Passive fetal monitoring sensor

An ambulatory, passive sensor for use in a fetal monitoring system is discussed. The invention is comprised of a piezoelectric polymer film, combined with a metallic mounting plate fastened to a belt, and electrically connected to a signal processing unit by means of a shielded cable. The purpose of the sensor is to receive pressure pulses emitted by a fetus inside an expectant mother. Additionally, the monitor will filter out pressure pulses arising from other sources, such as the maternal heart

Weekly platinum-based chemotherapy versus 3-weekly platinum-based chemotherapy for newly diagnosed ovarian cancer (ICON8): quality-of-life results of a phase 3, randomised, controlled trial

BACKGROUND: The ICON8 study reported no significant improvement in progression-free survival (a primary endpoint) with weekly chemotherapy compared with standard 3-weekly treatment among patients with epithelial ovarian cancer. All ICON8 patients were eligible to take part in the accompanying health-related quality-of-life study, which measured the effect of treatment on self-reported wellbeing, reported here. METHODS: In this open-label, randomised, controlled, phase 3, three-arm, Gynecologic Cancer Intergroup (GCIG) trial done at 117 hospital sites in the UK, Australia, New Zealand, Mexico, South Korea, and Republic of Ireland, women (aged at least 18 years) with newly diagnosed, histologically confirmed International Federation of Gynecology and Obstetrics stage IC-IV ovarian cancer and an Eastern Cooperative Oncology Group performance status of 0-2 were randomly assigned (1:1:1) centrally using minimisation to group 1 (intravenous carboplatin area under the curve [AUC]5 or AUC6 and 175 mg/m2 intravenous paclitaxel every 3 weeks), group 2 (carboplatin AUC5 or AUC6 every 3 weeks and 80 mg/m2 paclitaxel weekly), or group 3 (carboplatin AUC2 weekly and 80 mg/m2 paclitaxel weekly). Randomisation was stratified by GCIG group, disease stage, and outcome and timing of surgery. Patients and clinicians were not masked to treatment assignment. Patients underwent immediate or delayed primary surgery according to clinicians' choice. Patients were asked to complete European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-OV28 questionnaires at enrolment, before each chemotherapy cycle, then 6-weekly up to 9 months, 3-monthly up to 2 years, and 6-monthly up to 5 years. Quality of life was a prespecified secondary outcome of the ICON8 study. Within the quality-of-life study, the co-primary endpoints were QLQ-C30 global health score at 9 months (cross-sectional analysis) and mean QLQ-C30 global health score from randomisation to 9 months (longitudinal analysis). Data analyses were done on an intention-to-treat basis. The trial is registered on ClinicalTrials.gov, NCT01654146 and ISRCTN Registry, ISRCTN10356387, and is currently in long-term follow up. FINDINGS: Between June 6, 2011, and Nov 28, 2014, 1566 patients were recruited into ICON8 (522 were included in group 1, 523 in group 2, and 521 in group 3). Baseline quality-of-life questionnaires were completed by 1438 (92%) of 1566 patients and 9-month questionnaires by 882 (69%) of 1280 patients. We observed no significant difference in global health score at 9 months (cross-sectional analysis) between study groups (group 2 vs group 1, difference in mean score 2·3, 95% CI -0·4 to 4·9, p=0·095; group 3 vs group 1, -0·8, -3·8 to 2·2, p=0·61). Using longitudinal analysis, we found lower global health scores for those receiving weekly paclitaxel than for those receiving 3-weekly chemotherapy (group 2 vs group 1, mean difference -1·8, 95% CI -3·6 to -0·1, p=0·043; group 3 vs group 1, -2·9, -4·7 to -1·1, p=0·0018). INTERPRETATION: We found no evidence of a difference in global quality of life between treatment groups at 9 months; however, patients receiving weekly treatment reported lower mean quality of life across the 9-month period after randomisation. Taken together with the lack of progression-free survival benefit, these findings do not support routine use of weekly paclitaxel-containing regimens in the management of newly diagnosed ovarian cancer. FUNDING: Cancer Research UK, Medical Research Council, Health Research Board Ireland, Irish Cancer Society, and Cancer Australia

Weekly platinum-based chemotherapy versus 3-weekly platinum-based chemotherapy for newly diagnosed ovarian cancer (ICON8): quality-of-life results of a phase 3, randomised, controlled trial

