Analysis of Spatial Trends in Smoking Status Among Patients with Obstructive Airway Diseases Highlight Potential for Targeted Smoking Cessation Interventions.

Because chronic obstructive airway diseases like asthma, chronic obstructive pulmonary disease (COPD) and asthma-COPD overlap (ACO) increase individual susceptibility to the harmful effects of cigarettes, smoking cessation programs could strengthen their public health impact by targeting smokers with these conditions. We performed spatial analyses on data derived from the Electronic Health Records (EHRs) of 25,119 asthma, 3,323 COPD, and 3,620 ACO patients and a community-based health survey of 18,740 residents to identify regions in the Greater Philadelphia Area with a high density of current smokers among patients with obstructive airway diseases and the general population. We identified areas in North and West Philadelphia with high prevalence of current smokers across all patient groups and community members that should be prioritized in smoking cessation initiatives. Neighborhood deprivation, which was linked to patient data using residential geocodes, was associated with greater smoking prevalence in these regions.

Enhancing Electronic Health Record Data with Geospatial Information.

Electronic Health Record (EHR)-derived data is a valuable resource for research, and efforts are underway to overcome some of its limitations by using data from external sources to gain a fuller picture of patient characteristics, symptoms, and exposures. Our goal was to assess the utility of augmenting EHR data with geocoded patient addresses to identify geospatial variation of disease that is not explained by EHR-derived demographic factors. Using 2011-2014 encounter data from 27,604 University of Pennsylvania Hospital System asthma patients, we identified factors associated with asthma exacerbations: risk was higher in female, black, middle aged to elderly, and obese patients, as well as those with positive smoking history and with Medicare or Medicaid vs. private insurance. Significant geospatial variability of asthma exacerbations was found using generalized additive models, even after adjusting for demographic factors. Our work shows that geospatial data can be used to cost-effectively enhance EHR data.

Protein cysteine phosphorylation of SarA/MgrA family transcriptional regulators mediates bacterial virulence and antibiotic resistance.

Protein posttranslational modifications (PTMs), particularly phosphorylation, dramatically expand the complexity of cellular regulatory networks. Although cysteine (Cys) in various proteins can be subject to multiple PTMs, its phosphorylation was previously considered a rare PTM with almost no regulatory role assigned. We report here that phosphorylation occurs to a reactive cysteine residue conserved in the staphylococcal accessary regulator A (SarA)/MarR family global transcriptional regulator A (MgrA) family of proteins, and is mediated by the eukaryotic-like kinase-phosphatase pair Stk1-Stp1 in Staphylococcus aureus. Cys-phosphorylation is crucial in regulating virulence determinant production and bacterial resistance to vancomycin. Cell wall-targeting antibiotics, such as vancomycin and ceftriaxone, inhibit the kinase activity of Stk1 and lead to decreased Cys-phosphorylation of SarA and MgrA. An in vivo mouse model of infection established that the absence of stp1, which results in elevated protein Cys-phosphorylation, significantly reduces staphylococcal virulence. Our data indicate that Cys-phosphorylation is a unique PTM that can play crucial roles in bacterial signaling and regulation.

Quorum-sensing agr mediates bacterial oxidation response via an intramolecular disulfide redox switch in the response regulator AgrA.

Oxidation sensing and quorum sensing significantly affect bacterial physiology and host-pathogen interactions. However, little attention has been paid to the cross-talk between these two seemingly orthogonal signaling pathways. Here we show that the quorum-sensing agr system has a built-in oxidation-sensing mechanism through an intramolecular disulfide switch possessed by the DNA-binding domain of the response regulator AgrA. Biochemical and mass spectrometric analysis revealed that oxidation induces the intracellular disulfide bond formation between Cys-199 and Cys-228, thus leading to dissociation of AgrA from DNA. Molecular dynamics (MD) simulations suggest that the disulfide bond formation generates a steric clash responsible for the abolished DNA binding of the oxidized AgrA. Mutagenesis studies further established that Cys-199 is crucial for oxidation sensing. The oxidation-sensing role of Cys-199 is further supported by the observation that the mutant Staphylococcus aureus strain expressing AgrAC199S is more susceptible to H(2)O(2) owing to repression of the antioxidant bsaA gene under oxidative stress. Together, our results show that oxidation sensing is a component of the quorum-sensing agr signaling system, which serves as an intrinsic checkpoint to ameliorate the oxidation burden caused by intense metabolic activity and potential host immune response.