Journal: JAMA

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Abstract

Pathophysiology, Transmission, Diagnosis, and Treatment of Coronavirus Disease 2019 (COVID-19): A Review.

Wiersinga WJ, Rhodes A, Cheng AC, Peacock SJ, Prescott HC
Importance
The coronavirus disease 2019 (COVID-19) pandemic, due to the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused a worldwide sudden and substantial increase in hospitalizations for pneumonia with multiorgan disease. This review discusses current evidence regarding the pathophysiology, transmission, diagnosis, and management of COVID-19.
Observations
SARS-CoV-2 is spread primarily via respiratory droplets during close face-to-face contact. Infection can be spread by asymptomatic, presymptomatic, and symptomatic carriers. The average time from exposure to symptom onset is 5 days, and 97.5% of people who develop symptoms do so within 11.5 days. The most common symptoms are fever, dry cough, and shortness of breath. Radiographic and laboratory abnormalities, such as lymphopenia and elevated lactate dehydrogenase, are common, but nonspecific. Diagnosis is made by detection of SARS-CoV-2 via reverse transcription polymerase chain reaction testing, although false-negative test results may occur in up to 20% to 67% of patients; however, this is dependent on the quality and timing of testing. Manifestations of COVID-19 include asymptomatic carriers and fulminant disease characterized by sepsis and acute respiratory failure. Approximately 5% of patients with COVID-19, and 20% of those hospitalized, experience severe symptoms necessitating intensive care. More than 75% of patients hospitalized with COVID-19 require supplemental oxygen. Treatment for individuals with COVID-19 includes best practices for supportive management of acute hypoxic respiratory failure. Emerging data indicate that dexamethasone therapy reduces 28-day mortality in patients requiring supplemental oxygen compared with usual care (21.6% vs 24.6%; age-adjusted rate ratio, 0.83 [95% CI, 0.74-0.92]) and that remdesivir improves time to recovery (hospital discharge or no supplemental oxygen requirement) from 15 to 11 days. In a randomized trial of 103 patients with COVID-19, convalescent plasma did not shorten time to recovery. Ongoing trials are testing antiviral therapies, immune modulators, and anticoagulants. The case-fatality rate for COVID-19 varies markedly by age, ranging from 0.3 deaths per 1000 cases among patients aged 5 to 17 years to 304.9 deaths per 1000 cases among patients aged 85 years or older in the US. Among patients hospitalized in the intensive care unit, the case fatality is up to 40%. At least 120 SARS-CoV-2 vaccines are under development. Until an effective vaccine is available, the primary methods to reduce spread are face masks, social distancing, and contact tracing. Monoclonal antibodies and hyperimmune globulin may provide additional preventive strategies.
Conclusions and relevance
As of July 1, 2020, more than 10 million people worldwide had been infected with SARS-CoV-2. Many aspects of transmission, infection, and treatment remain unclear. Advances in prevention and effective management of COVID-19 will require basic and clinical investigation and public health and clinical interventions.



JAMA: 24 Aug 2020; 324:782-793
Wiersinga WJ, Rhodes A, Cheng AC, Peacock SJ, Prescott HC
JAMA: 24 Aug 2020; 324:782-793 | PMID: 32648899
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Abstract

Presence of Genetic Variants Among Young Men With Severe COVID-19.

van der Made CI, Simons A, Schuurs-Hoeijmakers J, van den Heuvel G, ... van de Veerdonk FL, Hoischen A
Importance
Severe coronavirus disease 2019 (COVID-19) can occur in younger, predominantly male, patients without preexisting medical conditions. Some individuals may have primary immunodeficiencies that predispose to severe infections caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
Objective
To explore the presence of genetic variants associated with primary immunodeficiencies among young patients with COVID-19.
Design, setting, and participants
Case series of pairs of brothers without medical history meeting the selection criteria of young (age <35 years) brother pairs admitted to the intensive care unit (ICU) due to severe COVID-19. Four men from 2 unrelated families were admitted to the ICUs of 4 hospitals in the Netherlands between March 23 and April 12, 2020. The final date of follow-up was May 16, 2020. Available family members were included for genetic variant segregation analysis and as controls for functional experiments.
Exposure
Severe COVID-19.
Main outcome and measures
Results of rapid clinical whole-exome sequencing, performed to identify a potential monogenic cause. Subsequently, basic genetic and immunological tests were performed in primary immune cells isolated from the patients and family members to characterize any immune defects.
Results
The 4 male patients had a mean age of 26 years (range, 21-32), with no history of major chronic disease. They were previously well before developing respiratory insufficiency due to severe COVID-19, requiring mechanical ventilation in the ICU. The mean duration of ventilatory support was 10 days (range, 9-11); the mean duration of ICU stay was 13 days (range, 10-16). One patient died. Rapid clinical whole-exome sequencing of the patients and segregation in available family members identified loss-of-function variants of the X-chromosomal TLR7. In members of family 1, a maternally inherited 4-nucleotide deletion was identified (c.2129_2132del; p.[Gln710Argfs*18]); the affected members of family 2 carried a missense variant (c.2383G>T; p.[Val795Phe]). In primary peripheral blood mononuclear cells from the patients, downstream type I interferon (IFN) signaling was transcriptionally downregulated, as measured by significantly decreased mRNA expression of IRF7, IFNB1, and ISG15 on stimulation with the TLR7 agonist imiquimod as compared with family members and controls. The production of IFN-γ, a type II IFN, was decreased in patients in response to stimulation with imiquimod.
Conclusions and relevance
In this case series of 4 young male patients with severe COVID-19, rare putative loss-of-function variants of X-chromosomal TLR7 were identified that were associated with impaired type I and II IFN responses. These preliminary findings provide insights into the pathogenesis of COVID-19.



JAMA: 23 Jul 2020; epub ahead of print
van der Made CI, Simons A, Schuurs-Hoeijmakers J, van den Heuvel G, ... van de Veerdonk FL, Hoischen A
JAMA: 23 Jul 2020; epub ahead of print | PMID: 32706371
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Abstract

Heart Failure With Reduced Ejection Fraction: A Review.

Murphy SP, Ibrahim NE, Januzzi JL
Importance
Worldwide, the burden of heart failure has increased to an estimated 23 million people, and approximately 50% of cases are HF with reduced ejection fraction (HFrEF).
Observations
Heart failure is a clinical syndrome characterized by dyspnea or exertional limitation due to impairment of ventricular filling or ejection of blood or both. HFrEF occurs when the left ventricular ejection fraction (LVEF) is 40% or less and is accompanied by progressive left ventricular dilatation and adverse cardiac remodeling. Assessment for heart failure begins with obtaining a medical history and physical examination. Also central to diagnosis are elevated natriuretic peptides above age- and context-specific thresholds and identification of left ventricular systolic dysfunction with LVEF of 40% or less as measured by echocardiography. Treatment strategies include the use of diuretics to relieve symptoms and application of an expanding armamentarium of disease-modifying drug and device therapies. Unless there are specific contraindications, patients with HFrEF should be treated with a β-blocker and one of an angiotensin receptor-neprilysin inhibitor, angiotensin-converting enzyme inhibitor, or angiotensin receptor blocker as foundational therapy, with addition of a mineralocorticoid receptor antagonist in patients with persistent symptoms. Ivabradine and hydralazine/isosorbide dinitrate also have a role in the care of certain patients with HFrEF. More recently, sodium-glucose cotransporter 2 (SGLT2) inhibitors have further improved disease outcomes, significantly reducing cardiovascular and all-cause mortality irrespective of diabetes status, and vericiguat, a soluble guanylate cyclase stimulator, reduces heart failure hospitalization in high-risk patients with HFrEF. Device therapies may be beneficial in specific subpopulations, such as cardiac resynchronization therapy in patients with interventricular dyssynchrony, transcatheter mitral valve repair in patients with severe secondary mitral regurgitation, and implantable cardiac defibrillators in patients with more severe left ventricular dysfunction particularly of ischemic etiology.
Conclusions and relevance
HFrEF is a major public health concern with substantial morbidity and mortality. The management of HFrEF has seen significant scientific breakthrough in recent decades, and the ability to alter the natural history of the disease has never been better. Recent developments include SGLT2 inhibitors, vericiguat, and transcatheter mitral valve repair, all of which incrementally improve prognosis beyond foundational neurohormonal therapies. Disease morbidity and mortality remain high, with a 5-year survival rate of 25% after hospitalization for HFrEF.



