Effectiveness of mRNA Covid-19 Vaccine among U.S. Health Care Personnel.

BACKGROUND: The prioritization of U.S. health care personnel for early receipt of messenger RNA (mRNA) vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (Covid-19), allowed for the evaluation of the effectiveness of these new vaccines in a real-world setting. METHODS: We conducted a test-negative case-control study involving health care personnel across 25 U.S. states. Cases were defined on the basis of a positive polymerase-chain-reaction (PCR) or antigen-based test for SARS-CoV-2 and at least one Covid-19-like symptom. Controls were defined on the basis of a negative PCR test for SARS-CoV-2, regardless of symptoms, and were matched to cases according to the week of the test date and site. Using conditional logistic regression with adjustment for age, race and ethnic group, underlying conditions, and exposures to persons with Covid-19, we estimated vaccine effectiveness for partial vaccination (assessed 14 days after receipt of the first dose through 6 days after receipt of the second dose) and complete vaccination (assessed ≥7 days after receipt of the second dose). RESULTS: The study included 1482 case participants and 3449 control participants. Vaccine effectiveness for partial vaccination was 77.6% (95% confidence interval [CI], 70.9 to 82.7) with the BNT162b2 vaccine (Pfizer-BioNTech) and 88.9% (95% CI, 78.7 to 94.2) with the mRNA-1273 vaccine (Moderna); for complete vaccination, vaccine effectiveness was 88.8% (95% CI, 84.6 to 91.8) and 96.3% (95% CI, 91.3 to 98.4), respectively. Vaccine effectiveness was similar in subgroups defined according to age (<50 years or ≥50 years), race and ethnic group, presence of underlying conditions, and level of patient contact. Estimates of vaccine effectiveness were lower during weeks 9 through 14 than during weeks 3 through 8 after receipt of the second dose, but confidence intervals overlapped widely. CONCLUSIONS: The BNT162b2 and mRNA-1273 vaccines were highly effective under real-world conditions in preventing symptomatic Covid-19 in health care personnel, including those at risk for severe Covid-19 and those in racial and ethnic groups that have been disproportionately affected by the pandemic. (Funded by the Centers for Disease Control and Prevention.).

Incidence and Progression of Fibrotic Lung Disease in an At-Risk Cohort.

Rationale: Relatives of patients with familial interstitial pneumonia (FIP) are at increased risk for pulmonary fibrosis and develop preclinical pulmonary fibrosis (PrePF). Objectives: We defined the incidence and progression of new-onset PrePF and its relationship to survival among first-degree relatives of families with FIP. Methods: This is a cohort study of family members with FIP who were initially screened with a health questionnaire and chest high-resolution computed tomography (HRCT) scan, and approximately 4 years later, the evaluation was repeated. A total of 493 asymptomatic first-degree relatives of patients with FIP were evaluated at baseline, and 296 (60%) of the original subjects participated in the subsequent evaluation. Measurements and Main Results: The median interval between HRCTs was 3.9 years (interquartile range, 3.5-4.4 yr). A total of 252 subjects who agreed to repeat evaluation were originally determined not to have PrePF at baseline; 16 developed PrePF. A conservative estimate of the annual incidence of PrePF is 1,023 per 100,000 person-years (95% confidence interval, 511-1,831 per 100,000 person-years). Of 44 subjects with PrePF at baseline, 38.4% subjects had worsening dyspnea compared with 15.4% of those without PrePF (P = 0.002). Usual interstitial pneumonia by HRCT (P < 0.0002) and baseline quantitative fibrosis score (P < 0.001) are also associated with worsening dyspnea. PrePF at the initial screen is associated with decreased survival (P < 0.001). Conclusions: The incidence of PrePF in this at-risk population is at least 100-fold higher than that reported for sporadic idiopathic pulmonary fibrosis (IPF). Although PrePF and IPF represent distinct entities, our study demonstrates that PrePF, like IPF, is progressive and associated with decreased survival.

Anyone Anytime for Anything: The History of Emergency Medicine in Missouri.

The history of Emergency Medicine (EM) in Missouri reflects the larger history of EM as a burgeoning specialty throughout the United States, but with some important and unique contributions that may not be generally appreciated. We discuss historical events and important leaders of EM, but there are many we could not mention. Much of the information comes from personal interviews with the physicians who "were in the room where it happened.". We hope the article will illuminate the progress made in caring for critical illness and injury through the development of a new specialty focused on that goal. We recognize there are many emergency physicians not mentioned that have played a large role in maintaining and growing the academic programs, improving the delivery of care through administrative and legislative actions, and navigating the specialty through enormously challenging times.

