Journal: JAMA

Sorted by: date / impact
Abstract

Ethical Considerations for the Inclusion of Patient-Reported Outcomes in Clinical Research: The PRO Ethics Guidelines.

Cruz Rivera S, Aiyegbusi OL, Ives J, Draper H, ... Yap C, Calvert MJ
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.



JAMA: 17 May 2022; 327:1910-1919
Cruz Rivera S, Aiyegbusi OL, Ives J, Draper H, ... Yap C, Calvert MJ
JAMA: 17 May 2022; 327:1910-1919 | PMID: 35579638
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Impact:
Abstract

Effect of Transcatheter Aortic Valve Implantation vs Surgical Aortic Valve Replacement on All-Cause Mortality in Patients With Aortic Stenosis: A Randomized Clinical Trial.

UK TAVI Trial Investigators, Toff WD, Hildick-Smith D, Kovac J, ... Gunning MG, Ridley PD
Importance
Transcatheter aortic valve implantation (TAVI) is a less invasive alternative to surgical aortic valve replacement and is the treatment of choice for patients at high operative risk. The role of TAVI in patients at lower risk is unclear.
Objective
To determine whether TAVI is noninferior to surgery in patients at moderately increased operative risk.
Design, setting, and participants
In this randomized clinical trial conducted at 34 UK centers, 913 patients aged 70 years or older with severe, symptomatic aortic stenosis and moderately increased operative risk due to age or comorbidity were enrolled between April 2014 and April 2018 and followed up through April 2019.
Interventions
TAVI using any valve with a CE mark (indicating conformity of the valve with all legal and safety requirements for sale throughout the European Economic Area) and any access route (n = 458) or surgical aortic valve replacement (surgery; n = 455).
Main outcomes and measures
The primary outcome was all-cause mortality at 1 year. The primary hypothesis was that TAVI was noninferior to surgery, with a noninferiority margin of 5% for the upper limit of the 1-sided 97.5% CI for the absolute between-group difference in mortality. There were 36 secondary outcomes (30 reported herein), including duration of hospital stay, major bleeding events, vascular complications, conduction disturbance requiring pacemaker implantation, and aortic regurgitation.
Results
Among 913 patients randomized (median age, 81 years [IQR, 78 to 84 years]; 424 [46%] were female; median Society of Thoracic Surgeons mortality risk score, 2.6% [IQR, 2.0% to 3.4%]), 912 (99.9%) completed follow-up and were included in the noninferiority analysis. At 1 year, there were 21 deaths (4.6%) in the TAVI group and 30 deaths (6.6%) in the surgery group, with an adjusted absolute risk difference of -2.0% (1-sided 97.5% CI, -∞ to 1.2%; P < .001 for noninferiority). Of 30 prespecified secondary outcomes reported herein, 24 showed no significant difference at 1 year. TAVI was associated with significantly shorter postprocedural hospitalization (median of 3 days [IQR, 2 to 5 days] vs 8 days [IQR, 6 to 13 days] in the surgery group). At 1 year, there were significantly fewer major bleeding events after TAVI compared with surgery (7.2% vs 20.2%, respectively; adjusted hazard ratio [HR], 0.33 [95% CI, 0.24 to 0.45]) but significantly more vascular complications (10.3% vs 2.4%; adjusted HR, 4.42 [95% CI, 2.54 to 7.71]), conduction disturbances requiring pacemaker implantation (14.2% vs 7.3%; adjusted HR, 2.05 [95% CI, 1.43 to 2.94]), and mild (38.3% vs 11.7%) or moderate (2.3% vs 0.6%) aortic regurgitation (adjusted odds ratio for mild, moderate, or severe [no instance of severe reported] aortic regurgitation combined vs none, 4.89 [95% CI, 3.08 to 7.75]).

Conclusions:
and relevance
Among patients aged 70 years or older with severe, symptomatic aortic stenosis and moderately increased operative risk, TAVI was noninferior to surgery with respect to all-cause mortality at 1 year.
Trial registration
isrctn.com Identifier: ISRCTN57819173.



JAMA: 17 May 2022; 327:1875-1887
UK TAVI Trial Investigators, Toff WD, Hildick-Smith D, Kovac J, ... Gunning MG, Ridley PD
JAMA: 17 May 2022; 327:1875-1887 | PMID: 35579641
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Impact:
Abstract

Effect of Oral Methylprednisolone on Decline in Kidney Function or Kidney Failure in Patients With IgA Nephropathy: The TESTING Randomized Clinical Trial.

Lv J, Wong MG, Hladunewich MA, Jha V, ... Perkovic V, TESTING Study Group
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.



JAMA: 17 May 2022; 327:1888-1898
Lv J, Wong MG, Hladunewich MA, Jha V, ... Perkovic V, TESTING Study Group
JAMA: 17 May 2022; 327:1888-1898 | PMID: 35579642
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Impact:
Abstract

Effect of Awake Prone Positioning on Endotracheal Intubation in Patients With COVID-19 and Acute Respiratory Failure: A Randomized Clinical Trial.

Alhazzani W, Parhar KKS, Weatherald J, Al Duhailib Z, ... Arabi YM, COVI-PRONE Trial Investigators and the Saudi Critical Care Trials Group
Importance
The efficacy and safety of prone positioning is unclear in nonintubated patients with acute hypoxemia and COVID-19.
Objective
To evaluate the efficacy and adverse events of prone positioning in nonintubated adult patients with acute hypoxemia and COVID-19.
Design, setting, and participants
Pragmatic, unblinded randomized clinical trial conducted at 21 hospitals in Canada, Kuwait, Saudi Arabia, and the US. Eligible adult patients with COVID-19 were not intubated and required oxygen (≥40%) or noninvasive ventilation. A total of 400 patients were enrolled between May 19, 2020, and May 18, 2021, and final follow-up was completed in July 2021.
Intervention
Patients were randomized to awake prone positioning (n = 205) or usual care without prone positioning (control; n = 195).
Main outcomes and measures
The primary outcome was endotracheal intubation within 30 days of randomization. The secondary outcomes included mortality at 60 days, days free from invasive mechanical ventilation or noninvasive ventilation at 30 days, days free from the intensive care unit or hospital at 60 days, adverse events, and serious adverse events.
Results
Among the 400 patients who were randomized (mean age, 57.6 years [SD, 12.83 years]; 117 [29.3%] were women), all (100%) completed the trial. In the first 4 days after randomization, the median duration of prone positioning was 4.8 h/d (IQR, 1.8 to 8.0 h/d) in the awake prone positioning group vs 0 h/d (IQR, 0 to 0 h/d) in the control group. By day 30, 70 of 205 patients (34.1%) in the prone positioning group were intubated vs 79 of 195 patients (40.5%) in the control group (hazard ratio, 0.81 [95% CI, 0.59 to 1.12], P = .20; absolute difference, -6.37% [95% CI, -15.83% to 3.10%]). Prone positioning did not significantly reduce mortality at 60 days (hazard ratio, 0.93 [95% CI, 0.62 to 1.40], P = .54; absolute difference, -1.15% [95% CI, -9.40% to 7.10%]) and had no significant effect on days free from invasive mechanical ventilation or noninvasive ventilation at 30 days or on days free from the intensive care unit or hospital at 60 days. There were no serious adverse events in either group. In the awake prone positioning group, 21 patients (10%) experienced adverse events and the most frequently reported were musculoskeletal pain or discomfort from prone positioning (13 of 205 patients [6.34%]) and desaturation (2 of 205 patients [0.98%]). There were no reported adverse events in the control group.

Conclusions:
and relevance
In patients with acute hypoxemic respiratory failure from COVID-19, prone positioning, compared with usual care without prone positioning, did not significantly reduce endotracheal intubation at 30 days. However, the effect size for the primary study outcome was imprecise and does not exclude a clinically important benefit.
Trial registration
ClinicalTrials.gov Identifier: NCT04350723.



JAMA: 15 May 2022; epub ahead of print
Alhazzani W, Parhar KKS, Weatherald J, Al Duhailib Z, ... Arabi YM, COVI-PRONE Trial Investigators and the Saudi Critical Care Trials Group
JAMA: 15 May 2022; epub ahead of print | PMID: 35569448
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Impact:
Abstract

Effect of Robot-Assisted Radical Cystectomy With Intracorporeal Urinary Diversion vs Open Radical Cystectomy on 90-Day Morbidity and Mortality Among Patients With Bladder Cancer: A Randomized Clinical Trial.

Catto JWF, Khetrapal P, Ricciardi F, Ambler G, ... Kelly JD, iROC Study Team
Importance
Robot-assisted radical cystectomy is being performed with increasing frequency, but it is unclear whether total intracorporeal surgery improves recovery compared with open radical cystectomy for bladder cancer.
Objectives
To compare recovery and morbidity after robot-assisted radical cystectomy with intracorporeal reconstruction vs open radical cystectomy.
Design, setting, and participants
Randomized clinical trial of patients with nonmetastatic bladder cancer recruited at 9 sites in the UK, from March 2017-March 2020. Follow-up was conducted at 90 days, 6 months, and 12 months, with final follow-up on September 23, 2021.
Interventions
Participants were randomized to receive robot-assisted radical cystectomy with intracorporeal reconstruction (n = 169) or open radical cystectomy (n = 169).
Main outcomes and measures
The primary outcome was the number of days alive and out of the hospital within 90 days of surgery. There were 20 secondary outcomes, including complications, quality of life, disability, stamina, activity levels, and survival. Analyses were adjusted for the type of diversion and center.
Results
Among 338 randomized participants, 317 underwent radical cystectomy (mean age, 69 years; 67 women [21%]; 107 [34%] received neoadjuvant chemotherapy; 282 [89%] underwent ileal conduit reconstruction); the primary outcome was analyzed in 305 (96%). The median number of days alive and out of the hospital within 90 days of surgery was 82 (IQR, 76-84) for patients undergoing robotic surgery vs 80 (IQR, 72-83) for open surgery (adjusted difference, 2.2 days [95% CI, 0.50-3.85]; P = .01). Thromboembolic complications (1.9% vs 8.3%; difference, -6.5% [95% CI, -11.4% to -1.4%]) and wound complications (5.6% vs 16.0%; difference, -11.7% [95% CI, -18.6% to -4.6%]) were less common with robotic surgery than open surgery. Participants undergoing open surgery reported worse quality of life vs robotic surgery at 5 weeks (difference in mean European Quality of Life 5-Dimension, 5-Level instrument scores, -0.07 [95% CI, -0.11 to -0.03]; P = .003) and greater disability at 5 weeks (difference in World Health Organization Disability Assessment Schedule 2.0 scores, 0.48 [95% CI, 0.15-0.73]; P = .003) and at 12 weeks (difference in WHODAS 2.0 scores, 0.38 [95% CI, 0.09-0.68]; P = .01); the differences were not significant after 12 weeks. There were no statistically significant differences in cancer recurrence (29/161 [18%] vs 25/156 [16%] after robotic and open surgery, respectively) and overall mortality (23/161 [14.3%] vs 23/156 [14.7%]), respectively) at median follow-up of 18.4 months (IQR, 12.8-21.1).

Conclusions:
and relevance
Among patients with nonmetastatic bladder cancer undergoing radical cystectomy, treatment with robot-assisted radical cystectomy with intracorporeal urinary diversion vs open radical cystectomy resulted in a statistically significant increase in days alive and out of the hospital over 90 days. However, the clinical importance of these findings remains uncertain.
Trial registration
ISRCTN Identifier: ISRCTN13680280; ClinicalTrials.gov Identifier: NCT03049410.



JAMA: 15 May 2022; epub ahead of print
Catto JWF, Khetrapal P, Ricciardi F, Ambler G, ... Kelly JD, iROC Study Team
JAMA: 15 May 2022; epub ahead of print | PMID: 35569079
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Impact:
Abstract

Association of Prior BNT162b2 COVID-19 Vaccination With Symptomatic SARS-CoV-2 Infection in Children and Adolescents During Omicron Predominance.

