IDENTIFICATION OF THE ORIGINS OF ELEVATED ATMOSPHERIC MERCURY EPISODES USING A LAGRANGIAN MODELLING SYSTEM

We report the application of a receptor-oriented transport model, the Stochastic Time-Inverted Lagrangian Transport (STILT) model, to the interpretation of hourly total gaseous mercury (TGM) concentrations at three monitoring sites in Southern Ontario during four episodes of high TGM. STILT is a Lagrangian modelling system (Lin, J.C. et al. 2003) that simulates the transport of ensembles of air parcels backward in time from an observation point to upstream locations where surface inputs of target species occurred. A complete inventory of anthropogenic and natural mercury sources were used to compute the emissions. The study was initiated by simulating the mercury concentrations in a North American domain using CMAQ-Hg, a regional Eulerian chemical transport model (CTM). The STILT model was applied to several short episodes (usually lasting for 1-4 days) in which the TGM measurements at four air quality measurement stations in Southern Ontario significantly exceeded the predictions of the CTM. The STILT analysis compared the origins of air parcels arriving during the elevated TGM episodes with those of air parcels arriving at proximal times when the measurements and the CTM predictions were both low. The results consist of the STILT–predicted hourly concentrations at the measurement site as well as the surface footprint where the mercury responsible for the episode was emitted. The temporal STILT prediction is in better agreement with the measured time series than that of CMAQ-Hg. We believe this is partly due to the superior ability of STILT to capture near-field influences and partly due to the spatial averaging inherent in Eulerian modelling. Also, the predicted footprint locations were reasonable, coinciding with known locations of large mercury sources during the high episodes and with cleaner areas otherwise

The [Ne III]/[Ne II] line ratio in NGC 253

We present results of the mapping of the nucleus of the starburst galaxy NGC 253 and its immediate surroundings using the Infrared Spectrograph on board the Spitzer Space Telescope. The map is centered on the nucleus of the galaxy and spans the inner 800 × 688 pc^2. We perform a brief investigation of the implications of these measurement on the properties of the star formation in this region using theories developed to explain the deficiency of massive stars in starbursts

Spitzer Infrared Spectrograph Observations of M, L, and T Dwarfs

We present the first mid-infrared spectra of brown dwarfs, together with observations of a low-mass star. Our targets are the M3.5 dwarf GJ 1001A, the L8 dwarf DENIS-P J0255-4700, and the T1/T6 binary system epsilon Indi Ba/Bb. As expected, the mid-infrared spectral morphology of these objects changes rapidly with spectral class due to the changes in atmospheric chemistry resulting from their differing effective temperatures and atmospheric structures. By taking advantage of the unprecedented sensitivity of the Infrared Spectrograph on the Spitzer Space Telescope we have detected the 7.8 micron methane and 10 micron ammonia bands for the first time in brown dwarf spectra.Comment: 4 pages, 2 figure

Predictors of Enucleation and Morcellation Time During Holmium Laser Enucleation of the Prostate.

Objective To examine predictors of enucleation and morcellation times within a large cohort of men undergoing holmium laser enucleation of the prostate (HoLEP) for benign prostatic hypertrophy. Materials and Methods Preoperative, perioperative, and postoperative clinical characteristics were available from men treated with HoLEP between 1998 and 2013 at Indiana University Health Methodist Hospital. Stepwise linear regression was performed to determine clinical variables which are associated with enucleation and morcellation times. Results We identified 960 patients who underwent HoLEP. Average (range) enucleation time was 65.7 (11-245) minutes and morcellation time was 19.7 (3-260) minutes. History of anticoagulation was associated with a small decrease in enucleation time (P = .013) whereas increasing HoLEP specimen weight was associated with increasing enucleation time (P <.001). History of intermittent catheterization, urinary tract infections (UTI), presence of dense prostatic tissue (colloquially referred to as “beach balls”), and increasing specimen weight were associated with increasing morcellation time (P <.05 each). Having HoLEP performed by a less experienced urologist was associated with longer enucleation and morcellation times. Conclusion Prostate volume is significantly associated with increased enucleation and morcellation times during HoLEP. Additionally, history of UTI and clean intermittent catheterization (CIC) is associated with modest increases in enucleation and morcellation times. Dense enucleated prostate tissue significantly impacts the ability to morcellate effectively. Increasing surgeon experience can significantly improve both enucleation and morcellation efficiency

