Journal: JAMA

Sorted by: date / impact
Abstract

Effect of Poloxamer 188 vs Placebo on Painful Vaso-Occlusive Episodes in Children and Adults With Sickle Cell Disease: A Randomized Clinical Trial.

Casella JF, Barton BA, Kanter J, Black LV, ... Kato GJ, Gladwin MT
Importance
Although effective agents are available to prevent painful vaso-occlusive episodes of sickle cell disease (SCD), there are no disease-modifying therapies for ongoing painful vaso-occlusive episodes; treatment remains supportive. A previous phase 3 trial of poloxamer 188 reported shortened duration of painful vaso-occlusive episodes in SCD, particularly in children and participants treated with hydroxyurea.
Objective
To reassess the efficacy of poloxamer 188 for vaso-occlusive episodes.
Design, setting, and participants
Phase 3, randomized, double-blind, placebo-controlled, multicenter, international trial conducted from May 2013 to February 2016 that included 66 hospitals in 12 countries and 60 cities; 388 individuals with SCD (hemoglobin SS, SC, S-β0 thalassemia, or S-β+ thalassemia disease) aged 4 to 65 years with acute moderate to severe pain typical of painful vaso-occlusive episodes requiring hospitalization were included.
Interventions
A 1-hour 100-mg/kg loading dose of poloxamer 188 intravenously followed by a 12-hour to 48-hour 30-mg/kg/h continuous infusion (n = 194) or placebo (n = 194).
Main outcomes and measures
Time in hours from randomization to the last dose of parenteral opioids among all participants and among those younger than 16 years as a separate subgroup.
Results
Of 437 participants assessed for eligibility, 388 were randomized (mean age, 15.2 years; 176 [45.4%] female), the primary outcome was available for 384 (99.0%), 15-day follow-up contacts were available for 357 (92.0%), and 30-day follow-up contacts were available for 368 (94.8%). There was no significant difference between the groups for the mean time to last dose of parenteral opioids (81.8 h for the poloxamer 188 group vs 77.8 h for the placebo group; difference, 4.0 h [95% CI, -7.8 to 15.7]; geometric mean ratio, 1.2 [95% CI, 1.0-1.5]; P = .09). Based on a significant interaction of age and treatment (P = .01), there was a treatment difference in time from randomization to last administration of parenteral opioids for participants younger than 16 years (88.7 h in the poloxamer 188 group vs 71.9 h in the placebo group; difference, 16.8 h [95% CI, 1.7-32.0]; geometric mean ratio, 1.4 [95% CI, 1.1-1.8]; P = .008). Adverse events that were more common in the poloxamer 188 group than the placebo group included hyperbilirubinemia (12.7% vs 5.2%); those more common in the placebo group included hypoxia (12.0% vs 5.3%).

Conclusions:
and relevance
Among children and adults with SCD, poloxamer 188 did not significantly shorten time to last dose of parenteral opioids during vaso-occlusive episodes. These findings do not support the use of poloxamer 188 for vaso-occlusive episodes.
Trial registration
ClinicalTrials.gov Identifier: NCT01737814.



JAMA: 19 Apr 2021; 325:1513-1523
Casella JF, Barton BA, Kanter J, Black LV, ... Kato GJ, Gladwin MT
JAMA: 19 Apr 2021; 325:1513-1523 | PMID: 33877274
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Impact:
Abstract

Oral Antiplatelet Therapy After Acute Coronary Syndrome: A Review.

Kamran H, Jneid H, Kayani WT, Virani SS, ... Nambi V, Khalid U
Importance
Acute coronary syndrome (ACS) is a major cause of morbidity and mortality in the United States with an annual incidence of approximately 1 million. Dual antiplatelet therapy (DAPT), consisting of aspirin and a P2Y12 inhibitor (clopidogrel, ticagrelor, or prasugrel) reduces cardiovascular event rates after ACS.
Observations
In 2016, the updated guidelines from the American College of Cardiology/American Heart Association (ACC/AHA) recommended aspirin plus a P2Y12 inhibitor for at least 12 months for patients with ACS. Since these recommendations were published, new randomized clinical trials have studied different regimens and durations of antiplatelet therapy. Recommendations vary according to the risk of bleeding. If bleeding risk is low, prolonged DAPT may be considered, although the optimal duration of prolonged DAPT beyond 1 year is not well established. If bleeding risk is high, shorter duration (ie, 3-6 months) of DAPT may be reasonable. A high risk of bleeding traditionally is defined as a 1-year risk of serious bleeding (either fatal or associated with a ≥3-g/dL drop in hemoglobin) of at least 4% or a risk of an intracranial hemorrhage of at least 1%. Patients at higher risk are 65 years old or older; have low body weight (BMI <18.5), diabetes, or prior bleeding; or take oral anticoagulants. The newest P2Y12 inhibitors, prasugrel and ticagrelor, are more potent, with high on-treatment residual platelet reactivity of about 3% vs 30% to 40% with clopidogrel and act within 30 minutes compared with 2 hours for clopidogrel. Clinicians should avoid prescribing prasugrel to patients with a history of stroke or transient ischemic attack because of an increased risk of cerebrovascular events (6.5% vs 1.2% with clopidogrel, P = .002) and should avoid prescribing it to patients older than 75 years or who weigh less than 60 kg. The ISAR-REACT-5 trial found that prasugrel reduced rates of death, myocardial infarction, or stroke at 1 year compared with ticagrelor among patients with ACS undergoing percutaneous coronary intervention (9.3% vs 6.9%, P = .006) with no significant difference in bleeding. Recent trials suggested that discontinuing aspirin rather than the P2Y12 inhibitor may be associated with better outcomes.

Conclusions:
and relevance
Dual antiplatelet therapy reduces rates of cardiovascular events in patients with acute coronary syndrome. Specific combinations and duration of dual antiplatelet therapy should be based on patient characteristics-risk of bleeding myocardial ischemia.



JAMA: 19 Apr 2021; 325:1545-1555
Kamran H, Jneid H, Kayani WT, Virani SS, ... Nambi V, Khalid U
JAMA: 19 Apr 2021; 325:1545-1555 | PMID: 33877270
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Impact:
Abstract

Effect of Ivermectin on Time to Resolution of Symptoms Among Adults With Mild COVID-19: A Randomized Clinical Trial.

López-Medina E, López P, Hurtado IC, Dávalos DM, ... Rios CA, Caicedo I
Importance
Ivermectin is widely prescribed as a potential treatment for COVID-19 despite uncertainty about its clinical benefit.
Objective
To determine whether ivermectin is an efficacious treatment for mild COVID-19.
Design, setting, and participants
Double-blind, randomized trial conducted at a single site in Cali, Colombia. Potential study participants were identified by simple random sampling from the state\'s health department electronic database of patients with symptomatic, laboratory-confirmed COVID-19 during the study period. A total of 476 adult patients with mild disease and symptoms for 7 days or fewer (at home or hospitalized) were enrolled between July 15 and November 30, 2020, and followed up through December 21, 2020.
Intervention
Patients were randomized to receive ivermectin, 300 μg/kg of body weight per day for 5 days (n = 200) or placebo (n = 200).
Main outcomes and measures
Primary outcome was time to resolution of symptoms within a 21-day follow-up period. Solicited adverse events and serious adverse events were also collected.
Results
Among 400 patients who were randomized in the primary analysis population (median age, 37 years [interquartile range {IQR}, 29-48]; 231 women [58%]), 398 (99.5%) completed the trial. The median time to resolution of symptoms was 10 days (IQR, 9-13) in the ivermectin group compared with 12 days (IQR, 9-13) in the placebo group (hazard ratio for resolution of symptoms, 1.07 [95% CI, 0.87 to 1.32]; P = .53 by log-rank test). By day 21, 82% in the ivermectin group and 79% in the placebo group had resolved symptoms. The most common solicited adverse event was headache, reported by 104 patients (52%) given ivermectin and 111 (56%) who received placebo. The most common serious adverse event was multiorgan failure, occurring in 4 patients (2 in each group).

Conclusion:
and relevance
Among adults with mild COVID-19, a 5-day course of ivermectin, compared with placebo, did not significantly improve the time to resolution of symptoms. The findings do not support the use of ivermectin for treatment of mild COVID-19, although larger trials may be needed to understand the effects of ivermectin on other clinically relevant outcomes.
Trial registration
ClinicalTrials.gov Identifier: NCT04405843.



JAMA: 12 Apr 2021; 325:1426-1435
López-Medina E, López P, Hurtado IC, Dávalos DM, ... Rios CA, Caicedo I
JAMA: 12 Apr 2021; 325:1426-1435 | PMID: 33662102
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Impact:
Abstract

Screening for Vitamin D Deficiency in Adults: US Preventive Services Task Force Recommendation Statement.

US Preventive Services Task Force, Krist AH, Davidson KW, Mangione CM, ... Tseng CW, Wong JB
Importance
Vitamin D is a fat-soluble vitamin that performs an important role in calcium homeostasis and bone metabolism and also affects many other cellular regulatory functions outside the skeletal system. Vitamin D requirements may vary by individual; thus, no one serum vitamin D level cutpoint defines deficiency, and no consensus exists regarding the precise serum levels of vitamin D that represent optimal health or sufficiency.
Objective
To update its 2014 recommendation, the US Preventive Services Task Force (USPSTF) commissioned a systematic review on screening for vitamin D deficiency, including the benefits and harms of screening and early treatment.
Population
Community-dwelling, nonpregnant adults who have no signs or symptoms of vitamin D deficiency or conditions for which vitamin D treatment is recommended.
Evidence assessment
The USPSTF concludes that the overall evidence on the benefits of screening for vitamin D deficiency is lacking. Therefore, the balance of benefits and harms of screening for vitamin D deficiency in asymptomatic adults cannot be determined.
Recommendation
The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for vitamin D deficiency in asymptomatic adults. (I statement).



