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Importance: The use of spinal cord stimulation for chronic pain after lumbar spine surgery is increasing, yet rigorous evidence of its efficacy is lacking.Objective: To investigate the efficacy of spinal cord burst stimulation, which involves the placement of an implantable pulse generator connected to electrodes with leads that travel into the epidural space posterior to the spinal cord dorsal columns, in patients with chronic radiculopathy after surgery for degenerative lumbar spine disorders.Design, Setting, and Participants: This placebo-controlled, crossover, randomized clinical trial in 50 patients was conducted at St Olavs University Hospital in Norway, with study enrollment from September 5, 2018, through April 28, 2021. The date of final follow-up was May 20, 2022.Interventions: Patients underwent two 3-month periods with spinal cord burst stimulation and two 3-month periods with placebo stimulation in a randomized order. Burst stimulation consisted of closely spaced, high-frequency electrical stimuli delivered to the spinal cord. The stimulus consisted of a 40-Hz burst mode of constant-current stimuli with 4 spikes per burst and an amplitude corresponding to 50% to 70% of the paresthesia perception threshold.Main Outcomes and Measures: The primary outcome was difference in change from baseline in the self-reported Oswestry Disability Index (ODI; range, 0 points [no disability] to 100 points [maximum disability]; the minimal clinically important difference was 10 points) score between periods with burst stimulation and placebo stimulation. The secondary outcomes were leg and back pain, quality of life, physical activity levels, and adverse events.Results: Among 50 patients who were randomized (mean age, 52.2 [SD, 9.9] years; 27 [54%] were women), 47 (94%) had at least 1 follow-up ODI score and 42 (84%) completed all stimulation randomization periods and ODI measurements. The mean ODI score at baseline was 44.7 points and the mean changes in ODI score were -10.6 points for the burst stimulation periods and -9.3 points for the placebo stimulation periods, resulting in a mean between-group difference of -1.3 points (95% CI, -3.9 to 1.3 points; P = .32). None of the prespecified secondary outcomes showed a significant difference. Nine patients (18%) experienced adverse events, including 4 (8%) who required surgical revision of the implanted system.Conclusions and Relevance: Among patients with chronic radicular pain after lumbar spine surgery, spinal cord burst stimulation, compared with placebo stimulation, after placement of a spinal cord stimulator resulted in no significant difference in the change from baseline in self-reported back pain-related disability.Trial Registration: ClinicalTrials.gov Identifier: NCT03546738. [ABSTRACT FROM AUTHOR]

Importance: Prescription drug spending is a topic of increased interest to the public and policymakers. However, prior assessments have been limited by focusing on retail spending (Part D-covered drugs), omitting clinician-administered (Part B-covered) drug spending, or focusing on all fee-for-service Medicare beneficiaries, regardless of their enrollment into prescription drug coverage.Objective: To estimate the proportion of health care spending contributed by prescription drugs and to assess spending for retail and clinician-administered prescriptions.Design, Setting, and Participants: Descriptive, serial, cross-sectional analysis of a 20% random sample of fee-for-service Medicare beneficiaries in the United States from 2008 to 2019 who were continuously enrolled in Parts A (hospital), B (medical), and D (prescription drug) benefits, and not in Medicare Advantage.Exposure: Calendar year.Main Outcomes and Measures: Net spending on retail (Part D-covered) and clinician-administered (Part B-covered) prescription drugs; prescription drug spending (spending on Part B-covered and Part D-covered drugs) as a percentage of total per-capita health care spending. Measures were adjusted for inflation and for postsale rebates (for Part D-covered drugs).Results: There were 3 201 284 beneficiaries enrolled in Parts A, B, and D in 2008 and 4 502 718 in 2019. In 2019, beneficiaries had a mean (SD) age of 71.7 (12.0) years, documented sex was female for 57.7%, and 69.5% had no low-income subsidies. Total per-capita spending was $16 345 in 2008 and $20 117 in 2019. Comparing 2008 with 2019, per-capita Part A spending was $7106 (95% CI, $7084-$7128) vs $7120 (95% CI, $7098-$7141), Part B drug spending was $720 (95% CI, $713-$728) vs $1641 (95% CI, $1629-$1653), Part B nondrug spending was $5113 (95% CI, $5105-$5122) vs $6702 (95% CI, $6692-$6712), and Part D net spending was $3122 (95% CI, $3117-$3127) vs $3477 (95% CI, $3466-$3489). The proportion of total annual spending attributed to prescription drugs increased from 24.0% in 2008 to 27.2% in 2019, net of estimated rebates and discounts.Conclusions and Relevance: In 2019, spending on prescription drugs represented approximately 27% of total spending among fee-for-service Medicare beneficiaries enrolled in Part D, even after accounting for postsale rebates. [ABSTRACT FROM AUTHOR]