Background: The ICON8 study reported no significant improvement in progression-free survival (a primary endpoint) with weekly chemotherapy compared with standard 3-weekly treatment among patients with epithelial ovarian cancer. All ICON8 patients were eligible to take part in the accompanying health-related quality-of-life study, which measured the effect of treatment on self-reported wellbeing, reported here. Methods: In this open-label, randomised, controlled, phase 3, three-arm, Gynecologic Cancer Intergroup (GCIG) trial done at 117 hospital sites in the UK, Australia, New Zealand, Mexico, South Korea, and Republic of Ireland, women (aged at least 18 years) with newly diagnosed, histologically confirmed International Federation of Gynecology and Obstetrics stage IC–IV ovarian cancer and an Eastern Cooperative Oncology Group performance status of 0–2 were randomly assigned (1:1:1) centrally using minimisation to group 1 (intravenous carboplatin area under the curve [AUC]5 or AUC6 and 175 mg/m2 intravenous paclitaxel every 3 weeks), group 2 (carboplatin AUC5 or AUC6 every 3 weeks and 80 mg/m2 paclitaxel weekly), or group 3 (carboplatin AUC2 weekly and 80 mg/m2 paclitaxel weekly). Randomisation was stratified by GCIG group, disease stage, and outcome and timing of surgery. Patients and clinicians were not masked to treatment assignment. Patients underwent immediate or delayed primary surgery according to clinicians' choice. Patients were asked to complete European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-OV28 questionnaires at enrolment, before each chemotherapy cycle, then 6-weekly up to 9 months, 3-monthly up to 2 years, and 6-monthly up to 5 years. Quality of life was a prespecified secondary outcome of the ICON8 study. Within the quality-of-life study, the co-primary endpoints were QLQ-C30 global health score at 9 months (cross-sectional analysis) and mean QLQ-C30 global health score from randomisation to 9 months (longitudinal analysis). Data analyses were done on an intention-to-treat basis. The trial is registered on ClinicalTrials.gov, NCT01654146 and ISRCTN Registry, ISRCTN10356387, and is currently in long-term follow up. Findings: Between June 6, 2011, and Nov 28, 2014, 1566 patients were recruited into ICON8 (522 were included in group 1, 523 in group 2, and 521 in group 3). Baseline quality-of-life questionnaires were completed by 1438 (92%) of 1566 patients and 9-month questionnaires by 882 (69%) of 1280 patients. We observed no significant difference in global health score at 9 months (cross-sectional analysis) between study groups (group 2 vs group 1, difference in mean score 2·3, 95% CI −0·4 to 4·9, p=0·095; group 3 vs group 1, −0·8, −3·8 to 2·2, p=0·61). Using longitudinal analysis, we found lower global health scores for those receiving weekly paclitaxel than for those receiving 3-weekly chemotherapy (group 2 vs group 1, mean difference −1·8, 95% CI −3·6 to −0·1, p=0·043; group 3 vs group 1, −2·9, −4·7 to −1·1, p=0·0018). Interpretation: We found no evidence of a difference in global quality of life between treatment groups at 9 months; however, patients receiving weekly treatment reported lower mean quality of life across the 9-month period after randomisation. Taken together with the lack of progression-free survival benefit, these findings do not support routine use of weekly paclitaxel-containing regimens in the management of newly diagnosed ovarian cancer. Funding: Cancer Research UK, Medical Research Council, Health Research Board Ireland, Irish Cancer Society, and Cancer Australia

Differences in genotype and virulence among four multidrug-resistant <i>Streptococcus pneumoniae</i> isolates belonging to the PMEN1 clone

