Phase II assessment of talabostat and cisplatin in second-line stage IV melanoma

<p>Abstract</p> <p>Background</p> <p>Metastatic melanoma is an incurable disease with an average survival of less than one year. Talabostat is a novel dipeptidyl peptidase inhibitor with immunostimulatory properties.</p> <p>Methods</p> <p>This phase II, open label, single arm study was conducted to evaluate the safety and efficacy of 75–100 mg/m²cisplatin combined with 300–400 mcg talabostat bid for 6, 21-day cycles. The primary endpoint was overall response. The rate of complete responses, duration of overall objective response, progression-free survival (PFS), and overall survival were the secondary endpoints.</p> <p>Results</p> <p>Six objective partial responses were recorded in the 74 patients (8.1%) in the intention-to-treat population. Five of these responses involved the 40 evaluable patients (12.5%). Thirty-one percent of patients reported SAEs to the combination of talabostat and cisplatin.</p> <p>Conclusion</p> <p>Acceptable tolerability was observed in the intention-to-treat population and antitumor activity was observed in 12.5% of evaluable patients, which is not greater than historical expectation with cisplatin alone.</p

Multilocus haplotypes reveal variable levels of diversity and population structure of Plasmodium falciparum in Papua New Guinea, a region of intense perennial transmission

<p>Abstract</p> <p>Background</p> <p>The South West Pacific nation of Papua New Guinea has intense year round transmission of <it>Plasmodium falciparum </it>on the coast and in the low-lying inland areas. Local heterogeneity in the epidemiology of malaria suggests that parasites from multiple locations will need to be surveyed to define the population biology of <it>P. falciparum </it>in the region. This study describes the population genetics of <it>P. falciparum </it>in thirteen villages spread over four distinct catchment areas of Papua New Guinea.</p> <p>Methods</p> <p>Ten microsatellite loci were genotyped in 318 <it>P. falciparum </it>isolates from the parasite populations of two inland catchment areas, namely Wosera (number of villages (n) = 7) and Utu (n = 1) and; and two coastal catchments, Malala (n = 3) and Mugil (n = 3). Analysis of the resultant multilocus haplotypes was done at different spatial scales (2-336 km) to define the genetic diversity (allelic richness and expected heterozygosity), linkage disequilibrium and population structure throughout the study area.</p> <p>Results</p> <p>Although genetic diversity was high in all parasite populations, it was also variable with a lower allelic richness and expected heterozygosity for inland populations compared to those from the more accessible coast. This variability was not correlated with two proxy measures of transmission intensity, the infection prevalence and the proportion multiple infections. Random associations among the microsatellite loci were observed in all four catchments showing that a substantial degree of out-crossing occurs in the region. Moderate to very high levels of population structure were found but the amount of genetic differentiation (<it>F_ST</it>) did not correlate with geographic distance suggesting that parasite populations are fragmented. Population structure was also identified between villages within the Malala area, with the haplotypes of one parasite population clustering with the neighbouring catchment of Mugil.</p> <p>Conclusion</p> <p>The observed population genetics of <it>P. falciparum </it>in this region is likely to be a consequence of the high transmission intensity combined with the isolation of human and vector populations, especially those located inland and migration of parasites via human movement into coastal populations. The variable genetic diversity and population structure of <it>P. falciparum </it>has important implications for malaria control strategies and warrants further fine scale sampling throughout Papua New Guinea.</p

The GALEX Ultraviolet Atlas of Nearby Galaxies

We present images, integrated photometry, and surface-brightness and color profiles for a total of 1034 nearby galaxies recently observed by the Galaxy Evolution Explorer (GALEX) satellite in its far-ultraviolet (FUV; λ_(eff) = 1516 Å) and near-ultraviolet (NUV; λ_(eff) = 2267 Å) bands. Our catalog of objects is derived primarily from the GALEX Nearby Galaxies Survey (NGS) supplemented by galaxies larger than 1' in diameter serendipitously found in these fields and in other GALEX exposures of similar of greater depth. The sample analyzed here adequately describes the distribution and full range of properties (luminosity, color, star formation rate [SFR]) of galaxies in the local universe. From the surface brightness profiles obtained we have computed asymptotic magnitudes, colors, and luminosities, along with the concentration indices C31 and C42. We have also morphologically classified the UV surface brightness profiles according to their shape. This data set has been complemented with archival optical, near-infrared, and far-infrared fluxes and colors. We find that the integrated (FUV − K) color provides robust discrimination between elliptical and spiral/irregular galaxies and also among spiral galaxies of different subtypes. Elliptical galaxies with brighter K-band luminosities (i.e., more massive) are redder in (NUV − K) color but bluer in (FUV − NUV) (a color sensitive to the presence of a strong UV upturn) than less massive ellipticals. In the case of the spiral/irregular galaxies our analysis shows the presence of a relatively tight correlation between the (FUV − NUV) color (or, equivalently, the slope of the UV spectrum, β) and the total infrared-to-UV ratio. The correlation found between (FUV − NUV) color and K-band luminosity (with lower luminosity objects being bluer than more luminous ones) can be explained as due to an increase in the dust content with galaxy luminosity. The images in this Atlas along with the profiles and integrated properties are publicly available through a dedicated Web page