Fleming-Dutra KE, Britton A, Shang N, Derado G, ... Verani JR, Schrag SJ
Importance
Efficacy of 2 doses of the BNT162b2 COVID-19 vaccine (Pfizer-BioNTech) against COVID-19 was high in pediatric trials conducted before the SARS-CoV-2 Omicron variant emerged. Among adults, estimated vaccine effectiveness (VE) of 2 BNT162b2 doses against symptomatic Omicron infection was reduced compared with prior variants, waned rapidly, and increased with a booster.
Objective
To evaluate the association of symptomatic infection with prior vaccination with BNT162b2 to estimate VE among children and adolescents during Omicron variant predominance.
Design, setting, and participants
A test-negative, case-control analysis was conducted using data from 6897 pharmacy-based, drive-through SARS-CoV-2 testing sites across the US from a single pharmacy chain in the Increasing Community Access to Testing platform. This analysis included 74 208 tests from children 5 to 11 years of age and 47 744 tests from adolescents 12 to 15 years of age with COVID-19-like illness who underwent SARS-CoV-2 nucleic acid amplification testing from December 26, 2021, to February 21, 2022.
Exposures
Two BNT162b2 doses 2 weeks or more before SARS-CoV-2 testing vs no vaccination for children; 2 or 3 doses 2 weeks or more before testing vs no vaccination for adolescents (who are recommended to receive a booster dose).
Main outcomes and measures
Symptomatic infection. The adjusted odds ratio (OR) for the association of prior vaccination and symptomatic SARS-CoV-2 infection was used to estimate VE: VE = (1 - OR) × 100%.
Results
A total of 30 999 test-positive cases and 43 209 test-negative controls were included from children 5 to 11 years of age, as well as 22 273 test-positive cases and 25 471 test-negative controls from adolescents 12 to 15 years of age. The median age among those with included tests was 10 years (IQR, 7-13); 61 189 (50.2%) were female, 75 758 (70.1%) were White, and 29 034 (25.7%) were Hispanic/Latino. At 2 to 4 weeks after dose 2, among children, the adjusted OR was 0.40 (95% CI, 0.35-0.45; estimated VE, 60.1% [95% CI, 54.7%-64.8%]) and among adolescents, the OR was 0.40 (95% CI, 0.29-0.56; estimated VE, 59.5% [95% CI, 44.3%-70.6%]). During month 2 after dose 2, among children, the OR was 0.71 (95% CI, 0.67-0.76; estimated VE, 28.9% [95% CI, 24.5%-33.1%]) and among adolescents, the OR was 0.83 (95% CI, 0.76-0.92; estimated VE, 16.6% [95% CI, 8.1%-24.3%]). Among adolescents, the booster dose OR 2 to 6.5 weeks after the dose was 0.29 (95% CI, 0.24-0.35; estimated VE, 71.1% [95% CI, 65.5%-75.7%]).

Conclusions:
and relevance
Among children and adolescents, estimated VE for 2 doses of BNT162b2 against symptomatic infection was modest and decreased rapidly. Among adolescents, the estimated effectiveness increased after a booster dose.



JAMA: 13 May 2022; epub ahead of print
Fleming-Dutra KE, Britton A, Shang N, Derado G, ... Verani JR, Schrag SJ
JAMA: 13 May 2022; epub ahead of print | PMID: 35560036
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Impact:
Abstract

Screening for Chronic Obstructive Pulmonary Disease: US Preventive Services Task Force Reaffirmation Recommendation Statement.

US Preventive Services Task Force, Mangione CM, Barry MJ, Nicholson WK, ... Tseng CW, Wong JB
Importance
Chronic obstructive pulmonary disease (COPD) is an irreversible reduction of airflow in the lungs. Progression to severe disease can prevent participation in normal activities because of deterioration of lung function. In 2020 it was estimated that approximately 6% of US adults had been diagnosed with COPD. Chronic lower respiratory disease, composed mainly of COPD, is the sixth leading cause of death in the US.
Objective
To update its 2016 recommendation, the US Preventive Services Task Force (USPSTF) commissioned a reaffirmation evidence update that focused on targeted key questions for benefits and harms of screening for COPD in asymptomatic adults and treatment in screen-detected or screen-relevant adults.
Population
Asymptomatic adults who do not recognize or report respiratory symptoms.
Evidence assessment
Using a reaffirmation process, the USPSTF concludes with moderate certainty that screening for COPD in asymptomatic adults has no net benefit.
Recommendation
The USPSTF recommends against screening for COPD in asymptomatic adults. (D recommendation).



JAMA: 10 May 2022; 327:1806-1811
US Preventive Services Task Force, Mangione CM, Barry MJ, Nicholson WK, ... Tseng CW, Wong JB
JAMA: 10 May 2022; 327:1806-1811 | PMID: 35536260
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Impact:
Abstract

Screening for Chronic Obstructive Pulmonary Disease: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.

Webber EM, Lin JS, Thomas RG
Importance
Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality in the US.
Objective
To conduct a targeted systematic review to update the evidence on the effectiveness of screening for COPD and the treatment of COPD to inform the US Preventive Services Task Force (USPSTF) update of the 2016 recommendation statement on COPD screening.
Data sources
MEDLINE, the Cochrane Central Register of Controlled Trials, and CINAHL for relevant studies published between January 1, 2015, to January 22, 2021; surveillance through March 25, 2022.
Study selection
English-language studies of screening in individuals who do not recognize or report respiratory symptoms; studies of treatment in persons with mild or moderate, or minimally symptomatic, COPD.
Data extraction and synthesis
Two reviewers independently appraised the articles and extracted relevant data from fair- or good-quality studies; no quantitative synthesis was conducted.
Main outcomes and measures
COPD-related morbidity or mortality, measures of health-related quality of life, and adverse events.
Results
The review included no trials on the effectiveness of screening, 3 trials or analyses (n = 20 058) of pharmacologic treatment published since 2015, 13 trials (n = 3657) on nonpharmacologic interventions, and 2 large observational studies (n = 243 517) addressing the harms of pharmacologic treatment published since 2015. The results from the clinical trials of pharmacologic therapy are consistent with the previous review supporting the USPSTF that bronchodilators with or without inhaled corticosteroids can reduce COPD exacerbations and tiotropium can improve health-related quality of life in adults with moderate COPD. Overall, there was no consistent benefit observed for any type of nonpharmacologic intervention across a range of patient outcomes. None of the included treatment trials that reported adverse effects found significant harms. Two large observational studies in a screen-relevant population demonstrated an association of the initiation of a long-acting muscarinic antagonist or long-acting beta agonist with the risk of a serious cardiovascular event in treatment-naïve patients and an association of inhaled corticosteroids use with the risk of developing diabetes.

Conclusions:
and relevance
The findings of this targeted evidence update are generally consistent with the findings of the previous systematic review supporting the 2016 USPSTF recommendation. Evidence of pharmacologic treatment was still largely limited to persons with moderate airflow obstruction, and there was no consistent benefit observed for a range of nonpharmacologic interventions in mild to moderate COPD or in minimally symptomatic persons with COPD.



JAMA: 10 May 2022; 327:1812-1816
Webber EM, Lin JS, Thomas RG
JAMA: 10 May 2022; 327:1812-1816 | PMID: 35536261
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Impact:
Abstract

Association Between Use of a Flying Intervention Team vs Patient Interhospital Transfer and Time to Endovascular Thrombectomy Among Patients With Acute Ischemic Stroke in Nonurban Germany.

Hubert GJ, Hubert ND, Maegerlein C, Kraus F, ... Audebert HJ, Haberl RL
Importance
The benefit of endovascular thrombectomy (EVT) for acute ischemic stroke is highly time-dependent, and it is challenging to expedite treatment for patients in remote areas.
Objective
To determine whether deployment of a flying intervention team, compared with patient interhospital transfer, is associated with a shorter time to endovascular thrombectomy and improved clinical outcomes for patients with acute ischemic stroke.
Design, setting, and participants
This was a nonrandomized controlled intervention study comparing 2 systems of care in alternating weeks. The study was conducted in a nonurban region in Germany including 13 primary telemedicine-assisted stroke centers within a telestroke network. A total of 157 patients with acute ischemic stroke for whom decision to pursue thrombectomy had been made and deployment of flying intervention team or patient interhospital transfer was initiated were enrolled between February 1, 2018, and October 24, 2019. The date of final follow-up was January 31, 2020.
Exposures
Deployment of a flying intervention team for EVT in a primary stroke center vs patient interhospital transfer for EVT to a referral center.
Main outcomes and measures
The primary outcome was time delay from decision to pursue thrombectomy to start of the procedure in minutes. Secondary outcomes included functional outcome after 3 months, determined by the distribution of the modified Rankin Scale score (a disability score ranging from 0 [no deficit] to 6 [death]).
Results
Among the 157 patients included (median [IQR] age, 75 [66-80] y; 80 [51%] women), 72 received flying team care and 85 were transferred. EVT was performed in 60 patients (83%) in the flying team group vs 57 (67%) in the transfer group. Median (IQR) time from decision to pursue EVT to start of the procedure was 58 (51-71) minutes in the flying team group and 148 (124-177) minutes in the transfer group (difference, 90 minutes [95% CI, 75-103]; P < .001). There was no significant difference in modified Rankin Scale score after 3 months between patients in the flying team (n = 59) and transfer (n = 57) groups who received EVT (median [IQR] score, 3 [2-6] vs 3 [2-5]; adjusted common odds ratio for less disability, 1.91 [95% CI, 0.96-3.88]; P = .07).

Conclusions:
and relevance
In a nonurban stroke network in Germany, deployment of a flying intervention team to local stroke centers, compared with patient interhospital transfer to referral centers, was significantly associated with shorter time to EVT for patients with acute ischemic stroke. The findings may support consideration of a flying intervention team for some stroke systems of care, although further research is needed to confirm long-term clinical outcomes and to understand applicability to other geographic settings.



JAMA: 05 May 2022; epub ahead of print
Hubert GJ, Hubert ND, Maegerlein C, Kraus F, ... Audebert HJ, Haberl RL
JAMA: 05 May 2022; epub ahead of print | PMID: 35510389
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Impact:
Abstract

Effect of Direct Transportation to Thrombectomy-Capable Center vs Local Stroke Center on Neurological Outcomes in Patients With Suspected Large-Vessel Occlusion Stroke in Nonurban Areas: The RACECAT Randomized Clinical Trial.

Pérez de la Ossa N, Abilleira S, Jovin TG, García-Tornel Á, ... Ribo M, RACECAT Trial Investigators
Importance
In nonurban areas with limited access to thrombectomy-capable centers, optimal prehospital transport strategies in patients with suspected large-vessel occlusion stroke are unknown.
Objective
To determine whether, in nonurban areas, direct transport to a thrombectomy-capable center is beneficial compared with transport to the closest local stroke center.
Design, setting, and participants
Multicenter, population-based, cluster-randomized trial including 1401 patients with suspected acute large-vessel occlusion stroke attended by emergency medical services in areas where the closest local stroke center was not capable of performing thrombectomy in Catalonia, Spain, between March 2017 and June 2020. The date of final follow-up was September 2020.
Interventions
Transportation to a thrombectomy-capable center (n = 688) or the closest local stroke center (n = 713).
Main outcomes and measures
The primary outcome was disability at 90 days based on the modified Rankin Scale (mRS; scores range from 0 [no symptoms] to 6 [death]) in the target population of patients with ischemic stroke. There were 11 secondary outcomes, including rate of intravenous tissue plasminogen activator administration and thrombectomy in the target population and 90-day mortality in the safety population of all randomized patients.
Results
Enrollment was halted for futility following a second interim analysis. The 1401 enrolled patients were included in the safety analysis, of whom 1369 (98%) consented to participate and were included in the as-randomized analysis (56% men; median age, 75 [IQR, 65-83] years; median National Institutes of Health Stroke Scale score, 17 [IQR, 11-21]); 949 (69%) comprised the target ischemic stroke population included in the primary analysis. For the primary outcome in the target population, median mRS score was 3 (IQR, 2-5) vs 3 (IQR, 2-5) (adjusted common odds ratio [OR], 1.03; 95% CI, 0.82-1.29). Of 11 reported secondary outcomes, 8 showed no significant difference. Compared with patients first transported to local stroke centers, patients directly transported to thrombectomy-capable centers had significantly lower odds of receiving intravenous tissue plasminogen activator (in the target population, 229/482 [47.5%] vs 282/467 [60.4%]; OR, 0.59; 95% CI, 0.45-0.76) and significantly higher odds of receiving thrombectomy (in the target population, 235/482 [48.8%] vs 184/467 [39.4%]; OR, 1.46; 95% CI, 1.13-1.89). Mortality at 90 days in the safety population was not significantly different between groups (188/688 [27.3%] vs 194/713 [27.2%]; adjusted hazard ratio, 0.97; 95% CI, 0.79-1.18).

Conclusions:
and relevance
In nonurban areas in Catalonia, Spain, there was no significant difference in 90-day neurological outcomes between transportation to a local stroke center vs a thrombectomy-capable referral center in patients with suspected large-vessel occlusion stroke. These findings require replication in other settings.
Trial registration
ClinicalTrials.gov Identifier: NCT02795962.



JAMA: 05 May 2022; epub ahead of print
Pérez de la Ossa N, Abilleira S, Jovin TG, García-Tornel Á, ... Ribo M, RACECAT Trial Investigators
JAMA: 05 May 2022; epub ahead of print | PMID: 35510397
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Impact:
Abstract

Effect of Early vs Standard Approach to Tracheostomy on Functional Outcome at 6 Months Among Patients With Severe Stroke Receiving Mechanical Ventilation: The SETPOINT2 Randomized Clinical Trial.

