Journal: JAMA

Sorted by: date / impact
Abstract

Effect of Platelet-Rich Plasma Injections vs Placebo on Ankle Symptoms and Function in Patients With Ankle Osteoarthritis: A Randomized Clinical Trial.

Paget LDA, Reurink G, de Vos RJ, Weir A, ... Tol JL, PRIMA Study Group
Importance
Approximately 3.4% of adults have ankle (tibiotalar) osteoarthritis and, among younger patients, ankle osteoarthritis is more common than knee and hip osteoarthritis. Few effective nonsurgical interventions exist, but platelet-rich plasma (PRP) injections are widely used, with some evidence of efficacy in knee osteoarthritis.
Objective
To determine the effect of PRP injections on symptoms and function in patients with ankle osteoarthritis.
Design, setting, and participants
A multicenter, block-randomized, double-blinded, placebo-controlled clinical trial performed at 6 sites in the Netherlands that included 100 patients with pain greater than 40 on a visual analog scale (range, 0-100) and tibiotalar joint space narrowing. Enrollment began on August 24, 2018, and follow-up was completed on December 3, 2020.
Interventions
Patients were randomly assigned (1:1) to receive 2 ultrasonography-guided intra-articular injections of either PRP (n = 48) or placebo (saline; n = 52).
Main outcomes and measures
The primary outcome was the validated American Orthopaedic Foot and Ankle Society score (range, 0-100; higher scores indicate less pain and better function; minimal clinically important difference, 12 points) over 26 weeks.
Results
Among 100 randomized patients (mean age, 56 years; 45 [45%] women), no patients were lost to follow-up for the primary outcome. Compared with baseline values, the mean American Orthopaedic Foot and Ankle Society score improved by 10 points in the PRP group (from 63 to 73 points [95% CI, 6-14]; P < .001) and 11 points in the placebo group (from 64 to 75 points [95% CI, 7-15]; P < .001). The adjusted between-group difference over 26 weeks was -1 ([95% CI, -6 to 3]; P = .56). One serious adverse event was reported in the placebo group, which was unrelated to the intervention; there were 13 other adverse events in the PRP group and 8 in the placebo group.

Conclusions:
and relevance
Among patients with ankle osteoarthritis, intra-articular PRP injections, compared with placebo injections, did not significantly improve ankle symptoms and function over 26 weeks. The results of this study do not support the use of PRP injections for ankle osteoarthritis.
Trial registration
Netherlands Trial Register: NTR7261.



JAMA: 25 Oct 2021; 326:1595-1605
Paget LDA, Reurink G, de Vos RJ, Weir A, ... Tol JL, PRIMA Study Group
JAMA: 25 Oct 2021; 326:1595-1605 | PMID: 34698782
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Impact:
Abstract

Strengthening the Reporting of Observational Studies in Epidemiology Using Mendelian Randomization: The STROBE-MR Statement.

Skrivankova VW, Richmond RC, Woolf BAR, Yarmolinsky J, ... Egger M, Richards JB
Importance
Mendelian randomization (MR) studies use genetic variation associated with modifiable exposures to assess their possible causal relationship with outcomes and aim to reduce potential bias from confounding and reverse causation.
Objective
To develop the STROBE-MR Statement as a stand-alone extension to the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guideline for the reporting of MR studies.
Design, setting, and participants
The development of the STROBE-MR Statement followed the Enhancing the Quality and Transparency of Health Research (EQUATOR) framework guidance and used the STROBE Statement as a starting point to draft a checklist tailored to MR studies. The project was initiated in 2018 by reviewing the literature on the reporting of instrumental variable and MR studies. A group of 17 experts, including MR methodologists, MR study design users, developers of previous reporting guidelines, and journal editors, participated in a workshop in May 2019 to define the scope of the Statement and draft the checklist. The draft checklist was published as a preprint in July 2019 and discussed on the preprint platform, in social media, and at the 4th Mendelian Randomization Conference. The checklist was then revised based on comments, further refined through 2020, and finalized in July 2021.
Findings
The STROBE-MR checklist is organized into 6 sections (Title and Abstract, Introduction, Methods, Results, Discussion, and Other Information) and includes 20 main items and 30 subitems. It covers both 1-sample and 2-sample MR studies that assess 1 or multiple exposures and outcomes, and addresses MR studies that follow a genome-wide association study and are reported in the same article. The checklist asks authors to justify why MR is a helpful method to address the study question and state prespecified causal hypotheses. The measurement, quality, and selection of genetic variants must be described and attempts to assess validity of MR-specific assumptions should be well reported. An item on data sharing includes reporting when the data and statistical code required to replicate the analyses can be accessed.

Conclusions:
and relevance
STROBE-MR provides guidelines for reporting MR studies. Improved reporting of these studies could facilitate their evaluation by editors, peer reviewers, researchers, clinicians, and other readers, and enhance the interpretation of their results.



JAMA: 25 Oct 2021; 326:1614-1621
Skrivankova VW, Richmond RC, Woolf BAR, Yarmolinsky J, ... Egger M, Richards JB
JAMA: 25 Oct 2021; 326:1614-1621 | PMID: 34698778
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Impact:
Abstract

USPSTF Approach to Addressing Sex and Gender When Making Recommendations for Clinical Preventive Services.

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



JAMA: 24 Oct 2021; epub ahead of print
Caughey AB, Krist AH, Wolff TA, Barry MJ, ... Simon MA, Mangione CM
JAMA: 24 Oct 2021; epub ahead of print | PMID: 34694343
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Impact:
Abstract

Effect of 12 mg vs 6 mg of Dexamethasone on the Number of Days Alive Without Life Support in Adults With COVID-19 and Severe Hypoxemia: The COVID STEROID 2 Randomized Trial.

COVID STEROID 2 Trial Group, Munch MW, Myatra SN, Vijayaraghavan BKT, ... Venkatesh B, Perner A
Importance
A daily dose with 6 mg of dexamethasone is recommended for up to 10 days in patients with severe and critical COVID-19, but a higher dose may benefit those with more severe disease.
Objective
To assess the effects of 12 mg/d vs 6 mg/d of dexamethasone in patients with COVID-19 and severe hypoxemia.
Design, setting, and participants
A multicenter, randomized clinical trial was conducted between August 2020 and May 2021 at 26 hospitals in Europe and India and included 1000 adults with confirmed COVID-19 requiring at least 10 L/min of oxygen or mechanical ventilation. End of 90-day follow-up was on August 19, 2021.
Interventions
Patients were randomized 1:1 to 12 mg/d of intravenous dexamethasone (n = 503) or 6 mg/d of intravenous dexamethasone (n = 497) for up to 10 days.
Main outcomes and measures
The primary outcome was the number of days alive without life support (invasive mechanical ventilation, circulatory support, or kidney replacement therapy) at 28 days and was adjusted for stratification variables. Of the 8 prespecified secondary outcomes, 5 are included in this analysis (the number of days alive without life support at 90 days, the number of days alive out of the hospital at 90 days, mortality at 28 days and at 90 days, and ≥1 serious adverse reactions at 28 days).
Results
Of the 1000 randomized patients, 982 were included (median age, 65 [IQR, 55-73] years; 305 [31%] women) and primary outcome data were available for 971 (491 in the 12 mg of dexamethasone group and 480 in the 6 mg of dexamethasone group). The median number of days alive without life support was 22.0 days (IQR, 6.0-28.0 days) in the 12 mg of dexamethasone group and 20.5 days (IQR, 4.0-28.0 days) in the 6 mg of dexamethasone group (adjusted mean difference, 1.3 days [95% CI, 0-2.6 days]; P = .07). Mortality at 28 days was 27.1% in the 12 mg of dexamethasone group vs 32.3% in the 6 mg of dexamethasone group (adjusted relative risk, 0.86 [99% CI, 0.68-1.08]). Mortality at 90 days was 32.0% in the 12 mg of dexamethasone group vs 37.7% in the 6 mg of dexamethasone group (adjusted relative risk, 0.87 [99% CI, 0.70-1.07]). Serious adverse reactions, including septic shock and invasive fungal infections, occurred in 11.3% in the 12 mg of dexamethasone group vs 13.4% in the 6 mg of dexamethasone group (adjusted relative risk, 0.83 [99% CI, 0.54-1.29]).

Conclusions:
and relevance
Among patients with COVID-19 and severe hypoxemia, 12 mg/d of dexamethasone compared with 6 mg/d of dexamethasone did not result in statistically significantly more days alive without life support at 28 days. However, the trial may have been underpowered to identify a significant difference.
Trial registration
ClinicalTrials.gov Identifier: NCT04509973 and ctri.nic.in Identifier: CTRI/2020/10/028731.



JAMA: 20 Oct 2021; epub ahead of print
COVID STEROID 2 Trial Group, Munch MW, Myatra SN, Vijayaraghavan BKT, ... Venkatesh B, Perner A
JAMA: 20 Oct 2021; epub ahead of print | PMID: 34673895
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Impact:
Abstract

How to Interpret and Use a Clinical Practice Guideline or Recommendation: Users\' Guides to the Medical Literature.

