Search

Background Gastroenteropancreatic neuroendocrine tumours (GEP-NETs) are slow-growing cancers that arise from diffuse endocrine cells in the gastrointestinal tract (GI-NETs) or the pancreas (P-NETs). They are relatively uncommon, accounting for 2% of all gastrointestinal malignancies. The usual treatment options in advanced GEP-NET patients with metastatic disease include chemotherapy, biological therapies, and peptide receptor radionuclide therapy. Understanding the impact of treatment on GEP-NET patients is paramount given the nature of the disease. Health-related quality of life (HRQoL) is increasingly important as a concept reflecting the patients' perspective in conjunction with the disease presentation, severity and treatment. Aim To conduct a systematic literature review to identify literature reporting HRQoL data in patients with GEP-NETs between January 1985 and November 2019. Methods The PRISMA guiding principles were applied. MEDLINE, Embase and the Cochrane library were searched. Data extracted from the publications included type of study, patient population data (mid-gut/hind-gut/GI-NET/P-NET), sample size, intervention/comparators, HRQoL instruments, average and data spread of overall and sub-scores, and follow-up time for data collection. Results Forty-three publications met the inclusion criteria. The heterogeneous nature of the different study populations was evident; the percentage of female participants ranged between 30%-60%, whilst average age ranged from 53.8 to 67.0 years. Eight studies investigated GI-NET patients only, six studies focused exclusively on P-NET patients and the remaining studies involved both patient populations or did not report the location of the primary tumour. The most commonly used instrument was the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (n = 28) with consistent results across studies; the GI-NET-specific module Quality of Life Questionnaire-GINET21 was used in six of these studies. A number of randomised trials demonstrated no HRQoL changes between active treatment and placebo arms. The Phase III NETTER-1 study provides the best data available for advanced GEP-NET patients; it shows that peptide receptor radionuclide therapy can significantly improve GEP-NET patients' HRQoL. Conclusion HRQoL instruments offer a means to monitor patients' general disease condition, disease progression and their physical and mental well-being. Instruments including the commonly used European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 and GINET21 lack, however, validation and a defined minimal clinical important difference specifically for GI-NET and P-NET patients.

Te reo Māori (referred to as Māori), New Zealand's indigenous language, is under-resourced in language technology. Māori speakers are bilingual, where Māori is code-switched with English. Unfortunately, there are minimal resources available for Māori language technology, language detection and code-switch detection between Māori-English pair. Both English and Māori use Roman-derived orthography making rule-based systems for detecting language and code-switching restrictive. Most Māori language detection is done manually by language experts. This research builds a Māori-English bilingual database of 66,016,807 words with word-level language annotation. The New Zealand Parliament Hansard debates reports were used to build the database. The language labels are assigned using language-specific rules and expert manual annotations. Words with the same spelling, but different meanings, exist for Māori and English. These words could not be categorised as Māori or English based on word-level language rules. Hence, manual annotations were necessary. An analysis reporting the various aspects of the database such as metadata, year-wise analysis, frequently occurring words, sentence length and N-grams is also reported. The database developed here is a valuable tool for future language and speech technology development for Aotearoa New Zealand. The methodology followed to label the database can also be followed by other low-resourced language pairs., Submitted to Springer Language Resources and Evaluation Journal 2022

With the rise of robotics and artificial intelligence, good communication between humans and machines becomes more important. However, users with language and hearing disadvantages may find synthetic speech systems to be difficult to understand. In this study, we explore the types of sentence structure and level of word complexity that affect intelligibility of speech in unfamiliar context. Using semantically unpredictable sentences, we found that sentence with more complex syntax such as relative pronouns and question words are harder to comprehend, while on the word level, it is the shorter and simpler words that contribute to misunderstandings. We found that although word frequency affects how well a word is recognised, the effect from the occurring frequency is much less than the effect of how phonetically distinctive the word is. There was also evidence of significant difference between native speakers and non-native speakers on how well they could understand the sentences. These results may help us in designing better dialogue system for machine to human interactions, especially in the healthcare arena, where often users have disadvantages in language and hearing abilities.

