Journal: Ann Intern Med

Sorted by: date / impact
Abstract

Is Comprehensive Geriatric Assessment Admission Avoidance Hospital at Home an Alternative to Hospital Admission for Older Persons? : A Randomized Trial.

Shepperd S, Butler C, Cradduck-Bamford A, Ellis G, ... Yu LM, Young J
Background
Delivering hospital-level care with comprehensive geriatric assessment (CGA) in the home is one approach to deal with the increased demand for bed-based hospital care, but clinical effectiveness is uncertain.
Objective
To assess the clinical effectiveness of admission avoidance hospital at home (HAH) with CGA for older persons.
Design
Multisite randomized trial. (ISRCTN registry number: ISRCTN60477865).
Setting
9 hospital and community sites in the United Kingdom.
Patients
1055 older persons who were medically unwell, were physiologically stable, and were referred for a hospital admission.
Intervention
Admission avoidance HAH with CGA versus hospital admission with CGA when available using 2:1 randomization.
Measurements
The primary outcome of living at home was measured at 6 months. Secondary outcomes were new admission to long-term residential care, death, health status, delirium, and patient satisfaction.
Results
Participants had a mean age of 83.3 years (SD, 7.0). At 6-month follow-up, 528 of 672 (78.6%) participants in the CGA HAH group versus 247 of 328 (75.3%) participants in the hospital group were living at home (relative risk [RR], 1.05 [95% CI, 0.95 to 1.15]; P = 0.36); 114 of 673 (16.9%) versus 58 of 328 (17.7%) had died (RR, 0.98 [CI, 0.65 to 1.47]; P = 0.92); and 37 of 646 (5.7%) versus 27 of 311 (8.7%) were in long-term residential care (RR, 0.58 [CI, 0.45 to 0.76]; P < 0.001).
Limitation
The findings are most applicable to older persons referred from a hospital short-stay acute medical assessment unit; episodes of delirium may have been undetected.
Conclusion
Admission avoidance HAH with CGA led to similar outcomes as hospital admission in the proportion of older persons living at home as well as a decrease in admissions to long-term residential care at 6 months. This type of service can provide an alternative to hospitalization for selected older persons.
Primary funding source
The National Institute for Health Research Health Services and Delivery Research Programme (12/209/66).



Ann Intern Med: 19 Apr 2021; epub ahead of print
Shepperd S, Butler C, Cradduck-Bamford A, Ellis G, ... Yu LM, Young J
Ann Intern Med: 19 Apr 2021; epub ahead of print | PMID: 33872045
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Impact:
Abstract

Treatment Patterns and Clinical Outcomes After the Introduction of the Medicare Sepsis Performance Measure (SEP-1).

Barbash IJ, Davis BS, Yabes JG, Seymour CW, Angus DC, Kahn JM
Background
Medicare requires that hospitals report on their adherence to the Severe Sepsis and Septic Shock Early Management Bundle (SEP-1).
Objective
To evaluate the effect of SEP-1 on treatment patterns and patient outcomes.
Design
Longitudinal study of hospitals using repeated cross-sectional cohorts of patients.
Setting
11 hospitals within an integrated health system.
Patients
54 225 encounters between January 2013 and December 2017 for adults with sepsis who were hospitalized through the emergency department.
Intervention
Onset of the SEP-1 reporting requirement in October 2015.
Measurements
Changes in SEP-1-targeted processes, including antibiotic administration, lactate measurement, and fluid administration at 3 hours from sepsis onset; repeated lactate and vasopressor administration for hypotension within 6 hours of sepsis onset; and sepsis outcomes, including risk-adjusted intensive care unit (ICU) admission, in-hospital mortality, and home discharge among survivors.
Results
Two years after its implementation, SEP-1 was associated with variable changes in process measures, with the greatest effect being an increase in lactate measurement within 3 hours of sepsis onset (absolute increase, 23.7 percentage points [95% CI, 20.7 to 26.7 percentage points]; P < 0.001). There were small increases in antibiotic administration (absolute increase, 4.7 percentage points [CI, 1.9 to 7.6 percentage points]; P = 0.001) and fluid administration of 30 mL/kg of body weight within 3 hours of sepsis onset (absolute increase, 3.4 percentage points [CI, 1.5 to 5.2 percentage points]; P < 0.001). There was no change in vasopressor administration. There was a small increase in ICU admissions (absolute increase, 2.0 percentage points [CI, 0 to 4.0 percentage points]; P = 0.055) and no changes in mortality (absolute change, 0.1 percentage points [CI, -0.9 to 1.1 percentage points]; P = 0.87) or discharge to home.
Limitation
Data are from a single health system.
Conclusion
Implementation of the SEP-1 mandatory reporting program was associated with variable changes in process measures, without improvements in clinical outcomes. Revising the measure may optimize its future effect.
Primary funding source
Agency for Healthcare Research and Quality.



Ann Intern Med: 19 Apr 2021; epub ahead of print
Barbash IJ, Davis BS, Yabes JG, Seymour CW, Angus DC, Kahn JM
Ann Intern Med: 19 Apr 2021; epub ahead of print | PMID: 33872042
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Impact:
Abstract

Pulmonary Hypertension.

Poch D, Mandel J
Pulmonary hypertension is the term used to describe a group of disorders characterized by abnormally high pressures in the pulmonary arteries. Initial evaluation is focused on identifying the cause, which helps guide appropriate treatment. Pulmonary hypertension is often a feature of advanced common diseases, such as chronic obstructive pulmonary disease and left heart disease, and treatment is focused primarily on the underlying disease. More rarely, pulmonary hypertension results from chronic organized thromboemboli or a primary vasculopathy. The former requires evaluation for surgical intervention, and the latter is treated with advanced medical therapies.



Ann Intern Med: 12 Apr 2021; epub ahead of print
Poch D, Mandel J
Ann Intern Med: 12 Apr 2021; epub ahead of print | PMID: 33844574
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Impact:
Abstract

A Deferred-Vaccination Design to Assess Durability of COVID-19 Vaccine Effect After the Placebo Group Is Vaccinated.

Follmann D, Fintzi J, Fay MP, Janes HE, ... Gilbert PB, Neuzil KM
Multiple candidate vaccines to prevent COVID-19 have entered large-scale phase 3 placebo-controlled randomized clinical trials, and several have demonstrated substantial short-term efficacy. At some point after demonstration of substantial efficacy, placebo recipients should be offered the efficacious vaccine from their trial, which will occur before longer-term efficacy and safety are known. The absence of a placebo group could compromise assessment of longer-term vaccine effects. However, by continuing follow-up after vaccination of the placebo group, this study shows that placebo-controlled vaccine efficacy can be mathematically derived by assuming that the benefit of vaccination over time has the same profile for the original vaccine recipients and the original placebo recipients after their vaccination. Although this derivation provides less precise estimates than would be obtained by a standard trial where the placebo group remains unvaccinated, this proposed approach allows estimation of longer-term effect, including durability of vaccine efficacy and whether the vaccine eventually becomes harmful for some. Deferred vaccination, if done open-label, may lead to riskier behavior in the unblinded original vaccine group, confounding estimates of long-term vaccine efficacy. Hence, deferred vaccination via blinded crossover, where the vaccine group receives placebo and vice versa, would be the preferred way to assess vaccine durability and potential delayed harm. Deferred vaccination allows placebo recipients timely access to the vaccine when it would no longer be proper to maintain them on placebo, yet still allows important insights about immunologic and clinical effectiveness over time.



Ann Intern Med: 12 Apr 2021; epub ahead of print
Follmann D, Fintzi J, Fay MP, Janes HE, ... Gilbert PB, Neuzil KM
Ann Intern Med: 12 Apr 2021; epub ahead of print | PMID: 33844575
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Impact:
Abstract

LDL-C-lowering therapies reduce major vascular events in patients aged ≥75 y.

Elgendy IY, Elshazly MB
Source citation
Gencer B, Marston NA, Im K, et al. Efficacy and safety of lowering LDL cholesterol in older patients: a systematic review and meta-analysis of randomised controlled trials. Lancet. 2020;396:1637-43. 33186535.



Ann Intern Med: 05 Apr 2021; epub ahead of print
Elgendy IY, Elshazly MB
Ann Intern Med: 05 Apr 2021; epub ahead of print | PMID: 33819068
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Impact:
Abstract

In older adults without CVD, treating 100 persons with statins for 2.5 y prevents 1 MACE.

Lim LS
Source citation
Yourman LC, Cenzer IS, Boscardin WJ, et al. Evaluation of time to benefit of statins for the primary prevention of cardiovascular events in adults aged 50 to 75 years: a meta-analysis. JAMA Intern Med. 2021;181:179-85. 33196766.



Ann Intern Med: 05 Apr 2021; epub ahead of print
Lim LS
Ann Intern Med: 05 Apr 2021; epub ahead of print | PMID: 33819067
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Impact:
Abstract

In eosinophilic esophagitis, budesonide orodispersible tablets maintained remission at 48 wk.

Srinivasan S, Sharma P
Source citation
Straumann A, Lucendo AJ, Miehlke S, et al. Budesonide orodispersible tablets maintain remission in a randomized, placebo-controlled trial of patients with eosinophilic esophagitis. Gastroenterology. 2020;159:1672-85. 32721437.



Ann Intern Med: 05 Apr 2021; epub ahead of print
Srinivasan S, Sharma P
Ann Intern Med: 05 Apr 2021; epub ahead of print | PMID: 33819066
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Impact:
Abstract

In statin-treated patients at high CV risk, adding omega-3 fatty acidsvs. corn oil to usual care did not reduce MACE.

Budenholzer B
Source citation
Nicholls SJ, Lincoff AM, Garcia M, et al. Effect of high-dose omega-3 fatty acids vs corn oil on major adverse cardiovascular events in patients at high cardiovascular risk: the STRENGTH randomized clinical trial. JAMA. 2020;324:2268-80. 33190147.



Ann Intern Med: 05 Apr 2021; epub ahead of print
Budenholzer B
Ann Intern Med: 05 Apr 2021; epub ahead of print | PMID: 33819062
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Impact:
Abstract

In imaging-selected ischemic stroke with unknown onset, alteplase increases favorable outcomes and death at 90 d.

