Bulimia nervosa, binge eating, and psychogenic vomiting: a controlled treatment study and long term outcome.
An "epidemic" prevalence of binge eating and vomiting (bulimia nervosa) has been reported, and treatment has been claimed to be difficult. This paper describes a short term outpatient treatment programme of eclectic orientation capable of being conducted by non-specialist staff, under medical supervision, in local centres. The treatment programme was evaluated in a controlled trial and in long term follow up. In 30 women with severe bulimia the treatment programme significantly reduced their incidence of dietary manipulation without producing weight gain, weight disorder, or neurotic illness. After treatment all the women had fewer symptoms; 24 stopped binge eating and vomiting at the end of treatment, and a further four stopped shortly afterwards. During formal follow up 20 showed no dietary abuse and a further eight reduced their attacks to an average of three episodes a year: all judged treatment to be a success. Pretreatment indicators of poorer prognosis include alcohol abuse and a history of anorexia nervosa. Married patients experienced marital difficulties or illness in the spouse.


Pain coping skills training and lifestyle behavioral weight management in patients with knee osteoarthritis: a randomized controlled study.
Overweight and obese patients with osteoarthritis (OA) experience more OA pain and disability than patients who are not overweight. This study examined the long-term efficacy of a combined pain coping skills training (PCST) and lifestyle behavioral weight management (BWM) intervention in overweight and obese OA patients. Patients (n=232) were randomized to a 6-month program of: 1) PCST+BWM; 2) PCST-only; 3) BWM-only; or 4) standard care control. Assessments of pain, physical disability (Arthritis Impact Measurement Scales [AIMS] physical disability, stiffness, activity, and gait), psychological disability (AIMS psychological disability, pain catastrophizing, arthritis self-efficacy, weight self-efficacy), and body weight were collected at 4 time points (pretreatment, posttreatment, and 6 months and 12 months after the completion of treatment). Patients randomized to PCST+BWM demonstrated significantly better treatment outcomes (average of all 3 posttreatment values) in terms of pain, physical disability, stiffness, activity, weight self-efficacy, and weight when compared to the other 3 conditions (Ps<0.05). PCST+BWM also did significantly better than at least one of the other conditions (ie, PCST-only, BWM-only, or standard care) in terms of psychological disability, pain catastrophizing, and arthritis self-efficacy. Interventions teaching overweight and obese OA patients pain coping skills and weight management simultaneously may provide the more comprehensive long-term benefits.


Effect of a cysteinyl leukotriene receptor antagonist on experimental emphysema and asthma combined with emphysema.
The incidence of overlapping bronchial asthma and chronic obstructive pulmonary disease has increased in recent years. Cysteinyl leukotrienes (CysLTs) play an important role in asthma, and the type 1 CysLT receptor (CysLT1R) is expressed by many inflammatory cells. We evaluated the effect of montelukast, a CysLT1R antagonist, on mouse models of asthma, porcine pancreatic elastase (PPE)-induced emphysema, and asthma combined with emphysema. Mice were sensitized with ovalbumin (OVA) on Days 0 and 14 and subsequently challenged with OVA on Days 28, 29, and 30. Pulmonary emphysema was induced by intratracheal instillation of PPE on Day 25. Mice were treated subcutaneously with montelukast or vehicle from Day 25 to Day 31. Airway hyperresponsiveness (AHR), static compliance; the number of inflammatory cells, the levels of cytokines, chemokines, LTs, and perforin in the bronchoalveolar lavage fluid, and the quantitative morphometry of lung sections were analyzed on Day 32. Treatment with montelukast significantly attenuated the AHR and eosinophilic airway inflammation in OVA-sensitized and OVA-challenged mice. Administration of montelukast significantly reduced the AHR, static compliance, and neutrophilic airway inflammation, while attenuating emphysematous lung changes, in PPE-treated mice. In PPE-treated mice subjected to allergen sensitization and challenges, montelukast significantly suppressed the AHR, static compliance, and eosinophilic and neutrophilic airway inflammation in addition to the development of experimentally induced emphysema in the lungs. Our data suggest that CysLT1R antagonists may be effective in ameliorating the consequences of PPE-induced lung damage and the changes that follow allergen sensitization and challenges.


