HARMONi-A Study Investigators, Fang W, Zhao Y
… +68 more, Luo Y, Yang R, Huang Y, He Z, Zhao H, Li M, Li K, Song Q, Du X, Sun Y, Li W, Sun L, Wang Z, Yang K, Fan Y, Liu B, Zhao H, Hu Y, Jia L, Xu S, Yi T, Lv D, Lan H, Li M, Liang W, Wang Y, Yang H, Jia Y, Chen Y, Lu J, Shi M, Liu C, Zhou M, Zhou J, Liu X, Zhou N, He M, Dong X, Chen H, Chen Y, Su H, Li X, Zhang Z, Yang L, Liu Y, Chen L, Hou X, Zhang Y, Guo J, Ma R, Lu H, Wu D, Feng W, Li W, Huang J, Wang Y, Song X, Peng J, Liu L, Guo Y, Li W, Xia M, Lu D, Hu M, Wang ZM, Li B, Xia MY, Zhang L
IMPORTANCE: Patients with epidermal growth factor receptor (EGFR) gene variant nonsquamous non-small cell lung cancer (NSCLC) who have disease progression after prior EGFR tyrosine kinase inhibitor (TKI) therapy have lim...IMPORTANCE: Patients with epidermal growth factor receptor (EGFR) gene variant nonsquamous non-small cell lung cancer (NSCLC) who have disease progression after prior EGFR tyrosine kinase inhibitor (TKI) therapy have limited treatment options, creating a need for more effective subsequent therapies. OBJECTIVE: To provide final overall results of a trial assessing whether adding ivonescimab (a bispecific antibody targeting programmed cell death protein 1 and vascular endothelial growth factor) to chemotherapy improves overall survival in this population. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, placebo-controlled phase 3 trial conducted at 55 sites in China. From January 25 to November 2, 2022, a total of 322 adult patients with locally advanced or metastatic EGFR-variant nonsquamous NSCLC who had received prior EGFR-TKI therapy were enrolled. The data cutoff date was April 12, 2025. INTERVENTIONS: Patients were randomized 1:1 to receive ivonescimab (20 mg/kg; n = 161) or placebo (n = 161) plus chemotherapy with pemetrexed and carboplatin once every 3 weeks for 4 cycles, followed by maintenance therapy. MAIN OUTCOMES AND MEASURES: This final results report focuses on overall survival, the key secondary end point, tested in a hierarchical manner (the primary end point was progression-free survival assessed by an independent radiology review committee). RESULTS: The 322 enrolled patients had a median age of 59.4 years, and 51.6% were female. During a median follow-up of 32.5 months, ivonescimab plus chemotherapy improved overall survival compared with chemotherapy alone (median survival, 16.8 months vs 14.1 months; stratified hazard ratio, 0.74; 95% CI, 0.58-0.95; P = .02). The absolute difference in median overall survival was 2.7 months. Estimated 30-month survival rates were 29.1% (95% CI, 22.1%-36.4%) with ivonescimab and 18.4% (95% CI, 12.8%-24.8%) with placebo. Grade 3 or higher treatment-emergent adverse events occurred in 67.1% and 54.7% of patients receiving ivonescimab and placebo, respectively. CONCLUSIONS AND RELEVANCE: Ivonescimab plus chemotherapy provided a statistically significant and clinically meaningful improvement in overall survival with an acceptable safety profile in patients with EGFR-variant NSCLC after EGFR-TKI therapy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05184712.
