Risk Stratification in Patients with Complicated Parapneumonic Effusions and Empyema Using the RAPID Score.

PURPOSE: Complicated parapneumonic effusions and empyema are a leading cause of morbidity in the United States with over 1 million admissions annually and a mortality rate that remains high in spite of recent advances in diagnosis and treatment. The identification of high risk patients is crucial for improved management and the provision of cost-effective care. The RAPID score is a scoring system comprised of the following variables: renal function, age, purulence, infection source, and dietary factors and has been shown to predict outcomes in patients with pleural space infections. METHODS: In a single center retrospective study, we evaluated 98 patients with complicated parapneumonic effusions and empyema who had tube thoracostomy (with or without Intrapleural fibrinolytic therapy) and assessed treatment success rates, mortality, length of hospital stay, and direct hospitalization costs stratified by three RAPID score categories: low-risk (0-2), medium risk (3-4), and high-risk (5-7) groups. RESULTS: Treatment success rate was 71%, and the 90 day mortality rate was 12%. There was a positive-graded association between the low, medium and high RAPID score categories and mortality, (5.3%, 8.3% and 22.6%, respectively), length of hospital stay (10, 21, 19 days, respectively), and direct hospitalization costs ($19,909, $36,317 and $43,384, respectively). CONCLUSION: Our findings suggest that the RAPID score is a robust tool which could be used to identify patients with complicated parapneumonic effusions and empyema who may be at an increased risk of mortality, prolonged hospitalization, and who may incur a higher cost of treatment. Randomized controlled trials identifying the most effective initial treatment modality for medium- and high-risk patients are needed.

Genomic hotspots for adaptation: the population genetics of Müllerian mimicry in Heliconius erato.

Wing pattern evolution in Heliconius butterflies provides some of the most striking examples of adaptation by natural selection. The genes controlling pattern variation are classic examples of Mendelian loci of large effect, where allelic variation causes large and discrete phenotypic changes and is responsible for both convergent and highly divergent wing pattern evolution across the genus. We characterize nucleotide variation, genotype-by-phenotype associations, linkage disequilibrium (LD), and candidate gene expression patterns across two unlinked genomic intervals that control yellow and red wing pattern variation among mimetic forms of Heliconius erato. Despite very strong natural selection on color pattern, we see neither a strong reduction in genetic diversity nor evidence for extended LD across either patterning interval. This observation highlights the extent that recombination can erase the signature of selection in natural populations and is consistent with the hypothesis that either the adaptive radiation or the alleles controlling it are quite old. However, across both patterning intervals we identified SNPs clustered in several coding regions that were strongly associated with color pattern phenotype. Interestingly, coding regions with associated SNPs were widely separated, suggesting that color pattern alleles may be composed of multiple functional sites, conforming to previous descriptions of these loci as "supergenes." Examination of gene expression levels of genes flanking these regions in both H. erato and its co-mimic, H. melpomene, implicate a gene with high sequence similarity to a kinesin as playing a key role in modulating pattern and provides convincing evidence for parallel changes in gene regulation across co-mimetic lineages. The complex genetic architecture at these color pattern loci stands in marked contrast to the single casual mutations often identified in genetic studies of adaptation, but may be more indicative of the type of genetic changes responsible for much of the adaptive variation found in natural populations.

Primary care physician perspectives on screening for axial spondyloarthritis: A qualitative study.