Bösel J, Niesen WD, Salih F, Morris NA, ... Seder DB, SETPOINT2 and the IGNITE Study Groups
Importance
Many patients with severe stroke have impaired airway protective reflexes, resulting in prolonged invasive mechanical ventilation.
Objective
To test whether early vs standard tracheostomy improved functional outcome among patients with stroke receiving mechanical ventilation.
Design, setting, and participants
In this randomized clinical trial, 382 patients with severe acute ischemic or hemorrhagic stroke receiving invasive ventilation were randomly assigned (1:1) to early tracheostomy (≤5 days of intubation) or ongoing ventilator weaning with standard tracheostomy if needed from day 10. Patients were randomized between July 28, 2015, and January 24, 2020, at 26 US and German neurocritical care centers. The final date of follow-up was August 9, 2020.
Interventions
Patients were assigned to an early tracheostomy strategy (n = 188) or to a standard tracheostomy (control group) strategy (n = 194).
Main outcomes and measures
The primary outcome was functional outcome at 6 months, based on the modified Rankin Scale score (range, 0 [best] to 6 [worst]) dichotomized to a score of 0 (no disability) to 4 (moderately severe disability) vs 5 (severe disability) or 6 (death).
Results
Among 382 patients randomized (median age, 59 years; 49.8% women), 366 (95.8%) completed the trial with available follow-up data on the primary outcome (177 patients [94.1%] in the early group; 189 patients [97.4%] in the standard group). A tracheostomy (predominantly percutaneously) was performed in 95.2% of the early tracheostomy group in a median of 4 days after intubation (IQR, 3-4 days) and in 67% of the control group in a median of 11 days after intubation (IQR, 10-12 days). The proportion without severe disability (modified Rankin Scale score, 0-4) at 6 months was not significantly different in the early tracheostomy vs the control group (43.5% vs 47.1%; difference, -3.6% [95% CI, -14.3% to 7.2%]; adjusted odds ratio, 0.93 [95% CI, 0.60-1.42]; P = .73). Of the serious adverse events, 5.0% (6 of 121 reported events) in the early tracheostomy group vs 3.4% (4 of 118 reported events) were related to tracheostomy.

Conclusions:
and relevance
Among patients with severe stroke receiving mechanical ventilation, a strategy of early tracheostomy, compared with a standard approach to tracheostomy, did not significantly improve the rate of survival without severe disability at 6 months. However, the wide confidence intervals around the effect estimate may include a clinically important difference, so a clinically relevant benefit or harm from a strategy of early tracheostomy cannot be excluded.
Trial registration
ClinicalTrials.gov Identifier: NCT02377167.



JAMA: 04 May 2022; epub ahead of print
Bösel J, Niesen WD, Salih F, Morris NA, ... Seder DB, SETPOINT2 and the IGNITE Study Groups
JAMA: 04 May 2022; epub ahead of print | PMID: 35506515
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Impact:
Abstract

Diagnosis and Management of Lumbar Spinal Stenosis: A Review.

Katz JN, Zimmerman ZE, Mass H, Makhni MC
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.



JAMA: 03 May 2022; 327:1688-1699
Katz JN, Zimmerman ZE, Mass H, Makhni MC
JAMA: 03 May 2022; 327:1688-1699 | PMID: 35503342
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Impact:
Abstract

Effect of Self-monitoring of Blood Pressure on Blood Pressure Control in Pregnant Individuals With Chronic or Gestational Hypertension: The BUMP 2 Randomized Clinical Trial.

Chappell LC, Tucker KL, Galal U, Yu LM, ... McManus RJ, BUMP 2 Investigators
Importance
Inadequate management of elevated blood pressure is a significant contributing factor to maternal deaths. The role of blood pressure self-monitoring in pregnancy in improving clinical outcomes for the pregnant individual and infant is unclear.
Objective
To evaluate the effect of blood pressure self-monitoring, compared with usual care alone, on blood pressure control and other related maternal and infant outcomes, in individuals with pregnancy hypertension.
Design, setting, and participants
Unblinded, randomized clinical trial that recruited between November 2018 and September 2019 in 15 hospital maternity units in England. Individuals with chronic hypertension (enrolled up to 37 weeks\' gestation) or with gestational hypertension (enrolled between 20 and 37 weeks\' gestation). Final follow-up was in May 2020.
Interventions
Participants were randomized to either blood pressure self-monitoring using a validated monitor and a secure telemonitoring system in addition to usual care (n = 430) or to usual care alone (n = 420). Usual care comprised blood pressure measured by health care professionals at regular antenatal clinics.
Main outcomes and measures
The primary maternal outcome was the difference in mean systolic blood pressure recorded by health care professionals between randomization and birth.
Results
Among 454 participants with chronic hypertension (mean age, 36 years; mean gestation at entry, 20 weeks) and 396 with gestational hypertension (mean age, 34 years; mean gestation at entry, 33 weeks) who were randomized, primary outcome data were available from 444 (97.8%) and 377 (95.2%), respectively. In the chronic hypertension cohort, there was no statistically significant difference in mean systolic blood pressure for the self-monitoring groups vs the usual care group (133.8 mm Hg vs 133.6 mm Hg, respectively; adjusted mean difference, 0.03 mm Hg [95% CI, -1.73 to 1.79]). In the gestational hypertension cohort, there was also no significant difference in mean systolic blood pressure (137.6 mm Hg compared with 137.2 mm Hg; adjusted mean difference, -0.03 mm Hg [95% CI, -2.29 to 2.24]). There were 8 serious adverse events in the self-monitoring group (4 in each cohort) and 3 in the usual care group (2 in the chronic hypertension cohort and 1 in the gestational hypertension cohort).

Conclusions:
and relevance
Among pregnant individuals with chronic or gestational hypertension, blood pressure self-monitoring with telemonitoring, compared with usual care, did not lead to significantly improved clinic-based blood pressure control.
Trial registration
ClinicalTrials.gov Identifier: NCT03334149.



JAMA: 03 May 2022; 327:1666-1678
Chappell LC, Tucker KL, Galal U, Yu LM, ... McManus RJ, BUMP 2 Investigators
JAMA: 03 May 2022; 327:1666-1678 | PMID: 35503345
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Impact:
Abstract

Effect of Self-monitoring of Blood Pressure on Diagnosis of Hypertension During Higher-Risk Pregnancy: The BUMP 1 Randomized Clinical Trial.

Tucker KL, Mort S, Yu LM, Campbell H, ... McManus RJ, BUMP Investigators
Importance
Inadequate management of elevated blood pressure (BP) is a significant contributing factor to maternal deaths. Self-monitoring of BP in the general population has been shown to improve the diagnosis and management of hypertension; however, little is known about its use in pregnancy.
Objective
To determine whether self-monitoring of BP in higher-risk pregnancies leads to earlier detection of pregnancy hypertension.
Design, setting, and participants
Unblinded, randomized clinical trial that included 2441 pregnant individuals at higher risk of preeclampsia and recruited at a mean of 20 weeks\' gestation from 15 hospital maternity units in England between November 2018 and October 2019. Final follow-up was completed in April 2020.
Interventions
Participating individuals were randomized to either BP self-monitoring with telemonitoring (n = 1223) plus usual care or usual antenatal care alone (n = 1218) without access to telemonitored BP.
Main outcomes and measures
The primary outcome was time to first recorded hypertension measured by a health care professional.
Results
Among 2441 participants who were randomized (mean [SD] age, 33 [5.6] years; mean gestation, 20 [1.6] weeks), 2346 (96%) completed the trial. The time from randomization to clinic recording of hypertension was not significantly different between individuals in the self-monitoring group (mean [SD], 104.3 [32.6] days) vs in the usual care group (mean [SD], 106.2 [32.0] days) (mean difference, -1.6 days [95% CI, -8.1 to 4.9]; P = .64). Eighteen serious adverse events were reported during the trial with none judged as related to the intervention (12 [1%] in the self-monitoring group vs 6 [0.5%] in the usual care group).

Conclusions:
and relevance
Among pregnant individuals at higher risk of preeclampsia, blood pressure self-monitoring with telemonitoring, compared with usual care, did not lead to significantly earlier clinic-based detection of hypertension.
Trial registration
ClinicalTrials.gov Identifier: NCT03334149.



JAMA: 03 May 2022; 327:1656-1665
Tucker KL, Mort S, Yu LM, Campbell H, ... McManus RJ, BUMP Investigators
JAMA: 03 May 2022; 327:1656-1665 | PMID: 35503346
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Impact:
Abstract

Association of SARS-CoV-2 Infection During Pregnancy With Maternal and Perinatal Outcomes.

McClymont E, Albert AY, Alton GD, Boucoiran I, ... Money D, CANCOVID-Preg Team
Importance
There are limited high-quality, population-level data about the effect of SARS-CoV-2 infection on pregnancy using contemporaneous comparator cohorts.
Objectives
To describe maternal and perinatal outcomes associated with SARS-CoV-2 infection in pregnancy and to assess variables associated with severe disease in the pregnant population.
Design, setting, and participants
CANCOVID-Preg is an observational surveillance program for SARS-CoV-2-affected pregnancies in Canada. This analysis presents exploratory, population-level data from 6 Canadian provinces for the period of March 1, 2020, to October 31, 2021. A total of 6012 pregnant persons with a positive SARS-CoV-2 polymerase chain reaction test result at any time in pregnancy (primarily due to symptomatic presentation) were included and compared with 2 contemporaneous groups including age-matched female individuals with SARS-CoV-2 and unaffected pregnant persons from the pandemic time period.
Exposure
SARS-CoV-2 infection during pregnancy. Incident infections in pregnancy were reported to CANCOVID-Preg by participating provinces/territories.
Main outcomes and measures
Maternal and perinatal outcomes associated with SARS-CoV-2 infection as well as risk factors for severe disease (ie, disease requiring hospitalization, admission to an intensive care unit/critical care unit, and/or oxygen therapy).
Results
Among 6012 pregnant individuals with SARS-CoV-2 in Canada (median age, 31 [IQR, 28-35] years), the greatest proportion of cases were diagnosed at 28 to 37 weeks\' gestation (35.7%). Non-White individuals were disproportionately represented. Being pregnant was associated with a significantly increased risk of SARS-CoV-2-related hospitalization compared with SARS-CoV-2 cases among all women aged 20 to 49 years in the general population of Canada (7.75% vs 2.93%; relative risk, 2.65 [95% CI, 2.41-2.88]) as well as an increased risk of intensive care unit/critical care unit admission (2.01% vs 0.37%; relative risk, 5.46 [95% CI, 4.50-6.53]). Increasing age, preexisting hypertension, and greater gestational age at diagnosis were significantly associated with worse maternal outcomes. The risk of preterm birth was significantly elevated among SARS-CoV-2-affected pregnancies (11.05% vs 6.76%; relative risk, 1.63 [95% CI, 1.52-1.76]), even in cases of milder disease not requiring hospitalization, compared with unaffected pregnancies during the same time period.

Conclusions:
and relevance
In this exploratory surveillance study conducted in Canada from March 2020 to October 2021, SARS-CoV-2 infection during pregnancy was significantly associated with increased risk of adverse maternal outcomes and preterm birth.



JAMA: 02 May 2022; epub ahead of print
McClymont E, Albert AY, Alton GD, Boucoiran I, ... Money D, CANCOVID-Preg Team
JAMA: 02 May 2022; epub ahead of print | PMID: 35499852
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Impact:
Abstract

Aspirin Use to Prevent Cardiovascular Disease: US Preventive Services Task Force Recommendation Statement.

US Preventive Services Task Force, Davidson KW, Barry MJ, Mangione CM, ... Tseng CW, Wong JB
Importance
Cardiovascular disease (CVD) is the leading cause of mortality in the US, accounting for more than 1 in 4 deaths. Each year, an estimated 605 000 people in the US have a first myocardial infarction and an estimated 610 000 experience a first stroke.
Objective
To update its 2016 recommendation, the US Preventive Services Task Force (USPSTF) commissioned a systematic review on the effectiveness of aspirin to reduce the risk of CVD events (myocardial infarction and stroke), cardiovascular mortality, and all-cause mortality in persons without a history of CVD. The systematic review also investigated the effect of aspirin use on colorectal cancer (CRC) incidence and mortality in primary CVD prevention populations, as well as the harms (particularly bleeding) associated with aspirin use. The USPSTF also commissioned a microsimulation modeling study to assess the net balance of benefits and harms from aspirin use for primary prevention of CVD and CRC, stratified by age, sex, and CVD risk level.
Population
Adults 40 years or older without signs or symptoms of CVD or known CVD (including history of myocardial infarction or stroke) who are not at increased risk for bleeding (eg, no history of gastrointestinal ulcers, recent bleeding, other medical conditions, or use of medications that increase bleeding risk).
Evidence assessment
The USPSTF concludes with moderate certainty that aspirin use for the primary prevention of CVD events in adults aged 40 to 59 years who have a 10% or greater 10-year CVD risk has a small net benefit. The USPSTF concludes with moderate certainty that initiating aspirin use for the primary prevention of CVD events in adults 60 years or older has no net benefit.
Recommendation
The decision to initiate low-dose aspirin use for the primary prevention of CVD in adults aged 40 to 59 years who have a 10% or greater 10-year CVD risk should be an individual one. Evidence indicates that the net benefit of aspirin use in this group is small. Persons who are not at increased risk for bleeding and are willing to take low-dose aspirin daily are more likely to benefit. (C recommendation) The USPSTF recommends against initiating low-dose aspirin use for the primary prevention of CVD in adults 60 years or older. (D recommendation).