Measures of vegetation structure are often key within ecological restoration monitoring programs because a change in structure is rapidly identifiable, measurements are straightforward, and structure is often a good surrogate for species composition. This paper investigates the use of drone-based digital aerial photogrammetry (DAP) for the characterization of the structure of regenerating vegetation as well as the ability to inform restoration programs through spatial arrangement assessment. We used cluster analysis on five DAP-derived metrics to classify vegetation structure into seven classes across three sites of ongoing restoration since linear disturbances in 2005, 2009, and 2014 in temperate and boreal coniferous forests in Alberta, Canada. The spatial arrangement of structure classes was assessed using land cover maps, mean patch size, and measures of local spatial association. We observed DAP heights of short-stature vegetation were consistently underestimated, but strong correlations (rs > 0.75) with field height were found for juvenile trees, shrubs, and perennials. Metrics of height and canopy complexity allowed for the extraction of relatively tall and complex vegetation structures, whereas canopy cover and height variability metrics enabled the classification of the shortest vegetation structures. We found that the boreal site disturbed in 2009 had the highest cover of classes associated with complex vegetation structures. This included early regenerative (22%) and taller (13.2%) wood-like structures as well as structures representative of tall graminoid and perennial vegetation (15.3%), which also showed the highest patchiness. The developed tools provide large-scale maps of the structure, enabling the identification and assessment of vegetational patterns, which is challenging based on traditional field sampling that requires pre-defined location-based hypotheses. The approach can serve as a basis for the evaluation of specialized restoration objectives as well as objectives tailored towards processes of ecological succession, and support prioritization of future inspections and mitigation measures.

Tongue motility is an essential physiological component of human feeding from infancy through adulthood. At present, it is a challenge to distinguish among the many pathologies of swallowing due to the absence of quantitative tools. We objectively quantified tongue kinematics from ultrasound imaging during infant and adult feeding. The functional advantage of this method is presented in several subjects with swallowing difficulties. We demonstrated for the first time the differences in tongue kinematics during breast‐ and bottle‐feeding, showing the arrhythmic sucking pattern during bottle‐feeding as compared with breastfeeding in the same infant with torticollis. The method clearly displayed the improvement of tongue motility after frenotomy in infants with either tongue‐tie or restrictive labial frenulum. The analysis also revealed the absence of posterior tongue peristalsis required for safe swallowing in an infant with dysphagia. We also analyzed for the first time the tongue kinematics in an adult during water bolus swallowing demonstrating tongue peristaltic‐like movements in both anterior and posterior segments. First, the anterior segment undulates to close off the oral cavity and the posterior segment held the bolus, and then, the posterior tongue propelled the bolus to the pharynx. The present methodology of quantitative imaging revealed highly conserved patterns of tongue kinematics that can differentiate between swallowing pathologies and evaluate treatment interventions. The method is novel and objective and has the potential to advance knowledge about the normal swallowing and management of feeding disorders., Tongue kinematics was objectively quantified from ultrasound imaging during feeding. Tongue and palate contours were traced in each frame of the video; tongue outlines were registered with respect to the hard anterior palate; and tongue motility characteristics were determined from intersections with polar coordinates in subsequent frames. Differences in tongue kinematics during breast‐ and bottle‐feeding are demonstrate in the same infant. The method detected improvement of tongue motility after frenotomy interventions and revealed absence of posterior tongue peristalsis in infant with dysphagia. It demonstrated tongue peristaltic‐like movements in both anterior and posterior segments in an adult during water bolus swallowing.

© The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2020. Endowing robots with the role of social assistance in silver care could be a powerful tool to combat chronic loneliness in ageing adults. These robots can be tasked with functional and affective care to support quotidian living and grant companionship that helps lessen the burden of cognitive decline and impairment emerging from social isolation. To accomplish such imperative tasks, artificial agents must be adept at communicating naturally with the human elder. In this work, we aim to enable human–robot interaction by designing human-like verbal and nonverbal behaviours of an autonomous robot companion. We employed the robot on a trial run using customisable algorithms to address a range of needs, while thriving social and emotional attachment with the potential senior user, with the final intent being that such endeavours can help achieve quality ageing in place.

Background Diphtheria is a potentially fatal respiratory disease caused by toxigenic Corynebacterium diphtheriae. Although resistance to erythromycin has been recognized, β-lactam resistance in toxigenic diphtheria has not been described. Here, we report a case of fatal respiratory diphtheria caused by toxigenic C. diphtheriae resistant to penicillin and all other β-lactam antibiotics, and describe a novel mechanism of inducible carbapenem resistance associated with the acquisition of a mobile resistance element. Methods Long-read whole-genome sequencing was performed using Pacific Biosciences Single Molecule Real-Time sequencing to determine the genome sequence of C. diphtheriae BQ11 and the mechanism of β-lactam resistance. To investigate the phenotypic inducibility of meropenem resistance, short-read sequencing was performed using an Illumina NextSeq500 sequencer on the strain both with and without exposure to meropenem. Results BQ11 demonstrated high-level resistance to penicillin (benzylpenicillin minimum inhibitory concentration [MIC] ≥ 256 μg/ml), β-lactam/β-lactamase inhibitors and cephalosporins (amoxicillin/clavulanic acid MIC ≥ 256 μg/mL; ceftriaxone MIC ≥ 8 μg/L). Genomic analysis of BQ11 identified acquisition of a novel transposon carrying the penicillin-binding protein (PBP) Pbp2c, responsible for resistance to penicillin and cephalosporins. When strain BQ11 was exposed to meropenem, selective pressure drove amplification of the transposon in a tandem array and led to a corresponding change from a low-level to a high-level meropenem-resistant phenotype. Conclusions We have identified a novel mechanism of inducible antibiotic resistance whereby isolates that appear to be carbapenem susceptible on initial testing can develop in vivo resistance to carbapenems with repeated exposure. This phenomenon could have significant implications for the treatment of C. diphtheriae infection, and may lead to clinical failure.

