a treat-to-target strategy that may allow a tailored approach with consideration for individual variability in drug response to statin therapy. Trial Registration: ClinicalTrials.gov Identifier: NCT02579499 This randomized clinical trial compares the efficacy of a treat-to-target low-density lipoprotein cholesterol (LDL-C) strategy of 50 to 70 mg/dL as the goal vs high-intensity statin therapy for the 3-year composite of death, myocardial infarction, stroke, or coronary revascularization in patients with coronary artery disease. [ABSTRACT FROM AUTHOR]

This randomized clinical trial investigates the effects of a smartphone-based self-management intervention for bipolar disorder on relapse risk, symptoms, and quality of life. Key Points: Question: Can a smartphone-based self-management intervention for bipolar disorder improve relapse risk, symptom burden, and quality of life? Findings: This randomized clinical trial of 205 individuals did not detect a decrease in the primary outcome of time to relapse for the smartphone-based self-management intervention. However, a significant decrease in relapse risk was observed for individuals in asymptomatic recovery but not for higher relapse risk individuals. Meaning: Results of this study suggest that further work is warranted to optimize the smartphone-based self-management intervention and confirm that the intervention decreases relapse risk for individuals in asymptomatic recovery. Importance: Bipolar disorder–specific psychotherapy combined with pharmacotherapy improves relapse risk, symptom burden, and quality of life, but psychotherapy is not easily accessible. Objective: To determine if a smartphone-based self-management intervention (LiveWell) can assist individuals with bipolar disorder to maintain wellness. Design, Setting, and Participants: An assessor-blind randomized clinical trial enrolled participants from March 20, 2017, to April 25, 2019, with 48-week follow-up ending on April 10, 2020. Participants were randomly assigned to usual care or usual care plus the smartphone intervention stratified by relapse risk based on initial clinical status (low risk: asymptomatic recovery; high risk: continued symptomatic, prodromal, recovering, symptomatic recovery). Participants with bipolar disorder I were recruited from clinics in the Chicago and Minneapolis-Saint Paul areas. Data were analyzed from June 19, 2020, to May 25, 2022. Interventions: The smartphone-based self-management intervention consisted of an application (app), coach, and website. Over 16 weeks, participants had a coach visit followed by 6 phone calls, and they completed daily and weekly app check-ins. The app provided adaptive feedback and information for developing a personalized wellness plan, the coach provided support, and the website provided summary data and alerts. Main Outcomes and Measures: The primary outcome was time to relapse. Secondary outcomes were percentage-time symptomatic, symptom severity, and quality of life. Results: Of the 205 randomized participants (mean [SD] age, 42 [12] years; 125 female individuals [61%]; 5 Asian [2%], 21 Black [10%], 13 Hispanic or Latino [6%], 7 multiracial [3%], 170 White [83%], 2 unknown race [1%]), 81 (40%) were randomly assigned to usual care, and 124 (60%) were randomly assigned to usual care plus the smartphone intervention. This clinical trial did not detect a reduction in relapse risk for the smartphone intervention (hazard ratio [HR], 0.65; 95% CI, 0.39-1.09; log-rank P =.08). However, decreased relapse was observed for low-risk individuals (HR, 0.32; 95% CI, 0.12-0.88; log-rank P =.02) but not high-risk individuals (HR, 0.86; 95% CI, 0.47-1.57; log-rank P =.62). Reduced manic symptom severity was observed for low-risk individuals (mean [SE] difference, −1.4 [0.4]; P =.001) but not for high-risk individuals (mean [SE] difference, 0 [0.3]; P =.95). The smartphone-based self-management intervention decreased depressive symptom severity (mean [SE] difference, −0.80 [0.34]; P =.02) and improved relational quality of life (mean [SE] difference, 1.03 [0.45]; P =.02) but did not decrease percentage-time symptomatic (mean [SE] difference, −5.6 [4.3]; P =.20). Conclusions and Relevance: This randomized clinical trial of a smartphone-based self-management intervention did not detect a significant improvement in the primary outcome of time to relapse. However, a significant decrease in relapse risk was observed for individuals in asymptomatic recovery. In addition, the intervention decreased depressive symptom severity and improved relational quality of life. These findings warrant further work to optimize the smartphone intervention and confirm that the intervention decreases relapse risk for individuals in asymptomatic recovery. Trial Registration: ClinicalTrials.gov Identifier: NCT03088462 [ABSTRACT FROM AUTHOR]

Discusses how editors, authors and readers of peer-reviewed journals such as the "Archives of Ophthalmology" can address the doubt and skepticism about the integrity of the process by which new medical and scientific findings are published. Causes for the loss of public confidence in the validity of reported scientific results; Public registration of clinical trials; Ethical responsibilities of editors, authors and readers.