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

The article discusses a study on the adverse outcomes of tramadol or codeine among residents of Catalonia, Spain, which references a research paper published within the issue. Topics discussed include the use of propensity score matching in the study, the incidence of all-cause mortality and cardiovascular events following tramadol and codeine prescriptions, and the difference in the patterns of codeine prescribing in the U.S. from Europe.

Importance: Intraoperative handovers of anesthesia care are common. Handovers might improve care by reducing physician fatigue, but there is also an inherent risk of losing critical information. Large observational analyses report associations between handover of anesthesia care and adverse events, including higher mortality.Objective: To determine the effect of handovers of anesthesia care on postoperative morbidity and mortality.Design, Setting, and Participants: This was a parallel-group, randomized clinical trial conducted in 12 German centers with patients enrolled between June 2019 and June 2021 (final follow-up, July 31, 2021). Eligible participants had an American Society of Anesthesiologists physical status 3 or 4 and were scheduled for major inpatient surgery expected to last at least 2 hours.Interventions: A total of 1817 participants were randomized to receive either a complete handover to receive anesthesia care by another clinician (n = 908) or no handover of anesthesia care (n = 909). None of the participating institutions used a standardized handover protocol.Main Outcomes and Measures: The primary outcome was a 30-day composite of all-cause mortality, hospital readmission, or serious postoperative complications. There were 19 secondary outcomes, including the components of the primary composite, along with intensive care unit and hospital lengths of stay.Results: Among 1817 randomized patients, 1772 (98%; mean age, 66 [SD, 12] years; 997 men [56%]; and 1717 [97%] with an American Society of Anesthesiologists physical status of 3) completed the trial. The median total duration of anesthesia was 267 minutes (IQR, 206-351 minutes), and the median time from start of anesthesia to first handover was 144 minutes in the handover group (IQR, 105-213 minutes). The composite primary outcome occurred in 268 of 891 patients (30%) in the handover group and in 284 of 881 (33%) in the no handover group (absolute risk difference [RD], -2.5%; 95% CI, -6.8% to 1.9%; odds ratio [OR], 0.89; 95% CI, 0.72 to 1.10; P = .27). Nineteen of 889 patients (2.1%) in the handover group and 30 of 873 (3.4%) in the no handover group experienced all-cause 30-day mortality (absolute RD, -1.3%; 95% CI, -2.8% to 0.2%; OR, 0.61; 95% CI, 0.34 to 1.10; P = .11); 115 of 888 (13%) vs 136 of 872 (16%) were readmitted to the hospital (absolute RD, -2.7%; 95% CI, -5.9% to 0.6%; OR, 0.80; 95% CI, 0.61 to 1.05; P = .12); and 195 of 890 (22%) vs 189 of 874 (22%) experienced serious postoperative complications (absolute RD, 0.3%; 95% CI, -3.6% to 4.1%; odds ratio, 1.02; 95% CI, 0.81 to 1.28; P = .91). None of the 19 prespecified secondary end points differed significantly.Conclusions and Relevance: Among adults undergoing extended surgical procedures, there was no significant difference between the patients randomized to receive handover of anesthesia care from one clinician to another, compared with the no handover group, in the composite primary outcome of mortality, readmission, or serious postoperative complications within 30 days.Trial Registration: ClinicalTrials.gov Identifier: NCT04016454. [ABSTRACT FROM AUTHOR]