There is increasing concern for the risk of hypernatremic dehydration in infants breastfeeding poorly. It is important to differentiate normal weight changes as infants adapt to extrauterine life from excessive weight loss from breastfeeding failure or mismanagement. We review recent data on normal weight changes in exclusively breastfeeding infants and those at risk for hypernatremic dehydration to help health professionals determine when infants require further scrutiny and supplementation. The data suggest that perinatal practices influence infant weight changes. Protecting normal birth and early initiation of breastfeeding should reduce the incidence of excessive weight loss and risk of hypernatremic dehydration

BackgroundOXA-48-like carbapenemases have become increasingly prevalent in healthcare settings worldwide. Their low-level activity against carbapenems makes them difficult to identify, causing problems for infection control. Here we present an outbreak of Escherichia coli producing OXA-181 (part of the OXA-48 family of carbapenemases) in a Queensland Hospital, and describe how we used whole genome sequencing (WGS) to identify the outbreak strain, determine the extent of transmission within the hospital and support infection control responses.Methods116 isolates were collected and sequenced on an Illumina NextSeq to determine species, sequence type (ST) and presence of resistance genes. Core single nucleotide polymorphisms were used to determine strain relatedness. Three isolates were also sequenced on an Oxford Nanopore MinION to determine the context of the resistance genes.ResultsOf 116 isolates, 85 (84 E. coli and one K. pneumoniae) from 78 patients (and two environmental sources) were related to the ongoing outbreak. The outbreak E. coli strain was found to be ST38 and carried blaOXA-181, blaCTX-M-15 and qnrS1 genes. Long read sequencing revealed blaOXA-181 to be carried on an IncX3 plasmid with qnrS1. blaCTX-M-15 was chromosomally integrated (via ISEcp1 insertion) in close proximity to a second qnrS1 gene. A search of the laboratory database identified an isolate with an identical unusual antibiogram from a patient recently admitted to a hospital in Vietnam, suggesting that the strain was introduced to the hospital. This conclusion was supported by WGS, as comparison of the strain to public data identified a close match to an E. coli recovered from Vietnam in 2011.ConclusionA blaOXA-181-carrying E. coli ST38 strain was introduced to a Brisbane hospital and spread undetected throughout multiple wards over several months. Using WGS, we characterized the outbreak strain and unambiguously detected its presence throughout the hospital. We show how both WGS and infection control measures can be utilized to effectively terminate widespread transmission of an elusory pathogen.

Objectives: To evaluate the outbreak size and hospital cost effects of bacterial whole-genome sequencing availability in managing a large-scale hospital outbreak. Methods: We built a hybrid discrete event/agent-based simulation model to replicate a serious bacterial outbreak of resistant Escherichia coli in a large metropolitan public hospital during 2017. We tested the 3 strategies of using whole-genome sequencing early, late (actual outbreak), or not using it and assessed their associated outbreak size and hospital cost. The model included ward dynamics, pathogen transmission, and associated hospital costs during a 5-month outbreak. Model parameters were determined using data from the Queensland Hospital Admitted Patient Data Collection (N = 4809 patient admissions) and local clinical knowledge. Sensitivity analyses were performed to address model and parameter uncertainty. Results: An estimated 197 patients were colonized during the outbreak, with 75 patients detected. The total outbreak cost was A$460 137 (US$317 117), with 6.1% spent on sequencing. Without sequencing, the outbreak was estimated to result in 352 colonized patients, costing A$766 921 (US$528 547). With earlier detection from use of routine sequencing, the estimated outbreak size was 3 patients and cost A$65 374 (US$45 054). Conclusions: Using whole-genome sequencing in hospital outbreak management was associated with smaller outbreaks and cost savings, with sequencing costs as a small fraction of total hospital costs, supporting the further investigation of the use of routine whole-genome sequencing in hospitals.

