Showing papers by "Public Health Research Institute published in 2014"

Metformin as adjunct antituberculosis therapy

Abstract: The global burden of tuberculosis (TB) morbidity and mortality remains immense. A potential new approach to TB therapy is to augment protective host immune responses. We report that the antidiabetic drug metformin (MET) reduces the intracellular growth of Mycobacterium tuberculosis (Mtb) in an AMPK (adenosine monophosphate-activated protein kinase)-dependent manner. MET controls the growth of drug-resistant Mtb strains, increases production of mitochondrial reactive oxygen species, and facilitates phagosome-lysosome fusion. In Mtb-infected mice, use of MET ameliorated lung pathology, reduced chronic inflammation, and enhanced the specific immune response and the efficacy of conventional TB drugs. Moreover, in two separate human cohorts, MET treatment was associated with improved control of Mtb infection and decreased disease severity. Collectively, these data indicate that MET is a promising candidate host-adjunctive therapy for improving the effective treatment of TB.

Vaccine-induced IgG antibodies to V1V2 regions of multiple HIV-1 subtypes correlate with decreased risk of HIV-1 infection

Abstract: In the RV144 HIV-1 vaccine efficacy trial, IgG antibody (Ab) binding levels to variable regions 1 and 2 (V1V2) of the HIV-1 envelope glycoprotein gp120 were an inverse correlate of risk of HIV-1 infection. To determine if V1V2-specific Abs cross-react with V1V2 from different HIV-1 subtypes, if the nature of the V1V2 antigen used to asses cross-reactivity influenced infection risk, and to identify immune assays for upcoming HIV-1 vaccine efficacy trials, new V1V2-scaffold antigens were designed and tested. Protein scaffold antigens carrying the V1V2 regions from HIV-1 subtypes A, B, C, D or CRF01_AE were assayed in pilot studies, and six were selected to assess cross-reactive Abs in the plasma from the original RV144 case-control cohort (41 infected vaccinees, 205 frequency-matched uninfected vaccinees, and 40 placebo recipients) using ELISA and a binding Ab multiplex assay. IgG levels to these antigens were assessed as correlates of risk in vaccine recipients using weighted logistic regression models. Levels of Abs reactive with subtype A, B, C and CRF01_AE V1V2-scaffold antigens were all significant inverse correlates of risk (p-values of 0.0008–0.05; estimated odds ratios of 0.53–0.68 per 1 standard deviation increase). Thus, levels of vaccine-induced IgG Abs recognizing V1V2 regions from multiple HIV-1 subtypes, and presented on different scaffolds, constitute inverse correlates of risk for HIV-1 infection in the RV144 vaccine trial. The V1V2 antigens provide a link between RV144 and upcoming HIV-1 vaccine trials, and identify reagents and methods for evaluating V1V2 Abs as possible correlates of protection against HIV-1 infection.

Echinocandin resistance: an emerging clinical problem?

Abstract: Purpose of review Echinocandin resistance in Candida is a great concern, as the echinocandin drugs are recommended as 1st line therapy for patients with invasive candidiasis. Here we review recent advances in our understanding of the epidemiology, underlying mechanisms, methods for detection and clinical implications.

