Synthesis and antitubercular activity of novel 4-arylalkyl substituted thio-, oxy- and sulfoxy-quinoline analogues targeting the cytochrome bc1 complex.

A library of 4-substituted quinolines was synthesised based on the structural features of the privileged 4-(benzylthio)-6-methoxy-2-methylquinoline scaffold. Quinoline-based chemical probes have proven to be effective anti-tuberculosis agents with the ability of inhibiting components of Mycobacterium tuberculosis (MTB) respiratory chain including the b subunit of the cytochrome bc1 complex. Novel 4-(arylalkyl)-thio, -oxy and sulfoxy-quinoline analogues were tested for their ability to inhibit the growth of MTB H37Rv and QcrB mutant strains, and the compounds mode of action was investigated. Members of the 4-subtituted thio- and sulfoxyquinoline series exhibited significant growth inhibitory activity in the high nanomolar range against wild-type MTB and induced depletion of intracellular ATP. These probes also showed reduced potency in the QcrB T313I mutant strain, thus indicating the cytochrome bc1 oxidase complex as the molecular target. Interestingly, new 4-(quinolin-2-yl)oxy-quinoline 4i was more selective for the QcrB T313I strain compared to the wild-type strain.

Triazolopyrimidines Target Aerobic Respiration in Mycobacterium tuberculosis.

We previously identified a series of triazolopyrimidines with antitubercular activity. We determined that Mycobacterium tuberculosis strains with mutations in QcrB, a subunit of the cytochrome bcc-aa3 supercomplex, were resistant. A cytochrome bd oxidase deletion strain was more sensitive to this series. We isolated resistant mutants with mutations in Rv1339. Compounds led to the depletion of intracellular ATP levels and were active against intracellular bacteria, but they did not inhibit human mitochondrial respiration. These data are consistent with triazolopyrimidines acting via inhibition of QcrB.

An assessment of marine, estuarine, and riverine habitat vulnerability to climate change in the Northeast U.S.

Climate change is impacting the function and distribution of habitats used by marine, coastal, and diadromous species. These impacts often exacerbate the anthropogenic stressors that habitats face, particularly in the coastal environment. We conducted a climate vulnerability assessment of 52 marine, estuarine, and riverine habitats in the Northeast U.S. to develop an ecosystem-scale understanding of the impact of climate change on these habitats. The trait-based assessment considers the overall vulnerability of a habitat to climate change to be a function of two main components, sensitivity and exposure, and relies on a process of expert elicitation. The climate vulnerability ranks ranged from low to very high, with living habitats identified as the most vulnerable. Over half of the habitats examined in this study are expected to be impacted negatively by climate change, while four habitats are expected to have positive effects. Coastal habitats were also identified as highly vulnerable, in part due to the influence of non-climate anthropogenic stressors. The results of this assessment provide regional managers and scientists with a tool to inform habitat conservation, restoration, and research priorities, fisheries and protected species management, and coastal and ocean planning.

Variability in sediment-water carbonate chemistry and bivalve abundance after bivalve settlement in Long Island Sound, Milford, Connecticut.

Cues that drive bivalve settlement and abundance in sediments are not well understood, but recent reports suggest that sediment carbonate chemistry may influence bivalve abundance. In 2013, we conducted field experiments to assess the relationship between porewater sediment carbonate chemistry (pH, alkalinity (At), dissolved inorganic carbon (DIC)), grain size, and bivalve abundance throughout the July-September settlement period at two sites in Long Island Sound (LIS), CT. Two dominate bivalves species were present during the study period Mya arenaria and Nucula spp. Akaike's linear information criterion models, indicated 29% of the total community abundance was predicted by grain size, salinity, and pH. When using 2 weeks of data during the period of peak bivalve settlement, pH and phosphate concentrations accounted 44% of total bivalve community composition and 71% of Nucula spp. abundance with pH, phosphate, and silica. These results suggest that sediment carbonate chemistry may influence bivalve abundance in LIS.

Interventions to Reduce Over-Utilized Tests and Treatments in Bronchiolitis.