Robust and efficient single-cell Hi-C clustering with approximate k-nearest neighbor graphs.
Hi-C technology provides insights into the 3D organization of the chromatin, and the single-cell Hi-C method enables researchers to gain knowledge about the chromatin state in individual cell levels. Single-cell Hi-C interaction matrices are high dimensional and very sparse. To cluster thousands of single-cell Hi-C interaction matrices, they are flattened and compiled into one matrix. Depending on the resolution, this matrix can have a few million or even billions of features; therefore, computations can be memory intensive. We present a single-cell Hi-C clustering approach using an approximate nearest neighbors method based on locality-sensitive hashing to reduce the dimensions and the computational resources. The presented method can process a 10 kb single-cell Hi-C dataset with 2600 cells and needs 40 GB of memory, while competitive approaches are not computable even with 1 TB of memory. It can be shown that the differentiation of the cells by their chromatin folding properties and, therefore, the quality of the clustering of single-cell Hi-C data is advantageous compared to competitive algorithms. The presented clustering algorithm is part of the scHiCExplorer, is available on Github https://github.com/joachimwolff/scHiCExplorer, and as a conda package via the bioconda channel. The approximate nearest neighbors implementation is available via https://github.com/joachimwolff/sparse-neighbors-search and as a conda package via the bioconda channel. Supplementary data are available at Bioinformatics online.


Identifying Behavioral Phenotypes of Loneliness and Social Isolation with Passive Sensing: Statistical Analysis, Data Mining and Machine Learning of Smartphone and Fitbit Data.
Feelings of loneliness are associated with poor physical and mental health. Detection of loneliness through passive sensing on personal devices can lead to the development of interventions aimed at decreasing rates of loneliness. The aim of this study was to explore the potential of using passive sensing to infer levels of loneliness and to identify the corresponding behavioral patterns. Data were collected from smartphones and Fitbits (Flex 2) of 160 college students over a semester. The participants completed the University of California, Los Angeles (UCLA) loneliness questionnaire at the beginning and end of the semester. For a classification purpose, the scores were categorized into high (questionnaire score>40) and low (≤40) levels of loneliness. Daily features were extracted from both devices to capture activity and mobility, communication and phone usage, and sleep behaviors. The features were then averaged to generate semester-level features. We used 3 analytic methods: (1) statistical analysis to provide an overview of loneliness in college students, (2) data mining using the Apriori algorithm to extract behavior patterns associated with loneliness, and (3) machine learning classification to infer the level of loneliness and the change in levels of loneliness using an ensemble of gradient boosting and logistic regression algorithms with feature selection in a leave-one-student-out cross-validation manner. The average loneliness score from the presurveys and postsurveys was above 43 (presurvey SD 9.4 and postsurvey SD 10.4), and the majority of participants fell into the high loneliness category (scores above 40) with 63.8% (102/160) in the presurvey and 58.8% (94/160) in the postsurvey. Scores greater than 1 standard deviation above the mean were observed in 12.5% (20/160) of the participants in both pre- and postsurvey scores. The majority of scores, however, fell between 1 standard deviation below and above the mean (pre=66.9% [107/160] and post=73.1% [117/160]). Our machine learning pipeline achieved an accuracy of 80.2% in detecting the binary level of loneliness and an 88.4% accuracy in detecting change in the loneliness level. The mining of associations between classifier-selected behavioral features and loneliness indicated that compared with students with low loneliness, students with high levels of loneliness were spending less time outside of campus during evening hours on weekends and spending less time in places for social events in the evening on weekdays (support=17% and confidence=92%). The analysis also indicated that more activity and less sedentary behavior, especially in the evening, was associated with a decrease in levels of loneliness from the beginning of the semester to the end of it (support=31% and confidence=92%). Passive sensing has the potential for detecting loneliness in college students and identifying the associated behavioral patterns. These findings highlight intervention opportunities through mobile technology to reduce the impact of loneliness on individuals' health and well-being.