Epidemic Klebsiella pneumoniae ST258 Is a Hybrid Strain

Abstract: Carbapenem-resistant Enterobacteriaceae (CRE), especially Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae, pose an urgent threat in health facilities in the United States and worldwide. K. pneumoniae isolates classified as sequence type 258 (ST258) by multilocus sequence typing are largely responsible for the global spread of KPC. A recent comparative genome study revealed that ST258 K. pneumoniae strains are two distinct genetic clades; however, the molecular origin of ST258 largely remains unknown, and our understanding of the evolution of the two genetic clades is incomplete. Here we compared the genetic structures and single-nucleotide polymorphism (SNP) distributions in the core genomes of strains from two ST258 clades and other STs (ST11, ST442, and ST42). We identified an ~1.1-Mbp region on ST258 genomes that is homogeneous to that of ST442, while the rest of the ST258 genome resembles that of ST11. Our results suggest ST258 is a hybrid clone—80% of the genome originated from ST11-like strains and 20% from ST442-like strains. Meanwhile, we sequenced an ST42 strain that carries the same K-antigen-encoding capsule polysaccharide biosynthesis gene ( cps ) region as ST258 clade I strains. Comparison of the cps -harboring regions between the ST42 and ST258 strains (clades I and II) suggests the ST258 clade I strains evolved from a clade II strain as a result of cps region replacement. Our findings unravel the molecular evolution history of ST258 strains, an important first step toward the development of diagnostic, therapeutic, and vaccine strategies to combat infections caused by multidrug-resistant K. pneumoniae. IMPORTANCE Recombination events and replacement of chromosomal regions have been documented in various bacteria, and these events have given rise to successful pathogenic clones. Here we used comparative genomic analyses to discover that the ST258 K. pneumoniae genome is a hybrid—80% of the chromosome is homologous to ST11 strains, while the remaining 20% is homologous to that of ST442. Meanwhile, a recent study indicated that ST258 strains can be segregated into two ST258 clades, with distinct capsule polysaccharide gene ( cps ) regions. Our analysis suggests ST258 clade I strains evolved from clade II through homologous recombination of cps region. Horizontal transfer of the cps region appears to be a key element driving the molecular diversification in K. pneumoniae strains. These findings not only extend our understanding of the molecular evolution of ST258 but are an important step toward the development of effective control and treatment strategies for multidrug-resistant K. pneumoniae.

Flaviviruses, an expanding threat in public health: focus on dengue, West Nile, and Japanese encephalitis virus

Abstract: The flaviviruses dengue, West Nile, and Japanese encephalitis represent three major mosquito-borne viruses worldwide. These pathogens impact the lives of millions of individuals and potentially could affect non-endemic areas already colonized by mosquito vectors. Unintentional transport of infected vectors (Aedes and Culex spp.), traveling within endemic areas, rapid adaptation of the insects into new geographic locations, climate change, and lack of medical surveillance have greatly contributed to the increase in flaviviral infections worldwide. The mechanisms by which flaviviruses alter the immune and the central nervous system have only recently been examined despite the alarming number of infections, related deaths, and increasing global distribution. In this review, we will discuss the expansion of the geographic areas affected by flaviviruses, the potential threats to previously unaffected countries, the mechanisms of pathogenesis, and the potential therapeutic interventions to limit the devastating consequences of these viruses.

Risk of Lactic Acidosis or Elevated Lactate Concentrations in Metformin Users With Renal Impairment: A Population-Based Cohort Study

Abstract: OBJECTIVE The objective of this study was to determine whether treatment with metformin in patients with renal impairment is associated with a higher risk of lactic acidosis or elevated lactate concentrations compared with users of a noninsulin antidiabetic drug (NIAD) who had never used metformin. RESEARCH DESIGN AND METHODS A cohort of 223,968 metformin users and 34,571 diabetic patients who had never used metformin were identified from the Clinical Practice Research Datalink (CPRD).The primary outcome was defined as either a CPRD READ code lactic acidosis or a record of a plasma lactate concentration >5 mmol/L. The associations between renal impairment, dose of metformin, and the risk of lactic acidosis or elevated lactate concentrations were determined with time-dependent Cox models and expressed as hazard ratios (HRs). RESULTS The crude incidence of lactic acidosis or elevated lactate concentrations in current metformin users was 7.4 per 100,000 person-years (vs. 2.2 per 100,000 person-years in nonusers). Compared with nonusers, risk of lactic acidosis or elevated lactate concentrations in current metformin users was significantly associated with a renal function 2 g) of metformin (adjusted HR 13.0 [95% CI 2.36–72.0]). CONCLUSIONS Our study is consistent with current recommendations that the renal function of metformin users should be adequately monitored and that the dose of metformin should be adjusted, if necessary, if renal function falls below 60 mL/min/1.73 m2.