JAMA: 26 Apr 2022; 327:1577-1584
US Preventive Services Task Force, Davidson KW, Barry MJ, Mangione CM, ... Tseng CW, Wong JB
JAMA: 26 Apr 2022; 327:1577-1584 | PMID: 35471505
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Impact:
Abstract

Aspirin Use to Prevent Cardiovascular Disease and Colorectal Cancer: Updated Modeling Study for the US Preventive Services Task Force.

Dehmer SP, O\'Keefe LR, Evans CV, Guirguis-Blake JM, Perdue LA, Maciosek MV
Importance
The US Preventive Services Task Force (USPSTF) is updating its 2016 recommendation on the use of aspirin for the primary prevention of cardiovascular disease (CVD) and colorectal cancer (CRC).
Objective
To provide updated model-based estimates of the net balance in benefits and harms from routine use of low-dose aspirin for primary prevention.
Design, setting, and participants
Microsimulation modeling was used to estimate long-term benefits and harms for hypothetical US cohorts of men and women aged 40 to 79 years with up to 20% 10-year risk for an atherosclerotic CVD event and without prior history of CVD or elevated bleeding risks.
Exposures
Low-dose (≤100 mg/d) aspirin for lifetime use, unless contraindicated by a bleeding event, and with stopping ages in 5-year intervals from age 65 to 85 years.
Main outcomes and measures
Primary outcomes were lifetime net benefits measured in quality-adjusted life-years (QALYs) and life-years. Benefits included reduced nonfatal myocardial infarction and ischemic stroke. Harms included increased nonfatal major gastrointestinal bleeding and intracranial hemorrhage. Reduced CRC incidence was considered in sensitivity analysis.
Results
Estimated lifetime net QALYs were positive for both men and women at 5% or greater 10-year CVD risk when starting between ages 40 and 59 years and at 10% or greater 10-year CVD risk when starting between ages 60 and 69 years. These estimates ranged from 2.3 (95% CI, -2.7 to 7.4) to 66.2 (95% CI, 58.2 to 74.1) QALYs per 1000 persons. Lifetime net life-years were positive for men at 5% or greater and women at 10% or greater 10-year CVD risk starting aspirin at ages 40 to 49 years and for men at 7.5% or greater and women at 15% or greater 10-year CVD risk at ages 50 to 59 years. These estimates ranged from 0.4 (95% CI, -6.1 to 6.9) to 52.4 (95% CI, 43.9 to 60.9) life-years per 1000 persons. Lifetime net life-years were negative in most cases for persons starting aspirin between ages 60 and 79 years, as were lifetime net QALYs for persons aged 70 to 79 years. Stopping aspirin between ages 65 and 85 years generally showed little advantage compared with lifetime use. Sensitivity analyses showed lifetime net benefits may be higher if aspirin reduced CRC incidence or CVD mortality and lower if aspirin increased fatal major gastrointestinal bleeding or reduced quality of life with routine use.

Conclusions:
and relevance
This microsimulation study suggested that several population groups may benefit from taking aspirin for the primary prevention of CVD, primarily in persons starting at younger ages with higher 10-year CVD risk.



JAMA: 26 Apr 2022; 327:1598-1607
Dehmer SP, O'Keefe LR, Evans CV, Guirguis-Blake JM, Perdue LA, Maciosek MV
JAMA: 26 Apr 2022; 327:1598-1607 | PMID: 35471506
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Impact:
Abstract

Aspirin Use to Prevent Cardiovascular Disease and Colorectal Cancer: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.

Guirguis-Blake JM, Evans CV, Perdue LA, Bean SI, Senger CA
Importance
Low-dose aspirin is used for primary cardiovascular disease prevention and may have benefits for colorectal cancer prevention.
Objective
To review the benefits and harms of aspirin in primary cardiovascular disease prevention and colorectal cancer prevention to inform the US Preventive Services Task Force.
Data sources
MEDLINE, PubMed, Embase, and the Cochrane Central Register of Controlled Trials through January 2021; literature surveillance through January 21, 2022.
Study selection
English-language randomized clinical trials (RCTs) of low-dose aspirin (≤100 mg/d) compared with placebo or no intervention in primary prevention populations.
Data extraction and synthesis
Single extraction, verified by a second reviewer. Quantitative synthesis using Peto fixed-effects meta-analysis.
Main outcomes and measures
Cardiovascular disease events and mortality, all-cause mortality, colorectal cancer incidence and mortality, major bleeding, and hemorrhagic stroke.
Results
Eleven RCTs (N = 134 470) and 1 pilot trial (N = 400) of low-dose aspirin for primary cardiovascular disease prevention were included. Low-dose aspirin was associated with a significant decrease in major cardiovascular disease events (odds ratio [OR], 0.90 [95% CI, 0.85-0.95]; 11 RCTs [n = 134 470]; I2 = 0%; range in absolute effects, -2.5% to 0.1%). Results for individual cardiovascular disease outcomes were significant, with similar magnitude of benefit. Aspirin was not significantly associated with reductions in cardiovascular disease mortality or all-cause mortality. There was limited trial evidence on benefits for colorectal cancer, with the findings highly variable by length of follow-up and statistically significant only when considering long-term observational follow-up beyond randomized trial periods. Low-dose aspirin was associated with significant increases in total major bleeding (OR, 1.44 [95% CI, 1.32-1.57]; 10 RCTs [n = 133 194]; I2 = 4.7%; range in absolute effects, 0.1% to 1.0%) and in site-specific bleeding, with similar magnitude.

Conclusions:
and relevance
Low-dose aspirin was associated with small absolute risk reductions in major cardiovascular disease events and small absolute increases in major bleeding. Colorectal cancer results were less robust and highly variable.



JAMA: 26 Apr 2022; 327:1585-1597
Guirguis-Blake JM, Evans CV, Perdue LA, Bean SI, Senger CA
JAMA: 26 Apr 2022; 327:1585-1597 | PMID: 35471507
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Impact:
Abstract

Trends in Prevalence of Cigarette Smoking Among US Adults With Major Depression or Substance Use Disorders, 2006-2019.

Han B, Volkow ND, Blanco C, Tipperman D, Einstein EB, Compton WM
Importance
Tobacco use is highly concentrated in persons with mental illness.
Objectives
To assess trends in past-month prevalence of cigarette smoking among adults with vs without past-year depression, substance use disorders (SUDs), or both, using nationally representative data.
Design, setting, and participants
Exploratory, serial, cross-sectional study based on data from 558 960 individuals aged 18 years or older who participated in the 2006-2019 US National Surveys on Drug Use and Health.
Exposure
Past-year major depressive episode (MDE) and SUD using Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision) criteria.
Main outcomes and measures
Past-month self-reported cigarette use, adjusted for sociodemographic characteristics.
Results
Of the sampled 558 960 adults, 41.4% (unweighted) were aged 18 to 25 years, 29.8% (unweighted) were aged 26 to 49 years, and 53.4% (unweighted) were women. From 2006 to 2019, the past-month self-reported cigarette smoking prevalence declined significantly among adults with MDE from 37.3% to 24.2% for an average annual percent change of -3.2 (95% CI, -3.5 to -2.8; P < .001), adults with SUD from 46.5% to 35.8% for an average annual percent change of -1.7 (95% CI, -2.8 to -0.6; P = .002), and adults with co-occurring MDE and SUD from 50.7% to 37.0% for an annual average annual percent change of -2.1 (95% CI, -3.1 to -1.2; P < .001). The prevalence declined significantly for each examined age, sex, and racial and ethnic subgroup with MDE and with SUD (all P < .05), except for no significant changes in American Indian or Alaska Native adults with MDE (P = .98) or with SUD (P = .46). Differences in prevalence of cigarette smoking between adults with vs without MDE declined significantly for adults overall from 11.5% to 6.6%, for an average annual percent change of -3.4 (95% CI, -4.1 to -2.7; P < .001); significant average annual percent change declines were also seen for men (-5.1 [95% CI, -7.2 to -2.9]; P < .001); for women (-2.7 [95% CI, -3.9 to -1.5]; P < .001); for those aged 18 through 25 years (-5.2 [95% CI, -7.6 to -2.8]; P < .001); for those aged 50 years or older (-4.7 [95% CI, -8.0 to -1.2]; P = .01); for Hispanic individuals (-4.4 [95% CI, -8.0 to -0.5]; P = .03), and for White individuals (-3.6 [95% CI, -4.5 to -2.7]; P < .001). For American Indian or Alaska Native adults, prevalence did not significantly differ between those with vs without MDE during 2006-2012 but was significantly higher for those with MDE during 2013-2019 (difference, 11.3%; 95% CI, 0.9 to 21.7; P = .04). Differences among those with vs without SUD declined for women for an average annual percent change of -1.8 (95% CI, -2.8 to -0.9; P = .001).

Conclusions:
and relevance
In this exploratory, serial, cross-sectional study, there were significant reductions in the prevalence of self-reported cigarette smoking among US adults with major depressive episode, substance use disorder, or both, between 2006 and 2019. However, continued efforts are needed to reduce the prevalence further.



JAMA: 26 Apr 2022; 327:1566-1576
Han B, Volkow ND, Blanco C, Tipperman D, Einstein EB, Compton WM
JAMA: 26 Apr 2022; 327:1566-1576 | PMID: 35471512
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Impact:
Abstract

Effect of Different Corticosteroid Dosing Regimens on Clinical Outcomes in Boys With Duchenne Muscular Dystrophy: A Randomized Clinical Trial.

Guglieri M, Bushby K, McDermott MP, Hart KA, ... Thangarajh M, Chang T
Importance
Corticosteroids improve strength and function in boys with Duchenne muscular dystrophy. However, there is uncertainty regarding the optimum regimen and dosage.
Objective
To compare efficacy and adverse effects of the 3 most frequently prescribed corticosteroid regimens in boys with Duchenne muscular dystrophy.
Design, setting, and participants
Double-blind, parallel-group randomized clinical trial including 196 boys aged 4 to 7 years with Duchenne muscular dystrophy who had not previously been treated with corticosteroids; enrollment occurred between January 30, 2013, and September 17, 2016, at 32 clinic sites in 5 countries. The boys were assessed for 3 years (last participant visit on October 16, 2019).
Interventions
Participants were randomized to daily prednisone (0.75 mg/kg) (n = 65), daily deflazacort (0.90 mg/kg) (n = 65), or intermittent prednisone (0.75 mg/kg for 10 days on and then 10 days off) (n = 66).
Main outcomes and measures
The global primary outcome comprised 3 end points: rise from the floor velocity (in rise/seconds), forced vital capacity (in liters), and participant or parent global satisfaction with treatment measured by the Treatment Satisfaction Questionnaire for Medication (TSQM; score range, 0 to 100), each averaged across all study visits after baseline. Pairwise group comparisons used a Bonferroni-adjusted significance level of .017.
Results
Among the 196 boys randomized (mean age, 5.8 years [SD, 1.0 years]), 164 (84%) completed the trial. Both daily prednisone and daily deflazacort were more effective than intermittent prednisone for the primary outcome (P < .001 for daily prednisone vs intermittent prednisone using a global test; P = .017 for daily deflazacort vs intermittent prednisone using a global test) and the daily regimens did not differ significantly (P = .38 for daily prednisone vs daily deflazacort using a global test). The between-group differences were principally attributable to rise from the floor velocity (0.06 rise/s [98.3% CI, 0.03 to 0.08 rise/s] for daily prednisone vs intermittent prednisone [P = .003]; 0.06 rise/s [98.3% CI, 0.03 to 0.09 rise/s] for daily deflazacort vs intermittent prednisone [P = .017]; and -0.004 rise/s [98.3% CI, -0.03 to 0.02 rise/s] for daily prednisone vs daily deflazacort [P = .75]). The pairwise comparisons for forced vital capacity and TSQM global satisfaction subscale score were not statistically significant. The most common adverse events were abnormal behavior (22 [34%] in the daily prednisone group, 25 [38%] in the daily deflazacort group, and 24 [36%] in the intermittent prednisone group), upper respiratory tract infection (24 [37%], 19 [29%], and 24 [36%], respectively), and vomiting (19 [29%], 17 [26%], and 15 [23%]).

Conclusions:
and relevance
Among patients with Duchenne muscular dystrophy, treatment with daily prednisone or daily deflazacort, compared with intermittent prednisone alternating 10 days on and 10 days off, resulted in significant improvement over 3 years in a composite outcome comprising measures of motor function, pulmonary function, and satisfaction with treatment; there was no significant difference between the 2 daily corticosteroid regimens. The findings support the use of a daily corticosteroid regimen over the intermittent prednisone regimen tested in this study as initial treatment for boys with Duchenne muscular dystrophy.
Trial registration
ClinicalTrials.gov Identifier: NCT01603407.