Brignardello-Petersen R, Carrasco-Labra A, Guyatt GH
Importance
Clinicians may rely on recommendations from clinical practice guidelines for management of patients.
Observations
A clinical practice guideline is a published statement that includes recommendations that are intended to optimize patient care. In the guideline development process, a panel of experts formulates recommendation questions that guide the retrieval of evidence that is used to inform the recommendations. Typically, methods of guideline development, a summary of the supporting evidence, and a justification of the panel\'s decisions accompany the recommendations. To use such guidelines optimally, clinicians must understand the implications of the recommendations, assess the trustworthiness of the development process, and evaluate the extent to which the recommendations are applicable to patients in their practice settings. Helpful recommendations are clear and actionable, and explicitly specify whether they are strong or weak, are appropriate for all patients, or depend on individual patients\' circumstances and values. Rigorous guidelines and recommendations are informed by appropriately conducted, up-to-date systematic reviews that consider outcomes important to patients. Because judgments are involved in the interpretation of the evidence and the process of moving from evidence to recommendations, useful guidelines consider all relevant factors that have a bearing in a clinical decision and are not influenced by conflicts of interest.

Conclusions:
and relevance
In considering a guideline\'s recommendations, clinicians must decide whether there are important differences between the factors the guideline panel has considered in making recommendations and their own practice setting.



JAMA: 18 Oct 2021; 326:1516-1523
Brignardello-Petersen R, Carrasco-Labra A, Guyatt GH
JAMA: 18 Oct 2021; 326:1516-1523 | PMID: 34665198
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Impact:
Abstract

Effect of Fractional Carbon Dioxide Laser vs Sham Treatment on Symptom Severity in Women With Postmenopausal Vaginal Symptoms: A Randomized Clinical Trial.

Li FG, Maheux-Lacroix S, Deans R, Nesbitt-Hawes E, ... Segelov E, Abbott JA
Importance
Postmenopausal vaginal symptoms are common and frequently detrimental to a woman\'s quality of life. Fractional carbon dioxide vaginal laser is increasingly offered as a treatment, but the efficacy remains unproven.
Objective
To determine the efficacy of fractional carbon dioxide laser for treatment of vaginal symptoms associated with menopause.
Design, setting, and participants
A double-blind, randomized, sham-controlled trial with 12-month follow-up was undertaken at a single tertiary referral hospital in Sydney, Australia. Enrollment commenced on September 19, 2016, with final follow-up on June 30, 2020. Participants were postmenopausal women with vaginal symptoms substantive enough to seek medical treatment. Of 232 participants approached, 85 were randomized.
Interventions
Three treatments using a fractional microablative carbon dioxide laser system performed 4 to 8 weeks apart, with 43 women randomized to the laser group and 42 to the sham group.
Main outcomes and measures
The co-primary outcomes were symptom severity assessed using a visual analog scale (VAS; range, 0-100; 0 indicates no symptoms and 100 indicates the most severe symptoms) and the Vulvovaginal Symptom Questionnaire (VSQ; range, 0-20; 0 indicates no symptoms and 20 indicates the most severe symptoms) at 12 months. The minimal clinically important difference was specified as a 50% decrease in both VAS and VSQ severity scores. There were 5 prespecified secondary outcomes, including quality of life (range, 0-100; higher scores indicate better quality of life), the Vaginal Health Index Score (range, 5-25; higher scores indicate better health), and vaginal histology (premenopausal or postmenopausal status).
Results
Of 85 randomized participants (mean [SD] age, 57 [8] years), 78 (91.7%) completed the 12-month follow-up. From baseline to 12 months, there was no significant difference between the carbon dioxide laser group and the sham group in change in symptom severity (VAS score for overall vaginal symptoms: -17.2 vs -26.6; difference, 9.4 [95% CI, -28.6 to 47.5]; VAS score for the most severe symptom: -24.5 vs -20.4; difference -4.1 [95% CI, -32.5 to 24.3]; VSQ score: -3.1 vs -1.6; difference, -1.5 [95% CI, -5.9 to 3.0]). There were no significant differences between the laser and sham group in the mean quality of life score (6.3 vs 1.4; difference, 4.8 [95% CI, -3.9 to 13.5]) and Vaginal Health Index Score (0.9 vs 1.3; difference, -0.4 [95% CI, -4.3 to 3.6]) or in histological comparisons between laser and sham treatment groups. There were 16 adverse events in the laser group and 17 in the sham group, including vaginal pain/discomfort (44% vs 68%), spotting, discharge, and lower urinary tract symptoms. No severe adverse events were reported in either group.

Conclusions:
and relevance
Among women with postmenopausal vaginal symptoms, treatment with fractional carbon dioxide laser vs sham treatment did not significantly improve vaginal symptoms after 12 months.
Trial registration
Australian and New Zealand Clinical Trials Registry: ACTRN12616001403426.



JAMA: 11 Oct 2021; 326:1381-1389
Li FG, Maheux-Lacroix S, Deans R, Nesbitt-Hawes E, ... Segelov E, Abbott JA
JAMA: 11 Oct 2021; 326:1381-1389 | PMID: 34636862
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Impact:
Abstract

Effect of Antithrombotic Therapy on Clinical Outcomes in Outpatients With Clinically Stable Symptomatic COVID-19: The ACTIV-4B Randomized Clinical Trial.

Connors JM, Brooks MM, Sciurba FC, Krishnan JA, ... Ridker PM, ACTIV-4B Investigators
Importance
Acutely ill inpatients with COVID-19 typically receive antithrombotic therapy, although the risks and benefits of this intervention among outpatients with COVID-19 have not been established.
Objective
To assess whether anticoagulant or antiplatelet therapy can safely reduce major adverse cardiopulmonary outcomes among symptomatic but clinically stable outpatients with COVID-19.
Design, setting, and participants
The ACTIV-4B Outpatient Thrombosis Prevention Trial was designed as a minimal-contact, adaptive, randomized, double-blind, placebo-controlled trial to compare anticoagulant and antiplatelet therapy among 7000 symptomatic but clinically stable outpatients with COVID-19. The trial was conducted at 52 US sites between September 2020 and June 2021; final follow-up was August 5, 2021. Prior to initiating treatment, participants were required to have platelet count greater than 100 000/mm3 and estimated glomerular filtration rate greater than 30 mL/min/1.73 m2.
Interventions
Random allocation in a 1:1:1:1 ratio to aspirin (81 mg orally once daily; n = 164), prophylactic-dose apixaban (2.5 mg orally twice daily; n = 165), therapeutic-dose apixaban (5 mg orally twice daily; n = 164), or placebo (n = 164) for 45 days.
Main outcomes and measures
The primary end point was a composite of all-cause mortality, symptomatic venous or arterial thromboembolism, myocardial infarction, stroke, or hospitalization for cardiovascular or pulmonary cause. The primary analyses for efficacy and bleeding events were limited to participants who took at least 1 dose of trial medication.
Results
On June 18, 2021, the trial data and safety monitoring board recommended early termination because of lower than anticipated event rates; at that time, 657 symptomatic outpatients with COVID-19 had been randomized (median age, 54 years [IQR, 46-59]; 59% women). The median times from diagnosis to randomization and from randomization to initiation of study treatment were 7 days and 3 days, respectively. Twenty-two randomized participants (3.3%) were hospitalized for COVID-19 prior to initiating treatment. Among the 558 patients who initiated treatment, the adjudicated primary composite end point occurred in 1 patient (0.7%) in the aspirin group, 1 patient (0.7%) in the 2.5-mg apixaban group, 2 patients (1.4%) in the 5-mg apixaban group, and 1 patient (0.7%) in the placebo group. The risk differences compared with placebo for the primary end point were 0.0% (95% CI not calculable) in the aspirin group, 0.7% (95% CI, -2.1% to 4.1%) in the 2.5-mg apixaban group, and 1.4% (95% CI, -1.5% to 5.0%) in the 5-mg apixaban group. Risk differences compared with placebo for bleeding events were 2.0% (95% CI, -2.7% to 6.8%), 4.5% (95% CI, -0.7% to 10.2%), and 6.9% (95% CI, 1.4% to 12.9%) among participants who initiated therapy in the aspirin, prophylactic apixaban, and therapeutic apixaban groups, respectively, although none were major. Findings inclusive of all randomized patients were similar.

Conclusions:
and relevance
Among symptomatic clinically stable outpatients with COVID-19, treatment with aspirin or apixaban compared with placebo did not reduce the rate of a composite clinical outcome. However, the study was terminated after enrollment of 9% of participants because of an event rate lower than anticipated.
Trial registration
ClinicalTrials.gov Identifier: NCT04498273.