JAMA: 12 Apr 2021; 325:1436-1442
US Preventive Services Task Force, Krist AH, Davidson KW, Mangione CM, ... Tseng CW, Wong JB
JAMA: 12 Apr 2021; 325:1436-1442 | PMID: 33847711
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Impact:
Abstract

Screening for Vitamin D Deficiency in Adults: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.

Kahwati LC, LeBlanc E, Weber RP, Giger K, ... Guisinger A, Viswanathan M
Importance
Low serum vitamin D levels have been associated with adverse clinical outcomes; identifying and treating deficiency may improve outcomes.
Objective
To review the evidence about screening for vitamin D deficiency in adults.
Data sources
PubMed, EMBASE, the Cochrane Library, and trial registries through March 12, 2020; bibliographies from retrieved articles, outside experts, and surveillance of the literature through November 30, 2020.
Study selection
Fair- or good-quality, English-language randomized clinical trials (RCTs) of screening with serum 25-hydroxyvitamin D (25[OH]D) compared with no screening, or treatment with vitamin D (with or without calcium) compared with placebo or no treatment conducted in nonpregnant adults; nonrandomized controlled intervention studies for harms only. Treatment was limited to studies enrolling or analyzing participants with low serum vitamin D levels.
Data extraction and synthesis
Two reviewers assessed titles/abstracts and full-text articles, extracted data, and assessed study quality; when at least 3 similar studies were available, meta-analyses were conducted.
Main outcomes and measures
Mortality, incident fractures, falls, diabetes, cardiovascular events, cancer, depression, physical functioning, and infection.
Results
Forty-six studies (N = 16 205) (77 publications) were included. No studies directly evaluated the health benefits or harms of screening. Among community-dwelling populations, treatment was not significantly associated with mortality (pooled absolute risk difference [ARD], 0.3% [95% CI, -0.6% to 1.1%]; 8 RCTs, n = 2006), any fractures (pooled ARD, -0.3% [95% CI, -2.1% to 1.6%]; 6 RCTs, n = 2186), incidence of diabetes (pooled ARD, 0.1% [95% CI, -1.3% to 1.6%]; 5 RCTs, n = 3356), incidence of cardiovascular disease (2 RCTs; hazard ratio, 1.00 [95% CI, 0.74 to 1.35] and 1.09 [95% CI, 0.68 to 1.76]), incidence of cancer (2 RCTs; hazard ratio, 0.97 [95% CI, 0.68 to 1.39] and 1.01 [95% CI, 0.65 to 1.58], or depression (3 RCTs, various measures reported). The pooled ARD for incidence of participants with 1 or more falls was -4.3% (95% CI, -11.6% to 2.9%; 6 RCTs). The evidence was mixed for the effect of treatment on physical functioning (2 RCTs) and limited for the effect on infection (1 RCT). The incidence of adverse events and kidney stones was similar between treatment and control groups.

Conclusions:
and relevance
No studies evaluated the direct benefits or harms of screening for vitamin D deficiency. Among asymptomatic, community-dwelling populations with low vitamin D levels, the evidence suggests that treatment with vitamin D has no effect on mortality or the incidence of fractures, falls, depression, diabetes, cardiovascular disease, cancer, or adverse events. The evidence is inconclusive about the effect of treatment on physical functioning and infection.



JAMA: 12 Apr 2021; 325:1443-1463
Kahwati LC, LeBlanc E, Weber RP, Giger K, ... Guisinger A, Viswanathan M
JAMA: 12 Apr 2021; 325:1443-1463 | PMID: 33847712
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Impact:
Abstract

Filtering Facepiece Respirator (N95 Respirator) Reprocessing: A Systematic Review.

Schumm MA, Hadaya JE, Mody N, Myers BA, Maggard-Gibbons M
Importance
The COVID-19 pandemic has resulted in a persistent shortage of personal protective equipment; therefore, a need exists for hospitals to reprocess filtering facepiece respirators (FFRs), such as N95 respirators.
Objective
To perform a systematic review to evaluate the evidence on effectiveness and feasibility of different processes used for decontaminating N95 respirators.
Evidence review
A search of PubMed and EMBASE (through January 31, 2021) was completed for 5 types of respirator-decontaminating processes including UV irradiation, vaporized hydrogen peroxide, moist-heat incubation, microwave-generated steam, and ethylene oxide. Data were abstracted on process method, pathogen removal, mask filtration efficiency, facial fit, user safety, and processing capability.
Findings
Forty-two studies were included that examined 65 total types of masks. All were laboratory studies (no clinical trials), and 2 evaluated respirator performance and fit with actual clinical use of N95 respirators. Twenty-seven evaluated UV germicidal irradiation, 19 vaporized hydrogen peroxide, 9 moist-heat incubation, 10 microwave-generated steam, and 7 ethylene oxide. Forty-three types of N95 respirators were treated with UV irradiation. Doses of 1 to 2 J/cm2 effectively sterilized most pathogens on N95 respirators (>103 reduction in influenza virus [4 studies], MS2 bacteriophage [3 studies], Bacillus spores [2 studies], Escherichia virus MS2 [1 study], vesicular stomatitis virus [1 study], and Middle East respiratory syndrome virus/SARS-CoV-1 [1 study]) without degrading respirator components. Doses higher than 1.5 to 2 J/cm2 may be needed based on 2 studies demonstrating greater than 103 reduction in SARS-CoV-2. Vaporized hydrogen peroxide eradicated the pathogen in all 7 efficacy studies (>104 reduction in SARS-CoV-2 [3 studies] and >106 reduction of Bacillus and Geobacillus stearothermophilus spores [4 studies]). Pressurized chamber systems with higher concentrations of hydrogen peroxide caused FFR damage (6 studies), while open-room systems did not degrade respirator components. Moist heat effectively reduced SARS-CoV-2 (2 studies), influenza virus by greater than 104 (2 studies), vesicular stomatitis virus (1 study), and Escherichia coli (1 study) and preserved filtration efficiency and facial fit for 11 N95 respirators using preheated containers/chambers at 60 °C to 85 °C (5 studies); however, diminished filtration performance was seen for the Caron incubator. Microwave-generated steam (1100-W to 1800-W devices; 40 seconds to 3 minutes) effectively reduced pathogens by greater than 103 (influenza virus [2 studies], MS2 bacteriophage [3 studies], and Staphylococcus aureus [1 study]) and maintained filtration performance in 10 N95 respirators; however, damage was noted in least 1 respirator type in 4 studies. In 6 studies, ethylene oxide preserved respirator components in 16 N95 respirator types but left residual carcinogenic by-product (1 study).

Conclusions:
and relevance
Ultraviolet germicidal irradiation, vaporized hydrogen peroxide, moist heat, and microwave-generated steam processing effectively sterilized N95 respirators and retained filtration performance. Ultraviolet irradiation and vaporized hydrogen peroxide damaged respirators the least. More research is needed on decontamination effectiveness for SARS-CoV-2 because few studies specifically examined this pathogen.



JAMA: 05 Apr 2021; 325:1296-1317
Schumm MA, Hadaya JE, Mody N, Myers BA, Maggard-Gibbons M
JAMA: 05 Apr 2021; 325:1296-1317 | PMID: 33656543
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Impact:
Abstract

Effect of Helmet Noninvasive Ventilation vs High-Flow Nasal Oxygen on Days Free of Respiratory Support in Patients With COVID-19 and Moderate to Severe Hypoxemic Respiratory Failure: The HENIVOT Randomized Clinical Trial.

Grieco DL, Menga LS, Cesarano M, Rosà T, ... Antonelli M, COVID-ICU Gemelli Study Group
Importance
High-flow nasal oxygen is recommended as initial treatment for acute hypoxemic respiratory failure and is widely applied in patients with COVID-19.
Objective
To assess whether helmet noninvasive ventilation can increase the days free of respiratory support in patients with COVID-19 compared with high-flow nasal oxygen alone.
Design, setting, and participants
Multicenter randomized clinical trial in 4 intensive care units (ICUs) in Italy between October and December 2020, end of follow-up February 11, 2021, including 109 patients with COVID-19 and moderate to severe hypoxemic respiratory failure (ratio of partial pressure of arterial oxygen to fraction of inspired oxygen ≤200).
Interventions
Participants were randomly assigned to receive continuous treatment with helmet noninvasive ventilation (positive end-expiratory pressure, 10-12 cm H2O; pressure support, 10-12 cm H2O) for at least 48 hours eventually followed by high-flow nasal oxygen (n = 54) or high-flow oxygen alone (60 L/min) (n = 55).
Main outcomes and measures
The primary outcome was the number of days free of respiratory support within 28 days after enrollment. Secondary outcomes included the proportion of patients who required endotracheal intubation within 28 days from study enrollment, the number of days free of invasive mechanical ventilation at day 28, the number of days free of invasive mechanical ventilation at day 60, in-ICU mortality, in-hospital mortality, 28-day mortality, 60-day mortality, ICU length of stay, and hospital length of stay.
Results
Among 110 patients who were randomized, 109 (99%) completed the trial (median age, 65 years [interquartile range {IQR}, 55-70]; 21 women [19%]). The median days free of respiratory support within 28 days after randomization were 20 (IQR, 0-25) in the helmet group and 18 (IQR, 0-22) in the high-flow nasal oxygen group, a difference that was not statistically significant (mean difference, 2 days [95% CI, -2 to 6]; P = .26). Of 9 prespecified secondary outcomes reported, 7 showed no significant difference. The rate of endotracheal intubation was significantly lower in the helmet group than in the high-flow nasal oxygen group (30% vs 51%; difference, -21% [95% CI, -38% to -3%]; P = .03). The median number of days free of invasive mechanical ventilation within 28 days was significantly higher in the helmet group than in the high-flow nasal oxygen group (28 [IQR, 13-28] vs 25 [IQR 4-28]; mean difference, 3 days [95% CI, 0-7]; P = .04). The rate of in-hospital mortality was 24% in the helmet group and 25% in the high-flow nasal oxygen group (absolute difference, -1% [95% CI, -17% to 15%]; P > .99).