The epidemiology of extra-articular manifestations in ankylosing spondylitis: a population-based matched cohort study

Abstract: Objective To assess the incidence and risks of common extra-articular manifestations (EAMs), that is, acute anterior uveitis (AAU), psoriasis and inflammatory bowel disease (IBD), in patients with ankylosing spondylitis (AS) compared with population-based controls Methods All incident patients with AS (n=4101) from the UK Clinical Practice Research Datalink (1987–2012) were matched with up to seven control subjects without AS by year of birth, sex and practice (n=28 591) Incidence rates, cumulative incidence rates and adjusted (adj) HRs for the development of EAMs were calculated, with time-dependent adjustments for age, sex, comorbidity and medication use Results At diagnosis of AS, the proportion of patients with an EAM was 114% for AAU, 44% for psoriasis and 37% for IBD Incidence rates of EAMs were 89/1000 person-years for AAU, 34/1000 person-years for psoriasis and 24 /1000 person-years for IBD in AS The 20-year cumulative incidence was 245%, 101% and 75%, respectively Risks of EAMs were 15-fold to 16-fold increased versus controls, with an adj HR of 155 (95% CI 116 to 207) for AAU, adj HR of 15 (95% CI 11 to 19) for psoriasis and adj HR of 33 (95% CI 23 to 48) for IBD For psoriasis and IBD, the highest risks were found in the 1st years after diagnosis, while developing AAU continued to be increased also 10 years after diagnosis of AS Conclusions The risk of, in particular AAU, but also of psoriasis and IBD, is significantly increased in patients with AS compared with controls Hazard patterns are different for each of the EAMs

Carbapenem-Resistant Klebsiella pneumoniae Exhibit Variability in Capsular Polysaccharide and Capsule Associated Virulence Traits

Abstract: Background. Novel therapies are urgently needed to treat carbapenem-resistant Klebsiella pneumoniae (CR-Kp)-mediated infection, which constitute a major health threat in the United States. In order to assess if it is feasible to develop anticapsular antibodies as a potential novel therapy, it is crucial to first systematically characterize capsular polysaccharide (CPS) and virulence traits in these strains. Methods. Forty CR-Kp were genotyped by pulsed field gel electrophoresis, multilocus sequence typing (MLST), and molecular capsule typing (C-patterns and wzi sequencing). Their biofilm formation, serum resistance, macrophage-mediated killing, and virulence in Galleria mellonella were compared. MAb (1C9) was generated by co-immunization with 2 CPSs, and cross-reactivity was investigated. Results. MLST assigned 80% of CR-Kp isolates to the ST258-clone. Molecular capsule typing identified new C-patterns, including C200/wzi-154, which was widely represented and associated with blaKPC-3-bearing strains. Heterogeneity was detected in biofilm formation and macrophage-mediated killing. Differences in serum resistance correlated with virulence in G. mellonella. ST258 strains carrying blaKPC-3 were less virulent than those with blaKPC-2. MAb 1C9 cross-reacted with 58% of CR-Kp CPSs. Conclusions. CR-Kp ST258 strains exhibit variability of virulence-associated traits. Differences were associated with the type of KPC gene and CPS. Identification of cross-reacting anti-CPS mAbs encourages their development as adjunctive therapy.

Exploring the Diversity of Conceptualizations of Work (Dis)ability: A Scoping Review of Published Definitions

Abstract: Purpose Researchers are confronted to numerous definitions of work ability/disability, influenced by their context of emergence, discipline, purpose, underlying paradigm and relationship to time. This study provides an in-depth analysis of the concept through a systematic scoping review and the development of an integrative concept map of work (dis)ability. The research questions are: How has work (dis)ability been conceptualized from the perspectives of research, practice, policy and industry in the published scientific literature? How has the conceptualization of work (dis)ability evolved over time? Methods A search strategy was designed with a library scientist to retrieve scientific publications containing explicit definition(s) of work (dis)ability in leading-edge databases. The screening and the extraction of the definitions were achieved by duplicate assessment. The definitions were subject to a comparative analysis based on the grounded theory approach. Results In total, 423 abstracts were retrieved from the bibliographic databases. After removing duplicates, 280 unique records were screened for inclusion. A final set of 115 publications containing unique original conceptual definitions served as basis for analysis. Conclusions The scientific literature does not reflect a shared, integrated vision of the exact nature and dimensions of work (dis)ability. However, except for a few definitions, there seems to be a consensus that work (dis)ability is a relational concept resulting from the interaction of multiple dimensions that influence each other through different ecological levels. The conceptualization of work (dis)ability also seems to have become more dynamic over time. The way work (dis)ability is defined has important implications for research, compensation and rehabilitation.

Demographic epidemiological and health transitions: Are they relevant to population health patterns in Africa?

