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Key Points: Question: What symptoms are differentially present in SARS-CoV-2–infected individuals 6 months or more after infection compared with uninfected individuals, and what symptom-based criteria can be used to identify postacute sequelae of SARS-CoV-2 infection (PASC) cases? Findings: In this analysis of data from 9764 participants in the RECOVER adult cohort, a prospective longitudinal cohort study, 37 symptoms across multiple pathophysiological domains were identified as present more often in SARS-CoV-2–infected participants at 6 months or more after infection compared with uninfected participants. A preliminary rule for identifying PASC was derived based on a composite symptom score. Meaning: A framework for identifying PASC cases based on symptoms is a first step to defining PASC as a new condition. These findings require iterative refinement that further incorporates clinical features to arrive at actionable definitions of PASC. Importance: SARS-CoV-2 infection is associated with persistent, relapsing, or new symptoms or other health effects occurring after acute infection, termed postacute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID. Characterizing PASC requires analysis of prospectively and uniformly collected data from diverse uninfected and infected individuals. Objective: To develop a definition of PASC using self-reported symptoms and describe PASC frequencies across cohorts, vaccination status, and number of infections. Design, Setting, and Participants: Prospective observational cohort study of adults with and without SARS-CoV-2 infection at 85 enrolling sites (hospitals, health centers, community organizations) located in 33 states plus Washington, DC, and Puerto Rico. Participants who were enrolled in the RECOVER adult cohort before April 10, 2023, completed a symptom survey 6 months or more after acute symptom onset or test date. Selection included population-based, volunteer, and convenience sampling. Exposure: SARS-CoV-2 infection. Main Outcomes and Measures: PASC and 44 participant-reported symptoms (with severity thresholds). Results: A total of 9764 participants (89% SARS-CoV-2 infected; 71% female; 16% Hispanic/Latino; 15% non-Hispanic Black; median age, 47 years [IQR, 35-60]) met selection criteria. Adjusted odds ratios were 1.5 or greater (infected vs uninfected participants) for 37 symptoms. Symptoms contributing to PASC score included postexertional malaise, fatigue, brain fog, dizziness, gastrointestinal symptoms, palpitations, changes in sexual desire or capacity, loss of or change in smell or taste, thirst, chronic cough, chest pain, and abnormal movements. Among 2231 participants first infected on or after December 1, 2021, and enrolled within 30 days of infection, 224 (10% [95% CI, 8.8%-11%]) were PASC positive at 6 months. Conclusions and Relevance: A definition of PASC was developed based on symptoms in a prospective cohort study. As a first step to providing a framework for other investigations, iterative refinement that further incorporates other clinical features is needed to support actionable definitions of PASC. This study aims to develop a definition of postacute sequelae of SARS-CoV-2 infection (PASC) based on self-reported symptoms and describe PASC frequencies across cohorts, vaccination status, and number of infections using a cohort of adults with and without SARS-CoV-2 infection. [ABSTRACT FROM AUTHOR]

Importance: Chronic breathlessness is common in people with chronic obstructive pulmonary disease (COPD). Regular, low-dose, extended-release morphine may relieve breathlessness, but evidence about its efficacy and dosing is needed.Objective: To determine the effect of different doses of extended-release morphine on worst breathlessness in people with COPD after 1 week of treatment.Design, Setting, and Participants: Multicenter, double-blind, placebo-controlled randomized clinical trial including people with COPD and chronic breathlessness (defined as a modified Medical Research Council score of 3 to 4) conducted at 20 centers in Australia. People were enrolled between September 1, 2016, and November 20, 2019, and followed up through December 26, 2019.Interventions: People were randomized 1:1:1 to 8 mg/d or 16 mg/d of oral extended-release morphine or placebo during week 1. At the start of weeks 2 and 3, people were randomized 1:1 to 8 mg/d of extended-release morphine, which was added to the prior week's dose, or placebo.Main Outcomes and Measures: The primary outcome was change in the intensity of worst breathlessness on a numerical rating scale (score range, 0 [none] to 10 [being worst or most intense]) using the mean score at baseline (from days -3 to -1) to the mean score after week 1 of treatment (from days 5 to 7) in the 8 mg/d and 16 mg/d of extended-release morphine groups vs the placebo group. Secondary outcomes included change in daily step count measured using an actigraphy device from baseline (day -1) to the mean step count from week 3 (from days 19 to 21).Results: Among the 160 people randomized, 156 were included in the primary analyses (median age, 72 years [IQR, 67 to 78 years]; 48% were women) and 138 (88%) completed treatment at week 1 (48 in the 8 mg/d of morphine group, 43 in the 16 mg/d of morphine group, and 47 in the placebo group). The change in the intensity of worst breathlessness at week 1 was not significantly different between the 8 mg/d of morphine group and the placebo group (mean difference, -0.3 [95% CI, -0.9 to 0.4]) or between the 16 mg/d of morphine group and the placebo group (mean difference, -0.3 [95%, CI, -1.0 to 0.4]). At week 3, the secondary outcome of change in mean daily step count was not significantly different between the 8 mg/d of morphine group and the placebo group (mean difference, -1453 [95% CI, -3310 to 405]), between the 16 mg/d of morphine group and the placebo group (mean difference, -1312 [95% CI, -3220 to 596]), between the 24 mg/d of morphine group and the placebo group (mean difference, -692 [95% CI, -2553 to 1170]), or between the 32 mg/d of morphine group and the placebo group (mean difference, -1924 [95% CI, -47 699 to 921]).Conclusions and Relevance: Among people with COPD and severe chronic breathlessness, daily low-dose, extended-release morphine did not significantly reduce the intensity of worst breathlessness after 1 week of treatment. These findings do not support the use of these doses of extended-release morphine to relieve breathlessness.Trial Registration: ClinicalTrials.gov Identifier: NCT02720822. [ABSTRACT FROM AUTHOR]

Importance: Current prevalence of obstructive sleep apnea (OSA) in the US is not well established; however, based on cohort and survey data, in 2007-2010 the estimated prevalence of at least mild OSA (defined as an apnea-hypoxia index [AHI] ≥5) plus symptoms of daytime sleepiness among adults aged 30 to 70 years was 14% for men and 5% for women, and the estimated prevalence of moderate to severe OSA (defined as AHI ≥15) was 13% for men and 6% for women. Severe OSA is associated with increased all-cause mortality. Other adverse health outcomes associated with untreated OSA include cardiovascular disease and cerebrovascular events, type 2 diabetes, cognitive impairment, decreased quality of life, and motor vehicle crashes.Objective: To update its 2017 recommendation, the US Preventive Services Task Force (USPSTF) commissioned a systematic review to evaluate the benefits and harms of screening for OSA in adults.Population: Asymptomatic adults (18 years or older) and adults with unrecognized symptoms of OSA.Evidence Assessment: The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for OSA in the general adult population.Recommendation: The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for OSA in the general adult population. (I statement). [ABSTRACT FROM AUTHOR]

Importance: Obstructive sleep apnea (OSA) is associated with adverse health outcomes.Objective: To review the evidence on screening for OSA in asymptomatic adults or those with unrecognized OSA symptoms to inform the US Preventive Services Task Force.Data Sources: PubMed/MEDLINE, Cochrane Library, Embase, and trial registries through August 23, 2021; surveillance through September 23, 2022.Study Selection: English-language studies of screening test accuracy, randomized clinical trials (RCTs) of screening or treatment of OSA reporting health outcomes or harms, and systematic reviews of treatment reporting changes in blood pressure and apnea-hypopnea index (AHI) scores.Data Extraction and Synthesis: Dual review of abstracts, full-text articles, and study quality. Meta-analysis of intervention trials.Main Outcomes and Measures: Test accuracy, excessive daytime sleepiness, sleep-related and general health-related quality of life (QOL), and harms.Results: Eighty-six studies were included (N = 11 051). No study directly compared screening with no screening. Screening accuracy of the Multivariable Apnea Prediction score followed by unattended home sleep testing for detecting severe OSA syndrome (AHI ≥30 and Epworth Sleepiness Scale [ESS] score >10) measured as the area under the curve in 2 studies (n = 702) was 0.80 (95% CI, 0.78 to 0.82) and 0.83 (95% CI, 0.77 to 0.90). Five studies assessing the accuracy of other screening tools were heterogeneous and results were inconsistent. Compared with inactive control, positive airway pressure was associated with a significant improvement in ESS score from baseline (pooled mean difference, -2.33 [95% CI, -2.75 to -1.90]; 47 trials; n = 7024), sleep-related QOL (standardized mean difference, 0.30 [95% CI, 0.19 to 0.42]; 17 trials; n = 3083), and general health-related QOL measured by the 36-Item Short Form Health Survey (SF-36) mental health component summary score change (pooled mean difference, 2.20 [95% CI, 0.95 to 3.44]; 15 trials; n = 2345) and SF-36 physical health component summary score change (pooled mean difference, 1.53 [95% CI, 0.29 to 2.77]; 13 trials; n = 2031). Use of mandibular advancement devices was also associated with a significantly larger ESS score change compared with controls (pooled mean difference, -1.67 [95% CI, 2.09 to -1.25]; 10 trials; n = 1540). Reporting of other health outcomes was sparse; no included trial found significant benefit associated with treatment on mortality, cardiovascular events, or motor vehicle crashes. In 3 systematic reviews, positive airway pressure was significantly associated with reduced blood pressure; however, the difference was relatively small (2-3 mm Hg).Conclusions and Relevance: The accuracy and clinical utility of OSA screening tools that could be used in primary care settings were uncertain. Positive airway pressure and mandibular advancement devices reduced ESS score. Trials of positive airway pressure found modest improvement in sleep-related and general health-related QOL but have not established whether treatment reduces mortality or improves most other health outcomes. [ABSTRACT FROM AUTHOR]

Importance: Of youths diagnosed with type 2 diabetes, many develop microvascular complications by young adulthood.Objective: To review the evidence on benefits and harms of screening children and adolescents for prediabetes and type 2 diabetes to inform the US Preventive Services Task Force (USPSTF).Data Sources: PubMed/MEDLINE, Cochrane Library, and trial registries through May 3, 2021; references; experts; literature surveillance through July 22, 2022.Study Selection: English-language controlled studies evaluating screening or interventions for prediabetes or type 2 diabetes that was screen detected or recently diagnosed.Data Extraction and Synthesis: Dual review of abstracts, full-text articles, and study quality; qualitative synthesis of findings.Main Outcomes and Measures: Mortality, cardiovascular morbidity, diabetes-related morbidity, development of diabetes, quality of life, and harms.Results: This review included 8 publications (856 participants; mean age, 14 years [range, 10-17 years]). Of those, 6 were from the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study. No eligible studies directly evaluated the benefits or harms of screening. One randomized clinical trial (RCT) (TODAY; n = 699 adolescents with obesity; mean age, 14 years) comparing metformin, metformin plus rosiglitazone, and metformin plus lifestyle intervention reported that 2 youths with recently diagnosed diabetes developed kidney impairment (0 vs 1 vs 1, respectively; P > .99) and 11 developed diabetic ketoacidosis (5 vs 3 vs 3, respectively; P = .70). One RCT of 75 adolescents (mean age, 13 years) with obesity with prediabetes compared an intensive lifestyle intervention with standard care and reported that no participants in either group developed diabetes, although follow-up was only 6 months. Regarding harms of interventions, 2 RCTs assessing different comparisons enrolled youths with recently diagnosed diabetes. Major hypoglycemic events were reported by less than 1% of participants. Minor hypoglycemic events were more common among youths treated with metformin plus rosiglitazone than among those treated with metformin or metformin plus lifestyle intervention in TODAY (8.2% vs 4.3% vs 3.4%, P = .05). In 1 study, gastrointestinal adverse events were more commonly reported by those taking metformin than by those taking placebo (abdominal pain: 25% vs 12%; nausea/vomiting: 17% vs 10%; P not reported).Conclusions and Relevance: No eligible studies directly evaluated the benefits or harms of screening for prediabetes and type 2 diabetes in children and adolescents. For youths with prediabetes or recently diagnosed (not screen-detected) diabetes, the only eligible trials reported few health outcomes and found no difference between groups, although evidence was limited by substantial imprecision and a duration of follow-up likely insufficient to assess health outcomes. [ABSTRACT FROM AUTHOR]