Key Points: Question: Does a weight loss and exercise program in community settings lead to improvement in knee pain in patients with osteoarthritis and overweight or obesity? Findings: This randomized clinical trial included 823 patients with knee osteoarthritis and overweight or obesity treated with diet and exercise vs an attention control. After 18 months, the adjusted mean difference in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score (range, 0-20) was −0.6, a difference that met statistical significance. Meaning: In patients with knee osteoarthritis and overweight or obesity, an 18-month program of weight loss and exercise based in community settings, compared with an attention control group, led to a small difference in knee pain of uncertain clinical importance. Importance: Some weight loss and exercise programs that have been successful in academic center–based trials have not been evaluated in community settings. Objective: To determine whether adaptation of a diet and exercise intervention to community settings resulted in a statistically significant reduction in pain, compared with an attention control group, at 18-month follow-up. Design, Setting, and Participants: Assessor-blinded randomized clinical trial conducted in community settings in urban and rural counties in North Carolina. Patients were men and women aged 50 years or older with knee osteoarthritis and overweight or obesity (body mass index ≥27). Enrollment (N = 823) occurred between May 2016 and August 2019, with follow-up ending in April 2021. Interventions: Patients were randomly assigned to either a diet and exercise intervention (n = 414) or an attention control (n = 409) group for 18 months. Main Outcomes and Measures: The primary outcome was the between-group difference in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) knee pain score (range, 0 [none] to 20 [severe]; minimum clinically important difference, 1.6) over 18 months, tested using a repeated-measures mixed linear model with adjustments for covariates. There were 7 secondary outcomes including body weight. Results: Among the 823 randomized patients (mean age, 64.6 years; 637 [77%] women), 658 (80%) completed the trial. At 18-month follow-up, the adjusted mean WOMAC pain score was 5.0 in the diet and exercise group (n = 329) compared with 5.5 in the attention control group (n = 316) (adjusted difference, −0.6; 95% CI, −1.0 to −0.1; P =.02). Of 7 secondary outcomes, 5 were significantly better in the intervention group compared with control. The mean change in unadjusted 18-month body weight for patients with available data was −7.7 kg (8%) in the diet and exercise group (n = 289) and −1.7 kg (2%) in the attention control group (n = 273) (mean difference, −6.0 kg; 95% CI, −7.3 kg to −4.7 kg). There were 169 serious adverse events; none were definitely related to the study. There were 729 adverse events; 32 (4%) were definitely related to the study, including 10 body injuries (9 in diet and exercise; 1 in attention control), 7 muscle strains (6 in diet and exercise; 1 in attention control), and 6 trip/fall events (all 6 in diet and exercise). Conclusions and Relevance: Among patients with knee osteoarthritis and overweight or obesity, diet and exercise compared with an attention control led to a statistically significant but small difference in knee pain over 18 months. The magnitude of the difference in pain between groups is of uncertain clinical importance. Trial Registration: ClinicalTrials.gov Identifier: NCT02577549 This randomized clinical trial assesses the effect of a diet and exercise intervention vs an attention control condition on knee pain at 18-month follow-up among individuals aged 50 years or older with knee osteoarthritis and overweight or obesity. [ABSTRACT FROM AUTHOR]

Key Points: Question: Does a remotely delivered, self-directed, behavioral lifestyle intervention improve weight and general health status? Findings: In this randomized clinical trial that included 511 participants, a behavioral intervention, compared with usual care, resulted in statistically significantly greater model-adjusted weight loss at 12 months (unadjusted mean, 2.5 kg vs 0.4 kg, respectively), and no significant model-adjusted difference in self-reported general physical health status (as measured with the Medical Outcomes Study 12-Item Short Form Health Survey [SF-12] physical component score [range, 0-100]) at 12 months; unadjusted mean, −0.4 vs −0.9, respectively. Meaning: Among adults with obesity, a remotely delivered, self-directed behavioral lifestyle intervention, compared with usual care, resulted in a statistically significant difference in weight loss that was not clinically important and no significant difference in general physical health status at 12 months. Importance: The effectiveness of remotely delivered, self-directed, weight loss programs in routine clinical practice is largely unknown. Objective: To test whether a self-directed, remotely administered behavioral lifestyle intervention improves weight and self-reported general health status compared with usual care. Design, Setting, and Participants: In this randomized clinical trial, 511 adults with a body mass index (BMI) of 30 or more and less than 45 (based on electronic health record [EHR] weight and height), were enrolled from 30 Veterans Health Administration (VHA) sites between February 15, 2018, and December 18, 2018 (final follow-up February 18, 2021). Interventions: Participants were randomly assigned to the intervention group (n = 254) or the control group (n = 257). Both received usual care. Participants randomized to the intervention received Diabetes Prevention Program–based self-directed videos, handouts, and coaching messages via an online platform or US mail for 12 months. Main Outcomes and Measures: Coprimary outcomes were weight measured in primary care and recorded in the EHR and self-reported general health status using the Medical Outcomes Study 12-Item Short Form Health Survey (SF-12) physical component score (PCS; higher scores are better [range, 0-100]) at the 12-month follow-up. The between-group minimal clinically important differences are 3 kg for weight and 5 points for the SF-12 PCS. Linear mixed models used weights and SF-12 PCS measured at either time point, with participants analyzed according to randomization assignment. Statistical significance for each coprimary outcome was based on a 2-sided α level of.025. Results: Among 511 participants randomized (mean age, 57.4 [SD, 13.9] years; 231 female [45%]), 429 (84.0%) had EHR-based weights and 410 (80.2%) had SF-12 PCS data at 12 months. The unadjusted mean weight at 12 months declined from 102.7 kg to 99.8 kg in the intervention group compared with 101.9 kg to 101.0 kg in the control group (adjusted between-group mean difference, −1.93 [97.5% CI, −3.24 to −0.61]; P =.001). At 12 months, the unadjusted mean SF-12 PCS scores declined from 44.8 to 44.3 among intervention participants compared with 44.5 to 43.2 among control participants (adjusted between-group mean difference, intervention minus control, 0.69 [97.5% CI, −1.11 to 2.49]; P =.39). Cardiovascular events represented the highest percentage of serious adverse events, accounting for 25% of events in the intervention group and 35% in the control group. Conclusions and Relevance: Among adults with obesity, a remotely delivered self-directed, behavioral lifestyle intervention, compared with usual care, resulted in statistically significantly greater weight loss at 12 months, although the difference was not clinically important. There was no significant difference in self-reported general physical health status at 12 months. Trial Registration: ClinicalTrials.gov Identifier: NCT03260140 This clinical trial evaluates the effect of a remotely delivered and self-directed intervention for weight management vs usual care among adults in Veterans Health Administration clinics. [ABSTRACT FROM AUTHOR]