Hill MD
Source citation
Thomalla G, Boutitie F, Ma H, et al. Intravenous alteplase for stroke with unknown time of onset guided by advanced imaging: systematic review and meta-analysis of individual patient data. Lancet. 2020;396:1574-84. 33176180.



Ann Intern Med: 05 Apr 2021; epub ahead of print
Hill MD
Ann Intern Med: 05 Apr 2021; epub ahead of print | PMID: 33819060
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Impact:
Abstract

Preventing Hospital Readmission for Patients With Comorbid Substance Use Disorder : A Randomized Trial.

Gryczynski J, Nordeck CD, Welsh C, Mitchell SG, O\'Grady KE, Schwartz RP
Background
Hospitalized patients with comorbid substance use disorders (SUDs) are at high risk for poor outcomes, including readmission and emergency department (ED) use.
Objective
To determine whether patient navigation services reduce hospital readmissions.
Design
Randomized controlled trial comparing Navigation Services to Avoid Rehospitalization (NavSTAR) versus treatment as usual (TAU). (ClinicalTrials.gov: NCT02599818).
Setting
Urban academic hospital in Baltimore, Maryland, with an SUD consultation service.
Participants
400 hospitalized adults with comorbid SUD (opioid, cocaine, or alcohol).
Intervention
NavSTAR used proactive case management, advocacy, service linkage, and motivational support to resolve internal and external barriers to care and address SUD, medical, and basic needs for 3 months after discharge.
Measurements
Data on inpatient readmissions (primary outcome) and ED visits for 12 months were obtained for all participants via the regional health information exchange. Entry into SUD treatment, substance use, and related outcomes were assessed at 3-, 6-, and 12-month follow-up.
Results
Participants had high levels of acute care use: 69% had an inpatient readmission and 79% visited the ED over the 12-month observation period. Event rates per 1000 person-days were 6.05 (NavSTAR) versus 8.13 (TAU) for inpatient admissions (hazard ratio, 0.74 [95% CI, 0.58 to 0.96]; P= 0.020) and 17.66 (NavSTAR) versus 27.85 (TAU) for ED visits (hazard ratio, 0.66 [CI, 0.49 to 0.89]; P= 0.006). Participants in the NavSTAR group were less likely to have an inpatient readmission within 30 days than those receiving TAU (15.5% vs. 30.0%; P< 0.001) and were more likely to enter community SUD treatment after discharge (P= 0.014; treatment entry within 3 months, 50.3% NavSTAR vs. 35.3% TAU).
Limitation
Single-site trial, which limits generalizability.
Conclusion
Patient navigation reduced inpatient readmissions and ED visits in this clinically challenging sample of hospitalized patients with comorbid SUDs.
Primary funding source
National Institute on Drug Abuse.



Ann Intern Med: 05 Apr 2021; epub ahead of print
Gryczynski J, Nordeck CD, Welsh C, Mitchell SG, O'Grady KE, Schwartz RP
Ann Intern Med: 05 Apr 2021; epub ahead of print | PMID: 33819055
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Impact:
Abstract

Appropriate Use of Short-Course Antibiotics in Common Infections: Best Practice Advice From the American College of Physicians.

Lee RA, Centor RM, Humphrey LL, Jokela JA, Andrews R, Qaseem A
Description
Antimicrobial overuse is a major health care issue that contributes to antibiotic resistance. Such overuse includes unnecessarily long durations of antibiotic therapy in patients with common bacterial infections, such as acute bronchitis with chronic obstructive pulmonary disease (COPD) exacerbation, community-acquired pneumonia (CAP), urinary tract infections (UTIs), and cellulitis. This article describes best practices for prescribing appropriate and short-duration antibiotic therapy for patients presenting with these infections.
Methods
The authors conducted a narrative literature review of published clinical guidelines, systematic reviews, and individual studies that addressed bronchitis with COPD exacerbations, CAP, UTIs, and cellulitis. This article is based on the best available evidence but was not a formal systematic review. Guidance was prioritized to the highest available level of synthesized evidence.
Best practice advice 1
Clinicians should limit antibiotic treatment duration to 5 days when managing patients with COPD exacerbations and acute uncomplicated bronchitis who have clinical signs of a bacterial infection (presence of increased sputum purulence in addition to increased dyspnea, and/or increased sputum volume).
Best practice advice 2
Clinicians should prescribe antibiotics for community-acquired pneumonia for a minimum of 5 days. Extension of therapy after 5 days of antibiotics should be guided by validated measures of clinical stability, which include resolution of vital sign abnormalities, ability to eat, and normal mentation.
Best practice advice 3
In women with uncomplicated bacterial cystitis, clinicians should prescribe short-course antibiotics with either nitrofurantoin for 5 days, trimethoprim-sulfamethoxazole (TMP-SMZ) for 3 days, or fosfomycin as a single dose. In men and women with uncomplicated pyelonephritis, clinicians should prescribe short-course therapy either with fluoroquinolones (5 to 7 days) or TMP-SMZ (14 days) based on antibiotic susceptibility.
Best practice advice 4
In patients with nonpurulent cellulitis, clinicians should use a 5- to 6-day course of antibiotics active against streptococci, particularly for patients able to self-monitor and who have close follow-up with primary care.



Ann Intern Med: 05 Apr 2021; epub ahead of print
Lee RA, Centor RM, Humphrey LL, Jokela JA, Andrews R, Qaseem A
Ann Intern Med: 05 Apr 2021; epub ahead of print | PMID: 33819054
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Impact:
Abstract

Impact of Population Growth and Aging on Estimates of Excess U.S. Deaths During the COVID-19 Pandemic, March to August 2020.

Shiels MS, Almeida JS, García-Closas M, Albert PS, Freedman ND, de González AB
Background
Excess death estimates quantify the full impact of the coronavirus disease 2019 (COVID-19) pandemic. Widely reported U.S. excess death estimates have not accounted for recent population changes, especially increases in the population older than 65 years.
Objective
To estimate excess deaths in the United States in 2020, after accounting for population changes.
Design
Surveillance study.
Setting
United States, March to August 2020.
Participants
All decedents.
Measurements
Age-specific excess deaths in the United States from 1 March to 31 August 2020 compared with 2015 to 2019 were estimated, after changes in population size and age were taken into account, by using Centers for Disease Control and Prevention provisional death data and U.S. Census Bureau population estimates. Cause-specific excess deaths were estimated by month and age.
Results
From March through August 2020, 1 671 400 deaths were registered in the United States, including 173 300 COVID-19 deaths. An average of 1 370 000 deaths were reported over the same months during 2015 to 2019, for a crude excess of 301 400 deaths (128 100 non-COVID-19 deaths). However, the 2020 U.S. population includes 5.04 million more persons aged 65 years and older than the average population in 2015 to 2019 (a 10% increase). After population changes were taken into account, an estimated 217 900 excess deaths occurred from March through August 2020 (173 300 COVID-19 and 44 600 non-COVID-19 deaths). Most excess non-COVID-19 deaths occurred in April, July, and August, and 34 900 (78%) were in persons aged 25 to 64 years. Diabetes, Alzheimer disease, and heart disease caused the most non-COVID-19 excess deaths.
Limitation
Provisional death data are underestimated because of reporting delays.
Conclusion
The COVID-19 pandemic resulted in an estimated 218 000 excess deaths in the United States between March and August 2020, and 80% of those deaths had COVID-19 as the underlying cause. Accounting for population changes substantially reduced the excess non-COVID-19 death estimates, providing important information for guiding future clinical and public health interventions.
Primary funding source
National Cancer Institute.



Ann Intern Med: 30 Mar 2021; 174:437-443
Shiels MS, Almeida JS, García-Closas M, Albert PS, Freedman ND, de González AB
Ann Intern Med: 30 Mar 2021; 174:437-443 | PMID: 33316174
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Impact:
Abstract

Population Mortality and Laws Encouraging Influenza Vaccination for Hospital Workers.

Carrera M, Lawler EC, White C
Background
Since 1995, 14 states have passed laws encouraging or mandating influenza vaccination for hospital workers. Although the Centers for Disease Control and Prevention recommends vaccinating health care workers to reduce disease transmission and patient risk, the effect of these laws on pneumonia and influenza mortality is unknown.
Objective
To measure the effect of state-level hospital worker influenza vaccination laws on pneumonia and influenza mortality.
Design
Quasi-experimental observational study.
Setting
United States.
Participants
Population of all states from 1995 to 2017.
Intervention
State adoption of a law promoting influenza vaccination for hospital workers.
Measurements
Pneumonia and influenza mortality per 100 000 persons by state and by month, both population-wide and separately by age group, obtained from restricted-access National Vital Statistics System files. Linear and log-linear models were used to compare changes in mortality rates for adopting versus nonadopting states.
Results
Implementation of state laws requiring hospitals to offer influenza vaccination to their employees was associated with a 2.5% reduction in the monthly pneumonia and influenza mortality rate (-0.16 deaths per 100 000 persons [95% CI, -0.29 to -0.02]; P = 0.022) during the years when the vaccine was well matched to the circulating strains. The largest effects occurred among elderly persons and during peak influenza months.
Limitation
Utilization of large-scale national data precluded analysis of more specific outcomes, such as laboratory-confirmed or hospital-acquired influenza.
Conclusion
State laws promoting hospital worker vaccination against influenza may be effective in preventing pneumonia- and influenza-related deaths, particularly among elderly persons. Vaccinating hospital workers may substantially reduce the spread of influenza and protect the most vulnerable populations.
Primary funding source
None.



Ann Intern Med: 30 Mar 2021; 174:444-452
Carrera M, Lawler EC, White C
Ann Intern Med: 30 Mar 2021; 174:444-452 | PMID: 33395343
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Impact:
Abstract

Transcatheter Aortic Valve Replacement Versus Surgical Aortic Valve Replacement: How Would You Manage This Patient With Severe Aortic Stenosis? : Grand Rounds Discussion From Beth Israel Deaconess Medical Center.