JAMA: 03 Aug 2020; 324:488-504
Murphy SP, Ibrahim NE, Januzzi JL
JAMA: 03 Aug 2020; 324:488-504 | PMID: 32749493
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Abstract

Determination of Brain Death/Death by Neurologic Criteria: The World Brain Death Project.

Greer DM, Shemie SD, Lewis A, Torrance S, ... Zirpe K, Sung G
Importance
There are inconsistencies in concept, criteria, practice, and documentation of brain death/death by neurologic criteria (BD/DNC) both internationally and within countries.
Objective
To formulate a consensus statement of recommendations on determination of BD/DNC based on review of the literature and expert opinion of a large multidisciplinary, international panel.
Process
Relevant international professional societies were recruited to develop recommendations regarding determination of BD/DNC. Literature searches of the Cochrane, Embase, and MEDLINE databases included January 1, 1992, through April 2020 identified pertinent articles for review. Because of the lack of high-quality data from randomized clinical trials or large observational studies, recommendations were formulated based on consensus of contributors and medical societies that represented relevant disciplines, including critical care, neurology, and neurosurgery.
Evidence synthesis
Based on review of the literature and consensus from a large multidisciplinary, international panel, minimum clinical criteria needed to determine BD/DNC in various circumstances were developed.
Recommendations
Prior to evaluating a patient for BD/DNC, the patient should have an established neurologic diagnosis that can lead to the complete and irreversible loss of all brain function, and conditions that may confound the clinical examination and diseases that may mimic BD/DNC should be excluded. Determination of BD/DNC can be done with a clinical examination that demonstrates coma, brainstem areflexia, and apnea. This is seen when (1) there is no evidence of arousal or awareness to maximal external stimulation, including noxious visual, auditory, and tactile stimulation; (2) pupils are fixed in a midsize or dilated position and are nonreactive to light; (3) corneal, oculocephalic, and oculovestibular reflexes are absent; (4) there is no facial movement to noxious stimulation; (5) the gag reflex is absent to bilateral posterior pharyngeal stimulation; (6) the cough reflex is absent to deep tracheal suctioning; (7) there is no brain-mediated motor response to noxious stimulation of the limbs; and (8) spontaneous respirations are not observed when apnea test targets reach pH <7.30 and Paco2 ≥60 mm Hg. If the clinical examination cannot be completed, ancillary testing may be considered with blood flow studies or electrophysiologic testing. Special consideration is needed for children, for persons receiving extracorporeal membrane oxygenation, and for those receiving therapeutic hypothermia, as well as for factors such as religious, societal, and cultural perspectives; legal requirements; and resource availability.
Conclusions and relevance
This report provides recommendations for the minimum clinical standards for determination of brain death/death by neurologic criteria in adults and children with clear guidance for various clinical circumstances. The recommendations have widespread international society endorsement and can serve to guide professional societies and countries in the revision or development of protocols and procedures for determination of brain death/death by neurologic criteria, leading to greater consistency within and between countries.



JAMA: 02 Aug 2020; epub ahead of print
Greer DM, Shemie SD, Lewis A, Torrance S, ... Zirpe K, Sung G
JAMA: 02 Aug 2020; epub ahead of print | PMID: 32761206
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Abstract

Effect of an Inactivated Vaccine Against SARS-CoV-2 on Safety and Immunogenicity Outcomes: Interim Analysis of 2 Randomized Clinical Trials.

Xia S, Duan K, Zhang Y, Zhao D, ... Guo W, Yang X
Importance
A vaccine against coronavirus disease 2019 (COVID-19) is urgently needed.
Objective
To evaluate the safety and immunogenicity of an investigational inactivated whole-virus COVID-19 vaccine in China.
Interventions
In the phase 1 trial, 96 participants were assigned to 1 of the 3 dose groups (2.5, 5, and 10 μg/dose) and an aluminum hydroxide (alum) adjuvant-only group (n = 24 in each group), and received 3 intramuscular injections at days 0, 28, and 56. In the phase 2 trial, 224 adults were randomized to 5 μg/dose in 2 schedule groups (injections on days 0 and 14 [n = 84] vs alum only [n = 28], and days 0 and 21 [n = 84] vs alum only [n = 28]).
Design, setting, and participants
Interim analysis of ongoing randomized, double-blind, placebo-controlled, phase 1 and 2 clinical trials to assess an inactivated COVID-19 vaccine. The trials were conducted in Henan Province, China, among 96 (phase 1) and 224 (phase 2) healthy adults aged between 18 and 59 years. Study enrollment began on April 12, 2020. The interim analysis was conducted on June 16, 2020, and updated on July 27, 2020.
Main outcomes and measures
The primary safety outcome was the combined adverse reactions 7 days after each injection, and the primary immunogenicity outcome was neutralizing antibody response 14 days after the whole-course vaccination, which was measured by a 50% plaque reduction neutralization test against live severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
Results
Among 320 patients who were randomized (mean age, 42.8 years; 200 women [62.5%]), all completed the trial up to 28 days after the whole-course vaccination. The 7-day adverse reactions occurred in 3 (12.5%), 5 (20.8%), 4 (16.7%), and 6 (25.0%) patients in the alum only, low-dose, medium-dose, and high-dose groups, respectively, in the phase 1 trial; and in 5 (6.0%) and 4 (14.3%) patients who received injections on days 0 and 14 for vaccine and alum only, and 16 (19.0%) and 5 (17.9%) patients who received injections on days 0 and 21 for vaccine and alum only, respectively, in the phase 2 trial. The most common adverse reaction was injection site pain, followed by fever, which were mild and self-limiting; no serious adverse reactions were noted. The geometric mean titers of neutralizing antibodies in the low-, medium-, and high-dose groups at day 14 after 3 injections were 316 (95% CI, 218-457), 206 (95% CI, 123-343), and 297 (95% CI, 208-424), respectively, in the phase 1 trial, and were 121 (95% CI, 95-154) and 247 (95% CI, 176-345) at day 14 after 2 injections in participants receiving vaccine on days 0 and 14 and on days 0 and 21, respectively, in the phase 2 trial. There were no detectable antibody responses in all alum-only groups.
Conclusions and relevance
In this interim report of the phase 1 and phase 2 trials of an inactivated COVID-19 vaccine, patients had a low rate of adverse reactions and demonstrated immunogenicity; the study is ongoing. Efficacy and longer-term adverse event assessment will require phase 3 trials.
Trial registration
Chinese Clinical Trial Registry Identifier: ChiCTR2000031809.



JAMA: 12 Aug 2020; epub ahead of print
Xia S, Duan K, Zhang Y, Zhao D, ... Guo W, Yang X
JAMA: 12 Aug 2020; epub ahead of print | PMID: 32789505
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Abstract

Effect of Ascorbic Acid, Corticosteroids, and Thiamine on Organ Injury in Septic Shock: The ACTS Randomized Clinical Trial.