Baudin F, Pouyau R, Subtil F
… +15 more, Jarrasse C, Tochon M, Afanetti M, Milési C, Piloquet JE, Mortamet G, Nallet Amate M, Launay V, Cour Andlauer F, Roche S, Levy M, Rambaud J, Portefaix A, Javouhey E, PROPOSITIS Investigators
IMPORTANCE: Prone positioning has been shown to improve respiratory mechanics and oxygenation, but its clinical benefit in infants with acute viral bronchiolitis receiving high-flow nasal cannula (HFNC) support remains u...IMPORTANCE: Prone positioning has been shown to improve respiratory mechanics and oxygenation, but its clinical benefit in infants with acute viral bronchiolitis receiving high-flow nasal cannula (HFNC) support remains unknown. OBJECTIVE: To investigate whether prone positioning in infants with moderate to severe acute bronchiolitis and HFNC support reduces escalation to noninvasive or invasive ventilation. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, randomized, open-label trial conducted in 15 pediatric intermediate or intensive care units in France. Infants aged 6 months or younger admitted for 24 hours or less with a diagnosis of acute bronchiolitis with moderate to severe respiratory distress requiring HFNC support were enrolled between January 2021 and November 2023 and followed up until hospital discharge (last patient discharged on December 11, 2023). INTERVENTIONS: Participants were randomly assigned to the prone position (n = 221) or supine position (n = 230). Infants in the prone position group received prone positioning for 24 hours or longer during the first 48 hours. All participants received standardized HFNC support at 2 L/kg/min. MAIN OUTCOMES AND MEASURES: The primary outcome was the need for escalation of care to noninvasive or invasive ventilation within the first 72 hours, according to prespecified criteria. Secondary outcomes included treatment failure, determined by an independent clinical adjudication committee; tolerance of prone positioning; length of hospital stay; duration of respiratory support; infant comfort; and adverse events. RESULTS: Among 451 infants randomized, 446 were included in the primary analysis (median age, 41 [IQR, 19-72] days; 54% male). Escalation of care occurred in 80 infants (17.9%), with no significant difference between the prone position (33/220 [15.0%]) and supine position (47/226 [20.8%]) groups (adjusted odds ratio, 0.66 [95% CI, 0.40-1.07]; P = .09). Secondary outcomes did not differ significantly between the 2 groups. In the safety analysis, serious adverse events occurred in 2 of 180 infants (1.1%) in the prone position group and 2 of 264 (0.8%) in the supine position group. CONCLUSIONS AND RELEVANCE: Prone positioning in infants with moderate to severe bronchiolitis receiving HFNC support did not significantly reduce escalation of care. However, the wide 95% confidence interval around the observed odds ratio suggests that this study was not definitive and further research is warranted. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03976895.
IMPORTANCE: Low back pain is defined as pain localized below the costal margin and above the inferior gluteal fold, with or without leg pain. Low back pain affects approximately 619 million people worldwide and is the le...IMPORTANCE: Low back pain is defined as pain localized below the costal margin and above the inferior gluteal fold, with or without leg pain. Low back pain affects approximately 619 million people worldwide and is the leading cause of years lived with disability worldwide. OBSERVATIONS: Approximately 90% of patients presenting for care with low back pain have nonspecific low back pain, which is defined as low back pain that is not associated with specific spinal disorders (such as lumbar radiculopathy, lumbar spinal stenosis, vertebral fracture, axial spondyloarthritis, infection, or malignancy). Low back pain is classified as acute if the duration is shorter than 6 weeks, subacute if the duration is 6 to 12 weeks, and chronic when the duration is longer than 12 weeks. The age-standardized prevalence of low back pain is higher in females (9330 per 100 000) than in males (5520 per 100 000). The prevalence of low back pain increases with age, peaking at approximately 85 years. Risk factors for low back pain include obesity, depressive symptoms, occupational exposures (eg, heavy lifting), tobacco use, chronic disease (eg, diabetes), and previous low back pain. Acute nonspecific low back pain is usually self-limited, and approximately 72% of individuals recover by 12 months. Prognosis is less favorable for chronic nonspecific low back pain, but 42% of patients recover within 12 months. Initial management of patients with low back pain of any duration includes reassurance that serious underlying disease is unlikely, discussion about the expected time course of recovery, and the recommendation to remain physically active. Patients should be encouraged to continue their usual activities (including work), avoid prolonged rest, and be advised to self-manage their condition, which consists of symptom-relief strategies (such as heat application) and activity pacing (maintaining or gradually increasing usual activities and work). For patients with acute nonspecific low back pain, first-line therapies include heat application, spinal manipulation, massage, and acupuncture (typically provided by physical therapists, chiropractors, acupuncturists, and massage therapists) as well as nonsteroidal anti-inflammatory drugs (NSAIDs; such as ibuprofen) and skeletal muscle relaxants (such as cyclobenzaprine). For chronic nonspecific low back pain, first-line therapies include exercise of any type, psychological therapies (eg, cognitive behavioral therapy), or combined multidisciplinary approaches (such as pain management programs and integrated exercise and psychological care) along with spinal manipulation, massage, and acupuncture. NSAIDs should be considered as second-line therapy for chronic nonspecific low back pain. CONCLUSIONS AND RELEVANCE: Low back pain is a leading cause of disability worldwide. Acute nonspecific low back pain is often self-limited, whereas chronic nonspecific low back pain has a less favorable prognosis. For patients with acute nonspecific low back pain, first-line treatments include selected nonpharmacological therapies and medications (such as NSAIDs and skeletal muscle relaxants). For patients with chronic nonspecific low back pain, first-line treatment consists of exercise, psychological therapies (such as cognitive behavioral therapy), and combined multidisciplinary care.