Reynolds EE, Baron SJ, Kaneko T, Libman H
Aortic stenosis (AS) is common, especially among the elderly. Left untreated, severe symptomatic AS is typically fatal. Surgical aortic valve replacement (SAVR) was the standard of care until transcatheter aortic valve replacement (TAVR) was shown to have lower mortality rates in patients at the highest surgical risk and was recommended for this group in the 2014 American Heart Association/American College of Cardiology (AHA/ACC) guidelines. In the 2017 AHA/ACC focused update, evidence of benefit and noninferiority extended the use of TAVR to intermediate-risk patients. More recent studies suggest potential benefit to low-risk patients, although no published guidelines yet recommend the use of TAVR for this population. An advantage of SAVR is a 30-year experience with valve durability, but SAVR may have higher rates of perioperative death and a slower return of quality of life. Although TAVR has less than 10-year experience with valve durability, it has lower or noninferior primary end points, such as mortality and stroke, and fewer periprocedural complications among anatomically permissive patients. Here, a cardiologist and a cardiothoracic surgeon debate the risks and benefits of TAVR versus SAVR for a patient with severe symptomatic AS who is at low risk for surgical death.



Ann Intern Med: 30 Mar 2021; 174:521-528
Reynolds EE, Baron SJ, Kaneko T, Libman H
Ann Intern Med: 30 Mar 2021; 174:521-528 | PMID: 33844572
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Impact:
Abstract

Spatial Inequities in COVID-19 Testing, Positivity, Confirmed Cases, and Mortality in 3 U.S. Cities : An Ecological Study.

Bilal U, Tabb LP, Barber S, Diez Roux AV
Background
Preliminary evidence has shown inequities in coronavirus disease 2019 (COVID-19)-related cases and deaths in the United States.
Objective
To explore the emergence of spatial inequities in COVID-19 testing, positivity, confirmed cases, and mortality in New York, Philadelphia, and Chicago during the first 6 months of the pandemic.
Design
Ecological, observational study at the ZIP code tabulation area (ZCTA) level from March to September 2020.
Setting
Chicago, New York, and Philadelphia.
Participants
All populated ZCTAs in the 3 cities.
Measurements
Outcomes were ZCTA-level COVID-19 testing, positivity, confirmed cases, and mortality cumulatively through the end of September 2020. Predictors were the Centers for Disease Control and Prevention Social Vulnerability Index and its 4 domains, obtained from the 2014-2018 American Community Survey. The spatial autocorrelation of COVID-19 outcomes was examined by using global and local Moran I statistics, and estimated associations were examined by using spatial conditional autoregressive negative binomial models.
Results
Spatial clusters of high and low positivity, confirmed cases, and mortality were found, co-located with clusters of low and high social vulnerability in the 3 cities. Evidence was also found for spatial inequities in testing, positivity, confirmed cases, and mortality. Specifically, neighborhoods with higher social vulnerability had lower testing rates and higher positivity ratios, confirmed case rates, and mortality rates.
Limitations
The ZCTAs are imperfect and heterogeneous geographic units of analysis. Surveillance data were used, which may be incomplete.
Conclusion
Spatial inequities exist in COVID-19 testing, positivity, confirmed cases, and mortality in 3 large U.S. cities.
Primary funding source
National Institutes of Health.



Ann Intern Med: 29 Mar 2021; epub ahead of print
Bilal U, Tabb LP, Barber S, Diez Roux AV
Ann Intern Med: 29 Mar 2021; epub ahead of print | PMID: 33780289
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Impact:
Abstract

Toward Understanding COVID-19 Recovery: National Institutes of Health Workshop on Postacute COVID-19.

Lerner AM, Robinson DA, Yang L, Williams CF, ... Adimora AA, Erbelding EJ
Over the past year, the SARS-CoV-2 pandemic has swept the globe, resulting in an enormous worldwide burden of infection and mortality. However, the additional toll resulting from long-term consequences of the pandemic has yet to be tallied. Heterogeneous disease manifestations and syndromes are now recognized among some persons after their initial recovery from SARS-CoV-2 infection, representing in the broadest sense a failure to return to a baseline state of health after acute SARS-CoV-2 infection. On 3 to 4 December 2020, the National Institute of Allergy and Infectious Diseases, in collaboration with other Institutes and Centers of the National Institutes of Health, convened a virtual workshop to summarize existing knowledge on postacute COVID-19 and to identify key knowledge gaps regarding this condition.



Ann Intern Med: 29 Mar 2021; epub ahead of print
Lerner AM, Robinson DA, Yang L, Williams CF, ... Adimora AA, Erbelding EJ
Ann Intern Med: 29 Mar 2021; epub ahead of print | PMID: 33780290
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Impact:
Abstract

Effectiveness and Safety of Direct Oral Anticoagulants Versus Warfarin in Patients With Valvular Atrial Fibrillation : A Population-Based Cohort Study.

Dawwas GK, Dietrich E, Cuker A, Barnes GD, Leonard CE, Lewis JD
Background
Direct oral anticoagulants (DOACs) are increasingly used in place of warfarin, but evidence about their effectiveness and safety in patients with valvular atrial fibrillation (AF) remains limited.
Objective
To assess the effectiveness and safety of DOACs compared with warfarin in patients with valvular AF.
Design
New-user retrospective propensity score-matched cohort study.
Setting
U.S.-based commercial health care database from 1 January 2010 to 30 June 2019.
Participants
Adults with valvular AF who were newly prescribed DOACs or warfarin.
Measurements
The primary effectiveness outcome was a composite of ischemic stroke or systemic embolism. The primary safety outcome was a composite of intracranial or gastrointestinal bleeding.
Results
Among a total of 56 336 patients with valvular AF matched on propensity score, use of DOACs (vs. warfarin) was associated with lower risk for ischemic stroke or systemic embolism (hazard ratio [HR], 0.64 [95% CI, 0.59 to 0.70]) and major bleeding events (HR, 0.67 [CI, 0.63 to 0.72]). The results for the effectiveness and safety outcomes remained consistent for apixaban (HRs, 0.54 [CI, 0.47 to 0.61] and 0.52 [CI, 0.47 to 0.57], respectively) and rivaroxaban (HRs, 0.74 [CI, 0.64 to 0.86] and 0.87 [CI, 0.79 to 0.96], respectively); with dabigatran, results were consistent for the major bleeding outcome (HR, 0.81 [CI, 0.68 to 0.97]) but not for effectiveness (HR, 1.03 [CI, 0.81 to 1.31]).
Limitation
Relatively short follow-up; inability to ascertain disease severity.
Conclusion
In this comparative effectiveness study using practice-based claims data, patients with valvular AF who were new users of DOACs had lower risks for ischemic stroke or systemic embolism and major bleeding than new users of warfarin. These data may be used to guide risk-benefit discussions regarding anticoagulant choices for patients with valvular AF.
Primary funding source
None.



Ann Intern Med: 29 Mar 2021; epub ahead of print
Dawwas GK, Dietrich E, Cuker A, Barnes GD, Leonard CE, Lewis JD
Ann Intern Med: 29 Mar 2021; epub ahead of print | PMID: 33780291
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Impact:
Abstract

Estimated Effect on Life Expectancy of Alleviating Primary Care Shortages in the United States.

Basu S, Phillips RS, Berkowitz SA, Landon BE, Bitton A, Phillips RL
Background
Prior studies have reported that greater numbers of primary care physicians (PCPs) per population are associated with reduced population mortality, but the effect of increasing PCP density in areas of low density is poorly understood.
Objective
To estimate how alleviating PCP shortages might change life expectancy and mortality.
Design
Generalized additive models, mixed-effects models, and generalized estimating equations.
Setting
3104 U.S. counties from 2010 to 2017.
Participants
Children and adults.
Measurements
Age-adjusted life expectancy; all-cause mortality; and mortality due to cardiovascular disease, cancer, infectious disease, respiratory disease, and substance use or injury.
Results
Persons living in counties with less than 1 physician per 3500 persons in 2017 had a mean life expectancy that was 310.9 days shorter than for persons living in counties above that threshold. In the low-density counties (n = 1218), increasing the density of PCPs above the 1:3500 threshold would be expected to increase mean life expectancy by 22.4 days (median, 19.4 days [95% CI, 0.9 to 45.6 days]), and all such counties would require 17 651 more physicians, or about 14.5 more physicians per shortage county. If counties with less than 1 physician per 1500 persons (n = 2636) were to reach the 1:1500 threshold, life expectancy would be expected to increase by 56.3 days (median, 55.6 days [CI, 4.2 to 105.6 days]), and all such counties would require 95 754 more physicians, or about 36.3 more physicians per shortage county.
Limitation
Some projections are based on extrapolations of the actual data.
Conclusion
In counties with fewer PCPs per population, increases in PCP density would be expected to substantially improve life expectancy.
Primary funding source
None.



Ann Intern Med: 22 Mar 2021; epub ahead of print
Basu S, Phillips RS, Berkowitz SA, Landon BE, Bitton A, Phillips RL
Ann Intern Med: 22 Mar 2021; epub ahead of print | PMID: 33750188
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Impact:
Abstract

The Value of Total Knee Replacement in Patients With Knee Osteoarthritis and a Body Mass Index of 40 kg/m or Greater : A Cost-Effectiveness Analysis.

Chen AT, Bronsther CI, Stanley EE, Paltiel AD, ... Katz JN, Losina E
Background
Total knee replacement (TKR) is an effective and cost-effective strategy for treating end-stage knee osteoarthritis. Greater risk for complications among TKR recipients with a body mass index (BMI) of 40 kg/m2 or greater has raised concerns about the value of TKR in this population.
Objective
To assess the value of TKR in recipients with a BMI of 40 kg/m2 or greater using a cost-effectiveness analysis.
Design
Osteoarthritis Policy Model to assess long-term clinical benefits, costs, and cost-effectiveness of TKR in patients with a BMI of 40 kg/m2 or greater.
Data sources
Total knee replacement parameters from longitudinal studies and published literature, and costs from Medicare Physician Fee Schedules, the Healthcare Cost and Utilization Project, and published data.
Target population
Recipients of TKR with a BMI of 40 kg/m2 or greater in the United States.
Time horizon
Lifetime.
Perspective
Health care sector.
Intervention
Total knee replacement.
Outcome measures
Cost, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs), discounted at 3% annually.
Results of base-case analysis
Total knee replacement increased QALYs by 0.71 year and lifetime medical costs by $25 200 among patients aged 50 to 65 years with a BMI of 40 kg/m2 or greater, resulting in an ICER of $35 200. Total knee replacement in patients older than 65 years with a BMI of 40 kg/m2 or greater increased QALYs by 0.39 year and costs by $21 100, resulting in an ICER of $54 100.
Results of sensitivity analysis
In TKR recipients with a BMI of 40 kg/m2 or greater and diabetes and cardiovascular disease, ICERs were below $75 000 per QALY. Results were most sensitive to complication rates and preoperative pain levels. In the probabilistic sensitivity analysis, at a $55 000-per-QALY willingness-to-pay threshold, TKR had a 100% and 90% likelihood of being a cost-effective strategy for patients aged 50 to 65 years and patients older than 65 years, respectively.
Limitation
Data are derived from several sources.
Conclusion
From a cost-effectiveness perspective, TKR offers good value in patients with a BMI of 40 kg/m2 or greater, including those with multiple comorbidities.
Primary funding source
National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health.