Importance: Cefepime/enmetazobactam is a novel β-lactam/β-lactamase inhibitor combination and a potential empirical therapy for resistant gram-negative infections.Objective: To evaluate whether cefepime/enmetazobactam was noninferior to piperacillin/tazobactam for the primary outcome of treatment efficacy in patients with complicated urinary tract infections (UTIs) or acute pyelonephritis.Design, Setting, and Participants: A phase 3, randomized, double-blind, active-controlled, multicenter, noninferiority clinical trial conducted at 90 sites in Europe, North and Central America, South America, and South Africa. Recruitment occurred between September 24, 2018, and November 2, 2019. Final follow-up occurred November 26, 2019. Participants were adult patients aged 18 years or older with a clinical diagnosis of complicated UTI or acute pyelonephritis caused by gram-negative urinary pathogens.Interventions: Eligible patients were randomized to receive either cefepime, 2 g/enmetazobactam, 0.5 g (n = 520), or piperacillin, 4 g/tazobactam, 0.5 g (n = 521), by 2-hour infusion every 8 hours for 7 days (up to 14 days in patients with a positive blood culture at baseline).Main Outcomes and Measures: The primary outcome was the proportion of patients in the primary analysis set (patients who received any amount of study drug with a baseline gram-negative pathogen not resistant to either treatment and ≥105 colony-forming units [CFU]/mL in urine culture or the same pathogen present in concurrent blood and urine cultures) who achieved overall treatment success (defined as clinical cure combined with microbiological eradication [<103 CFU/mL in urine] of infection). Two-sided 95% CIs were computed using the stratified Newcombe method. The prespecified noninferiority margin was -10%. If noninferiority was established, a superiority comparison was also prespecified.Results: Among 1041 patients randomized (mean age, 54.7 years; 573 women [55.0%]), 1034 (99.3%) received study drug and 995 (95.6%) completed the trial. Among the primary analysis set, the primary outcome occurred in 79.1% (273/345) of patients receiving cefepime/enmetazobactam compared with 58.9% (196/333) receiving piperacillin/tazobactam (between-group difference, 21.2% [95% CI, 14.3% to 27.9%]). Treatment-emergent adverse events occurred in 50.0% (258/516) of patients treated with cefepime/enmetazobactam and 44.0% (228/518) with piperacillin/tazobactam; most were mild to moderate in severity (89.9% vs 88.6%, respectively). A total of 1.7% (9/516) of participants who received cefepime/enmetazobactam and 0.8% (4/518) of those who received piperacillin/tazobactam did not complete the assigned therapy due to adverse events.Conclusions and Relevance: Among patients with complicated UTI or acute pyelonephritis caused by gram-negative pathogens, cefepime/enmetazobactam, compared with piperacillin/tazobactam, met criteria for noninferiority as well as superiority with respect to the primary outcome of clinical cure and microbiological eradication. Further research is needed to determine the potential role for cefepime/enmetazobactam in the treatment of complicated UTI and pyelonephritis.Trial Registration: ClinicalTrials.gov Identifier: NCT03687255. [ABSTRACT FROM AUTHOR]