OBJECTIVES: The American Academy of Pediatrics published bronchiolitis clinical practice guidelines in 2014 recommending against the routine use of bronchodilators, chest radiographs, or respiratory viral testing in children with a clinical diagnosis of bronchiolitis. Our aim in this project was to align care with the American Academy of Pediatrics clinical practice guidelines by decreasing the overuse of these interventions. METHODS: This study included patients who were admitted to a non-ICU setting with a primary or secondary diagnosis of bronchiolitis. The team used a multidisciplinary kickoff event to understand the problem and develop interventions, including sharing provider-specific data and asking providers to sign a pledge to reduce use. We used a novel, real-time data dashboard to collect and analyze data. RESULTS: Special cause variation on control charts indicated improvement for all outcomes for inpatients during the intervention season. Pre- and postanalyses in which we compared baseline to intervention values for all admitted patients and patients who were discharged from the emergency department or urgent care revealed a significant reduction in the ordering of chest radiographs (from 22.7% to 13.6%; P ≤ .001), respiratory viral testing (from 12.5% to 9.8%; P = .001), and bronchodilators (from 17.5% to 10.3%; P = .001) without changes in balancing measures (eg, hospital readmission within 7 days [1.7% (preanalysis) and 1.0% (postanalysis); P = .21]) for bronchiolitis. CONCLUSIONS: This multidisciplinary improvement initiative resulted in a significant reduction in use for bronchiolitis care at our institution. Our approach, which included a novel, real-time data dashboard and interventions such as individual providers pledging to reduce use, may have the potential to reduce overuse in other settings and diseases.

Innovative Use of the Electronic Health Record to Support Harm Reduction Efforts.

BACKGROUND AND OBJECTIVES: Awareness of the impact of preventable harm on patients and families has resulted in extensive efforts to make our health care systems safer. We determined that, in our hospital, patients experienced 1 of 9 types of preventable harm approximately every other day. In an effort to expedite early identification of patients at risk and provide timely intervention, we used the electronic health record's (EHR) documentation to enable decision support, data capture, and auditing and implemented reporting tools to reduce rates of harm. METHODS: Harm reduction strategies included aggregating data to generate a risk profile for hospital-acquired conditions (HACs) for all inpatients. The profile includes links to prevention bundles and available care guidelines. Additionally, lists of patients at risk for HACs autopopulate electronic audit tools contained within Research Electronic Data Capture, and data from observational audits and EHR documentation populate real-time dashboards of bundle compliance. Patient population summary reports promote the discussion of relevant HAC prevention measures during patient care and unit leadership rounds. RESULTS: The hospital has sustained a >30% reduction in harm for 9 types of HAC since 2012. In 2014, the number of HACs with >80% bundle adherence doubled coincident with the progressive rollout of these EHR-based interventions. CONCLUSIONS: Existing EHR documentation and reporting tools may be effective adjuncts to harm reduction initiatives. Additional study should include an evaluation of scalability across organizations, ongoing bundle adherence, and individual tests of change to isolate interventions with the highest impact on our results.

Blueberry necrotic ring blotch virus in Southern Highbush Blueberry: Insights into In Planta and In-Field Movement.

Blueberry necrotic ring blotch virus (BNRBV) causes an emerging disease of southern highbush blueberry (SHB) in the southeastern United States. Disease incidence and severity vary considerably from year to year within the same planting. Experiments were conducted to determine how the virus spreads in the field. Leaf tissue from symptomatic field plants tested positive for BNRBV in 2011, whereas the same plants were asymptomatic in 2012 and tested negative for the virus. Symptomatic and asymptomatic leaves from individual shoots were tested for the presence of the virus, and symptomatic leaves tested positive (100%), whereas 65.4% of the asymptomatic leaves from the same shoots tested negative. Leaves were selected in which half the leaf blade was symptomatic and the other half was not; symptomatic leaf halves tested positive (100%), whereas 76.0% of the asymptomatic halves from the same leaf tested negative for the virus. When virus-free, potted trap plants were interspersed in the field among established plants that had shown disease symptoms the previous year, disease onset in trap plants was observed 2 to 3 weeks after disease onset in field plants. In a separate experiment, asymptomatic softwood cuttings were collected from mother plants symptomatic for BNRBV, rooted, and monitored for symptom development for a period of 12 to 27 months. No BNRBV symptoms were observed in the progeny, whereas disease incidence was high for cuttings taken at the same time from plants infected with Blueberry red ringspot virus used as a control. Collectively, these studies suggest that BNRBV does not infect SHB plants systemically and is not transmitted through vegetative propagation, and that the virus likely does not persist in plants after natural defoliation in the fall.