JAMA: 10 Oct 2021; epub ahead of print
Connors JM, Brooks MM, Sciurba FC, Krishnan JA, ... Ridker PM, ACTIV-4B Investigators
JAMA: 10 Oct 2021; epub ahead of print | PMID: 34633405
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Impact:
Abstract

Association of Receipt of the Ad26.COV2.S COVID-19 Vaccine With Presumptive Guillain-Barré Syndrome, February-July 2021.

Woo EJ, Mba-Jonas A, Dimova RB, Alimchandani M, Zinderman CE, Nair N
Importance
As part of postauthorization safety surveillance, the US Food and Drug Administration (FDA) has identified a potential safety concern for Guillain-Barré syndrome (GBS) following receipt of the Ad26.COV2.S (Janssen/Johnson & Johnson) COVID-19 vaccine.
Objective
To assess reports of GBS received in the Vaccine Adverse Event Reporting System (VAERS) following Ad26.COV2.S vaccination.
Design, setting, and participants
Reports of presumptive GBS were identified in a US passive reporting system (VAERS) February-July 2021 and characterized, including demographics, clinical characteristics, and relevant medical history.
Exposures
Receipt of the Ad26.COV2.S vaccine; the comparator was the background rate of GBS in the general (unvaccinated) population that had been estimated and published based on a standardized case definition.
Main outcomes and measures
Presumptive GBS; the reporting rate was analyzed, including calculation of the observed to expected ratio based on background rates and vaccine administration data. Because of limited availability of medical records, cases were not assessed according to the Brighton Collaboration criteria for GBS.
Results
As of July 24, 2021, 130 reports of presumptive GBS were identified in VAERS following Ad26.COV2.S vaccination (median age, 56 years; IQR, 45-62 years; 111 individuals [86.0%] were < 65 years; 77 men [59.7%]). The median time to onset of GBS following vaccination was 13 days (IQR, 10-18 days), with 105 cases (81.4%) beginning within 21 days and 123 (95.3%) within 42 days. One hundred twenty-one reports (93.1%) were serious, including 1 death. With approximately 13 209 858 doses of vaccine administered to adults in the US, the estimated crude reporting rate was 1 case of GBS per 100 000 doses administered. The overall estimated observed to expected rate ratio was 4.18 (95% CI, 3.47-4.98) for the 42-day window, and in the worst-case scenario analysis for adults 18 years or older, corresponded to an estimated absolute rate increase of 6.36 per 100 000 person-years (based on a rate of approximately 8.36 cases per 100 000 person-years [123 cases per 1 472 162 person-years] compared with a background rate of approximately 2 cases per 100 000 person-years). For both risk windows, the observed to expected rate ratio was elevated in all age groups except individuals aged 18 through 29 years.

Conclusions:
and relevance
These findings suggest a potential small but statistically significant safety concern for Guillain-Barré syndrome following receipt of the Ad26.COV2.S vaccine. However, the findings are subject to the limitations of passive reporting systems and presumptive case definition, and they must be considered preliminary pending analysis of medical records to establish a definitive diagnosis.



JAMA: 06 Oct 2021; epub ahead of print
Woo EJ, Mba-Jonas A, Dimova RB, Alimchandani M, Zinderman CE, Nair N
JAMA: 06 Oct 2021; epub ahead of print | PMID: 34617967
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Impact:
Abstract

US Emergency Department Visits Attributed to Medication Harms, 2017-2019.

Budnitz DS, Shehab N, Lovegrove MC, Geller AI, Lind JN, Pollock DA
Importance
Assessing the scope of acute medication harms to patients should include both therapeutic and nontherapeutic medication use.
Objective
To describe the characteristics of emergency department (ED) visits for acute harms from both therapeutic and nontherapeutic medication use in the US.
Design, setting, and participants
Active, nationally representative, public health surveillance based on patient visits to 60 EDs in the US participating in the National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance Project from 2017 through 2019.
Exposures
Medications implicated in ED visits, with visits attributed to medication harms (adverse events) based on the clinicians\' diagnoses and supporting data documented in the medical record.
Main outcomes and measures
Nationally weighted estimates of ED visits and subsequent hospitalizations for medication harms.
Results
Based on 96 925 cases (mean patient age, 49 years; 55% female), there were an estimated 6.1 (95% CI, 4.8-7.5) ED visits for medication harms per 1000 population annually and 38.6% (95% CI, 35.2%-41.9%) resulted in hospitalization. Population rates of ED visits for medication harms were higher for patients aged 65 years or older than for those younger than 65 years (12.1 vs 5.0 [95% CI, 7.4-16.8 vs 4.1-5.8] per 1000 population). Overall, an estimated 69.1% (95% CI, 63.6%-74.7%) of ED visits for medication harms involved therapeutic medication use, but among patients younger than 45 years, an estimated 52.5% (95% CI, 48.1%-56.8%) of visits for medication harms involved nontherapeutic use. The proportions of ED visits for medication harms involving therapeutic use were lowest for barbiturates (6.3%), benzodiazepines (11.1%), nonopioid analgesics (15.7%), and antihistamines (21.8%). By age group, the most frequent medication types and intents of use associated with ED visits for medication harms were therapeutic use of anticoagulants (4.5 [95% CI, 2.3-6.7] per 1000 population) and diabetes agents (1.8 [95% CI, 1.3-2.3] per 1000 population) for patients aged 65 years and older; therapeutic use of diabetes agents (0.8 [95% CI, 0.5-1.0] per 1000 population) for patients aged 45 to 64 years; nontherapeutic use of benzodiazepines (1.0 [95% CI, 0.7-1.3] per 1000 population) for patients aged 25 to 44 years; and unsupervised medication exposures (2.2 [95% CI, 1.8-2.7] per 1000 population) and therapeutic use of antibiotics (1.4 [95% CI, 1.0-1.8] per 1000 population) for children younger than 5 years.

Conclusions:
and relevance
According to data from 60 nationally representative US emergency departments, visits attributed to medication harms in 2017-2019 were frequent, with variation in products and intent of use by age.



JAMA: 04 Oct 2021; 326:1299-1309
Budnitz DS, Shehab N, Lovegrove MC, Geller AI, Lind JN, Pollock DA
JAMA: 04 Oct 2021; 326:1299-1309 | PMID: 34609453
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Impact:
Abstract

Effect of Prophylactic Subcutaneous Scopolamine Butylbromide on Death Rattle in Patients at the End of Life: The SILENCE Randomized Clinical Trial.

van Esch HJ, van Zuylen L, Geijteman ECT, Oomen-de Hoop E, ... van der Heide A, van der Rijt CCD
Importance
Death rattle, defined as noisy breathing caused by the presence of mucus in the respiratory tract, is relatively common among dying patients. Although clinical guidelines recommend anticholinergic drugs to reduce the death rattle after nonpharmacological measures fail, evidence regarding their efficacy is lacking. Given that anticholinergics only decrease mucus production, it is unknown whether prophylactic application may be more appropriate.
Objective
To determine whether administration of prophylactic scopolamine butylbromide reduces the death rattle.
Design, setting, and participants
A multicenter, randomized, double-blind, placebo-controlled trial was performed in 6 hospices in the Netherlands. Patients with a life expectancy of 3 or more days who were admitted to the participating hospices were asked to give advance informed consent from April 10, 2017, through December 31, 2019. When the dying phase was recognized, patients fulfilling the eligibility criteria were randomized. Of the 229 patients who provided advance informed consent, 162 were ultimately randomized. The date of final follow-up was January 31, 2020.
Interventions
Administration of subcutaneous scopolamine butylbromide, 20 mg four times a day (n = 79), or placebo (n = 78).
Main outcomes and measures
The primary outcome was the occurrence of a grade 2 or higher death rattle as defined by Back (range, 0-3; 0, no rattle; 3, rattle audible standing in the door opening) measured at 2 consecutive time points with a 4-hour interval. Secondary outcomes included the time between recognizing the dying phase and the onset of a death rattle and anticholinergic adverse events.
Results
Among 162 patients who were randomized, 157 patients (97%; median age, 76 years [IQR, 66-84 years]; 56% women) were included in the primary analyses. A death rattle occurred in 10 patients (13%) in the scopolamine group compared with 21 patients (27%) in the placebo group (difference, 14%; 95% CI, 2%-27%, P = .02). Regarding secondary outcomes, an analysis of the time to death rattle yielded a subdistribution hazard ratio (HR) of 0.44 (95% CI, 0.20-0.92; P = .03; cumulative incidence at 48 hours: 8% in the scopolamine group vs 17% in the placebo group). In the scopolamine vs placebo groups, restlessness occurred in 22 of 79 patients (28%) vs 18 of 78 (23%), dry mouth in 8 of 79 (10%) vs 12 of 78 (15%), and urinary retention in 6 of 26 (23%) vs 3 of 18 (17%), respectively.

Conclusions:
and relevance
Among patients near the end of life, prophylactic subcutaneous scopolamine butylbromide, compared with placebo, significantly reduced the occurrence of the death rattle.
Trial registration
trialregister.nl Identifier: NTR6264.