Holographic laser Doppler imaging of microvascular blood flow.
We report on local superficial blood flow monitoring in biological tissue from laser Doppler holographic imaging. In time-averaging recording conditions, holography acts as a narrowband bandpass filter, which, combined with a frequency-shifted reference beam, permits frequency-selective imaging in the radio frequency range. These Doppler images are acquired with an off-axis Mach-Zehnder interferometer. Microvascular hemodynamic components mapping is performed in the cerebral cortex of the mouse and the eye fundus of the rat with near-infrared laser light without any exogenous marker. These measures are made from a basic inverse-method analysis of local first-order optical fluctuation spectra at low radio frequencies, from 0 Hz to 100 kHz. Local quadratic velocity is derived from Doppler broadenings induced by fluid flows, with elementary diffusing wave spectroscopy formalism in backscattering configuration. We demonstrate quadratic mean velocity assessment in the 0.1-10 mm/s range in vitro and imaging of superficial blood perfusion with a spatial resolution of about 10 micrometers in rodent models of cortical and retinal blood flow.


Escherichia coli mutants deficient in the aspartate and aromatic amino acid aminotransferases.
Two new mutations are described which, together, eliminate essentially all the aminotransferase activity required for de novo biosynthesis of tyrosine, phenylalanine, and aspartic acid in a K-12 strain of Escherichia coli. One mutation, designated tyrB, lies at about 80 min on the E. coli map and inactivates the "tyrosine-repressible" tyrosine/phenylalanine aminotransferase. The second mutation, aspC, maps at about 20 min and inactivates a nonrespressible aspartate aminotransferase that also has activity on the aromatic amino acids. In ilvE- strains, which lack the branched-chain amino acid aminotransferase, the presence of either the tyrosine-repressible aminotransferase or the aspartate aminotransferase is sufficient for growth in the absence of exogenous tyrosine, phenylalanine, or aspartate; the tyrosine-repressible enzyme is also active in leucine biosynthesis. The ilvE gene product alone can reverse a phenylalanine requirement. Biochemical studies on extracts of strains carrying combinations of these aminotransferase mutations confirm the existence of two distinct enzymes with overlapping specificities for the alpha-keto acid analogues of tyrosine, phenylalanine, and aspartate. These enzymes can be distinguished by electrophoretic mobilities, by kinetic parameters using various substrates, and by a difference in tyrosine repressibility. In extracts of an ilvE- tyrB- aspC- triple mutant, no aminotransferase activity for the alpha-keto acids of tyrosine, phenylalanine, or aspartate could be detected.


Renal scattered tubular-like cells confer protective effects in the stenotic murine kidney mediated by release of extracellular vesicles.
To test the hypothesis that intrinsic renal scattered tubular cells (STC-like cells) contribute to repairing injured tubular epithelial cells (TEC) by releasing extracellular vesicle (EV). EV released from primary cultured pig STC-like cells were confirmed by electron microscopy. Antimycin-A (AMA)-induced injured proximal TEC (PK1 cells) were co-cultured with STC-like cells, STC-like cells-derived EV, or EV-free conditioned-medium for 3 days. Cellular injury, oxidative stress and mitochondrial function were assessed. Transfer of mitochondria from STC-like cells to TEC was assessed using Mito-trackers, and their viability by mitochondrial membrane potential assays. STC-like cells-derived EV were intra-arterially injected into mice 2 weeks after induction of unilateral renal artery stenosis. Two weeks later, renal hemodynamics were studied using magnetic-resonance-imaging, and renal fibrosis assessed ex-vivo. Cultured STC-like cells released EV that were uptaken by TEC. A protective effect conferred by STC-like cells in AMA-induced TEC injury was partly mimicked by their EV. Furthermore, STC-like cells-EV carried and transferred mitochondrial material to injured TEC, which partly restored mitochondrial function. In vivo, STC-like cells-derived EV engrafted in the stenotic kidney, and improved its perfusion and oxygenation. STC-like cells-EV exert protective effects on injured tubular cells in vitro and in vivo, partly by transferring STC-like cells mitochondria, which remain at least partly functional in recipient TEC.