We report our clinical experience of sacubitril/valsartan (SV) use in heart failure (HF) patients at a large UK cardiac centre. Heart failure with reduced ejection fraction (HFrEF) patients seen in the HF clinic and started on SV from April 2016 to July 2017 were retrospectively evaluated.

BACKGROUND:While the RNA world hypothesis is widely accepted, it is still far from complete: the existence of self-replicating ribozyme, consisting of potentially hundreds of nucleotides, is a core assumption for the majority of RNA world models. The appearance of such long RNA molecules under prebiotic conditions is not self-evident. Recombination seems to be a plausible way of creating RNA diversity, resulting in the appearance of functional RNAs, capable of self-replicating.METHODS:We report here on the study of recombination process modelled with two 96 nts RNA fragments. Detection of recombination products was performed with RT-PCR followed by TA-cloning and Sanger sequencing.RESULTS:A wide range of recombinant products was detected. We found that (i) the most efficient ligation was observed for RNA species forming bulges or internal loops, with ligation partners located within the loop; (ii) a strong preference was observed for formation of a few types of major products with a large variety of minor products; (iii) ligation could occur with participation of either 2',3'-cyclophosphate or 5'-ppp; (iv) the presence of key reaction components, i.e. 5'ppp-RNAs, enabled the formation of additional types of product; (v) molecular dynamics simulations of one of the most abundant products suggests that the ligation results in a preferable formation of 2'-5'- rather than 3'-5'-linkages.CONCLUSIONS:The study demonstrates regularities of new RNA molecules formation with non-enzymatic recombination process.GENERAL SIGNIFICANCE:Our findings provide new data supporting the RNA World hypothesis and show the way of new RNA sequences emergence under prebiotic conditions.

A common analysis for Arabic emphatics and pharyngeals posits that their commonalities are due to the shared feature [RTR]. This, however, does not account for some phonological processes, and does not reflect their phonetic representation. This study provides ultrasound evidence that emphatics and pharyngeals do not exhibit a similar retraction of the tongue. Results indicate that while tongue retraction for the emphatics is characterized with simultaneous tongue dorsum and root retraction, the pharyngeals lower the tongue dorsum. Unlike the pharyngeals, the tongue root retraction of the emphatics and uvulars is always posterior to the tongue root position of the inter-speech posture. Such a consistent and significant displacement confirms that [RTR] is an active feature for the emphatics and uvulars. This is also evident from the retraction of following low vowels triggered by the emphatics and uvulars. These phonetic findings suggest that the pharyngeals and emphatics have different phonological representations.

This exploratory study adds to the very limited prior research on consumer attitudes toward mobile marketing in the context of smartphone technologies and applications, and specifically their response to the use of QR codes. An online questionnaire-based survey was conducted to gather data from a convenience sample of mobile phone users in the UK. The study suggests that as consumers move from earlier generation mobile technologies to smartphones the frequency with which they use their phones for all functions increases significantly. Nevertheless, they remain resistant to mobile marketing communications and generally regard text messages as intrusive. Acceptance can be enhanced by permission marketing, trust-building, a sense of being in control, and useful and entertaining website content. Users who had scanned a QR code had accessed a variety of different content on different types of items and in different locations. Ease of use, utility and incentives are drivers to continued use whilst lack of knowledge about on how-to scan or the benefits of QR codes may hinder adoption.

Young women engaged in exotic dancing have a higher need for reproductive health services than women not in this profession, and many also use drugs or exchange sex for money or drugs. Few report receiving reproductive health services. We describe a public health, academic, and community partnership that provided reproductive health services on needle exchange mobile vans in the “red light district” in downtown Baltimore, Maryland. Women made 220 visits to the vans in the first 21 months of the program's operation, and 65% of these visits involved provision of contraception. Programmatic costs were feasible. Joint provision of needle exchange and reproductive health services targeting exotic dancers has the potential to reduce unintended pregnancies and link pregnant, substance-abusing women to reproductive care, and such programs should be implemented more widely.

