Predictors of community-associated Staphylococcus aureus, methicillin-resistant and methicillin-susceptible Staphylococcus aureus skin and soft tissue infections in primary-care settings.

Skin and soft tissue infections (SSTIs) due to Staphylococcus aureus have become increasingly common in the outpatient setting; however, risk factors for differentiating methicillin-resistant S. aureus (MRSA) and methicillin-susceptible S. aureus (MSSA) SSTIs are needed to better inform antibiotic treatment decisions. We performed a case-case-control study within 14 primary-care clinics in South Texas from 2007 to 2015. Overall, 325 patients [S. aureus SSTI cases (case group 1, n = 175); MRSA SSTI cases (case group 2, n = 115); MSSA SSTI cases (case group 3, n = 60); uninfected control group (control, n = 150)] were evaluated. Each case group was compared to the control group, and then qualitatively contrasted to identify unique risk factors associated with S. aureus, MRSA, and MSSA SSTIs. Overall, prior SSTIs [adjusted odds ratio (aOR) 7·60, 95% confidence interval (CI) 3·31-17·45], male gender (aOR 1·74, 95% CI 1·06-2·85), and absence of healthcare occupation status (aOR 0·14, 95% CI 0·03-0·68) were independently associated with S. aureus SSTIs. The only unique risk factor for community-associated (CA)-MRSA SSTIs was a high body weight (⩾110 kg) (aOR 2·03, 95% CI 1·01-4·09).

Haemagglutinin mutations and glycosylation changes shaped the 2012/13 influenza A(H3N2) epidemic, Houston, Texas.

While the early start and higher intensity of the 2012/13 influenza A virus (IAV) epidemic was not unprecedented, it was the first IAV epidemic season since the 2009 H1N1 influenza pandemic where the H3N2 subtype predominated. We directly sequenced the genomes of 154 H3N2 clinical specimens collected throughout the epidemic to better understand the evolution of H3N2 strains and to inform the H3N2 vaccine selection process. Phylogenetic analyses indicated that multiple co-circulating clades and continual antigenic drift in the haemagglutinin (HA) of clades 5, 3A, and 3C, with the evolution of a new 3C subgroup (3C-2012/13), were the driving causes of the epidemic. Drift variants contained HA substitutions and alterations in the potential N-linked glycosylation sites of HA. Antigenic analysis demonstrated that viruses in the emerging subclade 3C.3 and subgroup 3C-2012/13 were not well inhibited by antisera generated against the 3C.1 vaccine strains used for the 2012/13 (A/Victoria/361/2011) or 2013/14 (A/Texas/50/2012) seasons. Our data support updating the H3N2 vaccine strain to a clade 3C.2 or 3C.3-like strain or a subclade that has drifted further. They also underscore the challenges in vaccine strain selection, particularly regarding HA and neuraminidase substitutions derived during laboratory passage that may alter antigenic testing accuracy.

Minimal structural elements of an inhibitory anti-ATF1/CREB single-chain antibody fragment (scFv41.4).

Antibody variable domains represent potential structural models for the rational design of therapeutic molecules that bind cellular proteins with high affinity and specificity. The Activating Transcription Factor 1 (ATF1)/Cyclic AMP Response Element Binding Protein (CREB) family of transcription factors are particularly relevant targets due to their strong association with melanoma and clear cell sarcoma. Biochemical and structural investigations were performed to optimize a single-chain antibody fragment (scFv), scFv41.4, that disrupts the binding of ATF1/CREB to cyclic-AMP response elements (CRE) in vitro and inhibits transcriptional activation in cells. Molecular modeling and ligand docking simulations suggested that scFv41.4 could function as a disulfide-deficient single domain scFv. Functional studies verified that deletion of the light chain did not result in reduced inhibitory activity. The isolated heavy chain was predicted to assume a relaxed structural conformation that maintained a functional antigen binding pocket. The minimal structural elements necessary for intracellular function were further analyzed by selective deletion of CDR1 and CDR2. V(H)-CDR1 and V(H)-CDR3 were shown to play a key role in antigen binding activity, but V(H)-CDR2 was dispensable. Thus, scFv41.4 represents a unique molecule with potential for use in the design of peptidomimetic derivatives having therapeutic application to human cancer.

Molecular approaches to sarcoma therapy.