Conclusions:
and relevance
Among patients with COVID-19 and moderate to severe hypoxemia, treatment with helmet noninvasive ventilation, compared with high-flow nasal oxygen, resulted in no significant difference in the number of days free of respiratory support within 28 days. Further research is warranted to determine effects on other outcomes, including the need for endotracheal intubation.
Trial registration
ClinicalTrials.gov Identifier: NCT04502576.



JAMA: 24 Mar 2021; epub ahead of print
Grieco DL, Menga LS, Cesarano M, Rosà T, ... Antonelli M, COVID-ICU Gemelli Study Group
JAMA: 24 Mar 2021; epub ahead of print | PMID: 33764378
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Impact:
Abstract

Effect of Intermediate-Dose vs Standard-Dose Prophylactic Anticoagulation on Thrombotic Events, Extracorporeal Membrane Oxygenation Treatment, or Mortality Among Patients With COVID-19 Admitted to the Intensive Care Unit: The INSPIRATION Randomized Clinical Trial.

INSPIRATION Investigators, Sadeghipour P, Talasaz AH, Rashidi F, ... Goldhaber SZ, Bikdeli B
Importance
Thrombotic events are commonly reported in critically ill patients with COVID-19. Limited data exist to guide the intensity of antithrombotic prophylaxis.
Objective
To evaluate the effects of intermediate-dose vs standard-dose prophylactic anticoagulation among patients with COVID-19 admitted to the intensive care unit (ICU).
Design, setting, and participants
Multicenter randomized trial with a 2 × 2 factorial design performed in 10 academic centers in Iran comparing intermediate-dose vs standard-dose prophylactic anticoagulation (first hypothesis) and statin therapy vs matching placebo (second hypothesis; not reported in this article) among adult patients admitted to the ICU with COVID-19. Patients were recruited between July 29, 2020, and November 19, 2020. The final follow-up date for the 30-day primary outcome was December 19, 2020.
Interventions
Intermediate-dose (enoxaparin, 1 mg/kg daily) (n = 276) vs standard prophylactic anticoagulation (enoxaparin, 40 mg daily) (n = 286), with modification according to body weight and creatinine clearance. The assigned treatments were planned to be continued until completion of 30-day follow-up.
Main outcomes and measures
The primary efficacy outcome was a composite of venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days, assessed in randomized patients who met the eligibility criteria and received at least 1 dose of the assigned treatment. Prespecified safety outcomes included major bleeding according to the Bleeding Academic Research Consortium (type 3 or 5 definition), powered for noninferiority (a noninferiority margin of 1.8 based on odds ratio), and severe thrombocytopenia (platelet count <20 ×103/µL). All outcomes were blindly adjudicated.
Results
Among 600 randomized patients, 562 (93.7%) were included in the primary analysis (median [interquartile range] age, 62 [50-71] years; 237 [42.2%] women). The primary efficacy outcome occurred in 126 patients (45.7%) in the intermediate-dose group and 126 patients (44.1%) in the standard-dose prophylaxis group (absolute risk difference, 1.5% [95% CI, -6.6% to 9.8%]; odds ratio, 1.06 [95% CI, 0.76-1.48]; P = .70). Major bleeding occurred in 7 patients (2.5%) in the intermediate-dose group and 4 patients (1.4%) in the standard-dose prophylaxis group (risk difference, 1.1% [1-sided 97.5% CI, -∞ to 3.4%]; odds ratio, 1.83 [1-sided 97.5% CI, 0.00-5.93]), not meeting the noninferiority criteria (P for noninferiority >.99). Severe thrombocytopenia occurred only in patients assigned to the intermediate-dose group (6 vs 0 patients; risk difference, 2.2% [95% CI, 0.4%-3.8%]; P = .01).

Conclusions:
and relevance
Among patients admitted to the ICU with COVID-19, intermediate-dose prophylactic anticoagulation, compared with standard-dose prophylactic anticoagulation, did not result in a significant difference in the primary outcome of a composite of adjudicated venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days. These results do not support the routine empirical use of intermediate-dose prophylactic anticoagulation in unselected patients admitted to the ICU with COVID-19.
Trial registration
ClinicalTrials.gov Identifier: NCT04486508.



JAMA: 17 Mar 2021; epub ahead of print
INSPIRATION Investigators, Sadeghipour P, Talasaz AH, Rashidi F, ... Goldhaber SZ, Bikdeli B
JAMA: 17 Mar 2021; epub ahead of print | PMID: 33734299
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Impact:
Abstract

Four-Month Clinical Status of a Cohort of Patients After Hospitalization for COVID-19.

Writing Committee for the COMEBAC Study Group, Morin L, Savale L, Pham T, ... Montani D, Monnet X
Importance
Little is known about long-term sequelae of COVID-19.
Objective
To describe the consequences at 4 months in patients hospitalized for COVID-19.
Design, setting, and participants
In a prospective uncontrolled cohort study, survivors of COVID-19 who had been hospitalized in a university hospital in France between March 1 and May 29, 2020, underwent a telephone assessment 4 months after discharge, between July 15 and September 18, 2020. Patients with relevant symptoms and all patients hospitalized in an intensive care unit (ICU) were invited for further assessment at an ambulatory care visit.
Exposures
Survival of hospitalization for COVID-19.
Main outcomes and measures
Respiratory, cognitive, and functional symptoms were assessed by telephone with the Q3PC cognitive screening questionnaire and a checklist of symptoms. At the ambulatory care visit, patients underwent pulmonary function tests, lung computed tomographic scan, psychometric and cognitive tests (including the 36-Item Short-Form Health Survey and 20-item Multidimensional Fatigue Inventory), and, for patients who had been hospitalized in the ICU or reported ongoing symptoms, echocardiography.
Results
Among 834 eligible patients, 478 were evaluated by telephone (mean age, 61 years [SD, 16 years]; 201 men, 277 women). During the telephone interview, 244 patients (51%) declared at least 1 symptom that did not exist before COVID-19: fatigue in 31%, cognitive symptoms in 21%, and new-onset dyspnea in 16%. There was further evaluation in 177 patients (37%), including 97 of 142 former ICU patients. The median 20-item Multidimensional Fatigue Inventory score (n = 130) was 4.5 (interquartile range, 3.0-5.0) for reduced motivation and 3.7 (interquartile range, 3.0-4.5) for mental fatigue (possible range, 1 [best] to 5 [worst]). The median 36-Item Short-Form Health Survey score (n = 145) was 25 (interquartile range, 25.0-75.0) for the subscale \"role limited owing to physical problems\" (possible range, 0 [best] to 100 [worst]). Computed tomographic lung-scan abnormalities were found in 108 of 171 patients (63%), mainly subtle ground-glass opacities. Fibrotic lesions were observed in 33 of 171 patients (19%), involving less than 25% of parenchyma in all but 1 patient. Fibrotic lesions were observed in 19 of 49 survivors (39%) with acute respiratory distress syndrome. Among 94 former ICU patients, anxiety, depression, and posttraumatic symptoms were observed in 23%, 18%, and 7%, respectively. The left ventricular ejection fraction was less than 50% in 8 of 83 ICU patients (10%). New-onset chronic kidney disease was observed in 2 ICU patients. Serology was positive in 172 of 177 outpatients (97%).

Conclusions:
and relevance
Four months after hospitalization for COVID-19, a cohort of patients frequently reported symptoms not previously present, and lung-scan abnormalities were common among those who were tested. These findings are limited by the absence of a control group and of pre-COVID assessments in this cohort. Further research is needed to understand longer-term outcomes and whether these findings reflect associations with the disease.



JAMA: 16 Mar 2021; epub ahead of print
Writing Committee for the COMEBAC Study Group, Morin L, Savale L, Pham T, ... Montani D, Monnet X
JAMA: 16 Mar 2021; epub ahead of print | PMID: 33729425
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Impact:
Abstract

Diagnosis and Management of Transient Ischemic Attack and Acute Ischemic Stroke: A Review.