Interim Estimates of Vaccine Effectiveness of Pfizer-BioNTech and Moderna COVID-19 Vaccines Among Health Care Personnel - 33 U.S. Sites, January-March 2021.

Throughout the COVID-19 pandemic, health care personnel (HCP) have been at high risk for exposure to SARS-CoV-2, the virus that causes COVID-19, through patient interactions and community exposure (1). The Advisory Committee on Immunization Practices recommended prioritization of HCP for COVID-19 vaccination to maintain provision of critical services and reduce spread of infection in health care settings (2). Early distribution of two mRNA COVID-19 vaccines (Pfizer-BioNTech and Moderna) to HCP allowed assessment of the effectiveness of these vaccines in a real-world setting. A test-negative case-control study is underway to evaluate mRNA COVID-19 vaccine effectiveness (VE) against symptomatic illness among HCP at 33 U.S. sites across 25 U.S. states. Interim analyses indicated that the VE of a single dose (measured 14 days after the first dose through 6 days after the second dose) was 82% (95% confidence interval [CI] = 74%-87%), adjusted for age, race/ethnicity, and underlying medical conditions. The adjusted VE of 2 doses (measured ≥7 days after the second dose) was 94% (95% CI = 87%-97%). VE of partial (1-dose) and complete (2-dose) vaccination in this population is comparable to that reported from clinical trials and recent observational studies, supporting the effectiveness of mRNA COVID-19 vaccines against symptomatic disease in adults, with strong 2-dose protection.

Emergence of Extended-Spectrum ß-Lactamase Urinary Tract Infections Among Hospitalized Emergency Department Patients in the United States.

STUDY OBJECTIVE: Enterobacteriaceae resistant to ceftriaxone, mediated through extended-spectrum ß-lactamases (ESBLs), commonly cause urinary tract infections worldwide, but have been less prevalent in North America. Current US rates are unknown. We determine Enterobacteriaceae antimicrobial resistance rates among US emergency department (ED) patients hospitalized for urinary tract infection. METHODS: We prospectively enrolled adults hospitalized for urinary tract infection from 11 geographically diverse university-affiliated hospital EDs during 2018 to 2019. Among participants with culture-confirmed infection, we evaluated prevalence of antimicrobial resistance, including that caused by ESBL-producing Enterobacteriaceae, resistance risk factors, and time to in vitro-active antibiotics. RESULTS: Of 527 total participants, 444 (84%) had cultures that grew Enterobacteriaceae; 89 of 435 participants (20.5%; 95% confidence interval 16.9% to 24.5%; 4.6% to 45.4% by site) whose isolates had confirmatory testing had bacteria that were ESBL producing. The overall prevalence of ESBL-producing Enterobacteriaceae infection among all participants with urinary tract infection was 17.2% (95% confidence interval 14.0% to 20.7%). ESBL-producing Enterobacteriaceae infection risk factors were hospital, long-term care, antibiotic exposure within 90 days, and a fluoroquinolone- or ceftriaxone-resistant isolate within 1 year. Enterobacteriaceae resistance rates for other antimicrobials were fluoroquinolone 32.3%, gentamicin 13.7%, amikacin 1.3%, and meropenem 0.3%. Ceftriaxone was the most common empirical antibiotic. In vitro-active antibiotics were not administered within 12 hours of presentation to 48 participants (53.9%) with ESBL-producing Enterobacteriaceae infection, including 17 (58.6%) with sepsis. Compared with other Enterobacteriaceae infections, ESBL infections were associated with longer time to in vitro-active treatment (17.3 versus 3.5 hours). CONCLUSION: Among adults hospitalized for urinary tract infection in many US locations, ESBL-producing Enterobacteriaceae have emerged as a common cause of infection that is often not initially treated with an in vitro-active antibiotic.

Perioperative anidulafungin combined with triazole prophylaxis for the prevention of early invasive candidiasis in lung transplant recipients.