Members of the KCTD family are major regulators of cAMP signaling

Cyclic adenosine monophosphate (cAMP) is a pivotal second messenger with an essential role in neuronal function. cAMP synthesis by adenylyl cyclases (AC) is controlled by G protein-coupled receptor (GPCR) signaling systems. However, the network of molecular players involved in the process is incompletely defined. Here, we used CRISPR/Cas9-based screening to identify that members of the potassium channel tetradimerization domain (KCTD) family are major regulators of cAMP signaling. Focusing on striatal neurons, we show that the dominant isoform KCTD5 exerts its effects through an unusual mechanism that modulates the influx of Zn2+ via the Zip14 transporter to exert unique allosteric effects on AC. We further show that KCTD5 controls the amplitude and sensitivity of stimulatory GPCR inputs to cAMP production by Gβγ-mediated AC regulation. Finally, we report that KCTD5 haploinsufficiency in mice leads to motor deficits that can be reversed by chelating Zn2+ Together, our findings uncover KCTD proteins as major regulators of neuronal cAMP signaling via diverse mechanisms

Linezolid pharmacokinetics in MDR-TB : a systematic review, meta-analysis and Monte Carlo simulation

This work was supported by the Wellcome Trust (grant numbers 109129/Z/15/Z to JM and 105620/Z/14/Z to DS and MC).Objectives The oxazolidinone linezolid is an effective component of drug - resistant TB treatment, but use is limited by toxicity and the optimum dose is uncertain . Current strategies are not informed by clinical pharmacokinetic/pharmacodynamic (PK/PD) data, we aimed to aimed to address this gap. Methods We defined linezolid PK/PD targets for efficacy; free area under the time - concentration curve: minimum inhibitory concentration ratio (ƒAUC0-24:M IC) >119m g/L/hr and safety; free minimum concentration (Cmin) <1.38mg/L . We extracted individual - level linezolid PK data from existing studies on TB patients and performed meta - analysis; producing summary estimates of ƒAUC0-24 and ƒCmin for published doses . Combining these with a published MIC distribution, we performed Monte Carlo simulations of target attainment. Results The efficacy target was attained in all simulated individuals at 300mg q12h and 600mg q12h , but only 20.7% missed the safety target at 300mg q12h versus 98.5% at 600mg q12h . Although suggesting 300mg q12h should be used preferentially, these data were reliant on a single centre . Efficacy and safety targets were missed by 41.0% and 24.2% respectively at 300mg q24h , and 44.5% and 27.5% at 600mg q24h . However, the confounding effect of between study heterogeneity on target attainment for q24h regimens was considerable. Conclusions 300mg q12h linezolid dosing may retain the efficacy of the 600mg q12h licensed dosing with improved safety. Data to evaluate commonly used 300mg q24h and 600mg q24h doses is limited. Comprehensive, prospectively obtained PK/PD data for linezolid doses in drug - resistant TB treatment are required.Publisher PDFPeer reviewe

Vitamin D deficiency in Malawian adults with pulmonary tuberculosis : risk factors and treatment outcomes

The study was supported by a Wellcome Trust (London, UK) Clinical PhD Fellowship awarded to DS (086757/Z/08/A) and the Malawi Liverpool Wellcome Trust (MLW) Core grant from the Wellcome Trust.SETTING: Vitamin D deficiency is common in African adults with tuberculosis (TB), and may be exacerbated by the metabolic effects of anti-tuberculosis drugs and antiretroviral therapy (ART). It is unclear whether vitamin D deficiency influences response to antituberculosis treatment. OBJECTIVES : To describe risk factors for baseline vitamin D deficiency in Malawian adults with pulmonary TB, assess the relationship between serum 25-hydroxy vitamin D (25[OH]D) concentration and treatment response, and evaluate whether the administration of anti-tuberculosis drugs and ART is deleterious to vitamin D status during treatment. DESIGN: A prospective longitudinal cohort study. RESULTS : The median baseline 25(OH)D concentration of the 169 patients (58% human immunodeficiency virus [HIV] infected) recruited was 57 nmol/l; 47 (28%) had vitamin D deficiency (<50 nmol/l). Baseline 25(OH)D concentrations were lower during the cold season (P < 0.001), with food insecurity (P = 0.034) or in patients who consumed alcohol (P = 0.019). No relationship between vitamin D status and anti-tuberculosis treatment response was found. 25(OH)D concentrations increased during anti-tuberculosis treatment, irrespective of HIV status or use of ART. CONCLUSIONS : Vitamin D deficiency is common among TB patients in Malawi, but this does not influence treatment response. Adverse metabolic effects of drug treatment may be compensated by the positive impact of clinical recovery preventing exacerbation of vitamin D deficiency during anti-tuberculosis treatment.Publisher PDFPeer reviewe