Moskowitz A, Huang DT, Hou PC, Gong J, ... Donnino MW,
Importance
The combination of ascorbic acid, corticosteroids, and thiamine has been identified as a potential therapy for septic shock.
Objective
To determine whether the combination of ascorbic acid, corticosteroids, and thiamine attenuates organ injury in patients with septic shock.
Design, setting, and participants
Randomized, blinded, multicenter clinical trial of ascorbic acid, corticosteroids, and thiamine vs placebo for adult patients with septic shock. Two hundred five patients were enrolled between February 9, 2018, and October 27, 2019, at 14 centers in the United States. Follow-up continued until November 26, 2019.
Interventions
Patients were randomly assigned to receive parenteral ascorbic acid (1500 mg), hydrocortisone (50 mg), and thiamine (100 mg) every 6 hours for 4 days (n = 103) or placebo in matching volumes at the same time points (n = 102).
Main outcomes and measures
The primary outcome was change in the Sequential Organ Failure Assessment (SOFA) score (range, 0-24; 0 = best) between enrollment and 72 hours. Key secondary outcomes included kidney failure and 30-day mortality. Patients who received at least 1 dose of study drug were included in analyses.
Results
Among 205 randomized patients (mean age, 68 [SD, 15] years; 90 [44%] women), 200 (98%) received at least 1 dose of study drug, completed the trial, and were included in the analyses (101 with intervention and 99 with placebo group). Overall, there was no statistically significant interaction between time and treatment group with regard to SOFA score over the 72 hours after enrollment (mean SOFA score change from 9.1 to 4.4 [-4.7] points with intervention vs 9.2 to 5.1 [-4.1] points with placebo; adjusted mean difference, -0.8; 95% CI, -1.7 to 0.2; P = .12 for interaction). There was no statistically significant difference in the incidence of kidney failure (31.7% with intervention vs 27.3% with placebo; adjusted risk difference, 0.03; 95% CI, -0.1 to 0.2; P = .58) or in 30-day mortality (34.7% vs 29.3%, respectively; hazard ratio, 1.3; 95% CI, 0.8-2.2; P = .26). The most common serious adverse events were hyperglycemia (12 patients with intervention and 7 patients with placebo), hypernatremia (11 and 7 patients, respectively), and new hospital-acquired infection (13 and 12 patients, respectively).
Conclusions and relevance
In patients with septic shock, the combination of ascorbic acid, corticosteroids, and thiamine, compared with placebo, did not result in a statistically significant reduction in SOFA score during the first 72 hours after enrollment. These data do not support routine use of this combination therapy for patients with septic shock.
Trial registration
ClinicalTrials.gov Identifier: NCT03389555.



JAMA: 17 Aug 2020; 324:642-650
Moskowitz A, Huang DT, Hou PC, Gong J, ... Donnino MW,
JAMA: 17 Aug 2020; 324:642-650 | PMID: 32809003
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Abstract

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

, Angus DC, Derde L, Al-Beidh F, ... Webb SA, Gordon AC
Importance
Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited.
Objective
To determine whether hydrocortisone improves outcome for patients with severe COVID-19.
Design, setting, and participants
An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020.
Interventions
The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108).
Main outcomes and measures
The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%).
Results
After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively.
Conclusions and relevance
Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions.
Trial registration
ClinicalTrials.gov Identifier: NCT02735707.



JAMA: 01 Sep 2020; epub ahead of print
, Angus DC, Derde L, Al-Beidh F, ... Webb SA, Gordon AC
JAMA: 01 Sep 2020; epub ahead of print | PMID: 32876697
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Abstract

Effect of Dexamethasone on Days Alive and Ventilator-Free in Patients With Moderate or Severe Acute Respiratory Distress Syndrome and COVID-19: The CoDEX Randomized Clinical Trial.

Tomazini BM, Maia IS, Cavalcanti AB, Berwanger O, ... Azevedo LCP,
Importance
Acute respiratory distress syndrome (ARDS) due to coronavirus disease 2019 (COVID-19) is associated with substantial mortality and use of health care resources. Dexamethasone use might attenuate lung injury in these patients.
Objective
To determine whether intravenous dexamethasone increases the number of ventilator-free days among patients with COVID-19-associated ARDS.
Design, setting, and participants
Multicenter, randomized, open-label, clinical trial conducted in 41 intensive care units (ICUs) in Brazil. Patients with COVID-19 and moderate to severe ARDS, according to the Berlin definition, were enrolled from April 17 to June 23, 2020. Final follow-up was completed on July 21, 2020. The trial was stopped early following publication of a related study before reaching the planned sample size of 350 patients.
Interventions
Twenty mg of dexamethasone intravenously daily for 5 days, 10 mg of dexamethasone daily for 5 days or until ICU discharge, plus standard care (n =151) or standard care alone (n = 148).
Main outcomes and measures
The primary outcome was ventilator-free days during the first 28 days, defined as being alive and free from mechanical ventilation. Secondary outcomes were all-cause mortality at 28 days, clinical status of patients at day 15 using a 6-point ordinal scale (ranging from 1, not hospitalized to 6, death), ICU-free days during the first 28 days, mechanical ventilation duration at 28 days, and Sequential Organ Failure Assessment (SOFA) scores (range, 0-24, with higher scores indicating greater organ dysfunction) at 48 hours, 72 hours, and 7 days.
Results
A total of 299 patients (mean [SD] age, 61 [14] years; 37% women) were enrolled and all completed follow-up. Patients randomized to the dexamethasone group had a mean 6.6 ventilator-free days (95% CI, 5.0-8.2) during the first 28 days vs 4.0 ventilator-free days (95% CI, 2.9-5.4) in the standard care group (difference, 2.26; 95% CI, 0.2-4.38; P = .04). At 7 days, patients in the dexamethasone group had a mean SOFA score of 6.1 (95% CI, 5.5-6.7) vs 7.5 (95% CI, 6.9-8.1) in the standard care group (difference, -1.16; 95% CI, -1.94 to -0.38; P = .004). There was no significant difference in the prespecified secondary outcomes of all-cause mortality at 28 days, ICU-free days during the first 28 days, mechanical ventilation duration at 28 days, or the 6-point ordinal scale at 15 days. Thirty-three patients (21.9%) in the dexamethasone group vs 43 (29.1%) in the standard care group experienced secondary infections, 47 (31.1%) vs 42 (28.3%) needed insulin for glucose control, and 5 (3.3%) vs 9 (6.1%) experienced other serious adverse events.
Conclusions and relevance
Among patients with COVID-19 and moderate or severe ARDS, use of intravenous dexamethasone plus standard care compared with standard care alone resulted in a statistically significant increase in the number of ventilator-free days (days alive and free of mechanical ventilation) over 28 days.
Trial registration
ClinicalTrials.gov Identifier: NCT04327401.



JAMA: 01 Sep 2020; epub ahead of print
Tomazini BM, Maia IS, Cavalcanti AB, Berwanger O, ... Azevedo LCP,
JAMA: 01 Sep 2020; epub ahead of print | PMID: 32876695
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Abstract

Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis.

, Sterne JAC, Murthy S, Diaz JV, ... Webb S, Marshall JC
Importance
Effective therapies for patients with coronavirus disease 2019 (COVID-19) are needed, and clinical trial data have demonstrated that low-dose dexamethasone reduced mortality in hospitalized patients with COVID-19 who required respiratory support.
Objective
To estimate the association between administration of corticosteroids compared with usual care or placebo and 28-day all-cause mortality.
Design, setting, and participants
Prospective meta-analysis that pooled data from 7 randomized clinical trials that evaluated the efficacy of corticosteroids in 1703 critically ill patients with COVID-19. The trials were conducted in 12 countries from February 26, 2020, to June 9, 2020, and the date of final follow-up was July 6, 2020. Pooled data were aggregated from the individual trials, overall, and in predefined subgroups. Risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was assessed using the I2 statistic. The primary analysis was an inverse variance-weighted fixed-effect meta-analysis of overall mortality, with the association between the intervention and mortality quantified using odds ratios (ORs). Random-effects meta-analyses also were conducted (with the Paule-Mandel estimate of heterogeneity and the Hartung-Knapp adjustment) and an inverse variance-weighted fixed-effect analysis using risk ratios.
Exposures
Patients had been randomized to receive systemic dexamethasone, hydrocortisone, or methylprednisolone (678 patients) or to receive usual care or placebo (1025 patients).
Main outcomes and measures
The primary outcome measure was all-cause mortality at 28 days after randomization. A secondary outcome was investigator-defined serious adverse events.
Results
A total of 1703 patients (median age, 60 years [interquartile range, 52-68 years]; 488 [29%] women) were included in the analysis. Risk of bias was assessed as \"low\" for 6 of the 7 mortality results and as \"some concerns\" in 1 trial because of the randomization method. Five trials reported mortality at 28 days, 1 trial at 21 days, and 1 trial at 30 days. There were 222 deaths among the 678 patients randomized to corticosteroids and 425 deaths among the 1025 patients randomized to usual care or placebo (summary OR, 0.66 [95% CI, 0.53-0.82]; P < .001 based on a fixed-effect meta-analysis). There was little inconsistency between the trial results (I2 = 15.6%; P = .31 for heterogeneity) and the summary OR was 0.70 (95% CI, 0.48-1.01; P = .053) based on the random-effects meta-analysis. The fixed-effect summary OR for the association with mortality was 0.64 (95% CI, 0.50-0.82; P < .001) for dexamethasone compared with usual care or placebo (3 trials, 1282 patients, and 527 deaths), the OR was 0.69 (95% CI, 0.43-1.12; P = .13) for hydrocortisone (3 trials, 374 patients, and 94 deaths), and the OR was 0.91 (95% CI, 0.29-2.87; P = .87) for methylprednisolone (1 trial, 47 patients, and 26 deaths). Among the 6 trials that reported serious adverse events, 64 events occurred among 354 patients randomized to corticosteroids and 80 events occurred among 342 patients randomized to usual care or placebo.
Conclusions and relevance
In this prospective meta-analysis of clinical trials of critically ill patients with COVID-19, administration of systemic corticosteroids, compared with usual care or placebo, was associated with lower 28-day all-cause mortality.