BACKGROUND: Invasive candidiasis (IC) is a substantial cause of morbidity and mortality among lung transplant recipients (LTRs). Postoperative factors include prolonged hospital stay, central lines, delayed chest closure, and dehiscence increase IC risk. Correspondingly, current guidelines propose targeted IC coverage early posttransplant with fluconazole or an echinocandin. METHODS: This retrospective analysis was performed on LTRs from January 2016 to January 2020 and evaluated effectiveness of a recent protocol utilizing perioperative anidulafungin for early IC prevention in addition to long-term triazole antifungal prophylaxis. Prior to this protocol, patients were primarily established on itraconazole prophylaxis alone. The primary endpoint was proven or probable IC within 90 days after transplant. Multivariable logistic regression modeling was used to assess risk factors for invasive fungal infection (IFI). RESULTS: Among 144 LTRs, there was a numerically lower incidence of IC in the protocol group, although not statistically significant (6% vs. 13%, p = 0.16). Incidence of proven or probable IFI was 7.5% in the protocol cohort and 19.5% in the pre-protocol cohort (p = 0.038). In multivariable analysis, when controlling for lung allocation score (OR 1.04, 95% CI 1.01-1.08), donor perioperative culture with fungal growth (OR 2.92, 95% CI 1.02-8.92), and dehiscence (OR 3.54, 95% CI 1.14-10.85), protocol cohort was not significantly associated with IFI (OR 0.41, 95% CI 0.12-1.23). CONCLUSIONS: To our knowledge, this is the first study investigating combination triazole/echinocandin use in the early post-lung transplant period. These findings demonstrate that in-hospital anidulafungin offers unclear benefit for early IC prevention when used in combination with triazole prophylaxis.

Derivation and Validation of a Clinical Decision Guideline for Influenza Testing in 4 US Emergency Departments.

BACKGROUND: An accurate diagnosis of influenza is essential for appropriate antiviral treatment, in accordance with Centers for Disease Control and Prevention (CDC) guidelines. However, no clear guidance exists on which patients should be tested. We sought to develop a clinical decision guideline (CDG) to inform influenza testing decisions for those adult emergency department (ED) patients deemed appropriate for antiviral treatment by CDC guidelines. METHODS: A prospective cohort study was performed at 4 US EDs. From November 2013 to April 2014, we enrolled adult ED patients with fever or respiratory symptoms who met criteria for antiviral treatment, per 2013 CDC guidelines. All patients were tested for influenza using polymerase chain reaction. Data were randomly split into derivation (80%) and validation (20%) data sets. A discrete set of independent variables was selected by logistic regression, using the derivation set to create a scoring system, with a target sensitivity of at least 90%. The derived CDG was then validated. RESULTS: Of 1941 enrolled participants, 183 (9.4%) had influenza. The derived CDG included new or increased cough (2 points), headache (1 point), subjective fever (1 point), and triage temperature >100.4°C (1 point), with a score of ≥3 indicating influenza testing was warranted. The CDG had a sensitivity and specificity of 94.1% and 36.6%, respectively, in the derivation set and of 91.5% and 34.6%, respectively, in the validation set. CONCLUSIONS: A CDG with high sensitivity was derived and validated. Incorporation into practice could standardize testing for high-risk patients in adult EDs during influenza seasons, potentially improving diagnoses and treatment. CLINICAL TRIAL REGISTRATION: NCT01947049.

Resequencing Study Confirms That Host Defense and Cell Senescence Gene Variants Contribute to the Risk of Idiopathic Pulmonary Fibrosis.

Rationale: Several common and rare genetic variants have been associated with idiopathic pulmonary fibrosis, a progressive fibrotic condition that is localized to the lung. Objectives: To develop an integrated understanding of the rare and common variants located in multiple loci that have been reported to contribute to the risk of disease. Methods: We performed deep targeted resequencing (3.69 Mb of DNA) in cases (n = 3,624) and control subjects (n = 4,442) across genes and regions previously associated with disease. We tested for associations between disease and 1) individual common variants via logistic regression and 2) groups of rare variants via sequence kernel association tests. Measurements and Main Results: Statistically significant common variant association signals occurred in all 10 of the regions chosen based on genome-wide association studies. The strongest risk variant is the MUC5B promoter variant rs35705950, with an odds ratio of 5.45 (95% confidence interval, 4.91-6.06) for one copy of the risk allele and 18.68 (95% confidence interval, 13.34-26.17) for two copies of the risk allele (P = 9.60 × 10-295). In addition to identifying for the first time that rare variation in FAM13A is associated with disease, we confirmed the role of rare variation in the TERT and RTEL1 gene regions in the risk of IPF, and found that the FAM13A and TERT regions have independent common and rare variant signals. Conclusions: A limited number of common and rare variants contribute to the risk of idiopathic pulmonary fibrosis in each of the resequencing regions, and these genetic variants focus on biological mechanisms of host defense and cell senescence.

Attention in visually typical and amblyopic children.