JAMA: 19 Apr 2022; 327:1456-1468
Guglieri M, Bushby K, McDermott MP, Hart KA, ... Thangarajh M, Chang T
JAMA: 19 Apr 2022; 327:1456-1468 | PMID: 35381069
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Impact:
Abstract

Association of Race and Ethnicity With Incidence of Dementia Among Older Adults.

Kornblith E, Bahorik A, Boscardin WJ, Xia F, Barnes DE, Yaffe K
Importance
The racial and ethnic diversity of the US, including among patients receiving their care at the Veterans Health Administration (VHA), is increasing. Dementia is a significant public health challenge and may have greater incidence among older adults from underrepresented racial and ethnic minority groups.
Objective
To determine dementia incidence across 5 racial and ethnic groups and by US geographical region within a large, diverse, national cohort of older veterans who received care in the largest integrated health care system in the US.
Design, setting, and participants
Retrospective cohort study within the VHA of a random sample (5% sample selected for each fiscal year) of 1 869 090 participants aged 55 years or older evaluated from October 1, 1999, to September 30, 2019 (the date of final follow-up).
Exposures
Self-reported racial and ethnic data were obtained from the National Patient Care Database. US region was determined using Centers for Disease Control and Prevention (CDC) regions from residential zip codes.
Main outcomes and measures
Incident diagnosis of dementia (9th and 10th editions of the International Classification of Diseases). Fine-Gray proportional hazards models were used to examine time to diagnosis, with age as the time scale and accounting for competing risk of death.
Results
Among the 1 869 090 study participants (mean age, 69.4 [SD, 7.9] years; 42 870 women [2%]; 6865 American Indian or Alaska Native [0.4%], 9391 Asian [0.5%], 176 795 Black [9.5%], 20 663 Hispanic [1.0%], and 1 655 376 White [88.6%]), 13% received a diagnosis of dementia over a mean follow-up of 10.1 years. Age-adjusted incidence of dementia per 1000 person-years was 14.2 (95% CI, 13.3-15.1) for American Indian or Alaska Native participants, 12.4 (95% CI, 11.7-13.1) for Asian participants, 19.4 (95% CI, 19.2-19.6) for Black participants, 20.7 (95% CI, 20.1-21.3) for Hispanic participants, and 11.5 (95% CI, 11.4-11.6) for White participants. Compared with White participants, the fully adjusted hazard ratios were 1.05 (95% CI, 0.98-1.13) for American Indian or Alaska Native participants, 1.20 (95% CI, 1.13-1.28) for Asian participants, 1.54 (95% CI, 1.51-1.57) for Black participants, and 1.92 (95% CI, 1.82-2.02) for Hispanic participants. Across most US regions, age-adjusted dementia incidence rates were highest for Black and Hispanic participants, with rates similar among American Indian or Alaska Native, Asian, and White participants.

Conclusions:
and relevance
Among older adults who received care at VHA medical centers, there were significant differences in dementia incidence based on race and ethnicity. Further research is needed to understand the mechanisms responsible for these differences.



JAMA: 19 Apr 2022; 327:1488-1495
Kornblith E, Bahorik A, Boscardin WJ, Xia F, Barnes DE, Yaffe K
JAMA: 19 Apr 2022; 327:1488-1495 | PMID: 35438728
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Impact:
Abstract

Association of COVID-19 Vaccination in Pregnancy With Adverse Peripartum Outcomes.

Fell DB, Dhinsa T, Alton GD, Török E, ... Dunn S, Bisnaire L
Importance
There is limited comparative epidemiological evidence on outcomes associated with COVID-19 vaccination during pregnancy; monitoring pregnancy outcomes in large populations is required.
Objective
To evaluate peripartum outcomes following COVID-19 vaccination during pregnancy.
Design, setting, and participants
Population-based retrospective cohort study in Ontario, Canada, using a birth registry linked with the provincial COVID-19 immunization database. All births between December 14, 2020, and September 30, 2021, were included.
Exposures
COVID-19 vaccination during pregnancy, COVID-19 vaccination after pregnancy, and no vaccination.
Main outcomes and measures
Postpartum hemorrhage, chorioamnionitis, cesarean delivery (overall and emergency cesarean delivery), admission to neonatal intensive care unit (NICU), and low newborn 5-minute Apgar score (<7). Linear and robust Poisson regression was used to generate adjusted risk differences (aRDs) and risk ratios (aRRs), respectively, comparing cumulative incidence of outcomes in those who received COVID-19 vaccination during pregnancy with those vaccinated after pregnancy and those with no record of COVID-19 vaccination at any point. Inverse probability of treatment weights were used to adjust for confounding.
Results
Among 97 590 individuals (mean [SD] age, 31.9 [4.9] years), 22 660 (23%) received at least 1 dose of COVID-19 vaccine during pregnancy (63.6% received dose 1 in the third trimester; 99.8% received an mRNA vaccine). Comparing those vaccinated during vs after pregnancy (n = 44 815), there were no significantly increased risks of postpartum hemorrhage (incidence: 3.0% vs 3.0%; aRD, -0.28 per 100 individuals [95% CI, -0.59 to 0.03]; aRR, 0.91 [95% CI, 0.82-1.02]), chorioamnionitis (0.5% vs 0.5%; aRD, -0.04 per 100 individuals [95% CI, -0.17 to 0.09]; aRR, 0.92 [95% CI, 0.70-1.21]), cesarean delivery (30.8% vs 32.2%; aRD, -2.73 per 100 individuals [95% CI, -3.59 to -1.88]; aRR, 0.92 [95% CI, 0.89-0.95]), NICU admission (11.0% vs 13.3%; aRD, -1.89 per 100 newborns [95% CI, -2.49 to -1.30]; aRR, 0.85 [95% CI, 0.80-0.90]), or low Apgar score (1.8% vs 2.0%; aRD, -0.31 per 100 newborns [95% CI, -0.56 to -0.06]; aRR, 0.84 [95% CI, 0.73-0.97]). Findings were qualitatively similar when compared with individuals who did not receive COVID-19 vaccination at any point (n = 30 115).

Conclusions:
and relevance
In this population-based cohort study in Ontario, Canada, COVID-19 vaccination during pregnancy, compared with vaccination after pregnancy and with no vaccination, was not significantly associated with increased risk of adverse peripartum outcomes. Study interpretation should consider that the vaccinations received during pregnancy were primarily mRNA vaccines administered in the second and third trimester.



JAMA: 19 Apr 2022; 327:1478-1487
Fell DB, Dhinsa T, Alton GD, Török E, ... Dunn S, Bisnaire L
JAMA: 19 Apr 2022; 327:1478-1487 | PMID: 35323842
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Impact:
Abstract

Association of SARS-CoV-2 Vaccination During Pregnancy With Pregnancy Outcomes.

Magnus MC, Örtqvist AK, Dahlqwist E, Ljung R, ... Håberg SE, Stephansson O
Importance
Data about the safety of vaccines against SARS-CoV-2 during pregnancy are limited.
Objective
To examine the risk of adverse pregnancy outcomes after vaccination against SARS-CoV-2 during pregnancy.
Design, setting, and participants
This registry-based retrospective cohort study included 157 521 singleton pregnancies ending after 22 gestational weeks from January 1, 2021, until January 12, 2022 (Sweden), or January 15, 2022 (Norway). The Pregnancy Register in Sweden and the Medical Birth Registry of Norway were linked to vaccination and other registries for identification of exposure and background characteristics.
Exposures
Data on mRNA vaccines-BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna)-and 1 viral vector vaccine-AZD1222 (AstraZeneca)-were collected from national vaccination registries.
Main outcomes and measures
The risk of preterm birth and stillbirth was evaluated using Cox regression models, with gestational day as the time metric and vaccination as a time-dependent exposure variable. The risk of small for gestational age, low Apgar score, and neonatal care admission was evaluated using logistic regression. Random-effects meta-analysis was used to combine results between countries.
Results
Among the 157 521 singleton births included in the study (103 409 in Sweden and 54 112 in Norway), the mean maternal age at the time of delivery was 31 years, and 28 506 (18%) were vaccinated against SARS-CoV-2 (12.9% with BNT162b2, 4.8% with mRNA-1273, and 0.3% with AZD1222) while pregnant. A total of 0.7%, 8.3%, and 9.1% of individuals delivering were vaccinated during the first, second, and third trimester, respectively. Vaccination against SARS-CoV-2 was not significantly associated with increased risk of preterm birth (6.2 vs 4.9 per 10 000 pregnancy days; adjusted hazard ratio [aHR], 0.98 [95% CI, 0.91 to 1.05]; I2 = 0%; P for heterogeneity = .60), stillbirth (2.1 vs 2.4 per 100 000 pregnancy days; aHR, 0.86 [95% CI, 0.63 to 1.17]), small for gestational age (7.8% vs 8.5%; difference, -0.6% [95% CI, -1.3% to 0.2%]; adjusted OR [aOR], 0.97 [95% CI, 0.90 to 1.04]), low Apgar score (1.5% vs 1.6%; difference, -0.05% [95% CI, -0.3% to 0.1%]; aOR, 0.97 [95% CI, 0.87 to 1.08]), or neonatal care admission (8.5% vs 8.5%; difference, 0.003% [95% CI, -0.9% to 0.9%]; aOR, 0.97 [95% CI, 0.86 to 1.10]).

Conclusions:
and relevance
In this population-based study conducted in Sweden and Norway, vaccination against SARS-CoV-2 during pregnancy, compared with no SARS-CoV-2 vaccination during pregnancy, was not significantly associated with an increased risk of adverse pregnancy outcomes. The majority of the vaccinations were with mRNA vaccines during the second and third trimesters of pregnancy, which should be considered in interpreting the findings.



JAMA: 19 Apr 2022; 327:1469-1477
Magnus MC, Örtqvist AK, Dahlqwist E, Ljung R, ... Håberg SE, Stephansson O
JAMA: 19 Apr 2022; 327:1469-1477 | PMID: 35323851
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Impact:
Abstract

Association of Transthyretin Val122Ile Variant With Incident Heart Failure Among Black Individuals.

Parcha V, Malla G, Ivin MR, Armstrong ND, ... Arora G, Arora P
Importance
A genetic variant in the TTR gene (rs76992529; Val122Ile), present more commonly in individuals with African ancestry (population frequency: 3%-4%), causes misfolding of the tetrameric transthyretin protein complex that accumulates as extracellular amyloid fibrils and results in hereditary transthyretin amyloidosis.
Objective
To estimate the association of the amyloidogenic Val122Ile TTR variant with the risk of heart failure and mortality in a large, geographically diverse cohort of Black individuals.
Design, setting, and participants
Retrospective population-based cohort study of 7514 self-identified Black individuals living in the US participating in the REGARDS (Reasons for Geographic and Racial Differences in Stroke) study with genetic data available and without heart failure at baseline. The participants were enrolled at the baseline visit (2003-2007). The end of follow-up for the majority of outcomes was on December 31, 2018. All-cause mortality data were available through December 31, 2020.
Exposures
TTR Val122Ile (rs76992529) genotype.
Main outcome and measures
The primary outcome was incident heart failure (first hospitalization for heart failure or death due to heart failure). The secondary outcomes were heart failure mortality, cardiovascular mortality, and all-cause mortality. The multivariable Cox proportional hazards regression analyses were adjusted for genetic ancestry and demographic, clinical, and social factors.
Results
Among 7514 Black participants (median age, 64 years [IQR, 57-70 years]; 61% women), the population frequency of the TTR Val122Ile variant was 3.1% (232 variant carriers and 7282 noncarriers). During a median follow-up of 11.1 years (IQR, 5.9-13.5 years), incident heart failure occurred in 535 individuals (34 variant carriers and 501 noncarriers) and the incidence of heart failure was 15.64 per 1000 person-years among variant carriers vs 7.16 per 1000 person-years among noncarriers (adjusted hazard ratio [HR], 2.43 [95% CI, 1.71-3.46]; P < .001). Deaths due to heart failure occurred in 141 individuals (13 variant carriers and 128 noncarriers) and the incidence of heart failure mortality was 6.11 per 1000 person-years among variant carriers vs 1.85 per 1000 person-years among noncarriers (adjusted HR, 4.19 [95% CI, 2.33-7.54]; P < .001). Deaths due to cardiovascular causes occurred in 793 individuals (34 variant carriers and 759 noncarriers) and the incidence of cardiovascular death was 15.18 per 1000 person-years among variant carriers vs 10.61 per 1000 person-years among noncarriers (adjusted HR, 1.69 [95% CI, 1.19-2.39]; P = .003). Deaths due to any cause occurred in 2715 individuals (100 variant carriers and 2615 noncarriers) and the incidence of all-cause mortality was 41.46 per 1000 person-years among variant carriers vs 33.94 per 1000 person-years among noncarriers (adjusted HR, 1.46 [95% CI, 1.19-1.78]; P < .001). There was no significant interaction between TTR variant carrier status and sex on incident heart failure and the secondary outcomes.

Conclusions:
and relevance
Among a cohort of Black individuals living in the US, being a carrier of the TTR Val122Ile variant was significantly associated with an increased risk of heart failure.