This study describes access to individual patient-level data from randomized clinical trials during the COVID-19 pandemic to determine whether the intent to share what was reported in the registry, publication, or preprint was consistent with actual data access. [ABSTRACT FROM AUTHOR]

Importance: Once-daily roflumilast cream, 0.3%, a potent phosphodiesterase 4 inhibitor, demonstrated efficacy and was well tolerated in a phase 2b trial of patients with psoriasis.Objective: To evaluate the efficacy of roflumilast cream, 0.3%, applied once daily for 8 weeks in 2 trials of patients with plaque psoriasis.Design, Setting, and Participants: Two phase 3, randomized, double-blind, controlled, multicenter trials (DERMIS-1 [trial 1; n = 439] and DERMIS-2 [trial 2; n = 442]) were conducted at 40 centers (trial 1) and 39 centers (trial 2) in the US and Canada between December 9, 2019, and November 16, 2020, and between December 9, 2019, and November 23, 2020, respectively. Patients aged 2 years or older with plaque psoriasis involving 2% to 20% of body surface area were enrolled. The dates of final follow-up were November 20, 2020, and November 23, 2020, for trial 1 and trial 2, respectively.Interventions: Patients were randomized 2:1 to receive roflumilast cream, 0.3% (trial 1: n = 286; trial 2: n = 290), or vehicle cream (trial 1: n = 153; trial 2: n = 152) once daily for 8 weeks.Main Outcomes and Measures: The primary efficacy end point was Investigator Global Assessment (IGA) success (clear or almost clear status plus ≥2-grade improvement from baseline [score range, 0-4]) at week 8, analyzed using a Cochran-Mantel-Haenszel test stratified by site, baseline IGA score, and intertriginous involvement. There were 9 secondary outcomes, including intertriginous IGA success, 75% reduction in Psoriasis Area and Severity Index (PASI) score, and Worst Itch Numeric Rating Scale score of 4 or higher at baseline achieving 4-point reduction (WI-NRS success) at week 8 (scale: 0 [no itch] to 10 [worst imaginable itch]; minimum clinically important difference, 4 points).Results: Among 881 participants (mean age, 47.5 years; 320 [36.3%] female), mean IGA scores in trial 1 were 2.9 [SD, 0.52] for roflumilast and 2.9 [SD, 0.45] for vehicle and in trial 2 were 2.9 [SD, 0.48] for roflumilast and 2.9 [SD, 0.47]) for vehicle. Statistically significantly greater percentages of roflumilast-treated patients than vehicle-treated patients had IGA success at week 8 (trial 1: 42.4% vs 6.1%; difference, 39.6% [95% CI, 32.3%-46.9%]; trial 2: 37.5% vs 6.9%; difference, 28.9% [95% CI, 20.8%-36.9%]; P < .001 for both). Of 9 secondary end points, statistically significant differences favoring roflumilast vs vehicle were observed for 8 in trial 1 and 9 in trial 2, including intertriginous IGA success (71.2% vs 13.8%; difference, 66.5% [95% CI, 47.1%-85.8%] and 68.1% vs 18.5%; difference, 51.6% [95% CI, 29.3%-73.8%]; P < .001 for both), 75% reduction in PASI score (41.6% vs 7.6%; difference, 36.1% [95% CI, 28.5%-43.8%] and 39.0% vs 5.3%; difference, 32.4% [95% CI, 24.9%-39.8%]; P < .001 for both), WI-NRS success (67.5% vs 26.8%; difference, 42.6% [95% CI, 31.3%-53.8%] and 69.4% vs 35.6%; difference, 30.2% [95% CI, 18.2%-42.2%]; P < .001 for both). The incidence of treatment-emergent adverse events was 25.2% with roflumilast vs 23.5% with vehicle in trial 1 and 25.9% with roflumilast vs 18.4% with vehicle in trial 2. The incidence of serious adverse events was 0.7% with roflumilast vs 0.7% with vehicle in trial 1 and 0% with roflumilast vs 0.7% with vehicle in trial 2.Conclusions and Relevance: Among patients with chronic plaque psoriasis, treatment with roflumilast cream, 0.3%, compared with vehicle cream resulted in better clinical status at 8 weeks. Further research is needed to assess efficacy compared with other active treatments and to assess longer-term efficacy and safety.Trial Registration: ClinicalTrials.gov Identifiers: NCT04211363, NCT04211389. [ABSTRACT FROM AUTHOR]

An editorial is presented which addresses pharmacogenic testing and the results of the Genetic Informatics Trial (GIFT) of Warfarin to Prevent Deep Vein Thrombosis, and it mentions the underdosage and overdosage of warfarin in clinical settings. The monitoring of the international normalized ratio (INR) phenotypic biomarker is examined, along with variants in the cytochrome P450 2C9 (CYP2C9) enzyme, the VKORC1 gene, and the leukotriene-B(4) omega-hydroxylase 1 (CYP4F2) enzyme.

