Gemfibrozil Inhibits Legionella pneumophila and Mycobacterium tuberculosis Enoyl Coenzyme A Reductases and Blocks Intracellular Growth of These Bacteria in Macrophages

We report here that gemfibrozil (GFZ) inhibits axenic and intracellular growth of Legionella pneumophila and of 27 strains of wild-type and multidrug-resistant Mycobacterium tuberculosis in bacteriological medium and in human and mouse macrophages, respectively. At a concentration of 0.4 mM, GFZ completely inhibited L. pneumophila fatty acid synthesis, while at 0.12 mM it promoted cytoplasmic accumulation of polyhydroxybutyrate. To assess the mechanism(s) of these effects, we cloned an L. pneumophila FabI enoyl reductase homolog that complemented for growth an Escherichia coli strain carrying a temperature-sensitive enoyl reductase and rendered the complemented E. coli strain sensitive to GFZ at the nonpermissive temperature. GFZ noncompetitively inhibited this L. pneumophila FabI homolog, as well as M. tuberculosis InhA and E. coli FabI

Biomechanical risk factors for carpal tunnel syndrome: a pooled study of 2474 workers

BACKGROUND: Between 2001 and 2010, five research groups conducted coordinated prospective studies of carpal tunnel syndrome (CTS) incidence among US workers from various industries and collected detailed subject-level exposure information with follow-up of symptoms, electrophysiological measures and job changes. OBJECTIVE: This analysis examined the associations between workplace biomechanical factors and incidence of dominant-hand CTS, adjusting for personal risk factors. METHODS: 2474 participants, without CTS or possible polyneuropathy at enrolment, were followed up to 6.5 years (5102 person-years). Individual workplace exposure measures of the dominant hand were collected for each task and included force, repetition, duty cycle and posture. Task exposures were combined across the workweek using time-weighted averaging to estimate job-level exposures. CTS case-criteria were based on symptoms and results of electrophysiological testing. HRs were estimated using Cox proportional hazard models. RESULTS: After adjustment for covariates, analyst (HR=2.17; 95% CI 1.38 to 3.43) and worker (HR=2.08; 95% CI 1.31 to 3.39) estimated peak hand force, forceful repetition rate (HR=1.84; 95% CI 1.19 to 2.86) and per cent time spent (eg, duty cycle) in forceful hand exertions (HR=2.05; 95% CI 1.34 to 3.15) were associated with increased risk of incident CTS. Associations were not observed between total hand repetition rate, per cent duration of all hand exertions, or wrist posture and incident CTS. CONCLUSIONS: In this prospective multicentre study of production and service workers, measures of exposure to forceful hand exertion were associated with incident CTS after controlling for important covariates. These findings may influence the design of workplace safety programmes for preventing work-related CTS

Personal and workplace psychosocial risk factors for carpal tunnel syndrome: a pooled study cohort

BACKGROUND: Between 2001 and 2010, six research groups conducted coordinated multiyear, prospective studies of carpal tunnel syndrome (CTS) incidence in US workers from various industries and collected detailed subject-level exposure information with follow-up symptom, physical examination, electrophysiological measures and job changes. OBJECTIVE: This analysis of the pooled cohort examined the incidence of dominant-hand CTS in relation to demographic characteristics and estimated associations with occupational psychosocial factors and years worked, adjusting for confounding by personal risk factors. METHODS: 3515 participants, without baseline CTS, were followed-up to 7 years. Case criteria included symptoms and an electrodiagnostic study consistent with CTS. Adjusted HRs were estimated in Cox proportional hazard models. Workplace biomechanical factors were collected but not evaluated in this analysis. RESULTS: Women were at elevated risk for CTS (HR=1.30; 95% CI 0.98 to 1.72), and the incidence of CTS increased linearly with both age and body mass index (BMI) over most of the observed range. High job strain increased risk (HR=1.86; 95% CI 1.11 to 3.14), and social support was protective (HR=0.54; 95% CI 0.31 to 0.95). There was an inverse relationship with years worked among recent hires with the highest incidence in the first 3.5 years of work (HR=3.08; 95% CI 1.55 to 6.12). CONCLUSIONS: Personal factors associated with an increased risk of developing CTS were BMI, age and being a woman. Workplace risk factors were high job strain, while social support was protective. The inverse relationship between CTS incidence and years worked among recent hires suggests the presence of a healthy worker survivor effect in the cohort

Developing a pooled job physical exposure data set from multiple independent studies: An example of a consortium study of carpal tunnel syndrome

BackgroundSix research groups independently conducted prospective studies of carpal tunnel syndrome (CTS) incidence in 54 US workplaces in 10 US States. Physical exposure variables were collected by all research groups at the individual worker level. Data from these research groups were pooled to increase the exposure spectrum and statistical power.ObjectiveThis paper provides a detailed description of the characteristics of the pooled physical exposure variables and the source data information from the individual research studies.MethodsPhysical exposure data were inspected and prepared by each of the individual research studies according to detailed instructions provided by an exposure subcommittee of the research consortium. Descriptive analyses were performed on the pooled physical exposure data set. Correlation analyses were performed among exposure variables estimating similar exposure aspects.ResultsAt baseline, there were a total of 3010 participants in the pooled physical exposure data set. Overall, the pooled data meaningfully increased the spectra of most exposure variables. The increased spectra were due to the wider range in exposure data of different jobs provided by the research studies. The correlations between variables estimating similar exposure aspects showed different patterns among data provided by the research studies.ConclusionsThe increased spectra of the physical exposure variables among the data pooled likely improved the possibility of detecting potential associations between these physical exposure variables and CTS incidence. It is also recognised that methods need to be developed for general use by all researchers for standardisation of physical exposure variable definition, data collection, processing and reduction