JAMA: 04 Oct 2021; 326:1268-1276
van Esch HJ, van Zuylen L, Geijteman ECT, Oomen-de Hoop E, ... van der Heide A, van der Rijt CCD
JAMA: 04 Oct 2021; 326:1268-1276 | PMID: 34609452
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Impact:
Abstract

Effect of a Pulmonary Embolism Diagnostic Strategy on Clinical Outcomes in Patients Hospitalized for COPD Exacerbation: A Randomized Clinical Trial.

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

Conclusions:
and relevance
Among patients hospitalized for an exacerbation of COPD, the addition of an active strategy for the diagnosis of PE to usual care, compared with usual care alone, did not significantly improve a composite health outcome. The study may not have had adequate power to assess individual components of the composite outcome.
Trial registration
ClinicalTrials.gov Identifier: NCT02238639.



JAMA: 04 Oct 2021; 326:1277-1285
Jiménez D, Agustí A, Tabernero E, Jara-Palomares L, ... Otero R, SLICE Trial Group
JAMA: 04 Oct 2021; 326:1277-1285 | PMID: 34609451
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Impact:
Abstract

Trends in Cardiovascular Risk Factors in US Adults by Race and Ethnicity and Socioeconomic Status, 1999-2018.

He J, Zhu Z, Bundy JD, Dorans KS, Chen J, Hamm LL
Importance
After decades of decline, the US cardiovascular disease mortality rate flattened after 2010, and racial and ethnic differences in cardiovascular disease mortality persisted.
Objective
To examine 20-year trends in cardiovascular risk factors in the US population by race and ethnicity and by socioeconomic status.
Design, setting, and participants
A total of 50 571 participants aged 20 years or older from the 1999-2018 National Health and Nutrition Examination Surveys, a series of cross-sectional surveys in nationally representative samples of the US population, were included.
Exposures
Calendar year, race and ethnicity, education, and family income.
Main outcomes and measures
Age- and sex-adjusted means or proportions of cardiovascular risk factors and estimated 10-year risk of atherosclerotic cardiovascular disease were calculated for each of 10 two-year cycles.
Results
The mean age of participants ranged from 49.0 to 51.8 years and the proportion of women from 48.2% to 51.3% in the surveys. From 1999-2000 to 2017-2018, age- and sex-adjusted mean body mass index increased from 28.0 (95% CI, 27.5-28.5) to 29.8 (95% CI, 29.2-30.4); mean hemoglobin A1c increased from 5.4% (95% CI, 5.3%-5.5%) to 5.7% (95% CI, 5.6%-5.7%) (both P < .001 for linear trends). Mean serum total cholesterol decreased from 203.3 mg/dL (95% CI, 200.9-205.8 mg/dL) to 188.5 mg/dL (95% CI, 185.2-191.9 mg/dL); prevalence of smoking decreased from 24.8% (95% CI, 21.8%-27.7%) to 18.1% (95% CI, 15.4%-20.8%) (both P < .001 for linear trends). Mean systolic blood pressure decreased from 123.5 mm Hg (95% CI, 122.2-124.8 mm Hg) in 1999-2000 to 120.5 mm Hg (95% CI, 119.6-121.3 mm Hg) in 2009-2010, then increased to 122.8 mm Hg (95% CI, 121.7-123.8 mm Hg) in 2017-2018 (P < .001 for nonlinear trend). Age- and sex-adjusted 10-year atherosclerotic cardiovascular disease risk decreased from 7.6% (95% CI, 6.9%-8.2%) in 1999-2000 to 6.5% (95% CI, 6.1%-6.8%) in 2011-2012, then did not significantly change. Age- and sex-adjusted body mass index, systolic blood pressure, and hemoglobin A1c were consistently higher, while total cholesterol was lower in non-Hispanic Black participants compared with non-Hispanic White participants (all P < .001 for group differences). Individuals with college or higher education or high family income had consistently lower levels of cardiovascular risk factors. The mean age- and sex-adjusted 10-year risk of atherosclerotic cardiovascular disease was significantly higher in non-Hispanic Black participants compared with non-Hispanic White participants (difference, 1.4% [95% CI, 1.0%-1.7%] in 1999-2008 and 2.0% [95% CI, 1.7%-2.4%] in 2009-2018]). This difference was attenuated (-0.3% [95% CI, -0.6% to 0.1%] in 1999-2008 and 0.7% [95% CI, 0.3%-1.0%] in 2009-2018) after further adjusting for education, income, home ownership, employment, health insurance, and access to health care.

Conclusions:
and relevance
In this serial cross-sectional survey study that estimated US trends in cardiovascular risk factors from 1999 through 2018, differences in cardiovascular risk factors persisted between Black and White participants; the difference may have been moderated by social determinants of health.



JAMA: 04 Oct 2021; 326:1286-1298
He J, Zhu Z, Bundy JD, Dorans KS, Chen J, Hamm LL
JAMA: 04 Oct 2021; 326:1286-1298 | PMID: 34609450
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Impact:
Abstract

Eosinophilic Esophagitis: A Review.

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

Conclusions:
and relevance
EoE has a prevalence of approximately 34.4/100 000 worldwide. Treatments consist of proton pump inhibitors, topical steroids, elemental diet, and empirical food elimination, with esophageal dilation reserved for patients with symptomatic esophageal narrowing.



JAMA: 04 Oct 2021; 326:1310-1318
Muir A, Falk GW
JAMA: 04 Oct 2021; 326:1310-1318 | PMID: 34609446
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Impact:
Abstract

Effect of Convalescent Plasma on Organ Support-Free Days in Critically Ill Patients With COVID-19: A Randomized Clinical Trial.

Writing Committee for the REMAP-CAP Investigators, Estcourt LJ, Turgeon AF, McQuilten ZK, ... Roberts DJ, Shankar-Hari M
Importance
The evidence for benefit of convalescent plasma for critically ill patients with COVID-19 is inconclusive.
Objective
To determine whether convalescent plasma would improve outcomes for critically ill adults with COVID-19.
Design, setting, and participants
The ongoing Randomized, Embedded, Multifactorial, Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) enrolled and randomized 4763 adults with suspected or confirmed COVID-19 between March 9, 2020, and January 18, 2021, within at least 1 domain; 2011 critically ill adults were randomized to open-label interventions in the immunoglobulin domain at 129 sites in 4 countries. Follow-up ended on April 19, 2021.
Interventions
The immunoglobulin domain randomized participants to receive 2 units of high-titer, ABO-compatible convalescent plasma (total volume of 550 mL ± 150 mL) within 48 hours of randomization (n = 1084) or no convalescent plasma (n = 916).
Main outcomes and measures
The primary ordinal end point was organ support-free days (days alive and free of intensive care unit-based organ support) up to day 21 (range, -1 to 21 days; patients who died were assigned -1 day). The primary analysis was an adjusted bayesian cumulative logistic model. Superiority was defined as the posterior probability of an odds ratio (OR) greater than 1 (threshold for trial conclusion of superiority >99%). Futility was defined as the posterior probability of an OR less than 1.2 (threshold for trial conclusion of futility >95%). An OR greater than 1 represented improved survival, more organ support-free days, or both. The prespecified secondary outcomes included in-hospital survival; 28-day survival; 90-day survival; respiratory support-free days; cardiovascular support-free days; progression to invasive mechanical ventilation, extracorporeal mechanical oxygenation, or death; intensive care unit length of stay; hospital length of stay; World Health Organization ordinal scale score at day 14; venous thromboembolic events at 90 days; and serious adverse events.
Results
Among the 2011 participants who were randomized (median age, 61 [IQR, 52 to 70] years and 645/1998 [32.3%] women), 1990 (99%) completed the trial. The convalescent plasma intervention was stopped after the prespecified criterion for futility was met. The median number of organ support-free days was 0 (IQR, -1 to 16) in the convalescent plasma group and 3 (IQR, -1 to 16) in the no convalescent plasma group. The in-hospital mortality rate was 37.3% (401/1075) for the convalescent plasma group and 38.4% (347/904) for the no convalescent plasma group and the median number of days alive and free of organ support was 14 (IQR, 3 to 18) and 14 (IQR, 7 to 18), respectively. The median-adjusted OR was 0.97 (95% credible interval, 0.83 to 1.15) and the posterior probability of futility (OR <1.2) was 99.4% for the convalescent plasma group compared with the no convalescent plasma group. The treatment effects were consistent across the primary outcome and the 11 secondary outcomes. Serious adverse events were reported in 3.0% (32/1075) of participants in the convalescent plasma group and in 1.3% (12/905) of participants in the no convalescent plasma group.

Conclusions:
and relevance
Among critically ill adults with confirmed COVID-19, treatment with 2 units of high-titer, ABO-compatible convalescent plasma had a low likelihood of providing improvement in the number of organ support-free days.
Trial registration
ClinicalTrials.gov Identifier: NCT02735707.