JAMA: 01 Sep 2020; epub ahead of print
, Sterne JAC, Murthy S, Diaz JV, ... Webb S, Marshall JC
JAMA: 01 Sep 2020; epub ahead of print | PMID: 32876694
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Impact:
Abstract

Effect of Hydrocortisone on 21-Day Mortality or Respiratory Support Among Critically Ill Patients With COVID-19: A Randomized Clinical Trial.

Dequin PF, Heming N, Meziani F, Plantefève G, ... Le Gouge A,
Importance
Coronavirus disease 2019 (COVID-19) is associated with severe lung damage. Corticosteroids are a possible therapeutic option.
Objective
To determine the effect of hydrocortisone on treatment failure on day 21 in critically ill patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and acute respiratory failure.
Design, setting, and participants
Multicenter randomized double-blind sequential trial conducted in France, with interim analyses planned every 50 patients. Patients admitted to the intensive care unit (ICU) for COVID-19-related acute respiratory failure were enrolled from March 7 to June 1, 2020, with last follow-up on June 29, 2020. The study intended to enroll 290 patients but was stopped early following the recommendation of the data and safety monitoring board.
Interventions
Patients were randomized to receive low-dose hydrocortisone (n = 76) or placebo (n = 73).
Main outcomes and measures
The primary outcome, treatment failure on day 21, was defined as death or persistent dependency on mechanical ventilation or high-flow oxygen therapy. Prespecified secondary outcomes included the need for tracheal intubation (among patients not intubated at baseline); cumulative incidences (until day 21) of prone position sessions, extracorporeal membrane oxygenation, and inhaled nitric oxide; Pao2:Fio2 ratio measured daily from day 1 to day 7, then on days 14 and 21; and the proportion of patients with secondary infections during their ICU stay.
Results
The study was stopped after 149 patients (mean age, 62.2 years; 30.2% women; 81.2% mechanically ventilated) were enrolled. One hundred forty-eight patients (99.3%) completed the study, and there were 69 treatment failure events, including 11 deaths in the hydrocortisone group and 20 deaths in the placebo group. The primary outcome, treatment failure on day 21, occurred in 32 of 76 patients (42.1%) in the hydrocortisone group compared with 37 of 73 (50.7%) in the placebo group (difference of proportions, -8.6% [95.48% CI, -24.9% to 7.7%]; P = .29). Of the 4 prespecified secondary outcomes, none showed a significant difference. No serious adverse events were related to the study treatment.
Conclusions and relevance
In this study of critically ill patients with COVID-19 and acute respiratory failure, low-dose hydrocortisone, compared with placebo, did not significantly reduce treatment failure (defined as death or persistent respiratory support) at day 21. However, the study was stopped early and likely was underpowered to find a statistically and clinically important difference in the primary outcome.
Trial registration
ClinicalTrials.gov Identifier: NCT02517489.



JAMA: 01 Sep 2020; epub ahead of print
Dequin PF, Heming N, Meziani F, Plantefève G, ... Le Gouge A,
JAMA: 01 Sep 2020; epub ahead of print | PMID: 32876689
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Impact:
Abstract

Effect of Multilevel Upper Airway Surgery vs Medical Management on the Apnea-Hypopnea Index and Patient-Reported Daytime Sleepiness Among Patients With Moderate or Severe Obstructive Sleep Apnea: The SAMS Randomized Clinical Trial.

MacKay S, Carney AS, Catcheside PG, Chai-Coetzer CL, ... Yeo A, McEvoy RD
Importance
Many adults with obstructive sleep apnea (OSA) use device treatments inadequately and remain untreated.
Objective
To determine whether combined palatal and tongue surgery to enlarge or stabilize the upper airway is an effective treatment for patients with OSA when conventional device treatment failed.
Design, setting, and participants
Multicenter, parallel-group, open-label randomized clinical trial of upper airway surgery vs ongoing medical management. Adults with symptomatic moderate or severe OSA in whom conventional treatments had failed were enrolled from August 2014 to November 2017, with follow-up until August 2018.
Interventions
Multilevel surgery (modified uvulopalatopharyngoplasty and minimally invasive tongue volume reduction; n = 51) or ongoing medical management (eg, advice on sleep positioning, weight loss; n = 51).
Main outcomes and measures
Primary outcome measures were the apnea-hypopnea index (AHI; ie, the number of apnea and hypopnea events/h; 15-30 indicates moderate and >30 indicates severe OSA) and the Epworth Sleepiness Scale (ESS; range, 0-24; >10 indicates pathological sleepiness). Baseline-adjusted differences between groups at 6 months were assessed. Minimal clinically important differences are 15 events per hour for AHI and 2 units for ESS.
Results
Among 102 participants who were randomized (mean [SD] age, 44.6 [12.8] years; 18 [18%] women), 91 (89%) completed the trial. The mean AHI was 47.9 at baseline and 20.8 at 6 months for the surgery group and 45.3 at baseline and 34.5 at 6 months for the medical management group (mean baseline-adjusted between-group difference at 6 mo, -17.6 events/h [95% CI, -26.8 to -8.4]; P < .001). The mean ESS was 12.4 at baseline and 5.3 at 6 months in the surgery group and 11.1 at baseline and 10.5 at 6 months in the medical management group (mean baseline-adjusted between-group difference at 6 mo, -6.7 [95% CI, -8.2 to -5.2]; P < .001). Two participants (4%) in the surgery group had serious adverse events (1 had a myocardial infarction on postoperative day 5 and 1 was hospitalized for observation following hematemesis of old blood).
Conclusions and relevance
In this preliminary study of adults with moderate or severe OSA in whom conventional therapy had failed, combined palatal and tongue surgery, compared with medical management, reduced the number of apnea and hypopnea events and patient-reported sleepiness at 6 months. Further research is needed to confirm these findings in additional populations and to understand clinical utility, long-term efficacy, and safety of multilevel upper airway surgery for treatment of patients with OSA.
Trial registration
Australian New Zealand Clinical Trials Registry: ACTRN12614000338662.



JAMA: 03 Sep 2020; epub ahead of print
MacKay S, Carney AS, Catcheside PG, Chai-Coetzer CL, ... Yeo A, McEvoy RD
JAMA: 03 Sep 2020; epub ahead of print | PMID: 32886102
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Impact:
Abstract

Trends in Blood Pressure Control Among US Adults With Hypertension, 1999-2000 to 2017-2018.