A treatment evaluator tool to monitor the real-world effectiveness of inhaled aztreonam lysine in cystic fibrosis

Background: Studies are required that evaluate real-world outcomes of inhaled aztreonam lysine in patients with cystic fibrosis (CF). Methods: Our treatment-evaluator tool assessed the effectiveness of inhaled aztreonam in routine practice in 117 CF patients across four time periods (6–12 (P2) and 0–6 months (P1) pre-initiation, and 0–6 (T1) and 6–12 months (T2) post-initiation). Outcomes were: changes in %-predicted forced expiratory volume in 1 s (FEV1), body-mass index (BMI), hospitalisation days and intravenous antibiotic usage. Results: Median FEV1% predicted for each 6-month period was 38.9%, 34.6%, 37.1% and 36.5%; median change was − 2.0% between P2 and P1, increasing to + 0.6% (p &lt; 0.001) between P1 and T1. Annualised hospital bed-days was reduced (p = 0.05) post-initiation, as was intravenous antibiotics days (p = 0.001). BMI increased over 6 months post-initiation (p ≤ 0.001). Conclusions: In patients with CF in routine practice, inhaled aztreonam lysine is associated with improved lung function and weight, and reduced hospitalisation and intravenous antibiotic use

Kinetic changes during a six-week minimal footwear and gait-retraining intervention in runners.

An evaluation of a six-week Combined minimal footwear transition and gait-retraining combination vs. gait retraining only on impact characteristics and leg stiffness. Twenty-four trained male runners were randomly assigned to either (1) Minimalist footwear transition Combined with gait-retraining over a six-week period ("Combined" group; n = 12) examined in both footwear, or (2) a gait-retraining group only with no minimalist footwear exposure ("Control"; n = 12). Participants were assessed for loading rate, impact peak, vertical, knee and ankle stiffness, and foot-strike using 3D and kinetic analysis. Loading rate was significantly higher in the Combined group in minimal shoes in pre-tests compared to a Control (P ≤ 0.001), reduced significantly in the Combined group over time (P ≤ 0.001), and was not different to the Control group in post-tests (P = 0.16). The impact peak (P = 0.056) and ankle stiffness reduced in both groups (P = 0.006). Loading rate and vertical stiffness was higher in minimalist footwear than conventional running shoes both pre (P ≤ 0.001) and post (P = 0.046) the intervention. There has a higher tendency to non-rearfoot strike in both interventions, but more acute changes in the minimalist footwear. A Combined intervention can potentially reduce impact variables. However, higher loading rate initially in minimalist footwear may increase the risk of injury in this condition

A Simplified Score to Quantify Comorbidity in COPD

Importance Comorbidities are common in COPD, but quantifying their burden is difficult. Currently there is a COPD-specific comorbidity index to predict mortality and another to predict general quality of life. We sought to develop and validate a COPD-specific comorbidity score that reflects comorbidity burden on patient-centered outcomes. Materials and Methods Using the COPDGene study (GOLD II-IV COPD), we developed comorbidity scores to describe patient-centered outcomes employing three techniques: 1) simple count, 2) weighted score, and 3) weighted score based upon statistical selection procedure. We tested associations, area under the Curve (AUC) and calibration statistics to validate scores internally with outcomes of respiratory disease-specific quality of life (St. George's Respiratory Questionnaire, SGRQ), six minute walk distance (6MWD), modified Medical Research Council (mMRC) dyspnea score and exacerbation risk, ultimately choosing one score for external validation in SPIROMICS. Results Associations between comorbidities and all outcomes were comparable across the three scores. All scores added predictive ability to models including age, gender, race, current smoking status, pack-years smoked and FEV1 (p<0.001 for all comparisons). Area under the curve (AUC) was similar between all three scores across outcomes: SGRQ (range 0·7624–0·7676), MMRC (0·7590–0·7644), 6MWD (0·7531–0·7560) and exacerbation risk (0·6831–0·6919). Because of similar performance, the comorbidity count was used for external validation. In the SPIROMICS cohort, the comorbidity count performed well to predict SGRQ (AUC 0·7891), MMRC (AUC 0·7611), 6MWD (AUC 0·7086), and exacerbation risk (AUC 0·7341). Conclusions Quantifying comorbidity provides a more thorough understanding of the risk for patient-centered outcomes in COPD. A comorbidity count performs well to quantify comorbidity in a diverse population with COPD