Abstract: Background : Studies of trends in population changes and epidemiological profiles in the developing world have overwhelmingly relied upon the concepts of demographic, epidemiological, and health transitions, even though their usefulness in describing and understanding population and health trends in developing countries has been repeatedly called into question. The issue is particularly relevant for the study of population health patterns in Africa and sub-Saharan Africa, as the history and experience there differs substantially from that of Western Europe and North America, for which these concepts were originally developed. Objective : The aim of this study is two-fold: to review and clarify any distinction between the concepts of demographic transition, epidemiological transition and health transition and to identify summary indicators of population health to test how well these concepts apply in Africa. Results : Notwithstanding the characteristically diverse African context, Africa is a continent of uncertainties and emergencies where discontinuities and interruptions of health, disease, and mortality trends reflect the enduring fragility and instability of countries and the vulnerabilities of individuals and populations in the continent. Africa as a whole remains the furthest behind the world’s regions in terms of health improvements and longevity, as do its sub-Saharan African regions and societies specifically. This study documents: 1) theoretically and empirically the similarities and differences between the demographic transition, epidemiological transition, and health transition; 2) simple summary indicators that can be used to evaluate their descriptive and predictive features; 3) marked disparities in the onset and pace of variations and divergent trends in health, disease, and mortality patterns as well as fertility and life expectancy trajectories among African countries and regions over the past 60 years; 4) the rapid decline in infant mortality and gains in life expectancy from the 1950s through the 1990s in a context of preponderant communicable diseases in all African countries; 5) the salient role of adult mortality, mostly ascribed to HIV/AIDS and co-morbidities, since the 1990s in reversing trends in mortality decline, its interruption of life expectancy improvements, and its reversal of gender differences in life expectancies disadvantaging women in several countries with the highest prevalence of HIV/AIDS; 6) the huge impact of wars in reversing the trends in under-five mortality decline in sub-Saharan countries in the 1990s and beyond. These assessments of these transition frameworks and these phenomena were not well documented to date for all five regions and 57 countries of Africa. Conclusion : Prevailing frameworks of demographic, epidemiological, and health transitions as descriptive and predictive models are incomplete or irrelevant for charting the population and health experiences and prospects of national populations in the African context. Keywords : systematic review; demographic transition; epidemiological transition; health transition; population health; epidemiology of population change; global health; Africa; sub-Saharan Africa; cross-national comparison; sex differentials (Published: 15 May 2014) Citation : Glob Health Action 2014, 7 : 22443 - http://dx.doi.org/10.3402/gha.v7.22443 Special Issue: This paper is part of the Special Issue: Epidemiological Transitions – Beyond Omran’s Theory . More papers from this issue can be found at http://www.globalhealthaction.net

Carbapenem-Resistant Klebsiella pneumoniae Strains Exhibit Diversity in Aminoglycoside-Modifying Enzymes, Which Exert Differing Effects on Plazomicin and Other Agents

Abstract: We measured in vitro activity of plazomicin, a next-generation aminoglycoside, and other aminoglycosides against 50 carbapenem-resistant Klebsiella pneumoniae strains from two centers and correlated the results with the presence of various aminoglycoside-modifying enzymes (AMEs). Ninety-four percent of strains were sequence type 258 (ST258) clones, which exhibited 5 ompK36 genotypes; 80% and 10% of strains produced Klebsiella pneumoniae carbapenemase 2 (KPC-2) and KPC-3, respectively. Ninety-eight percent of strains possessed AMEs, including AAC(6')-Ib (98%), APH(3')-Ia (56%), AAC(3)-IV (38%), and ANT(2")-Ia (2%). Gentamicin, tobramycin, and amikacin nonsusceptibility rates were 40, 98, and 16%, respectively. Plazomicin MICs ranged from 0.25 to 1 μg/ml. Tobramycin and plazomicin MICs correlated with gentamicin MICs (r = 0.75 and 0.57, respectively). Plazomicin exerted bactericidal activity against 17% (1× MIC) and 94% (4× MIC) of strains. All strains with AAC(6')-Ib were tobramycin-resistant; 16% were nonsusceptible to amikacin. AAC(6')-Ib combined with another AME was associated with higher gentamicin, tobramycin, and plazomicin MICs than AAC(6')-Ib alone (P = 0.01, 0.0008, and 0.046, respectively). The presence of AAC(3)-IV in a strain was also associated with higher gentamicin, tobramycin, and plazomicin MICs (P = 0.0006, P < 0.0001, and P = 0.01, respectively). The combination of AAC(6')-Ib and another AME, the presence of AAC(3)-IV, and the presence of APH(3')-Ia were each associated with gentamicin resistance (P = 0.0002, 0.003, and 0.01, respectively). In conclusion, carbapenem-resistant K. pneumoniae strains (including ST258 clones) exhibit highly diverse antimicrobial resistance genotypes and phenotypes. Plazomicin may offer a treatment option against strains resistant to other aminoglycosides. The development of molecular assays that predict antimicrobial responses among carbapenem-resistant K. pneumoniae strains should be a research priority.