Mendelson SJ, Prabhakaran S
Importance
Stroke is the fifth leading cause of death and a leading cause of disability in the United States, affecting nearly 800 000 individuals annually.
Observations
Sudden neurologic dysfunction caused by focal brain ischemia with imaging evidence of acute infarction defines acute ischemic stroke (AIS), while an ischemic episode with neurologic deficits but without acute infarction defines transient ischemic attack (TIA). An estimated 7.5% to 17.4% of patients with TIA will have a stroke in the next 3 months. Patients presenting with nondisabling AIS or high-risk TIA (defined as a score ≥4 on the age, blood pressure, clinical symptoms, duration, diabetes [ABCD2] instrument; range, 0-7 [7 indicating worst stroke risk]), who do not have severe carotid stenosis or atrial fibrillation, should receive dual antiplatelet therapy with aspirin and clopidigrel within 24 hours of presentation. Subsequently, combined aspirin and clopidigrel for 3 weeks followed by single antiplatelet therapy reduces stroke risk from 7.8% to 5.2% (hazard ratio, 0.66 [95% CI, 0.56-0.77]). Patients with symptomatic carotid stenosis should receive carotid revascularization and single antiplatelet therapy, and those with atrial fibrillation should receive anticoagulation. In patients presenting with AIS and disabling deficits interfering with activities of daily living, intravenous alteplase improves the likelihood of minimal or no disability by 39% with intravenous recombinant tissue plasminogen activator (IV rtPA) vs 26% with placebo (odds ratio [OR], 1.6 [95% CI, 1.1-2.6]) when administered within 3 hours of presentation and by 35.3% with IV rtPA vs 30.1% with placebo (OR, 1.3 [95% CI, 1.1-1.5]) when administered within 3 to 4.5 hours of presentation. Patients with disabling AIS due to anterior circulation large-vessel occlusions are more likely to be functionally independent when treated with mechanical thrombectomy within 6 hours of presentation vs medical therapy alone (46.0% vs 26.5%; OR, 2.49 [95% CI, 1.76-3.53]) or when treated within 6 to 24 hours after symptom onset if they have a large ratio of ischemic to infarcted tissue on brain magnetic resonance diffusion or computed tomography perfusion imaging (modified Rankin Scale score 0-2: 53% vs 18%; OR, 4.92 [95% CI, 2.87-8.44]).

Conclusions:
and relevance
Dual antiplatelet therapy initiated within 24 hours of symptom onset and continued for 3 weeks reduces stroke risk in select patients with high-risk TIA and minor stroke. For select patients with disabling AIS, thrombolysis within 4.5 hours and mechanical thrombectomy within 24 hours after symptom onset improves functional outcomes.



JAMA: 15 Mar 2021; 325:1088-1098
Mendelson SJ, Prabhakaran S
JAMA: 15 Mar 2021; 325:1088-1098 | PMID: 33724327
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Impact:
Abstract

Immunogenicity of the Ad26.COV2.S Vaccine for COVID-19.

Stephenson KE, Le Gars M, Sadoff J, de Groot AM, ... Schuitemaker H, Barouch DH
Importance
Control of the global COVID-19 pandemic will require the development and deployment of safe and effective vaccines.
Objective
To evaluate the immunogenicity of the Ad26.COV2.S vaccine (Janssen/Johnson & Johnson) in humans, including the kinetics, magnitude, and phenotype of SARS-CoV-2 spike-specific humoral and cellular immune responses.
Design, setting, and participants
Twenty-five participants were enrolled from July 29, 2020, to August 7, 2020, and the follow-up for this day 71 interim analysis was completed on October 3, 2020; follow-up to assess durability will continue for 2 years. This study was conducted at a single clinical site in Boston, Massachusetts, as part of a randomized, double-blind, placebo-controlled phase 1 clinical trial of Ad26.COV2.S.
Interventions
Participants were randomized to receive 1 or 2 intramuscular injections with 5 × 1010 viral particles or 1 × 1011 viral particles of Ad26.COV2.S vaccine or placebo administered on day 1 and day 57 (5 participants in each group).
Main outcomes and measures
Humoral immune responses included binding and neutralizing antibody responses at multiple time points following immunization. Cellular immune responses included immunospot-based and intracellular cytokine staining assays to measure T-cell responses.
Results
Twenty-five participants were randomized (median age, 42; age range, 22-52; 52% women, 44% male, 4% undifferentiated), and all completed the trial through the day 71 interim end point. Binding and neutralizing antibodies emerged rapidly by day 8 after initial immunization in 90% and 25% of vaccine recipients, respectively. By day 57, binding and neutralizing antibodies were detected in 100% of vaccine recipients after a single immunization. On day 71, the geometric mean titers of spike-specific binding antibodies were 2432 to 5729 and the geometric mean titers of neutralizing antibodies were 242 to 449 in the vaccinated groups. A variety of antibody subclasses, Fc receptor binding properties, and antiviral functions were induced. CD4+ and CD8+ T-cell responses were induced.

Conclusion:
and relevance
In this phase 1 study, a single immunization with Ad26.COV2.S induced rapid binding and neutralization antibody responses as well as cellular immune responses. Two phase 3 clinical trials are currently underway to determine the efficacy of the Ad26.COV2.S vaccine.
Trial registration
ClinicalTrials.gov Identifier: NCT04436276.



JAMA: 10 Mar 2021; epub ahead of print
Stephenson KE, Le Gars M, Sadoff J, de Groot AM, ... Schuitemaker H, Barouch DH
JAMA: 10 Mar 2021; epub ahead of print | PMID: 33704352
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Impact:
Abstract

Screening for Lung Cancer: US Preventive Services Task Force Recommendation Statement.

US Preventive Services Task Force, Krist AH, Davidson KW, Mangione CM, ... Tseng CW, Wong JB
Importance
Lung cancer is the second most common cancer and the leading cause of cancer death in the US. In 2020, an estimated 228 820 persons were diagnosed with lung cancer, and 135 720 persons died of the disease. The most important risk factor for lung cancer is smoking. Increasing age is also a risk factor for lung cancer. Lung cancer has a generally poor prognosis, with an overall 5-year survival rate of 20.5%. However, early-stage lung cancer has a better prognosis and is more amenable to treatment.
Objective
To update its 2013 recommendation, the US Preventive Services Task Force (USPSTF) commissioned a systematic review on the accuracy of screening for lung cancer with low-dose computed tomography (LDCT) and on the benefits and harms of screening for lung cancer and commissioned a collaborative modeling study to provide information about the optimum age at which to begin and end screening, the optimal screening interval, and the relative benefits and harms of different screening strategies compared with modified versions of multivariate risk prediction models.
Population
This recommendation statement applies to adults aged 50 to 80 years who have a 20 pack-year smoking history and currently smoke or have quit within the past 15 years.
Evidence assessment
The USPSTF concludes with moderate certainty that annual screening for lung cancer with LDCT has a moderate net benefit in persons at high risk of lung cancer based on age, total cumulative exposure to tobacco smoke, and years since quitting smoking.
Recommendation
The USPSTF recommends annual screening for lung cancer with LDCT in adults aged 50 to 80 years who have a 20 pack-year smoking history and currently smoke or have quit within the past 15 years. Screening should be discontinued once a person has not smoked for 15 years or develops a health problem that substantially limits life expectancy or the ability or willingness to have curative lung surgery. (B recommendation) This recommendation replaces the 2013 USPSTF statement that recommended annual screening for lung cancer with LDCT in adults aged 55 to 80 years who have a 30 pack-year smoking history and currently smoke or have quit within the past 15 years.



JAMA: 08 Mar 2021; 325:962-970
US Preventive Services Task Force, Krist AH, Davidson KW, Mangione CM, ... Tseng CW, Wong JB
JAMA: 08 Mar 2021; 325:962-970 | PMID: 33687470
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Impact:
Abstract

Diagnosis and Treatment of Irritable Bowel Syndrome: A Review.

Camilleri M
Importance
The prevalence of irritable bowel syndrome (IBS) in the United States is between 7% and 16%, most common in women and young people, with annual direct costs estimated at more than $1 billion dollars in the United States. Traditionally, the diagnosis of IBS has been based on the positive identification of symptoms that correlate with several different syndromes associated with disorders such as IBS diarrhea, IBS constipation, functional diarrhea, functional constipation, chronic functional abdominal pain, or bloating. Several peripheral and central mechanisms initiate gastrointestinal motor and sensory dysfunctions leading to IBS symptoms. Those dysfunctions may require evaluation in patients whose symptoms do not respond to first-line treatments.
Observations
Validation studies of consensus symptom-based criteria have identified deficiencies that favor a simpler identification of the predominant symptoms of abdominal pain, bowel dysfunction, and bloating and exclusion of alarm symptoms such as unintentional weight loss, rectal bleeding, or recent change in bowel function. Symptom-based diagnosis of IBS is enhanced with additional history for symptoms of somatoform and psychological disorders and alarm symptoms, physical examination including digital rectal examination, and screening tests to exclude organic disease (by measuring hemoglobin and C-reactive protein concentrations). The initial treatment plan should include patient education, reassurance, and first-line treatments such as fiber and osmotic laxatives for constipation, opioids for diarrhea, antispasmodics for pain and for management of associated psychological disorders. For patients who do not respond to those IBS treatments, testing for specific functional disorders may be required in a minority of patients with IBS. These disorders include rectal evacuation disorder, abnormal colonic transit, and bile acid diarrhea. Their identification is followed by individualized treatment, such as pelvic floor retraining for rectal evacuation disorders, sequestrants for bile acid diarrhea, and secretory agents for constipation, although there is only limited evidence that this individualized management approach is effective.

