A Population-Based Descriptive Atlas of Invasive Pneumococcal Strains Recovered Within the U.S. During 2015–2016

Invasive pneumococcal disease (IPD) has greatly decreased since implementation in the U.S. of the 7 valent conjugate vaccine (PCV7) in 2000 and 13 valent conjugate vaccine (PCV13) in 2010. We used whole genome sequencing (WGS) to predict phenotypic traits (serotypes, antimicrobial phenotypes, and pilus determinants) and determine multilocus genotypes from 5334 isolates (~90% of cases) recovered during 2015–2016 through Active Bacterial Core surveillance. We identified 44 serotypes; 26 accounted for 98% of the isolates. PCV13 serotypes (inclusive of serotype 6C) accounted for 1503 (28.2%) isolates, with serotype 3 most common (657/5334, 12.3%), while serotypes 1 and 5 were undetected. Of 305 isolates from children <5 yrs, 60 (19.7%) were of PCV13 serotypes 19A, 19F, 3, 6B, and 23F (58/60 were 19A, 19F, or 3). We quantitated MLST-based lineages first detected during the post-PCV era (since 2002) that potentially arose through serotype-switching. The 7 predominant emergent post-PCV strain complexes included 23B/CC338, 15BC/CC3280, 19A/CC244, 4/CC439, 15A/CC156, 35B/CC156, and 15BC/CC156. These strains accounted for 332 isolates (6.2% of total) and were more frequently observed in children <5 yrs (17.7%; 54/305). Fifty-seven categories of recently emerged (in the post PCV7 period) putative serotype-switch variants were identified, accounting for 402 isolates. Many of these putative switch variants represented newly emerged resistant strains. Penicillin-nonsusceptibility (MICs > 0.12 μg/ml) was found among 22.4% (1193/5334) isolates, with higher penicillin MICs (2–8 μg/ml) found in 8.0% (425/5334) of isolates that were primarily (372/425, 87.5%) serotypes 35B and 19A. Most (792/1193, 66.4%) penicillin-nonsusceptible isolates were macrolide-resistant, 410 (34.4%) of which were erm gene positive and clindamycin-resistant. The proportion of macrolide-resistant isolates increased with increasing penicillin MICs; even isolates with reduced penicillin susceptibility (MIC = 0.06 μg/ml) were much more likely to be macrolide-resistant than basally penicillin-susceptible isolates (MIC < 0.03 μg/ml). The contribution of recombination to strain diversification was assessed through quantitating 35B/CC558-specific bioinformatic pipeline features among non-CC558 CCs and determining the sizes of gene replacements. Although IPD has decreased greatly and stabilized in the post-PCV13 era, the species continually generates recombinants that adapt to selective pressures exerted by vaccines and antimicrobials. These data serve as a baseline for monitoring future changes within each invasive serotype

High-Frequency Oscillatory Ventilation Use and Severe Pediatric ARDS in the Pediatric Hematopoietic Cell Transplant Recipient

INTRODUCTION: The effectiveness of high-frequency oscillatory ventilation (HFOV) in the pediatric hematopoietic cell transplant patient has not been established. We sought to identify current practice patterns of HFOV, investigate parameters during HFOV and their association with mortality, and compare the use of HFOV to conventional mechanical ventilation in severe pediatric ARDS. METHODS: This is a retrospective analysis of a multi-center database of pediatric and young adult allogeneic hematopoietic cell transplant subjects requiring invasive mechanical ventilation for critical illness from 2009 through 2014. Twelve United States pediatric centers contributed data. Continuous variables were compared using a Wilcoxon rank-sum test or a Kruskal-Wallis analysis. For categorical variables, univariate analysis with logistic regression was performed. RESULTS: The database contains 222 patients, of which 85 subjects were managed with HFOV. Of this HFOV cohort, the overall pediatric ICU survival was 23.5% (n = 20). HFOV survivors were transitioned to HFOV at a lower oxygenation index than nonsurvivors (25.6, interquartile range 21.1-36.8, vs 37.2, interquartile range 26.5-52.2, P = .046). Survivors were transitioned to HFOV earlier in the course of mechanical ventilation, (day 0 vs day 2, P = .002). No subject survived who was transitioned to HFOV after 1 week of invasive mechanical ventilation. We compared subjects with severe pediatric ARDS treated only with conventional mechanical ventilation versus early HFOV (within 2 d of invasive mechanical ventilation) versus late HFOV. There was a trend toward difference in survival (conventional mechanical ventilation 24%, early HFOV 30%, and late HFOV 9%, P = .08). CONCLUSIONS: In this large database of pediatric allogeneic hematopoietic cell transplant subjects who had acute respiratory failure requiring invasive mechanical ventilation for critical illness with severe pediatric ARDS, early use of HFOV was associated with improved survival compared to late implementation of HFOV, and the subjects had outcomes similar to those treated only with conventional mechanical ventilation