Importance: Digital breast tomosynthesis (DBT) was developed with the expectation of improving cancer detection in women with dense breasts. Studies are needed to evaluate interval invasive and advanced breast cancer rates, intermediary outcomes related to breast cancer mortality, by breast density and breast cancer risk.Objective: To evaluate whether DBT screening is associated with a lower likelihood of interval invasive cancer and advanced breast cancer compared with digital mammography by extent of breast density and breast cancer risk.Design, Setting, and Participants: Cohort study of 504 427 women aged 40 to 79 years who underwent 1 003 900 screening digital mammography and 375 189 screening DBT examinations from 2011 through 2018 at 44 US Breast Cancer Surveillance Consortium (BCSC) facilities with follow-up for cancer diagnoses through 2019 by linkage to state or regional cancer registries.Exposures: Breast Imaging Reporting and Data System (BI-RADS) breast density; BCSC 5-year breast cancer risk.Main Outcomes and Measures: Rates per 1000 examinations of interval invasive cancer within 12 months of screening mammography and advanced breast cancer (prognostic pathologic stage II or higher) within 12 months of screening mammography, both estimated with inverse probability weighting.Results: Among 504 427 women in the study population, the median age at time of mammography was 58 years (IQR, 50-65 years). Interval invasive cancer rates per 1000 examinations were not significantly different for DBT vs digital mammography (overall, 0.57 vs 0.61, respectively; difference, -0.04; 95% CI, -0.14 to 0.06; P = .43) or among all the 836 250 examinations with BCSC 5-year risk less than 1.67% (low to average-risk) or all the 413 061 examinations with BCSC 5-year risk of 1.67% or higher (high risk) across breast density categories. Advanced cancer rates were not significantly different for DBT vs digital mammography among women at low to average risk or at high risk with almost entirely fatty, scattered fibroglandular densities, or heterogeneously dense breasts. Advanced cancer rates per 1000 examinations were significantly lower for DBT vs digital mammography for the 3.6% of women with extremely dense breasts and at high risk of breast cancer (13 291 examinations in the DBT group and 31 300 in the digital mammography group; 0.27 vs 0.80 per 1000 examinations; difference, -0.53; 95% CI, -0.97 to -0.10) but not for women at low to average risk (10 611 examinations in the DBT group and 37 796 in the digital mammography group; 0.54 vs 0.42 per 1000 examinations; difference, 0.12; 95% CI, -0.09 to 0.32).Conclusions and Relevance: Screening with DBT vs digital mammography was not associated with a significant difference in risk of interval invasive cancer and was associated with a significantly lower risk of advanced breast cancer among the 3.6% of women with extremely dense breasts and at high risk of breast cancer. No significant difference was observed in the 96.4% of women with nondense breasts, heterogeneously dense breasts, or with extremely dense breasts not at high risk. [ABSTRACT FROM AUTHOR]

Importance: Patient-reported outcomes (PROs) can inform health care decisions, regulatory decisions, and health care policy. They also can be used for audit/benchmarking and monitoring symptoms to provide timely care tailored to individual needs. However, several ethical issues have been raised in relation to PRO use.Objective: To develop international, consensus-based, PRO-specific ethical guidelines for clinical research.Evidence Review: The PRO ethics guidelines were developed following the Enhancing the Quality and Transparency of Health Research (EQUATOR) Network's guideline development framework. This included a systematic review of the ethical implications of PROs in clinical research. The databases MEDLINE (Ovid), Embase, AMED, and CINAHL were searched from inception until March 2020. The keywords patient reported outcome* and ethic* were used to search the databases. Two reviewers independently conducted title and abstract screening before full-text screening to determine eligibility. The review was supplemented by the SPIRIT-PRO Extension recommendations for trial protocol. Subsequently, a 2-round international Delphi process (n = 96 participants; May and August 2021) and a consensus meeting (n = 25 international participants; October 2021) were held. Prior to voting, consensus meeting participants were provided with a summary of the Delphi process results and information on whether the items aligned with existing ethical guidance.Findings: Twenty-three items were considered in the first round of the Delphi process: 6 relevant candidate items from the systematic review and 17 additional items drawn from the SPIRIT-PRO Extension. Ninety-six international participants voted on the relevant importance of each item for inclusion in ethical guidelines and 12 additional items were recommended for inclusion in round 2 of the Delphi (35 items in total). Fourteen items were recommended for inclusion at the consensus meeting (n = 25 participants). The final wording of the PRO ethical guidelines was agreed on by consensus meeting participants with input from 6 additional individuals. Included items focused on PRO-specific ethical issues relating to research rationale, objectives, eligibility requirements, PRO concepts and domains, PRO assessment schedules, sample size, PRO data monitoring, barriers to PRO completion, participant acceptability and burden, administration of PRO questionnaires for participants who are unable to self-report PRO data, input on PRO strategy by patient partners or members of the public, avoiding missing data, and dissemination plans.Conclusions and Relevance: The PRO ethics guidelines provide recommendations for ethical issues that should be addressed in PRO clinical research. Addressing ethical issues of PRO clinical research has the potential to ensure high-quality PRO data while minimizing participant risk, burden, and harm and protecting participant and researcher welfare. [ABSTRACT FROM AUTHOR]