L-4F, an apolipoprotein A-I (apoA-I) mimetic peptide (also known as APL180), was administered daily by either intravenous (IV) infusion for 7 days or by subcutaneous (SC) injection for 28 days in patients with coronary heart disease in two distinct clinical studies. L-4F was well tolerated at all doses tested. Despite achieving plasma levels (mean maximal plasma concentration of 2,907 ng/ml and 395 ng/ml, following IV infusion and SC injection, respectively), that were effective in previously published animal models, treatment with L-4F, as assessed by biomarkers of HDL function such as HDL-inflammatory index (HII), and paraoxonase activity, did not improve. Paradoxically, there was a 49% increase in high-sensitivity C-reactive protein (hs-CRP) levels after seven IV infusions of 30 mg L-4F (P < 0.05; compared with placebo) and a trend for hs-CRP increase in subjects receiving 30 mg SC injection for 28 days. In a subsequent, ex vivo study, addition of L-4F at concentrations of 150, 375, or 1,000 ng/ml to plasma from subjects prior to L-4F treatment resulted in significant dose-dependent HII improvement. In conclusion, in vivo L-4F treatment, delivered by either SC injection or IV infusion, did not improve HDL functional biomarkers despite achieving plasma levels that improved identical biomarkers ex vivo and in animal models.

The Māori tense/aspect marker ka has historically two allomorphs: one, /ka:/, which is used when the rest of the verb phrase consists of only two morae, and the other, /ka/, for longer phrases. Recordings of native speakers born toward the end of the nineteenth century show that this distribution was at that time observed with a high degree of consistency. However, more recent speaker groups show variable behavior in this respect, with modern younger speakers tending to show abandonment of the allomorphy in favor of consistent use of the short form. This shift is attributable both to a proportional increase in the use of longer phrases over the same period and to the decreasing use of Māori generally, so that opportunities to acquire the inherited rule have diminished considerably.

This article examines the relationship between the frontness of /u/ and the aspiration of /t/ in both Māori and New Zealand English (NZE). In both languages, these processes can be observed since the earliest recordings dating from the latter part of the nineteenth century. We report analyses of these developments for three groups of male speakers of Māori spanning the twentieth century. We compare the Māori analyses with analyses of related features of the speakers' English and of the English of monolingual contemporaries. The occurrence of these processes in Māori cannot be seen simply as interference from NZE as the Māori-speaking population became increasingly bilingual. We conclude that it was the arrival of English with its contrast between aspirated and unaspirated plosives, rather than direct borrowing, that was the trigger for the fronting of the hitherto stable back Māori /u/ vowel together with increased aspiration of /t/ before both /i/ and /u/.

Vildagliptin is a selective dipeptidyl peptidase IV inhibitor that augments meal-stimulated levels of biologically active glucagon-like peptide-1. Chronic vildagliptin treatment decreases postprandial glucose levels and reduces hemoglobin A1c in type 2 diabetic patients. However, little is known about the mechanism(s) by which vildagliptin promotes reduction in plasma glucose concentration.Sixteen patients with type 2 diabetes (age, 48+/-3 yr; body mass index, 34.4+/-1.7 kg/m2; hemoglobin A1c, 9.0+/-0.3%) participated in a randomized, double-blind, placebo-controlled trial. On separate days patients received 100 mg vildagliptin or placebo at 1730 h followed 30 min later by a meal tolerance test (MTT) performed with double tracer technique (3-(3)H-glucose iv and 1-(14)C-glucose orally).After vildagliptin, suppression of endogenous glucose production (EGP) during 6-h MTT was greater than with placebo (1.02+/-0.06 vs. 0.74+/-0.06 mg.kg-1.min-1; P=0.004), and insulin secretion rate increased by 21% (P=0.003) despite significant reduction in mean plasma glucose (213+/-4 vs. 230+/-4 mg/dl; P=0.006). Consequently, insulin secretion rate (area under the curve) divided by plasma glucose (area under the curve) increased by 29% (P=0.01). Suppression of plasma glucagon during MTT was 5-fold greater with vildagliptin (P0.02). The decline in EGP was positively correlated (r=0.55; P0.03) with the decrease in fasting plasma glucose (change=-14 mg/dl).During MTT, vildagliptin augments insulin secretion and inhibits glucagon release, leading to enhanced suppression of EGP. During the postprandial period, a single dose of vildagliptin reduced plasma glucose levels by enhancing suppression of EGP.