Soft tissue sarcomas comprise a heterogeneous group of aggressive tumors that have a relatively poor prognosis. Although conventional therapeutic regimens can effectively cytoreduce the overall tumor mass, they fail to consistently achieve a curative outcome. Alternative gene-based approaches that counteract the underlying neoplastic process by eliminating the clonal aberrations that potentiate malignant behavior have been proposed. As compared to the accumulation of gene alterations associated with epithelial carcinomas, sarcomas are frequently characterized by the unique presence of a single chromosomal translocation in each histological subtype. Similar to the Philadelphia chromosome associated with CML, these clonal abnormalities result in the fusion of two independent unrelated genes to generate a unique chimeric protein that displays aberrant activity believed to initiate cellular transformation. Secondary gene mutations may provide an additional growth advantage that further contributes to malignant progression. The recent clinical success of the tyrosine kinase inhibitor, STI571, suggests that therapeutic approaches specifically directed against essential survival factors in sarcoma cells may be effective. This review summarizes published approaches targeting a specific molecular mechanism associated with sarcomagenesis. The strategy and significance of published translational studies in six distinct areas are presented. These include: (1) the disruption of chimeric transcription factor activity; (2) inhibition of growth stimulatory post-translational modifications; (3) restoration of tumor suppressor function; (4) interference with angiogenesis; (5) induction of apoptotic pathways; and (6) introduction of toxic gene products. The potential for improving outcomes in sarcoma patients and the conceptual obstacles to be overcome are discussed.

Phosphorylation of the EWS IQ domain regulates transcriptional activity of the EWS/ATF1 and EWS/FLI1 fusion proteins.

Specific chromosomal translocations are commonly present in mesenchymal tumors and frequently involve genes encoding transcription factors. The combination of different domains from unrelated genes results in chimeric proteins believed to play a key role in the neoplastic process. The EWS/ATF1 and EWS/FLI1 fusion proteins associated with Clear Cell Sarcoma and Ewing's Sarcoma, respectively, were utilized to study the comparative effect of the EWS component on two different DNA binding partners. A potential regulatory site within the EWS IQ domain at serine266 was identified, and studies were performed to demonstrate that EWS is phosphorylated in cells and phosphorylation of serine266 regulates transcriptional activity. Mutational analysis showed that elimination of phosphorylation significantly reduced DNA binding activity by EMSA and reporter activation in luciferase assays, whereas phosphorylation mimicry resulted in a partial restoration to wild-type levels. Phosphorylation was also observed to mediate cellular compartmentalization. These studies confirm that IQ domain phosphorylation regulates the transcriptional activity of exogenous EWS/ATF1 and EWS/FLI1 and suggests that post-translational modifications may potentiate the neoplastic behavior of fusion proteins in general. Since the IQ domain is incorporated into only a subset of fusion transcripts, these findings may provide insight into the molecular mechanism underlying clinical heterogeneity observed in Ewing's sarcoma.

You can go home again: evidence from longitudinal data.

In this paper we analyze the economic and demographic factors that influence return migration, focusing on generation 1.5 immigrants. Using longitudinal data from the 1979 youth cohort of the National Longitudinal Surveys (NLSY79), we track residential histories of young immigrants to the United States and analyze the covariates associated with return migration to their home country. Overall, return migration appears to respond to economic incentives, as well as to cultural and linguistic ties to the United States and the home country. We find no role for welfare magnets in the decision to return, but we learn that welfare participation leads to lower probability of return migration. Finally, we see no evidence of a skill bias in return migration, where skill is measured by performance on the Armed Forces Qualifying Test.

Tumor cell viability in clear cell sarcoma requires DNA binding activity of the EWS/ATF1 fusion protein.

Chimeric proteins resulting from characteristic chromosomal translocations are believed to play a key role in the development of neoplasia. The consistent chromosomal translocation t(12;22) found in Clear Cell sarcoma (CCS) fuses the genes for Ewing's sarcoma protein (EWS) and activating transcription factor 1 (ATF1). Contribution of the chimeric EWS/ATF1 protein to maintenance of the tumor phenotype was investigated using intracellular expression of an inhibitory anti-ATF1 single chain antibody fragment (scFv4). Transfection of scFv4 into a cell line (SU-CCS-1) derived from CCS resulted in a 90% reduction in cyclic AMP response element-driven reporter activity. The delivery of scFv4 into SU-CCS-1 cells by a Moloney sarcoma retroviral vector (SRalpha-Fv4) significantly reduced viability and induced apoptosis as measured by terminal deoxynucleotidetransferase-mediated dUTP-biotin nick end labeling and flow cytometry. Conversely, scFv4 had no effect on viability of HeLa cells. The level of EWS/ATF1 expression was found to be significantly higher in primary tumor tissue than in SU-CCS-1 cells or in 293T cells following introduction of an EWS/ATF1 expression vector. These studies demonstrate a direct role for the EWS/ATF1 fusion protein in maintaining tumor cell viability of Clear Cell sarcoma and indicate that intracellular antibodies may be used to achieve a phenotypic knockout of tumor-related proteins as a method to explore their function.

Examination gloves as barriers to hand contamination in clinical practice.