Importance: HIV-associated cardiovascular disease is increasing in prevalence, but its mechanisms remain poorly understood.Objective: To systematically review data from advanced cardiovascular imaging studies evaluating computed tomographic coronary angiography, positron emission tomography (PET), and cardiac magnetic resonance (MR), in people living with HIV compared with uninfected individuals.Data Sources: Three databases and Google Scholar were searched for studies assessing cardiovascular pathology using computed tomographic coronary angiography, cardiac MR, PET, and HIV from inception to February 11, 2022.Study Selection: Two reviewers selected original studies without any restrictions on design, date, or language, investigating HIV and cardiovascular pathology.Data Extraction and Synthesis: One investigator extracted data checked by a second investigator. Prevalence ratios (PRs) and differences in inflammation among people living with HIV and uninfected individuals were qualitatively synthesized in terms of cardiovascular pathology. Study quality was assessed using the National Heart, Lung, and Blood Institute quality assessment tool for observational studies.Main Outcomes and Measures: Primary outcomes were computed tomographic coronary angiography-defined moderate to severe (≥50%) coronary stenosis, cardiac MR-defined myocardial fibrosis identified by late gadolinium enhancement, and PET-defined vascular and myocardial target to background ratio. Prevalence of moderate to severe coronary disease, as well as myocardial fibrosis, and PRs compared with uninfected individuals were reported alongside difference in vascular target to background ratio.Results: Forty-five studies including 5218 people living with HIV (mean age, 48.5 years) and 2414 uninfected individuals (mean age, 49.1 years) were identified. Sixteen studies (n = 5107 participants) evaluated computed tomographic coronary angiography; 16 (n = 1698), cardiac MRs; 10 (n = 681), vascular PET scans; and 3 (n = 146), both computed tomographic coronary angiography and vascular PET scans. No studies originated from low-income countries. Regarding risk of bias, 22% were classified as low; 47% moderate; and 31% high. Prevalence of moderate to severe coronary disease among those with vs without HIV ranged from 0% to 52% and 0% to 27%, respectively, with PRs ranging from 0.33 (95% CI, 0.01-15.90) to 5.19 (95% CI, 1.26-21.42). Prevalence of myocardial fibrosis among those with vs without HIV ranged from 5% to 84% and 0% to 68%, respectively, with PRs ranging from 1.01 (95% CI, 0.85-1.21) to 17.35 (95% CI, 1.10-274.28). Differences in vascular target to background ratio among those with vs without HIV ranged from 0.06 (95% CI, 0.01-0.11) to 0.37 (95% CI, 0.02-0.72).Conclusions and Relevance: In this systematic review of studies of advanced cardiovascular imaging, the estimates of the associations between HIV and cardiovascular pathologies demonstrated large amounts of heterogeneity. The findings provide a summary of the available data but may not be representative of all individuals living with HIV, including those from low-income countries with higher HIV endemicity. [ABSTRACT FROM AUTHOR]

Importance: Cardiovascular disease (CVD) is the leading cause of morbidity and death in the US and is the cause of more than 1 of every 4 deaths. Coronary heart disease is the single leading cause of death and accounts for 43% of deaths attributable to CVD in the US. In 2019, an estimated 558 000 deaths were caused by coronary heart disease and 109 000 deaths were caused by ischemic stroke.Objective: To update its 2016 recommendation, the US Preventive Services Task Force (USPSTF) commissioned a review of the evidence on the benefits and harms of statins for reducing CVD-related morbidity or mortality or all-cause mortality.Population: Adults 40 years or older without a history of known CVD and who do not have signs and symptoms of CVD.Evidence Assessment: The USPSTF concludes with moderate certainty that statin use for the prevention of CVD events and all-cause mortality in adults aged 40 to 75 years with no history of CVD and who have 1 or more CVD risk factors (ie, dyslipidemia, diabetes, hypertension, or smoking) and an estimated 10-year CVD event risk of 10% or greater has at least a moderate net benefit. The USPSTF concludes with moderate certainty that statin use for the prevention of CVD events and all-cause mortality in adults aged 40 to 75 years with no history of CVD and who have 1 or more of these CVD risk factors and an estimated 10-year CVD event risk of 7.5% to less than 10% has at least a small net benefit. The USPSTF concludes that the evidence is insufficient to determine the balance of benefits and harms of statin use for the primary prevention of CVD events and mortality in adults 76 years or older with no history of CVD.Recommendation: The USPSTF recommends that clinicians prescribe a statin for the primary prevention of CVD for adults aged 40 to 75 years who have 1 or more CVD risk factors (ie, dyslipidemia, diabetes, hypertension, or smoking) and an estimated 10-year CVD risk of 10% or greater. (B recommendation) The USPSTF recommends that clinicians selectively offer a statin for the primary prevention of CVD for adults aged 40 to 75 years who have 1 or more of these CVD risk factors and an estimated 10-year CVD risk of 7.5% to less than 10%. The likelihood of benefit is smaller in this group than in persons with a 10-year risk of 10% or greater. (C recommendation) The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of initiating a statin for the primary prevention of CVD events and mortality in adults 76 years or older. (I statement). [ABSTRACT FROM AUTHOR]

Importance: Concurrent chemoradiotherapy has been the standard treatment for stage II nasopharyngeal carcinoma (NPC) based on data using 2-dimensional conventional radiotherapy. There is limited evidence for the role of chemotherapy with use of intensity-modulated radiation therapy (IMRT).Objective: To assess whether concurrent chemotherapy can be safely omitted for patients with low-risk stage II/T3N0 NPC treated with IMRT.Design, Setting, and Participants: This multicenter, open-label, randomized, phase 3, noninferiority clinical trial was conducted at 5 Chinese hospitals, including 341 adult patients with low-risk NPC, defined as stage II/T3N0M0 without adverse features (all nodes <3 cm, no level IV/Vb nodes; no extranodal extension; Epstein-Barr virus DNA <4000 copies/mL), with enrollment between November 2015 and August 2020. The final date of follow-up was March 15, 2022.Interventions: Patients were randomly assigned to receive IMRT alone (n = 172) or concurrent chemoradiotherapy (IMRT with cisplatin, 100 mg/m2 every 3 weeks for 3 cycles [n = 169]).Main Outcomes and Measures: The primary end point was 3-year failure-free survival (time from randomization to any disease relapse or death), with a noninferiority margin of 10%. Secondary end points comprised overall survival, locoregional relapse-free survival, distant metastasis-free survival, adverse events, and health-related quality of life (QOL) measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30; range, 0-100 points; minimum clinically important difference ≥10 for physical function, symptom control, or health-related QOL; higher score indicates better functioning and global health status or worse symptoms).Results: Among 341 randomized patients (mean [SD] age, 48 [10] years; 30% women), 334 (98.0%) completed the trial. Median follow-up was 46 months (IQR, 34-58). Three-year failure-free survival was 90.5% for the IMRT-alone group vs 91.9% for the concurrent chemoradiotherapy group (difference, -1.4%; 1-sided 95% CI, -7.4% to ∞; P value for noninferiority, <.001). No significant differences were observed between groups in overall survival, locoregional relapse, or distant metastasis. The IMRT-alone group experienced a significantly lower incidence of grade 3 to 4 adverse events (17% vs 46%; difference, -29% [95% CI, -39% to -20%]), including hematologic toxicities (leukopenia, neutropenia) and nonhematologic toxicities (nausea, vomiting, anorexia, weight loss, mucositis). The IMRT-alone group had significantly better QOL scores during radiotherapy including the domains of global health status, social functioning, fatigue, nausea and vomiting, pain, insomnia, appetite loss, and constipation.Conclusions and Relevance: Among patients with low-risk NPC, treatment with IMRT alone resulted in 3-year failure-free survival that was not inferior to concurrent chemoradiotherapy.Trial Registration: ClinicalTrials.gov Identifier: NCT02633202. [ABSTRACT FROM AUTHOR]

Importance: Barrett esophagus is characterized by the replacement of normal esophageal squamous cell epithelium with columnar metaplasia and affects approximately 5% of people in the US and approximately 1% worldwide. Approximately 3% to 5% of patients with Barrett esophagus will be diagnosed with esophageal adenocarcinoma in their lifetime.Observations: Barrett esophagus affects approximately 2.3% to 8.3% of people with gastroesophageal reflux disease (GERD) and approximately 1.2% to 5.6% of people without GERD. Characteristics associated with Barrett esophagus include older age (prevalence of approximately 1.1% in individuals older than 50 years compared with 0.3% in those 50 years or younger), male sex, and smoking (prevalence of approximately 12% in people who smoke cigarettes compared with 1.1% in those who do not smoke cigarettes). The histopathology of Barrett esophagus progresses from metaplasia to dysplasia and, without treatment, can progress to adenocarcinoma. People with Barrett esophagus have approximately a 0.2% to 0.5% annual rate of developing esophageal adenocarcinoma. Management of Barrett esophagus primarily consists of acid-suppressive medications to reduce underlying GERD symptoms and surveillance endoscopy every 3 to 5 years. In patients with Barrett esophagus and dysplasia or early cancer, endoscopic therapy consisting of resection and ablation successfully treats 80% to 90% of patients.Conclusions and Relevance: Barrett esophagus affects approximately 5% of people in the US and approximately 1% worldwide and is associated with an increased risk of esophageal adenocarcinoma. First-line therapy for Barrett esophagus consists of proton-pump inhibitors for control of reflux symptoms, but their role in chemoprevention is unclear. Surveillance with upper endoscopy is recommended by practice guidelines to monitor for progression to esophageal adenocarcinoma, but randomized clinical trials are lacking. [ABSTRACT FROM AUTHOR]