Background Aldosterone synthase inhibition provides the potential to attenuate both the mineralocorticoid receptor-dependent and independent actions of aldosterone. In vitro studies with recombinant human enzymes showed LCI699 to be a potent, reversible, competitive inhibitor of aldosterone synthase (Ki = 1.4 ± 0.2 nmol/L in humans) with relative selectivity over 11β-hydroxylase. Methods Hormonal effects of orally administered LCI699 were examined in rat and monkey in vivo models of adrenocorticotropic hormone (ACTH) and angiotensin-II-stimulated aldosterone release, and were compared with the mineralocorticoid receptor antagonist eplerenone in a randomized, placebo-controlled study conducted in 99 healthy human subjects. The effects of LCI699 and eplerenone on cardiac and renal sequelae of aldosterone excess were investigated in a double-transgenic rat (dTG rat) model overexpressing human renin and angiotensinogen. Results Rat and monkey in vivo models of stimulated aldosterone release predicted human dose– and exposure–response relationships, but overestimated the selectivity of LCI699 in humans. In the dTG rat model, LCI699 dose-dependently blocked increases in aldosterone, prevented development of cardiac and renal functional abnormalities independent of blood pressure changes, and prolonged survival. Eplerenone prolonged survival to a similar extent, but was less effective in preventing cardiac and renal damage. In healthy human subjects, LCI699 0.5 mg selectively reduced plasma and 24 h urinary aldosterone by 49 ± 3% and 39 ± 6% respectively (Day 1, mean ± SEM; P

The extent to which it is necessary to model the dynamic behavior of vowel formants to enable vowel separation has been the subject of debate in recent years. To investigate this issue, a study has been made on the vowels of 132 Australian English speakers (male and female). The degree of vowel separation from the formant values at the target was contrasted to that from modeling the formant contour with discrete cosine transform coefficients. The findings are that, although it is necessary to model the formant contour to separate out the diphthongs, the formant values at the target, plus vowel duration are sufficient to separate out the monophthongs. However, further analysis revealed that there are formant contour differences which benefit the within-class separation of the tense/lax monophthong pairs.

CONTEXT: Out-of-school black males aged 15-24 have higher levels of sexual risk-taking than in-school black males of the same age. However few sexual risk reduction curricula are focused on out-of-school male youth. METHODS: A sexual and reproductive health intervention conducted at a Baltimore youth employment and training program in 2008-2010 was evaluated in a study involving 197 youth aged 16-24 from a predominantly black population. Ninety-eight participants received three one-hour curriculum sessions on consecutive days; 99 served as controls. At baseline and three months later participants completed a survey assessing demographic characteristics and various knowledge attitude and behavior measures. Regression analysis with random effects was used to assess differences between intervention participants and controls in changes in outcomes over time. RESULTS: In analyses adjusting for baseline characteristics intervention participants showed greater improvements in outcomes between baseline and follow-up than did controls. Specifically a male who received the intervention was more likely than a control male to report increases in knowledge of STDs and health care use (odds ratio 1.6 for each) frequency of condom use (1.8) use of lubricant with condoms (23.6) communication with a provider about STDs (12.3) and STD testing (16.6). CONCLUSION: These findings suggest the potential benefits of integrating safer-sex and health care information into a sexual and reproductive health curriculum for out-of-school male youth. Copyright (c) 2013 by the Guttmacher Institute.

The clinical features and increased mortality associated with Cushing's syndrome result from a chronic excess of circulating cortisol. As LCI699 potently inhibits 11β-hydroxylase, which catalyzes the final step of cortisol synthesis, it is a potential new treatment for Cushing's disease, the most common cause of endogenous Cushing's syndrome.Adult patients with moderate-to-severe Cushing's disease (urinary free cortisol [UFC] levels1.5 × ULN [upper limit of normal]) received oral LCI699 for 10 weeks in this proof-of-concept study. LCI699 was initiated at 4 mg/d in two equal doses; the dose was escalated every 14 days to 10, 20, 40, and 100 mg/d until UFC normalized, whereupon the dose was maintained until treatment ended (day 70). The primary endpoint was UFC ≤ ULN or a ≥50% decrease from baseline at day 70.Twelve patients were enrolled and completed the study. Baseline UFC ranged over 1.6-17.0 × ULN. All 12 patients achieved UFC ≤ULN or a ≥50% decrease from baseline at day 70; 11 (92%) had normal UFC levels at that time. After treatment discontinuation (day 84), UFC wasULN in 10 patients with available measurements. Mean 11-deoxycortisol, 11-deoxycorticosterone, and adrenocorticotropic hormone levels increased during treatment and declined after discontinuation. Mean systolic and diastolic blood pressure decreased from baseline by 10.0 and 6.0 mmHg, respectively. LCI699 was generally well tolerated; most adverse events (AEs) were mild or moderate. The most common AEs included fatigue (7/12), nausea (5/12), and headache (3/12). No serious drug-related AEs were reported.LCI699 was efficacious and well tolerated in patients with Cushing's disease enrolled in this proof-of-concept study.