We report on the comparative genomics and characterization of the virulence phenotypes of four &lt;i&gt;S. pneumoniae&lt;/i&gt; strains that belong to the multidrug resistant clone PMEN1 (Spain&lt;sup&gt;23F&lt;/sup&gt; ST81). Strains SV35-T23 and SV36-T3 were recovered in 1996 from the nasopharynx of patients at an AIDS hospice in New York. Strain SV36-T3 expressed capsule type 3 which is unusual for this clone and represents the product of an in vivo capsular switch event. A third PMEN1 isolate - PN4595-T23 - was recovered in 1996 from the nasopharynx of a child attending day care in Portugal, and a fourth strain - ATCC700669 - was originally isolated from a patient with pneumococcal disease in Spain in 1984. We compared the genomes among four PMEN1 strains and 47 previously sequenced pneumococcal isolates for gene possession differences and allelic variations within core genes. In contrast to the 47 strains - representing a variety of clonal types - the four PMEN1 strains grouped closely together, demonstrating high genomic conservation within this lineage relative to the rest of the species. In the four PMEN1 strains allelic and gene possession differences were clustered into 18 genomic regions including the capsule, the blp bacteriocins, erythromycin resistance, the MM1-2008 prophage and multiple cell wall anchored proteins. In spite of their genomic similarity, the high resolution chinchilla model was able to detect variations in virulence properties of the PMEN1 strains highlighting how small genic or allelic variation can lead to significant changes in pathogenicity and making this set of strains ideal for the identification of novel virulence determinant

Reynolds Number Effects at High Angles of Attack

Lessons learned from comparisons between ground-based tests and flight measurements for the high-angle-of-attack programs on the F-18 High Alpha Research Vehicle (HARV), the X-29 forward-swept wing aircraft, and the X-31 enhanced fighter maneuverability aircraft are presented. On all three vehicles, Reynolds number effects were evident on the forebodies at high angles of attack. The correlation between flight and wind tunnel forebody pressure distributions for the F-18 HARV were improved by using twin longitudinal grit strips on the forebody of the wind-tunnel model. Pressure distributions obtained on the X-29 wind-tunnel model at flight Reynolds numbers showed excellent correlation with the flight data up to alpha = 50 deg. Above (alpha = 50 deg. the pressure distributions for both flight and wind tunnel became asymmetric and showed poorer agreement, possibly because of the different surface finish of the model and aircraft. The detrimental effect of a very sharp nose apex was demonstrated on the X-31 aircraft. Grit strips on the forebody of the X-31 reduced the randomness but increased the magnitude of the asymmetry. Nose strakes were required to reduce the forebody yawing moment asymmetries and the grit strips on the flight test noseboom improved the aircraft handling qualities

Genotypic Diversity Is Associated with Clinical Outcome and Phenotype in Cryptococcal Meningitis across Southern Africa.

Cryptococcal meningitis is a major cause of mortality throughout the developing world, yet little is known about the genetic markers underlying Cryptococcal virulence and patient outcome. We studied a cohort of 230 Cryptococcus neoformans (Cn) isolates from HIV-positive South African clinical trial patients with detailed clinical follow-up using multi-locus sequence typing and in vitro phenotypic virulence assays, correlating these data with clinical and fungal markers of disease in the patient. South African Cn displayed high levels of genetic diversity and locus variability compared to globally distributed types, and we identified 50 sequence types grouped within the main molecular types VNI, VNII and VNB, with 72% of isolates typed into one of seven 'high frequency' sequence types. Spatial analysis of patients' cryptococcal genotype was not shown to be clustered geographically, which might argue against recent local acquisition and in favour of reactivation of latent infection. Through comparison of MLST genotyping data with clinical parameters, we found a relationship between genetic lineage and clinical outcome, with patients infected with the VNB lineage having significantly worse survival (n=8, HR 3.35, CI 1.51-7.20, p=0.003), and this was maintained even after adjustment for known prognostic indicators and treatment regimen. Comparison of fungal genotype with in vitro phenotype (phagocytosis, laccase activity and CSF survival) performed on a subset of 89 isolates revealed evidence of lineage-associated virulence phenotype, with the VNII lineage displaying increased laccase activity (p=0.001) and ex vivo CSF survival (p=0.0001). These findings show that Cryptococcus neoformans is a phenotypically heterogeneous pathogen, and that lineage plays an important role in cryptococcal virulence during human infection. Furthermore, a detailed understanding of the genetic diversity in Southern Africa will support further investigation into how genetic diversity is structured across African environments, allowing assessment of the risks different ecotypes pose to infection

Comparative analysis and supragenome modeling of twelve Moraxella catarrhalis clinical isolates