Importance: Gout is associated with cardiovascular diseases. The temporal association between gout flares and cardiovascular events has not been investigated.Objective: To investigate whether there is a transient increase in risk of cardiovascular events after a recent gout flare.Design, Setting, and Participants: A retrospective observational study was conducted using electronic health records from the Clinical Practice Research Datalink in England between January 1, 1997, and December 31, 2020. A multivariable nested case-control study was performed among 62 574 patients with gout, and a self-controlled case series, adjusted for season and age, was performed among 1421 patients with gout flare and cardiovascular event.Exposures: Gout flares were ascertained using hospitalization, primary care outpatient, and prescription records.Main Outcomes and Measures: The primary outcome was a cardiovascular event, defined as an acute myocardial infarction or stroke. Association with recent prior gout flares was measured using adjusted odds ratios (ORs) with 95% CIs in a nested case-control study and adjusted incidence rate ratios (IRRs) with 95% CIs in a self-controlled case series.Results: Among patients with a new diagnosis of gout (mean age, 76.5 years; 69.3% men, 30.7% women), 10 475 patients with subsequent cardiovascular events were matched with 52 099 patients without cardiovascular events. Patients with cardiovascular events, compared with those who did not have cardiovascular events, had significantly higher odds of gout flare within the prior 0 to 60 days (204/10 475 [2.0%] vs 743/52 099 [1.4%]; adjusted OR, 1.93 [95% CI, 1.57-2.38]) and within the prior 61 to 120 days (170/10 475 [1.6%] vs 628/52 099 [1.2%]; adjusted OR, 1.57 [95% CI, 1.26-1.96]). There was no significant difference in the odds of gout flare within the prior 121 to 180 days (148/10 475 [1.4%] vs 662/52 099 [1.3%]; adjusted OR, 1.06 [95% CI, 0.84-1.34]). In the self-controlled case series (N = 1421), cardiovascular event rates per 1000 person-days were 2.49 (95% CI, 2.16-2.82) within days 0 to 60; 2.16 (95% CI, 1.85-2.47) within days 61 to 120; and 1.70 (95% CI, 1.42-1.98) within days 121 to 180 after a gout flare, compared with cardiovascular event rates of 1.32 (95% CI, 1.23-1.41) per 1000 person-days within the 150 days before or the 181 to 540 days after the gout flare. Compared with 150 days before or the 181 to 540 days after a gout flare, incidence rate differences for cardiovascular events were 1.17 (95% CI, 0.83-1.52) per 1000 person-days, and adjusted IRRs were 1.89 (95% CI, 1.54-2.30) within days 0 to 60; 0.84 (95% CI, 0.52-1.17) per 1000 person-days and 1.64 (95% CI, 1.45-1.86) within days 61 to 120; and 0.38 (95% CI, 0.09-0.67) per 1000 person-days and 1.29 (95% CI, 1.02-1.64) within days 121 to 180 after a gout flare.Conclusions and Relevance: Among individuals with gout, those who experienced a cardiovascular event, compared with those who did not experience such an event, had significantly higher odds of a recent gout flare in the preceding days. These findings suggest gout flares are associated with a transient increase in cardiovascular events following the flare. [ABSTRACT FROM AUTHOR]

Importance: The effects of altered neural processing, defined as altering neural networks responsible for perceptions of pain and function, on chronic pain remains unclear.Objective: To estimate the effect of a graded sensorimotor retraining intervention (RESOLVE) on pain intensity in people with chronic low back pain.Design, Setting, and Participants: This parallel, 2-group, randomized clinical trial recruited participants with chronic (>3 months) nonspecific low back pain from primary care and community settings. A total of 276 adults were randomized (in a 1:1 ratio) to the intervention or sham procedure and attention control groups delivered by clinicians at a medical research institute in Sydney, Australia. The first participant was randomized on December 10, 2015, and the last was randomized on July 25, 2019. Follow-up was completed on February 3, 2020.Interventions: Participants randomized to the intervention group (n = 138) were asked to participate in 12 weekly clinical sessions and home training designed to educate them about and assist them with movement and physical activity while experiencing lower back pain. Participants randomized to the control group (n = 138) were asked to participate in 12 weekly clinical sessions and home training that required similar time as the intervention but did not focus on education, movement, and physical activity. The control group included sham laser and shortwave diathermy applied to the back and sham noninvasive brain stimulation.Main Outcomes and Measures: The primary outcome was pain intensity at 18 weeks, measured on an 11-point numerical rating scale (range, 0 [no pain] to 10 [worst pain imaginable]) for which the between-group minimum clinically important difference is 1.0 point.Results: Among 276 randomized patients (mean [SD] age, 46 [14.3] years; 138 [50%] women), 261 (95%) completed follow-up at 18 weeks. The mean pain intensity was 5.6 at baseline and 3.1 at 18 weeks in the intervention group and 5.8 at baseline and 4.0 at 18 weeks in the control group, with an estimated between-group mean difference at 18 weeks of -1.0 point ([95% CI, -1.5 to -0.4]; P = .001), favoring the intervention group.Conclusions and Relevance: In this randomized clinical trial conducted at a single center among patients with chronic low back pain, graded sensorimotor retraining, compared with a sham procedure and attention control, significantly improved pain intensity at 18 weeks. The improvements in pain intensity were small, and further research is needed to understand the generalizability of the findings.Trial Registration: ANZCTR Identifier: ACTRN12615000610538. [ABSTRACT FROM AUTHOR]

Importance: Hyponatremia is the most common electrolyte disorder and it affects approximately 5% of adults and 35% of hospitalized patients. Hyponatremia is defined by a serum sodium level of less than 135 mEq/L and most commonly results from water retention. Even mild hyponatremia is associated with increased hospital stay and mortality.Observations: Symptoms and signs of hyponatremia range from mild and nonspecific (such as weakness or nausea) to severe and life-threatening (such as seizures or coma). Symptom severity depends on the rapidity of development, duration, and severity of hyponatremia. Mild chronic hyponatremia is associated with cognitive impairment, gait disturbances, and increased rates of falls and fractures. In a prospective study, patients with hyponatremia more frequently reported a history of falling compared with people with normal serum sodium levels (23.8% vs 16.4%, respectively; P < .01) and had a higher rate of new fractures over a mean follow-up of 7.4 years (23.3% vs 17.3%; P < .004). Hyponatremia is a secondary cause of osteoporosis. When evaluating patients, clinicians should categorize them according to their fluid volume status (hypovolemic hyponatremia, euvolemic hyponatremia, or hypervolemic hyponatremia). For most patients, the approach to managing hyponatremia should consist of treating the underlying cause. Urea and vaptans can be effective treatments for the syndrome of inappropriate antidiuresis and hyponatremia in patients with heart failure, but have adverse effects (eg, poor palatability and gastric intolerance with urea; and overly rapid correction of hyponatremia and increased thirst with vaptans). Severely symptomatic hyponatremia (with signs of somnolence, obtundation, coma, seizures, or cardiorespiratory distress) is a medical emergency. US and European guidelines recommend treating severely symptomatic hyponatremia with bolus hypertonic saline to reverse hyponatremic encephalopathy by increasing the serum sodium level by 4 mEq/L to 6 mEq/L within 1 to 2 hours but by no more than 10 mEq/L (correction limit) within the first 24 hours. This treatment approach exceeds the correction limit in about 4.5% to 28% of people. Overly rapid correction of chronic hyponatremia may cause osmotic demyelination, a rare but severe neurological condition, which can result in parkinsonism, quadriparesis, or even death.Conclusions and Relevance: Hyponatremia affects approximately 5% of adults and 35% of patients who are hospitalized. Most patients should be managed by treating their underlying disease and according to whether they have hypovolemic, euvolemic, or hypervolemic hyponatremia. Urea and vaptans can be effective in managing the syndrome of inappropriate antidiuresis and hyponatremia in patients with heart failure; hypertonic saline is reserved for patients with severely symptomatic hyponatremia. [ABSTRACT FROM AUTHOR]

Importance: Sickle cell disease (SCD) is an inherited disorder of hemoglobin, characterized by formation of long chains of hemoglobin when deoxygenated within capillary beds, resulting in sickle-shaped red blood cells, progressive multiorgan damage, and increased mortality. An estimated 300 000 infants are born annually worldwide with SCD. Most individuals with SCD live in sub-Saharan Africa, India, the Mediterranean, and Middle East; approximately 100 000 individuals with SCD live in the US.Observations: SCD is diagnosed through newborn screening programs, where available, or when patients present with unexplained severe atraumatic pain or normocytic anemia. In SCD, sickling and hemolysis of red blood cells result in vaso-occlusion with associated ischemia. SCD is characterized by repeated episodes of severe acute pain and acute chest syndrome, and by other complications including stroke, chronic pain, nephropathy, retinopathy, avascular necrosis, priapism, and leg ulcers. In the US, nearly all children with SCD survive to adulthood, but average life expectancy remains 20 years less than the general population, with higher mortality as individuals transition from pediatric to adult-focused health care systems. Until 2017, hydroxyurea, which increases fetal hemoglobin and reduces red blood cell sickling, was the only disease-modifying therapy available for SCD and remains first-line therapy for most individuals with SCD. Three additional therapies, L-glutamine, crizanlizumab, and voxelotor, have been approved as adjunctive or second-line agents. In clinical trials, L-glutamine reduced hospitalization rates by 33% and mean length of stay from 11 to 7 days compared with placebo. Crizanlizumab reduced pain crises from 2.98 to 1.63 per year compared with placebo. Voxelotor increased hemoglobin by at least 1 g/dL, significantly more than placebo (51% vs 7%). Hematopoietic stem cell transplant is the only curative therapy, but it is limited by donor availability, with best results seen in children with a matched sibling donor. While SCD is characterized by acute and chronic pain, patients are not more likely to develop addiction to pain medications than the general population.Conclusions and Relevance: In the US, approximately 100 000 people have SCD, which is characterized by hemolytic anemia, acute and chronic pain, acute chest syndrome; increased incidence of stroke, nephropathy, and retinopathy; and a life span that is 20 years shorter than the general population. While hydroxyurea is first-line therapy for SCD, L-glutamine, crizanlizumab, and voxelotor have been approved in the US since 2017 as adjunctive or second-line treatments, and hematopoietic stem cell transplant with a matched sibling donor is now standard care for severe disease. [ABSTRACT FROM AUTHOR]