OBJECTIVE: To test the effectiveness of vinyl and latex gloves as barriers to hand contamination with gram-negative organisms and enterococci during routine hospital procedures. DESIGN AND INTERVENTIONS: We studied 137 procedures during which a health care worker's gloved hand contacted a patient's mucous membrane and was thus potentially contaminated with gram-negative rods or enterococci. Quantitative hand cultures were obtained from each health care worker before and after the gloved contact using a modified glove juice method, and the exterior glove surface was also quantitatively cultured after patient contact. Used gloves were then tested for leaks using the American Society for Testing and Materials' watertight test. SETTING: Harborview Medical Center, a 330-bed city-county hospital and level I regional trauma and burn center, is both a teaching facility affiliated with the University of Washington and the major provider of care to indigent and uninsured persons in Seattle-King County, Washington. PATIENTS AND OTHER PARTICIPANTS: Respiratory therapists performing endotracheal tube care on intubated intensive care unit patients, registered nurses performing digital rectal stimulation for bowel training on patients with spinal cord injury in the rehabilitation ward, and dentists performing routine dental examinations and procedures on healthy outpatients in the dental clinic. MAIN OUTCOME MEASURE AND RESULTS: Eighty-six of the 135 gloves cultured had gram-negative rods or enterococci on the external surface after use and were thus sources of potential hand contamination. Microbial contamination of the health care worker's hands occurred in 11 (13%; 95% confidence interval, 6% to 20%) of these 86 events, and was more frequent with vinyl (10 of 42) than latex (one of 44) gloves (P < .01). After use, glove leaks were also more frequent in vinyl gloves (26 of 61) than with latex gloves (six of 70) (P < .001). Even when leaks were present, gloves prevented hand contamination in 77% of instances and quantitative counts of microorganisms contaminating hands were 2 to 4 logs less than counts on external glove surfaces. Health care workers reported awareness of the presence of glove leaks in only seven (22%) of the 32 events in which leaks were subsequently demonstrated. CONCLUSIONS: Under conditions of routine use, gloves effectively function as a protective barrier even when leaks are present. Latex gloves were less frequently associated with leaks and hand contamination. Since hand contamination occurred after 13% of exposures and cannot be readily identified by health care workers, routine hand washing should be done after each patient contact.

Prevention of catheter-associated urinary tract infection with a silver oxide-coated urinary catheter: clinical and microbiologic correlates.

In a prospective clinical trial involving 482 acutely hospitalized patients, the overall incidence of catheter-associated urinary tract infection (UTI; 10%) was similar in recipients of a silver oxide-coated urinary catheter (silver catheter) or a control silicone catheter. However, female sex and absence of antimicrobial use were independently associated with an increased risk of UTI. After stratification for these variables, the silver catheter reduced the incidence of UTI among women not receiving antimicrobial agents (19% for control catheter vs. 0 for silver catheter, P = .04; confidence interval for the difference in incidence, 0.4%-38%) but not in the other subgroups. Gram-positive UTI was associated with absence of antimicrobial use, the control catheter, and catheter care violations. Gram-negative and candidal UTIs were more common after 7 days of catheterization, and candidal UTI was associated with being female and antimicrobial use. These findings demonstrate that several clinical variables influenced the incidence and microbiology of catheter-associated UTI and that the silver catheter appeared to prevent UTI among women not receiving antimicrobials.

Conception intervals and the substitution of fertility over time.

PIP: This paper applies the waiting-time regression methods of Olsen and Wolpin (1983) to an analysis of fertility. A utility maximizing model is set up and used to provide some guidance for an empirical analysis. The data are from an experimental guaranteed job program, the Youth Incentive Entitlement Pilot Project, aimed at young women 16 to 20 years old, from poverty-level families, and not yet high school graduates. The waiting-time regression method of estimation permits the youth in question to be used as her own control revealing how eligibility for the jobs program changes the durations of periods between live-birth conceptions. 3890 women surveyed had 1 birth, 429 had 2, 112 had 3, 26 had 4, and 7 had 5. Without this person specific control described here, the most important factors affecting fertility are number of siblings (negative effect), labor market attachment by parents, especially the father, and the presence of the natural father. With the person specific control, the results predicted from economic theory do emerge: even adolescent and young women consider the economic consequences of fertility reflected in effects of fertility when wages are high in favor of fertility with lower wages. Post program effects (taking place after youths lose eligibility for the program) are a rather rapid making up for foregone fertility, reducing likelihood of net reductions of total fertility.^ieng

Estimating the effect of child mortality on the number of births.

This article rigorously derives the properties of the regression of births on child deaths. It is shown how the raw regression coefficient may be corrected for the effects of fertility on mortality so that the rate at which dead children are replaced may be estimated. The method is applied to data from Colombia. It is found that the mortality rate differs across individuals and is correlated with fertility. Such conditions vitiate the use of birth intervals and parity progresssion ratios yet can be dealth with using the new method. On average each death produces 0.2 new births as a direct result of the death. Fertility hoarding may raise the total fertility response to roughly one-half birth per death.