BACKGROUND: Many patients with axial spondylarthritis (axSpA) experience lengthy diagnostic delays upwards of 14 years. (5-14 years). Screening tools for axSpA have been proposed for use in primary care settings, but whether this approach could be implemented into busy primary care settings remains unknown. OBJECTIVE: To solicit feedback from primary care physicians regarding questions from the Inflammatory Back Pain Assessment: the Assessment of Spondyloarthritis International Society (ASAS) Expert Criteria and gain insight about barriers and facilitators for implementing axSpA screening in primary care. METHODS: Guided by Consolidated Criteria for reporting Qualitative Research (COREQ-criteria), we recorded, transcribed, and analyzed in-depth interviews with eight family medicine physicians and ten internists (purposeful sampling) using immersion/crystallization techniques. RESULTS: Few physicians reported awareness of existing classification criteria for axSpA, and many reported a lack of confidence in their ability to distinguish between inflammatory and mechanical back pain. From three domains, 10 subthemes emerged: 1) typical work-up of axSpA patients in primary care, with subthemes including the clues involved in work-up and role of clinical examinations for axSpA; 2) feedback on questions from the Inflammatory Back Pain Assessment: ASAS Expert Criteria, with subthemes to evaluate contents/questions of a potential screening tool for axSpA; and 3) implementation of the screening tool in primary care settings, with subthemes of perceived barriers including awareness, time, other conditions to screen, rare disease, and lack of structured questionnaire for back pain and perceived facilitators including workflow issues and awareness. CONCLUSIONS: Primary care physicians believed that an improved screening instrument and a strong evidence-base to support the need for screening for axSpA are required. The implementation of axSpA screening into a busy primary care practice requires integration into the practice workflow, with use of technology suggested as a possible way to improve efficiency.

A Disintegrin and Metalloproteinase 9 Domain (ADAM9) Is a Major Susceptibility Factor in the Early Stages of Encephalomyocarditis Virus Infection.

Encephalomyocarditis virus (EMCV) is a picornavirus that produces lytic infections in murine and human cells. Employing a genome-wide CRISPR-Cas9 knockout screen to find host factors required for EMCV infection, we identified a role for ADAM9 in EMCV infection. CRISPR-mediated deletion of ADAM9 in multiple human cell lines rendered the cells highly resistant to EMCV infection and cell death. Primary fibroblasts from ADAM9 KO mice were also strongly resistant to EMCV infection and cell death. In contrast, ADAM9 KO and WT cells were equally susceptible to infection with other viruses, including the picornavirus Coxsackie virus B. ADAM9 KO cells failed to produce viral progeny when incubated with EMCV. However, bypassing EMCV entry into cells through delivery of viral RNA directly to the cytosol yielded infectious EMCV virions from ADAM9 KO cells, suggesting that ADAM9 is not required for EMCV replication post-entry. These findings establish that ADAM9 is required for the early stage of EMCV infection, likely for virus entry or viral genome delivery to the cytosol.IMPORTANCE Viral myocarditis is a leading cause of death in the United States, contributing to numerous unexplained deaths in people ≤35 years old. Enteroviruses contribute to many cases of human myocarditis. Encephalomyocarditis virus (EMCV) infection causes viral myocarditis in rodent models, but its receptor requirements have not been fully identified. CRISPR-Cas9 screens can identify host dependency factors essential for EMCV infection and enhance our understanding of key events that follow viral infection, potentially leading to new strategies for preventing viral myocarditis. Using a CRISPR-Cas9 screen, we identified adisintegrin and metalloproteinase 9 domain (ADAM9) as a major factor required for the early stages of EMCV infection in both human and murine infection.

Is the BPD epidemic diminishing?