IMPORTANCE: Studying how to prevent or delay not just 1 disease but multiple chronic conditions is of great importance for public health; however, few interventions have demonstrated success during long-term follow-up. O...IMPORTANCE: Studying how to prevent or delay not just 1 disease but multiple chronic conditions is of great importance for public health; however, few interventions have demonstrated success during long-term follow-up. OBJECTIVE: To examine the association of lifestyle or metformin compared with placebo on long-term multimorbidity in adults with prediabetes. DESIGN, SETTING, AND PARTICIPANTS: Observational follow-up cohort study of a randomized clinical trial conducted at 27 sites in the United States from June 1, 1996, to December 31, 2021. From June 1, 1996, through May 28, 1999, 3234 adults at high risk of diabetes enrolled in the 3-year Diabetes Prevention Program (DPP). They were subsequently enrolled in the DPP Outcomes Study (DPPOS). Of this cohort, Centers for Medicare & Medicaid Services (CMS) morbidity data were available through 2021 for 1173 participants who provided consent. Data were analyzed from June 5, 2024, to November 7, 2025. EXPOSURES: Participants in DPP were randomly assigned to intensive lifestyle intervention, metformin, or placebo. During DPPOS, medications were unmasked with discontinuation of placebo; metformin was continued. Group booster classes were offered to the lifestyle group semiannually and all participants were offered lifestyle classes quarterly until 2014. MAIN OUTCOMES AND MEASURES: The primary outcome was multimorbidity (presence of ≥2 of 15 prevalent conditions, defined in CMS' Chronic Condition Data Warehouse and adapted for Medicare Advantage encounters). Cox proportional hazard models were applied to estimate associations between randomized treatment groups and time to development of outcomes. RESULTS: Of the 1173 participants (median age, 74 years [IQR, 70-80]; 795 [68%] were female), 997 (85%) experienced greater than or equal to 2 conditions (median, 5 [IQR, 3-7]) by the end of follow-up (316 of 385 [82%], 327 of 385 [85%], and 350 of 403 [87%], respectively, among lifestyle, metformin, and placebo groups). The risk of multimorbidity was lower among lifestyle compared with placebo participants (hazard ratio [HR], 0.79; 95% CI, 0.68-0.93) after adjustment for relevant covariates. There was no difference between participants in the metformin and placebo groups (HR, 0.91; 95% CI, 0.78-1.07). These relationships persisted when diabetes was excluded from the multimorbidity definition. When restricted to dyads of the costliest conditions, the association with lifestyle vs placebo yielded an HR of 0.57 (95% CI, 0.38-0.85). CONCLUSIONS AND RELEVANCE: Among adults with prediabetes at baseline, lifestyle intervention, but not metformin, was associated with a lower burden of multimorbidity. Lifestyle programs may persistently lower the development of chronic conditions. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: DPP, NCT00004992; DPPOS, NCT00038727.