Importance: Obesity increases the incidence and mortality from some types of cancer, but it remains uncertain whether intentional weight loss can decrease this risk.Objective: To investigate whether bariatric surgery is associated with lower cancer risk and mortality in patients with obesity.Design, Setting, and Participants: In the SPLENDID (Surgical Procedures and Long-term Effectiveness in Neoplastic Disease Incidence and Death) matched cohort study, adult patients with a body mass index of 35 or greater who underwent bariatric surgery at a US health system between 2004 and 2017 were included. Patients who underwent bariatric surgery were matched 1:5 to patients who did not undergo surgery for their obesity, resulting in a total of 30 318 patients. Follow-up ended in February 2021.Exposures: Bariatric surgery (n = 5053), including Roux-en-Y gastric bypass and sleeve gastrectomy, vs nonsurgical care (n = 25 265).Main Outcomes and Measures: Multivariable Cox regression analysis estimated time to incident obesity-associated cancer (a composite of 13 cancer types as the primary end point) and cancer-related mortality.Results: The study included 30 318 patients (median age, 46 years; median body mass index, 45; 77% female; and 73% White) with a median follow-up of 6.1 years (IQR, 3.8-8.9 years). The mean between-group difference in body weight at 10 years was 24.8 kg (95% CI, 24.6-25.1 kg) or a 19.2% (95% CI, 19.1%-19.4%) greater weight loss in the bariatric surgery group. During follow-up, 96 patients in the bariatric surgery group and 780 patients in the nonsurgical control group had an incident obesity-associated cancer (incidence rate of 3.0 events vs 4.6 events, respectively, per 1000 person-years). The cumulative incidence of the primary end point at 10 years was 2.9% (95% CI, 2.2%-3.6%) in the bariatric surgery group and 4.9% (95% CI, 4.5%-5.3%) in the nonsurgical control group (absolute risk difference, 2.0% [95% CI, 1.2%-2.7%]; adjusted hazard ratio, 0.68 [95% CI, 0.53-0.87], P = .002). Cancer-related mortality occurred in 21 patients in the bariatric surgery group and 205 patients in the nonsurgical control group (incidence rate of 0.6 events vs 1.2 events, respectively, per 1000 person-years). The cumulative incidence of cancer-related mortality at 10 years was 0.8% (95% CI, 0.4%-1.2%) in the bariatric surgery group and 1.4% (95% CI, 1.1%-1.6%) in the nonsurgical control group (absolute risk difference, 0.6% [95% CI, 0.1%-1.0%]; adjusted hazard ratio, 0.52 [95% CI, 0.31-0.88], P = .01).Conclusions and Relevance: Among adults with obesity, bariatric surgery compared with no surgery was associated with a significantly lower incidence of obesity-associated cancer and cancer-related mortality. [ABSTRACT FROM AUTHOR]

Importance: Ablation of persistent atrial fibrillation (AF) remains a challenge. Left atrial fibrosis plays an important role in the pathophysiology of AF and has been associated with poor procedural outcomes.Objective: To investigate the efficacy and adverse events of targeting atrial fibrosis detected on magnetic resonance imaging (MRI) in reducing atrial arrhythmia recurrence in persistent AF.Design, Setting, and Participants: The Efficacy of Delayed Enhancement-MRI-Guided Fibrosis Ablation vs Conventional Catheter Ablation of Atrial Fibrillation trial was an investigator-initiated, multicenter, randomized clinical trial involving 44 academic and nonacademic centers in 10 countries. A total of 843 patients with symptomatic or asymptomatic persistent AF and undergoing AF ablation were enrolled from July 2016 to January 2020, with follow-up through February 19, 2021.Interventions: Patients with persistent AF were randomly assigned to pulmonary vein isolation (PVI) plus MRI-guided atrial fibrosis ablation (421 patients) or PVI alone (422 patients). Delayed-enhancement MRI was performed in both groups before the ablation procedure to assess baseline atrial fibrosis and at 3 months postablation to assess for ablation scar.Main Outcomes and Measures: The primary end point was time to first atrial arrhythmia recurrence after a 90-day blanking period postablation. The primary safety composite outcome was defined by the occurrence of 1 or more of the following events within 30 days postablation: stroke, PV stenosis, bleeding, heart failure, or death.Results: Among 843 patients who were randomized (mean age 62.7 years; 178 [21.1%] women), 815 (96.9%) completed the 90-day blanking period and contributed to the efficacy analyses. There was no significant difference in atrial arrhythmia recurrence between groups (fibrosis-guided ablation plus PVI patients, 175 [43.0%] vs PVI-only patients, 188 [46.1%]; hazard ratio [HR], 0.95 [95% CI, 0.77-1.17]; P = .63). Patients in the fibrosis-guided ablation plus PVI group experienced a higher rate of safety outcomes (9 [2.2%] vs 0 in PVI group; P = .001). Six patients (1.5%) in the fibrosis-guided ablation plus PVI group had an ischemic stroke compared with none in PVI-only group. Two deaths occurred in the fibrosis-guided ablation plus PVI group, and the first one was possibly related to the procedure.Conclusions and Relevance: Among patients with persistent AF, MRI-guided fibrosis ablation plus PVI, compared with PVI catheter ablation only, resulted in no significant difference in atrial arrhythmia recurrence. Findings do not support the use of MRI-guided fibrosis ablation for the treatment of persistent AF.Trial Registration: ClinicalTrials.gov Identifier: NCT02529319. [ABSTRACT FROM AUTHOR]

Importance: Acute infectious conjunctivitis is characterized by ocular redness and discharge, and is a common clinical entity. Evidence-based tools to aid the clinical diagnosis of viral vs bacterial conjunctivitis are lacking and may contribute to overprescribing of topical antibiotics.Objective: To determine the relative prevalence of viral vs bacterial conjunctivitis in adults and children, and to determine which symptoms or signs are suggestive of a viral vs bacterial etiology.Data Sources: A MEDLINE search (January 1946-March 2022) yielded 1891 articles. Included articles were rated using a quality score based on a modified Rational Clinical Examination grading system. Methodological quality levels 1 through 4 required a microbiological reference standard for diagnosis, whereas quality level 5 (the lowest quality) used a clinical reference standard for diagnosis.Study Selection: Consecutive series of patients presenting with acute infectious conjunctivitis and case series of viral or bacterial conjunctivitis alone. Thirty-two studies were included in a meta-analysis to determine prevalence and diagnostic accuracy measures; 27 used a microbiological reference standard for diagnosis and 5 used a clinical reference standard for diagnosis.Results: In studies involving children (5 studies; 881 patients; mean age, 4.7 years [age range, 1 month-18 years]), the prevalence of bacterial conjunctivitis was higher than viral conjunctivitis (71% vs 16%, respectively, P = .01). In the only study of adults (n = 207 patients; mean age, 25.7 years), the prevalence of viral conjunctivitis was higher than bacterial conjunctivitis (78% vs 16%, respectively, P < .001). For the primary analysis of level 1 (n = 6) and level 2 (n = 5) studies (1725 patients total), the clinical findings that best distinguished a viral etiology for conjunctivitis from a bacterial etiology included pharyngitis (sensitivity range, 0.55-0.58; specificity range, 0.89-0.94; positive likelihood ratio [LR] range, 5.4-9.9), preauricular lymphadenopathy (sensitivity range, 0.17-0.31; specificity range, 0.93-0.94; positive LR range, 2.5-5.6), and contact with another person with red eye (sensitivity, 0.18 [95% CI, 0.14-0.22]; specificity, 0.93 [95% CI, 0.90-0.95]; positive LR, 2.5 [95% CI, 1.6-3.7]). Mucopurulent ocular discharge (sensitivity, 0.76 [95% CI, 0.60-0.87); specificity, 0.66 [95% CI, 0.58-0.73]; positive LR, 2.1 [95% CI, 1.7-2.6]) and otitis media (sensitivity, 0.24 [95% CI, 0.20-0.29]; specificity, 0.91 [95% CI, 0.85-0.94]; positive LR, 2.5 [95% CI, 1.5-4.4]) were associated with the presence of bacterial conjunctivitis.Conclusions and Relevance: In this review, bacterial conjunctivitis was more common than viral conjunctivitis in children and viral conjunctivitis was more common than bacterial conjunctivitis in adults, although the prevalence estimates were based on limited evidence. Symptoms and signs associated with a higher likelihood of viral conjunctivitis in adults and children included concomitant pharyngitis, an enlarged preauricular node, and contact with another person with red eye, and signs associated with a higher likelihood of bacterial conjunctivitis included the presence of mucopurulent discharge and otitis media, but no single symptom or sign differentiated the 2 conditions with high certainty. [ABSTRACT FROM AUTHOR]

Importance: A 2016 review for the US Preventive Services Task Force (USPSTF) found that effective treatments are available for refractive errors, cataracts, and wet (advanced neovascular) or dry (atrophic) age-related macular degeneration (AMD), but there were no differences between visual screening vs no screening on visual acuity or other outcomes.Objective: To update the 2016 review on screening for impaired visual acuity in older adults, to inform the USPSTF.Data Sources: Ovid MEDLINE, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews (to February 2021); surveillance through January 21, 2022.Study Selection: Randomized clinical trials and controlled observational studies on screening, vascular endothelial growth factor (VEGF) inhibitors (wet AMD), and antioxidant vitamins and minerals (dry AMD); studies on screening diagnostic accuracy.Data Extraction and Synthesis: One investigator abstracted data and a second checked accuracy. Two investigators independently assessed study quality.Results: Twenty-five studies (N = 33 586) were included (13 trials, 11 diagnostic accuracy studies, and 1 systematic review [19 trials]). Four trials (n = 4819) found no significant differences between screening vs no screening in visual acuity or other outcomes. Visual acuity tests (3 studies; n = 6493) and screening question (3 studies; n = 5203) were associated with suboptimal diagnostic accuracy. For wet AMD, 4 trials (n = 2086) found VEGF inhibitors significantly associated with greater likelihood of 15 or more letters visual acuity gain (risk ratio [RR], 2.92 [95% CI, 1.20-7.12]; I2 = 76%; absolute risk difference [ARD], 10%) and less than 15 letters visual acuity loss (RR, 1.46 [95% CI, 1.22-1.75]; I2 = 80%; ARD, 27%) vs sham treatment, with no increased risk of serious harms. For dry AMD, a systematic review (19 trials) found antioxidant multivitamins significantly associated with decreased risk of progression to late AMD (3 trials, n = 2445; odds ratio [OR], 0.72 [95% CI, 0.58-0.90]) and 3 lines or more visual acuity loss (1 trial, n = 1791; OR, 0.77 [95% CI, 0.62-0.96]) vs placebo. Zinc was significantly associated with increased risk of genitourinary events and beta carotene with increased risk of lung cancer in former smokers; other serious harms were infrequent.Conclusions and Relevance: This review found that effective treatments are available for common causes of impaired visual acuity in older adults. However, direct evidence found no significant association between vision screening vs no screening in primary care and improved visual outcomes. [ABSTRACT FROM AUTHOR]