Ann Intern Med: 22 Mar 2021; epub ahead of print
Chen AT, Bronsther CI, Stanley EE, Paltiel AD, ... Katz JN, Losina E
Ann Intern Med: 22 Mar 2021; epub ahead of print | PMID: 33750190
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Impact:
Abstract

Weight and Metabolic Changes After Switching From Tenofovir Disoproxil Fumarate to Tenofovir Alafenamide in People Living With HIV : A Cohort Study.

Surial B, Mugglin C, Calmy A, Cavassini M, ... Wandeler G, Rauch A
Background
Tenofovir-based antiretroviral therapy (ART) has become first-line in all major HIV treatment guidelines. Compared with tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF) has a favorable renal and bone safety profile, but concerns about metabolic complications remain.
Objective
To assess weight changes, the development of overweight/obesity, and changes in lipid levels 18 months after replacing TDF with TAF.
Design
Cohort study.
Setting
5 university hospitals, affiliated hospitals, and private physicians in Switzerland.
Participants
4375 adults living with HIV who received TDF-containing ART for 6 months or longer.
Measurements
Changes in weight and lipid levels were assessed using mixed-effect models. Differences in proportions of newly overweight/obese participants were calculated using 2-proportions Z tests.
Results
4375 individuals were included, with follow-up between 1 January 2016 and 31 July 2019. Median age was 50 years (interquartile range, 43 to 56 years), 25.9% were female, and 51.7% had a normal body mass index (BMI); 3484 (79.6%) switched to TAF and 891 (20.4%) continued TDF. After 18 months, switching to TAF was associated with an adjusted mean weight increase of 1.7 kg (95% CI, 1.5 to 2.0 kg), compared with 0.7 kg (CI, 0.4 to 1.0 kg) with the continued use of TDF (between-group difference, 1.1 kg [CI, 0.7 to 1.4 kg]). Among individuals with a normal BMI, 13.8% who switched to TAF became overweight/obese, compared with 8.4% of those continuing TDF (difference, 5.4 percentage points [CI, 2.1 to 8.8 percentage points]). Switching to TAF led to increases in adjusted mean total cholesterol (0.25 mmol/L [9.5 mg/dL]), high-density lipoprotein cholesterol (0.05 mmol/L [1.9 mg/dL]), low-density lipoprotein cholesterol (0.12 mmol/L [4.7 mg/dL]), and triglyceride (0.18 mmol/L [16.1 mg/dL]) levels after 18 months.
Limitation
Short follow-up, small subgroup analyses, and potential residual confounding.
Conclusion
Replacing TDF with TAF is associated with adverse metabolic changes, including weight increase, development of obesity, and worsening serum lipid levels.
Primary funding source
Swiss National Science Foundation.



Ann Intern Med: 15 Mar 2021; epub ahead of print
Surial B, Mugglin C, Calmy A, Cavassini M, ... Wandeler G, Rauch A
Ann Intern Med: 15 Mar 2021; epub ahead of print | PMID: 33721521
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Impact:
Abstract

Ethical and Professionalism Implications of Physician Employment and Health Care Business Practices: A Policy Paper From the American College of Physicians.

DeCamp M, Snyder Sulmasy L
The environment in which physicians practice and patients receive care continues to change. Increasing employment of physicians, changing practice models, new regulatory requirements, and market dynamics all affect medical practice; some changes may also place greater emphasis on the business of medicine. Fundamental ethical principles and professional values about the patient-physician relationship, the primacy of patient welfare over self-interest, and the role of medicine as a moral community and learned profession need to be applied to the changing environment, and physicians must consider the effect the practice environment has on their ethical and professional responsibilities. Recognizing that all health care delivery arrangements come with advantages, disadvantages, and salient questions for ethics and professionalism, this American College of Physicians policy paper examines the ethical implications of issues that are particularly relevant today, including incentives in the shift to value-based care, physician contract clauses that affect care, private equity ownership, clinical priority setting, and physician leadership. Physicians should take the lead in helping to ensure that relationships and practices are structured to explicitly recognize and support the commitments of the physician and the profession of medicine to patients and patient care.



Ann Intern Med: 15 Mar 2021; epub ahead of print
DeCamp M, Snyder Sulmasy L
Ann Intern Med: 15 Mar 2021; epub ahead of print | PMID: 33721520
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Impact:
Abstract

Risk for Non-AIDS-Defining and AIDS-Defining Cancer of Early Versus Delayed Initiation of Antiretroviral Therapy : A Multinational Prospective Cohort Study.

Chammartin F, Lodi S, Logan R, Ryom L, ... Lundgren JD, Bucher HC
Background
Immediate initiation of antiretroviral therapy (ART) regardless of CD4 cell count reduces risk for AIDS and non-AIDS-related events in asymptomatic, HIV-positive persons and is the standard of care. However, most HIV-positive persons initiate ART when their CD4 count decreases below 500 × 109 cells/L. Consequences of delayed ART on risk for non-AIDS-defining and AIDS-defining cancer, one of the most common reasons for death in HIV, are unclear.
Objective
To estimate the long-term risk difference for cancer with the immediate ART strategy.
Design
Multinational prospective cohort study.
Setting
The D:A:D (Data collection on Adverse events of anti-HIV Drugs) study, which included HIV-positive persons from Europe, Australia, and the United States.
Participants
8318 HIV-positive persons with at least 1 measurement each of CD4 cell count and viral load while ART-naive (study period, 2006 to 2016).
Measurements
The parametric g-formula was used, with adjustment for baseline and time-dependent confounders (CD4 cell count and viral load), to assess the 10-year risk for non-AIDS-defining and AIDS-defining cancer of immediate versus deferred (at CD4 counts <350 and <500 × 109 cells/L) ART initiation strategies.
Results
During 64 021 person-years of follow-up, 231 cases of non-AIDS-defining cancer and 272 of AIDS-defining cancer occurred among HIV-positive persons with a median age of 36 years (interquartile range, 29 to 43 years). With immediate ART, the 10-year risk for non-AIDS-defining cancer was 2.97% (95% CI, 2.37% to 3.50%) and that for AIDS-defining cancer was 2.50% (CI, 2.37% to 3.38%). Compared with immediate ART initiation, the 10-year absolute risk differences when deferring ART to CD4 counts less than 500 × 109 cells/L and less than 350 × 109 cells/L were 0.12 percentage point (CI, -0.01 to 0.26 percentage point) and 0.29 percentage point (CI, -0.03 to 0.73 percentage point), respectively, for non-AIDS-defining cancer and 0.32 percentage point (CI, 0.21 to 0.44 percentage point) and 1.00 percentage point (CI, 0.67 to 1.44 percentage points), respectively, for AIDS-defining cancer.
Limitation
Potential residual confounding due to observational study design.
Conclusion
In this young cohort, effects of immediate ART on 10-year risk for cancer were small, and further supportive data are needed for non-AIDS-defining cancer.
Primary funding source
Highly Active Antiretroviral Therapy Oversight Committee.



Ann Intern Med: 15 Mar 2021; epub ahead of print
Chammartin F, Lodi S, Logan R, Ryom L, ... Lundgren JD, Bucher HC
Ann Intern Med: 15 Mar 2021; epub ahead of print | PMID: 33721519
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Impact:
Abstract

What Is the Antibody Response and Role in Conferring Natural Immunity After SARS-CoV-2 Infection? Rapid, Living Practice Points From the American College of Physicians (Version 1).

Qaseem A, Yost J, Etxeandia-Ikobaltzeta I, Forciea MA, ... Humphrey LL, Scientific Medical Policy Committee of the American College of Physician
Description: The widespread availability of SARS-CoV-2 antibody tests raises important questions for clinicians, patients, and public health professionals related to the appropriate use and interpretation of these tests. The Scientific Medical Policy Committee (SMPC) of the American College of Physicians developed these rapid, living practice points to summarize the current and best available evidence on the antibody response to SARS-CoV-2 infection, antibody durability after initial infection with SARS-CoV-2, and antibody protection against reinfection with SARS-CoV-2.
Methods:
The SMPC developed these rapid, living practice points based on a rapid and living systematic evidence review done by the Portland VA Research Foundation and funded by the Agency for Healthcare Research and Quality. Ongoing literature surveillance is planned through December 2021. When new studies are identified and a full update of the evidence review is published, the SMPC will assess the new evidence and any effect on the practice points. Practice Points:Practice Point 1: Do not use SARS-CoV-2 antibody tests for the diagnosis of SARS-CoV-2 infection.Practice Point 2: Antibody tests can be useful for the purpose of estimating community prevalence of SARS-CoV-2 infection.Practice Point 3: Current evidence is uncertain to predict presence, level, or durability of natural immunity conferred by SARS-CoV-2 antibodies against reinfection (after SARS-CoV-2 infection).




Ann Intern Med: 15 Mar 2021; epub ahead of print
Qaseem A, Yost J, Etxeandia-Ikobaltzeta I, Forciea MA, ... Humphrey LL, Scientific Medical Policy Committee of the American College of Physician
Ann Intern Med: 15 Mar 2021; epub ahead of print | PMID: 33721518
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Impact:
Abstract

Antibody Response After SARS-CoV-2 Infection and Implications for Immunity : A Rapid Living Review.