Muntner P, Hardy ST, Fine LJ, Jaeger BC, ... Levitan EB, Colantonio LD
Importance
Controlling blood pressure (BP) reduces the risk for cardiovascular disease.
Objective
To determine whether BP control among US adults with hypertension changed from 1999-2000 through 2017-2018.
Design, setting, and participants
Serial cross-sectional analysis of National Health and Nutrition Examination Survey data, weighted to be representative of US adults, between 1999-2000 and 2017-2018 (10 cycles), including 18 262 US adults aged 18 years or older with hypertension defined as systolic BP level of 140 mm Hg or higher, diastolic BP level of 90 mm Hg or higher, or use of antihypertensive medication. The date of final data collection was 2018.
Exposures
Calendar year.
Main outcomes and measures
Mean BP was computed using 3 measurements. The primary outcome of BP control was defined as systolic BP level lower than 140 mm Hg and diastolic BP level lower than 90 mm Hg.
Results
Among the 51 761 participants included in this analysis, the mean (SD) age was 48 (19) years and 25 939 (50.1%) were women; 43.2% were non-Hispanic White adults; 21.6%, non-Hispanic Black adults; 5.3%, non-Hispanic Asian adults; and 26.1%, Hispanic adults. Among the 18 262 adults with hypertension, the age-adjusted estimated proportion with controlled BP increased from 31.8% (95% CI, 26.9%-36.7%) in 1999-2000 to 48.5% (95% CI, 45.5%-51.5%) in 2007-2008 (P < .001 for trend), remained stable and was 53.8% (95% CI, 48.7%-59.0%) in 2013-2014 (P = .14 for trend), and then declined to 43.7% (95% CI, 40.2%-47.2%) in 2017-2018 (P = .003 for trend). Compared with adults who were aged 18 years to 44 years, it was estimated that controlled BP was more likely among those aged 45 years to 64 years (49.7% vs 36.7%; multivariable-adjusted prevalence ratio, 1.18 [95% CI, 1.02-1.37]) and less likely among those aged 75 years or older (37.3% vs 36.7%; multivariable-adjusted prevalence ratio, 0.81 [95% CI, 0.65-0.97]). It was estimated that controlled BP was less likely among non-Hispanic Black adults vs non-Hispanic White adults (41.5% vs 48.2%, respectively; multivariable-adjusted prevalence ratio, 0.88; 95% CI, 0.81-0.96). Controlled BP was more likely among those with private insurance (48.2%), Medicare (53.4%), or government health insurance other than Medicare or Medicaid (43.2%) vs among those without health insurance (24.2%) (multivariable-adjusted prevalence ratio, 1.40 [95% CI, 1.08-1.80], 1.47 [95% CI, 1.15-1.89], and 1.36 [95% CI, 1.04-1.76], respectively). Controlled BP was more likely among those with vs those without a usual health care facility (48.4% vs 26.5%, respectively; multivariable-adjusted prevalence ratio, 1.48 [95% CI, 1.13-1.94]) and among those who had vs those who had not had a health care visit in the past year (49.1% vs 8.0%; multivariable-adjusted prevalence ratio, 5.23 [95% CI, 2.88-9.49]).
Conclusions and relevance
In a series of cross-sectional surveys weighted to be representative of the adult US population, the prevalence of controlled BP increased between 1999-2000 and 2007-2008, did not significantly change from 2007-2008 through 2013-2014, and then decreased after 2013-2014.



JAMA: 08 Sep 2020; epub ahead of print
Muntner P, Hardy ST, Fine LJ, Jaeger BC, ... Levitan EB, Colantonio LD
JAMA: 08 Sep 2020; epub ahead of print | PMID: 32902588
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Impact:
Abstract

Association of Lumbar Puncture With Spinal Hematoma in Patients With and Without Coagulopathy.

Bodilsen J, Mariager T, Vestergaard HH, Christiansen MH, ... Bjarkam CR, Nielsen H
Importance
Coagulopathy may deter physicians from performing a lumbar puncture.
Objective
To determine the risk of spinal hematoma after lumbar puncture in patients with and without coagulopathy.
Design, setting, and participants
Danish nationwide, population-based cohort study using medical registries to identify persons who underwent lumbar puncture and had cerebrospinal fluid analysis (January 1, 2008-December 31, 2018; followed up through October 30, 2019). Coagulopathy was defined as platelets lower than 150 × 109/L, international normalized ratio (INR) greater than 1.4, or activated partial thromboplastin time (APTT) longer than 39 seconds.
Exposures
Coagulopathy at the time of lumbar puncture.
Main outcomes and measures
Thirty-day risk of spinal hematoma. Risks were provided as numbers and percentages with 95% CIs. Secondary analyses included risks of traumatic lumbar puncture (>300 × 106 erythrocytes/L after excluding patients diagnosed with subarachnoid hemorrhage). Adjusted hazard rate ratios (HRs) were computed using Cox regression models.
Results
A total of 83 711 individual lumbar punctures were identified among 64 730 persons (51% female; median age, 43 years [interquartile range, 22-62 years]) at the time of the procedure. Thrombocytopenia was present in 7875 patients (9%), high INR levels in 1393 (2%), and prolonged APTT in 2604 (3%). Follow-up was complete for more than 99% of the study participants. Overall, spinal hematoma occurred within 30 days for 99 of 49 526 patients (0.20%; 95% CI, 0.16%-0.24%) without coagulopathy vs 24 of 10 371 patients (0.23%; 95% CI, 0.15%-0.34%) with coagulopathy. Independent risk factors for spinal hematoma were male sex (adjusted hazard ratio [HR], 1.72; 95% CI, 1.15-2.56), those aged 41 through 60 years (adjusted HR, 1.96; 95% CI, 1.01-3.81) and those aged 61 through 80 years (adjusted HR, 2.20; 95% CI, 1.12-4.33). Risks did not increase significantly according to overall severity of coagulopathy, in subgroup analyses of severity of coagulopathy by pediatric specialty or medical indication (infection, neurological condition, and hematological malignancy), nor by cumulative number of procedures. Traumatic lumbar punctures occurred more frequently among patients with INR levels of 1.5 to 2.0 (36.8%; 95% CI, 33.3%-40.4%), 2.1 to 2.5 (43.7%; 95% CI, 35.8%-51.8%), and 2.6 to 3.0 (41.9% 95% CI 30.5-53.9) vs those with normal INR (28.2%; 95% CI, 27.7%-28.75%). Traumatic spinal tap occurred more often in patients with an APTT of 40 to 60 seconds (26.3%; 95% CI, 24.2%-28.5%) vs those with normal APTT (21.3%; 95% CI, 20.6%-21.9%) yielding a risk difference of 5.1% (95% CI, 2.9%-7.2%).
Conclusions and relevance
In this Danish cohort study, risk of spinal hematoma following lumbar puncture was 0.20% among patients without coagulopathy and 0.23% among those with coagulopathy. Although these findings may inform decision-making about lumbar puncture by describing rates in this sample, the observed rates may reflect bias due to physicians selecting relatively low-risk patients for lumbar puncture.



JAMA: 12 Oct 2020; 324:1419-1428
Bodilsen J, Mariager T, Vestergaard HH, Christiansen MH, ... Bjarkam CR, Nielsen H
JAMA: 12 Oct 2020; 324:1419-1428 | PMID: 33048155
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Impact:
Abstract

Effect of Sustained Smoking Cessation Counseling and Provision of Medication vs Shorter-term Counseling and Medication Advice on Smoking Abstinence in Patients Recently Diagnosed With Cancer: A Randomized Clinical Trial.