Using PCR-Based Detection and Genotyping to Trace Streptococcus salivarius Meningitis Outbreak Strain to Oral Flora of Radiology Physician Assistant

We recently investigated three cases of bacterial meningitis that were reported from a midwestern radiology clinic where facemasks were not worn during spinal injection of contrast agent during myelography procedures. Using pulsed field gel electrophoresis we linked a case strain of S. salivarius to an oral specimen of a radiology physician assistant (RPA). We also used a real-time PCR assay to detect S. salivarius DNA within a culture-negative cerebrospinal fluid (CSF) specimen. Here we extend this investigation through using a nested PCR/sequencing strategy to link the culture-negative CSF specimen to the case strain. We also provide validation of the real-time PCR assay used, demonstrating that it is not solely specific for Streptococcus salivarius, but is also highly sensitive for detection of the closely related oral species Streptococcus vestibularis. Through using multilocus sequence typing and 16S rDNA sequencing we further strengthen the link between the CSF case isolate and the RPA carriage isolate. We also demonstrate that the newly characterized strains from this study are distinct from previously characterized S. salivarius strains associated with carriage and meningitis

Atrial Fibrillation Burden and Atrial Shunt Therapy in Heart Failure With Preserved Ejection Fraction

Background: Atrial fibrillation (AF) is a common comorbidity in patients with heart failure with preserved ejection fraction (HFpEF) and in heart failure with mildly reduced ejection fraction (HFmrEF). Objectives: This study sought to describe AF burden and its clinical impact among individuals with HFpEF and HFmrEF who participated in a randomized clinical trial of atrial shunt therapy (REDUCE LAP-HF II [A Study to Evaluate the Corvia Medical, Inc IASD System II to Reduce Elevated Left Atrial Pressure in Patients with Heart Failure]) and to evaluate the effect of atrial shunt therapy on AF burden. Methods: Study investigators characterized AF burden among patients in the REDUCE LAP-HF II trial by using ambulatory cardiac patch monitoring at baseline (median patch wear time, 6 days) and over a 12-month follow-up (median patch wear time, 125 days). The investigators determined the association of baseline AF burden with long-term clinical events and examined the effect of atrial shunt therapy on AF burden over time. Results: Among 367 patients with cardiac monitoring data at baseline and follow-up, 194 (53%) had a history of AF or atrial flutter (AFL), and median baseline AF burden was 0.012% (IQR: 0%-1.3%). After multivariable adjustment, baseline AF burden ≥0.012% was significantly associated with heart failure (HF) events (HR: 2.00; 95% CI: 1.17-3.44; P = 0.01) both with and without a history of AF or AFL (P for interaction = 0.68). Adjustment for left atrial reservoir strain attenuated the baseline AF burden-HF event association (HR: 1.71; 95% CI: 0.93-3.14; P = 0.08). Of the 367 patients, 141 (38%) had patch-detected AF during follow-up without a history of AF or AFL. Atrial shunt therapy did not change AF incidence or burden during follow-up. Conclusions: In HFpEF and HFmrEF, nearly 40% of patients have subclinical AF by 1 year. Baseline AF burden, even at low levels, is associated with HF events. Atrial shunt therapy does not affect AF incidence or burden.</p

Streptococcus infantis, Streptococcus mitis, and Streptococcus oralis Strains With Highly Similar cps5 Loci and Antigenic Relatedness to Serotype 5 Pneumococci