Comparative Genomic Analysis of KPC-Encoding pKpQIL-Like Plasmids and Their Distribution in New Jersey and New York Hospitals

Abstract: The global spread of Klebsiella pneumoniae carbapenemase (KPC) is predominately associated with K. pneumoniae strains genotyped as sequence type 258 (ST258). The first ST258-associated plasmid, pKpQIL, was described in Israel in 2006, but its history in the northeastern United States remains unknown. Six pKpQIL-like plasmids from four K. pneumoniae isolates (three ST258 and one ST234), one Escherichia coli isolate, and one Enterobacter aerogenes isolate, collected from 2003 to 2010 in New York (NY) and New Jersey (NJ) hospitals, were completely sequenced. The sequences and overall sizes of the six plasmids are highly similar to those of pKpQIL; the major difference is that five of six NJ/NY strains harbor blaKPC-2, while pKpQIL contains blaKPC-3. Moreover, a 26.7-kb fragment was inverted in pKpQIL-234 (from ST234 K. pneumoniae), while a 14.5-kb region was deleted in pKpQIL-Ec (from ST131 E. coli). PCR screening of 284 other clinical K. pneumoniae isolates identified 101 (35.6%) harboring pKpQIL-like plasmids from 9 of 10 surveyed hospitals, demonstrating the wide dissemination of pKpQIL in this region of endemicity. Among the positive isolates, 87.1% were typed as ST258 and 88.1% carried blaKPC-2. The finding of pKpQIL-like plasmid in this study from strains that predate the initial report of KPC in Israel provides evidence that pKpQIL may have originated in the United States. Our findings demonstrate that pKpQIL plasmids are both spreading clonally in ST258 strains and spreading horizontally to different sequence types and species, further highlighting the clinical and public health concerns associated with carbapenem resistance.

Cutting Edge: Vitamin D Regulates Lipid Metabolism in Mycobacterium tuberculosis Infection

Abstract: Vitamin D has long been linked to resistance to tuberculosis, an infectious respiratory disease that is increasingly hard to treat because of multidrug resistance. Previous work established that vitamin D induces macrophage antimicrobial functions against Mycobacterium tuberculosis. In this article, we report a novel, metabolic role for vitamin D in tuberculosis identified through integrated transcriptome and mechanistic studies. Transcriptome analysis revealed an association between vitamin D receptor (VDR) and lipid metabolism in human tuberculosis and infected macrophages. Vitamin D treatment of infected macrophages abrogated infection-induced accumulation of lipid droplets, which are required for intracellular M. tuberculosis growth. Additional transcriptomics results showed that vitamin D downregulates the proadipogenic peroxisome proliferator-activated receptor γ (PPARγ) in infected macrophages. PPARγ agonists reversed the antiadipogenic and the antimicrobial effects of VDR, indicating a link between VDR and PPARγ signaling in regulating both vitamin D functions. These findings suggest the potential for host-based, adjunct antituberculosis therapy targeting lipid metabolism.

Long Live Love. The implementation of a school-based sex-education program in the Netherlands

Abstract: Implementation of health education programs is often inadequately considered or not considered at all in planning, developing and evaluating interventions. With the focus being predominantly on the adoption stage, little is known about the factors influencing the implementation and continuation stages of the diffusion process. This study contributes to the understanding of factors that promote or impede each stage of the diffusion process in the school setting using the sex education program Long Live Love (LLL) as an example. A survey integrating different diffusion-related concepts was completed by 130 teachers. Results showed that teacher curriculum-related beliefs were associated with all stages in the diffusion process. Although adoption of LLL was predominantly related to teacher curriculum-related beliefs, implementation completeness and fidelity and continued use of LLL were also enhanced by contextual factors, namely teacher training and interactive context variables (school policy, governing body support and student response), respectively. The results of this study can be used to optimize the adoption, implementation and continuation of school-based (sexual) health promotion programs.