Importance: The effect of glucocorticoids on major kidney outcomes and adverse events in IgA nephropathy has been uncertain.Objective: To evaluate the efficacy and adverse effects of methylprednisolone in patients with IgA nephropathy at high risk of kidney function decline.Design, Setting, and Participants: An international, multicenter, double-blind, randomized clinical trial that enrolled 503 participants with IgA nephropathy, proteinuria greater than or equal to 1 g per day, and estimated glomerular filtration rate (eGFR) of 20 to 120 mL/min/1.73 m2 after at least 3 months of optimized background care from 67 centers in Australia, Canada, China, India, and Malaysia between May 2012 and November 2019, with follow-up until June 2021.Interventions: Participants were randomized in a 1:1 ratio to receive oral methylprednisolone (initially 0.6-0.8 mg/kg/d, maximum 48 mg/d, weaning by 8 mg/d/mo; n = 136) or placebo (n = 126). After 262 participants were randomized, an excess of serious infections was identified, leading to dose reduction (0.4 mg/kg/d, maximum 32 mg/d, weaning by 4 mg/d/mo) and addition of antibiotic prophylaxis for pneumocystis pneumonia for subsequent participants (121 in the oral methylprednisolone group and 120 in the placebo group).Main Outcomes And Measures: The primary end point was a composite of 40% decline in eGFR, kidney failure (dialysis, transplant), or death due to kidney disease. There were 11 secondary outcomes, including kidney failure.Results: Among 503 randomized patients (mean age, 38 years; 198 [39%] women; mean eGFR, 61.5 mL/min/1.73 m2; mean proteinuria, 2.46 g/d), 493 (98%) completed the trial. Over a mean of 4.2 years of follow-up, the primary outcome occurred in 74 participants (28.8%) in the methylprednisolone group compared with 106 (43.1%) in the placebo group (hazard ratio [HR], 0.53 [95% CI, 0.39-0.72]; P < .001; absolute annual event rate difference, -4.8% per year [95% CI, -8.0% to -1.6%]). The effect on the primary outcome was seen across each dose compared with the relevant participants in the placebo group recruited to each regimen (P for heterogeneity = .11): full-dose HR, 0.58 (95% CI, 0.41-0.81); reduced-dose HR, 0.27 (95% CI, 0.11-0.65). Of the 11 prespecified secondary end points, 9 showed significant differences in favor of the intervention, including kidney failure (50 [19.5%] vs 67 [27.2%]; HR, 0.59 [95% CI, 0.40-0.87]; P = .008; annual event rate difference, -2.9% per year [95% CI, -5.4% to -0.3%]). Serious adverse events were more frequent with methylprednisolone vs placebo (28 [10.9%] vs 7 [2.8%] patients with serious adverse events), primarily with full-dose therapy compared with its matching placebo (22 [16.2%] vs 4 [3.2%]).Conclusions and Relevance: Among patients with IgA nephropathy at high risk of progression, treatment with oral methylprednisolone for 6 to 9 months, compared with placebo, significantly reduced the risk of the composite outcome of kidney function decline, kidney failure, or death due to kidney disease. However, the incidence of serious adverse events was increased with oral methylprednisolone, mainly with high-dose therapy.Trial Registration: ClinicalTrials.gov Identifier: NCT01560052. [ABSTRACT FROM AUTHOR]

Importance: Coronary plaques that are prone to rupture and cause adverse cardiac events are characterized by large plaque burden, large lipid content, and thin fibrous caps. Statins can halt the progression of coronary atherosclerosis; however, the effect of the proprotein convertase subtilisin kexin type 9 inhibitor alirocumab added to statin therapy on plaque burden and composition remains largely unknown.Objective: To determine the effects of alirocumab on coronary atherosclerosis using serial multimodality intracoronary imaging in patients with acute myocardial infarction.Design, Setting, and Participants: The PACMAN-AMI double-blind, placebo-controlled, randomized clinical trial (enrollment: May 9, 2017, through October 7, 2020; final follow-up: October 13, 2021) enrolled 300 patients undergoing percutaneous coronary intervention for acute myocardial infarction at 9 academic European hospitals.Interventions: Patients were randomized to receive biweekly subcutaneous alirocumab (150 mg; n = 148) or placebo (n = 152), initiated less than 24 hours after urgent percutaneous coronary intervention of the culprit lesion, for 52 weeks in addition to high-intensity statin therapy (rosuvastatin, 20 mg).Main Outcomes and Measures: Intravascular ultrasonography (IVUS), near-infrared spectroscopy, and optical coherence tomography were serially performed in the 2 non-infarct-related coronary arteries at baseline and after 52 weeks. The primary efficacy end point was the change in IVUS-derived percent atheroma volume from baseline to week 52. Two powered secondary end points were changes in near-infrared spectroscopy-derived maximum lipid core burden index within 4 mm (higher values indicating greater lipid content) and optical coherence tomography-derived minimal fibrous cap thickness (smaller values indicating thin-capped, vulnerable plaques) from baseline to week 52.Results: Among 300 randomized patients (mean [SD] age, 58.5 [9.7] years; 56 [18.7%] women; mean [SD] low-density lipoprotein cholesterol level, 152.4 [33.8] mg/dL), 265 (88.3%) underwent serial IVUS imaging in 537 arteries. At 52 weeks, mean change in percent atheroma volume was -2.13% with alirocumab vs -0.92% with placebo (difference, -1.21% [95% CI, -1.78% to -0.65%], P < .001). Mean change in maximum lipid core burden index within 4 mm was -79.42 with alirocumab vs -37.60 with placebo (difference, -41.24 [95% CI, -70.71 to -11.77]; P = .006). Mean change in minimal fibrous cap thickness was 62.67 μm with alirocumab vs 33.19 μm with placebo (difference, 29.65 μm [95% CI, 11.75-47.55]; P = .001). Adverse events occurred in 70.7% of patients treated with alirocumab vs 72.8% of patients receiving placebo.Conclusions and Relevance: Among patients with acute myocardial infarction, the addition of subcutaneous biweekly alirocumab, compared with placebo, to high-intensity statin therapy resulted in significantly greater coronary plaque regression in non-infarct-related arteries after 52 weeks. Further research is needed to understand whether alirocumab improves clinical outcomes in this population.Trial Registration: ClinicalTrials.gov Identifier: NCT03067844. [ABSTRACT FROM AUTHOR]

Importance: Lumbar spinal stenosis is a prevalent and disabling cause of low back and leg pain in older persons, affecting an estimated 103 million persons worldwide. Most are treated nonoperatively. Approximately 600 000 surgical procedures are performed in the US each year for lumbar spinal stenosis.Observations: The prevalence of the clinical syndrome of lumbar spinal stenosis in US adults is approximately 11% and increases with age. The diagnosis can generally be made based on a clinical history of back and lower extremity pain that is provoked by lumbar extension, relieved by lumbar flexion, and confirmed with cross-sectional imaging, such as computed tomography or magnetic resonance imaging (MRI). Nonoperative treatment includes activity modification such as reducing periods of standing or walking, oral medications to diminish pain such as nonsteroidal anti-inflammatory drugs (NSAIDs), and physical therapy. In a series of patients with lumbar spinal stenosis followed up for up to 3 years without operative intervention, approximately one-third of patients reported improvement, approximately 50% reported no change in symptoms, and approximately 10% to 20% of patients reported that their back pain, leg pain, and walking were worse. Long-term benefits of epidural steroid injections for lumbar spinal stenosis have not been demonstrated. Surgery appears effective in carefully selected patients with back, buttock, and lower extremity pain who do not improve with conservative management. For example, in a randomized trial of 94 participants with symptomatic and radiographic degenerative lumbar spinal stenosis, decompressive laminectomy improved symptoms more than nonoperative therapy (difference, 7.8 points; 95% CI, 0.8-14.9; minimum clinically important difference, 10-12.8) on the Oswestry Disability Index (score range, 0-100). Among persons with lumbar spinal stenosis and concomitant spondylolisthesis, lumbar fusion increased symptom resolution in 1 trial (difference, 5.7 points; 95% CI, 0.1 to 11.3) on the 36-Item Short Form Health Survey physical dimension score (range, 0-100), but 2 other trials showed either no important differences between the 2 therapies or noninferiority of lumbar decompression alone compared with lumbar decompression plus spinal fusion (MCID, 2-4.9 points). In a noninferiority trial, 71.4% treated with lumbar decompression alone vs 72.9% of those receiving decompression plus fusion achieved a 30% or more reduction in Oswestry Disability Index score, consistent with the prespecified noninferiority hypothesis. Fusion is associated with greater risk of complications such as blood loss, infection, longer hospital stays, and higher costs. Thus, the precise indications for concomitant lumbar fusion in persons with lumbar spinal stenosis and spondylolisthesis remain unclear.Conclusions and Relevance: Lumbar spinal stenosis affects approximately 103 million people worldwide and 11% of older adults in the US. First-line therapy is activity modification, analgesia, and physical therapy. Long-term benefits from epidural steroid injections have not been established. Selected patients with continued pain and activity limitation may be candidates for decompressive surgery. [ABSTRACT FROM AUTHOR]

Importance: Gallbladder disease affects approximately 20 million people in the US. Acute cholecystitis is diagnosed in approximately 200 000 people in the US each year.Observations: Gallstone-associated cystic duct obstruction is responsible for 90% to 95% of the cases of acute cholecystitis. Approximately 5% to 10% of patients with acute cholecystitis have acalculous cholecystitis, defined as acute inflammation of the gallbladder without gallstones, typically in the setting of severe critical illness. The typical presentation of acute cholecystitis consists of acute right upper quadrant pain, fever, and nausea that may be associated with eating and physical examination findings of right upper quadrant tenderness. Ultrasonography of the right upper quadrant has a sensitivity of approximately 81% and a specificity of approximately 83% for the diagnosis of acute cholecystitis. When an ultrasound result does not provide a definitive diagnosis, hepatobiliary scintigraphy (a nuclear medicine study that includes the intravenous injection of a radiotracer excreted in the bile) is the gold standard diagnostic test. Following diagnosis, early (performed within 1-3 days) vs late (performed after 3 days) laparoscopic cholecystectomy is associated with improved patient outcomes, including fewer composite postoperative complications (11.8% for early vs 34.4% for late), a shorter length of hospital stay (5.4 days vs 10.0 days), and lower hospital costs. During pregnancy, early laparoscopic cholecystectomy, compared with delayed operative management, is associated with a lower risk of maternal-fetal complications (1.6% for early vs 18.4% for delayed) and is recommended during all trimesters. In people older than 65 years of age, laparoscopic cholecystectomy is associated with lower mortality at 2-year follow-up (15.2%) compared with nonoperative management (29.3%). A percutaneous cholecystostomy tube, in which a drainage catheter is placed in the gallbladder lumen under image guidance, is an effective therapy for patients with an exceptionally high perioperative risk. However, percutaneous cholecystostomy tube placement in a randomized trial was associated with higher rates of postprocedural complications (65%) compared with laparoscopic cholecystectomy (12%). For patients with acalculous acute cholecystitis, percutaneous cholecystostomy tube should be reserved for patients who are severely ill at the time of diagnosis; all others should undergo a laparoscopic cholecystectomy.Conclusions and Relevance: Acute cholecystitis, typically due to gallstone obstruction of the cystic duct, affects approximately 200 000 people in the US annually. In most patient populations, laparoscopic cholecystectomy, performed within 3 days of diagnosis, is the first-line therapy for acute cholecystitis. [ABSTRACT FROM AUTHOR]