JAMA: 03 Oct 2021; epub ahead of print
Writing Committee for the REMAP-CAP Investigators, Estcourt LJ, Turgeon AF, McQuilten ZK, ... Roberts DJ, Shankar-Hari M
JAMA: 03 Oct 2021; epub ahead of print | PMID: 34606578
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Impact:
Abstract

Effect of Vasopressin and Methylprednisolone vs Placebo on Return of Spontaneous Circulation in Patients With In-Hospital Cardiac Arrest: A Randomized Clinical Trial.

Andersen LW, Isbye D, Kjærgaard J, Kristensen CM, ... Holmberg MJ, Granfeldt A
Importance
Previous trials have suggested that vasopressin and methylprednisolone administered during in-hospital cardiac arrest might improve outcomes.
Objective
To determine whether the combination of vasopressin and methylprednisolone administered during in-hospital cardiac arrest improves return of spontaneous circulation.
Design, setting, and participants
Multicenter, randomized, double-blind, placebo-controlled trial conducted at 10 hospitals in Denmark. A total of 512 adult patients with in-hospital cardiac arrest were included between October 15, 2018, and January 21, 2021. The last 90-day follow-up was on April 21, 2021.
Intervention
Patients were randomized to receive a combination of vasopressin and methylprednisolone (n = 245) or placebo (n = 267). The first dose of vasopressin (20 IU) and methylprednisolone (40 mg), or corresponding placebo, was administered after the first dose of epinephrine. Additional doses of vasopressin or corresponding placebo were administered after each additional dose of epinephrine for a maximum of 4 doses.
Main outcomes and measures
The primary outcome was return of spontaneous circulation. Secondary outcomes included survival and favorable neurologic outcome at 30 days (Cerebral Performance Category score of 1 or 2).
Results
Among 512 patients who were randomized, 501 met all inclusion and no exclusion criteria and were included in the analysis (mean [SD] age, 71 [13] years; 322 men [64%]). One hundred of 237 patients (42%) in the vasopressin and methylprednisolone group and 86 of 264 patients (33%) in the placebo group achieved return of spontaneous circulation (risk ratio, 1.30 [95% CI, 1.03-1.63]; risk difference, 9.6% [95% CI, 1.1%-18.0%]; P = .03). At 30 days, 23 patients (9.7%) in the intervention group and 31 patients (12%) in the placebo group were alive (risk ratio, 0.83 [95% CI, 0.50-1.37]; risk difference: -2.0% [95% CI, -7.5% to 3.5%]; P = .48). A favorable neurologic outcome was observed in 18 patients (7.6%) in the intervention group and 20 patients (7.6%) in the placebo group at 30 days (risk ratio, 1.00 [95% CI, 0.55-1.83]; risk difference, 0.0% [95% CI, -4.7% to 4.9%]; P > .99). In patients with return of spontaneous circulation, hyperglycemia occurred in 77 (77%) in the intervention group and 63 (73%) in the placebo group. Hypernatremia occurred in 28 (28%) and 27 (31%), in the intervention and placebo groups, respectively.

Conclusions:
and relevance
Among patients with in-hospital cardiac arrest, administration of vasopressin and methylprednisolone, compared with placebo, significantly increased the likelihood of return of spontaneous circulation. However, there is uncertainty whether this treatment results in benefit or harm for long-term survival.
Trial registration
ClinicalTrials.gov Identifier: NCT03640949.



JAMA: 28 Sep 2021; epub ahead of print
Andersen LW, Isbye D, Kjærgaard J, Kristensen CM, ... Holmberg MJ, Granfeldt A
JAMA: 28 Sep 2021; epub ahead of print | PMID: 34587236
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Impact:
Abstract

Association of Labor Epidural Analgesia With Autism Spectrum Disorder in Children.

Mikkelsen AP, Greiber IK, Scheller NM, Lidegaard Ø
Importance
A recent cohort study found that epidural analgesia during labor was associated with an increased risk of autism in offspring.
Objective
To investigate if labor epidural increases the risk of autism in offspring.
Design, setting, and participants
This nationwide retrospective cohort study identified all live-born children in Denmark between January 2006 and December 2013. Follow-up commenced at children\'s first birthday and ended in December 2017. Among 485 093 live-born children, 5915 were excluded because of occurrences during the first year of life including death, emigration, misregistration of birth, diagnosis of disease inherently linked to autism, or diagnosis of autism.
Exposures
Administration of epidural analgesia during labor, as identified by procedure code.
Main outcomes and measures
The main outcome of interest was incident diagnosis of autism spectrum disorder based on International Statistical Classification of Diseases and Related Health Problems, 10th Revision codes in the Danish Psychiatric Central Register or National Patient Register. Hazard ratios were estimated using Cox regression, adjusted for covariates describing maternal comorbidity, sociodemographic factors, lifestyle, pregnancy, psychiatric illness, psychotropic medication, medical-seeking behavior, and family history of autism. A secondary analysis used a within-mother design including only children of mothers with both exposure and nonexposure to labor epidural analgesia in different deliveries.
Results
The cohort included 479 178 children (233 405 girls [48.7%]; median maternal age at delivery, 30.9 [IQR, 27.6-34.2] years); of these, 92 900 (19.4%) were exposed to epidural analgesia during labor. Median follow-up was 7.0 years (IQR, 4.9-9.0 years), and by the end of follow-up, 6428 children (1.3%) had been diagnosed with autism. Exposed children had an autism diagnosis incidence rate of 23.1 per 10 000 person-years compared with 18.5 per 10 000 person-years in the unexposed group (crude hazard ratio, 1.29 [95% CI, 1.21-1.37]; adjusted hazard ratio, 1.05 [95% CI, 0.98-1.11]). A secondary within-mother analysis including 59 154 children (12.3%) estimated an autism diagnosis incidence rate of 20.8 per 10 000 person-years in the exposed group and 17.1 per 10 000 person-years in the unexposed group (adjusted hazard ratio, 1.05 [95% CI, 0.90-1.21]).

Conclusions:
and relevance
In this nationwide cohort study of Danish children, maternal exposure to epidural analgesia during labor was not significantly associated with autism spectrum disorder in offspring.



JAMA: 27 Sep 2021; 326:1170-1177
Mikkelsen AP, Greiber IK, Scheller NM, Lidegaard Ø
JAMA: 27 Sep 2021; 326:1170-1177 | PMID: 34581738
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Impact:
Abstract

Effect of Thrombectomy With Combined Contact Aspiration and Stent Retriever vs Stent Retriever Alone on Revascularization in Patients With Acute Ischemic Stroke and Large Vessel Occlusion: The ASTER2 Randomized Clinical Trial.

Lapergue B, Blanc R, Costalat V, Desal H, ... Piotin M, ASTER2 Trial Investigators
Importance
Mechanical thrombectomy using a stent retriever or contact aspiration is widely used for treatment of patients with acute ischemic stroke due to anterior circulation large vessel occlusion, but the additional benefit of combining contact aspiration with stent retriever is uncertain.
Objective
To determine whether mechanical thrombectomy for treatment of anterior circulation large vessel occlusion stroke with initial contact aspiration and stent retriever combined results in better final angiographic outcome than with standard stent retriever alone.
Design, setting, and participants
This trial was a multicenter randomized, open-label, blinded end point evaluation that enrolled 408 patients from October 16, 2017, to May 29, 2018, in 11 French comprehensive stroke centers, with a 12-month outcome follow-up. Patients with a large vessel occlusion in the anterior circulation were included up to 8 hours after symptom onset. The final date of follow-up was June, 19, 2019.
Interventions
Patients were randomly assigned (1:1 allocation) to receive initial thrombectomy with contact aspiration and stent retriever combined (205) or stent retriever alone (203).
Main outcomes and measures
The primary outcome was the rate of expanded Thrombolysis In Cerebral Infarction score of 2c or 3 (eTICI 2c/3; ie, scores indicate near-total and total reperfusion grades) at the end of the procedure.
Results
Among the 408 patients who were randomized, 3 were excluded, and 405 (99.3%) patients (mean age, 73 years; 220 [54%] women and 185 [46%] men) were included in the primary analysis. The rate of eTICI 2c/3 at the end of the endovascular procedure was not significantly different between the 2 thrombectomy groups (64.5% [131 of 203 patients] for contact aspiration and stent retriever combined vs 57.9% [117 of 202 patients] for stent retriever alone; risk difference, 6.6% [95% CI, -3.0% to 16.2%]; adjusted odds ratio [OR], 1.33 [95% CI, 0.88 to 1.99]; P = .17). Of 14 prespecified secondary efficacy end points, 12 showed no significant difference. A higher rate of successful reperfusion was achieved in the contact aspiration combined with stent retriever group vs the stent retriever alone group (eTICI 2b50/2c/3, 86.2% vs 72.3%; adjusted OR, 2.54 [95% CI, 1.51 to 4.28]; P < .001) and of near-total or total reperfusion (eTICI 2c/3, 59.6% vs 49.5%; adjusted OR, 1.52 [95% CI, 1.02 to 2.27]; P = .04) after the assigned initial intervention alone.