Conclusions:
and relevance
Advances in the identification of specific dysfunctions as causes of individual symptoms in the \"IBS spectrum\" leads to the potential to enhance the diagnosis and management of symptoms for the majority of patients for whom first-line therapies of IBS and management of comorbid psychological disorders are insufficient.



JAMA: 01 Mar 2021; 325:865-877
Camilleri M
JAMA: 01 Mar 2021; 325:865-877 | PMID: 33651094
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Impact:
Abstract

Effect of Oral Moxifloxacin vs Intravenous Ertapenem Plus Oral Levofloxacin for Treatment of Uncomplicated Acute Appendicitis: The APPAC II Randomized Clinical Trial.

Sippola S, Haijanen J, Grönroos J, Rautio T, ... Paajanen H, Salminen P
Importance
Antibiotics are an effective and safe alternative to appendectomy for managing uncomplicated acute appendicitis, but the optimal antibiotic regimen is not known.
Objective
To compare oral antibiotics with combined intravenous followed by oral antibiotics in the management of computed tomography-confirmed uncomplicated acute appendicitis.
Design, setting, and participants
The Appendicitis Acuta (APPAC) II multicenter, open-label, noninferiority randomized clinical trial was conducted from April 2017 until November 2018 in 9 Finnish hospitals. A total of 599 patients aged 18 to 60 years with computed tomography-confirmed uncomplicated acute appendicitis were enrolled in the trial. The last date of follow-up was November 29, 2019.
Interventions
Patients randomized to receive oral monotherapy (n = 295) received oral moxifloxacin (400 mg/d) for 7 days. Patients randomized to receive intravenous antibiotics followed by oral antibiotics (n = 288) received intravenous ertapenem (1 g/d) for 2 days followed by oral levofloxacin (500 mg/d) and metronidazole (500 mg 3 times/d) for 5 days.
Main outcomes and measures
The primary end point was treatment success (≥65%) for both groups, defined as discharge from hospital without surgery and no recurrent appendicitis during 1-year follow-up, and to determine whether oral antibiotics alone were noninferior to intravenous and oral antibiotics, with a margin of 6% for difference.
Results
Among 599 patients who were randomized (mean [SD] age, 36 [12] years; 263 [44%] women), 581 (99.7%) were available for the 1-year follow-up. The treatment success rate at 1 year was 70.2% (1-sided 95% CI, 65.8% to ∞) for patients treated with oral antibiotics and 73.8% (1-sided 95% CI, 69.5% to ∞) for patients treated with intravenous followed by oral antibiotics. The difference was -3.6% ([1-sided 95% CI, -9.7% to ∞]; P = .26 for noninferiority), with the confidence limit exceeding the noninferiority margin.

Conclusion:
and relevance
Among adults with uncomplicated acute appendicitis, treatment with 7 days of oral moxifloxacin compared with 2 days of intravenous ertapenem followed by 5 days of levofloxacin and metronidazole resulted in treatment success rates greater than 65% in both groups, but failed to demonstrate noninferiority for treatment success of oral antibiotics compared with intravenous followed by oral antibiotics.
Trial registration
ClinicalTrials.gov Identifier: NCT03236961; EudraCT Identifier: 2015-003633-10.



JAMA: 25 Jan 2021; 325:353-362
Sippola S, Haijanen J, Grönroos J, Rautio T, ... Paajanen H, Salminen P
JAMA: 25 Jan 2021; 325:353-362 | PMID: 33427870
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Impact:
Abstract

Acute Pancreatitis: A Review.

Mederos MA, Reber HA, Girgis MD
Importance
In the United States, acute pancreatitis is one of the leading causes of hospital admission from gastrointestinal diseases, with approximately 300 000 emergency department visits each year. Outcomes from acute pancreatitis are influenced by risk stratification, fluid and nutritional management, and follow-up care and risk-reduction strategies, which are the subject of this review.
Observations
MEDLINE was searched via PubMed as was the Cochrane databases for English-language studies published between January 2009 and August 2020 for current recommendations for predictive scoring tools, fluid management and nutrition, and follow-up and risk-reduction strategies for acute pancreatitis. Several scoring systems, such as the Bedside Index of Severity in Acute Pancreatitis (BISAP) and the Acute Physiology and Chronic Health Evaluation (APACHE) II tools, have good predictive capabilities for disease severity (mild, moderately severe, and severe per the revised Atlanta classification) and mortality, but no one tool works well for all forms of acute pancreatitis. Early and aggressive fluid resuscitation and early enteral nutrition are associated with lower rates of mortality and infectious complications, yet the optimal type and rate of fluid resuscitation have yet to be determined. The underlying etiology of acute pancreatitis should be sought in all patients, and risk-reduction strategies, such as cholecystectomy and alcohol cessation counseling, should be used during and after hospitalization for acute pancreatitis.

Conclusions:
and relevance
Acute pancreatitis is a complex disease that varies in severity and course. Prompt diagnosis and stratification of severity influence proper management. Scoring systems are useful adjuncts but should not supersede clinical judgment. Fluid management and nutrition are very important aspects of care for acute pancreatitis.



JAMA: 25 Jan 2021; 325:382-390
Mederos MA, Reber HA, Girgis MD
JAMA: 25 Jan 2021; 325:382-390 | PMID: 33496779
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Impact:
Abstract

Effect of Behavioral Therapy With In-Clinic or Telephone Group Visits vs In-Clinic Individual Visits on Weight Loss Among Patients With Obesity in Rural Clinical Practice: A Randomized Clinical Trial.

Befort CA, VanWormer JJ, Desouza C, Ellerbeck EF, ... Eiland L, Drincic A
Importance
Rural populations have a higher prevalence of obesity and poor access to weight loss programs. Effective models for treating obesity in rural clinical practice are needed.
Objective
To compare the Medicare Intensive Behavioral Therapy for Obesity fee-for-service model with 2 alternatives: in-clinic group visits based on a patient-centered medical home model and telephone-based group visits based on a disease management model.
Design, setting, and participants
Cluster randomized trial conducted in 36 primary care practices in the rural Midwestern US. Inclusion criteria included age 20 to 75 years and body mass index of 30 to 45. Participants were enrolled from February 2016 to October 2017. Final follow-up occurred in December 2019.
Interventions
All participants received a lifestyle intervention focused on diet, physical activity, and behavior change strategies. In the fee-for-service intervention (n = 473), practice-employed clinicians provided 15-minute in-clinic individual visits at a frequency similar to that reimbursed by Medicare (weekly for 1 month, biweekly for 5 months, and monthly thereafter). In the in-clinic group intervention (n = 468), practice-employed clinicians delivered group visits that were weekly for 3 months, biweekly for 3 months, and monthly thereafter. In the telephone group intervention (n = 466), patients received the same intervention as the in-clinic group intervention, but sessions were delivered remotely via conference calls by centralized staff.
Main outcomes and measures
The primary outcome was weight change at 24 months. A minimum clinically important difference was defined as 2.75 kg.
Results
Among 1407 participants (mean age, 54.7 [SD, 11.8] years; baseline body mass index, 36.7 [SD, 4.0]; 1081 [77%] women), 1220 (87%) completed the trial. Mean weight loss at 24 months was -4.4 kg (95% CI, -5.5 to -3.4 kg) in the in-clinic group intervention, -3.9 kg (95% CI, -5.0 to -2.9 kg) in the telephone group intervention, and -2.6 kg (95% CI, -3.6 to -1.5 kg) in the in-clinic individual intervention. Compared with the in-clinic individual intervention, the mean difference in weight change was -1.9 kg (97.5% CI, -3.5 to -0.2 kg; P = .01) for the in-clinic group intervention and -1.4 kg (97.5% CI, -3.0 to 0.3 kg; P = .06) for the telephone group intervention.

Conclusions:
and relevance
Among patients with obesity in rural primary care clinics, in-clinic group visits but not telephone-based group visits, compared with in-clinic individual visits, resulted in statistically significantly greater weight loss at 24 months. However, the differences were small in magnitude and of uncertain clinical importance.
Trial registration
ClinicalTrials.gov Identifier: NCT02456636.



JAMA: 25 Jan 2021; 325:363-372
Befort CA, VanWormer JJ, Desouza C, Ellerbeck EF, ... Eiland L, Drincic A
JAMA: 25 Jan 2021; 325:363-372 | PMID: 33496775
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Impact:
Abstract

Incidence of Transient Ischemic Attack and Association With Long-term Risk of Stroke.