HIV infection and its association with an excess risk of clinical fractures: a nationwide case-control study.

Abstract: BACKGROUND: Different studies have reported an association between HIV infection, antiretroviral therapies, and impaired bone metabolism, but data on their impact on fracture risk are scarce. We studied the association between a clinical diagnosis of HIV infection and fracture risk. METHODS: We conducted a case-control study using data from the Danish National Health Service registries, including 124,655 fracture cases and 373,962 age- and gender-matched controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression. RESULTS: A total of 50 (0.40/1000) patients in the fracture group and 52 (0.14/1000) controls had an HIV diagnosis. The risk of any fracture was thus significantly increased among HIV-infected patients (age- and gender-matched OR = 2.89, 95% CI: 1.99 to 4.18). Similarly, significant increases in the risk of hip (OR = 8.99, 95% CI: 1.39 to 58.0), forearm (OR = 3.50, 95% CI: 1.26 to 9.72), and spine fractures (OR = 9.00, 95% CI: 1.39 to 58.1) were observed. CONCLUSIONS: HIV infection is associated with an almost 3-fold increase in fracture risk compared with that of age- and gender-matched uninfected patients. HIV patients are also at an almost 9-fold higher risk of hip fracture.

Role clarification processes for better integration of nurse practitioners into primary healthcare teams: a multiple-case study.

Abstract: Role clarity is a crucial issue for effective interprofessional collaboration. Poorly defined roles can become a source of conflict in clinical teams and reduce the effectiveness of care and services delivered to the population. Our objective in this paper is to outline processes for clarifying professional roles when a new role is introduced into clinical teams, that of the primary healthcare nurse practitioner (PHCNP). To support our empirical analysis we used the Canadian National Interprofessional Competency Framework, which defines the essential components for role clarification among professionals. A qualitative multiple-case study was conducted on six cases in which the PHCNP role was introduced into primary care teams. Data collection included 34 semistructured interviews with key informants involved in the implementation of the PHCNP role. Our results revealed that the best performing primary care teams were those that used a variety of organizational and individual strategies to carry out role clarification processes. From this study, we conclude that role clarification is both an organizational process to be developed and a competency that each member of the primary care team must mobilize to ensure effective interprofessional collaboration.

Role of Pannexin-1 hemichannels and purinergic receptors in the pathogenesis of human diseases

Abstract: In the last decade several groups have determined the key role of hemichannels formed by pannexins or connexins, extracellular ATP and purinergic receptors in physiological and pathological conditions. Our work and the work of others, indicate that the opening of Pannexin-1 hemichannels and activation of purinergic receptors by extracellular ATP is essential for HIV infection, cellular migration, inflammation, atherosclerosis, stroke, and apoptosis. Thus, this review discusses the importance of purinergic receptors, Panx-1 hemichannels and extracellular ATP in the pathogenesis of several human diseases and their potential use to design novel therapeutic approaches.

Regulatory Proteins That Control Late-Growth Development

Abstract: Upon encountering nutrient deprivation, Bacillus and other soil organisms initiate a series of responses that allow survival in the hostile environment. Among these responses are synthesis and secretion of degradative enzymes, production of antibiotics, development of motility and competence, and finally, appearance of spores. These dormant, resistant life forms will germinate and start a new round of vegetative growth when exposed to adequate food supplies. One of the most actively studied areas in Bacillus physiology and molecular biology is the decision-making process whereby the cell faced with nutrient stress chooses one of the alternative late-growth pathways. Several proteins that affect these pathways have been described. This chapter discusses the specific functions of these proteins, the regulation of their synthesis, and their roles in the circuitry controlling late-growth development in B. subtilis and closely related bacteria, where these processes are understood. In recent years, several genes that affect late-growth development have been cloned and characterized, and it has been demonstrated, usually by creating mutations in the chromosomal gene or by disrupting the gene on a multicopy plasmid, that the protein products of these genes are the functional agents for their effects. Among these proteins are AbrB, ComA, DegQ, DegR, DegU, DegT, Hpr, Pai (ORF1 and ORF2), SinR (and SinI), Sen, Spo0A, TenA, and TenI. The best characterized proteins in terms of their functions and control of their synthesis are AbrB, ComA, DegU, Spo0A, Hpr, and SinR.