JAMA: 12 Apr 2022; 327:1368-1378
Parcha V, Malla G, Ivin MR, Armstrong ND, ... Arora G, Arora P
JAMA: 12 Apr 2022; 327:1368-1378 | PMID: 35377943
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Impact:
Abstract

Diagnosis and Treatment of Pulmonary Arterial Hypertension: A Review.

Ruopp NF, Cockrill BA
Importance
Pulmonary arterial hypertension (PAH) is a subtype of pulmonary hypertension (PH), characterized by pulmonary arterial remodeling. The prevalence of PAH is approximately 10.6 cases per 1 million adults in the US. Untreated, PAH progresses to right heart failure and death.
Observations
Pulmonary hypertension is defined by a mean pulmonary artery pressure greater than 20 mm Hg and is classified into 5 clinical groups based on etiology, pathophysiology, and treatment. Pulmonary arterial hypertension is 1 of the 5 groups of PH and is hemodynamically defined by right heart catheterization demonstrating a mean pulmonary artery pressure greater than 20 mm Hg, a pulmonary artery wedge pressure of 15 mm Hg or lower, and a pulmonary vascular resistance of 3 Wood units or greater. Pulmonary arterial hypertension is further divided into subgroups based on underlying etiology, consisting of idiopathic PAH, heritable PAH, drug- and toxin-associated PAH, pulmonary veno-occlusive disease, PAH in long-term responders to calcium channel blockers, and persistent PH of the newborn, as well as PAH associated with other medical conditions including connective tissue disease, HIV, and congenital heart disease. Early presenting symptoms are nonspecific and typically consist of dyspnea on exertion and fatigue. Currently approved therapy for PAH consists of drugs that enhance the nitric oxide-cyclic guanosine monophosphate biological pathway (sildenafil, tadalafil, or riociguat), prostacyclin pathway agonists (epoprostenol or treprostinil), and endothelin pathway antagonists (bosentan and ambrisentan). With these PAH-specific therapies, 5-year survival has improved from 34% in 1991 to more than 60% in 2015. Current treatment consists of combination drug therapy that targets more than 1 biological pathway, such as the nitric oxide-cyclic guanosine monophosphate and endothelin pathways (eg, ambrisentan and tadalafil), and has shown demonstrable improvement in morbidity and mortality compared with the previous conventional single-pathway targeted monotherapy.

Conclusions:
and relevance
Pulmonary arterial hypertension affects an estimated 10.6 per 1 million adults in the US and, without treatment, typically progresses to right heart failure and death. First-line therapy with drug combinations that target multiple biological pathways are associated with improved survival.



JAMA: 12 Apr 2022; 327:1379-1391
Ruopp NF, Cockrill BA
JAMA: 12 Apr 2022; 327:1379-1391 | PMID: 35412560
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Impact:
Abstract

Effect of a Home-Based, Walking Exercise Behavior Change Intervention vs Usual Care on Walking in Adults With Peripheral Artery Disease: The MOSAIC Randomized Clinical Trial.

Bearne LM, Volkmer B, Peacock J, Sekhon M, ... Bieles J, MOSAIC Trial Collaboration
Importance
Home-based walking exercise interventions are recommended for people with peripheral artery disease (PAD), but evidence of their efficacy has been mixed.
Objective
To investigate the effect of a home-based, walking exercise behavior change intervention delivered by physical therapists in adults with PAD and intermittent claudication compared with usual care.
Design, setting, and participants
Multicenter randomized clinical trial including 190 adults with PAD and intermittent claudication in 6 hospitals in the United Kingdom between January 2018 and March 2020; final follow-up was September 8, 2020.
Interventions
Participants were randomized to receive a walking exercise behavior change intervention delivered by physical therapists trained to use a motivational approach (n = 95) or usual care (n = 95).
Main outcomes and measures
The primary outcome was 6-minute walking distance at 3-month follow-up (minimal clinically important difference, 8-20 m). There were 8 secondary outcomes, 3 of which were the Walking Estimated Limitation Calculated by History (WELCH) questionnaire (score range, 0 [best performance] to 100), the Brief Illness Perceptions Questionnaire (score range, 0 to 80 [80 indicates negative perception of illness]), and the Theory of Planned Behavior Questionnaire (score range, 3 to 21 [21 indicates best attitude, subjective norms, perceived behavioral control, or intentions]); a minimal clinically important difference was not defined for these instruments.
Results
Among 190 randomized participants (mean age 68 years, 30% women, 79% White race, mean baseline 6-minute walking distance, 361.0 m), 148 (78%) completed 3-month follow-up. The 6-minute walking distance changed from 352.9 m at baseline to 380.6 m at 3 months in the intervention group and from 369.8 m to 372.1 m in the usual care group (adjusted mean between-group difference, 16.7 m [95% CI, 4.2 m to 29.2 m]; P = .009). Of the 8 secondary outcomes, 5 were not statistically significant. At 6-month follow-up, baseline WELCH scores changed from 18.0 to 27.8 in the intervention group and from 20.7 to 20.7 in the usual care group (adjusted mean between-group difference, 7.4 [95% CI, 2.5 to 12.3]; P = .003), scores on the Brief Illness Perceptions Questionnaire changed from 45.7 to 38.9 in the intervention group and from 44.0 to 45.8 in the usual care group (adjusted mean between-group difference, -6.6 [95% CI, -9.9 to -3.4]; P < .001), and scores on the attitude component of the Theory of Planned Behavior Questionnaire changed from 14.7 to 15.4 in the intervention group and from 14.6 to 13.9 in the usual care group (adjusted mean between-group difference, 1.4 [95% CI, 0.3 to 2.5]; P = .02). Thirteen serious adverse events occurred in the intervention group, compared with 3 in the usual care group. All were determined to be unrelated or unlikely to be related to the study.

Conclusions:
and relevance
Among adults with PAD and intermittent claudication, a home-based, walking exercise behavior change intervention, compared with usual care, resulted in improved walking distance at 3 months. Further research is needed to determine the durability of these findings.
Trial registrations
ISRCTN Identifier: 14501418; ClinicalTrials.gov Identifier: NCT03238222.



JAMA: 12 Apr 2022; 327:1344-1355
Bearne LM, Volkmer B, Peacock J, Sekhon M, ... Bieles J, MOSAIC Trial Collaboration
JAMA: 12 Apr 2022; 327:1344-1355 | PMID: 35412564
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Impact:
Abstract

Risk of Adverse Pregnancy Outcomes Among Pregnant Individuals With Gestational Diabetes by Race and Ethnicity in the United States, 2014-2020.

Venkatesh KK, Lynch CD, Powe CE, Costantine MM, ... Grobman WA, Landon MB
Importance
Gestational diabetes, which increases the risk of adverse pregnancy outcomes, has been increasing in frequency across all racial and ethnic subgroups in the US.
Objective
To assess whether the frequency of adverse pregnancy outcomes among those in the US with gestational diabetes changed over time and whether the risk of these outcomes differed by maternal race and ethnicity.
Design, setting, and participants
Exploratory serial, cross-sectional, descriptive study using US National Center for Health Statistics natality data for 1 560 822 individuals with gestational diabetes aged 15 to 44 years with singleton nonanomalous live births from 2014 to 2020 in the US.
Exposures
Year of delivery and race and ethnicity, as reported on the birth certificate, stratified as non-Hispanic American Indian, non-Hispanic Asian/Pacific Islander, non-Hispanic Black, Hispanic/Latina, and non-Hispanic White (reference group).
Main outcomes and measures
Maternal outcomes of interest included cesarean delivery, primary cesarean delivery, preeclampsia or gestational hypertension, intensive care unit (ICU) admission, and transfusion; neonatal outcomes included large for gestational age (LGA), macrosomia (>4000 g at birth), small for gestational age (SGA), preterm birth, and neonatal ICU (NICU) admission, as measured by the frequency (per 1000 live births) with estimation of mean annual percentage change (APC), disparity ratios, and adjusted risk ratios.
Results
Of 1 560 822 included pregnant individuals with gestational diabetes (mean [SD] age, 31 [5.5] years), 1% were American Indian, 13% were Asian/Pacific Islander, 12% were Black, 27% were Hispanic/Latina, and 48% were White. From 2014 to 2020, there was a statistically significant increase in the overall frequency (mean APC per year) of preeclampsia or gestational hypertension (4.2% [95% CI, 3.3% to 5.2%]), transfusion (8.0% [95% CI, 3.8% to 12.4%]), preterm birth at less than 37 weeks (0.9% [95% CI, 0.3% to 1.5%]), and NICU admission (1.0% [95% CI, 0.3% to 1.7%]). There was a significant decrease in cesarean delivery (-1.4% [95% CI, -1.7% to -1.1%]), primary cesarean delivery (-1.2% [95% CI, -1.5% to -0.9%]), LGA (-2.3% [95% CI, -2.8% to -1.8%]), and macrosomia (-4.7% [95% CI, -5.3% to -4.0%]). There was no significant change in maternal ICU admission and SGA. In comparison with White individuals, Black individuals were at significantly increased risk of all assessed outcomes, except LGA and macrosomia; American Indian individuals were at significantly increased risk of all assessed outcomes except cesarean delivery and SGA; and Hispanic/Latina and Asian/Pacific Islander individuals were at significantly increased risk of maternal ICU admission, preterm birth, NICU admission, and SGA. Differences in adverse outcomes by race and ethnicity persisted through these years.

Conclusions:
and relevance
From 2014 through 2020, the frequency of multiple adverse pregnancy outcomes in the US increased among pregnant individuals with gestational diabetes. Differences in adverse outcomes by race and ethnicity persisted.



JAMA: 12 Apr 2022; 327:1356-1367
Venkatesh KK, Lynch CD, Powe CE, Costantine MM, ... Grobman WA, Landon MB
JAMA: 12 Apr 2022; 327:1356-1367 | PMID: 35412565
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Impact:
Abstract

Effect of High-Flow Nasal Cannula Therapy vs Continuous Positive Airway Pressure Following Extubation on Liberation From Respiratory Support in Critically Ill Children: A Randomized Clinical Trial.

Ramnarayan P, Richards-Belle A, Drikite L, Saull M, ... Rowan KM, FIRST-ABC Step-Down RCT Investigators and the Paediatric Critical Care Society Study Group
Importance
The optimal first-line mode of noninvasive respiratory support following extubation of critically ill children is not known.
Objective
To evaluate the noninferiority of high-flow nasal cannula (HFNC) therapy as the first-line mode of noninvasive respiratory support following extubation, compared with continuous positive airway pressure (CPAP), on time to liberation from respiratory support.
Design, setting, and participants
This was a pragmatic, multicenter, randomized, noninferiority trial conducted at 22 pediatric intensive care units in the United Kingdom. Six hundred children aged 0 to 15 years clinically assessed to require noninvasive respiratory support within 72 hours of extubation were recruited between August 8, 2019, and May 18, 2020, with last follow-up completed on November 22, 2020.
Interventions
Patients were randomized 1:1 to start either HFNC at a flow rate based on patient weight (n = 299) or CPAP of 7 to 8 cm H2O (n = 301).
Main outcomes and measures
The primary outcome was time from randomization to liberation from respiratory support, defined as the start of a 48-hour period during which the child was free from all forms of respiratory support (invasive or noninvasive), assessed against a noninferiority margin of an adjusted hazard ratio (HR) of 0.75. There were 6 secondary outcomes, including mortality at day 180 and reintubation within 48 hours.
Results
Of the 600 children who were randomized, 553 children (HFNC, 281; CPAP, 272) were included in the primary analysis (median age, 3 months; 241 girls [44%]). HFNC failed to meet noninferiority, with a median time to liberation of 50.5 hours (95% CI, 43.0-67.9) vs 42.9 hours (95% CI, 30.5-48.2) for CPAP (adjusted HR, 0.83; 1-sided 97.5% CI, 0.70-∞). Similar results were seen across prespecified subgroups. Of the 6 prespecified secondary outcomes, 5 showed no significant difference, including the rate of reintubation within 48 hours (13.3% for HFNC vs 11.5 % for CPAP). Mortality at day 180 was significantly higher for HFNC (5.6% vs 2.4% for CPAP; adjusted odds ratio, 3.07 [95% CI, 1.1-8.8]). The most common adverse events were abdominal distension (HFNC: 8/281 [2.8%] vs CPAP: 7/272 [2.6%]) and nasal/facial trauma (HFNC: 14/281 [5.0%] vs CPAP: 15/272 [5.5%]).

Conclusions:
and relevance
Among critically ill children requiring noninvasive respiratory support following extubation, HFNC compared with CPAP following extubation failed to meet the criterion for noninferiority for time to liberation from respiratory support.
Trial registration
isrctn.org Identifier: ISRCTN60048867.



JAMA: 07 Apr 2022; epub ahead of print
Ramnarayan P, Richards-Belle A, Drikite L, Saull M, ... Rowan KM, FIRST-ABC Step-Down RCT Investigators and the Paediatric Critical Care Society Study Group
JAMA: 07 Apr 2022; epub ahead of print | PMID: 35390113
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Impact:
Abstract

Antiseizure Medications for Adults With Epilepsy: A Review.