Amblyopia is a cortical visual disorder caused by unequal visual input to the brain from the two eyes during development. Amblyopes show reduced visual acuity and contrast sensitivity and abnormal binocularity, as well as more "global" perceptual losses, such as figure-ground segregation and global form integration. Currently, there is no consensus on the neural basis for these higher-order perceptual losses. One contributing factor could be that amblyopes have deficiencies in attention, such that the attentional processes that control the selection of information favor the better eye. Previous studies in amblyopic adults are conflicting as to whether attentional deficits exist. However, studies where intact attentional ability has been shown to exist were conducted in adults; it is possible that it was acquired through experience. To test this hypothesis, we studied attentional processing in amblyopic children. We examined covert endogenous attention using a classical spatial cueing paradigm in amblyopic and visually typical 5- to 10-year old children. We found that all children, like adults, independently of visual condition, benefited from attentional cueing: They performed significantly better on trials with an informative (valid) cue than with the uninformative (neutral) cue. Response latencies were also significantly shorter for the valid cue condition. No statistically significant difference was found between the performance of the amblyopic and the visually typical children or between dominant and nondominant eyes of all children. The results showed that covert spatial attention is intact in amblyopic and visually typical children and is therefore not likely to account for higher-order perceptual losses in amblyopic children.

Trimethoprim-Sulfamethoxazole versus Placebo for Uncomplicated Skin Abscess.

BACKGROUND: U.S. emergency department visits for cutaneous abscess have increased with the emergence of methicillin-resistant Staphylococcus aureus (MRSA). The role of antibiotics for patients with a drained abscess is unclear. METHODS: We conducted a randomized trial at five U.S. emergency departments to determine whether trimethoprim-sulfamethoxazole (at doses of 320 mg and 1600 mg, respectively, twice daily, for 7 days) would be superior to placebo in outpatients older than 12 years of age who had an uncomplicated abscess that was being treated with drainage. The primary outcome was clinical cure of the abscess, assessed 7 to 14 days after the end of the treatment period. RESULTS: The median age of the participants was 35 years (range, 14 to 73); 45.3% of the participants had wound cultures that were positive for MRSA. In the modified intention-to-treat population, clinical cure of the abscess occurred in 507 of 630 participants (80.5%) in the trimethoprim-sulfamethoxazole group versus 454 of 617 participants (73.6%) in the placebo group (difference, 6.9 percentage points; 95% confidence interval [CI], 2.1 to 11.7; P=0.005). In the per-protocol population, clinical cure occurred in 487 of 524 participants (92.9%) in the trimethoprim-sulfamethoxazole group versus 457 of 533 participants (85.7%) in the placebo group (difference, 7.2 percentage points; 95% CI, 3.2 to 11.2; P<0.001). Trimethoprim-sulfamethoxazole was superior to placebo with respect to most secondary outcomes in the per-protocol population, resulting in lower rates of subsequent surgical drainage procedures (3.4% vs. 8.6%; difference, -5.2 percentage points; 95% CI, -8.2 to -2.2), skin infections at new sites (3.1% vs. 10.3%; difference, -7.2 percentage points; 95% CI, -10.4 to -4.1), and infections in household members (1.7% vs. 4.1%; difference, -2.4 percentage points; 95% CI, -4.6 to -0.2) 7 to 14 days after the treatment period. Trimethoprim-sulfamethoxazole was associated with slightly more gastrointestinal side effects (mostly mild) than placebo. At 7 to 14 days after the treatment period, invasive infections had developed in 2 of 524 participants (0.4%) in the trimethoprim-sulfamethoxazole group and in 2 of 533 participants (0.4%) in the placebo group; at 42 to 56 days after the treatment period, an invasive infection had developed in 1 participant (0.2%) in the trimethoprim-sulfamethoxazole group. CONCLUSIONS: In settings in which MRSA was prevalent, trimethoprim-sulfamethoxazole treatment resulted in a higher cure rate among patients with a drained cutaneous abscess than placebo. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT00729937.).

MUC5B variant is associated with visually and quantitatively detected preclinical pulmonary fibrosis.

