Publications

Sickle cell trait (HbAS) is the best-characterized genetic polymorphism known to protect against falciparum malaria. Although the protective effect of HbAS against malaria is well known, the mechanism(s) of protection remain unclear. A number of biochemical and immune-mediated mechanisms have been proposed, and it is likely that multiple complex mechanisms are responsible for the observed protection. Increased evidence for an immune component of protection as well as novel mechanisms, such as enhanced tolerance to disease mediated by HO-1 and reduced parasitic growth due to translocation of host micro-RNA into the parasite, have recently been described. A better understanding of relevant mechanisms will provide valuable insight into the host-parasite relationship, including the role of the host immune system in protection against malaria.

Next-generation sequencing was used for discovery and de novo assembly of a novel, highly divergent DNA virus at the interface between the Parvoviridae and Circoviridae. The virus, provisionally named parvovirus-like hybrid virus (PHV), is nearly identical by sequence to another DNA virus, NIH-CQV, previously detected in Chinese patients with seronegative (non-A-E) hepatitis. Although we initially detected PHV in a wide range of clinical samples, with all strains sharing ∼99% nucleotide and amino acid identity with each other and with NIH-CQV, the exact origin of the virus was eventually traced to contaminated silica-binding spin columns used for nucleic acid extraction. Definitive confirmation of the origin of PHV, and presumably NIH-CQV, was obtained by in-depth analyses of water eluted through contaminated spin columns. Analysis of environmental metagenome libraries detected PHV sequences in coastal marine waters of North America, suggesting that a potential association between PHV and diatoms (algae) that generate the silica matrix used in the spin columns may have resulted in inadvertent viral contamination during manufacture. The confirmation of PHV/NIH-CQV as laboratory reagent contaminants and not bona fide infectious agents of humans underscores the rigorous approach needed to establish the validity of new viral genomes discovered by next-generation sequencing.

Vitamin D receptors (VDR) are found in cells throughout the cardiovascular system. A variety of experimental studies indicate that the liganded VDR may play an important role in controlling cardiac hypertrophy and fibrosis, regulating blood pressure, and suppressing the development of atherosclerosis. Some, but not all, observational studies in humans provide support for these experimental findings, raising the possibility that vitamin D or its analogs might prove useful therapeutically in the prevention or treatment of cardiovascular disease.

IMPORTANCE

Most evaluations of pay-for-performance (P4P) incentives have focused on large-group practices. Thus, the effect of P4P in small practices, where many US residents receive care, is largely unknown. Furthermore, whether electronic health records (EHRs) with chronic disease management capabilities support small-practice response to P4P has not been studied.

OBJECTIVE

To assess the effect of P4P incentives on quality in EHR-enabled small practices in the context of an established quality improvement initiative.

DESIGN, SETTING, AND PARTICIPANTS

A cluster-randomized trial of small (<10 clinicians) primary care clinics in New York City from April 2009 through March 2010. A city program provided all participating clinics with the same EHR software with decision support and patient registry functionalities and quality improvement specialists offering technical assistance.

INTERVENTIONS

Incentivized clinics were paid for each patient whose care met the performance criteria, but they received higher payments for patients with comorbidities, who had Medicaid insurance, or who were uninsured (maximum payments: $200/patient; $100,000/clinic). Quality reports were given quarterly to both the intervention and control groups.

MAIN OUTCOMES AND MEASURES

Comparison of differences in performance improvement, from the beginning to the end of the study, between control and intervention clinics for aspirin or antithrombotic prescription, blood pressure control, cholesterol control, and smoking cessation interventions. Mixed-effects logistic regression was used to account for clustering of patients within clinics, with a treatment by time interaction term assessing the statistical significance of the effect of the intervention.

RESULTS

Participating clinics (n = 42 for each group) had similar baseline characteristics, with a mean of 4592 (median, 2500) patients at the intervention group clinics and 3042 (median, 2000) at the control group clinics. Intervention clinics had greater adjusted absolute improvement in rates of appropriate antithrombotic prescription (12.0% vs 6.1%, difference: 6.0% [95% CI, 2.2% to 9.7%], P = .001 for interaction term), blood pressure control (no comorbidities: 9.7% vs 4.3%, difference: 5.5% [95% CI, 1.6% to 9.3%], P = .01 for interaction term; with diabetes mellitus: 9.0% vs 1.2%, difference: 7.8% [95% CI, 3.2% to 12.4%], P = .007 for interaction term; with diabetes mellitus or ischemic vascular disease: 9.5% vs 1.7%, difference: 7.8% [95% CI, 3.0% to 12.6%], P = .01 for interaction term), and in smoking cessation interventions (12.4% vs 7.7%, difference: 4.7% [95% CI, -0.3% to 9.6%], P = .02 for interaction term). Intervention clinics performed better on all measures for Medicaid and uninsured patients except cholesterol control, but no differences were statistically significant.

CONCLUSIONS AND RELEVANCE

Among small EHR-enabled clinics, a P4P incentive program compared with usual care resulted in modest improvements in cardiovascular care processes and outcomes. Because most proposed P4P programs are intended to remain in place more than a year, further research is needed to determine whether this effect increases or decreases over time.

TRIAL REGISTRATION

clinicaltrials.gov Identifier: NCT00884013.

UNLABELLED

Streptococcus pneumoniae is an important commensal and pathogen responsible for almost a million deaths annually in children under five. The formation of biofilms by S. pneumoniae is important in nasopharyngeal colonization, pneumonia, and otitis media. Pneumolysin (Ply) is a toxin that contributes significantly to the virulence of S. pneumoniae and is an important candidate as a serotype-independent vaccine target. Having previously demonstrated that a luxS knockout mutant was unable to form early biofilms and expressed less ply mRNA than the wild type, we conducted a study to investigate the role of Ply in biofilm formation. We found that Ply was expressed in early phases of biofilm development and localized to cellular aggregates as early as 4 h postinoculation. S. pneumoniae ply knockout mutants in D39 and TIGR4 backgrounds produced significantly less biofilm biomass than wild-type strains at early time points, both on polystyrene and on human respiratory epithelial cells, cultured under static or continuous-flow conditions. Ply's role in biofilm formation appears to be independent of its hemolytic activity, as S. pneumoniae serotype 1 strains, which produce a nonhemolytic variant of Ply, were still able to form biofilms. Transmission electron microscopy of biofilms grown on A549 lung cells using immunogold demonstrated that Ply was located both on the surfaces of pneumococcal cells and in the extracellular biofilm matrix. Altogether, our studies demonstrate a novel role for pneumolysin in the assembly of S. pneumoniae biofilms that is likely important during both carriage and disease and therefore significant for pneumolysin-targeting vaccines under development.

IMPORTANCE

The bacterium Streptococcus pneumoniae (commonly known as the pneumococcus) is commonly carried in the human nasopharynx and can spread to other body sites to cause disease. In the nasopharynx, middle ear, and lungs, the pneumococcus forms multicellular surface-associated structures called biofilms. Pneumolysin is an important toxin produced by almost all S. pneumoniae strains, extensively studied for its ability to cause damage to human tissue. In this paper, we demonstrate that pneumolysin has a previously unrecognized role in biofilm formation by showing that strains without pneumolysin are unable to form the same amount of biofilm on plastic and human cell substrates. Furthermore, we show that the role of pneumolysin in biofilm formation is separate from the hemolytic activity responsible for tissue damage during pneumococcal diseases. This novel role for pneumolysin suggests that pneumococcal vaccines directed against this protein should be investigated for their potential impact on biofilms formed during carriage and disease.