Importance: Approximately 40% of children who experience an in-hospital cardiac arrest survive to hospital discharge. Achieving threshold intra-arrest diastolic blood pressure (BP) targets during cardiopulmonary resuscitation (CPR) and systolic BP targets after the return of circulation may be associated with improved outcomes.Objective: To evaluate the effectiveness of a bundled intervention comprising physiologically focused CPR training at the point of care and structured clinical event debriefings.Design, Setting, and Participants: A parallel, hybrid stepped-wedge, cluster randomized trial (Improving Outcomes from Pediatric Cardiac Arrest-the ICU-Resuscitation Project [ICU-RESUS]) involving 18 pediatric intensive care units (ICUs) from 10 clinical sites in the US. In this hybrid trial, 2 clinical sites were randomized to remain in the intervention group and 2 in the control group for the duration of the study, and 6 were randomized to transition from the control condition to the intervention in a stepped-wedge fashion. The index (first) CPR events of 1129 pediatric ICU patients were included between October 1, 2016, and March 31, 2021, and were followed up to hospital discharge (final follow-up was April 30, 2021).Intervention: During the intervention period (n = 526 patients), a 2-part ICU resuscitation quality improvement bundle was implemented, consisting of CPR training at the point of care on a manikin (48 trainings/unit per month) and structured physiologically focused debriefings of cardiac arrest events (1 debriefing/unit per month). The control period (n = 548 patients) consisted of usual pediatric ICU management of cardiac arrest.Main Outcomes and Measures: The primary outcome was survival to hospital discharge with a favorable neurologic outcome defined as a Pediatric Cerebral Performance Category score of 1 to 3 or no change from baseline (score range, 1 [normal] to 6 [brain death or death]). The secondary outcome was survival to hospital discharge.Results: Among 1389 cardiac arrests experienced by 1276 patients, 1129 index CPR events (median patient age, 0.6 [IQR, 0.2-3.8] years; 499 girls [44%]) were included and 1074 were analyzed in the primary analysis. There was no significant difference in the primary outcome of survival to hospital discharge with favorable neurologic outcomes in the intervention group (53.8%) vs control (52.4%); risk difference (RD), 3.2% (95% CI, -4.6% to 11.4%); adjusted OR, 1.08 (95% CI, 0.76 to 1.53). There was also no significant difference in survival to hospital discharge in the intervention group (58.0%) vs control group (56.8%); RD, 1.6% (95% CI, -6.2% to 9.7%); adjusted OR, 1.03 (95% CI, 0.73 to 1.47).Conclusions and Relevance: In this randomized clinical trial conducted in 18 pediatric intensive care units, a bundled intervention of cardiopulmonary resuscitation training at the point of care and physiologically focused structured debriefing, compared with usual care, did not significantly improve patient survival to hospital discharge with favorable neurologic outcome among pediatric patients who experienced cardiac arrest in the ICU.Trial Registration: ClinicalTrials.gov Identifier: NCT02837497. [ABSTRACT FROM AUTHOR]

Importance: Approximately 23 700 US children undergo invasive mechanical ventilation for acute respiratory failure annually, with unknown long-term effects on neurocognitive function.Objective: To evaluate neurocognitive outcomes of children who survive pediatric intensive care unit (PICU) hospitalization for acute respiratory failure compared with their biological siblings.Design, Setting, and Participants: Prospective sibling-matched cohort study conducted at 31 US PICUs and associated neuropsychology testing centers. Patients were 8 years or younger with a Pediatric Cerebral Performance Category score of 1 (normal) before PICU admission and less than or equal to 3 (no worse than moderate neurocognitive dysfunction) at PICU discharge, excluding patients with a history of neurocognitive deficits or who were readmitted and underwent mechanical ventilation. Biological siblings were aged 4 to 16 years at testing, with Pediatric Cerebral Performance Category score of 1 and no history of mechanical ventilation or general anesthesia. A total of 121 sibling pairs were enrolled from September 2, 2014, to December 13, 2017, and underwent neurocognitive testing starting March 14, 2015. The date of the final follow-up was November 6, 2018.Exposures: Critical illness and PICU treatment for acute respiratory failure.Main Outcomes and Measures: The primary outcome was IQ, estimated by the age-appropriate Vocabulary and Block Design subtests of the Wechsler Intelligence Scale. Secondary outcomes included measures of attention, processing speed, learning and memory, visuospatial skills, motor skills, language, and executive function. Evaluations occurred 3 to 8 years after hospital discharge.Results: Patients (n = 121; 55 [45%] female patients) underwent PICU care at a median (IQR) age of 1.0 (0.2-3.2) years, received a median (IQR) of 5.5 (3.1-7.7) days of invasive mechanical ventilation, and were tested at a median (IQR) age of 6.6 (5.4-9.1) years. Matched siblings (n = 121; 72 [60%] female siblings) were tested at a median (IQR) age of 8.4 (7.0-10.2) years. Patients had a lower mean estimated IQ than matched siblings (101.5 vs 104.3; mean difference, -2.8 [95% CI, -5.4 to -0.2]). Among secondary outcomes, patients had significantly lower scores than matched siblings on nonverbal memory (mean difference, -0.9 [95% CI, -1.6 to -0.3]), visuospatial skills (mean difference, -0.9 [95% CI, -1.8 to -0.1]), and fine motor control (mean difference, -3.1 [95% CI, -4.9 to -1.4]) and significantly higher scores on processing speed (mean difference, 4.4 [95% CI, 0.2-8.5]). There were no significant differences in the remaining secondary outcomes, including attention, verbal memory, expressive language, and executive function.Conclusions and Relevance: Among children, survival of PICU hospitalization for respiratory failure and discharge without severe cognitive dysfunction was associated with significantly lower subsequent IQ scores compared with matched siblings. However, the magnitude of the difference was small and of uncertain clinical importance. [ABSTRACT FROM AUTHOR]

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]

Importance: The comparative effectiveness of rivaroxaban and apixaban, the most frequently prescribed oral anticoagulants for ischemic stroke prevention in patients with atrial fibrillation, is uncertain.Objective: To compare major ischemic and hemorrhagic outcomes in patients with atrial fibrillation treated with rivaroxaban or apixaban.Design, Setting, and Participants: Retrospective cohort study using computerized enrollment and claims files for US Medicare beneficiaries 65 years or older. Between January 1, 2013, and November 30, 2018, a total of 581 451 patients with atrial fibrillation began rivaroxaban or apixaban treatment and were followed up for 4 years, through November 30, 2018.Exposures: Rivaroxaban (n = 227 572) and apixaban (n = 353 879), either standard or reduced dose.Main Outcomes and Measures: The primary outcome was a composite of major ischemic (stroke/systemic embolism) and hemorrhagic (intracerebral hemorrhage/other intracranial bleeding/fatal extracranial bleeding) events. Secondary outcomes were nonfatal extracranial bleeding and total mortality (fatal ischemic/hemorrhagic event or other death during follow-up). Rates, hazard ratios (HRs), and rate differences (RDs) were adjusted for baseline differences in comorbidity with inverse probability of treatment weighting.Results: Study patients (mean age, 77.0 years; 291 966 [50.2%] women; 134 393 [23.1%] receiving reduced dose) had 474 605 person-years of follow-up (median [IQR] of 174 [62-397] days). The adjusted primary outcome rate for rivaroxaban was 16.1 per 1000 person-years vs 13.4 per 1000 person-years for apixaban (RD, 2.7 [95% CI, 1.9-3.5]; HR, 1.18 [95% CI, 1.12-1.24]). The rivaroxaban group had increased risk for both major ischemic events (8.6 vs 7.6 per 1000 person-years; RD, 1.1 [95% CI, 0.5-1.7]; HR, 1.12 [95% CI, 1.04-1.20]) and hemorrhagic events (7.5 vs 5.9 per 1000 person-years; RD, 1.6 [95% CI, 1.1-2.1]; HR, 1.26 [95% CI, 1.16-1.36]), including fatal extracranial bleeding (1.4 vs 1.0 per 1000 person-years; RD, 0.4 [95% CI, 0.2-0.7]; HR, 1.41 [95% CI, 1.18-1.70]). Patients receiving rivaroxaban had increased risk of nonfatal extracranial bleeding (39.7 vs 18.5 per 1000 person-years; RD, 21.1 [95% CI, 20.0-22.3]; HR, 2.07 [95% CI, 1.99-2.15]), fatal ischemic/hemorrhagic events (4.5 vs 3.3 per 1000 person-years; RD, 1.2 [95% CI, 0.8-1.6]; HR, 1.34 [95% CI, 1.21-1.48]), and total mortality (44.2 vs 41.0 per 1000 person-years; RD, 3.1 [95% CI, 1.8-4.5]; HR, 1.06 [95% CI, 1.02-1.09]). The risk of the primary outcome was increased for rivaroxaban in both those receiving the reduced dose (27.4 vs 21.0 per 1000 person-years; RD, 6.4 [95% CI, 4.1-8.7]; HR, 1.28 [95% CI, 1.16-1.40]) and the standard dose (13.2 vs 11.4 per 1000 person-years; RD, 1.8 [95% CI, 1.0-2.6]; HR, 1.13 [95% CI, 1.06-1.21]) groups.Conclusions and Relevance: Among Medicare beneficiaries 65 years or older with atrial fibrillation, treatment with rivaroxaban compared with apixaban was associated with a significantly increased risk of major ischemic or hemorrhagic events. [ABSTRACT FROM AUTHOR]

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: Dental caries is the most common chronic disease in children in the US. According to the 2011-2016 National Health and Nutrition Examination Survey, approximately 23% of children aged 2 to 5 years had dental caries in their primary teeth. Prevalence is higher in Mexican American children (33%) and non-Hispanic Black children (28%) than in non-Hispanic White children (18%). Dental caries in early childhood is associated with pain, loss of teeth, impaired growth, decreased weight gain, negative effects on quality of life, poor school performance, and future dental caries.Objective: To update its 2014 recommendation, the US Preventive Services Task Force (USPSTF) commissioned a systematic review on screening and interventions to prevent dental caries in children younger than 5 years.Population: Asymptomatic children younger than 5 years.Evidence Assessment: The USPSTF concludes with moderate certainty that there is a moderate net benefit of preventing future dental caries with oral fluoride supplementation at recommended doses in children 6 months or older whose water supply is deficient in fluoride. The USPSTF concludes with moderate certainty that there is a moderate net benefit of preventing future dental caries with fluoride varnish application in all children younger than 5 years. The USPSTF concludes that the evidence is insufficient on performing routine oral screening examinations for dental caries by primary care clinicians in children younger than 5 years and that the balance of benefits and harms of screening cannot be determined.Recommendation: The USPSTF recommends that primary care clinicians prescribe oral fluoride supplementation starting at age 6 months for children whose water supply is deficient in fluoride. (B recommendation) The USPSTF recommends that primary care clinicians apply fluoride varnish to the primary teeth of all infants and children starting at the age of primary tooth eruption. (B recommendation) The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of routine screening examinations for dental caries performed by primary care clinicians in children younger than 5 years. (I statement). [ABSTRACT FROM AUTHOR]