Zhang S, Ran A, Zhou J
… +46 more, Ling A, Sham K, Zhang Y, Tang Z, Nguyen TX, Yang D, Lam N, Yuen HKL, Chan VTT, Ho M, Chan JYY, Lam TCH, Yim CCL, Chow CWY, Cheung SSL, Lam MCW, Lai ACH, Wong CYK, Yu AHY, Hui VWK, Mak ACY, Li SL, Chan NCY, Yip WWK, Young AL, Ozaki R, Loo KM, Luk AOY, Chan JCN, Chan P, Luk MMH, Lai LKP, Wong DHT, Shiu J, Wang X, Heng PA, Lin H, Sivaprasad S, Wong TY, Li KKW, Chan CKM, Pang CP, Tham CC, Lai TYY, Szeto SKH, Cheung CY
IMPORTANCE: Screening for diabetic retinopathy using fundus photographs is the global standard of care but results in high false-positive referrals to evaluate diabetic macular edema (DME), placing a substantial burden o...IMPORTANCE: Screening for diabetic retinopathy using fundus photographs is the global standard of care but results in high false-positive referrals to evaluate diabetic macular edema (DME), placing a substantial burden on specialist eye clinics. Integrating an AI-based optical coherence tomography (AI-OCT) system into screening pathways may reduce potentially unnecessary referrals. OBJECTIVE: To evaluate the diagnostic and referral performance of an AI-OCT system for DME detection within a diabetic retinopathy screening pathway in clinical settings. DESIGN, SETTING, AND PARTICIPANTS: Stepwise evaluation conducted in Hong Kong Special Administrative Region: a prospective silent-mode validation (February 2020 to July 2023) recruiting 603 patients with diabetes at a tertiary hospital triage unit, followed by a multicenter noninferiority RCT (September 2023 to April 2025), with follow-up completed in May 2025, recruiting 276 patients with suspected DME referred from a territory-wide diabetic retinopathy screening program. INTERVENTIONS: RCT participants were randomized to intervention (referral for DME evaluation based on both fundus photograph-based screening reports and AI-OCT reports [n = 137]) or control (automatic referral based solely on fundus photograph-based screening reports [n = 139]) groups. The AI-OCT system incorporated image-quality assessment, DME detection, and uncertainty flagging. Study outcomes focused on referral rates under the 2 pathways; for ethical reasons, all participants ultimately underwent specialist evaluation. MAIN OUTCOMES AND MEASURES: The primary outcome was false-positive DME referral rate, with a prespecified noninferiority margin of 20%. The secondary outcomes included sensitivity and specificity for DME detection and DME referral. RESULTS: In prospective silent-mode validation (mean age, 64.7 [SD, 9.4] years; 56.2% male), 86 of 1200 scans (7.2%) were identified as ungradable and 49 of 1114 gradable scans (4.4%) were classified as uncertain. The system achieved 98.8% (95% CI, 94.5%-100.0%) sensitivity and 90.7% (95% CI, 88.7%-92.4%) specificity for DME detection. In the RCT (mean age, 63.9 [SD, 10.9] years; 54.7% male), DME prevalence was similar in the intervention and control groups (30.9% vs 29.9%). The false-positive DME referral rate was 24.1% (95% CI, 14.6%-37.0%) and 69.1% (95% CI, 61.0%-76.1%), respectively (absolute difference, -45% [95% CI, -58.2% to -31.9%; P < .001 for noninferiority]; upper bound of the CI below the prespecified noninferiority margin of 20%). Sensitivity for DME referral was 100.0% (95% CI, 100.0%-100.0%) in both groups. Specificity for DME referral was 86.5% (95% CI, 79.3%-92.9%) in the intervention group and 0.0% (95% CI, 0.0%-0.0%) in the control group. No cases of DME occurred among nonreferred participants in the intervention group. CONCLUSIONS AND RELEVANCE: Compared with standard practice, incorporation of the AI-OCT system as a secondary screening tool was noninferior with respect to false-positive referral rates and was associated with a substantial reduction in potentially unnecessary DME referrals without compromising sensitivity. TRIAL REGISTRATION: Chinese Clinical Trial Registry: ChiCTR2300075087.