Importance: Acute agitation is common in patients with bipolar disorder and requires urgent management to relieve distress and to prevent escalation to aggressive behavior.Objective: To evaluate the effect of orally absorbed, sublingual dexmedetomidine, a selective α2A-adrenergic receptor agonist on symptoms of acute agitation in patients with bipolar disorder.Design, Setting, and Participants: Phase 3, randomized, double-blind, placebo-controlled trial conducted in 15 sites in the US with enrollment between February 24, 2020, and April 27, 2020, and final follow-up on May 21, 2020. A total of 380 adults with bipolar I or II disorder were randomized and 362 completed the study.Interventions: Participants were randomized to 3 groups: sublingual dexmedetomidine 180 μg (n = 127), sublingual dexmedetomidine 120 μg (n = 127), or placebo (n = 126).Main Outcomes and Measures: The primary efficacy end point was the mean change from baseline at 2 hours for the Positive and Negative Syndrome Scale-Excited Component (PEC) total score. The range of possible total scores is 5 (absence of agitation) to 35 (extremely severe). The secondary end point was the earliest time of a statistically significant change in PEC total score from baseline for the drug vs placebo. On the primary efficacy end point, to account for multiplicity associated with comparing 2 sublingual dexmedetomidine doses with placebo, the 2-sided significance level for each dose vs placebo was set at .025.Results: Of 380 patients randomized (mean age, 45.6 years; 54.8% women; and 56.1% Black individuals), 378 (99.5%) self-administered the study medication and completed the study. Baseline agitation was mild to moderate, with an overall mean PEC total score of 18.0. Two hours after taking the medication, the mean changes from baseline in PEC total score were -10.4 for sublingual dexmedetomidine 180 μg, -9.0 for sublingual dexmedetomidine 120 μg, and -4.9 for placebo. Least-square mean differences from placebo in the sublingual dexmedetomidine groups at 2 hours were -5.4 (97.5% CI, -6.6 to -4.2) for 180 μg and -4.1 (97.5% CI, -5.3 to -2.9) for 120 μg (both doses P < .001 vs placebo). Treatment effects began 20 minutes after taking the medication among patients in the sublingual dexmedetomidine groups (least-square mean difference for 180 μg, -1.1 [97.5% CI, -2.0 to -0.2]; P = .007; for 120 μg, -1.0 [97.5% CI, -1.9 to -0.1]; P = .009). Adverse events occurred in 35.7% of patients taking 180 μg of dexmedetomidine, 34.9% taking 120 μg, and 17.5% taking placebo. The most common adverse events (≥5%) in the respective 180 μg, 120 μg, and placebo groups were somnolence (21.4% and 20.6% vs 4.8%); dry mouth (4.8% and 7.1% vs 0.8%); hypotension (6.3% and 4.8% vs 0%); and dizziness (5.6% and 5.6% vs 0.8%).Conclusions and Relevance: Among patients with mild to moderate agitation associated with bipolar disorder, treatment with a sublingual film formulation of dexmedetomidine 120 μg or 180 μg, compared with placebo, resulted in significantly greater reduction in the agitation score at 2 hours. Further research is needed to understand the spectrum of patients for whom this treatment would be effective and feasible and to better understand the clinical importance of the observed effect size.Trial Registration: ClinicalTrials.gov Identifier: NCT04276883. [ABSTRACT FROM AUTHOR]

This article presents a review and meta-analysis on the efficacy and safety of incretin therapy in type 2 diabetes. The efficacy of available therapies diminishes as the disease progresses because of a steady decline in pancreatic beta cell function. Research into the incretin effect on the pathophysiology of type 2 diabetes has led to the development of different hypoglycemic agents. This paper seeks to assess the efficacy and safety of this therapy on adults with type 2 diabetes. The analysis showed that incretin therapy is an alternative option for nonpregnant adults, has modest efficacy and a favorable weight-change profile. The authors caution that further testing is needed to determine the role of this class of drugs.

Presents an information about the "Archives of Dermatology," an international dermatologic journal. Manuscript criteria and information; Instructions for preparing reports of randomized controlled trials; Directions for preparing structured abstracts.