Importance: No therapy has been shown to reduce the risk of serious adverse outcomes in patients with nonalcoholic steatohepatitis (NASH).Objective: To investigate the long-term relationship between bariatric surgery and incident major adverse liver outcomes and major adverse cardiovascular events (MACE) in patients with obesity and biopsy-proven fibrotic NASH without cirrhosis.Design, Setting, and Participants: In the SPLENDOR (Surgical Procedures and Long-term Effectiveness in NASH Disease and Obesity Risk) study, of 25 828 liver biopsies performed at a US health system between 2004 and 2016, 1158 adult patients with obesity were identified who fulfilled enrollment criteria, including confirmed histological diagnosis of NASH and presence of liver fibrosis (histological stages 1-3). Baseline clinical characteristics, histological disease activity, and fibrosis stage of patients who underwent simultaneous liver biopsy at the time of bariatric surgery were balanced with a nonsurgical control group using overlap weighting methods. Follow-up ended in March 2021.Exposures: Bariatric surgery (Roux-en-Y gastric bypass, sleeve gastrectomy) vs nonsurgical care.Main Outcomes and Measures: The primary outcomes were the incidence of major adverse liver outcomes (progression to clinical or histological cirrhosis, development of hepatocellular carcinoma, liver transplantation, or liver-related mortality) and MACE (a composite of coronary artery events, cerebrovascular events, heart failure, or cardiovascular death), estimated using the Firth penalized method in a multivariable-adjusted Cox regression analysis framework.Results: A total of 1158 patients (740 [63.9%] women; median age, 49.8 years [IQR, 40.9-57.9 years], median body mass index, 44.1 [IQR, 39.4-51.4]), including 650 patients who underwent bariatric surgery and 508 patients in the nonsurgical control group, with a median follow-up of 7 years (IQR, 4-10 years) were analyzed. Distribution of baseline covariates, including histological severity of liver injury, was well-balanced after overlap weighting. At the end of the study period in the unweighted data set, 5 patients in the bariatric surgery group and 40 patients in the nonsurgical control group experienced major adverse liver outcomes, and 39 patients in the bariatric surgery group and 60 patients in the nonsurgical group experienced MACE. Among the patients analyzed with overlap weighting methods, the cumulative incidence of major adverse liver outcomes at 10 years was 2.3% (95% CI, 0%-4.6%) in the bariatric surgery group and 9.6% (95% CI, 6.1%-12.9%) in the nonsurgical group (adjusted absolute risk difference, 12.4% [95% CI, 5.7%-19.7%]; adjusted hazard ratio, 0.12 [95% CI, 0.02-0.63]; P = .01). The cumulative incidence of MACE at 10 years was 8.5% (95% CI, 5.5%-11.4%) in the bariatric surgery group and 15.7% (95% CI, 11.3%-19.8%) in the nonsurgical group (adjusted absolute risk difference, 13.9% [95% CI, 5.9%-21.9%]; adjusted hazard ratio, 0.30 [95% CI, 0.12-0.72]; P = .007). Within the first year after bariatric surgery, 4 patients (0.6%) died from surgical complications, including gastrointestinal leak (n = 2) and respiratory failure (n = 2).Conclusions and Relevance: Among patients with NASH and obesity, bariatric surgery, compared with nonsurgical management, was associated with a significantly lower risk of incident major adverse liver outcomes and MACE. [ABSTRACT FROM AUTHOR]

Importance: Most clinical guidelines do not recommend platelet-rich plasma (PRP) for knee osteoarthritis (OA) because of lack of high-quality evidence on efficacy for symptoms and joint structure, but the guidelines emphasize the need for rigorous studies. Despite this, use of PRP in knee OA is increasing.Objective: To evaluate the effects of intra-articular PRP injections on symptoms and joint structure in patients with symptomatic mild to moderate radiographic medial knee OA.Design, Setting, and Participants: This randomized, 2-group, placebo-controlled, participant-, injector-, and assessor-blinded clinical trial enrolled community-based participants (n = 288) aged 50 years or older with symptomatic medial knee OA (Kellgren and Lawrence grade 2 or 3) in Sydney and Melbourne, Australia, from August 24, 2017, to July 5, 2019. The 12-month follow-up was completed on July 22, 2020.Interventions: Interventions involved 3 intra-articular injections at weekly intervals of either leukocyte-poor PRP using a commercially available product (n = 144 participants) or saline placebo (n = 144 participants).Main Outcomes and Measures: The 2 primary outcomes were 12-month change in overall average knee pain scores (11-point scale; range, 0-10, with higher scores indicating worse pain; minimum clinically important difference of 1.8) and percentage change in medial tibial cartilage volume as assessed by magnetic resonance imaging (MRI). Thirty-one secondary outcomes (25 symptom related and 6 MRI assessed; minimum clinically important difference not known) evaluated pain, function, quality of life, global change, and joint structures at 2-month and/or 12-month follow-up.Results: Among 288 patients who were randomized (mean age, 61.9 [SD, 6.5] years; 169 [59%] women), 269 (93%) completed the trial. In both groups, 140 participants (97%) received all 3 injections. After 12 months, treatment with PRP vs placebo injection resulted in a mean change in knee pain scores of -2.1 vs -1.8 points, respectively (difference, -0.4 [95% CI, -0.9 to 0.2] points; P = .17). The mean change in medial tibial cartilage volume was -1.4% vs -1.2%, respectively (difference, -0.2% [95% CI, -1.9% to 1.5%]; P = .81). Of 31 prespecified secondary outcomes, 29 showed no significant between-group differences.Conclusions and Relevance: Among patients with symptomatic mild to moderate radiographic knee OA, intra-articular injection of PRP, compared with injection of saline placebo, did not result in a significant difference in symptoms or joint structure at 12 months. These findings do not support use of PRP for the management of knee OA.Trial Registration: Australian New Zealand Clinical Trials Registry Identifier: ACTRN12617000853347. [ABSTRACT FROM AUTHOR]

Importance: Mental stress-induced myocardial ischemia is a recognized phenomenon in patients with coronary heart disease (CHD), but its clinical significance in the contemporary clinical era has not been investigated.Objective: To compare the association of mental stress-induced or conventional stress-induced ischemia with adverse cardiovascular events in patients with CHD.Design, Setting, and Participants: Pooled analysis of 2 prospective cohort studies of patients with stable CHD from a university-based hospital network in Atlanta, Georgia: the Mental Stress Ischemia Prognosis Study (MIPS) and the Myocardial Infarction and Mental Stress Study 2 (MIMS2). Participants were enrolled between June 2011 and March 2016 (last follow-up, February 2020).Exposures: Provocation of myocardial ischemia with a standardized mental stress test (public speaking task) and with a conventional (exercise or pharmacological) stress test, using single-photon emission computed tomography.Main Outcomes and Measures: The primary outcome was a composite of cardiovascular death or first or recurrent nonfatal myocardial infarction. The secondary end point additionally included hospitalizations for heart failure.Results: Of the 918 patients in the total sample pool (mean age, 60 years; 34% women), 618 participated in MIPS and 300 in MIMS2. Of those, 147 patients (16%) had mental stress-induced ischemia, 281 (31%) conventional stress ischemia, and 96 (10%) had both. Over a 5-year median follow-up, the primary end point occurred in 156 participants. The pooled event rate was 6.9 per 100 patient-years among patients with and 2.6 per 100 patient-years among patients without mental stress-induced ischemia. The multivariable adjusted hazard ratio (HR) for patients with vs those without mental stress-induced ischemia was 2.5 (95% CI, 1.8-3.5). Compared with patients with no ischemia (event rate, 2.3 per 100 patient-years), patients with mental stress-induced ischemia alone had a significantly increased risk (event rate, 4.8 per 100 patient-years; HR, 2.0; 95% CI, 1.1-3.7) as did patients with both mental stress ischemia and conventional stress ischemia (event rate, 8.1 per 100 patient-years; HR, 3.8; 95% CI, 2.6-5.6). Patients with conventional stress ischemia alone did not have a significantly increased risk (event rate, 3.1 per 100 patient-years; HR, 1.4; 95% CI, 0.9-2.1). Patients with both mental stress ischemia and conventional stress ischemia had an elevated risk compared with patients with conventional stress ischemia alone (HR, 2.7; 95% CI, 1.7-4.3). The secondary end point occurred in 319 participants. The event rate was 12.6 per 100 patient-years for patients with and 5.6 per 100 patient-years for patients without mental stress-induced ischemia (adjusted HR, 2.0; 95% CI, 1.5-2.5).Conclusions and Relevance: Among patients with stable coronary heart disease, the presence of mental stress-induced ischemia, compared with no mental stress-induced ischemia, was significantly associated with an increased risk of cardiovascular death or nonfatal myocardial infarction. Although these findings may provide insights into mechanisms of myocardial ischemia, further research is needed to assess whether testing for mental stress-induced ischemia has clinical value. [ABSTRACT FROM AUTHOR]

Importance: Active search for pulmonary embolism (PE) may improve outcomes in patients hospitalized for exacerbations of chronic obstructive pulmonary disease (COPD).Objective: To compare usual care plus an active strategy for diagnosing PE with usual care alone in patients hospitalized for COPD exacerbation.Design, Setting, and Participants: Randomized clinical trial conducted across 18 hospitals in Spain. A total of 746 patients were randomized from September 2014 to July 2020 (final follow-up was November 2020).Interventions: Usual care plus an active strategy for diagnosing PE (D-dimer testing and, if positive, computed tomography pulmonary angiogram) (n = 370) vs usual care (n = 367).Main Outcomes and Measures: The primary outcome was a composite of nonfatal symptomatic venous thromboembolism (VTE), readmission for COPD, or death within 90 days after randomization. There were 4 secondary outcomes, including nonfatal new or recurrent VTE, readmission for COPD, and death from any cause within 90 days. Adverse events were also collected.Results: Among the 746 patients who were randomized, 737 (98.8%) completed the trial (mean age, 70 years; 195 [26%] women). The primary outcome occurred in 110 patients (29.7%) in the intervention group and 107 patients (29.2%) in the control group (absolute risk difference, 0.5% [95% CI, -6.2% to 7.3%]; relative risk, 1.02 [95% CI, 0.82-1.28]; P = .86). Nonfatal new or recurrent VTE was not significantly different in the 2 groups (0.5% vs 2.5%; risk difference, -2.0% [95% CI, -4.3% to 0.1%]). By day 90, a total of 94 patients (25.4%) in the intervention group and 84 (22.9%) in the control group had been readmitted for exacerbation of COPD (risk difference, 2.5% [95% CI, -3.9% to 8.9%]). Death from any cause occurred in 23 patients (6.2%) in the intervention group and 29 (7.9%) in the control group (risk difference, -1.7% [95% CI, -5.7% to 2.3%]). Major bleeding occurred in 3 patients (0.8%) in the intervention group and 3 patients (0.8%) in the control group (risk difference, 0% [95% CI, -1.9% to 1.8%]; P = .99).Conclusions and Relevance: Among patients hospitalized for an exacerbation of COPD, the addition of an active strategy for the diagnosis of PE to usual care, compared with usual care alone, did not significantly improve a composite health outcome. The study may not have had adequate power to assess individual components of the composite outcome.Trial Registration: ClinicalTrials.gov Identifier: NCT02238639. [ABSTRACT FROM AUTHOR]

Editorial Intracranial atherosclerosis (ICAS) is a major cause of stroke worldwide. The medical therapy included dual antiplatelet therapy, commenced 3 to 5 days prior to the procedure and continued for 90 days after, and guideline-recommended use of statins and antihypertensive therapy to manage stroke risk factors. In a post hoc analysis, stroke or death at 30 days occurred in 9 patients (5.1%) in the stenting group (5 with ischemic stroke and 4 with hemorrhagic stroke) and in 4 patients (2.2%) in the medical therapy group (4 with ischemic stroke). [Extracted from the article]