BACKGROUND: Relatives of patients with familial interstitial pneumonia (FIP) are at increased risk for pulmonary fibrosis. We assessed the prevalence and risk factors for preclinical pulmonary fibrosis (PrePF) in first-degree relatives of patients with FIP and determined the utility of deep learning in detecting PrePF on CT. METHODS: First-degree relatives of patients with FIP over 40 years of age who believed themselves to be unaffected by pulmonary fibrosis underwent CT scans of the chest. Images were visually reviewed, and a deep learning algorithm was used to quantify lung fibrosis. Genotyping for common idiopathic pulmonary fibrosis risk variants in MUC5B and TERT was performed. FINDINGS: In 494 relatives of patients with FIP from 263 families of patients with FIP, the prevalence of PrePF on visual CT evaluation was 15.6% (95% CI 12.6 to 19.0). Compared with visual CT evaluation, deep learning quantitative CT analysis had 84% sensitivity (95% CI 0.72 to 0.89) and 86% sensitivity (95% CI 0.83 to 0.89) for discriminating subjects with visual PrePF diagnosis. Subjects with PrePF were older (65.9, SD 10.1 years) than subjects without fibrosis (55.8 SD 8.7 years), more likely to be male (49% vs 37%), more likely to have smoked (44% vs 27%) and more likely to have the MUC5B promoter variant rs35705950 (minor allele frequency 0.29 vs 0.21). MUC5B variant carriers had higher quantitative CT fibrosis scores (mean difference of 0.36%), a difference that remains significant when controlling for age and sex. INTERPRETATION: PrePF is common in relatives of patients with FIP. Its prevalence increases with age and the presence of a common MUC5B promoter variant. Quantitative CT analysis can detect these imaging abnormalities.

Effect of Initial Bedside Ultrasonography on Emergency Department Skin and Soft Tissue Infection Management.

STUDY OBJECTIVE: We examine the utility of emergency department (ED) ultrasonography in treatment of skin and soft tissue infections. METHODS: We enrolled ED patients with skin and soft tissue infections and surveyed clinicians in regard to their pre-ultrasonography certainty about the presence or absence of an abscess, their planned management, post-ultrasonography findings, and actual management. We determined sensitivity and specificity of ultrasonography and clinical evaluation, and assessed appropriateness of management changes based on initial clinical assessment and outcomes through 1-week follow-up. RESULTS: Among 1,216 patients, clinicians were uncertain of abscess presence in 105 cases (8.6%) and certain for 1,111 cases (91.4%). Based on surgical exploration and follow-up through 1 week, sensitivity and specificity for abscess detection by clinical evaluation were 90.3% and 97.7%, and by ultrasonography were 94.0% and 94.1%, respectively. Among 1,111 cases for which the clinician was certain, sensitivity and specificity of clinical evaluation were 96.6% and 97.3% compared with ultrasonographic evaluation sensitivity and specificity of 95.7% and 96.2%, respectively. Of 105 uncertain cases, sensitivity and specificity of ultrasonography were 68.5% and 80.4%. Ultrasonography changed management in 13 of 1,111 certain cases (1.2%), appropriately in 10 of 13 (76.9%) and inappropriately in 3 of 13 (23.1%). Of 105 uncertain cases, ultrasonography changed management in 25 (23.8%), appropriately in 21 of 25 (84.0%) and inappropriately in 4 of 25 (16.0%). CONCLUSION: Ultrasonography rarely changed management when clinicians were certain about the presence or absence of an abscess. When they were uncertain, ultrasonography changed drainage decisions in approximately one quarter of cases, of which most (84%) were appropriate.

Effects of size and sex on the courting success and foraging behaviour of Embiotoca jacksoni.

To test life-history theory that body size and sex should influence how animals allocate time to foraging versus reproductive activities, we measured the effects of size and sex on courting success and foraging behaviour of black surfperch Embiotoca jacksoni off Santa Catalina Island, southern California. Observations of focal fish were made while snorkelling, during which the length of each fish (estimated to the nearest cm), total duration of courting encounters and foraging rates were recorded. We made observations during and outside the mating season. Courtship occurred only between pairs and its duration increased with the size of both the male and female. Although males would court females that were smaller or larger than themselves, pairs that were closely matched in size had long courting sessions, whereas those that differed considerably in size courted only briefly. Small fish foraged more than larger fish, both during and outside the mating season. Males and females foraged at similar rates outside of the mating season, but during the mating season males reduced their foraging rates to less than half that seen outside of the mating season, whereas females continued to forage at the same rate. This decrease in foraging rate of males during the mating season was seen in all sizes of males but was proportionally greatest in the largest males. These observations indicate that males trade off time spent on foraging for time spent courting during the mating season, whereas females do not.

Reproductive behaviour and concurrent sound production of Gulf grouper Mycteroperca jordani (Epinephelidae) at a spawning aggregation site.