Molecular Survey of the Dissemination of Two blaKPC-Harboring IncFIA Plasmids in New Jersey and New York Hospitals

Abstract: Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae strains have spread worldwide and become a major threat in health care facilities. Transmission of blaKPC, the plasmid-borne KPC gene, can be mediated by clonal spread and horizontal transfer. Here, we report the complete nucleotide sequences of two novel blaKPC-3-harboring IncFIA plasmids, pBK30661 and pBK30683. pBK30661 is 74 kb in length, with a mosaic plasmid structure; it exhibits homologies to several other plasmids but lacks the plasmid transfer operon (tra) and the origin of transfer (oriT) that are required for plasmid transfer. pBK30683 is a conjugative plasmid with a cointegrated plasmid structure, comprising a 72-kb element that highly resembles pBK30661 (>99.9% nucleotide identities) and an extra 68-kb element that harbors tra and oriT. A PCR scheme was designed to detect the distribution of blaKPC-harboring IncFIA (pBK30661-like and pBK30683-like) plasmids in a collection of clinical Enterobacteriaceae isolates from 10 hospitals in New Jersey and New York. KPC-harboring IncFIA plasmids were found in 20% of 491 K. pneumoniae isolates, and all carried blaKPC-3. pBK30661-like plasmids were identified mainly in the epidemic sequence type 258 (ST258) K. pneumoniae clone, while pBK30683-like plasmids were widely distributed in ST258 and other K. pneumoniae sequence types and among non-K. pneumoniae Enterobacteriaceae species. This suggests that both clonal spread and horizontal plasmid transfer contributed to the dissemination of blaKPC-harboring IncFIA plasmids in our area. Further studies are needed to understand the distribution of this plasmid group in other health care regions and to decipher the origins of pBK30661-like and pBK30683-like plasmids.

Complete Sequence of a KPC-Producing IncN Multidrug-Resistant Plasmid from an Epidemic Escherichia coli Sequence Type 131 Strain in China

Abstract: We report here the nucleotide sequence of a novel blaKPC-2-harboring incompatibility group N (IncN) plasmid, pECN580, from a multidrug-resistant Escherichia coli sequence type 131 (ST131) isolate recovered from Beijing, China. pECN580 harbors β-lactam resistance genes blaKPC-2, blaCTX-M-3, and blaTEM-1; aminoglycoside acetyltransferase gene aac(6′)-Ib-cr; quinolone resistance gene qnrS1; rifampin resistance gene arr-3; and trimethoprim resistance gene dfrA14. The emergence of a blaKPC-2-harboring multidrug-resistant plasmid in an epidemic E. coli ST131 clone poses a significant potential threat in community and hospital settings.

Production of an attenuated phenol-soluble modulin variant unique to the MRSA clonal complex 30 increases severity of bloodstream infection.

Abstract: Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of morbidity and death. Phenol-soluble modulins (PSMs) are recently-discovered toxins with a key impact on the development of Staphylococcus aureus infections. Allelic variants of PSMs and their potential impact on pathogen success during infection have not yet been described. Here we show that the clonal complex (CC) 30 lineage, a major cause of hospital-associated sepsis and hematogenous complications, expresses an allelic variant of the PSMα3 peptide. We found that this variant, PSMα3N22Y, is characteristic of CC30 strains and has significantly reduced cytolytic and pro-inflammatory potential. Notably, CC30 strains showed reduced cytolytic and chemotactic potential toward human neutrophils, and increased hematogenous seeding in a bacteremia model, compared to strains in which the genome was altered to express non-CC30 PSMα3. Our findings describe a molecular mechanism contributing to attenuated pro-inflammatory potential in a main MRSA lineage. They suggest that reduced pathogen recognition via PSMs allows the bacteria to evade elimination by innate host defenses during bloodstream infections. Furthermore, they underscore the role of point mutations in key S. aureus toxin genes in that adaptation and the pivotal importance PSMs have in defining key S. aureus immune evasion and virulence mechanisms.