Importance: Out-of-hospital cardiac arrest (OHCA) has poor outcome. Whether intra-arrest transport, extracorporeal cardiopulmonary resuscitation (ECPR), and immediate invasive assessment and treatment (invasive strategy) is beneficial in this setting remains uncertain.Objective: To determine whether an early invasive approach in adults with refractory OHCA improves neurologically favorable survival.Design, Setting, and Participants: Single-center, randomized clinical trial in Prague, Czech Republic, of adults with a witnessed OHCA of presumed cardiac origin without return of spontaneous circulation. A total of 256 participants, of a planned sample size of 285, were enrolled between March 2013 and October 2020. Patients were observed until death or day 180 (last patient follow-up ended on March 30, 2021).Interventions: In the invasive strategy group (n = 124), mechanical compression was initiated, followed by intra-arrest transport to a cardiac center for ECPR and immediate invasive assessment and treatment. Regular advanced cardiac life support was continued on-site in the standard strategy group (n = 132).Main Outcomes and Measures: The primary outcome was survival with a good neurologic outcome (defined as Cerebral Performance Category [CPC] 1-2) at 180 days after randomization. Secondary outcomes included neurologic recovery at 30 days (defined as CPC 1-2 at any time within the first 30 days) and cardiac recovery at 30 days (defined as no need for pharmacological or mechanical cardiac support for at least 24 hours).Results: The trial was stopped at the recommendation of the data and safety monitoring board when prespecified criteria for futility were met. Among 256 patients (median age, 58 years; 44 [17%] women), 256 (100%) completed the trial. In the main analysis, 39 patients (31.5%) in the invasive strategy group and 29 (22.0%) in the standard strategy group survived to 180 days with good neurologic outcome (odds ratio [OR], 1.63 [95% CI, 0.93 to 2.85]; difference, 9.5% [95% CI, -1.3% to 20.1%]; P = .09). At 30 days, neurologic recovery had occurred in 38 patients (30.6%) in the invasive strategy group and in 24 (18.2%) in the standard strategy group (OR, 1.99 [95% CI, 1.11 to 3.57]; difference, 12.4% [95% CI, 1.9% to 22.7%]; P = .02), and cardiac recovery had occurred in 54 (43.5%) and 45 (34.1%) patients, respectively (OR, 1.49 [95% CI, 0.91 to 2.47]; difference, 9.4% [95% CI, -2.5% to 21%]; P = .12). Bleeding occurred more frequently in the invasive strategy vs standard strategy group (31% vs 15%, respectively).Conclusions and Relevance: Among patients with refractory out-of-hospital cardiac arrest, the bundle of early intra-arrest transport, ECPR, and invasive assessment and treatment did not significantly improve survival with neurologically favorable outcome at 180 days compared with standard resuscitation. However, the trial was possibly underpowered to detect a clinically relevant difference.Trial Registration: ClinicalTrials.gov Identifier: NCT01511666. [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: Implementation of guideline-recommended depression screening in medical oncology remains challenging. Evidence suggests that multicomponent care pathways with algorithm-based referral and management are effective, yet implementation of sustainable programs remains limited and implementation-science guided approaches are understudied.Objective: To evaluate the effectiveness of an implementation-strategy guided depression screening program for patients with breast cancer in a community setting.Design, Setting, and Participants: A pragmatic cluster randomized clinical trial conducted within Kaiser Permanente Southern California (KPSC). The trial included 6 medical centers and 1436 patients diagnosed with new primary breast cancer who had a consultation with medical oncology between October 1, 2017, through September 30, 2018. Patients were followed up through study end date of May 31, 2019.Interventions: Six medical centers in Southern California participated and were randomized 1:1 to tailored implementation strategies (intervention, 3 sites, n = 744 patients) or education-only (control, 3 sites, n = 692 patients) groups. The program consisted of screening with the 9-item Patient Health Questionnaire (PHQ-9) and algorithm-based scoring and referral to behavioral health services based on low, moderate, or high score. Clinical teams at tailored intervention sites received program education, audit, and feedback of performance data and implementation facilitation, and clinical workflows were adapted to suit local context. Education-only controls sites received program education.Main Outcomes and Measures: The primary outcome was percent of eligible patients screened and referred (based on PHQ-9 score) at intervention vs control groups measured at the patient level. Secondary outcomes included outpatient health care utilization for behavioral health, primary care, oncology, urgent care, and emergency department.Results: All 1436 eligible patients were randomized at the center level (mean age, 61.5 years; 99% women; 18% Asian, 17% Black, 26% Hispanic, and 37% White) and were followed up to the end of the study, insurance disenrollment, or death. Groups were similar in demographic and tumor characteristics. For the primary outcome, 7.9% (59 of 744) of patients at tailored sites were referred compared with 0.1% (1 of 692) at education-only sites (difference, 7.8%; 95% CI, 5.8%-9.8%). Referrals to a behavioral health clinician were completed by 44 of 59 patients treated at the intervention sites (75%) intervention sites vs 1 of 1 patient at the education-only sites (100%). In adjusted models patients at tailored sites had significantly fewer outpatient visits in medical oncology (rate ratio, 0.86; 95% CI, 0.86-0.89; P = .001), and no significant difference in utilization of primary care, urgent care, and emergency department visits.Conclusions and Relevance: Among patients with breast cancer treated in community-based oncology practices, tailored strategies for implementation of routine depression screening compared with an education-only control group resulted in a greater proportion of referrals to behavioral care. Further research is needed to understand the clinical benefit and cost-effectiveness of this program.Trial Registration: ClinicalTrials.gov Identifier: NCT02941614. [ABSTRACT FROM AUTHOR]