Conclusions:
and relevance
Among patients with acute ischemic stroke due to large vessel occlusion, an initial thrombectomy technique consisting of contact aspiration and stent retriever combined, compared with stent retriever alone, did not significantly improve the rate of near-total or total reperfusion (eTICI 2c/3) at the end of the endovascular procedure, although the trial may have been underpowered to detect smaller differences between groups.
Trial registration
ClinicalTrials.gov Identifier: NCT03290885.



JAMA: 27 Sep 2021; 326:1158-1169
Lapergue B, Blanc R, Costalat V, Desal H, ... Piotin M, ASTER2 Trial Investigators
JAMA: 27 Sep 2021; 326:1158-1169 | PMID: 34581737
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Impact:
Abstract

Association of Epidural Analgesia During Labor and Delivery With Autism Spectrum Disorder in Offspring.

Hanley GE, Bickford C, Ip A, Lanphear N, ... Zwaigenbaum L, Oberlander TF
Importance
Evidence from studies investigating the association of epidural analgesia use during labor and delivery with risk of autism spectrum disorder (ASD) in offspring is conflicting.
Objective
To assess the association of maternal use of epidural analgesia during labor and delivery with ASD in offspring using a large population-based data set with clinical data on ASD case status.
Design, setting, and participants
This population-based retrospective cohort study included term singleton children born in British Columbia, Canada, between April 1, 2000, and December 31, 2014. Stillbirths and cesarean deliveries were excluded. Clinical ASD diagnostic data were obtained from the British Columbia Autism Assessment Network and the British Columbia Ministry of Education. All children were followed up until clinical diagnosis of ASD, death, or the study end date of December 31, 2016.
Exposures
Use of epidural analgesia during labor and delivery.
Main outcomes and measures
A clinical diagnosis of ASD made by pediatricians, psychiatrists, and psychologists with specialty training to assess ASD. Cox proportional hazards models were used to estimate the hazard ratio of epidural analgesia use and ASD. Models were adjusted for maternal sociodemographics; maternal conditions during pregnancy; labor, delivery, and antenatal care characteristics; infant sex; gestational age; and status of small or large for gestational age. A conditional logistic regression model matching women with 2 births or more and discordance in ASD status of the offspring also was performed.
Results
Of the 388 254 children included in the cohort (49.8% female; mean gestational age, 39.2 [SD, 1.2] weeks; mean follow-up, 9.05 [SD, 4.3] years), 5192 were diagnosed with ASD (1.34%) and 111 480 (28.7%) were exposed to epidural analgesia. A diagnosis of ASD was made for 1710 children (1.53%) among the 111 480 deliveries exposed to epidural analgesia (94 157 women) vs a diagnosis of ASD in 3482 children (1.26%) among the 276 774 deliveries not exposed to epidural analgesia (192 510 women) (absolute risk difference, 0.28% [95% CI, 0.19%-0.36%]). The unadjusted hazard ratio was 1.32 (95% CI, 1.24-1.40) and the fully adjusted hazard ratio was 1.09 (95% CI, 1.00-1.15). There was no statistically significant association of epidural analgesia use during labor and delivery with ASD in the within-woman matched conditional logistic regression (839/1659 [50.6%] in the exposed group vs 1905/4587 [41.5%] in the unexposed group; fully adjusted hazard ratio, 1.07 [95% CI, 0.87-1.30]).

Conclusions:
and relevance
In this population-based study, maternal epidural analgesia use during labor and delivery was associated with a small increase in the risk of autism spectrum disorder in offspring that met the threshold for statistical significance. However, given the likelihood of residual confounding that may account for the results, these findings do not provide strong supporting evidence for this association.



JAMA: 27 Sep 2021; 326:1178-1185
Hanley GE, Bickford C, Ip A, Lanphear N, ... Zwaigenbaum L, Oberlander TF
JAMA: 27 Sep 2021; 326:1178-1185 | PMID: 34581736
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Impact:
Abstract

Aspirin Use to Prevent Preeclampsia and Related Morbidity and Mortality: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.

Henderson JT, Vesco KK, Senger CA, Thomas RG, Redmond N
Importance
Preeclampsia is a hypertensive disorder of pregnancy that poses serious maternal and infant health risks. Previous systematic reviews have established benefits of low-dose aspirin taken during pregnancy to prevent preeclampsia and its sequelae.
Objective
To update evidence for the US Preventive Services Task Force (USPSTF) on effectiveness of aspirin use in preventing preeclampsia in individuals at increased risk based on clinical risk factors or measurements associated with higher disease incidence than in the general population.
Data sources
Studies from previous USPSTF review (2014), literature published January 2013 through May 15, 2020, in MEDLINE, PubMed (for publisher-supplied records only), EMBASE, and Cochrane Central Register of Controlled Trials. Ongoing surveillance through January 22, 2021.
Study selection
Good- and fair-quality randomized clinical trials (RCTs) of low-dose aspirin use during pregnancy to prevent preeclampsia among individuals at increased risk; studies conducted in general populations to evaluate potential harms.
Data extraction and synthesis
Dual article screening and risk-of-bias assessment. Study data abstracted into prespecified forms, checked for accuracy. Random-effects meta-analysis.
Main outcomes and measures
Diagnosis of preeclampsia; adverse pregnancy health outcomes and complications including eclampsia, perinatal mortality, preterm birth, small for gestational age, and potential bleeding harms or infant/child harms from aspirin exposure.
Results
A total of 23 randomized clinical trials (RCTs) (N = 26 952) were included; 18 were conducted among participants at increased preeclampsia risk. Aspirin dosages ranged from 50 mg/d to 150 mg/d. Most trials enrolled majority White populations selected based on a range of risk factors. The incidence of preeclampsia among the trials of participants at increased risk ranged from 4% to 30%. Aspirin use was significantly associated with lower risk of preeclampsia (pooled relative risk [RR], 0.85 [95% CI, 0.75-0.95]; 16 RCTs [n = 14 093]; I2 = 0%), perinatal mortality (pooled RR, 0.79 [95% CI, 0.66-0.96]; 11 RCTs [n = 13 860]; I2 = 0%), preterm birth (pooled RR, 0.80 [95% CI, 0.67-0.95]; 13 RCTs [n = 13 619]; I2 = 49%), and intrauterine growth restriction (pooled RR, 0.82 [95% CI, 0.68-0.99]; 16 RCTs [n = 14 385]; I2 = 41%). There were no significant associations of aspirin use with risk of postpartum hemorrhage (pooled RR, 1.03 [95% CI, 0.94-1.12]; 9 RCTs [n = 23 133]; I2 = 0%) and other bleeding-related harms, or with rare perinatal or longer-term harms. Absolute risk reductions for preeclampsia associated with aspirin use ranged from -1% to -6% across larger trials (n >300) and were greater in smaller trials. For perinatal mortality, absolute risk reductions ranged from 0.5% to 1.1% in the 3 largest trials.

Conclusions:
and relevance
Daily low-dose aspirin during pregnancy was associated with lower risks of serious perinatal outcomes for individuals at increased risk for preeclampsia, without evident harms.



JAMA: 27 Sep 2021; 326:1192-1206
Henderson JT, Vesco KK, Senger CA, Thomas RG, Redmond N
JAMA: 27 Sep 2021; 326:1192-1206 | PMID: 34581730
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Impact:
Abstract

Aspirin Use to Prevent Preeclampsia and Related Morbidity and Mortality: US Preventive Services Task Force Recommendation Statement.

US Preventive Services Task Force, Davidson KW, Barry MJ, Mangione CM, ... Tseng CW, Wong JB
Importance
Preeclampsia is one of the most serious health problems that affect pregnant persons. It is a complication in approximately 4% of pregnancies in the US and contributes to both maternal and infant morbidity and mortality. Preeclampsia also accounts for 6% of preterm births and 19% of medically indicated preterm births in the US. There are racial and ethnic disparities in the prevalence of and mortality from preeclampsia. Non-Hispanic Black women are at greater risk for developing preeclampsia than other women and experience higher rates of maternal and infant morbidity and perinatal mortality.
Objective
To update its 2014 recommendation, the USPSTF commissioned a systematic review to evaluate the effectiveness of low-dose aspirin use to prevent preeclampsia.
Population
Pregnant persons at high risk for preeclampsia who have no prior adverse effects with or contraindications to low-dose aspirin.
Evidence assessment
The USPSTF concludes with moderate certainty that there is a substantial net benefit of daily low-dose aspirin use to reduce the risk for preeclampsia, preterm birth, small for gestational age/intrauterine growth restriction, and perinatal mortality in pregnant persons at high risk for preeclampsia.
Recommendation
The USPSTF recommends the use of low-dose aspirin (81 mg/d) as preventive medication for preeclampsia after 12 weeks of gestation in persons who are at high risk for preeclampsia. (B recommendation).