The reproductive and acoustic behaviours of Gulf grouper Mycteroperca jordani were studied at a spawning aggregation site in the southern Gulf of California, México. In May 2015-2017, divers located and surveyed a spawning aggregation site within Cabo Pulmo National Park. Adult M. jordani conformed to a lek mating system in which large males formed territories over sand adjacent to a rocky reef that were spatially segregated from smaller females outside of courtship and spawning periods. Females moved into male territories during evening hours to spawn. Male courtship behaviours targeted a single female, included head shakes and burst rises and preceded pair spawning prior to sunset. Males and females displayed three shared colour phases, but four phases were sex-specific. During evening hours, courtship and spawning, both sexes exhibited sexual dichromatism concurrent with reproductive behaviours. The pair-spawning mating system and observations of bimodal size distributions by sex support previous claims of protogyny in the species. Males produced sounds during territorial patrols, courtship and spawning rushes, which corroborated the importance of acoustic communication within the behavioural repertoire associated with spawning. Long-term acoustic monitoring revealed increases in total sounds detected day-1 from March through June with diel increases (e.g., evenings) that may be indicative of the spawning season. Observations of spawning on 12 consecutive evenings in May 2017 coupled with extended periods of sound production suggest that spawning does not follow a lunar rhythm. This first description of the mating system and sounds of the endangered M. jordani facilitates future development of seasonal and areal protections to restore and manage the species.

Subgroup Analysis of Antibiotic Treatment for Skin Abscesses.

STUDY OBJECTIVE: Two large randomized trials recently demonstrated efficacy of methicillin-resistant Staphylococcus aureus (MRSA)-active antibiotics for drained skin abscesses. We determine whether outcome advantages observed in one trial exist across lesion sizes and among subgroups with and without guideline-recommended antibiotic indications. METHODS: We conducted a planned subgroup analysis of a double-blind, randomized trial at 5 US emergency departments, demonstrating superiority of trimethoprim-sulfamethoxazole (320/1,600 mg twice daily for 7 days) compared with placebo for patients older than 12 years with a drained skin abscess. We determined between-group differences in rates of clinical (no new antibiotics) and composite cure (no new antibiotics or drainage) through 7 to 14 and 42 to 56 days after treatment among subgroups with and without abscess cavity or erythema diameter greater than or equal to 5 cm, history of MRSA, fever, diabetes, and comorbidities. We also evaluated treatment effect by lesion size and culture result. RESULTS: Among 1,057 mostly adult participants, median abscess cavity and erythema diameters were 2.5 cm (range 0.1 to 16.0 cm) and 6.5 cm (range 1.0 to 38.5), respectively; 44.3% grew MRSA. Overall, for trimethoprim-sulfamethoxazole and placebo groups, clinical cure rate at 7 to 14 days was 92.9% and 85.7%; composite cure rate at 7 to 14 days was 86.5% and 74.3%, and at 42 to 56 days, it was 82.4% and 70.2%. For all outcomes, across lesion sizes and among subgroups with and without guideline antibiotic criteria, trimethoprim-sulfamethoxazole was associated with improved outcomes. Treatment effect was greatest with history of MRSA infection, fever, and positive MRSA culture. CONCLUSION: Treatment with trimethoprim-sulfamethoxazole was associated with improved outcomes regardless of lesion size or guideline antibiotic criteria.

Desmoplakin Variants Are Associated with Idiopathic Pulmonary Fibrosis.

RATIONALE: Sequence variation, methylation differences, and transcriptional changes in desmoplakin (DSP) have been observed in patients with idiopathic pulmonary fibrosis (IPF). OBJECTIVES: To identify novel variants in DSP associated with IPF and to characterize the relationship of these IPF sequence variants with DSP gene expression in human lung. METHODS: A chromosome 6 locus (7,370,061-7,606,946) was sequenced in 230 subjects with IPF and 228 control subjects. Validation genotyping of disease-associated variants was conducted in 936 subjects with IPF and 936 control subjects. DSP gene expression was measured in lung tissue from 334 subjects with IPF and 201 control subjects. MEASUREMENTS AND MAIN RESULTS: We identified 23 sequence variants in the chromosome 6 locus associated with IPF. Genotyping of selected variants in our validation cohort revealed that noncoding intron 1 variant rs2744371 (odds ratio = 0.77, 95% confidence interval [CI] = 0.66-0.91, P = 0.002) is protective for IPF, and a previously described IPF-associated intron 5 variant (rs2076295) is associated with increased risk of IPF (odds ratio = 1.36, 95% CI = 1.19-1.56, P < 0.001) after controlling for sex and age. DSP expression is 2.3-fold increased (95% CI = 1.91-2.71) in IPF lung tissue (P < 0.0001). Only the minor allele at rs2076295 is associated with decreased DSP expression (P = 0.001). Staining of fibrotic and normal human lung tissue localized DSP to airway epithelia. CONCLUSIONS: Sequence variants in DSP are associated with IPF, and rs2076295 genotype is associated with differential expression of DSP in the lung. DSP expression is increased in IPF lung and concentrated in the airway epithelia, suggesting a potential role for DSP in the pathogenesis of IPF.