Kanner AM, Bicchi MM
Importance
Epilepsy affects approximately 65 million people worldwide. Persistent seizures are associated with a 20% to 40% risk of bodily injuries (eg, fractures, burns, concussions) over 12-month follow-up. The primary goal of epilepsy treatment is to eliminate seizures while minimizing adverse effects of antiseizure drugs (ASDs).
Observations
An epileptic seizure is defined as a sudden occurrence of transient signs and symptoms caused by abnormal and excessive or synchronous neuronal activity in the brain. Focal and generalized epilepsy are the 2 most frequent types of epilepsy; diagnosis is based on the type of seizures. There are 26 US Food and Drug Administration-approved medications for epilepsy, of which 24 have similar antiseizure efficacy for focal epilepsy and 9 have similar efficacy for generalized epilepsy. The decision to initiate an ASD should be individualized, but should be strongly considered after 2 unprovoked seizures or after 1 unprovoked seizure that occurred during sleep and/or in the presence of epileptiform activity on an electroencephalogram and/or in the presence of a structural lesion on the brain magnetic resonance imaging. The ASDs must be selected based on the seizure and epilepsy types, the epilepsy syndrome, and the adverse effects associated with the drug. For focal epilepsy, oxcarbazepine and lamotrigine are first-line therapy, while levetiracetam can be also considered if there is no history of psychiatric disorder. For generalized epilepsy, the selection of the ASD is based on the type of epilepsy syndrome and the patient\'s sex, age, and psychiatric history. Seizure freedom is achieved in approximately 60% to 70% of all patients. A total of 25% to 50% of patients also experience neurologic, psychiatric, cognitive, or medical disorders, such as mood, anxiety, and attention deficit disorders and migraines. For these patients, selecting an ASD should consider the presence of these disorders and concomitant use of medications to treat them. ASDs with cytochrome P450 enzyme-inducing properties (eg, carbamazepine, phenytoin) may worsen comorbid coronary and cerebrovascular disease by causing hyperlipidemia and accelerating the metabolism of concomitant drugs used for their treatment. They can also facilitate the development of osteopenia and osteoporosis.

Conclusions:
and relevance
Epilepsy affects approximately 65 million people worldwide and is associated with increased rates of bodily injuries and mortality when not optimally treated. For focal and generalized epilepsy, selection of ASDs should consider the seizure and epilepsy types and epilepsy syndrome, as well as the patient\'s age and sex, comorbidities, and potential drug interactions.



JAMA: 05 Apr 2022; 327:1269-1281
Kanner AM, Bicchi MM
JAMA: 05 Apr 2022; 327:1269-1281 | PMID: 35380580
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Impact:
Abstract

Effect of Antiplatelet Therapy on Survival and Organ Support-Free Days in Critically Ill Patients With COVID-19: A Randomized Clinical Trial.

REMAP-CAP Writing Committee for the REMAP-CAP Investigators, Bradbury CA, Lawler PR, Stanworth SJ, ... Webb SA, Gordon AC
Importance
The efficacy of antiplatelet therapy in critically ill patients with COVID-19 is uncertain.
Objective
To determine whether antiplatelet therapy improves outcomes for critically ill adults with COVID-19.
Design, setting, and participants
In an ongoing adaptive platform trial (REMAP-CAP) testing multiple interventions within multiple therapeutic domains, 1557 critically ill adult patients with COVID-19 were enrolled between October 30, 2020, and June 23, 2021, from 105 sites in 8 countries and followed up for 90 days (final follow-up date: July 26, 2021).
Interventions
Patients were randomized to receive either open-label aspirin (n = 565), a P2Y12 inhibitor (n = 455), or no antiplatelet therapy (control; n = 529). Interventions were continued in the hospital for a maximum of 14 days and were in addition to anticoagulation thromboprophylaxis.
Main outcomes and measures
The primary end point was organ support-free days (days alive and free of intensive care unit-based respiratory or cardiovascular organ support) within 21 days, ranging from -1 for any death in hospital (censored at 90 days) to 22 for survivors with no organ support. There were 13 secondary outcomes, including survival to discharge and major bleeding to 14 days. The primary analysis was a bayesian cumulative logistic model. An odds ratio (OR) greater than 1 represented improved survival, more organ support-free days, or both. Efficacy was defined as greater than 99% posterior probability of an OR greater than 1. Futility was defined as greater than 95% posterior probability of an OR less than 1.2 vs control. Intervention equivalence was defined as greater than 90% probability that the OR (compared with each other) was between 1/1.2 and 1.2 for 2 noncontrol interventions.
Results
The aspirin and P2Y12 inhibitor groups met the predefined criteria for equivalence at an adaptive analysis and were statistically pooled for further analysis. Enrollment was discontinued after the prespecified criterion for futility was met for the pooled antiplatelet group compared with control. Among the 1557 critically ill patients randomized, 8 patients withdrew consent and 1549 completed the trial (median age, 57 years; 521 [33.6%] female). The median for organ support-free days was 7 (IQR, -1 to 16) in both the antiplatelet and control groups (median-adjusted OR, 1.02 [95% credible interval {CrI}, 0.86-1.23]; 95.7% posterior probability of futility). The proportions of patients surviving to hospital discharge were 71.5% (723/1011) and 67.9% (354/521) in the antiplatelet and control groups, respectively (median-adjusted OR, 1.27 [95% CrI, 0.99-1.62]; adjusted absolute difference, 5% [95% CrI, -0.2% to 9.5%]; 97% posterior probability of efficacy). Among survivors, the median for organ support-free days was 14 in both groups. Major bleeding occurred in 2.1% and 0.4% of patients in the antiplatelet and control groups (adjusted OR, 2.97 [95% CrI, 1.23-8.28]; adjusted absolute risk increase, 0.8% [95% CrI, 0.1%-2.7%]; 99.4% probability of harm).

Conclusions:
and relevance
Among critically ill patients with COVID-19, treatment with an antiplatelet agent, compared with no antiplatelet agent, had a low likelihood of providing improvement in the number of organ support-free days within 21 days.
Trial registration
ClinicalTrials.gov Identifier: NCT02735707.



JAMA: 05 Apr 2022; 327:1247-1259
REMAP-CAP Writing Committee for the REMAP-CAP Investigators, Bradbury CA, Lawler PR, Stanworth SJ, ... Webb SA, Gordon AC
JAMA: 05 Apr 2022; 327:1247-1259 | PMID: 35315874
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Impact:
Abstract

Association Between 2-Dose vs 3-Dose Hepatitis B Vaccine and Acute Myocardial Infarction.

Bruxvoort K, Slezak J, Qian L, Sy LS, ... Mercado C, Jacobsen SJ
Importance
The 2-dose hepatitis B vaccine with a cytosine phosphoguanine adjuvant (HepB-CpG vaccine; Heplisav-B) generated higher seroprotection in prelicensure trials than did a 3-dose hepatitis B vaccine with an aluminum hydroxide adjuvant (HepB-alum vaccine; Engerix-B). However, in 1 trial, a higher number of acute myocardial infarction (MI) events were observed among those who received the HepB-CpG vaccine than among those who received the HepB-alum vaccine, an outcome requiring further study.
Objective
To compare the rate of acute MI between recipients of HepB-CpG vaccine and HepB-alum vaccine.
Design, setting, and participants
This prospective cohort noninferiority study was conducted at Kaiser Permanente Southern California (KPSC), an integrated health care system with 15 medical centers and approximately 4.7 million members. The study included 69 625 adults not undergoing dialysis who received at least 1 dose of a hepatitis B vaccine in either family medicine or internal medicine departments at KPSC from August 7, 2018, to October 31, 2019 (November 30, 2020, final follow-up).
Exposures
Receipt of HepB-CpG vaccine vs HepB-alum vaccine. The first dose during the study period was the index dose.
Main outcomes and measures
Individuals were followed up for 13 months after the index dose for occurrence of type 1 acute MI. Potential events were identified using diagnosis codes and adjudicated by cardiologists. The adjusted hazard ratio (HR) of acute MI was estimated comparing recipients of HepB-CpG vaccine with recipients of HepB-alum vaccine, with inverse probability of treatment weighting (IPTW) to adjust for demographic and clinical characteristics. The upper limit of the 1-sided 97.5% CI was compared with a noninferiority margin of 2.
Results
Of the 31 183 recipients of HepB-CpG vaccine (median age, 49 years; IQR, 38-56 years), 51.2% (n = 15 965) were men, and 52.7% (n = 16 423) were Hispanic. Of the 38 442 recipients of HepB-alum (median age, 49 years; IQR, 39-56 years), 50.8% (19 533) were men, and 47.1% (n = 18 125) were Hispanic. Characteristics were well-balanced between vaccine groups after IPTW. Fifty-two type 1 acute MI events were confirmed among recipients of HepB-CpG vaccine for a rate of 1.67 per 1000-person-years, and 71 type 1 acute MI events were confirmed among recipients of HepB-alum vaccine for a rate of 1.86 per 1000 person-years (absolute rate difference, -0.19 [95% CI, -0.82 to 0.44]; adjusted HR, 0.92 [1-sided 97.5% CI, ∞ to 1.32], which was below the noninferiority margin; P < .001 for noninferiority).

Conclusions:
and relevance
In this cohort study, receipt of HepB-CpG vaccine compared with HepB-alum vaccine did not meet the statistical criterion for increased risk of acute myocardial infarction.



JAMA: 05 Apr 2022; 327:1260-1268
Bruxvoort K, Slezak J, Qian L, Sy LS, ... Mercado C, Jacobsen SJ
JAMA: 05 Apr 2022; 327:1260-1268 | PMID: 35333303
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Impact:
Abstract

Single Ascending Dose Study of a Short Interfering RNA Targeting Lipoprotein(a) Production in Individuals With Elevated Plasma Lipoprotein(a) Levels.

Nissen SE, Wolski K, Balog C, Swerdlow DI, ... Melgaard C, Campion GV
Importance
Lipoprotein(a) (Lp[a]) is an important risk factor for atherothrombotic cardiovascular disease and aortic stenosis, for which there are no treatments approved by regulatory authorities.
Objectives
To assess adverse events and tolerability of a short interfering RNA (siRNA) designed to reduce hepatic production of apolipoprotein(a) and to assess associated changes in plasma concentrations of Lp(a) at different doses.
Design, setting, and participants
A single ascending dose study of SLN360, an siRNA targeting apolipoprotein(a) synthesis conducted at 5 clinical research unit sites located in the US, United Kingdom, and Australia. The study enrolled adults with Lp(a) plasma concentrations of 150 nmol/L or greater at screening and no known clinically overt cardiovascular disease. Participants were enrolled between November 18, 2020, and July 21, 2021, with last follow-up on December 29, 2021.
Interventions
Participants were randomized to receive placebo (n = 8) or single doses of SLN360 at 30 mg (n = 6), 100 mg (n = 6), 300 mg (n = 6), or 600 mg (n = 6), administered subcutaneously.
Main outcomes and measures
The primary outcome was evaluation of safety and tolerability. Secondary outcomes included change in plasma concentrations of Lp(a) to a maximum follow-up of 150 days.
Results
Among 32 participants who were randomized and received the study intervention (mean age, 50 [SD, 13.5] years; 17 women [53%]), 32 (100%) completed the trial. One participant experienced 2 serious adverse event episodes: admission to the hospital for headache following SARS-CoV-2 vaccination and later for complications of cholecystitis, both of which were judged to be unrelated to study drug. Median baseline Lp(a) concentrations were as follows: placebo, 238 (IQR, 203-308) nmol/L; 30-mg SLN360, 171 (IQR, 142-219) nmol/L; 100-mg SLN360, 217 (IQR, 202-274) nmol/L; 300-mg SLN360, 285 (IQR, 195-338) nmol/L; and 600-mg SLN360, 231 (IQR, 179-276) nmol/L. Maximal median changes in Lp(a) were -20 (IQR, -61 to 3) nmol/L, -89 (IQR, -119 to -61) nmol/L, -185 (IQR, -226 to -163) nmol/L, -268 (IQR, -292 to -189) nmol/L, and -227 (IQR, -270 to -174) nmol/L, with maximal median percentage changes of -10% (IQR, -16% to 1%), -46% (IQR, -64% to -40%), -86% (IQR, -92% to -82%), -96% (IQR, -98% to -89%), and -98% (IQR, -98% to -97%), for the placebo group and the 30-mg, 100-mg, 300-mg, and 600-mg SLN360 groups, respectively. The duration of Lp(a) lowering was dose dependent, persisting for at least 150 days after administration.

Conclusions:
and relevance
In this phase 1 study of 32 participants with elevated Lp(a) levels and no known cardiovascular disease, the siRNA SLN360 was well tolerated, and a dose-dependent lowering of plasma Lp(a) concentrations was observed. The findings support further study to determine the safety and efficacy of this siRNA.
Trial registration
ClinicalTrials.gov Identifier: NCT04606602; EudraCT Identifier: 2020-002471-35.