Importance: Patent foramen ovale (PFO)-associated strokes comprise approximately 10% of ischemic strokes in adults aged 18 to 60 years. While device closure decreases stroke recurrence risk overall, the best treatment for any individual is often unclear.Objective: To evaluate heterogeneity of treatment effect of PFO closure on stroke recurrence based on previously developed scoring systems.Design, Setting, and Participants: Investigators for the Systematic, Collaborative, PFO Closure Evaluation (SCOPE) Consortium pooled individual patient data from all 6 randomized clinical trials that compared PFO closure plus medical therapy vs medical therapy alone in patients with PFO-associated stroke, and included a total of 3740 participants. The trials were conducted worldwide from 2000 to 2017.Exposures: PFO closure plus medical therapy vs medical therapy alone. Subgroup analyses used the Risk of Paradoxical Embolism (RoPE) Score (a 10-point scoring system in which higher scores reflect younger age and the absence of vascular risk factors) and the PFO-Associated Stroke Causal Likelihood (PASCAL) Classification System, which combines the RoPE Score with high-risk PFO features (either an atrial septal aneurysm or a large-sized shunt) to classify patients into 3 categories of causal relatedness: unlikely, possible, and probable.Main Outcomes and Measures: Ischemic stroke.Results: Over a median follow-up of 57 months (IQR, 24-64), 121 outcomes occurred in 3740 patients. The annualized incidence of stroke with medical therapy was 1.09% (95% CI, 0.88%-1.36%) and with device closure was 0.47% (95% CI, 0.35%-0.65%) (adjusted hazard ratio [HR], 0.41 [95% CI, 0.28-0.60]). The subgroup analyses showed statistically significant interaction effects. Patients with low vs high RoPE Score had HRs of 0.61 (95% CI, 0.37-1.00) and 0.21 (95% CI, 0.11-0.42), respectively (P for interaction = .02). Patients classified as unlikely, possible, and probable using the PASCAL Classification System had HRs of 1.14 (95% CI, 0.53-2.46), 0.38 (95% CI, 0.22-0.65), and 0.10 (95% CI, 0.03-0.35), respectively (P for interaction = .003). The 2-year absolute risk reduction was -0.7% (95% CI, -4.0% to 2.6%), 2.1% (95% CI, 0.6%-3.6%), and 2.1% (95% CI, 0.9%-3.4%) in the unlikely, possible, and probable PASCAL categories, respectively. Device-associated adverse events were generally higher among patients classified as unlikely; the absolute risk increases in atrial fibrillation beyond day 45 after randomization with a device were 4.41% (95% CI, 1.02% to 7.80%), 1.53% (95% CI, 0.33% to 2.72%), and 0.65% (95% CI, -0.41% to 1.71%) in the unlikely, possible, and probable PASCAL categories, respectively.Conclusions and Relevance: Among patients aged 18 to 60 years with PFO-associated stroke, risk reduction for recurrent stroke with device closure varied across groups classified by their probabilities that the stroke was causally related to the PFO. Application of this classification system has the potential to guide individualized decision-making. [ABSTRACT FROM AUTHOR]

Importance: Evidence-based guidance is limited on how clinicians should screen for social risk factors and which interventions related to these risk factors improve health outcomes.Objective: To describe research on screening and interventions for social risk factors to inform US Preventive Services Task Force considerations of the implications for its portfolio of recommendations.Data Sources: Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Ovid MEDLINE, Sociological Abstracts, and Social Services Abstracts (through 2018); Social Interventions Research and Evaluation Network evidence library (January 2019 through May 2021); surveillance through May 21, 2021; interviews with 17 key informants.Study Selection: Individual-level and health care system-level interventions with a link to the health care system that addressed at least 1 of 7 social risk domains: housing instability, food insecurity, transportation difficulties, utility needs, interpersonal safety, education, and financial strain.Data Extraction and Synthesis: One investigator abstracted data from studies and a second investigator evaluated data abstractions for completeness and accuracy; key informant interviews were recorded, transcribed, summarized, and integrated with evidence from the literature; narrative synthesis with supporting tables and figures.Main Outcomes and Measures: Validity of multidomain social risk screening tools; all outcomes reported for social risk-related interventions; challenges or unintended consequences of screening and interventions.Results: Many multidomain social risk screening tools have been developed, but they vary widely in their assessment of social risk and few have been validated. This technical brief identified 106 social risk intervention studies (N = 5 978 596). Of the interventions studied, 73 (69%; n = 127 598) addressed multiple social risk domains. The most frequently addressed domains were food insecurity (67/106 studies [63%], n = 141 797), financial strain (52/106 studies [49%], n = 111 962), and housing instability (63/106 studies [59%], n = 5 881 222). Food insecurity, housing instability, and transportation difficulties were identified by key informants as the most important social risk factors to identify in health care. Thirty-eight studies (36%, n = 5 850 669) used an observational design with no comparator, and 19 studies (18%, n = 15 205) were randomized clinical trials. Health care utilization measures were the most commonly reported outcomes in the 68 studies with a comparator (38 studies [56%], n = 111 102). The literature and key informants described many perceived or potential challenges to implementation of social risk screening and interventions in health care.Conclusions and Relevance: Many interventions to address food insecurity, financial strain, and housing instability have been studied, but more randomized clinical trials that report health outcomes from social risk screening and intervention are needed to guide widespread implementation in health care. [ABSTRACT FROM AUTHOR]