Dominance, submissivity (and homosexuality) in general population: testing of evolutionary hypothesis of sadomasochism by Internet-trap-method.
Dominance and submissiveness represent strong sexual arousal stimuli for a considerable part of population. In contrast to men's sexual dominance and women's sexual submissiveness, the opposite preferences represent an evolutionary enigma. Here, we studied prevalence and strength of particular preferences in general population by Internet-trap-method. The subjects who clicked the banner displayed in the web interface of e-mail boxes were allowed to choose icons with homosexual or heterosexual partner of different hierarchical position. Dominant partner was chosen by 13.8% men and 20.5% women, and submissive partner by 36.6% men and 19.8% women. Homosexual partners were chosen by 7.3% men and 12.2% women. The response times for the submissive and dominant stimuli did not differ while for the equal-status stimuli were significantly longer, suggesting that part of subjects with equal-status preferences probably intentionally mask their natural interests. Large number of people who chose unequal sexual partner suggests that hierarchical status plays important role in human mating system.


Managing clustering effects and learning effects in the design and analysis of multicentre randomised trials: a survey to establish current practice.
Patient outcomes can depend on the treating centre, or health professional, delivering the intervention. A health professional's skill in delivery improves with experience, meaning that outcomes may be associated with learning. Considering differences in intervention delivery at trial design will ensure that any appropriate adjustments can be made during analysis. This work aimed to establish practice for the allowance of clustering and learning effects in the design and analysis of randomised multicentre trials. A survey that drew upon quotes from existing guidelines, references to relevant publications and example trial scenarios was delivered. Registered UK Clinical Research Collaboration Registered Clinical Trials Units were invited to participate. Forty-four Units participated (N = 50). Clustering was managed through design by stratification, more commonly by centre than by treatment provider. Managing learning by design through defining a minimum expertise level for treatment provider was common (89%). One-third reported experience in expertise-based designs. The majority of Units had adjusted for clustering during analysis, although approaches varied. Analysis of learning was rarely performed for the main analysis (n = 1), although it was explored by other means. The insight behind the approaches used within and reasons for, or against, alternative approaches were provided. Widespread awareness of challenges in designing and analysing multicentre trials is identified. Approaches used, and opinions on these, vary both across and within Units, indicating that approaches are dependent on the type of trial. Agreeing principles to guide trial design and analysis across a range of realistic clinical scenarios should be considered.


On the mechanism of the Dakin-West reaction.
The mechanism of the Dakin-West reaction has been thoroughly investigated by monitoring the reaction using ESI-MS/MS techniques in combination with M06-2X/6-311++G(d,p) calculations. Several of the key intermediates in the previously proposed "azlactone" mechanism have been experimentally detected and characterized. In particular, interception of the mixed anhydrides involved in the early and late stages of the mechanistic scheme, as well as of the cyclic acyl-oxazolone intermediate, supports the original pathway suggested by Dakin and West. All intermediates and transition structures involved in several competing mechanisms have been calculated. The theoretical calculations support the experimental results and corroborate the proposed "azlactone" mechanism. The pathway involving the cyclic oxazolone ("azlactone") intermediate represents an energy barrier more than 3 kcal mol(-1) lower than for the competing aldol-type mechanism, thus ruling out this alternative mechanism. The DFT calculations explain the observed ESI-MS data and assess those intermediates which the experiments cannot fully elucidate.


Latent gene sequencing reveals familial relationships among Chinese Epstein-Barr virus strains and evidence for positive selection of A11 epitope changes.
Epstein-Barr virus (EBV) strains from the highly HLA-A11-positive Chinese population are predominantly type 1 and show a variety of sequence changes (relative to the contemporary Caucasian prototype strain B95.8) in the nuclear antigen EBNA3B sequences encoding two immunodominant HLA-A11 epitopes, here called IVT and AVF. This has been interpreted by some as evidence of immune selection and by others as random genetic drift. To study epitope variation in a broader genomic context, we sequenced the whole of EBNA3B and parts of the EBNA2, 3A, and 3C genes from each of 31 Chinese EBV isolates. At each locus, type 1 viruses showed <2% nucleotide divergence from the B95.8 prototype while type 2 sequences remained even closer to the contemporary African prototype Ag876. However, type 1 isolates could clearly be divided into families based on linked patterns of sequence divergence from B95.8 across all four EBNA loci. Different patterns of IVT and AVF variation were associated with the different type 1 families, and there was additional epitope diversity within families. When the EBNA3 gene sequences of type 1 Chinese strains were subject to computer-based analysis, particular codons within the A11-epitope-coding region were among the few identified as being under positive or diversifying selection pressure. From these results, and the observation that mutant epitopes are consistently nonimmunogenic in vivo, we conclude that the immune selection hypothesis remains viable and worthy of further investigation.