JAMA: 03 Apr 2022; epub ahead of print
Nissen SE, Wolski K, Balog C, Swerdlow DI, ... Melgaard C, Campion GV
JAMA: 03 Apr 2022; epub ahead of print | PMID: 35368052
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Impact:
Abstract

Effect of Alirocumab Added to High-Intensity Statin Therapy on Coronary Atherosclerosis in Patients With Acute Myocardial Infarction: The PACMAN-AMI Randomized Clinical Trial.

Räber L, Ueki Y, Otsuka T, Losdat S, ... Koskinas KC, PACMAN-AMI collaborators
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.



JAMA: 03 Apr 2022; epub ahead of print
Räber L, Ueki Y, Otsuka T, Losdat S, ... Koskinas KC, PACMAN-AMI collaborators
JAMA: 03 Apr 2022; epub ahead of print | PMID: 35368058
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Impact:
Abstract

Collaboration and Shared Decision-Making Between Patients and Clinicians in Preventive Health Care Decisions and US Preventive Services Task Force Recommendations.

US Preventive Services Task Force, Davidson KW, Mangione CM, Barry MJ, ... Tseng CW, Wong JB
The US Preventive Services Task Force (USPSTF) works to improve the health of people nationwide by making evidence-based recommendations for preventive services. Patient-centered care is a core value in US health care. Shared decision-making (SDM), in which patients and clinicians make health decisions together, ensures patients\' rights to be informed and involved in preventive care decisions and that these decisions are patient-centered. SDM has a role across the spectrum of USPSTF recommendations. For A or B recommendations (judged by the USPSTF to have high or moderate certainty of a moderate or substantial net benefit at the population level), SDM allows individual patients to decide whether to accept such services based on their personal values and preferences. For C recommendations (indicating at least moderate certainty of a small net benefit at the population level), SDM is critical for individual patients to decide whether the net benefit for them is worthwhile. For D recommendations (reflecting at least moderate certainty of a zero or negative net benefit) or I statements (low certainty of net benefit), clinicians should be prepared to discuss these services if patients ask. More evidence is needed to determine if, in addition to promoting patient-centeredness, SDM reduces inequities in preventive care, as well as to define new strategies to find time for discussion of preventive services in primary care.



JAMA: 22 Mar 2022; 327:1171-1176
US Preventive Services Task Force, Davidson KW, Mangione CM, Barry MJ, ... Tseng CW, Wong JB
JAMA: 22 Mar 2022; 327:1171-1176 | PMID: 35315879
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Impact:
Abstract

Association of Neonatal Hypoglycemia With Academic Performance in Mid-Childhood.

Shah R, Dai DWT, Alsweiler JM, Brown GTL, ... McKinlay CJD, Children With Hypoglycaemia and Their Later Development (CHYLD) Study Team
Importance
Neonatal hypoglycemia is associated with increased risk of poor executive and visual-motor function, but implications for later learning are uncertain.
Objective
To test the hypothesis that neonatal hypoglycemia is associated with educational performance at age 9 to 10 years.
Design, setting, and participants
Prospective cohort study of moderate to late preterm and term infants born at risk of hypoglycemia. Blood and masked interstitial sensor glucose concentrations were measured for up to 7 days. Infants with hypoglycemic episodes (blood glucose concentration <47 mg/dL [2.6 mmol/L]) were treated to maintain a blood glucose concentration of at least 47 mg/dL. Six hundred fourteen infants were recruited at Waikato Hospital, Hamilton, New Zealand, in 2006-2010; 480 were assessed at age 9 to 10 years in 2016-2020.
Exposures
Hypoglycemia was defined as at least 1 hypoglycemic event, representing the sum of nonconcurrent hypoglycemic and interstitial episodes (sensor glucose concentration <47 mg/dL for ≥10 minutes) more than 20 minutes apart.
Main outcomes and measures
The primary outcome was low educational achievement, defined as performing below or well below the normative curriculum level in standardized tests of reading comprehension or mathematics. There were 47 secondary outcomes related to executive function, visual-motor function, psychosocial adaptation, and general health.
Results
Of 587 eligible children (230 [48%] female), 480 (82%) were assessed at a mean age of 9.4 (SD, 0.3) years. Children who were and were not exposed to neonatal hypoglycemia did not significantly differ on rates of low educational achievement (138/304 [47%] vs 82/176 [48%], respectively; adjusted risk difference, -2% [95% CI, -11% to 8%]; adjusted relative risk, 0.95 [95% CI, 0.78-1.15]). Children who were exposed to neonatal hypoglycemia, compared with those not exposed, were significantly less likely to be rated by teachers as being below or well below the curriculum level for reading (68/281 [24%] vs 49/157 [31%], respectively; adjusted risk difference, -9% [95% CI, -17% to -1%]; adjusted relative risk, 0.72 [95% CI, 0.53-0.99; P = .04]). Groups were not significantly different for other secondary end points.

Conclusions:
and relevance
Among participants at risk of neonatal hypoglycemia who were screened and treated if needed, exposure to neonatal hypoglycemia compared with no such exposure was not significantly associated with lower educational achievement in mid-childhood.



JAMA: 22 Mar 2022; 327:1158-1170
Shah R, Dai DWT, Alsweiler JM, Brown GTL, ... McKinlay CJD, Children With Hypoglycaemia and Their Later Development (CHYLD) Study Team
JAMA: 22 Mar 2022; 327:1158-1170 | PMID: 35315886
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Impact:
Abstract

Effect of Sotrovimab on Hospitalization or Death Among High-risk Patients With Mild to Moderate COVID-19: A Randomized Clinical Trial.

Gupta A, Gonzalez-Rojas Y, Juarez E, Crespo Casal M, ... Shapiro AE, COMET-ICE Investigators
Importance
Older patients and those with comorbidities who are infected with SARS-CoV-2 may be at increased risk of hospitalization and death. Sotrovimab is a neutralizing antibody for the treatment of high-risk patients to prevent COVID-19 progression.
Objective
To evaluate the efficacy and adverse events of sotrovimab in preventing progression of mild to moderate COVID-19 to severe disease.
Design, setting, and participants
Randomized clinical trial including 1057 nonhospitalized patients with symptomatic, mild to moderate COVID-19 and at least 1 risk factor for progression conducted at 57 sites in Brazil, Canada, Peru, Spain, and the US from August 27, 2020, through March 11, 2021; follow-up data were collected through April 8, 2021.
Interventions
Patients were randomized (1:1) to an intravenous infusion with 500 mg of sotrovimab (n = 528) or placebo (n = 529).
Main outcomes and measures
The primary outcome was the proportion of patients with COVID-19 progression through day 29 (all-cause hospitalization lasting >24 hours for acute illness management or death); 5 secondary outcomes were tested in hierarchal order, including a composite of all-cause emergency department (ED) visit, hospitalization of any duration for acute illness management, or death through day 29 and progression to severe or critical respiratory COVID-19 requiring supplemental oxygen or mechanical ventilation.
Results
Enrollment was stopped early for efficacy at the prespecified interim analysis. Among 1057 patients randomized (median age, 53 years [IQR, 42-62], 20% were ≥65 years of age, and 65% Latinx), the median duration of follow-up was 103 days for sotrovimab and 102 days for placebo. All-cause hospitalization lasting longer than 24 hours or death was significantly reduced with sotrovimab (6/528 [1%]) vs placebo (30/529 [6%]) (adjusted relative risk [RR], 0.21 [95% CI, 0.09 to 0.50]; absolute difference, -4.53% [95% CI, -6.70% to -2.37%]; P < .001). Four of the 5 secondary outcomes were statistically significant in favor of sotrovimab, including reduced ED visit, hospitalization, or death (13/528 [2%] for sotrovimab vs 39/529 [7%] for placebo; adjusted RR, 0.34 [95% CI, 0.19 to 0.63]; absolute difference, -4.91% [95% CI, -7.50% to -2.32%]; P < .001) and progression to severe or critical respiratory COVID-19 (7/528 [1%] for sotrovimab vs 28/529 [5%] for placebo; adjusted RR, 0.26 [95% CI, 0.12 to 0.59]; absolute difference, -3.97% [95% CI, -6.11% to -1.82%]; P = .002). Adverse events were infrequent and similar between treatment groups (22% for sotrovimab vs 23% for placebo); the most common events were diarrhea with sotrovimab (n = 8; 2%) and COVID-19 pneumonia with placebo (n = 22; 4%).

Conclusions:
and relevance
Among nonhospitalized patients with mild to moderate COVID-19 and at risk of disease progression, a single intravenous dose of sotrovimab, compared with placebo, significantly reduced the risk of a composite end point of all-cause hospitalization or death through day 29. The findings support sotrovimab as a treatment option for nonhospitalized, high-risk patients with mild to moderate COVID-19, although efficacy against SARS-CoV-2 variants that have emerged since the study was completed is unknown.
Trial registration
ClinicalTrials.gov Identifier: NCT04545060.



JAMA: 13 Mar 2022; epub ahead of print
Gupta A, Gonzalez-Rojas Y, Juarez E, Crespo Casal M, ... Shapiro AE, COMET-ICE Investigators
JAMA: 13 Mar 2022; epub ahead of print | PMID: 35285853
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Impact:
Abstract

Acute Cholecystitis: A Review.

Gallaher JR, Charles A
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.



JAMA: 07 Mar 2022; 327:965-975
Gallaher JR, Charles A
JAMA: 07 Mar 2022; 327:965-975 | PMID: 35258527
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Impact:
Abstract

Predictive Accuracy of a Perioperative Laboratory Test-Based Prediction Model for Moderate to Severe Acute Kidney Injury After Cardiac Surgery.

Demirjian S, Bashour CA, Shaw A, Schold JD, ... Soltesz E, Gadegbeku CA
Importance
Effective treatment of acute kidney injury (AKI) is predicated on timely diagnosis; however, the lag in the increase in serum creatinine levels after kidney injury may delay therapy initiation.
Objective
To determine the derivation and validation of predictive models for AKI after cardiac surgery.
Design, setting, and participants
Multivariable prediction models were derived based on a retrospective observational cohort of adult patients undergoing cardiac surgery between January 2000 and December 2019 from a US academic medical center (n = 58 526) and subsequently validated on an external cohort from 3 US community hospitals (n = 4734). The date of final follow-up was January 15, 2020.
Exposures
Perioperative change in serum creatinine and postoperative blood urea nitrogen, serum sodium, potassium, bicarbonate, and albumin from the first metabolic panel after cardiac surgery.
Main outcomes and measures
Area under the receiver-operating characteristic curve (AUC) and calibration measures for moderate to severe AKI, per Kidney Disease: Improving Global Outcomes (KDIGO), and AKI requiring dialysis prediction models within 72 hours and 14 days following surgery.
Results
In a derivation cohort of 58 526 patients (median [IQR] age, 66 [56-74] years; 39 173 [67%] men; 51 503 [91%] White participants), the rates of moderate to severe AKI and AKIrequiring dialysis were 2674 (4.6%) and 868 (1.48%) within 72 hours and 3156 (5.4%) and 1018 (1.74%) within 14 days after surgery. The median (IQR) interval to first metabolic panel from conclusion of the surgical procedure was 10 (7-12) hours. In the derivation cohort, the metabolic panel-based models had excellent predictive discrimination for moderate to severe AKI within 72 hours (AUC, 0.876 [95% CI, 0.869-0.883]) and 14 days (AUC, 0.854 [95% CI, 0.850-0.861]) after the surgical procedure and for AKI requiring dialysis within 72 hours (AUC, 0.916 [95% CI, 0.907-0.926]) and 14 days (AUC, 0.900 [95% CI, 0.889-0.909]) after the surgical procedure. In the validation cohort of 4734 patients (median [IQR] age, 67 (60-74) years; 3361 [71%] men; 3977 [87%] White participants), the models for moderate to severe AKI after the surgical procedure showed AUCs of 0.860 (95% CI, 0.838-0.882) within 72 hours and 0.842 (95% CI, 0.820-0.865) within 14 days and the models for AKI requiring dialysis and 14 days had an AUC of 0.879 (95% CI, 0.840-0.918) within 72 hours and 0.873 (95% CI, 0.836-0.910) within 14 days after the surgical procedure. Calibration assessed by Spiegelhalter z test showed P >.05 indicating adequate calibration for both validation and derivation models.

Conclusions:
and relevance
Among patients undergoing cardiac surgery, a prediction model based on perioperative basic metabolic panel laboratory values demonstrated good predictive accuracy for moderate to severe acute kidney injury within 72 hours and 14 days after the surgical procedure. Further research is needed to determine whether use of the risk prediction tool improves clinical outcomes.



JAMA: 07 Mar 2022; 327:956-964
Demirjian S, Bashour CA, Shaw A, Schold JD, ... Soltesz E, Gadegbeku CA
JAMA: 07 Mar 2022; 327:956-964 | PMID: 35258532
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Impact:

This program is still in alpha version.