‘Active play may be lots of fun, but it's certainly not frivolous’: the emergence of active play as a health practice in Canadian public health

Abstract: In the context of what has been termed a childhood obesity epidemic, public health institutions have recently begun to promote active play as a means of addressing childhood obesity, thus advancing play for health. Drawing on Foucault, this article problematises the way that children's play is being taken up as a health practice and further considers some of the effects this may have for children. Six Canadian public health websites were examined, from which 150 documents addressing children's health, physical activity, obesity, leisure activities and play were selected and coded deductively (theoretical themes) and inductively (emerging themes). Bacchi's () question-posing approach to critical discourse analysis deepened our analysis of dominant narratives. Our findings suggest that several taken-for-granted assumptions and practices underlie this discourse: (i) play is viewed as a productive activity legitimises it as a health practice; (ii) tropes of 'fun' and 'pleasure' are drawn on to promote physical activity; (iii) children are encouraged to self-govern their leisure time to promote health. We underscore the need to recognise this discourse as contingent and as only one of many ways of conceptualising children's leisure activities and their health and social lives more generally.

Dispersion Method for Safety Research on Manufactured Nanomaterials

Abstract: Nanomaterials tend to agglomerate in aqueous media, resulting in inaccurate safety assessment of the biological response to these substances. The present study searched for suitable dispersion methods for the preparation of nanomaterial suspensions. Titanium dioxide (TiO2) and zinc oxide (ZnO) nanoparticles were dispersed in a biocompatible dispersion medium by direct probe-type sonicator and indirect cup-type sonicator. Size characterization was completed using dynamic light scattering and transmission electron microscopy. A series of dispersion time and out- put power, as well as two different particle concentrations were tested. Microscopic contamination of metal titanium that broke away from the tip of the probe into the suspension was found. Size of agglomerated nanoparticles decreased with increase in sonication time or output power. Particle concentration did not show obvious effect on size distribution of TiO2 nanoparticles, while signifi- cant reduction of secondary diameter of ZnO was observed at higher concentration. A practicable protocol was then adopted and sizes of well-dispersed nanoparticles increased by less than 10% at 7 d after sonication. Multi-walled carbon nanotubes were also well dispersed by the same protocol. The cup-type sonicator might be a useful alternative to the traditional bath-type sonicator or probe- type sonicator based on its effective energy delivery and assurance of suspension purity.

Improving the risk assessment of lipophilic persistent environmental chemicals in breast milk.

Abstract: Lipophilic persistent environmental chemicals (LPECs) have the potential to accumulate within a woman's body lipids over the course of many years prior to pregnancy, to partition into human milk, and to transfer to infants upon breastfeeding. As a result of this accumulation and partitioning, a breastfeeding infant's intake of these LPECs may be much greater than his/her mother's average daily exposure. Because the developmental period sets the stage for lifelong health, it is important to be able to accurately assess chemical exposures in early life. In many cases, current human health risk assessment methods do not account for differences between maternal and infant exposures to LPECs or for lifestage-specific effects of exposure to these chemicals. Because of their persistence and accumulation in body lipids and partitioning into breast milk, LPECs present unique challenges for each component of the human health risk assessment process, including hazard identification, dose–response assessment,...

Evidence-Based Medicine or Cookbook Medicine? Addressing Concerns over the Standardization of Care

Abstract: Evidence-based medicine (EBM), which advocates clinical decisions are based on evidence from medical research, has become an important ideal pursued in contemporary medicine. EBM relies on two key principles: the evidence hierarchy and clinical practice guidelines. Both principles have been fiercely criticized, and critics often invoke the term ‘Cookbook medicine’ to stress the dangers and limitations of EBM. This article reviews diverse critical literature on EBM by drawing on the newly proposed subfield of “Sociology of Standards.” It reframes the manifold critiques on EBM as concerns over the harm that standardization can bring about and demonstrates how empirical sociological studies have contributed to a better understanding of EBM's justificatory basis and regulatory impact. First, it discusses the ‘politics of Evidence’ inherent in EBM's epistemological basis, secondly, explores the actual ‘evidence-base’ of its tools in practice, and third, addresses sociological debates on EBM's regulatory impact. In the concluding section, I argue that a ‘Sociology of Standards’ opens up new research avenues by allowing scholars to challenge – or at least empirically investigate – a host of dichotomies. By doing so, the role of the patient in EBM can be reframed to allow for more productive empirical investigations.