Lioutas VA, Ivan CS, Himali JJ, Aparicio HJ, ... Beiser AS, Seshadri S
Importance
Accurate estimation of the association between transient ischemic attack (TIA) and risk of subsequent stroke can help to improve preventive efforts and limit the burden of stroke in the population.
Objective
To determine population-based incidence of TIA and the timing and long-term trends of stroke risk after TIA.
Design, setting, and participants
Retrospective cohort study (Framingham Heart Study) of prospectively collected data of 14 059 participants with no history of TIA or stroke at baseline, followed up from 1948-December 31, 2017. A sample of TIA-free participants was matched to participants with first incident TIA on age and sex (ratio, 5:1).
Exposures
Calendar time (TIA incidence calculation, time-trends analyses), TIA (matched longitudinal cohort).
Main outcomes and measures
The main outcomes were TIA incidence rates; proportion of stroke occurring after TIA in the short term (7, 30, and 90 days) vs the long term (>1-10 years); stroke after TIA vs stroke among matched control participants without TIA; and time trends of stroke risk at 90 days after TIA assessed in 3 epochs: 1954-1985, 1986-1999, and 2000-2017.
Results
Among 14 059 participants during 66 years of follow-up (366 209 person-years), 435 experienced TIA (229 women; mean age, 73.47 [SD, 11.48] years and 206 men; mean age, 70.10 [SD, 10.64] years) and were matched to 2175 control participants without TIA. The estimated incidence rate of TIA was 1.19/1000 person-years. Over a median of 8.86 years of follow-up after TIA, 130 participants (29.5%) had a stroke; 28 strokes (21.5%) occurred within 7 days, 40 (30.8%) occurred within 30 days, 51 (39.2%) occurred within 90 days, and 63 (48.5%) occurred more than 1 year after the index TIA; median time to stroke was 1.64 (interquartile range, 0.07-6.6) years. The age- and sex-adjusted cumulative 10-year hazard of incident stroke for patients with TIA (130 strokes among 435 cases) was 0.46 (95% CI, 0.39-0.55) and for matched control participants without TIA (165 strokes among 2175) was 0.09 (95% CI, 0.08-0.11); fully adjusted hazard ratio [HR], 4.37 (95% CI, 3.30-5.71; P < .001). Compared with the 90-day stroke risk after TIA in 1948-1985 (16.7%; 26 strokes among 155 patients with TIA), the risk between 1986-1999 was 11.1% (18 strokes among 162 patients) and between 2000-2017 was 5.9% (7 strokes among 118 patients). Compared with the first epoch, the HR for 90-day risk of stroke in the second epoch was 0.60 (95% CI, 0.33-1.12) and in the third epoch was 0.32 (95% CI, 0.14-0.75) (P = .005 for trend).

Conclusions:
and relevance
In this population-based cohort study from 1948-2017, the estimated crude TIA incidence was 1.19/1000 person-years, the risk of stroke was significantly greater after TIA compared with matched control participants who did not have TIA, and the risk of stroke after TIA was significantly lower in the most recent epoch from 2000-2017 compared with an earlier period from 1948-1985.



JAMA: 25 Jan 2021; 325:373-381
Lioutas VA, Ivan CS, Himali JJ, Aparicio HJ, ... Beiser AS, Seshadri S
JAMA: 25 Jan 2021; 325:373-381 | PMID: 33496774
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Impact:
Abstract

Diagnosis and Treatment of Multiple Sclerosis: A Review.

McGinley MP, Goldschmidt CH, Rae-Grant AD
Importance
Multiple sclerosis (MS) is an autoimmune-mediated neurodegenerative disease of the central nervous system characterized by inflammatory demyelination with axonal transection. MS affects an estimated 900 000 people in the US. MS typically presents in young adults (mean age of onset, 20-30 years) and can lead to physical disability, cognitive impairment, and decreased quality of life. This review summarizes current evidence regarding diagnosis and treatment of MS.
Observations
MS typically presents in young adults aged 20 to 30 years with unilateral optic neuritis, partial myelitis, sensory disturbances, or brainstem syndromes such as internuclear ophthalmoplegia developing over several days. The prevalence of MS worldwide ranges from 5 to 300 per 100 000 people and increases at higher latitudes. Overall life expectancy is less than in the general population (75.9 vs 83.4 years), and MS more commonly affects women (female to male sex distribution of nearly 3:1). Diagnosis is made based on a combination of signs and symptoms, radiographic findings (eg, magnetic resonance imaging [MRI] T2 lesions), and laboratory findings (eg, cerebrospinal fluid-specific oligoclonal bands), which are components of the 2017 McDonald Criteria. Nine classes of disease-modifying therapies (DMTs), with varying mechanisms of action and routes of administration, are available for relapsing-remitting MS, defined as relapses at onset with stable neurologic disability between episodes, and secondary progressive MS with activity, defined as steadily increasing neurologic disability following a relapsing course with evidence of ongoing inflammatory activity. These drugs include interferons, glatiramer acetate, teriflunomide, sphingosine 1-phosphate receptor modulators, fumarates, cladribine, and 3 types of monoclonal antibodies. One additional DMT, ocrelizumab, is approved for primary progressive MS. These DMTs reduce clinical relapses and MRI lesions (new T2 lesions, gadolinium-enhancing lesions). Efficacy rates of current DMTs, defined by reduction in annualized relapse rates compared with placebo or active comparators, range from 29%-68%. Adverse effects include infections, bradycardia, heart blocks, macular edema, infusion reactions, injection-site reactions, and secondary autoimmune adverse effects, such as autoimmune thyroid disease.

Conclusions:
and relevance
MS is characterized by physical disability, cognitive impairment, and other symptoms that affect quality of life. Treatment with DMT can reduce the annual relapse rate by 29% to 68% compared with placebo or active comparator.



JAMA: 22 Jan 2021; 325:765-779
McGinley MP, Goldschmidt CH, Rae-Grant AD
JAMA: 22 Jan 2021; 325:765-779 | PMID: 33620411
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Impact:
Abstract

Effect of High-Dose Baclofen on Agitation-Related Events Among Patients With Unhealthy Alcohol Use Receiving Mechanical Ventilation: A Randomized Clinical Trial.

Vourc\'h M, Garret C, Gacouin A, Lacherade JC, ... Asehnoune K, BACLOREA study group
Importance
Unhealthy alcohol use can lead to agitation in the intensive care unit (ICU).
Objective
To assess whether high-dose baclofen reduces agitation-related events compared with placebo in patients with unhealthy alcohol use receiving mechanical ventilation.
Design, settings, and participants
This phase 3, double-blind, placebo-controlled, randomized clinical trial conducted in 18 ICUs in France recruited adults receiving mechanical ventilation who met criteria for unhealthy alcohol use. Patients were enrolled from June 2016 to February 2018; the last follow-up was in May 2019.
Interventions
Baclofen (n = 159), adjusted from 50 to 150 mg per day based on estimated glomerular filtration rate, or placebo (n = 155) during mechanical ventilation up to a maximum of 15 days before gradual dose reduction over 3 to 6 days.
Main outcomes and measures
The primary end point was the percentage of patients with at least 1 agitation-related event over the treatment period. Secondary outcomes included duration of mechanical ventilation, length of ICU stay, and 28-day mortality.
Results
Among 314 patients who were randomized (mean age, 57 years; 60 [17.2%] women), 313 (99.7%) completed the trial. There was a statistically significant decrease in the percentage of patients who experienced at least 1 agitation-related event in the baclofen group vs the placebo group (31 [19.7%] vs 46 [29.7%]; difference, -9.93% [95% CI, -19.45% to -0.42%]; adjusted odds ratio, 0.59 [95% CI, 0.35-0.99]). Of 18 prespecified secondary end points, 14 were not significantly different. Compared with the placebo group, the baclofen group had a significantly longer median length of mechanical ventilation (9 vs 8 days; difference, 2.00 [95% CI, 0.00-3.00]; hazard ratio [HR] for extubation, 0.76 [95% CI, 0.60-0.97]) and stay in the ICU (14 vs 11 days; difference, 2.00 [95% CI, 0.00-4.00]; HR for discharge, 0.70 [95% CI, 0.54-0.90]). At 28 days, there was no significant difference in mortality in the baclofen vs placebo group (25.3% vs 21.6%; adjusted odds ratio, 1.24 [95% CI, 0.72-2.13]). Delayed awakening (no eye opening at 72 hours after cessation of sedatives and analgesics) occurred in 14 patients (8.9%) in the baclofen group vs 3 (1.9%) in the placebo group.

Conclusions:
and relevance
Among patients with unhealthy alcohol use receiving mechanical ventilation, treatment with high-dose baclofen, compared with placebo, resulted in a statistically significant reduction in agitation-related events. However, considering the modest effect and the totality of findings for the secondary end points and adverse events, further research is needed to determine the possible role of baclofen in this setting and to potentially optimize dosing.
Trial registration
ClinicalTrials.gov Identifier: NCT02723383.



JAMA: 22 Jan 2021; 325:732-741
Vourc'h M, Garret C, Gacouin A, Lacherade JC, ... Asehnoune K, BACLOREA study group
JAMA: 22 Jan 2021; 325:732-741 | PMID: 33620407
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Impact:
Abstract

Association of Rare CYP39A1 Variants With Exfoliation Syndrome Involving the Anterior Chamber of the Eye.