Although OSA is common in both settings and is associated with worse clinical outcomes, the benefit of screening for and treatment of OSA in these settings remains to be demonstrated. The objective of the updated systematic review was to "review the evidence on screening for OSA in asymptomatic adults or those with unrecognized OSA symptoms...."[8] For the truly asymptomatic patient, the USPSTF recommendation is sensible, even for most patients with known cardiovascular illness. However, while much remains to be learned about the potential benefits of screening for asymptomatic OSA, this should not deter clinicians from identifying and appropriately managing the care of the many symptomatic patients whose OSA symptoms are currently unrecognized. [Extracted from the article]

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]

Clinical preventive service recommendations from the US Preventive Services Task Force (USPSTF) are based on transparent, systematic, and rigorous methods that consider the certainty of the evidence and magnitude of net benefit. These guidelines aim to address the needs of diverse populations. Biological sex and gender identity are sources of diversity that are not often considered in studies of clinical preventive services that inform the recommendations, resulting in challenges when evaluating the evidence and communicating recommendations for persons in specific gender identification categories (man/woman/gender nonbinary/gender nonconforming/transgender). To advance its methods, the USPSTF reviewed its past recommendations that included the use of sex and gender terms, reviewed the approaches of other guideline-making bodies, and pilot tested strategies to address sex and gender diversity. Based on the findings, the USPSTF intends to use an inclusive approach to identify issues related to sex and gender at the start of the guideline development process; assess the applicability, variability, and quality of evidence as a function of sex and gender; ensure clarity in the use of language regarding sex and gender; and identify evidence gaps related to sex and gender. Evidence reviews will identify the limitations of applying findings to diverse groups from underlying studies that used unclear terminology regarding sex and gender. The USPSTF will use gender-neutral language when appropriate to communicate that recommendations are inclusive of people of any gender and will clearly state when recommendations apply to individuals with specific anatomy associated with biological sex (male/female) or to specific categories of gender identity. The USPSTF recognizes limited evidence to inform the preventive care of populations based on gender identity. [ABSTRACT FROM AUTHOR]