Importance: Psychotherapists possess strengths and weaknesses in treating different mental health problems, yet performance information is rarely harnessed in mental health care (MHC). To our knowledge, no prior studies have tested the causal efficacy of prospectively matching patients to therapists with empirically derived strengths in treating patients' specific concerns.Objective: To test the effect of measurement-based matching vs case assignment as usual (CAU) on psychotherapy outcomes.Design, Setting, and Participants: In this randomized clinical trial, adult outpatients were recruited between November 2017 and April 2019. Assessments occurred at baseline and repeatedly during treatment at 6 community MHC clinics in Cleveland, Ohio. To be eligible, patients had to make their own MHC decisions. Of 1329 individuals screened, 288 were randomized. Excluding those who withdrew or provided no assessments beyond baseline, 218 patients treated by 48 therapists were included in the primary modified intent-to-treat analyses.Interventions: Therapist performance was assessed pretrial across 15 or more historical cases based on patients' pre-post reporting across 12 problem domains of the routinely administered Treatment Outcome Package (TOP). Therapists were classified in each domain as effective (on average, patients' symptoms reliably improved), neutral (on average, patients' symptoms neither reliably improved nor deteriorated), or ineffective (on average, patients' symptoms reliably deteriorated). Trial patients were randomly assigned to good-fitting therapists (matched group) or were assigned to therapists pragmatically (CAU group). There were multiple match levels, ranging from therapists being effective on the 3 most elevated domains reported by patients and not ineffective on any others (highest) to not effective on the most elevated domains reported by patients but also not ineffective on any domain (lowest). Therapists treated patients in the matched and CAU groups, and treatment was unmanipulated.Main Outcomes and Measures: General symptomatic and functional impairment across all TOP domains (average z scores relative to the general population mean; higher scores indicate greater impairment), global distress (Symptom Checklist-10; higher scores indicate greater distress), and domain-specific impairment on each individual's most elevated TOP-assessed problem.Results: Of 218 patients, 147 (67.4%) were female, and 193 (88.5%) were White. The mean (SD) age was 33.9 (11.2) years. Multilevel modeling indicated a match effect on reductions in weekly general symptomatic and functional impairment (γ110 = -0.03; 95% CI, -0.05 to -0.01; d = 0.75), global distress (γ110 = -0.16; 95% CI, -0.30 to -0.02; d = 0.50), and domain-specific impairment (γ110 = -0.01; 95% CI -0.01 to -0.006; d = 0.60), with no adverse events.Conclusions and Relevance: Matching patients with therapists based on therapists' performance strengths can improve MHC outcomes.Trial Registration: ClinicalTrials.gov Identifier: NCT02990000. [ABSTRACT FROM AUTHOR]

Importance: Cognitive impairment is a core feature of schizophrenia, with negative consequences on functional outcomes. Although cognitive remediation (CR) is effective and mentioned in treatment guidance for schizophrenia, its active ingredients and ideal candidates are still debated.Objective: To provide a comprehensive update on CR effectiveness for cognition and functioning in schizophrenia and analyze the core ingredients of efficacy and role of patient characteristics.Data Sources: The reference list of the last comprehensive meta-analysis in 2011 was screened against eligibility criteria. Then, electronic databases (PubMed, Scopus, and PsycInfo) were systematically searched for articles published from January 2011 to February 2020. Reference lists of included articles and relevant reviews were hand searched, and Google Scholar was manually inspected.Study Selection: Eligible studies were randomized clinical trials comparing CR with any other control condition in patients diagnosed with schizophrenia spectrum disorders (with an unrestricted clinical status). Screening was performed by at least 2 independent reviewers.Data Extraction and Synthesis: The PRISMA guidelines were followed. Study data were independently extracted and pooled using random-effect models. Cohen d was used to measure outcomes. Trial methodological quality was evaluated with the Clinical Trials Assessment Measure.Main Outcomes and Measures: Primary outcomes were changes in global cognition and overall functioning from baseline to after treatment, subsequently investigated through metaregressions, subgroup, and sensitivity analyses based on prespecified hypotheses, to identify potential moderators of response associated with treatment modality and patient characteristics.Results: Of 1815 identified reports, 358 full texts were assessed and 194 reports on 130 studies were included. Based on 130 studies with 8851 participants, CR was effective on cognition (d, 0.29 [95% CI, 0.24-0.34]) and functioning (d, 0.22 [95% CI, 0.16-0.29]). An active and trained therapist (cognition: χ21, 4.14; P = .04; functioning: χ21, 4.26; P = .04), structured development of cognitive strategies (cognition: χ21, 9.34; P = .002; functioning: χ21, 8.12; P = .004), and integration with psychosocial rehabilitation (cognition: χ21, 5.66; functioning: χ21, 12.08) were crucial ingredients of efficacy. Patients with fewer years of education (global cognition: coefficient, -0.055 [95% CI, -0.103 to -0.006]; P = .03; global functioning: coefficient, -0.061 [95% CI, -0.112 to -0.011]; P = .02), lower premorbid IQ (global functioning: coefficient, -0.013 [-0.025 to -0.001]; P = .04), and higher baseline symptom severity (global cognition: coefficient, 0.006 [95% CI, 0.002 to 0.010]; P = .005) emerged as optimal candidates.Conclusions and Relevance: These findings show that CR is an evidence-based intervention that should be included consistently into clinical guidelines for the treatment of individuals with schizophrenia and implemented more widely in clinical practice. [ABSTRACT FROM AUTHOR]