Arkhipova-Jenkins I, Helfand M, Armstrong C, Gean E, ... Paynter RA, Mackey K
Background
The clinical significance of the antibody response after SARS-CoV-2 infection remains unclear.
Purpose
To synthesize evidence on the prevalence, levels, and durability of detectable antibodies after SARS-CoV-2 infection and whether antibodies to SARS-CoV-2 confer natural immunity.
Data sources
MEDLINE (Ovid), Embase, CINAHL, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, World Health Organization global literature database, and Covid19reviews.org from 1 January through 15 December 2020, limited to peer-reviewed publications available in English.
Study selection
Primary studies characterizing the prevalence, levels, and duration of antibodies in adults with SARS-CoV-2 infection confirmed by reverse transcriptase polymerase chain reaction (RT-PCR); reinfection incidence; and unintended consequences of antibody testing.
Data extraction
Two investigators sequentially extracted study data and rated quality.
Data synthesis
Moderate-strength evidence suggests that most adults develop detectable levels of IgM and IgG antibodies after infection with SARS-CoV-2 and that IgG levels peak approximately 25 days after symptom onset and may remain detectable for at least 120 days. Moderate-strength evidence suggests that IgM levels peak at approximately 20 days and then decline. Low-strength evidence suggests that most adults generate neutralizing antibodies, which may persist for several months like IgG. Low-strength evidence also suggests that older age, greater disease severity, and presence of symptoms may be associated with higher antibody levels. Some adults do not develop antibodies after SARS-CoV-2 infection for reasons that are unclear.
Limitation
Most studies were small and had methodological limitations; studies used immunoassays of variable accuracy.
Conclusion
Most adults with SARS-CoV-2 infection confirmed by RT-PCR develop antibodies. Levels of IgM peak early in the disease course and then decline, whereas IgG peaks later and may remain detectable for at least 120 days.
Primary funding source
Agency for Healthcare Research and Quality. (PROSPERO: CRD42020207098).



Ann Intern Med: 15 Mar 2021; epub ahead of print
Arkhipova-Jenkins I, Helfand M, Armstrong C, Gean E, ... Paynter RA, Mackey K
Ann Intern Med: 15 Mar 2021; epub ahead of print | PMID: 33721517
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Impact:
Abstract

Clinical and Economic Effects of Widespread Rapid Testing to Decrease SARS-CoV-2 Transmission.

Paltiel AD, Zheng A, Sax PE
Background
The value of frequent, rapid testing to reduce community transmission of SARS-CoV-2 is poorly understood.
Objective
To define performance standards and predict the clinical, epidemiologic, and economic outcomes of nationwide, home-based antigen testing.
Design
A simple compartmental epidemic model that estimated viral transmission, portrayed disease progression, and forecast resource use, with and without testing.
Data sources
Parameter values and ranges as informed by Centers for Disease Control and Prevention guidance and published literature.
Target population
U.S. population.
Time horizon
60 days.
Perspective
Societal; costs included testing, inpatient care, and lost workdays.
Intervention
Home-based SARS-CoV-2 antigen testing.
Outcome measures
Cumulative infections and deaths, number of persons isolated and hospitalized, and total costs.
Results of base-case analysis
Without a testing intervention, the model anticipates 11.6 million infections, 119 000 deaths, and $10.1 billion in costs ($6.5 billion in inpatient care and $3.5 billion in lost productivity) over a 60-day horizon. Weekly availability of testing would avert 2.8 million infections and 15 700 deaths, increasing costs by $22.3 billion. Lower inpatient outlays ($5.9 billion) would partially offset additional testing expenditures ($12.5 billion) and workdays lost ($14.0 billion), yielding incremental cost-effectiveness ratios of $7890 per infection averted and $1 430 000 per death averted.
Results of sensitivity analysis
Outcome estimates vary widely under different behavioral assumptions and testing frequencies. However, key findings persist across all scenarios, with large reductions in infections, mortality, and hospitalizations. Costs per death averted are roughly an order of magnitude lower than commonly accepted willingness-to-pay values per statistical life saved ($5 to $17 million).
Limitations
Analysis was restricted to at-home testing. There are uncertainties concerning test performance.
Conclusion
High-frequency home testing for SARS-CoV-2 with an inexpensive, imperfect test could contribute to pandemic control at justifiable cost and warrants consideration as part of a national containment strategy.
Primary funding source
National Institutes of Health.



Ann Intern Med: 08 Mar 2021; epub ahead of print
Paltiel AD, Zheng A, Sax PE
Ann Intern Med: 08 Mar 2021; epub ahead of print | PMID: 33683930
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Impact:
Abstract

Development of Severe COVID-19 Adaptive Risk Predictor (SCARP), a Calculator to Predict Severe Disease or Death in Hospitalized Patients With COVID-19.

Wongvibulsin S, Garibaldi BT, Antar AAR, Wen J, ... Zeger SL, Robinson ML
Background
Predicting the clinical trajectory of individual patients hospitalized with coronavirus disease 2019 (COVID-19) is challenging but necessary to inform clinical care. The majority of COVID-19 prognostic tools use only data present upon admission and do not incorporate changes occurring after admission.
Objective
To develop the Severe COVID-19 Adaptive Risk Predictor (SCARP) (https://rsconnect.biostat.jhsph.edu/covid_trajectory/), a novel tool that can provide dynamic risk predictions for progression from moderate disease to severe illness or death in patients with COVID-19 at any time within the first 14 days of their hospitalization.
Design
Retrospective observational cohort study.
Setting
Five hospitals in Maryland and Washington, D.C.
Patients
Patients who were hospitalized between 5 March and 4 December 2020 with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) confirmed by nucleic acid test and symptomatic disease.
Measurements
A clinical registry for patients hospitalized with COVID-19 was the primary data source; data included demographic characteristics, admission source, comorbid conditions, time-varying vital signs, laboratory measurements, and clinical severity. Random forest for survival, longitudinal, and multivariate (RF-SLAM) data analysis was applied to predict the 1-day and 7-day risks for progression to severe disease or death for any given day during the first 14 days of hospitalization.
Results
Among 3163 patients admitted with moderate COVID-19, 228 (7%) became severely ill or died in the next 24 hours; an additional 355 (11%) became severely ill or died in the next 7 days. The area under the receiver-operating characteristic curve (AUC) for 1-day risk predictions for progression to severe disease or death was 0.89 (95% CI, 0.88 to 0.90) and 0.89 (CI, 0.87 to 0.91) during the first and second weeks of hospitalization, respectively. The AUC for 7-day risk predictions for progression to severe disease or death was 0.83 (CI, 0.83 to 0.84) and 0.87 (CI, 0.86 to 0.89) during the first and second weeks of hospitalization, respectively.
Limitation
The SCARP tool was developed by using data from a single health system.
Conclusion
Using the predictive power of RF-SLAM and longitudinal data from more than 3000 patients hospitalized with COVID-19, an interactive tool was developed that rapidly and accurately provides the probability of an individual patient\'s progression to severe illness or death on the basis of readily available clinical information.
Primary funding source
Hopkins inHealth and COVID-19 Administrative Supplement for the HHS Region 3 Treatment Center from the Office of the Assistant Secretary for Preparedness and Response.



Ann Intern Med: 01 Mar 2021; epub ahead of print
Wongvibulsin S, Garibaldi BT, Antar AAR, Wen J, ... Zeger SL, Robinson ML
Ann Intern Med: 01 Mar 2021; epub ahead of print | PMID: 33646849
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Impact:
Abstract

Comparative Effectiveness and Harms of Antibiotics for Outpatient Diverticulitis : Two Nationwide Cohort Studies.

Gaber CE, Kinlaw AC, Edwards JK, Lund JL, ... Sandler RS, Peery AF
Background
Outpatient diverticulitis is commonly treated with either a combination of metronidazole and a fluoroquinolone (metronidazole-with-fluoroquinolone) or amoxicillin-clavulanate alone. The U.S. Food and Drug Administration advised that fluoroquinolones be reserved for conditions with no alternative treatment options. The comparative effectiveness of metronidazole-with-fluoroquinolone versus amoxicillin-clavulanate for diverticulitis is uncertain.
Objective
To determine the effectiveness and harms of metronidazole-with-fluoroquinolone versus amoxicillin-clavulanate for outpatient diverticulitis.
Design
Active-comparator, new-user, retrospective cohort studies.
Setting
Nationwide population-based claims data on U.S. residents aged 18 to 64 years with private employer-sponsored insurance (2000 to 2018) or those aged 65 years or older with Medicare (2006 to 2015).
Participants
Immunocompetent adults with diverticulitis in the outpatient setting.
Intervention
Metronidazole-with-fluoroquinolone or amoxicillin-clavulanate.
Measurements
1-year risks for inpatient admission, urgent surgery, and Clostridioides difficile infection (CDI) and 3-year risk for elective surgery.
Results
In MarketScan (IBM Watson Health), new users of metronidazole-with-fluoroquinolone (n = 106 361) and amoxicillin-clavulanate (n = 13 160) were identified. There were no differences in 1-year admission risk (risk difference, 0.1 percentage points [95% CI, -0.3 to 0.6]), 1-year urgent surgery risk (risk difference, 0.0 percentage points [CI, -0.1 to 0.1]), 3-year elective surgery risk (risk difference, 0.2 percentage points [CI, -0.3 to 0.7]), or 1-year CDI risk (risk difference, 0.0 percentage points [CI, -0.1 to 0.1]) between groups. In Medicare, new users of metronidazole-with-fluoroquinolone (n = 17 639) and amoxicillin-clavulanate (n = 2709) were identified. There were no differences in 1-year admission risk (risk difference, 0.1 percentage points [CI, -0.7 to 0.9]), 1-year urgent surgery risk (risk difference, -0.2 percentage points [CI, -0.6 to 0.1]), or 3-year elective surgery risk (risk difference, -0.3 percentage points [CI, -1.1 to 0.4]) between groups. The 1-year CDI risk was higher for metronidazole-with-fluoroquinolone than for amoxicillin-clavulanate (risk difference, 0.6 percentage points [CI, 0.2 to 1.0]).
Limitation
Residual confounding is possible, and not all harms associated with these antibiotics, most notably drug-induced liver injury, could be assessed.
Conclusion
Treating diverticulitis in the outpatient setting with amoxicillin-clavulanate may reduce the risk for fluoroquinolone-related harms without adversely affecting diverticulitis-specific outcomes.
Primary funding source
National Institutes of Health.