Importance: The optimal dose and duration of oral amoxicillin for children with community-acquired pneumonia (CAP) are unclear.Objective: To determine whether lower-dose amoxicillin is noninferior to higher dose and whether 3-day treatment is noninferior to 7 days.Design, Setting, and Participants: Multicenter, randomized, 2 × 2 factorial noninferiority trial enrolling 824 children, aged 6 months and older, with clinically diagnosed CAP, treated with amoxicillin on discharge from emergency departments and inpatient wards of 28 hospitals in the UK and 1 in Ireland between February 2017 and April 2019, with last trial visit on May 21, 2019.Interventions: Children were randomized 1:1 to receive oral amoxicillin at a lower dose (35-50 mg/kg/d; n = 410) or higher dose (70-90 mg/kg/d; n = 404), for a shorter duration (3 days; n = 413) or a longer duration (7 days; n = 401).Main Outcomes and Measures: The primary outcome was clinically indicated antibiotic re-treatment for respiratory infection within 28 days after randomization. The noninferiority margin was 8%. Secondary outcomes included severity/duration of 9 parent-reported CAP symptoms, 3 antibiotic-related adverse events, and phenotypic resistance in colonizing Streptococcus pneumoniae isolates.Results: Of 824 participants randomized into 1 of the 4 groups, 814 received at least 1 dose of trial medication (median [IQR] age, 2.5 years [1.6-2.7]; 421 [52%] males and 393 [48%] females), and the primary outcome was available for 789 (97%). For lower vs higher dose, the primary outcome occurred in 12.6% with lower dose vs 12.4% with higher dose (difference, 0.2% [1-sided 95% CI -∞ to 4.0%]), and in 12.5% with 3-day treatment vs 12.5% with 7-day treatment (difference, 0.1% [1-sided 95% CI -∞ to 3.9]). Both groups demonstrated noninferiority with no significant interaction between dose and duration (P = .63). Of the 14 prespecified secondary end points, the only significant differences were 3-day vs 7-day treatment for cough duration (median 12 days vs 10 days; hazard ratio [HR], 1.2 [95% CI, 1.0 to 1.4]; P = .04) and sleep disturbed by cough (median, 4 days vs 4 days; HR, 1.2 [95% CI, 1.0 to 1.4]; P = .03). Among the subgroup of children with severe CAP, the primary end point occurred in 17.3% of lower-dose recipients vs 13.5% of higher-dose recipients (difference, 3.8% [1-sided 95% CI, -∞ to10%]; P value for interaction = .18) and in 16.0% with 3-day treatment vs 14.8% with 7-day treatment (difference, 1.2% [1-sided 95% CI, -∞ to 7.4%]; P value for interaction = .73).Conclusions and Relevance: Among children with CAP discharged from an emergency department or hospital ward (within 48 hours), lower-dose outpatient oral amoxicillin was noninferior to higher dose, and 3-day duration was noninferior to 7 days, with regard to need for antibiotic re-treatment. However, disease severity, treatment setting, prior antibiotics received, and acceptability of the noninferiority margin require consideration when interpreting the findings.Trial Registration: ISRCTN Identifier: ISRCTN76888927. [ABSTRACT FROM AUTHOR]