Importance: Platelet-rich plasma injections are used as a treatment for chronic midportion Achilles tendinopathy, but evidence for this treatment is limited.Objective: In adults with midportion Achilles tendinopathy, to assess the effects of a single platelet-rich plasma injection, compared with sham injection, on the outcome of the Victorian Institute of Sport Assessment-Achilles (VISA-A) score (a single composite measure of Achilles tendinopathy severity).Design, Setting, and Participants: A participant-blinded, multicenter randomized clinical trial that included 240 people from 24 sites assigned to either a platelet-rich plasma injection or a sham injection between April 2016 and February 2020. Final follow-up was July 2020. Participants were older than 18 years with midportion Achilles tendon pain for more than 3 months as confirmed by ultrasound, magnetic resonance imaging, or both.Interventions: A single intratendinous platelet-rich plasma injection (n = 121) or a single sham injection (insertion of a subcutaneous dry needle not entering the tendon) (n = 119).Main Outcomes and Measures: The primary outcome was the VISA-A score, measured 6 months after treatment allocation. The VISA-A score contains 8 questions that cover 3 domains of pain, function, and activity, analyzed as a composite score (range, 0 [worst symptoms] to 100 [no symptoms]; minimal clinically important difference in score, 12 points). The primary analysis was adjusted for laterality, age, sex, and baseline VISA-A score.Results: Among 240 patients assigned to a platelet-rich plasma or sham injection (mean age, 52 years; 138 [58%] women), 221 (92%) completed the trial. At 6-month follow-up, mean VISA-A score values in the plasma-rich plasma group vs the sham injection group were 54.4 vs 53.4 (adjusted mean difference, -2.7 [95% CI, -8.8 to 3.3]). The most common adverse events compared between patients in the platelet-rich plasma group vs the sham group were injection site discomfort (97 vs 73 patients), swelling (56 vs 52 patients) and bruising (48 vs 49 patients).Conclusions and Relevance: Among patients with chronic midportion Achilles tendinopathy, treatment with a single injection of intratendinous platelet-rich plasma, compared with insertion of a subcutaneous dry needle, did not reduce Achilles tendon dysfunction at 6 months. These findings do not support the use of this treatment for chronic midportion Achilles tendinopathy.Trial Registration: isrctn.org Identifier: ISRCTN13254422. [ABSTRACT FROM AUTHOR]

Importance: Patients with ischemic stroke attributed to large- or small-vessel disease are not considered at high risk for atrial fibrillation (AF), and the AF incidence rate in this population is unknown.Objectives: To determine whether long-term cardiac monitoring is more effective than usual care for AF detection in patients with stroke attributed to large- or small-vessel disease through 12 months of follow-up.Design, Setting, and Participants: The STROKE-AF trial was a randomized (1:1), multicenter (33 sites in the US) clinical trial that enrolled 496 patients between April 2016 and July 2019, with primary end point follow-up through August 2020. Eligible patients were aged 60 years or older or aged 50 to 59 years with at least 1 additional stroke risk factor and had an index stroke attributed to large- or small-vessel disease within 10 days prior to insertable cardiac monitor (ICM) insertion.Interventions: Patients randomized to the intervention group (n = 242) received ICM insertion within 10 days of the index stroke; patients in the control group (n = 250) received site-specific usual care consisting of external cardiac monitoring, such as 12-lead electrocardiograms, Holter monitoring, telemetry, or event recorders.Main Outcomes and Measures: Incident AF lasting more than 30 seconds through 12 months.Results: Among 492 patients who were randomized (mean [SD] age, 67.1 [9.4] years; 185 [37.6%] women), 417 (84.8%) completed 12 months of follow-up. The median (interquartile range) CHA2DS2-VASc (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke or transient ischemic attack, vascular disease, age 65 to 74 years, sex category) score was 5 (4-6). AF detection at 12 months was significantly higher in the ICM group vs the control group (27 patients [12.1%] vs 4 patients [1.8%]; hazard ratio, 7.4 [95% CI, 2.6-21.3]; P < .001). Among the 221 patients in the ICM group who received an ICM, 4 (1.8%) had ICM procedure-related adverse events (1 site infection, 2 incision site hemorrhages, and 1 implant site pain).Conclusions and Relevance: Among patients with stroke attributed to large- or small-vessel disease, monitoring with an ICM compared with usual care detected significantly more AF over 12 months. However, further research is needed to understand whether identifying AF in these patients is of clinical importance.Trial Registration: ClinicalTrials.gov Identifier: NCT02700945. [ABSTRACT FROM AUTHOR]