JAMA: 27 Sep 2021; 326:1186-1191
US Preventive Services Task Force, Davidson KW, Barry MJ, Mangione CM, ... Tseng CW, Wong JB
JAMA: 27 Sep 2021; 326:1186-1191 | PMID: 34581729
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Impact:
Abstract

Association Between Transcatheter Aortic Valve Replacement for Bicuspid vs Tricuspid Aortic Stenosis and Mortality or Stroke Among Patients at Low Surgical Risk.

Makkar RR, Yoon SH, Chakravarty T, Kapadia SR, ... Leon MB, Thourani VH
Importance
There are limited data on outcomes of transcatheter aortic valve replacement (TAVR) for bicuspid aortic stenosis in patients at low surgical risk.
Objective
To compare the outcomes of TAVR with a balloon-expandable valve for bicuspid vs tricuspid aortic stenosis in patients who are at low surgical risk.
Design, setting, and participants
Registry-based cohort study of patients undergoing TAVR at 684 US centers. Participants were enrolled in the Society of Thoracic Surgeons (STS)/American College of Cardiology Transcatheter Valve Therapies Registry from June 2015 to October 2020. Among 159 661 patients (7058 bicuspid, 152 603 tricuspid), 37 660 patients (3243 bicuspid and 34 417 tricuspid) who were at low surgical risk (defined as STS risk score <3%) were included in the analysis.
Exposures
TAVR for bicuspid vs tricuspid aortic stenosis.
Main outcomes and measures
Coprimary outcomes were 30-day and 1-year mortality and stroke. Secondary outcomes included procedural complications and valve hemodynamics.
Results
Among 159 661 patients (7058 bicuspid; 152 603 tricuspid), 3168 propensity-matched pairs of patients with bicuspid and tricuspid aortic stenosis at low surgical risk were analyzed (mean age, 69 years; 69.8% men; mean [SD] STS-predicted risk of mortality, 1.7% [0.6%] for bicuspid and 1.7% [0.7%] for tricuspid). There was no significant difference between the bicuspid and tricuspid groups\' rates of death at 30 days (0.9% vs 0.8%; hazard ratio [HR], 1.18 [95% CI, 0.68-2.03]; P = .55) and at 1 year (4.6% vs 6.6%; HR, 0.75 [95% CI, 0.55-1.02]; P = .06) or stroke at 30 days (1.4% vs 1.2%; HR, 1.14 [95% CI, 0.73-1.78]; P = .55) and at 1 year (2.0% vs 2.1%; HR 1.03 [95% CI, 0.69-1.53]; P = .89).There were no significant differences between the bicuspid and tricuspid groups in procedural complications, valve hemodynamics (aortic valve gradient: 13.2 mm Hg vs 13.5 mm Hg; absolute risk difference [RD], 0.3 mm Hg [95% CI, -0.9 to 0.3 mm Hg]), and moderate or severe paravalvular leak (3.4% vs 2.1%; absolute RD, 1.3% [95% CI, -0.6% to 3.2%]).

Conclusions:
and relevance
In this preliminary, registry-based study of propensity-matched patients at low surgical risk who had undergone TAVR for aortic stenosis, patients treated for bicuspid vs tricuspid aortic stenosis had no significant difference in mortality or stroke at 30 days or 1 year. Because of the potential for selection bias and absence of a control group treated surgically for bicuspid aortic stenosis, randomized trials are needed to adequately assess the efficacy and safety of transcatheter aortic valve replacement for bicuspid aortic stenosis in patients at low surgical risk.



JAMA: 20 Sep 2021; 326:1034-1044
Makkar RR, Yoon SH, Chakravarty T, Kapadia SR, ... Leon MB, Thourani VH
JAMA: 20 Sep 2021; 326:1034-1044 | PMID: 34546301
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Impact:
Abstract

Surveillance for Adverse Events After COVID-19 mRNA Vaccination.

Klein NP, Lewis N, Goddard K, Fireman B, ... DeStefano F, Weintraub ES
Importance
Safety surveillance of vaccines against COVID-19 is critical to ensure safety, maintain trust, and inform policy.
Objectives
To monitor 23 serious outcomes weekly, using comprehensive health records on a diverse population.
Design, setting, and participants
This study represents an interim analysis of safety surveillance data from Vaccine Safety Datalink. The 10 162 227 vaccine-eligible members of 8 participating US health plans were monitored with administrative data updated weekly and supplemented with medical record review for selected outcomes from December 14, 2020, through June 26, 2021.
Exposures
Receipt of BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) COVID-19 vaccination, with a risk interval of 21 days for individuals after vaccine dose 1 or 2 compared with an interval of 22 to 42 days for similar individuals after vaccine dose 1 or 2.
Main outcomes and measures
Incidence of serious outcomes, including acute myocardial infarction, Bell palsy, cerebral venous sinus thrombosis, Guillain-Barré syndrome, myocarditis/pericarditis, pulmonary embolism, stroke, and thrombosis with thrombocytopenia syndrome. Incidence of events that occurred among vaccine recipients 1 to 21 days after either dose 1 or 2 of a messenger RNA (mRNA) vaccine was compared with that of vaccinated concurrent comparators who, on the same calendar day, had received their most recent dose 22 to 42 days earlier. Rate ratios (RRs) were estimated by Poisson regression, adjusted for age, sex, race and ethnicity, health plan, and calendar day. For a signal, a 1-sided P < .0048 was required to keep type I error below .05 during 2 years of weekly analyses. For 4 additional outcomes, including anaphylaxis, only descriptive analyses were conducted.
Results
A total of 11 845 128 doses of mRNA vaccines (57% BNT162b2; 6 175 813 first doses and 5 669 315 second doses) were administered to 6.2 million individuals (mean age, 49 years; 54% female individuals). The incidence of events per 1 000 000 person-years during the risk vs comparison intervals for ischemic stroke was 1612 vs 1781 (RR, 0.97; 95% CI, 0.87-1.08); for appendicitis, 1179 vs 1345 (RR, 0.82; 95% CI, 0.73-0.93); and for acute myocardial infarction, 935 vs 1030 (RR, 1.02; 95% CI, 0.89-1.18). No vaccine-outcome association met the prespecified requirement for a signal. Incidence of confirmed anaphylaxis was 4.8 (95% CI, 3.2-6.9) per million doses of BNT162b2 and 5.1 (95% CI, 3.3-7.6) per million doses of mRNA-1273.

Conclusions:
and relevance
In interim analyses of surveillance of mRNA COVID-19 vaccines, incidence of selected serious outcomes was not significantly higher 1 to 21 days postvaccination compared with 22 to 42 days postvaccination. While CIs were wide for many outcomes, surveillance is ongoing.



JAMA: 02 Sep 2021; epub ahead of print
Klein NP, Lewis N, Goddard K, Fireman B, ... DeStefano F, Weintraub ES
JAMA: 02 Sep 2021; epub ahead of print | PMID: 34477808
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Impact:
Abstract

Estimated US Infection- and Vaccine-Induced SARS-CoV-2 Seroprevalence Based on Blood Donations, July 2020-May 2021.

Jones JM, Stone M, Sulaeman H, Fink RV, ... Opsomer J, Busch MP
Importance
People who have been infected with or vaccinated against SARS-CoV-2 have reduced risk of subsequent infection, but the proportion of people in the US with SARS-CoV-2 antibodies from infection or vaccination is uncertain.
Objective
To estimate trends in SARS-CoV-2 seroprevalence related to infection and vaccination in the US population.
Design, setting, and participants
In a repeated cross-sectional study conducted each month during July 2020 through May 2021, 17 blood collection organizations with blood donations from all 50 US states; Washington, DC; and Puerto Rico were organized into 66 study-specific regions, representing a catchment of 74% of the US population. For each study region, specimens from a median of approximately 2000 blood donors were selected and tested each month; a total of 1 594 363 specimens were initially selected and tested. The final date of blood donation collection was May 31, 2021.
Exposure
Calendar time.
Main outcomes and measures
Proportion of persons with detectable SARS-CoV-2 spike and nucleocapsid antibodies. Seroprevalence was weighted for demographic differences between the blood donor sample and general population. Infection-induced seroprevalence was defined as the prevalence of the population with both spike and nucleocapsid antibodies. Combined infection- and vaccination-induced seroprevalence was defined as the prevalence of the population with spike antibodies. The seroprevalence estimates were compared with cumulative COVID-19 case report incidence rates.
Results
Among 1 443 519 specimens included, 733 052 (50.8%) were from women, 174 842 (12.1%) were from persons aged 16 to 29 years, 292 258 (20.2%) were from persons aged 65 years and older, 36 654 (2.5%) were from non-Hispanic Black persons, and 88 773 (6.1%) were from Hispanic persons. The overall infection-induced SARS-CoV-2 seroprevalence estimate increased from 3.5% (95% CI, 3.2%-3.8%) in July 2020 to 20.2% (95% CI, 19.9%-20.6%) in May 2021; the combined infection- and vaccination-induced seroprevalence estimate in May 2021 was 83.3% (95% CI, 82.9%-83.7%). By May 2021, 2.1 SARS-CoV-2 infections (95% CI, 2.0-2.1) per reported COVID-19 case were estimated to have occurred.