Effect of Cephalexin Plus Trimethoprim-Sulfamethoxazole vs Cephalexin Alone on Clinical Cure of Uncomplicated Cellulitis: A Randomized Clinical Trial.

IMPORTANCE: Emergency department visits for skin infections in the United States have increased with the emergence of methicillin-resistant Staphylococcus aureus (MRSA). For cellulitis without purulent drainage, ß-hemolytic streptococci are presumed to be the predominant pathogens. It is unknown if antimicrobial regimens possessing in vitro MRSA activity provide improved outcomes compared with treatments lacking MRSA activity. OBJECTIVE: To determine whether cephalexin plus trimethoprim-sulfamethoxazole yields a higher clinical cure rate of uncomplicated cellulitis than cephalexin alone. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, double-blind, randomized superiority trial in 5 US emergency departments among outpatients older than 12 years with cellulitis and no wound, purulent drainage, or abscess enrolled from April 2009 through June 2012. All participants had soft tissue ultrasound performed at the time of enrollment to exclude abscess. Final follow-up was August 2012. INTERVENTIONS: Cephalexin, 500 mg 4 times daily, plus trimethoprim-sulfamethoxazole, 320 mg/1600 mg twice daily, for 7 days (n = 248 participants) or cephalexin plus placebo for 7 days (n = 248 participants). MAIN OUTCOMES AND MEASURES: The primary outcome determined a priori in the per-protocol group was clinical cure, defined as absence of these clinical failure criteria at follow-up visits: fever; increase in erythema (>25%), swelling, or tenderness (days 3-4); no decrease in erythema, swelling, or tenderness (days 8-10); and more than minimal erythema, swelling, or tenderness (days 14-21). A clinically significant difference was defined as greater than 10%. RESULTS: Among 500 randomized participants, 496 (99%) were included in the modified intention-to-treat analysis and 411 (82.2%) in the per-protocol analysis (median age, 40 years [range, 15-78 years]; 58.4% male; 10.9% had diabetes). Median length and width of erythema were 13.0 cm and 10.0 cm. In the per-protocol population, clinical cure occurred in 182 (83.5%) of 218 participants in the cephalexin plus trimethoprim-sulfamethoxazole group vs 165 (85.5%) of 193 in the cephalexin group (difference, -2.0%; 95% CI, -9.7% to 5.7%; P = .50). In the modified intention-to-treat population, clinical cure occurred in 189 (76.2%) of 248 participants in the cephalexin plus trimethoprim-sulfamethoxazole group vs 171 (69.0%) of 248 in the cephalexin group (difference, 7.3%; 95% CI, -1.0% to 15.5%; P = .07). Between-group adverse event rates and secondary outcomes through 7 to 9 weeks, including overnight hospitalization, recurrent skin infections, and similar infection in household contacts, did not differ significantly. CONCLUSIONS AND RELEVANCE: Among patients with uncomplicated cellulitis, the use of cephalexin plus trimethoprim-sulfamethoxazole compared to cephalexin alone did not result in higher rates of clinical resolution of cellulitis in the per-protocol analysis. However, because imprecision around the findings in the modified intention-to-treat analysis included a clinically important difference favoring cephalexin plus trimethoprim-sulfamethoxazole, further research may be needed. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00729937.

A Randomized Trial of Clindamycin Versus Trimethoprim-sulfamethoxazole for Uncomplicated Wound Infection.

BACKGROUND: With the emergence of community-associated methicillin-resistant Staphylococcus aureus (MRSA) in the United States, visits for skin infections greatly increased. Staphylococci and streptococci are considered predominant causes of wound infections. Clindamycin and trimethoprim-sulfamethoxazole (TMP-SMX) are commonly prescribed, but the efficacy of TMP-SMX has been questioned. METHODS: We conducted a randomized, double-blind, superiority trial at 5 US emergency departments. Patients >12 years of age with an uncomplicated wound infection received oral clindamycin 300 mg 4 times daily or TMP-SMX 320 mg/1600 mg twice daily, each for 7 days. We compared the primary outcome, wound infection cure at 7-14 days, and secondary outcomes through 6-8 weeks after treatment, in the per-protocol population. RESULTS: Subjects had a median age of 40 years (range, 14-76 years); 40.1% of wound specimens grew MRSA, 25.7% methicillin-susceptible S. aureus, and 5.0% streptococci. The wound infection was cured at 7-14 days in 187 of 203 (92.1%) clindamycin-treated and 182 of 198 (91.9%) TMP-SMX-treated subjects (difference, 0.2%; 95% confidence interval [CI], -5.8% to 6.2%; P = not significant). The clindamycin group had a significantly lower rate of recurrence at 7-14 days (1.5% vs 6.6%; difference, -5.1%; 95% CI, -9.4% to -.8%) and through 6-8 weeks following treatment (2.0% vs 7.1%; difference, -5.1%; 95% CI, -9.7% to -.6%). Other secondary outcomes were statistically similar between groups but tended to favor clindamycin. Adverse event rates were similar. CONCLUSIONS: In settings where MRSA is prevalent, clindamycin and TMP-SMX produce similar cure and adverse event rates among patients with an uncomplicated wound infection. Further study evaluating differential effects of antibiotics on recurrent infection may be warranted. CLINICAL TRIALS REGISTRATION: NCT00729937.