Lough Neagh is the largest and the most economically important lake in Ireland. It is also one of the most nutrient rich amongst the world's major lakes. In this study, 16S rRNA analysis of total metagenomic DNA from the water column of Lough Neagh has revealed a high proportion of Cyanobacteria and low levels of Actinobacteria, Acidobacteria, Chloroflexi, and Firmicutes. The planktonic virome of Lough Neagh has been sequenced and 2,298,791 2×300 bp Illumina reads analysed. Comparison with previously characterised lakes demonstrates that the Lough Neagh viral community has the highest level of sequence diversity. Only about 15% of reads had homologs in the RefSeq database and tailed bacteriophages (Caudovirales) were identified as a major grouping. Within the Caudovirales, the Podoviridae and Siphoviridae were the two most dominant families (34.3% and 32.8% of the reads with sequence homology to the RefSeq database), while ssDNA bacteriophages constituted less than 1% of the virome. Putative cyanophages were found to be abundant. 66,450 viral contigs were assembled with the largest one being 58,805 bp; its existence, and that of another 34,467 bp contig, in the water column was confirmed. Analysis of the contigs confirmed the high abundance of cyanophages in the water column. ispartof: PLoS One vol:11 issue:2 ispartof: location:United States status: published

We report the first administration of an orally active aldosterone synthase inhibitor, LCI699, to 14 patients with primary aldosteronism. After a 2-week placebo run-in, patients received oral LCI699 (0.5 mg BID) for 2 weeks, LCI699 (1.0 mg BID) for 2 weeks, and placebo for 1 week. We assessed changes in hormone concentrations, plasma potassium levels, and 24-hour ambulatory systolic blood pressure and safety. The supine plasma aldosterone concentration decreased from 540 pmol/L (95% CI: 394 to 739 pmol/L) to 171 pmol/L (95% CI: 128 to 230 pmol/L) after 0.5 mg of LCI699 (−68%; P P P P P P =0.046). Basal plasma cortisol concentrations remained unchanged, whereas plasma adrenocorticotropic hormone concentrations increased by 35% after 0.5 mg of LCI699 ( P =0.08) and by 113% after 1.0 mg of LCI699 ( P

Publication in the conference proceedings of EUSIPCO, Glasgow, Scotland, 2009

OBJECTIVE—To evaluate the effect of treatment with the dipeptidyl peptidase (DPP)-4 inhibitor vildagliptin on insulin sensitivity and β-cell function in subjects with impaired fasting glucose (IFG). RESEARCH DESIGN AND METHODS—A total of 22 subjects with IFG (11 female and 11 male, mean ± SD age 59.6 ± 11.5 years) were treated orally with 100 mg vildagliptin once daily in a single-blind study. Subjects received placebo for 2 weeks (run-in) followed by vildagliptin for 6 weeks (treatment) and then placebo for 2 weeks (washout). A frequently sampled intravenous glucose tolerance test (FSIGT), followed by a 2-h meal tolerance test (MTT), was performed at 2, 8, and 10 weeks. From the FSIGT, the acute insulin response to glucose (AIRg) and insulin sensitivity index (SI) were determined and used to compute the disposition index (AIRg × SI) as a measure of β-cell function. RESULTS—Fasting plasma glucose did not change after 6 weeks of vildagliptin treatment. With treatment, mean ± SEM AIRg increased from 224 ± 44 to 286 ± 52 pmol/l (P < 0.05), and SI improved from 2.8 ± 0.5 to 3.5 ± 0.5 × 10−5 · min−1 · pmol−1 · l (P < 0.01), resulting in an increase in the disposition index from 688 ± 180 to 1,164 ± 318 × 10−5/min (P < 0.05). These effects were not sustained after washout. During the MTT, the incremental area under the glucose curve was significantly decreased after treatment (240 ± 15 vs. 191 ± 14 mmol · l−1 · min−1; P = 0.002), but this effect was not sustained after washout. CONCLUSIONS—The DPP-4 inhibitor vildagliptin improves insulin sensitivity and β-cell function, leading to improved postprandial glycemia in subjects with IFG, who are known to have β-cell dysfunction. Thus, vildagliptin may prevent progression to diabetes in high-risk subjects.