In a previous study of very low birth weight neonates, < or = 1500 g, admitted to the Vanderbilt University Neonatal Intensive Care Unit (NICU) from 1976-1990, improvements in survival were accompanied by a corresponding increase in the incidence of bronchopulmonary dysplasia (BPD). Since then, certain neonatal and perinatal interventions have been introduced and may influence neonatal outcomes. In this study, we have continued the analysis of the incidence of 3 outcomes: 1) Neonatal death (NEOD), 2) BPD, and 3) NEOD or BPD (NEOD/BPD) for an additional 7 years, 1991-1997. A retrospective study was performed of 3,837 patients with birth weight < or = 1500 g and admitted to the Vanderbilt NICU within 24 hours of birth from 1976 through 1997. The outcomes NEOD, BPD, or NEOD/BPD were modeled by using multiple logistic regression with the following risk factors included as covariates: birth weight, gestational age, Apgar scores at 1 and 5 minutes, gender, race, birth location, diagnosis of hyaline membrane disease, maternal age, maternal diabetes, delivery method, multiple births, duration of ruptured membranes, and biologically relevant interactions among these covariates. To assess time trends in the risk factors and outcomes, patients were divided into time periods (1 = 1976-80, 2 = 1981-85, 3 = 1986-90, 4 = 1991-95, and 5 = 1996-97). For each outcome, only covariates or interactions among covariates found to be significant were retained in the final model. Adjusted odds ratios and 95% confidence intervals were calculated to measure the risk associated with a given time period in comparison to the preceding period. There was a progressive decline in NEOD across all time periods. The previously described increase in BPD from period 1 through period 3 is followed by a decrease in periods 4 and 5. The risk of NEOD/BPD remained fairly constant from period 1 to period 3, but then showed a significant decrease over the two most recent periods. Prior to 1991, the cost of improved survival among very low birth weight infants in this large NICU was an increased incidence of BPD. Since 1991, the risk of BPD has been decreasing even though survival continues to improve. If these findings are also representative of other NICUs, they signify an important reduction in the impact of BPD as one of the costly sequelae of prematurity.

Multi-allelic major effect genes interact with minor effect QTLs to control adaptive color pattern variation in Heliconius erato.

Recent studies indicate that relatively few genomic regions are repeatedly involved in the evolution of Heliconius butterfly wing patterns. Although this work demonstrates a number of cases where homologous loci underlie both convergent and divergent wing pattern change among different Heliconius species, it is still unclear exactly how many loci underlie pattern variation across the genus. To address this question for Heliconius erato, we created fifteen independent crosses utilizing the four most distinct color pattern races and analyzed color pattern segregation across a total of 1271 F2 and backcross offspring. Additionally, we used the most variable brood, an F2 cross between H. himera and the east Ecuadorian H. erato notabilis, to perform a quantitative genetic analysis of color pattern variation and produce a detailed map of the loci likely involved in the H. erato color pattern radiation. Using AFLP and gene based markers, we show that fewer major genes than previously envisioned control the color pattern variation in H. erato. We describe for the first time the genetic architecture of H. erato wing color pattern by assessing quantitative variation in addition to traditional linkage mapping. In particular, our data suggest three genomic intervals modulate the bulk of the observed variation in color. Furthermore, we also identify several modifier loci of moderate effect size that contribute to the quantitative wing pattern variation. Our results are consistent with the two-step model for the evolution of mimetic wing patterns in Heliconius and support a growing body of empirical data demonstrating the importance of major effect loci in adaptive change.

Cimetidine does not prevent lung injury in newborn premature infants.

Animal studies have shown that induction of cytochrome P450 (CYP) in the lung by oxygen exposure may result in the release of free radical oxidants and arachidonic acid metabolites, which can cause lung injury that is reduced by treatment with cimetidine, a CYP inhibitor. To determine whether cimetidine would reduce lung injury in human infants at risk for chronic lung disease, we conducted a randomized clinical trial in which we administered either cimetidine or a placebo for 10 d beginning < 24 h after birth to 84 newborn infants weighing < or = 1250 g who were receiving O2 and mechanical ventilation. Cimetidine had no significant effect on severity of respiratory insufficiency assessed at 10 d postnatal age. F2-isoprostane levels (a marker of oxidant injury) in tracheal aspirates were significantly higher in the cimetidine group at 4 d and at 10 d. There were no significant differences between the groups in tracheal aspirate levels of inflammatory markers (leukotriene B4, IL-8, and nucleated cell count) or arachidonic acid metabolites. We conclude that cimetidine does not reduce lung injury in newborn premature infants receiving O2 and mechanical ventilation. It is possible that cimetidine was not an adequate CYP inhibitor in this context.