Kinetics of Mycobacterium tuberculosis-specific IFN-γ responses and sputum bacillary clearance in HIV-infected adults during treatment of pulmonary tuberculosis

This work was supported by funding from the Wellcome Trust (UK) through Fellowships 092773/Z/10/Z (to D.T.M), 086757/Z/08/Z (to D.J.S) and 088696/Z/09/Z (to H.C.M). Core funding from the Wellcome Trust supports the laboratory and office facilities at the Malawi-Liverpool-Wellcome Trust Clinical Research Programme.In HIV-uninfected adults with pulmonary tuberculosis (TB), anti-TB treatment is associated with changes in Mycobacterium tuberculosis (Mtb)-specific immune responses, which correlate with sputum bacillary load. It is unclear if this occurs in HIV-infected TB patients. We investigated changes in Mtb-specific immune responses and sputum bacillary clearance during anti-TB treatment in HIV-infected and HIV-uninfected adults with pulmonary TB. Sputum bacillary load was assessed by smear microscopy and culture. Mtb-specific IFN-γ secreting peripheral blood mononuclear cells were enumerated using an ELISPOT assay following stimulation with PPD, ESAT-6 and CFP-10. The baseline frequency of Mtb-specific IFN-γ secreting cells was lower in HIV-infected than HIV-uninfected patients (median PPD 32 vs. 104 Spot Forming Units (SFU), p = 0.05; CFP-10 19 vs. 74 SFU, p = 0.01). ESAT-6-specific IFN-γ secreting cells and sputum bacillary load declined progressively during treatment in both HIV-infected and HIV-uninfected patients. HIV infection did not influence the 2-month sputum culture conversion rate (Odds Ratio 0.89, p = 0.95). These findings suggest that changes in ESAT-6-specific immune responses during anti-TB treatment correspond with changes in sputum bacillary load irrespective of host HIV infection status. The utility of Mtb-specific IFN-γ responses as a proxy measure of treatment response in HIV-infected TB patients warrants further evaluation in other settings.Publisher PDFPeer reviewe

Combining Survival and Toxicity Effect Sizes from Clinical Trials: NCCTG 89-20-52 (Alliance)

Background: How can a clinician and patient incorporate survival and toxicity information into a single expression of comparative treatment benefit? Sloan et al. recently extended the ½ standard deviation concept for judging the clinical importance of findings from clinical trials to survival and tumor response endpoints. A new method using this approach to combine survival and toxicity effect sizes from clinical trials into a quality-adjusted effect size is presented.Methods: The quality-adjusted survival effect size (QASES) is calculated as survival effect size (ESS) minus the calibrated toxicity effect sizes (EST) (QASES=ESS-EST). This combined effect size can be weighted to adjust for the relative emphasis placed by the patient on survival and toxicity effects.Results: As an example, consider clinical trial NCCTG 89-20-52 which randomized patients to once-daily thoracic radiotherapy (ODTRT) versus twice-daily treatment of thoracic radiotherapy (TDRT) for the treatment of lung cancer. The ODTRT vs. TDRT arms had median survival time of 22 vs. 20 months (p=0.49) and toxicity rate of 39% vs. 54%, (p&lt;0.05). The QASES of 0.18 standard deviations translates to a quality-adjusted survival difference of 5.7 months advantage for the ODRT arm over the TDRT treatment arm (22(16.3) months), p&lt;0.05). Similar results are presented for the four possible case combinations of significant/non-significant survival and toxicity benefits using completed clinical trials.Conclusions: We used a novel approach to re-analyze clinical trial data to produce a single estimate for each treatment that combines survival and toxicity data. The QASES approach is an intuitive and mathematically simple yet robust approach