The dipeptidyl peptidase IV inhibitor, vildagliptin, increases levels of intact glucagon-like peptide-1 (GLP-1) and improves glycemic control in patients with type 2 diabetes. Although GLP-1 is known to stimulate insulin secretion, vildagliptin does not affect plasma insulin levels in diabetic patients, suggesting that more sophisticated measures are necessary to ascertain the influence of vildagliptin on beta-cell function.This study examined the effects of 28-d treatment with vildagliptin (100 mg, twice daily; n = 9) vs. placebo (n = 11) on beta-cell function in diabetic patients using a mathematical model that describes the insulin secretory rate as a function of glucose levels (beta-cell dose response), the change in glucose with time (derivative component), and a potentiation factor, which is a function of time and may reflect the actions of nonglucose secretagogues and other factors.Vildagliptin significantly increased the insulin secretory rate at 7 mmol/liter glucose (secretory tone), calculated from the dose response; the difference in least squares mean (deltaLSM) was 101 +/- 51 pmol.min(-1).m(-2) (P = 0.002). The slope of the beta-cell dose response, the derivative component, and the potentiation factor were not affected. Vildagliptin also significantly decreased mean prandial glucose (deltaLSM, -1.2 +/- 0.4 mmol/liter; P = 0.01) and glucagon (deltaLSM, -10.7 +/- 4.8 ng/liter; P = 0.03) levels and increased plasma levels of intact GLP-1 (deltaLSM, +10.8 +/- 1.6 pmol/liter; P0.0001) and gastric inhibitory polypeptide (deltaLSM, +43.4 +/- 9.4 pmol/liter; P0.0001) relative to placebo.Vildagliptin is an incretin degradation inhibitor that improves beta-cell function in diabetic patients by increasing the insulin secretory tone.

The effect of diminished auditory feedback on monophthong and diphthong production was examined in postlingually deafened Australian-English speaking adults. The participants were 4 female and 3 male speakers with severe to profound hearing loss, who were compared to 11 age- and accent-matched normally hearing speakers. The test materials were 5 repetitions of hVd words containing 18 vowels. Acoustic measures that were studied included F1, F2, discrete cosine transform coefficients (DCTs), and vowel duration information. The durational analyses revealed increased total vowel durations with a maintenance of the tense/lax vowel distinctions in the deafened speakers. The deafened speakers preserved a differentiated vowel space, although there were some gender-specific differences seen. For example, there was a retraction of F2 in the front vowels for the female speakers that did not occur in the males. However, all deafened speakers showed a close correspondence between the monophthong and diphthong formant movements that did occur. Gaussian classification highlighted vowel confusions resulting from changes in the deafened vowel space. The results support the view that postlingually deafened speakers maintain reasonably good speech intelligibility, in part by employing production strategies designed to bolster auditory feedback.

Elizabeth II's traditional pronunciation has been influenced by modern trends. The pronunciation of all languages changes subtly over time1, mainly owing to the younger members of the community2. What is unknown is whether older members unwittingly adapt their accent towards community changes. Here we analyse vowel sounds from the annual Christmas messages broadcast by HRH Queen Elizabeth II during the period between the 1950s and 1980s. Our analysis reveals that the Queen's pronunciation of some vowels has been influenced by the standard southern-British accent of the 1980s which is more typically associated with speakers who are younger and lower in the social hierarchy.

The paper describes the results of a comparison of two annotation systems for intonation, the tone-based TOBI approach and the tune-based approach proposed by Systemic Functional Grammar (SFG). The goal of this comparison is to define a mapping between the two systems for the purpose of concept-to-speech generation of English. Since TOBI is widely used in speech synthesis and SFG is widely used in natural language generation and offers a linguistically motivated account of intonation, it appears a promising step to combine the two approaches for concept-to-speech. A corpus of English utterances has been analysed with both TOBI and SFG categories; comparison of the analysis results has lead to the identification of some basic equivalents between the two systems on which a mapping can be based.

Formant frequencies of sung vowels are modified at higher pitches because of formant tuning, leading to a reduction in intelligibility as the formants converge with increasing F0. Formant frequencies are also dependent on language‐specific pronunciation requirements. The question of whether language‐specific characteristics of sung vowels are maintained through pitch‐effected formant tuning has not previously been examined. Sustained vowels from five similar positions on the vowel quadrilateral in four languages, English, Dutch, French, and Hungarian, were sung in a similar singing style over a range of pitches by a professional female singer who was proficient in singing each of these languages. Formant frequencies were extracted and the magnitudes of the voice partials computed from the average spectrum. The results showed an increase in F1 for the high vowels of all languages, but in the mid–low vowels there were some language differences in the direction of vowel shift as F0 increased. In addition, th...

The study is concerned with a longitudinal acoustic analysis of two sets of recordings from the same four speakers over an interval of between 29 and 50 years. The aim was to determine whether there is any evidence for age-related acoustic changes. Our analysis showed that the same speakers have lower f0, a lower F1, a marginally lower F2, and an unchanging or sometimes higher F3 in their later recordings. There is some suggestion from these data that the change in F1-f0 in Bark from earlier to late recordings is proportional to the change in F3-F2 in Bark. This suggests that there is shift in the speaker space roughly along a diagonal in the phonetic height x backness plane with increasing age.