Ann Intern Med: 22 Feb 2021; epub ahead of print
Gaber CE, Kinlaw AC, Edwards JK, Lund JL, ... Sandler RS, Peery AF
Ann Intern Med: 22 Feb 2021; epub ahead of print | PMID: 33617725
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Impact:
Abstract

A Double-Blind, Randomized, Placebo-Controlled Phase 1 Study of Ad26.ZIKV.001, an Ad26-Vectored Anti-Zika Virus Vaccine.

Salisch NC, Stephenson KE, Williams K, Cox F, ... Schuitemaker H, Barouch DH
Background
Zika virus (ZIKV) may cause severe congenital disease after maternal-fetal transmission. No vaccine is currently available.
Objective
To assess the safety and immunogenicity of Ad26.ZIKV.001, a prophylactic ZIKV vaccine candidate.
Design
Phase 1 randomized, double-blind, placebo-controlled clinical study. (ClinicalTrials.gov: NCT03356561).
Setting
United States.
Participants
100 healthy adult volunteers.
Intervention
Ad26.ZIKV.001, an adenovirus serotype 26 vector encoding ZIKV M-Env, administered in 1- or 2-dose regimens of 5 × 1010 or 1 × 1011 viral particles (vp), or placebo.
Measurements
Local and systemic adverse events; neutralization titers by microneutralization assay (MN50) and T-cell responses by interferon-γ enzyme-linked immunospot and intracellular cytokine staining; and protectivity of vaccine-induced antibodies in a subset of participants through transfer in an exploratory mouse ZIKV challenge model.
Results
All regimens were well tolerated, with no safety concerns identified. In both 2-dose regimens, ZIKV neutralizing titers peaked 14 days after the second vaccination, with geometric mean MN50 titers (GMTs) of 1065.6 (95% CI, 494.9 to 2294.5) for 5 × 1010 vp and 956.6 (595.8 to 1535.8) for 1 × 1011 vp. Titers persisted for at least 1 year at a GMT of 68.7 (CI, 26.4-178.9) for 5 × 1010 vp and 87.0 (CI, 29.3 to 258.6) for 1 × 1011 vp. A 1-dose regimen of 1 × 1011 vp Ad26.ZIKV.001 induced seroconversion in all participants 56 days after the first vaccination (GMT, 103.4 [CI, 52.7 to 202.9]), with titers persisting for at least 1 year (GMT, 90.2 [CI, 38.4 to 212.2]). Env-specific cellular responses were induced. Protection against ZIKV challenge was observed after antibody transfer from participants into mice, and MN50 titers correlated with protection in this model.
Limitation
The study was conducted in a nonendemic area, so it did not assess safety and immunogenicity in a flavivirus-exposed population.
Conclusion
The safety and immunogenicity profile makes Ad26.ZIKV.001 a promising candidate for further development if the need reemerges.
Primary funding source
Janssen Vaccines and Infectious Diseases.



Ann Intern Med: 15 Feb 2021; epub ahead of print
Salisch NC, Stephenson KE, Williams K, Cox F, ... Schuitemaker H, Barouch DH
Ann Intern Med: 15 Feb 2021; epub ahead of print | PMID: 33587687
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Impact:
Abstract

Safety and Efficacy of Checkpoint Inhibition in Patients With Melanoma and Preexisting Autoimmune Disease : A Cohort Study.

van der Kooij MK, Suijkerbuijk KPM, Aarts MJB, van den Berkmortel FWPJ, ... Dekkers OM, Kapiteijn E
Background
Because immune checkpoint inhibition (ICI) can cause immune-related adverse events (irAEs) mimicking immunologic diseases, patients with preexisting autoimmune disease (AID) have been excluded from clinical trials.
Objective
To evaluate the safety and efficacy of ICI in patients with advanced melanoma with and without AID.
Design
Nationwide cohort study.
Setting
The Netherlands.
Patients
4367 patients with advanced melanoma enrolled in the Dutch Melanoma Treatment Registry (DMTR) between July 2013 and July 2018 and followed through February 2019.
Measurements
Patient, clinical, and treatment characteristics; irAEs of grade 3 or higher; treatment response; and survival.
Results
A total of 415 patients (9.5%) had AID, categorized as rheumatologic AID (n = 227), endocrine AID (n = 143), inflammatory bowel disease (IBD) (n = 55), or \"other\" (n = 8). Of these, 228 patients (55%) were treated with ICI (vs. 2546 [58%] without AID); 87 were treated with anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4), 187 with anti-programmed cell death 1 (PD-1), and 34 with the combination. The incidences of irAEs of grade 3 or higher in patients with AID were 30% (95% CI, 21% to 41%) with anti-CTLA-4, 17% (CI, 12% to 23%) with anti-PD-1, and 44% (CI, 27% to 62%) with combination therapy; for patients without AID, the incidences were 30% (CI, 27% to 33%) (n = 916), 13% (CI, 12% to 15%) (n = 1540), and 48% (CI, 43% to 53%) (n = 388), respectively. Patients with AID more often discontinued anti-PD-1 treatment because of toxicity than patients without AID (17% [CI, 12% to 23%] vs. 9% [CI, 8% to 11%]). Patients with IBD were more prone to anti-PD-1-induced colitis (6 / 31 = 19% [CI, 7% to 37%]) than patients with other AIDs (3% [CI, 0% to 6%]) and patients without AID (2% [CI, 2% to 3%]). The objective response rate was similar in patients with versus without AID who were treated with anti-CTLA-4 (10% [CI, 5% to 19%] vs. 16% [CI, 14% to 19%]), anti-PD-1 (40% [CI, 33% to 47%] vs. 44% [CI, 41% to 46%]), or the combination (39% [CI, 20% to 59%] vs. 43% [CI, 38% to 49%]). Survival did not differ between patients with and those without AID (median, 13 months [CI, 10 to 16 months] vs. 14 months [CI, 13 to 15 months]).
Limitation
Information was limited on AID severity and immunosuppressive treatment.
Conclusion
Response to ICI with anti-CTLA-4, anti-PD-1, or their combination for advanced melanoma and overall incidence of any irAEs of grade 3 or higher were similar in patients with and without preexisting AID. However, severe colitis and toxicity requiring early discontinuation of treatment occurred more frequently among patients with preexisting IBD, warranting close follow-up.
Primary funding source
The Netherlands Organization for Health Research and Development.



Ann Intern Med: 15 Feb 2021; epub ahead of print
van der Kooij MK, Suijkerbuijk KPM, Aarts MJB, van den Berkmortel FWPJ, ... Dekkers OM, Kapiteijn E
Ann Intern Med: 15 Feb 2021; epub ahead of print | PMID: 33587686
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Impact:
Abstract

Racial Disparities in COVID-19 Testing and Outcomes : Retrospective Cohort Study in an Integrated Health System.

Escobar GJ, Adams AS, Liu VX, Soltesz L, ... Dlott R, Lee C
Background
Racial disparities exist in outcomes after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.
Objective
To evaluate the contribution of race/ethnicity in SARS-CoV-2 testing, infection, and outcomes.
Design
Retrospective cohort study (1 February 2020 to 31 May 2020).
Setting
Integrated health care delivery system in Northern California.
Participants
Adult health plan members.
Measurements
Age, sex, neighborhood deprivation index, comorbid conditions, acute physiology indices, and race/ethnicity; SARS-CoV-2 testing and incidence of positive test results; and hospitalization, illness severity, and mortality.
Results
Among 3 481 716 eligible members, 42.0% were White, 6.4% African American, 19.9% Hispanic, and 18.6% Asian; 13.0% were of other or unknown race. Of eligible members, 91 212 (2.6%) were tested for SARS-CoV-2 infection and 3686 had positive results (overall incidence, 105.9 per 100 000 persons; by racial group, White, 55.1; African American, 123.1; Hispanic, 219.6; Asian, 111.7; other/unknown, 79.3). African American persons had the highest unadjusted testing and mortality rates, White persons had the lowest testing rates, and those with other or unknown race had the lowest mortality rates. Compared with White persons, adjusted testing rates among non-White persons were marginally higher, but infection rates were significantly higher; adjusted odds ratios [aORs] for African American persons, Hispanic persons, Asian persons, and persons of other/unknown race were 2.01 (95% CI, 1.75 to 2.31), 3.93 (CI, 3.59 to 4.30), 2.19 (CI, 1.98 to 2.42), and 1.57 (CI, 1.38 to 1.78), respectively. Geographic analyses showed that infections clustered in areas with higher proportions of non-White persons. Compared with White persons, adjusted hospitalization rates for African American persons, Hispanic persons, Asian persons, and persons of other/unknown race were 1.47 (CI, 1.03 to 2.09), 1.42 (CI, 1.11 to 1.82), 1.47 (CI, 1.13 to 1.92), and 1.03 (CI, 0.72 to 1.46), respectively. Adjusted analyses showed no racial differences in inpatient mortality or total mortality during the study period. For testing, comorbid conditions made the greatest relative contribution to model explanatory power (77.9%); race only accounted for 8.1%. Likelihood of infection was largely due to race (80.3%). For other outcomes, age was most important; race only contributed 4.5% for hospitalization, 12.8% for admission illness severity, 2.3% for in-hospital death, and 0.4% for any death.
Limitation
The study involved an insured population in a highly integrated health system.
Conclusion
Race was the most important predictor of SARS-CoV-2 infection. After infection, race was associated with increased hospitalization risk but not mortality.
Primary funding source
The Permanente Medical Group, Inc.



Ann Intern Med: 08 Feb 2021; epub ahead of print
Escobar GJ, Adams AS, Liu VX, Soltesz L, ... Dlott R, Lee C
Ann Intern Med: 08 Feb 2021; epub ahead of print | PMID: 33556278
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Impact:
Abstract

A SARS-CoV-2 Cluster in an Acute Care Hospital.