Park ER, Perez GK, Regan S, Muzikansky A, ... O\'Brien M, Ostroff JS
Importance
Persistent smoking may cause adverse outcomes among patients with cancer. Many cancer centers have not fully implemented evidence-based tobacco treatment into routine care.
Objective
To determine the effectiveness of sustained telephone counseling and medication (intensive treatment) compared with shorter-term telephone counseling and medication advice (standard treatment) to assist patients recently diagnosed with cancer to quit smoking.
Design, setting, and participants
This unblinded randomized clinical trial was conducted at Massachusetts General Hospital/Dana-Farber/Harvard Cancer Center and Memorial Sloan Kettering Cancer Center. Adults who had smoked 1 cigarette or more within 30 days, spoke English or Spanish, and had recently diagnosed breast, gastrointestinal, genitourinary, gynecological, head and neck, lung, lymphoma, or melanoma cancers were eligible. Enrollment occurred between November 2013 and July 2017; assessments were completed by the end of February 2018.
Interventions
Participants randomized to the intensive treatment (n = 153) and the standard treatment (n = 150) received 4 weekly telephone counseling sessions and medication advice. The intensive treatment group also received 4 biweekly and 3 monthly telephone counseling sessions and choice of Food and Drug Administration-approved cessation medication (nicotine replacement therapy, bupropion, or varenicline).
Main outcome and measures
The primary outcome was biochemically confirmed 7-day point prevalence tobacco abstinence at 6-month follow-up. Secondary outcomes were treatment utilization rates.
Results
Among 303 patients who were randomized (mean age, 58.3 years; 170 women [56.1%]), 221 (78.1%) completed the trial. Six-month biochemically confirmed quit rates were 34.5% (n = 51 in the intensive treatment group) vs 21.5% (n = 29 in the standard treatment group) (difference, 13.0% [95% CI, 3.0%-23.3%]; odds ratio, 1.92 [95% CI, 1.13-3.27]; P < .02). The median number of counseling sessions completed was 8 (interquartile range, 4-11) in the intensive treatment group. A total of 97 intensive treatment participants (77.0%) vs 68 standard treatment participants (59.1%) reported cessation medication use (difference, 17.9% [95% CI, 6.3%-29.5%]; odds ratio, 2.31 [95% CI, 1.32-4.04]; P = .003). The most common adverse events in the intensive treatment and standard treatment groups, respectively, were nausea (n = 13 and n = 6), rash (n = 4 and n = 1), hiccups (n = 4 and n = 1), mouth irritation (n = 4 and n = 0), difficulty sleeping (n = 3 and n = 2), and vivid dreams (n = 3 and n = 2).
Conclusions and relevance
Among smokers recently diagnosed with cancer in 2 National Cancer Institute-designated Comprehensive Cancer Centers, sustained counseling and provision of free cessation medication compared with 4-week counseling and medication advice resulted in higher 6-month biochemically confirmed quit rates. However, the generalizability of the study findings is uncertain and requires further research.
Trial registration
ClinicalTrials.gov Identifier: NCT01871506.



JAMA: 12 Oct 2020; 324:1406-1418
Park ER, Perez GK, Regan S, Muzikansky A, ... O'Brien M, Ostroff JS
JAMA: 12 Oct 2020; 324:1406-1418 | PMID: 33048154
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Impact:
Abstract

Association of Geographic Differences in Prevalence of Uncontrolled Chronic Conditions With Changes in Individuals\' Likelihood of Uncontrolled Chronic Conditions.

Baum A, Wisnivesky J, Basu S, Siu AL, Schwartz MD
Importance
The prevalence of leading risk factors for morbidity and mortality in the US significantly varies across regions, states, and neighborhoods, but the extent these differences are associated with a person\'s place of residence vs the characteristics of the people who live in different places remains unclear.
Objective
To estimate the degree to which geographic differences in leading risk factors are associated with a person\'s place of residence by comparing trends in health outcomes among individuals who moved to different areas or did not move.
Design, setting, and participants
This retrospective cohort study estimated the association between the differences in the prevalence of uncontrolled chronic conditions across movers\' destination and origin zip codes and changes in individuals\' likelihood of uncontrolled chronic conditions after moving, adjusting for person-specific fixed effects, the duration of time since the move, and secular trends among movers and those who did not move. Electronic health records from the Veterans Health Administration were analyzed. The primary analysis included 5 342 207 individuals with at least 1 Veterans Health Administration outpatient encounter between 2008 and 2018 who moved zip codes exactly once or never moved.
Exposures
The difference in the prevalence of uncontrolled chronic conditions between a person\'s origin zip code and destination zip code (excluding the individual mover\'s outcomes).
Main outcomes and measures
Prevalence of uncontrolled blood pressure (systolic blood pressure level >140 mm Hg or diastolic blood pressure level >90 mm Hg), uncontrolled diabetes (hemoglobin A1c level >8%), obesity (body mass index >30), and depressive symptoms (2-item Patient Health Questionnaire score ≥2) per quarter-year during the 3 years before and the 3 years after individuals moved.
Results
The study population included 5 342 207 individuals (mean age, 57.6 [SD, 17.4] years, 93.9% men, 72.5% White individuals, and 12.7% Black individuals), of whom 1 095 608 moved exactly once and 4 246 599 never moved during the study period. Among the movers, the change after moving in the prevalence of uncontrolled blood pressure was 27.5% (95% CI, 23.8%-31.3%) of the between-area difference in the prevalence of uncontrolled blood pressure. Similarly, the change after moving in the prevalence of uncontrolled diabetes was 5.0% (95% CI, 2.7%-7.2%) of the between-area difference in the prevalence of uncontrolled diabetes; the change after moving in the prevalence of obesity was 3.1% (95% CI, 2.0%-4.2%) of the between-area difference in the prevalence of obesity; and the change after moving in the prevalence of depressive symptoms was 15.2% (95% CI, 13.1%-17.2%) of the between-area difference in the prevalence of depressive symptoms.
Conclusions and relevance
In this retrospective cohort study of individuals receiving care at Veterans Health Administration facilities, geographic differences in prevalence were associated with a substantial percentage of the change in individuals\' likelihood of poor blood pressure control or depressive symptoms, and a smaller percentage of the change in individuals\' likelihood of poor diabetes control and obesity. Further research is needed to understand the source of these associations with a person\'s place of residence.



JAMA: 12 Oct 2020; 324:1429-1438
Baum A, Wisnivesky J, Basu S, Siu AL, Schwartz MD
JAMA: 12 Oct 2020; 324:1429-1438 | PMID: 33048153
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Impact:
Abstract

Association of Receipt of Palliative Care Interventions With Health Care Use, Quality of Life, and Symptom Burden Among Adults With Chronic Noncancer Illness: A Systematic Review and Meta-analysis.

Quinn KL, Shurrab M, Gitau K, Kavalieratos D, ... Detsky AS, Bell CM
Importance
The evidence for palliative care exists predominantly for patients with cancer. The effect of palliative care on important end-of-life outcomes in patients with noncancer illness is unclear.
Objective
To measure the association between palliative care and acute health care use, quality of life (QOL), and symptom burden in adults with chronic noncancer illnesses.
Data sources
MEDLINE, Embase, CINAHL, PsycINFO, and PubMed from inception to April 18, 2020.
Study selection
Randomized clinical trials of palliative care interventions in adults with chronic noncancer illness. Studies involving at least 50% of patients with cancer were excluded.
Data extraction and synthesis
Two reviewers independently screened, selected, and extracted data from studies. Narrative synthesis was conducted for all trials. All outcomes were analyzed using random-effects meta-analysis.
Main outcomes and measures
Acute health care use (hospitalizations and emergency department use), disease-generic and disease-specific quality of life (QOL), and symptoms, with estimates of QOL translated to units of the Functional Assessment of Chronic Illness Therapy-Palliative Care scale (range, 0 [worst] to 184 [best]; minimal clinically important difference, 9 points) and symptoms translated to units of the Edmonton Symptom Assessment Scale global distress score (range, 0 [best] to 90 [worst]; minimal clinically important difference, 5.7 points).
Results
Twenty-eight trials provided data on 13 664 patients (mean age, 74 years; 46% were women). Ten trials were of heart failure (n = 4068 patients), 11 of mixed disease (n = 8119), 4 of dementia (n = 1036), and 3 of chronic obstructive pulmonary disease (n = 441). Palliative care, compared with usual care, was statistically significantly associated with less emergency department use (9 trials [n = 2712]; 20% vs 24%; odds ratio, 0.82 [95% CI, 0.68-1.00]; I2 = 3%), less hospitalization (14 trials [n = 3706]; 38% vs 42%; odds ratio, 0.80 [95% CI, 0.65-0.99]; I2 = 41%), and modestly lower symptom burden (11 trials [n = 2598]; pooled standardized mean difference (SMD), -0.12; [95% CI, -0.20 to -0.03]; I2 = 0%; Edmonton Symptom Assessment Scale score mean difference, -1.6 [95% CI, -2.6 to -0.4]). Palliative care was not significantly associated with disease-generic QOL (6 trials [n = 1334]; SMD, 0.18 [95% CI, -0.24 to 0.61]; I2 = 87%; Functional Assessment of Chronic Illness Therapy-Palliative Care score mean difference, 4.7 [95% CI, -6.3 to 15.9]) or disease-specific measures of QOL (11 trials [n = 2204]; SMD, 0.07 [95% CI, -0.09 to 0.23]; I2 = 68%).
Conclusions and relevance
In this systematic review and meta-analysis of randomized clinical trials of patients with primarily noncancer illness, palliative care, compared with usual care, was statistically significantly associated with less acute health care use and modestly lower symptom burden, but there was no significant difference in quality of life. Analyses for some outcomes were based predominantly on studies of patients with heart failure, which may limit generalizability to other chronic illnesses.