The GALEX Ultraviolet Atlas of Nearby Galaxies

We present images, integrated photometry, surface-brightness and color profiles for a total of 1034 nearby galaxies recently observed by the GALEX satellite in its far-ultraviolet (FUV; 1516A) and near-ultraviolet (NUV; 2267A) bands. (...) This data set has been complemented with archival optical, near-infrared, and far-infrared fluxes and colors. We find that the integrated (FUV-K) color provides robust discrimination between elliptical and spiral/irregular galaxies and also among spiral galaxies of different sub-types. Elliptical galaxies with brighter K-band luminosities (i.e. more massive) are redder in (NUV-K) color but bluer in (FUV-NUV) than less massive ellipticals. In the case of the spiral/irregular galaxies our analysis shows the presence of a relatively tight correlation between the (FUV-NUV) color and the total infrared-to-UV ratio. The correlation found between (FUV-NUV) color and K-band luminosity (with lower luminosity objects being bluer than more luminous ones) can be explained as due to an increase in the dust content with galaxy luminosity. The images in this Atlas along with the profiles and integrated properties are publicly available through a dedicated web page at http://nedwww.ipac.caltech.edu/level5/GALEX_Atlas/Comment: 181 pages, 10 figures, accepted for publication in ApJS (abstract abridged

Interobserver reliability and diagnostic performance of Chiari II malformation measures in MR imaging—part 2

PURPOSE: Brain MR imaging is essential in the assessment of Chiari II malformation in clinical and research settings concerning spina bifida. However, the interpretation of MR images of the malformation is not always straightforward. Morphometric analyses of the extent of Chiari II malformation may improve the assessment. In an attempt to select appropriate morphometric measures for this purpose, we investigated the interobserver reliability and diagnostic performance of several morphometric measures of Chiari II malformation on MR images. METHODS: Brain MR images of 79 children [26 with open spinal dysraphism, 17 with closed spinal dysraphism, and 36 without spinal dysraphism; mean age 10.6 (SD 3.2; range, 6-16) years] were evaluated. All children had been assessed for Chiari II malformation (defined as cerebellar herniation in combination with open spinal dysraphism; n = 23). Three observers blindly and independently reviewed the MR images for 21 measures of the cerebellum, brainstem, and posterior fossa in three planes. The interobserver reliability was assessed by an agreement index (AI = 1 - RRE) and the diagnostic performance by receiver operating characteristic analyses. RESULTS: Reliability was good for most measures, except for the degree of herniation of the vermis and tonsil. Most values differed statistically significantly between children with and without Chiari II malformation. The measures mamillopontine distance and cerebellar width showed excellent diagnostic performance. CONCLUSIONS: Morphometric measures may reliably quantify the morphological distortions of Chiari II malformation on MR images and provide additional tools to assess the severity of Chiari II malformation in clinical and research settings

Non-emphysematous chronic obstructive pulmonary disease is associated with diabetes mellitus

Abstract Background Chronic obstructive pulmonary disease (COPD) has been classically divided into blue bloaters and pink puffers. The utility of these clinical subtypes is unclear. However, the broader distinction between airway-predominant and emphysema-predominant COPD may be clinically relevant. The objective was to define clinical features of emphysema-predominant and non-emphysematous COPD patients. Methods Current and former smokers from the Genetic Epidemiology of COPD Study (COPDGene) had chest computed tomography (CT) scans with quantitative image analysis. Emphysema-predominant COPD was defined by low attenuation area at -950 Hounsfield Units (LAA-950) ≥10%. Non-emphysematous COPD was defined by airflow obstruction with minimal to no emphysema (LAA-950 < 5%). Results Out of 4197 COPD subjects, 1687 were classified as emphysema-predominant and 1817 as non-emphysematous; 693 had LAA-950 between 5–10% and were not categorized. Subjects with emphysema-predominant COPD were older (65.6 vs 60.6 years, p < 0.0001) with more severe COPD based on airflow obstruction (FEV1 44.5 vs 68.4%, p < 0.0001), greater exercise limitation (6-minute walk distance 1138 vs 1331 ft, p < 0.0001) and reduced quality of life (St. George’s Respiratory Questionnaire score 43 vs 31, p < 0.0001). Self-reported diabetes was more frequent in non-emphysematous COPD (OR 2.13, p < 0.001), which was also confirmed using a strict definition of diabetes based on medication use. The association between diabetes and non-emphysematous COPD was replicated in the ECLIPSE study. Conclusions Non-emphysematous COPD, defined by airflow obstruction with a paucity of emphysema on chest CT scan, is associated with an increased risk of diabetes. COPD patients without emphysema may warrant closer monitoring for diabetes, hypertension, and hyperlipidemia and vice versa. Trial registration Clinicaltrials.gov identifiers: COPDGene NCT00608764 , ECLIPSE NCT00292552 .http://deepblue.lib.umich.edu/bitstream/2027.42/109496/1/12890_2014_Article_599.pd