Klompas M, Baker MA, Rhee C, Tucker R, ... Sinclair J, Morris CA
Background
Little is known about clusters of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in acute care hospitals.
Objective
To describe the detection, mitigation, and analysis of a large cluster of SARS-CoV-2 infections in an acute care hospital with mature infection control policies.
Design
Descriptive study.
Setting
Brigham and Women\'s Hospital, Boston, Massachusetts.
Participants
Patients and staff with cluster-related SARS-CoV-2 infections.
Intervention
Close contacts of infected patients and staff were identified and tested every 3 days, patients on affected units were preemptively isolated and repeatedly tested, affected units were cleaned, room ventilation was measured, and specimens were sent for whole-genome sequencing. A case-control study was done to compare clinical interactions, personal protective equipment use, and breakroom and workroom practices in SARS-CoV-2-positive versus negative staff.
Measurements
Description of the cluster, mitigation activities, and risk factor analysis.
Results
Fourteen patients and 38 staff members were included in the cluster per whole-genome sequencing and epidemiologic associations. The index case was a symptomatic patient in whom isolation was discontinued after 2 negative results on nasopharyngeal polymerase chain reaction testing. The patient subsequently infected multiple roommates and staff, who then infected others. Seven of 52 (13%) secondary infections were detected only on second or subsequent tests. Eight of 9 (89%) patients who shared rooms with potentially contagious patients became infected. Potential contributing factors included high viral loads, nebulization, and positive pressure in the index patient\'s room. Risk factors for transmission to staff included presence during nebulization, caring for patients with dyspnea or cough, lack of eye protection, at least 15 minutes of exposure to case patients, and interactions with SARS-CoV-2-positive staff in clinical areas. Whole-genome sequencing confirmed that 2 staff members were infected despite wearing surgical masks and eye protection.
Limitation
Findings may not be generalizable.
Conclusion
SARS-CoV-2 clusters can occur in hospitals despite robust infection control policies. Insights from this cluster may inform additional measures to protect patients and staff.
Primary funding source
None.



Ann Intern Med: 08 Feb 2021; epub ahead of print
Klompas M, Baker MA, Rhee C, Tucker R, ... Sinclair J, Morris CA
Ann Intern Med: 08 Feb 2021; epub ahead of print | PMID: 33556277
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Abstract

Incorporating Baseline Breast Density When Screening Women at Average Risk for Breast Cancer : A Cost-Effectiveness Analysis.

Shih YT, Dong W, Xu Y, Etzioni R, Shen Y
Background
Breast density classification is largely determined by mammography, making the timing of the first screening mammogram clinically important.
Objective
To evaluate the cost-effectiveness of breast cancer screening strategies that are stratified by breast density.
Design
Microsimulation model to generate the natural history of breast cancer for women with and those without dense breasts and assessment of the cost-effectiveness of strategies tailored to breast density and nontailored strategies.
Data sources
Model parameters from the literature; statistical modeling; and analysis of Surveillance, Epidemiology, and End Results-Medicare data.
Target population
Women aged 40 years or older.
Time horizon
Lifetime.
Perspective
Societal.
Intervention
No screening; biennial or triennial mammography from age 50 to 75 years; annual mammography from age 50 to 75 years for women with dense breasts at age 50 years and biennial or triennial mammography from age 50 to 75 years for those without dense breasts at age 50 years; and annual mammography at age 40 to 75 years for women with dense breasts at age 40 years and biennial or triennial mammography at age 50 to 75 years for those without dense breasts at age 40 years.
Outcome measures
Lifetime costs and quality-adjusted life-years (QALYs), discounted at 3% annually.
Results of base-case analysis
Baseline screening at age 40 years followed by annual screening at age 40 to 75 years for women with dense breasts and biennial screening at age 50 to 75 years for women without dense breasts was effective and cost-effective, yielding an incremental cost-effectiveness ratio of $36 200 per QALY versus the biennial strategy at age 50 to 75 years.
Results of sensitivity analysis
At a societal willingness-to-pay threshold of $100 000 per QALY, the probability that the density-stratified strategy at age 40 years was optimal was 56% compared with 6 other strategies.
Limitation
Findings may not be generalizable outside the United States.
Conclusion
The study findings advocate for breast density-stratified screening with baseline mammography at age 40 years.
Primary funding source
National Cancer Institute.



Ann Intern Med: 08 Feb 2021; epub ahead of print
Shih YT, Dong W, Xu Y, Etzioni R, Shen Y
Ann Intern Med: 08 Feb 2021; epub ahead of print | PMID: 33556275
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Abstract

Public Health Interventions, Epidemic Growth, and Regional Variation of the 1918 Influenza Pandemic Outbreak in a Swiss Canton and Its Greater Regions.

Staub K, Jüni P, Urner M, Matthes KL, ... Gruebner O, Floris J
Public health interventions implemented during the coronavirus disease 2019 (COVID-19) pandemic are based on experience gained from past pandemics. The 1918 influenza pandemic is the most extensively researched historical influenza outbreak. All 9335 reports available in the State Archives on 121 152 cases of influenza-like illness from the canton of Bern from 473 of 497 municipalities (95.2%) were collected; the cases were registered between 30 June 1918 and 30 June 1919. The overall incidence rates of newly registered cases per week for the 9 greater regions of Bern for both the first and second waves of the pandemic were calculated. Relative incidence rate ratios (RIRRs) were calculated to estimate the change in the slope of incidence curves associated with public health interventions. During the first wave, school closures (RIRR, 0.16 [95% CI, 0.15 to 0.17]) and restrictions of mass gatherings (RIRR, 0.57 [CI, 0.54 to 0.61]) were associated with a deceleration of epidemic growth. During the second wave, in autumn 1918, cantonal authorities initially reacted hesitantly and delegated the responsibility to enact interventions to municipal authorities, which was associated with a lack of containment of the second wave. A premature relaxation of restrictions on mass gatherings was associated with a resurgence of the epidemic (RIRR, 1.18 [CI, 1.12 to 1.25]). Strikingly similar patterns were found in the management of the COVID-19 outbreak in Switzerland, with a considerably higher amplitude and prolonged duration of the second wave and much higher associated rates of hospitalization and mortality.



Ann Intern Med: 08 Feb 2021; epub ahead of print
Staub K, Jüni P, Urner M, Matthes KL, ... Gruebner O, Floris J
Ann Intern Med: 08 Feb 2021; epub ahead of print | PMID: 33556268
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Abstract

Major Update: Remdesivir for Adults With COVID-19 : A Living Systematic Review and Meta-analysis for the American College of Physicians Practice Points.

Kaka AS, MacDonald R, Greer N, Vela K, ... Obley A, Wilt TJ
Background
Remdesivir is being studied and used for treatment of coronavirus disease 2019 (COVID-19).
Purpose
To update a previous review of remdesivir for adults with COVID-19, including new meta-analyses of patients with COVID-19 of any severity compared with control.
Data sources
Several sources from 1 January 2020 through 7 December 2020.
Study selection
English-language, randomized controlled trials (RCTs) of remdesivir for COVID-19. New evidence is incorporated by using living review methods.
Data extraction
1 reviewer abstracted data; a second reviewer verified the data. The Cochrane Risk of Bias Tool and GRADE (Grading of Recommendations Assessment, Development and Evaluation) method were used.
Data synthesis
The update includes 5 RCTs, incorporating data from a new large RCT and the final results of a previous RCT. Compared with control, a 10-day course of remdesivir probably results in little to no reduction in mortality (risk ratio [RR], 0.93 [95% CI, 0.82 to 1.06]; 4 RCTs) but may result in a small reduction in the proportion of patients receiving mechanical ventilation (RR, 0.71 [CI, 0.56 to 0.90]; 3 RCTs). Remdesivir probably results in a moderate increase in the percentage of patients who recovered and a moderate decrease in serious adverse events and may result in a large reduction in time to recovery. Effect on hospital length of stay or percentage remaining hospitalized is mixed. Compared with a 10-day course for those not requiring ventilation at baseline, a 5-day course may reduce mortality, the need for ventilation, and serious adverse events while increasing the percentage of patients who recovered or clinically improved.
Limitation
Summarizing findings was challenging because of varying disease severity definitions and outcomes.
Conclusion
In hospitalized adults with COVID-19, remdesivir probably results in little to no mortality difference but probably improves the percentage recovered and reduces serious harms and may result in a small reduction in the proportion receiving ventilation. For patients not receiving ventilation, a 5-day course may provide greater benefits and fewer harms with lower drug costs than a 10-day course.
Primary funding source
U.S. Department of Veterans Affairs.



Ann Intern Med: 08 Feb 2021; epub ahead of print
Kaka AS, MacDonald R, Greer N, Vela K, ... Obley A, Wilt TJ
Ann Intern Med: 08 Feb 2021; epub ahead of print | PMID: 33560863
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Abstract

The Use of Rifaximin in the Prevention of Overt Hepatic Encephalopathy After Transjugular Intrahepatic Portosystemic Shunt : A Randomized Controlled Trial.

Bureau C, Thabut D, Jezequel C, Archambeaud I, ... Péron JM, Vinel JP
Background
The efficacy of rifaximin in the secondary prevention of overt hepatic encephalopathy (HE) is well documented, but its effectiveness in preventing a first episode in patients after transjugular intrahepatic portosystemic shunt (TIPS) has not been established.
Objective
To determine whether rifaximin prevents overt HE after TIPS compared with placebo.
Design
Randomized, double-blind, multicenter, placebo-controlled trial. (ClinicalTrials.gov: NCT02016196).
Participants
197 patients with cirrhosis undergoing TIPS for intractable ascites or prevention of variceal rebleeding.
Intervention
Patients were randomly assigned to receive rifaximin (600 mg twice daily) or placebo, beginning 14 days before TIPS and continuing for 168 days after the procedure.
Measurements
The primary efficacy end point was incidence of overt HE within 168 days after the TIPS procedure.
Results
An episode of overt HE occurred in 34% (95% CI, 25% to 44%) of patients in the rifaximin group (n = 93) and 53% (CI, 43% to 63%) in the placebo group (n = 93) during the postprocedure period (odds ratio, 0.48 [CI, 0.27 to 0.87]). Neither the incidence of adverse events nor transplant-free survival was significantly different between the 2 groups.
Limitations
The study\'s conclusion applies mainly to patients with alcoholic cirrhosis, who made up the study population. The potential benefit of rifaximin 6 months after TIPS and beyond remains to be investigated.
Conclusion
In patients with cirrhosis treated with TIPS, rifaximin was well tolerated and reduced the risk for overt HE. Rifaximin should therefore be considered for prophylaxis of post-TIPS HE.
Primary funding source
French Public Health Ministry.