JAMA: 12 Oct 2020; 324:1439-1450
Quinn KL, Shurrab M, Gitau K, Kavalieratos D, ... Detsky AS, Bell CM
JAMA: 12 Oct 2020; 324:1439-1450 | PMID: 33048152
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Impact:
Abstract

Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults: 2020 Recommendations of the International Antiviral Society-USA Panel.

Saag MS, Gandhi RT, Hoy JF, Landovitz RJ, ... Jacobsen DM, Volberding PA
Importance
Data on the use of antiretroviral drugs, including new drugs and formulations, for the treatment and prevention of HIV infection continue to guide optimal practices.
Objective
To evaluate new data and incorporate them into current recommendations for initiating HIV therapy, monitoring individuals starting on therapy, changing regimens, preventing HIV infection for those at risk, and special considerations for older people with HIV.
Evidence review
New evidence was collected since the previous International Antiviral (formerly AIDS) Society-USA recommendations in 2018, including data published or presented at peer-reviewed scientific conferences through August 22, 2020. A volunteer panel of 15 experts in HIV research and patient care considered these data and updated previous recommendations.
Findings
From 5316 citations about antiretroviral drugs identified, 549 were included to form the evidence basis for these recommendations. Antiretroviral therapy is recommended as soon as possible for all individuals with HIV who have detectable viremia. Most patients can start with a 3-drug regimen or now a 2-drug regimen, which includes an integrase strand transfer inhibitor. Effective options are available for patients who may be pregnant, those who have specific clinical conditions, such as kidney, liver, or cardiovascular disease, those who have opportunistic diseases, or those who have health care access issues. Recommended for the first time, a long-acting antiretroviral regimen injected once every 4 weeks for treatment or every 8 weeks pending approval by regulatory bodies and availability. For individuals at risk for HIV, preexposure prophylaxis with an oral regimen is recommended or, pending approval by regulatory bodies and availability, with a long-acting injection given every 8 weeks. Monitoring before and during therapy for effectiveness and safety is recommended. Switching therapy for virological failure is relatively rare at this time, and the recommendations for switching therapies for convenience and for other reasons are included. With the survival benefits provided by therapy, recommendations are made for older individuals with HIV. The current coronavirus disease 2019 pandemic poses particular challenges for HIV research, care, and efforts to end the HIV epidemic.
Conclusion and relevance
Advances in HIV prevention and management with antiretroviral drugs continue to improve clinical care and outcomes among individuals at risk for and with HIV.



JAMA: 13 Oct 2020; epub ahead of print
Saag MS, Gandhi RT, Hoy JF, Landovitz RJ, ... Jacobsen DM, Volberding PA
JAMA: 13 Oct 2020; epub ahead of print | PMID: 33052386
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Impact:
Abstract

Effect of Praliciguat on Peak Rate of Oxygen Consumption in Patients With Heart Failure With Preserved Ejection Fraction: The CAPACITY HFpEF Randomized Clinical Trial.

Udelson JE, Lewis GD, Shah SJ, Zile MR, ... Profy AT, Konstam MA
Importance
Heart failure with preserved ejection fraction (HFpEF) is often characterized by nitric oxide deficiency.
Objective
To evaluate the efficacy and adverse effects of praliciguat, an oral soluble guanylate cyclase stimulator, in patients with HFpEF.
Design, setting, and participants
CAPACITY HFpEF was a randomized, double-blind, placebo-controlled, phase 2 trial. Fifty-nine sites enrolled 196 patients with heart failure and an ejection fraction of at least 40%, impaired peak rate of oxygen consumption (peak V̇o2), and at least 2 conditions associated with nitric oxide deficiency (diabetes, hypertension, obesity, or advanced age). The trial randomized patients to 1 of 3 praliciguat dose groups or a placebo group, but was refocused early to a comparison of the 40-mg praliciguat dose vs placebo. Participants were enrolled from November 15, 2017, to April 30, 2019, with final follow-up on August 19, 2019.
Interventions
Patients were randomized to receive 12 weeks of treatment with 40 mg of praliciguat daily (n = 91) or placebo (n = 90).
Main outcomes and measures
The primary efficacy end point was the change from baseline in peak V̇o2 in patients who completed at least 8 weeks of assigned dosing. Secondary end points included the change from baseline in 6-minute walk test distance and in ventilatory efficiency (ventilation/carbon dioxide production slope). The primary adverse event end point was the incidence of treatment-emergent adverse events (TEAEs).
Results
Among 181 patients (mean [SD] age, 70 [9] years; 75 [41%] women), 155 (86%) completed the trial. In the placebo (n = 78) and praliciguat (n = 65) groups, changes in peak V̇o2 were 0.04 mL/kg/min (95% CI, -0.49 to 0.56) and -0.26 mL/kg/min (95% CI, -0.83 to 0.31), respectively; the placebo-adjusted least-squares between-group difference in mean change from baseline was -0.30 mL/kg/min ([95% CI, -0.95 to 0.35]; P = .37). None of the 3 prespecified secondary end points were statistically significant. In the placebo and praliciguat groups, changes in 6-minute walk test distance were 58.1 m (95% CI, 26.1-90.1) and 41.4 m (95% CI, 8.2-74.5), respectively; the placebo-adjusted least-squares between-group difference in mean change from baseline was -16.7 m (95% CI, -47.4 to 13.9). In the placebo and praliciguat groups, the placebo-adjusted least-squares between-group difference in mean change in ventilation/carbon dioxide production slope was -0.3 (95% CI, -1.6 to 1.0). There were more dizziness (9.9% vs 1.1%), hypotension (8.8% vs 0%), and headache (11% vs 6.7%) TEAEs with praliciguat compared with placebo. The frequency of serious TEAEs was similar between the groups (10% in the praliciguat group and 11% in the placebo group).
Conclusions and relevance
Among patients with HFpEF, the soluble guanylate cyclase stimulator praliciguat, compared with placebo, did not significantly improve peak V̇o2 from baseline to week 12. These findings do not support the use of praliciguat in patients with HFpEF.
Trial registration
ClinicalTrials.gov Identifier: NCT03254485.



JAMA: 19 Oct 2020; 324:1522-1531
Udelson JE, Lewis GD, Shah SJ, Zile MR, ... Profy AT, Konstam MA
JAMA: 19 Oct 2020; 324:1522-1531 | PMID: 33079154
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Impact:
Abstract

Effect of Vericiguat vs Placebo on Quality of Life in Patients With Heart Failure and Preserved Ejection Fraction: The VITALITY-HFpEF Randomized Clinical Trial.