Genetics of Exfoliation Syndrome Partnership, Li Z, Wang Z, Lee MC, ... Tam WL, Khor CC
Importance
Exfoliation syndrome is a systemic disorder characterized by progressive accumulation of abnormal fibrillar protein aggregates manifesting clinically in the anterior chamber of the eye. This disorder is the most commonly known cause of glaucoma and a major cause of irreversible blindness.
Objective
To determine if exfoliation syndrome is associated with rare, protein-changing variants predicted to impair protein function.
Design, setting, and participants
A 2-stage, case-control, whole-exome sequencing association study with a discovery cohort and 2 independently ascertained validation cohorts. Study participants from 14 countries were enrolled between February 1999 and December 2019. The date of last clinical follow-up was December 2019. Affected individuals had exfoliation material on anterior segment structures of at least 1 eye as visualized by slit lamp examination. Unaffected individuals had no signs of exfoliation syndrome.
Exposures
Rare, coding-sequence genetic variants predicted to be damaging by bioinformatic algorithms trained to recognize alterations that impair protein function.
Main outcomes and measures
The primary outcome was the presence of exfoliation syndrome. Exome-wide significance for detected variants was defined as P < 2.5 × 10-6. The secondary outcomes included biochemical enzymatic assays and gene expression analyses.
Results
The discovery cohort included 4028 participants with exfoliation syndrome (median age, 78 years [interquartile range, 73-83 years]; 2377 [59.0%] women) and 5638 participants without exfoliation syndrome (median age, 72 years [interquartile range, 65-78 years]; 3159 [56.0%] women). In the discovery cohort, persons with exfoliation syndrome, compared with those without exfoliation syndrome, were significantly more likely to carry damaging CYP39A1 variants (1.3% vs 0.30%, respectively; odds ratio, 3.55 [95% CI, 2.07-6.10]; P = 6.1 × 10-7). This outcome was validated in 2 independent cohorts. The first validation cohort included 2337 individuals with exfoliation syndrome (median age, 74 years; 1132 women; n = 1934 with demographic data) and 2813 individuals without exfoliation syndrome (median age, 72 years; 1287 women; n = 2421 with demographic data). The second validation cohort included 1663 individuals with exfoliation syndrome (median age, 75 years; 587 women; n = 1064 with demographic data) and 3962 individuals without exfoliation syndrome (median age, 74 years; 951 women; n = 1555 with demographic data). Of the individuals from both validation cohorts, 5.2% with exfoliation syndrome carried CYP39A1 damaging alleles vs 3.1% without exfoliation syndrome (odds ratio, 1.82 [95% CI, 1.47-2.26]; P < .001). Biochemical assays classified 34 of 42 damaging CYP39A1 alleles as functionally deficient (median reduction in enzymatic activity compared with wild-type CYP39A1, 94.4% [interquartile range, 78.7%-98.2%] for the 34 deficient variants). CYP39A1 transcript expression was 47% lower (95% CI, 30%-64% lower; P < .001) in ciliary body tissues from individuals with exfoliation syndrome compared with individuals without exfoliation syndrome.

Conclusions:
and relevance
In this whole-exome sequencing case-control study, presence of exfoliation syndrome was significantly associated with carriage of functionally deficient CYP39A1 sequence variants. Further research is needed to understand the clinical implications of these findings.



JAMA: 22 Jan 2021; 325:753-764
Genetics of Exfoliation Syndrome Partnership, Li Z, Wang Z, Lee MC, ... Tam WL, Khor CC
JAMA: 22 Jan 2021; 325:753-764 | PMID: 33620406
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Impact:
Abstract

Effect of Vitamin C, Thiamine, and Hydrocortisone on Ventilator- and Vasopressor-Free Days in Patients With Sepsis: The VICTAS Randomized Clinical Trial.

Sevransky JE, Rothman RE, Hager DN, Bernard GR, ... Wright DW, VICTAS Investigators
Importance
Sepsis is a common syndrome with substantial morbidity and mortality. A combination of vitamin C, thiamine, and corticosteroids has been proposed as a potential treatment for patients with sepsis.
Objective
To determine whether a combination of vitamin C, thiamine, and hydrocortisone every 6 hours increases ventilator- and vasopressor-free days compared with placebo in patients with sepsis.
Design, setting, and participants
Multicenter, randomized, double-blind, adaptive-sample-size, placebo-controlled trial conducted in adult patients with sepsis-induced respiratory and/or cardiovascular dysfunction. Participants were enrolled in the emergency departments or intensive care units at 43 hospitals in the United States between August 2018 and July 2019. After enrollment of 501 participants, funding was withheld, leading to an administrative termination of the trial. All study-related follow-up was completed by January 2020.
Interventions
Participants were randomized to receive intravenous vitamin C (1.5 g), thiamine (100 mg), and hydrocortisone (50 mg) every 6 hours (n = 252) or matching placebo (n = 249) for 96 hours or until discharge from the intensive care unit or death. Participants could be treated with open-label corticosteroids by the clinical team, with study hydrocortisone or matching placebo withheld if the total daily dose was greater or equal to the equivalent of 200 mg of hydrocortisone.
Main outcomes and measures
The primary outcome was the number of consecutive ventilator- and vasopressor-free days in the first 30 days following the day of randomization. The key secondary outcome was 30-day mortality.
Results
Among 501 participants randomized (median age, 62 [interquartile range {IQR}, 50-70] years; 46% female; 30% Black; median Acute Physiology and Chronic Health Evaluation II score, 27 [IQR, 20.8-33.0]; median Sequential Organ Failure Assessment score, 9 [IQR, 7-12]), all completed the trial. Open-label corticosteroids were prescribed to 33% and 32% of the intervention and control groups, respectively. Ventilator- and vasopressor-free days were a median of 25 days (IQR, 0-29 days) in the intervention group and 26 days (IQR, 0-28 days) in the placebo group, with a median difference of -1 day (95% CI, -4 to 2 days; P = .85). Thirty-day mortality was 22% in the intervention group and 24% in the placebo group.

Conclusions:
and relevance
Among critically ill patients with sepsis, treatment with vitamin C, thiamine, and hydrocortisone, compared with placebo, did not significantly increase ventilator- and vasopressor-free days within 30 days. However, the trial was terminated early for administrative reasons and may have been underpowered to detect a clinically important difference.
Trial registration
ClinicalTrials.gov Identifier: NCT03509350.



JAMA: 22 Jan 2021; 325:742-750
Sevransky JE, Rothman RE, Hager DN, Bernard GR, ... Wright DW, VICTAS Investigators
JAMA: 22 Jan 2021; 325:742-750 | PMID: 33620405
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Impact:
Abstract

Association of Convalescent Plasma Treatment With Clinical Outcomes in Patients With COVID-19: A Systematic Review and Meta-analysis.

Janiaud P, Axfors C, Schmitt AM, Gloy V, ... Ioannidis JPA, Hemkens LG
Importance
Convalescent plasma is a proposed treatment for COVID-19.
Objective
To assess clinical outcomes with convalescent plasma treatment vs placebo or standard of care in peer-reviewed and preprint publications or press releases of randomized clinical trials (RCTs).
Data sources
PubMed, the Cochrane COVID-19 trial registry, and the Living Overview of Evidence platform were searched until January 29, 2021.
Study selection
The RCTs selected compared any type of convalescent plasma vs placebo or standard of care for patients with confirmed or suspected COVID-19 in any treatment setting.
Data extraction and synthesis
Two reviewers independently extracted data on relevant clinical outcomes, trial characteristics, and patient characteristics and used the Cochrane Risk of Bias Assessment Tool. The primary analysis included peer-reviewed publications of RCTs only, whereas the secondary analysis included all publicly available RCT data (peer-reviewed publications, preprints, and press releases). Inverse variance-weighted meta-analyses were conducted to summarize the treatment effects. The certainty of the evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation.
Main outcomes and measures
All-cause mortality, length of hospital stay, clinical improvement, clinical deterioration, mechanical ventilation use, and serious adverse events.
Results
A total of 1060 patients from 4 peer-reviewed RCTs and 10 722 patients from 6 other publicly available RCTs were included. The summary risk ratio (RR) for all-cause mortality with convalescent plasma in the 4 peer-reviewed RCTs was 0.93 (95% CI, 0.63 to 1.38), the absolute risk difference was -1.21% (95% CI, -5.29% to 2.88%), and there was low certainty of the evidence due to imprecision. Across all 10 RCTs, the summary RR was 1.02 (95% CI, 0.92 to 1.12) and there was moderate certainty of the evidence due to inclusion of unpublished data. Among the peer-reviewed RCTs, the summary hazard ratio was 1.17 (95% CI, 0.07 to 20.34) for length of hospital stay, the summary RR was 0.76 (95% CI, 0.20 to 2.87) for mechanical ventilation use (the absolute risk difference for mechanical ventilation use was -2.56% [95% CI, -13.16% to 8.05%]), and there was low certainty of the evidence due to imprecision for both outcomes. Limited data on clinical improvement, clinical deterioration, and serious adverse events showed no significant differences.

Conclusions:
and relevance
Treatment with convalescent plasma compared with placebo or standard of care was not significantly associated with a decrease in all-cause mortality or with any benefit for other clinical outcomes. The certainty of the evidence was low to moderate for all-cause mortality and low for other outcomes.



JAMA: 22 Jan 2021; 325:1185-1195
Janiaud P, Axfors C, Schmitt AM, Gloy V, ... Ioannidis JPA, Hemkens LG
JAMA: 22 Jan 2021; 325:1185-1195 | PMID: 33635310
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Impact:
Abstract

Screening for Hearing Loss in Older Adults: US Preventive Services Task Force Recommendation Statement.

US Preventive Services Task Force, Krist AH, Davidson KW, Mangione CM, ... Tseng CW, Wong JB
Importance
Age-related sensorineural hearing loss is a common health problem among adults. Nearly 16% of US adults 18 years or older report difficulty hearing. The prevalence of perceived hearing loss increases with age. Hearing loss can adversely affect an individual\'s quality of life and ability to function independently and has been associated with increased risk of falls, hospitalizations, social isolation, and cognitive decline.
Objective
To update its 2012 recommendation, the US Preventive Services Task Force (USPSTF) commissioned a systematic review on screening for hearing loss in adults 50 years or older.
Population
Asymptomatic adults 50 years or older with age-related hearing loss.
Evidence assessment
Because of a lack of evidence, the USPSTF concludes that the benefits and harms of screening for hearing loss in asymptomatic older adults are uncertain and that the balance of benefits and harms cannot be determined. More research is needed.
Recommendation
The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for hearing loss in older adults. (I statement).