Importance: Chlamydia and gonorrhea are among the most common sexually transmitted infections in the US. Infection rates are highest among adolescents and young adults of both sexes. Chlamydial and gonococcal infections in women are usually asymptomatic and may lead to pelvic inflammatory disease and its associated complications. Newborns of pregnant persons with untreated infection may develop neonatal chlamydial pneumonia or gonococcal or chlamydial ophthalmia. Infection in men may lead to urethritis and epididymitis. Both types of infection can increase risk of acquiring or transmitting HIV.Objective: To update its 2014 recommendation, the US Preventive Services Task Force (USPSTF) commissioned a systematic review to evaluate the benefits and harms of screening for chlamydia and gonorrhea in sexually active adolescents and adults, including pregnant persons.Population: Asymptomatic, sexually active adolescents and adults, including pregnant persons.Evidence Assessment: The USPSTF concludes with moderate certainty that screening for chlamydia in all sexually active women 24 years or younger and in women 25 years or older who are at increased risk for infection has moderate net benefit. The USPSTF concludes with moderate certainty that screening for gonorrhea in all sexually active women 24 years or younger and in women 25 years or older who are at increased risk for infection has moderate net benefit. The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for chlamydia and gonorrhea in men.Recommendation: The USPSTF recommends screening for chlamydia in all sexually active women 24 years or younger and in women 25 years or older who are at increased risk for infection. (B recommendation) The USPSTF recommends screening for gonorrhea in all sexually active women 24 years or younger and in women 25 years or older who are at increased risk for infection. (B recommendation) The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for chlamydia and gonorrhea in men. (I statement). [ABSTRACT FROM AUTHOR]

Importance: The 2014 US Preventive Services Task Force (USPSTF) recommendation statement supported the effectiveness of screening for chlamydia and gonorrhea in asymptomatic, sexually active women 24 years or younger and in older women at increased risk for infection, although evidence for screening in men was insufficient.Objective: To update the 2014 USPSTF review on screening for chlamydial and gonococcal infection in adults and adolescents, including those who are pregnant.Data Sources: Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Ovid MEDLINE (January 1, 2014, through May 28, 2020) with surveillance through May 21, 2021.Study Selection: Randomized clinical trials and observational studies of screening effectiveness, accuracy of risk stratification and alternative screening methods, accuracy of tests, and screening harms.Data Extraction and Synthesis: One investigator abstracted data; a second checked accuracy. Two investigators independently assessed study quality.Main Outcomes and Measures: Complications of infection; infection transmission or acquisition; diagnostic accuracy of anatomical site-specific testing and collection methods; screening harms.Results: Twenty-seven studies were included (N = 179 515). Chlamydia screening compared with no screening was significantly associated with reduced risk of pelvic inflammatory disease (PID) in 2 of 4 trials and with reduced hospital-diagnosed PID (0.24% vs 0.38%); relative risk, 0.6 [95% CI, 0.4-1.0]), but not clinic-diagnosed PID or epididymitis, in the largest trial. In studies of risk prediction instruments in asymptomatic women, age younger than 22 years demonstrated comparable accuracy to extensive criteria. Sensitivity of chlamydial testing was similar at endocervical (89%-100%) and self- and clinician-collected vaginal (90%-100%) sites for women and at meatal (100%), urethral (99%), and rectal (92%) sites for men but lower at pharyngeal sites (69.2%) for men who have sex with men. Sensitivity of gonococcal testing was 89% or greater for all anatomical samples. False-positive and false-negative testing rates were low across anatomical sites and collection methods.Conclusions and Relevance: Screening for chlamydial infection was significantly associated with a lower risk of PID in young women. Risk prediction criteria demonstrated limited accuracy beyond age. Testing for asymptomatic chlamydial and gonococcal infections was highly accurate at most anatomical sites, including urine and self-collected specimens. Effectiveness of screening in men and during pregnancy, optimal screening intervals, and adverse effects of screening require further evaluation. [ABSTRACT FROM AUTHOR]

In fact, best practices in bariatric surgery recommend completed preoperative cancer screening for all surgery candidates.[12] It makes sense that patients who are candidates for bariatric surgery and patients who have undergone bariatric surgery may have more enhanced cancer screening compared with individuals who are not pursuing bariatric surgery. During a median follow-up of 6.1 years, 96 patients in the bariatric surgery group and 780 patients in the nonsurgical control group had an incident obesity-associated cancer (incidence rate of 3.0 events vs 4.6 events, respectively, per 1000 person-years). Most studies that have evaluated the association between bariatric surgery and cancer risk have little detail on cancer screening, early detection, and treatment in the study cohorts. [Extracted from the article]

The authors discuss a study by W. A. Ray and colleagues which compared rivaroxaban with apixaban, which account for nearly all direct-acting oral anticoagulant (DOAC) prescriptions in the U.S. Topics include fee-for-service Medicare beneficiaries included in the study, comparison of the risk of the primary outcome of major ischemic or hemorrhagic events between patients who received apixaban and patients who received rivaroxaban, and association between apixaban and lower bleeding risk.

The authors reflect on the importance of using harnessing clinical trial evidence to decide on individualized treatment of patients with patent foramen ovale (PFO). Also cited are the randomized clinical trials comparing outcome of PFO closure against treatment with antiplatelet or anticoagulation agents, and the study using the Risk of Paradoxical Embolism (RoPE) Score and the PFO-Associated Stroke Causal Likelihood (PASCAL) Classification System.

The study compared symptoms between those with and without SARS-CoV-2 infection to identify the symptoms most likely to characterize postacute sequelae. Editorial Early in the COVID-19 pandemic, patients and clinicians reported the persistence of initial symptoms and the onset of new symptoms after the acute phase of SARS-CoV-2 infection, collectively referred to as I postacute sequelae of SARS-CoV-2 infection i (PASC), or more colloquially called I long COVID i .[1] Persistent anosmia as well as debilitating physical symptoms, such as chronic cough, gastrointestinal symptoms, fatigue, malaise, myalgias, pain, and lack of clarity of thought ("brain fog"), with or without obvious organ dysfunction, were prominent ailments identified by numerous patients after acute COVID-19.[[1]] This phenomenon has been a major focus of research. However, before developing a case definition for PASC, it is important to consider whether these sequelae represent a single pathophysiologic process or rather multiple different conditions triggered by antecedent SARS-CoV-2 infection.[3] In addition, it is important to know whether they are direct sequelae of infection itself or are mediated by specific organ injury and dysfunction. [Extracted from the article]

Comment & Response B In Reply b Drs Sivarajan and Akhter raise several interesting points about our iROC trial.[1] First, we agree that NAC for invasive bladder cancer is standard of care in suitable patients,[2] and we encourage this treatment within our practice.[3] Within iROC, 107 participants (34%) received NAC. Effect of Robot-Assisted Radical Cystectomy vs Open Radical Cystectomy on 90-Day Morbidity and Mortality Among Patients With Bladder Cancer - Reply Of the 107 participants who received NAC, post-radical cystectomy histology revealed that 24% had pT0 tumors (ie, complete response) and 12% had a partial response, down-staging to pTis-pT1. [Extracted from the article]

Effect of oral methylprednisolone on decline in kidney function or kidney failure in patients with IgA nephropathy: the TESTING randomized clinical trial. This reduced-dose cohort had a shorter median follow-up duration of 2.5 years, which may have contributed to a larger estimated effect size given the observation that the benefits of methylprednisolone therapy may diminish over the years after treatment is completed. Comment & Response B In Reply b In their Letter about the recent TESTING trial,[1] Drs Ye and Liu point out that previous studies have suggested that individuals of Asian descent may have a worse kidney prognosis than individuals of European descent.[2] However, this does not necessarily mean that the effects of treatment vary by ethnicity. [Extracted from the article]

Effect of oral methylprednisolone on decline in kidney function or kidney failure in patients with IgA nephropathy: the TESTING randomized clinical trial. Comment & Response B To the Editor b We have some comments about the recent TESTING trial[1] that found that oral methylprednisolone significantly reduced the risk of the composite outcome of kidney function decline in patients with IgA nephropathy. [Extracted from the article]

Comment & Response B To the Editor b The recently published PACMAN-AMI trial[1] is yet another solid piece of evidence that for cardiovascular disease prevention, the lower the low-density lipoprotein cholesterol (LDL-C), the better. Although 20-mg rosuvastatin is a "high-intensity statin", as described in the study's title, it is not the maximally effective statin dose nor is it the most effective oral LDL-C-lowering medication regimen.[[2]] Comparing alirocumab with a less-than-optimal treatment regimen could introduce bias favoring alirocumab.

Alirocumab Added to High-Intensity Statin Therapy and Coronary Atherosclerosis in Patients With Acute Myocardial Infarction - Reply Comment & Response B In Reply b Dr Benson expresses concerns about the selection of lipid-lowering treatment in the placebo group of our study[1] and suggests that a higher dose of rosuvastatin (40 mg) in combination with ezetimibe should have been selected. For example, only 48% of patients in the SWEDEHEART registry[3] were treated with a high-intensity statin and had a median LDL-C level of 77 mg/dL, and only 59% of patients in the placebo group of the GLAGOV trial[2] used a high-intensity statin and had a median LDL-C level of 93 mg/dL.

Blood pressure directed booster trainings improve intensive care unit provider retention of excellent cardiopulmonary resuscitation skills. Point-of-Care Cardiopulmonary Resuscitation Training and Survival With Favorable Neurologic Outcome in Cardiac Arrest in Pediatric ICUs - Reply Comment & Response B In Reply b We agree that clinicians and educators should interpret our study[1] findings carefully and not conclude that these types of physiologic point-of-care CPR trainings and debriefings are ineffective based on a trial that was negative for the primary outcome. [Extracted from the article]

Effect of physiologic point-of-care cardiopulmonary resuscitation training on survival with favorable neurologic outcome in cardiac arrest in pediatric ICUs: a randomized clinical trial. Comment & Response B To the Editor b We have some concerns about a recent trial[1] that demonstrated that a bundled intervention of CPR training and postcardiac arrest debriefings did not improve patient survival to hospital discharge with favorable neurologic outcome among pediatric patients with cardiac arrest. First, a critical mediator between the physiologic point-of-care CPR training and patient survival to hospital discharge with favorable neurologic outcomes is clinician improvement in CPR skills and post-cardiac arrest management. [Extracted from the article]

That may well be true in the palliative care setting but is not typically needed for acute agitation in bipolar disorder, in which the treatment goals are to rapidly reduce patient distress, prevent its persistence or escalation, and allow for timely assessment and triage. Comment & Response B In Reply b We read the comments by Dr Abe and colleagues, who work in palliative care medicine at a cancer center, as arising from a clinical care model that is quite different from the typical short-term agitated states of individuals with bipolar disorder. Sublingual Dexmedetomidine vs Placebo and Acute Agitation Associated With Bipolar Disorder - Reply. [Extracted from the article]

Comment & Response B To the Editor b A recent study[1] introduced the sublingual formulation of dexmedetomidine, bringing this potent -agonist out of the intensive care unit and into other psychiatric settings. Hypotension and orthostatic hypotension affected about 10% of the treatment group in total, with the average participant experiencing a decrease in systolic blood pressure of 15 to 18 mm Hg. [Extracted from the article]