MUC5B promoter polymorphism and interstitial lung abnormalities.

BACKGROUND: A common promoter polymorphism (rs35705950) in MUC5B, the gene encoding mucin 5B, is associated with idiopathic pulmonary fibrosis. It is not known whether this polymorphism is associated with interstitial lung disease in the general population. METHODS: We performed a blinded assessment of interstitial lung abnormalities detected in 2633 participants in the Framingham Heart Study by means of volumetric chest computed tomography (CT). We evaluated the relationship between the abnormalities and the genotype at the rs35705950 locus. RESULTS: Of the 2633 chest CT scans that were evaluated, interstitial lung abnormalities were present in 177 (7%). Participants with such abnormalities were more likely to have shortness of breath and chronic cough and reduced measures of total lung and diffusion capacity, as compared with participants without such abnormalities. After adjustment for covariates, for each copy of the minor rs35705950 allele, the odds of interstitial lung abnormalities were 2.8 times greater (95% confidence interval [CI], 2.0 to 3.9; P<0.001), and the odds of definite CT evidence of pulmonary fibrosis were 6.3 times greater (95% CI, 3.1 to 12.7; P<0.001). Although the evidence of an association between the MUC5B genotype and interstitial lung abnormalities was greater among participants who were older than 50 years of age, a history of cigarette smoking did not appear to influence the association. CONCLUSIONS: The MUC5B promoter polymorphism was found to be associated with interstitial lung disease in the general population. Although this association was more apparent in older persons, it did not appear to be influenced by cigarette smoking. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT00005121.).

Genome-wide imputation study identifies novel HLA locus for pulmonary fibrosis and potential role for auto-immunity in fibrotic idiopathic interstitial pneumonia.

BACKGROUND: Fibrotic idiopathic interstitial pneumonias (fIIP) are a group of fatal lung diseases with largely unknown etiology and without definitive treatment other than lung transplant to prolong life. There is strong evidence for the importance of both rare and common genetic risk alleles in familial and sporadic disease. We have previously used genome-wide single nucleotide polymorphism data to identify 10 risk loci for fIIP. Here we extend that work to imputed genome-wide genotypes and conduct new RNA sequencing studies of lung tissue to identify and characterize new fIIP risk loci. RESULTS: We performed genome-wide genotype imputation association analyses in 1616 non-Hispanic white (NHW) cases and 4683 NHW controls followed by validation and replication (878 cases, 2017 controls) genotyping and targeted gene expression in lung tissue. Following meta-analysis of the discovery and replication populations, we identified a novel fIIP locus in the HLA region of chromosome 6 (rs7887 P meta = 3.7 × 10(-09)). Imputation of classic HLA alleles identified two in high linkage disequilibrium that are associated with fIIP (DRB1*15:01 P = 1.3 × 10(-7) and DQB1*06:02 P = 6.1 × 10(-8)). Targeted RNA-sequencing of the HLA locus identified 21 genes differentially expressed between fibrotic and control lung tissue (Q < 0.001), many of which are involved in immune and inflammatory response regulation. In addition, the putative risk alleles, DRB1*15:01 and DQB1*06:02, are associated with expression of the DQB1 gene among fIIP cases (Q < 1 × 10(-16)). CONCLUSIONS: We have identified a genome-wide significant association between the HLA region and fIIP. Two HLA alleles are associated with fIIP and affect expression of HLA genes in lung tissue, indicating that the potential genetic risk due to HLA alleles may involve gene regulation in addition to altered protein structure. These studies reveal the importance of the HLA region for risk of fIIP and a basis for the potential etiologic role of auto-immunity in fIIP.