Armstrong PW, Lam CSP, Anstrom KJ, Ezekowitz J, ... Butler J,
Importance
Patients with heart failure and preserved ejection fraction (HFpEF) are at high risk of mortality, hospitalizations, and reduced functional capacity and quality of life.
Objective
To assess the efficacy of the oral soluble guanylate cyclase stimulator vericiguat on the physical limitation score (PLS) of the Kansas City Cardiomyopathy Questionnaire (KCCQ).
Design, setting, and participants
Phase 2b randomized, double-blind, placebo-controlled, multicenter trial of 789 patients with chronic HFpEF and left ventricular ejection fraction 45% or higher with New York Heart Association class II-III symptoms, within 6 months of a recent decompensation (HF hospitalization or intravenous diuretics for HF without hospitalization), and with elevated natriuretic peptides, enrolled at 167 sites in 21 countries from June 15, 2018, through March 27, 2019; follow-up was completed on November 4, 2019.
Interventions
Patients were randomized to receive vericiguat, up-titrated to 15-mg (n = 264) or 10-mg (n = 263) daily oral dosages, compared with placebo (n = 262) and randomized 1:1:1.
Main outcomes and measures
The primary outcome was change in the KCCQ PLS (range, 0-100; higher values indicate better functioning) after 24 weeks of treatment. The secondary outcome was 6-minute walking distance from baseline to 24 weeks.
Results
Among 789 randomized patients, the mean age was 72.7 (SD, 9.4) years; 385 (49%) were female; mean EF was 56%; and median N-terminal pro-brain natriuretic peptide level was 1403 pg/mL; 761 (96.5%) completed the trial. The baseline and 24-week KCCQ PLS means for the 15-mg/d vericiguat, 10-mg/d vericiguat, and placebo groups were 60.0 and 68.3, 57.3 and 69.0, and 59.0 and 67.1, respectively, and the least-squares mean changes were 5.5, 6.4, and 6.9, respectively. The least-squares mean difference in scores between the 15-mg/d vericiguat and placebo groups was -1.5 (95% CI, -5.5 to 2.5; P = .47) and between the 10-mg/d vericiguat and placebo groups was -0.5 (95% CI, -4.6 to 3.5; P = .80). The baseline and 24-week 6-minute walking distance mean scores in the 15-mg/d vericiguat, 10-mg/d vericiguat, and placebo groups were 295.0 m and 311.8m , 292.1 m and 318.3 m, and 295.8 m and 311.4 m, and the least-squares mean changes were 5.0 m, 8.7 m, and 10.5 m, respectively. The least-squares mean difference between the 15-mg/d vericiguat and placebo groups was -5.5 m (95% CI, -19.7 m to 8.8 m; P = .45) and between the 10-mg/d vericiguat and placebo groups was -1.8 m (95% CI, -16.2 m to 12.6 m; P = .81), respectively. The proportions of patients who experienced symptomatic hypotension were 6.4% in the 15-mg/d vericiguat group, 4.2% in the 10-mg/d vericiguat group, and 3.4% in the placebo group; those with syncope were 1.5%, 0.8%, and 0.4%, respectively.
Conclusions and relevance
Among patients with HFpEF and recent decompensation, 24-week treatment with vericiguat at either 15-mg/d or 10-mg/d dosages compared with placebo did not improve the physical limitation score of the KCCQ.
Trial registration
ClinicalTrials.gov Identifier: NCT03547583.



JAMA: 19 Oct 2020; 324:1512-1521
Armstrong PW, Lam CSP, Anstrom KJ, Ezekowitz J, ... Butler J,
JAMA: 19 Oct 2020; 324:1512-1521 | PMID: 33079152
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Abstract

Medical Care of Adults With Down Syndrome: A Clinical Guideline.

Tsou AY, Bulova P, Capone G, Chicoine B, ... Whitten MS,
Importance
Down syndrome is the most common chromosomal condition, and average life expectancy has increased substantially, from 25 years in 1983 to 60 years in 2020. Despite the unique clinical comorbidities among adults with Down syndrome, there are no clinical guidelines for the care of these patients.
Objective
To develop an evidence-based clinical practice guideline for adults with Down syndrome.
Evidence review
The Global Down Syndrome Foundation Medical Care Guidelines for Adults with Down Syndrome Workgroup (n = 13) developed 10 Population/Intervention/ Comparison/Outcome (PICO) questions for adults with Down syndrome addressing multiple clinical areas including mental health (2 questions), dementia, screening or treatment of diabetes, cardiovascular disease, obesity, osteoporosis, atlantoaxial instability, thyroid disease, and celiac disease. These questions guided the literature search in MEDLINE, EMBASE, PubMed, PsychINFO, Cochrane Library, and the TRIP Database, searched from January 1, 2000, to February 26, 2018, with an updated search through August 6, 2020. Using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) methodology and the Evidence-to-Decision framework, in January 2019, the 13-member Workgroup and 16 additional clinical and scientific experts, nurses, patient representatives, and a methodologist developed clinical recommendations. A statement of good practice was made when there was a high level of certainty that the recommendation would do more good than harm, but there was little direct evidence.
Findings
From 11 295 literature citations associated with 10 PICO questions, 20 relevant studies were identified. An updated search identified 2 additional studies, for a total of 22 included studies (3 systematic reviews, 19 primary studies), which were reviewed and synthesized. Based on this analysis, 14 recommendations and 4 statements of good practice were developed. Overall, the evidence base was limited. Only 1 strong recommendation was formulated: screening for Alzheimer-type dementia starting at age 40 years. Four recommendations (managing risk factors for cardiovascular disease and stroke prevention, screening for obesity, and evaluation for secondary causes of osteoporosis) agreed with existing guidance for individuals without Down syndrome. Two recommendations for diabetes screening recommend earlier initiation of screening and at shorter intervals given the high prevalence and earlier onset in adults with Down syndrome.
Conclusions and relevance
These evidence-based clinical guidelines provide recommendations to support primary care of adults with Down syndrome. The lack of high-quality evidence limits the strength of the recommendations and highlights the need for additional research.



JAMA: 19 Oct 2020; 324:1543-1556
Tsou AY, Bulova P, Capone G, Chicoine B, ... Whitten MS,
JAMA: 19 Oct 2020; 324:1543-1556 | PMID: 33079159
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Abstract

Lifetime Prevalence of Cervical Cancer Screening in 55 Low- and Middle-Income Countries.

Lemp JM, De Neve JW, Bussmann H, Chen S, ... Bärnighausen T, Geldsetzer P
Importance
The World Health Organization is developing a global strategy to eliminate cervical cancer, with goals for screening prevalence among women aged 30 through 49 years. However, evidence on prevalence levels of cervical cancer screening in low- and middle-income countries (LMICs) is sparse.
Objective
To determine lifetime cervical cancer screening prevalence in LMICs and its variation across and within world regions and countries.
Design, setting, and participants
Analysis of cross-sectional nationally representative household surveys carried out in 55 LMICs from 2005 through 2018. The median response rate across surveys was 93.8% (range, 64.0%-99.3%). The population-based sample consisted of 1 136 289 women aged 15 years or older, of whom 6885 (0.6%) had missing information for the survey question on cervical cancer screening.
Exposures
World region, country; countries\' economic, social, and health system characteristics; and individuals\' sociodemographic characteristics.
Main outcomes and measures
Self-report of having ever had a screening test for cervical cancer.
Results
Of the 1 129 404 women included in the analysis, 542 475 were aged 30 through 49 years. A country-level median of 43.6% (interquartile range [IQR], 13.9%-77.3%; range, 0.3%-97.4%) of women aged 30 through 49 years self-reported to have ever been screened, with countries in Latin America and the Caribbean having the highest prevalence (country-level median, 84.6%; IQR, 65.7%-91.1%; range, 11.7%-97.4%) and those in sub-Saharan Africa the lowest prevalence (country-level median, 16.9%; IQR, 3.7%-31.0%; range, 0.9%-50.8%). There was large variation in the self-reported lifetime prevalence of cervical cancer screening among countries within regions and among countries with similar levels of per capita gross domestic product and total health expenditure. Within countries, women who lived in rural areas, had low educational attainment, or had low household wealth were generally least likely to self-report ever having been screened.
Conclusions and relevance
In this cross-sectional study of data collected in 55 low- and middle-income countries from 2005 through 2018, there was wide variation between countries in the self-reported lifetime prevalence of cervical cancer screening. However, the median prevalence was only 44%, supporting the need to increase the rate of screening.



JAMA: 19 Oct 2020; 324:1532-1542
Lemp JM, De Neve JW, Bussmann H, Chen S, ... Bärnighausen T, Geldsetzer P
JAMA: 19 Oct 2020; 324:1532-1542 | PMID: 33079153
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This program is still in alpha version.