Contains fulltext : 97744.pdf (publisher's version ) (Open Access)BACKGROUND: M. catarrhalis is a gram-negative, gamma-proteobacterium and an opportunistic human pathogen associated with otitis media (OM) and exacerbations of chronic obstructive pulmonary disease (COPD). With direct and indirect costs for treating these conditions annually exceeding $33 billion in the United States alone, and nearly ubiquitous resistance to beta-lactam antibiotics among M. catarrhalis clinical isolates, a greater understanding of this pathogen's genome and its variability among isolates is needed. RESULTS: The genomic sequences of ten geographically and phenotypically diverse clinical isolates of M. catarrhalis were determined and analyzed together with two publicly available genomes. These twelve genomes were subjected to detailed comparative and predictive analyses aimed at characterizing the supragenome and understanding the metabolic and pathogenic potential of this species. A total of 2383 gene clusters were identified, of which 1755 are core with the remaining 628 clusters unevenly distributed among the twelve isolates. These findings are consistent with the distributed genome hypothesis (DGH), which posits that the species genome possesses a far greater number of genes than any single isolate. Multiple and pair-wise whole genome alignments highlight limited chromosomal re-arrangement. CONCLUSIONS: M. catarrhalis gene content and chromosomal organization data, although supportive of the DGH, show modest overall genic diversity. These findings are in stark contrast with the reported heterogeneity of the species as a whole, as wells as to other bacterial pathogens mediating OM and COPD, providing important insight into M. catarrhalis pathogenesis that will aid in the development of novel therapeutic regimens

Multi-Locus Phylogeographic and Population Genetic Analysis of Anolis carolinensis: Historical Demography of a Genomic Model Species

The green anole (Anolis carolinensis) has been widely used as an animal model in physiology and neurobiology but has recently emerged as an important genomic model. The recent sequencing of its genome has shed new light on the evolution of vertebrate genomes and on the process that govern species diversification. Surprisingly, the patterns of genetic diversity within natural populations of this widespread and abundant North American lizard remain relatively unknown. In the present study, we use 10 novel nuclear DNA sequence loci (N = 62 to 152) and one mitochondrial locus (N = 226) to delimit green anole populations and infer their historical demography. We uncovered four evolutionarily distinct and geographically restricted lineages of green anoles using phylogenetics, Bayesian clustering, and genetic distance methods. Molecular dating indicates that these lineages last shared a common ancestor ∼2 million years ago. Summary statistics and analysis of the frequency distributions of DNA polymorphisms strongly suggest range-wide expansions in population size. Using Bayesian Skyline Plots, we inferred the timing of population size expansions, which differ across lineages, and found evidence for a relatively recent and rapid westward expansion of green anoles across the Gulf Coastal Plain during the mid-Pleistocene. One surprising result is that the distribution of genetic diversity is not consistent with a latitudinal shift caused by climatic oscillations as is observed for many co-distributed taxa. This suggests that the most recent Pleistocene glacial cycles had a limited impact on the geographic distribution of the green anole at the northern limits of its range

Evolutionary Patterning: A Novel Approach to the Identification of Potential Drug Target Sites in Plasmodium falciparum

Malaria continues to be the most lethal protozoan disease of humans. Drug development programs exhibit a high attrition rate and parasite resistance to chemotherapeutic drugs exacerbates the problem. Strategies that limit the development of resistance and minimize host side-effects are therefore of major importance. In this study, a novel approach, termed evolutionary patterning (EP), was used to identify suitable drug target sites that would minimize the emergence of parasite resistance. EP uses the ratio of non-synonymous to synonymous substitutions (ω) to assess the patterns of evolutionary change at individual codons in a gene and to identify codons under the most intense purifying selection (ω≤0.1). The extreme evolutionary pressure to maintain these residues implies that resistance mutations are highly unlikely to develop, which makes them attractive chemotherapeutic targets. Method validation included a demonstration that none of the residues providing pyrimethamine resistance in the Plasmodium falciparum dihydrofolate reductase enzyme were under extreme purifying selection. To illustrate the EP approach, the putative P. falciparum glycerol kinase (PfGK) was used as an example. The gene was cloned and the recombinant protein was active in vitro, verifying the database annotation. Parasite and human GK gene sequences were analyzed separately as part of protozoan and metazoan clades, respectively, and key differences in the evolutionary patterns of the two molecules were identified. Potential drug target sites containing residues under extreme evolutionary constraints were selected. Structural modeling was used to evaluate the functional importance and drug accessibility of these sites, which narrowed down the number of candidates. The strategy of evolutionary patterning and refinement with structural modeling addresses the problem of targeting sites to minimize the development of drug resistance. This represents a significant advance for drug discovery programs in malaria and other infectious diseases