Conclusions:
and relevance
Based on a sample of blood donations in the US from July 2020 through May 2021, vaccine- and infection-induced SARS-CoV-2 seroprevalence increased over time and varied by age, race and ethnicity, and geographic region. Despite weighting to adjust for demographic differences, these findings from a national sample of blood donors may not be representative of the entire US population.



JAMA: 01 Sep 2021; epub ahead of print
Jones JM, Stone M, Sulaeman H, Fink RV, ... Opsomer J, Busch MP
JAMA: 01 Sep 2021; epub ahead of print | PMID: 34473201
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Impact:
Abstract

Screening and Interventions for Social Risk Factors: Technical Brief to Support the US Preventive Services Task Force.

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

Conclusions:
and relevance
Many interventions to address food insecurity, financial strain, and housing instability have been studied, but more randomized clinical trials that report health outcomes from social risk screening and intervention are needed to guide widespread implementation in health care.



JAMA: 31 Aug 2021; epub ahead of print
Eder M, Henninger M, Durbin S, Iacocca MO, ... Gottlieb LM, Lin JS
JAMA: 31 Aug 2021; epub ahead of print | PMID: 34468710
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Impact:
Abstract

Incorporation of Social Risk in US Preventive Services Task Force Recommendations and Identification of Key Challenges for Primary Care.

Davidson KW, Krist AH, Tseng CW, Simon M, ... Mills J, Borsky A
Importance
In its mission to improve health, the US Preventive Services Task Force (USPSTF) recognizes the strong relationship between a person\'s health and social and economic circumstances as well as persistent inequities in health care delivery.
Objective
To assess how social risks have been considered in USPSTF recommendation statements and identify current gaps in evidence needed to expand the systematic inclusion of social risks in future recommendations.
Evidence
The USPSTF commissioned a technical brief that reviewed existing literature on screening and interventions for social risk factors and also audited the 85 USPSTF recommendation statements active as of December 2019 to determine how social risks were addressed in clinical preventive services recommendations.
Findings
Among the 85 USPSTF recommendation statements reviewed, 14 were focused on preventive services that considered health-related social risks. Social risks were commonly referenced in parts of USPSTF recommendations, with 57 of 85 recommendations including some comment on social risks within the recommendation statement, although many comments were not separate prevention services. Social risks were commented on in USPSTF recommendations as part of risk assessment, as a marker of worse health outcomes from the condition of focus, as a consideration for clinicians when implementing the preventive service, and as a research need or gap on the topic.

Conclusions:
and relevance
This report identified how social risks have been considered in the USPSTF recommendation statements. It serves as a benchmark and foundation for ongoing work to advance the goal of ensuring that health equity and social risks are incorporated in USPSTF methods and recommendations.



JAMA: 31 Aug 2021; epub ahead of print
Davidson KW, Krist AH, Tseng CW, Simon M, ... Mills J, Borsky A
JAMA: 31 Aug 2021; epub ahead of print | PMID: 34468692
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Impact:
Abstract

Trends in Differences in Health Status and Health Care Access and Affordability by Race and Ethnicity in the United States, 1999-2018.

Mahajan S, Caraballo C, Lu Y, Valero-Elizondo J, ... Herrin J, Krumholz HM
Importance
The elimination of racial and ethnic differences in health status and health care access is a US goal, but it is unclear whether the country has made progress over the last 2 decades.
Objective
To determine 20-year trends in the racial and ethnic differences in self-reported measures of health status and health care access and affordability among adults in the US.
Design, setting, and participants
Serial cross-sectional study of National Health Interview Survey data, 1999-2018, that included 596 355 adults.
Exposures
Self-reported race, ethnicity, and income level.
Main outcomes and measures
Rates and racial and ethnic differences in self-reported health status and health care access and affordability.
Results
The study included 596 355 adults (mean [SE] age, 46.2 [0.07] years, 51.8% [SE, 0.10] women), of whom 4.7% were Asian, 11.8% were Black, 13.8% were Latino/Hispanic, and 69.7% were White. The estimated percentages of people with low income were 28.2%, 46.1%, 51.5%, and 23.9% among Asian, Black, Latino/Hispanic, and White individuals, respectively. Black individuals with low income had the highest estimated prevalence of poor or fair health status (29.1% [95% CI, 26.5%-31.7%] in 1999 and 24.9% [95% CI, 21.8%-28.3%] in 2018), while White individuals with middle and high income had the lowest (6.4% [95% CI, 5.9%-6.8%] in 1999 and 6.3% [95% CI, 5.8%-6.7%] in 2018). Black individuals had a significantly higher estimated prevalence of poor or fair health status than White individuals in 1999, regardless of income strata (P < .001 for the overall and low-income groups; P = .03 for middle and high-income group). From 1999 to 2018, racial and ethnic gaps in poor or fair health status did not change significantly, with or without income stratification, except for a significant decrease in the difference between White and Black individuals with low income (-6.7 percentage points [95% CI, -11.3 to -2.0]; P = .005); the difference in 2018 was no longer statistically significant (P = .13). Black and White individuals had the highest levels of self-reported functional limitations, which increased significantly among all groups over time. There were significant reductions in the racial and ethnic differences in some self-reported measures of health care access, but not affordability, with and without income stratification.

Conclusions:
and relevance
In a serial cross-sectional survey study of US adults from 1999 to 2018, racial and ethnic differences in self-reported health status, access, and affordability improved in some subgroups, but largely persisted.



JAMA: 16 Aug 2021; 326:637-648
Mahajan S, Caraballo C, Lu Y, Valero-Elizondo J, ... Herrin J, Krumholz HM
JAMA: 16 Aug 2021; 326:637-648 | PMID: 34402830
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Impact:
Abstract

Effect of Intravenous Fluid Treatment With a Balanced Solution vs 0.9% Saline Solution on Mortality in Critically Ill Patients: The BaSICS Randomized Clinical Trial.

Zampieri FG, Machado FR, Biondi RS, Freitas FGR, ... Cavalcanti AB, BaSICS investigators and the BRICNet members
Importance
Intravenous fluids are used for almost all intensive care unit (ICU) patients. Clinical and laboratory studies have questioned whether specific fluid types result in improved outcomes, including mortality and acute kidney injury.
Objective
To determine the effect of a balanced solution vs saline solution (0.9% sodium chloride) on 90-day survival in critically ill patients.
Design, setting, and participants
Double-blind, factorial, randomized clinical trial conducted at 75 ICUs in Brazil. Patients who were admitted to the ICU with at least 1 risk factor for worse outcomes, who required at least 1 fluid expansion, and who were expected to remain in the ICU for more than 24 hours were randomized between May 29, 2017, and March 2, 2020; follow-up concluded on October 29, 2020. Patients were randomized to 2 different fluid types (a balanced solution vs saline solution reported in this article) and 2 different infusion rates (reported separately).
Interventions
Patients were randomly assigned 1:1 to receive either a balanced solution (n = 5522) or 0.9% saline solution (n = 5530) for all intravenous fluids.
Main outcomes and measures
The primary outcome was 90-day survival.
Results
Among 11 052 patients who were randomized, 10 520 (95.2%) were available for the analysis (mean age, 61.1 [SD, 17] years; 44.2% were women). There was no significant interaction between the 2 interventions (fluid type and infusion speed; P = .98). Planned surgical admissions represented 48.4% of all patients. Of all the patients, 60.6% had hypotension or vasopressor use and 44.3% required mechanical ventilation at enrollment. Patients in both groups received a median of 1.5 L of fluid during the first day after enrollment. By day 90, 1381 of 5230 patients (26.4%) assigned to a balanced solution died vs 1439 of 5290 patients (27.2%) assigned to saline solution (adjusted hazard ratio, 0.97 [95% CI, 0.90-1.05]; P = .47). There were no unexpected treatment-related severe adverse events in either group.

Conclusion:
and relevance
Among critically ill patients requiring fluid challenges, use of a balanced solution compared with 0.9% saline solution did not significantly reduce 90-day mortality. The findings do not support the use of this balanced solution.
Trial registration
ClinicalTrials.gov Identifier: NCT02875873.



JAMA: 09 Aug 2021; epub ahead of print
Zampieri FG, Machado FR, Biondi RS, Freitas FGR, ... Cavalcanti AB, BaSICS investigators and the BRICNet members
JAMA: 09 Aug 2021; epub ahead of print | PMID: 34375394
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Impact:

This program is still in alpha version.