JAMA: 22 Jan 2021; 325:1196-1201
US Preventive Services Task Force, Krist AH, Davidson KW, Mangione CM, ... Tseng CW, Wong JB
JAMA: 22 Jan 2021; 325:1196-1201 | PMID: 33755083
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Impact:
Abstract

Screening for Hearing Loss in Older Adults: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.

Feltner C, Wallace IF, Kistler CE, Coker-Schwimmer M, Jonas DE
Importance
Hearing loss is common in older adults and associated with adverse health and social outcomes.
Objective
To update the evidence review on screening for hearing loss in adults 50 years or older to inform the US Preventive Services Task Force.
Data sources
MEDLINE, Cochrane Library, EMBASE, and trial registries through January 17, 2020; references; and experts; literature surveillance through October 8, 2020.
Study selection
English-language studies of accuracy, screening, and interventions for screen-detected or newly detected hearing loss.
Data extraction and synthesis
Dual review of abstracts, full-text articles, and study quality. Meta-analysis of screening test accuracy studies.
Main outcomes and measures
Quality of life and function, other health and social outcomes, test accuracy, and harms.
Results
Forty-one studies (N = 26 386) were included, 18 of which were new since the previous review. One trial enrolling US veterans (n = 2305) assessed the benefits of screening; there was no significant difference in the proportion of participants experiencing a minimum clinically important difference in hearing-related function at 1 year (36%-40% in the screened groups vs 36% in the nonscreened group). Thirty-four studies (n = 23 228) evaluated test accuracy. For detecting mild hearing loss (>20-25 dB), single-question screening had a pooled sensitivity of 66% (95% CI, 58%-73%) and a pooled specificity of 76% (95% CI, 68%-83%) (10 studies, n = 12 637); for detecting moderate hearing loss (>35-40 dB), pooled sensitivity was 80% (95% CI, 68%-88%) and pooled specificity was 74% (95% CI, 59%-85%) (6 studies, n = 8774). In 5 studies (n = 2820) on the Hearing Handicap Inventory for the Elderly-Screening to detect moderate hearing loss (>40 dB), pooled sensitivity was 68% (95% CI, 52%-81%) and pooled specificity was 78% (95% CI, 67%-86%). Six trials (n = 853) evaluated amplification vs control in populations with screen-detected or recently detected hearing loss over 6 weeks to 4 months. Five measured hearing-related function via the Hearing Handicap Inventory for the Elderly; only 3 that enrolled veterans (n = 684) found a significant difference considered to represent a minimal important difference (>18.7 points). Few trials reported on other eligible outcomes, and no studies reported on harms of screening or interventions.

Conclusions:
and relevance
Several screening tests can adequately detect hearing loss in older adults; no studies reported on the harms of screening or treatment. Evidence showing benefit from hearing aids on hearing-related function among adults with screen-detected or newly detected hearing loss is limited to studies enrolling veterans.



JAMA: 22 Jan 2021; 325:1202-1215
Feltner C, Wallace IF, Kistler CE, Coker-Schwimmer M, Jonas DE
JAMA: 22 Jan 2021; 325:1202-1215 | PMID: 33755082
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Impact:
Abstract

Ventilator Weaning and Discontinuation Practices for Critically Ill Patients.

Burns KEA, Rizvi L, Cook DJ, Lebovic G, ... Meade MO, Canadian Critical Care Trials Group
Importance
Although most critically ill patients receive invasive mechanical ventilation (IMV), few studies have characterized how IMV is discontinued in practice.
Objective
To describe practice variation in IMV discontinuation internationally, associations between initial discontinuation events and outcomes, and factors associated with the use of select discontinuation strategies and failed initial spontaneous breathing trials (SBTs).
Design, setting, and participants
Prospective, multinational, observational study of critically ill adults who received IMV for at least 24 hours from 142 intensive care units (ICUs) in 19 countries within 6 regions (27 in Canada, 23 in India, 22 in the UK, 26 in Europe, 21 in Australia/New Zealand, and 23 in the US).
Exposures
Receiving IMV.
Main outcomes and measures
Primary analyses characterized types of initial IMV discontinuation events (extubation, SBT, or tracheostomy) and associations with clinical outcomes (including duration of ventilation, ICU and hospital mortality, and ICU and hospital length of stay). Secondary analyses examined the associations between SBT outcome and SBT timing and clinical outcomes.
Results
Among 1868 patients (median [interquartile range] age, 61.8 [48.9-73.1] years; 1173 [62.8%] men) 424 (22.7%) underwent direct extubation, 930 (49.8%) had an initial SBT (761 [81.8%] successful), 150 (8.0%) underwent direct tracheostomy, and 364 (19.5%) died before a weaning attempt. Across regions, there was variation in the use of written directives to guide care, daily screening, SBT techniques, ventilator modes, and the roles played by clinicians involved in weaning. Compared with initial direct extubation, patients who had an initial SBT had higher ICU mortality (20 [4.7%] vs 96 [10.3%]; absolute difference, 5.6% [95% CI, 2.6%-8.6%]), longer duration of ventilation (median of 2.9 vs 4.1 days; absolute difference, 1.2 days [95% CI, 0.7-1.6]), and longer ICU stay (median of 6.7 vs 8.1 days; absolute difference, 1.4 days [95% CI, 0.8-2.4]). Patients whose initial SBT failed (vs passed) had higher ICU mortality (29 [17.2%] vs 67 [8.8%]; absolute difference, 8.4% [95% CI, 2.0%-14.7%]), longer duration of ventilation (median of 6.1 vs 3.5 days; absolute difference, 2.6 days [95% CI, 1.6-3.6]), and longer ICU stay (median of 10.6 vs 7.7 days; absolute difference, 2.8 days [95% CI, 1.1-5.2]). Compared with patients who underwent early initial SBTs, patients who underwent late initial SBTs (>2.3 days after intubation) had longer duration of ventilation (median of 2.1 vs 6.1 days; absolute difference, 4.0 days [95% CI, 3.7-4.5]), longer ICU stay (median of 5.9 vs 10.8 days; absolute difference, 4.9 days [95% CI, 4.0-6.3]), and longer hospital stay (median of 14.3 vs 22.8 days; absolute difference, 8.5 days [95% CI, 6.0-11.0]).

Conclusions:
and relevance
In this observational study of invasive mechanical ventilation discontinuation in 142 ICUs in Canada, India, the UK, Europe, Australia/New Zealand, and the US from 2013 to 2016, weaning practices varied internationally.
Trial registration
ClinicalTrials.gov Identifier: NCT03955874.



JAMA: 22 Jan 2021; 325:1173-1184
Burns KEA, Rizvi L, Cook DJ, Lebovic G, ... Meade MO, Canadian Critical Care Trials Group
JAMA: 22 Jan 2021; 325:1173-1184 | PMID: 33755077
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Impact:
Abstract

Intubation Practices and Adverse Peri-intubation Events in Critically Ill Patients From 29 Countries.

Russotto V, Myatra SN, Laffey JG, Tassistro E, ... Bellani G, INTUBE Study Investigators
Importance
Tracheal intubation is one of the most commonly performed and high-risk interventions in critically ill patients. Limited information is available on adverse peri-intubation events.
Objective
To evaluate the incidence and nature of adverse peri-intubation events and to assess current practice of intubation in critically ill patients.
Design, setting, and participants
The International Observational Study to Understand the Impact and Best Practices of Airway Management in Critically Ill Patients (INTUBE) study was an international, multicenter, prospective cohort study involving consecutive critically ill patients undergoing tracheal intubation in the intensive care units (ICUs), emergency departments, and wards, from October 1, 2018, to July 31, 2019 (August 28, 2019, was the final follow-up) in a convenience sample of 197 sites from 29 countries across 5 continents.
Exposures
Tracheal intubation.
Main outcomes and measures
The primary outcome was the incidence of major adverse peri-intubation events defined as at least 1 of the following events occurring within 30 minutes from the start of the intubation procedure: cardiovascular instability (either: systolic pressure <65 mm Hg at least once, <90 mm Hg for >30 minutes, new or increase need of vasopressors or fluid bolus >15 mL/kg), severe hypoxemia (peripheral oxygen saturation <80%) or cardiac arrest. The secondary outcomes included intensive care unit mortality.
Results
Of 3659 patients screened, 2964 (median age, 63 years; interquartile range [IQR], 49-74 years; 62.6% men) from 197 sites across 5 continents were included. The main reason for intubation was respiratory failure in 52.3% of patients, followed by neurological impairment in 30.5%, and cardiovascular instability in 9.4%. Primary outcome data were available for all patients. Among the study patients, 45.2% experienced at least 1 major adverse peri-intubation event. The predominant event was cardiovascular instability, observed in 42.6% of all patients undergoing emergency intubation, followed by severe hypoxemia (9.3%) and cardiac arrest (3.1%). Overall ICU mortality was 32.8%.

Conclusions:
and relevance
In this observational study of intubation practices in critically ill patients from a convenience sample of 197 sites across 29 countries, major adverse peri-intubation events-in particular cardiovascular instability-were observed frequently.



JAMA: 22 Jan 2021; 325:1164-1172
Russotto V, Myatra SN, Laffey JG, Tassistro E, ... Bellani G, INTUBE Study Investigators
JAMA: 22 Jan 2021; 325:1164-1172 | PMID: 33755076
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Impact:

This program is still in alpha version.