Ann Intern Med: 01 Feb 2021; epub ahead of print
Bureau C, Thabut D, Jezequel C, Archambeaud I, ... Péron JM, Vinel JP
Ann Intern Med: 01 Feb 2021; epub ahead of print | PMID: 33524293
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Impact:
Abstract

Quantification of Occupational and Community Risk Factors for SARS-CoV-2 Seropositivity Among Health Care Workers in a Large U.S. Health Care System.

Baker JM, Nelson KN, Overton E, Lopman BA, ... Fridkin SK, Steinberg JP
Background
Identifying occupational risk factors for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among health care workers (HCWs) can improve HCW and patient safety.
Objective
To quantify demographic, occupational, and community risk factors for SARS-CoV-2 seropositivity among HCWs in a large health care system.
Design
A logistic regression model was fitted to data from a cross-sectional survey conducted in April to June 2020, linking risk factors for occupational and community exposure to coronavirus disease 2019 (COVID-19) with SARS-CoV-2 seropositivity.
Setting
A large academic health care system in the Atlanta, Georgia, metropolitan area.
Participants
Employees and medical staff members elected to participate in SARS-CoV-2 serology testing offered to all HCWs as part of a quality initiative and completed a survey on exposure to COVID-19 and use of personal protective equipment.
Measurements
Demographic risk factors for COVID-19, residential ZIP code incidence of COVID-19, occupational exposure to HCWs or patients who tested positive on polymerase chain reaction test, and use of personal protective equipment as potential risk factors for infection. The outcome was SARS-CoV-2 seropositivity.
Results
Adjusted SARS-CoV-2 seropositivity was estimated to be 3.8% (95% CI, 3.4%-4.3%) (positive, n = 582) among the 10 275 HCWs (35% of the Emory Healthcare workforce) who participated in the survey. Community contact with a person known or suspected to have COVID-19 (adjusted odds ratio [aOR], 1.9 [CI, 1.4 to 2.6]; 77 positive persons [10.3%]) and community COVID-19 incidence (aOR, 1.5 [CI, 1.0 to 2.2]) increased the odds of infection. Black individuals were at high risk (aOR, 2.1 [CI, 1.7 to 2.6]; 238 positive persons [8.3%]).
Limitations
Participation rates were modest and key workplace exposures, including job and infection prevention practices, changed rapidly in the early phases of the pandemic.
Conclusion
Demographic and community risk factors, including contact with a COVID-19-positive person and Black race, are more strongly associated with SARS-CoV-2 seropositivity among HCWs than is exposure in the workplace.
Primary funding source
Emory COVID-19 Response Collaborative.



Ann Intern Med: 28 Jan 2021; epub ahead of print
Baker JM, Nelson KN, Overton E, Lopman BA, ... Fridkin SK, Steinberg JP
Ann Intern Med: 28 Jan 2021; epub ahead of print | PMID: 33513035
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Abstract

Thrombosis, Bleeding, and the Observational Effect of Early Therapeutic Anticoagulation on Survival in Critically Ill Patients With COVID-19.

Al-Samkari H, Gupta S, Leaf RK, Wang W, ... Leaf DE, STOP-COVID-19 Investigators
Background
Hypercoagulability may be a key mechanism of death in patients with coronavirus disease 2019 (COVID-19).
Objective
To evaluate the incidence of venous thromboembolism (VTE) and major bleeding in critically ill patients with COVID-19 and examine the observational effect of early therapeutic anticoagulation on survival.
Design
In a multicenter cohort study of 3239 critically ill adults with COVID-19, the incidence of VTE and major bleeding within 14 days after intensive care unit (ICU) admission was evaluated. A target trial emulation in which patients were categorized according to receipt or no receipt of therapeutic anticoagulation in the first 2 days of ICU admission was done to examine the observational effect of early therapeutic anticoagulation on survival. A Cox model with inverse probability weighting to adjust for confounding was used.
Setting
67 hospitals in the United States.
Participants
Adults with COVID-19 admitted to a participating ICU.
Measurements
Time to death, censored at hospital discharge, or date of last follow-up.
Results
Among the 3239 patients included, the median age was 61 years (interquartile range, 53 to 71 years), and 2088 (64.5%) were men. A total of 204 patients (6.3%) developed VTE, and 90 patients (2.8%) developed a major bleeding event. Independent predictors of VTE were male sex and higher D-dimer level on ICU admission. Among the 2809 patients included in the target trial emulation, 384 (11.9%) received early therapeutic anticoagulation. In the primary analysis, during a median follow-up of 27 days, patients who received early therapeutic anticoagulation had a similar risk for death as those who did not (hazard ratio, 1.12 [95% CI, 0.92 to 1.35]).
Limitation
Observational design.
Conclusion
Among critically ill adults with COVID-19, early therapeutic anticoagulation did not affect survival in the target trial emulation.
Primary funding source
None.



Ann Intern Med: 25 Jan 2021; epub ahead of print
Al-Samkari H, Gupta S, Leaf RK, Wang W, ... Leaf DE, STOP-COVID-19 Investigators
Ann Intern Med: 25 Jan 2021; epub ahead of print | PMID: 33493012
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Abstract

The Effect of Preconception-Initiated Low-Dose Aspirin on Human Chorionic Gonadotropin-Detected Pregnancy, Pregnancy Loss, and Live Birth : Per Protocol Analysis of a Randomized Trial.

Naimi AI, Perkins NJ, Sjaarda LA, Mumford SL, ... Silver RM, Schisterman EF
Background
A previous large randomized trial indicated that preconception-initiated low-dose aspirin (LDA) therapy did not have a positive effect on pregnancy outcomes. However, this trial was subject to nonadherence, which was not taken into account by the intention-to-treat approach.
Objective
To estimate per protocol effects of preconception-initiated LDA on pregnancy loss and live birth.
Design
The EAGeR (Effects of Aspirin on Gestation and Reproduction) trial was used to construct a prospective cohort for a post hoc analysis. (ClinicalTrials.gov: NCT00467363).
Setting
4 university medical centers in the United States.
Participants
1227 women between the ages of 18 and 40 years who had 1 or 2 previous pregnancy losses and were attempting pregnancy.
Measurements
Adherence to LDA or placebo, assessed by measuring pill bottle weights at regular intervals during follow-up. Primary outcomes were human chorionic gonadotropin (hCG)-detected pregnancies, pregnancy losses, and live births, determined by pregnancy tests and medical records.
Results
Relative to placebo, adhering to LDA for 5 of 7 days per week led to 8 more hCG-detected pregnancies (95% CI, 4.64 to 10.96 pregnancies), 15 more live births (CI, 7.65 to 21.15 births), and 6 fewer pregnancy losses (CI, -12.00 to -0.20 losses) for every 100 women in the trial. In addition, compared with placebo, postconception initiation of LDA therapy led to a reduction in the estimated effects. Furthermore, effects were obtained in a minimum of 4 of 7 days per week.
Limitation
The EAGeR trial data for this study were analyzed as observational data, thus are subject to the limitations of prospective observational studies.
Conclusion
Per protocol results suggest that preconception use of LDA at least 4 days per week may improve reproductive outcomes for women who have had 1 or 2 pregnancy losses. Increasing adherence to daily LDA seems to be key to improving effectiveness.
Primary funding source
National Institutes of Health.



Ann Intern Med: 25 Jan 2021; epub ahead of print
Naimi AI, Perkins NJ, Sjaarda LA, Mumford SL, ... Silver RM, Schisterman EF
Ann Intern Med: 25 Jan 2021; epub ahead of print | PMID: 33493011
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Impact:
Abstract

The Proportion of SARS-CoV-2 Infections That Are Asymptomatic : A Systematic Review.

Oran DP, Topol EJ
Background
Asymptomatic infection seems to be a notable feature of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pathogen that causes coronavirus disease 2019 (COVID-19), but the prevalence is uncertain.
Purpose
To estimate the proportion of persons infected with SARS-CoV-2 who never develop symptoms.
Data sources
Searches of Google News, Google Scholar, medRxiv, and PubMed using the keywords antibodies, asymptomatic, coronavirus, COVID-19, PCR, seroprevalence, and SARS-CoV-2.
Study selection
Observational, descriptive studies and reports of mass screening for SARS-CoV-2 that were either cross-sectional or longitudinal in design; were published through 17 November 2020; and involved SARS-CoV-2 nucleic acid or antibody testing of a target population, regardless of current symptomatic status, over a defined period.
Data extraction
The authors collaboratively extracted data on the study design, type of testing performed, number of participants, criteria for determining symptomatic status, testing results, and setting.
Data synthesis
Sixty-one eligible studies and reports were identified, of which 43 used polymerase chain reaction (PCR) testing of nasopharyngeal swabs to detect current SARS-CoV-2 infection and 18 used antibody testing to detect current or prior infection. In the 14 studies with longitudinal data that reported information on the evolution of symptomatic status, nearly three quarters of persons who tested positive but had no symptoms at the time of testing remained asymptomatic. The highest-quality evidence comes from nationwide, representative serosurveys of England (n = 365 104) and Spain (n = 61 075), which suggest that at least one third of SARS-CoV-2 infections are asymptomatic.
Limitation
For PCR-based studies, data are limited to distinguish presymptomatic from asymptomatic infection. Heterogeneity precluded formal quantitative syntheses.
Conclusion
Available data suggest that at least one third of SARS-CoV-2 infections are asymptomatic. Longitudinal studies suggest that nearly three quarters of persons who receive a positive PCR test result but have no symptoms at the time of testing will remain asymptomatic. Control strategies for COVID-19 should be altered, taking into account the prevalence and transmission risk of asymptomatic SARS-CoV-2 infection.
Primary funding source
National Institutes of Health.



Ann Intern Med: 21 Jan 2021; epub ahead of print
Oran DP, Topol EJ
Ann Intern Med: 21 Jan 2021; epub ahead of print | PMID: 33481642
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Impact:

This program is still in alpha version.