Importance: Eosinophilic esophagitis (EoE) is a chronic immune-mediated inflammatory disease of the esophagus that affects an estimated 34.4/100 000 people in Europe and North America. EoE affects both children and adults, and causes dysphagia, food impaction of the esophagus, and esophageal strictures.Observations: EoE is defined by symptoms of esophageal dysfunction, such as vomiting, dysphagia, or feeding difficulties, in a patient with an esophageal biopsy demonstrating at least 15 eosinophils per high-power field in the absence of other conditions associated with esophageal eosinophilia such as gastroesophageal reflux disease or achalasia. Genetic factors and environmental factors, such as exposure to antibiotics early in life, are associated with EoE. Current therapies include proton pump inhibitors; topical steroid preparations, such as fluticasone and budesonide; dietary therapy with amino acid formula or empirical food elimination; and endoscopic dilation. In a systematic review of observational studies that included 1051 patients with EoE, proton pump inhibitor therapy was associated with a histologic response, defined as less than 15 eosinophils per high-power field on endoscopic biopsy, in 41.7% of patients, while placebo was associated with a 13.3% response rate. In a systematic review of 8 randomized trials of 437 patients with EoE, topical corticosteroid treatment was associated with histologic remission in 64.9% of patients compared with 13.3% for placebo. Patients with esophageal narrowing may require dilation. Objective assessment of therapeutic response typically requires endoscopy with biopsy.Conclusions and Relevance: EoE has a prevalence of approximately 34.4/100 000 worldwide. Treatments consist of proton pump inhibitors, topical steroids, elemental diet, and empirical food elimination, with esophageal dilation reserved for patients with symptomatic esophageal narrowing. [ABSTRACT FROM AUTHOR]

Importance: Hyperoxemia may increase organ dysfunction in critically ill patients, but optimal oxygenation targets are unknown.Objective: To determine whether a low-normal Pao2 target compared with a high-normal target reduces organ dysfunction in critically ill patients with systemic inflammatory response syndrome (SIRS).Design, Setting, and Participants: Multicenter randomized clinical trial in 4 intensive care units in the Netherlands. Enrollment was from February 2015 to October 2018, with end of follow-up to January 2019, and included adult patients admitted with 2 or more SIRS criteria and expected stay of longer than 48 hours. A total of 9925 patients were screened for eligibility, of whom 574 fulfilled the enrollment criteria and were randomized.Interventions: Target Pao2 ranges were 8 to 12 kPa (low-normal, n = 205) and 14 to 18 kPa (high-normal, n = 195). An inspired oxygen fraction greater than 0.60 was applied only when clinically indicated.Main Outcomes and Measures: Primary end point was SOFARANK, a ranked outcome of nonrespiratory organ failure quantified by the nonrespiratory components of the Sequential Organ Failure Assessment (SOFA) score, summed over the first 14 study days. Participants were ranked from fastest organ failure improvement (lowest scores) to worsening organ failure or death (highest scores). Secondary end points were duration of mechanical ventilation, in-hospital mortality, and hypoxemic measurements.Results: Among the 574 patients who were randomized, 400 (70%) were enrolled within 24 hours (median age, 68 years; 140 women [35%]), all of whom completed the trial. The median Pao2 difference between the groups was -1.93 kPa (95% CI, -2.12 to -1.74; P < .001). The median SOFARANK score was -35 points in the low-normal Pao2 group vs -40 in the high-normal Pao2 group (median difference, 10 [95% CI, 0 to 21]; P = .06). There was no significant difference in median duration of mechanical ventilation (3.4 vs 3.1 days; median difference, -0.15 [95% CI, -0.88 to 0.47]; P = .59) and in-hospital mortality (32% vs 31%; odds ratio, 1.04 [95% CI, 0.67 to 1.63]; P = .91). Mild hypoxemic measurements occurred more often in the low-normal group (1.9% vs 1.2%; median difference, 0.73 [95% CI, 0.30 to 1.20]; P < .001). Acute kidney failure developed in 20 patients (10%) in the low-normal Pao2 group and 21 patients (11%) in the high-normal Pao2 group, and acute myocardial infarction in 6 patients (2.9%) in the low-normal Pao2 group and 7 patients (3.6%) in the high-normal Pao2 group.Conclusions and Relevance: Among critically ill patients with 2 or more SIRS criteria, treatment with a low-normal Pao2 target compared with a high-normal Pao2 target did not result in a statistically significant reduction in organ dysfunction. However, the study may have had limited power to detect a smaller treatment effect than was hypothesized.Trial Registration: ClinicalTrials.gov Identifier: NCT02321072. [ABSTRACT FROM AUTHOR]

This Medical News feature explores the past and present of proteomics. [ABSTRACT FROM AUTHOR]