Streptococcus pneumoniae is a highly impactful bacterial pathogen on a global scale. The principal pneumococcal virulence factor and target of effective vaccines is its polysaccharide capsule, of which there are many structurally distinct forms. Here, we describe four distinct strains of three Mitis group commensal species (Streptococcus infantis, Streptococcus mitis, and Streptococcus oralis) recovered from upper respiratory tract specimens from adults in Kenya and the United States that were PCR-positive for the pneumococcal serotype 5 specific gene, wzy5. For each of the four strains, the 15 genes comprising the capsular polysaccharide biosynthetic gene cluster (cps5) shared the same order found in serotype 5 pneumococci, and each of the serotype 5-specific genes from the serotype 5 pneumococcal reference strain shared 76–99% sequence identity with the non-pneumococcal counterparts. Double-diffusion experiments demonstrated specific reactivity of the non-pneumococcal strains with pneumococcal serotype 5 typing sera. Antiserum raised against S. mitis strain KE67013 specifically reacted with serotype 5 pneumococci for a positive Quellung reaction and stimulated serotype 5 specific opsonophagocytic killing of pneumococci. Four additional commensal strains, identified using PCR serotyping assays on pharyngeal specimens, revealed loci highly homologous to those of pneumococci of serotypes 12F, 15A, 18C, and 33F. These data, in particular the species and strain diversity shown for serotype 5, highlight the existence of a broad non-pneumococcal species reservoir in the upper respiratory tract for the expression of capsular polysaccharides that are structurally related or identical to those corresponding to epidemiologically significant serotypes. Very little is known about the genetic and antigenic capsular diversity among the vast array of commensal streptococcal strains that represent multiple diverse species. The discovery of serotype 5 strains within three different commensal species suggests that extensive capsular serologic overlap exists between pneumococci and other members of the diverse Mitis group. These findings may have implications for our current understanding of naturally acquired immunity to S. pneumoniae and pneumococcal serotype distributions in different global regions. Further characterization of commensal strains carrying homologs of serotype-specific genes previously thought to be specific for pneumococci of known serotypes may shed light on the evolution of these important loci

Identifying Cognate Binding Pairs among a Large Set of Paralogs: The Case of PE/PPE Proteins of Mycobacterium tuberculosis

We consider the problem of how to detect cognate pairs of proteins that bind when each belongs to a large family of paralogs. To illustrate the problem, we have undertaken a genomewide analysis of interactions of members of the PE and PPE protein families of Mycobacterium tuberculosis. Our computational method uses structural information, operon organization, and protein coevolution to infer the interaction of PE and PPE proteins. Some 289 PE/PPE complexes were predicted out of a possible 5,590 PE/PPE pairs genomewide. Thirty-five of these predicted complexes were also found to have correlated mRNA expression, providing additional evidence for these interactions. We show that our method is applicable to other protein families, by analyzing interactions of the Esx family of proteins. Our resulting set of predictions is a starting point for genomewide experimental interaction screens of the PE and PPE families, and our method may be generally useful for detecting interactions of proteins within families having many paralogs

Activity of pomalidomide in patients with immunoglobulin light-chain amyloidosis

Immunoglobulin light-chain (AL) amyloidosis is a rare, incurable plasma cell disorder. Its therapy has benefited immensely from the expanding drug armamentarium available for multiple myeloma. Pomalidomide in combination with weekly dexamethasone (Pom/dex) is active among patients with relapsed myeloma. In the present study, we explored the Pom/dex combination in patients with previously treated AL. Patients were eligible for this prospective phase 2 trial if they had had at least one prior regimen and if they had reasonably preserved organ function. Patients were treated with oral Pom/dex. Thirty-three patients were enrolled. The median age was 66 years. Median time from diagnosis to on-study was 37 months. Eighty-two percent had cardiac involvement. The confirmed hematologic response rate was 48%, with a median time to response of 1.9 months. Organ improvement was documented in 5 patients. The median overall and progression-free survival rates were 28 and 14 months, respectively; the 1-year overall and progression-free survival rates were 76% and 59%, respectively. There was a discordance between the hematologic response and the N-terminal probrain natriuretic peptide response. The most common grade 3-5 adverse events, regardless of attribution, were neutropenia and fatigue. We conclude that pomalidomide appears to be a valuable drug covering an unmet clinical need in patients with previously treated AL. The trial is registered at www.clinicaltrials.gov as NCT00558896. (Blood. 2012;119(23): 5397-5404

In Support of a Patient-Driven Initiative and Petition to Lower the High Price of Cancer Drugs

Comment in Lowering the High Cost of Cancer Drugs--III. [Mayo Clin Proc. 2016] Lowering the High Cost of Cancer Drugs--I. [Mayo Clin Proc. 2016] Lowering the High Cost of Cancer Drugs--IV. [Mayo Clin Proc. 2016] In Reply--Lowering the High Cost of Cancer Drugs. [Mayo Clin Proc. 2016] US oncologists call for government regulation to curb drug price rises. [BMJ. 2015