Exposure-response relationships for the ACGIH threshold limit value for hand-activity level: results from a pooled data study of carpal tunnel syndrome

OBJECTIVE: This paper aimed to quantify exposure–response relationships between the American Conference of Governmental Industrial Hygienists’ (ACGIH) threshold limit value (TLV) for hand-activity level (HAL) and incidence of carpal tunnel syndrome (CTS). METHODS: Manufacturing and service workers previously studied by six research institutions had their data combined and re-analyzed. CTS cases were defined by symptoms and abnormal nerve conduction. Hazard ratios (HR) were calculated using proportional hazards regression after adjusting for age, gender, body mass index, and CTS predisposing conditions. RESULTS: The longitudinal study comprised 2751 incident-eligible workers, followed prospectively for up to 6.4 years and contributing 6243 person-years of data. Associations were found between CTS and TLV for HAL both as a continuous variable [HR 1.32 per unit, 95% confidence interval (95% CI) 1.11–1.57] and when categorized using the ACGIH action limit (AL) and TLV. Those between the AL and TLV and above the TLV had HR of 1.7 (95% CI 1.2–2.5) and 1.5 (95% CI 1.0–2.1), respectively. As independent variables (in the same adjusted model) the HR for peak force (PF) and HAL were 1.14 per unit (95% CI 1.05–1.25), and 1.04 per unit (95% CI 0.93–1.15), respectively. CONCLUSION: Those with exposures above the AL were at increased risk of CTS, but there was no further increase in risk for workers above the TLV. This suggests that the current AL may not be sufficiently protective of workers. Combinations of PF and HAL are useful for predicting risk of CTS

Pooling job physical exposure data from multiple independent studies in a consortium study of carpal tunnel syndrome

Pooling data from different epidemiological studies of musculoskeletal disorders (MSDs) is necessary to improve statistical power and to more precisely quantify exposure–response relationships for MSDs. The pooling process is difficult and time-consuming, and small methodological differences could lead to different exposure–response relationships. A subcommittee of a six-study research consortium studying carpal tunnel syndrome: (i) visited each study site, (ii) documented methods used to collect physical exposure data and (iii) determined compatibility of exposure variables across studies. Certain measures of force, frequency of exertion and duty cycle were collected by all studies and were largely compatible. A portion of studies had detailed data to investigate simultaneous combinations of force, frequency and duration of exertions. Limited compatibility was found for hand/wrist posture. Only two studies could calculate compatible Strain Index scores, but Threshold Limit Value for Hand Activity Level could be determined for all studies. Challenges of pooling data, resources required and recommendations for future researchers are discussed

Simplified Models for LHC New Physics Searches

This document proposes a collection of simplified models relevant to the design of new-physics searches at the LHC and the characterization of their results. Both ATLAS and CMS have already presented some results in terms of simplified models, and we encourage them to continue and expand this effort, which supplements both signature-based results and benchmark model interpretations. A simplified model is defined by an effective Lagrangian describing the interactions of a small number of new particles. Simplified models can equally well be described by a small number of masses and cross-sections. These parameters are directly related to collider physics observables, making simplified models a particularly effective framework for evaluating searches and a useful starting point for characterizing positive signals of new physics. This document serves as an official summary of the results from the "Topologies for Early LHC Searches" workshop, held at SLAC in September of 2010, the purpose of which was to develop a set of representative models that can be used to cover all relevant phase space in experimental searches. Particular emphasis is placed on searches relevant for the first ~50-500 pb-1 of data and those motivated by supersymmetric models. This note largely summarizes material posted at http://lhcnewphysics.org/, which includes simplified model definitions, Monte Carlo material, and supporting contacts within the theory community. We also comment on future developments that may be useful as more data is gathered and analyzed by the experiments.Comment: 40 pages, 2 figures. This document is the official summary of results from "Topologies for Early LHC Searches" workshop (SLAC, September 2010). Supplementary material can be found at http://lhcnewphysics.or

Effects of varying case definition on carpal tunnel syndrome prevalence estimates in a pooled cohort

OBJECTIVE: To analyze differences in carpal tunnel syndrome (CTS) prevalence using a combination of electrodiagnostic studies (EDSs) and symptoms using EDS criteria varied across a range of cutpoints and compared with symptoms in both ≥1 and ≥2 median nerve–served digits. DESIGN: Pooled data from 5 prospective cohorts. SETTING: Hand-intensive industrial settings, including manufacturing, assembly, production, service, construction, and health care. PARTICIPANTS: Employed, working-age participants who are able to provide consent and undergo EDS testing (N=3130). INTERVENTIONS: None. MAIN OUTCOME MEASURES: CTS prevalence was estimated while varying the thresholds for median sensory latency, median motor latency, and transcarpal delta latency difference. EDS criteria examined included the following: median sensory latency of 3.3 to 4.1 milliseconds, median motor latency of 4.1 to 4.9 milliseconds, and median-ulnar sensory difference of 0.4 to 1.2 milliseconds. EDS criteria were combined with symptoms in ≥1 or ≥2 median nerve–served digits. EDS criteria from other published studies were applied to allow for comparison. RESULTS: CTS prevalence ranged from 6.3% to 11.7%. CTS prevalence estimates changed most per millisecond of sensory latency compared with motor latency or transcarpal delta. CTS prevalence decreased by 0.9% to 2.0% if the criteria required symptoms in 2 digits instead of 1. CONCLUSIONS: There are meaningful differences in CTS prevalence when different EDS criteria are applied. The digital sensory latency criteria result in the largest variance in prevalence