Geometry-dependent terahertz emission of silicon nanowires.
THz emission was observed from the vertically aligned silicon nanowire (Si NW) arrays, upon the excitation using a fs Ti-sapphire laser pulse (800 nm). The Si NWs (length = 0.3 approximately 9 microm) were synthesized by the chemical etching of n-type silicon substrates. The THz emission exhibits significant length dependence; the intensity increases sharply up to a length of 3 mum and then almost saturates. Their efficient THz emission is attributed to strong local field enhancement by coherent surface plasmons, with distinctive geometry dependence.


Sugar alcohols, caries incidence, and remineralization of caries lesions: a literature review.
Remineralization of minor enamel defects is a normal physiological process that is well known to clinicians and researchers in dentistry and oral biology. This process can be facilitated by various dietary and oral hygiene procedures and may also concern dentin caries lesions. Dental caries is reversible if detected and treated sufficiently early. Habitual use of xylitol, a sugar alcohol of the pentitol type, can be associated with significant reduction in caries incidence and with tooth remineralization. Other dietary polyols that can remarkably lower the incidence of caries include erythritol which is a tetritol-type alditol. Based on known molecular parameters of simple dietary alditols, it is conceivable to predict that their efficacy in caries prevention will follow the homologous series, that is, that the number of OH-groups present in the alditol molecule will determine the efficacy as follows: erythritol >/= xylitol > sorbitol. The possible difference between erythritol and xylitol must be confirmed in future clinical trials.


'Le Rouge et le Noir': a decline in flavone formation correlates with the rare color of black dahlia (Dahlia variabilis hort.) flowers.
More than 20,000 cultivars of garden dahlia (Dahlia variabilis hort.) are available showing flower colour from white, yellow and orange to every imaginable hue of red and purple tones. Thereof, only a handful of cultivars are so-called black dahlias showing distinct black-red tints. Flower colour in dahlia is a result of the accumulation of red anthocyanins, yellow anthochlors (6'-deoxychalcones and 4-deoxyaurones) and colourless flavones and flavonols, which act as copigments. White and yellow coloration occurs only if the pathway leading to anthocyanins is incomplete. Not in all cultivars the same step of the anthocyanin pathway is affected, but the lack of dihydroflavonol 4-reductase activity is frequently observed and this seems to be based on the suppression of the transcription factor DvIVS. The hitherto unknown molecular background for black colour in dahlia is here presented. Black cultivars accumulate high amounts of anthocyanins, but show drastically reduced flavone contents. High activities were observed for all enzymes from the anthocyanin pathway whereas FNS II activity could not be detected or only to a low extent in 13 of 14 cultivars. cDNA clones and genomic clones of FNS II were isolated. Independently from the colour type, heterologous expression of the cDNA clones resulted in functionally active enzymes. FNS II possesses one intron of varying length. Quantitative Real-time PCR showed that FNS II expression in black cultivars is low compared to other cultivars. No differences between black and red cultivars were observed in the expression of transcription factors IVS and possible regulatory genes WDR1, WDR2, MYB1, MYB2, 3RMYB and DEL or the structural genes of the flavonoid pathway. Despite the suppression of FHT expression, flavanone 3-hydroxylase (FHT, synonym F3H) enzyme activity was clearly present in the yellow and white cultivars. An increased accumulation of anthocyanins establishes the black flowering phenotypes. In the majority of black cultivars this is due to decreased flavone accumulation and thus a lack of competition for flavanones as the common precursors of flavone formation and the anthocyanin pathway. The low FNS II activity is reflected by decreased FNS II expression.


Prediction of peptide affinity to HLA DRB1*0401.
A method to predict quantitatively peptide binding to HLA DRB1*0401 has been developed using a data set of the relative contributions of each of the naturally occurring amino acids in the context of a simplified peptide back-bone. The prediction assumed that the relative role of each of the peptide side chains could be treated independently and could be measured by assaying each of the 20 naturally occurring amino acids at the central 11 positions of a 13-residue peptide previously shown to contain the minimal requirements for high-affinity binding to HLA-DR proteins. The resultant database was shown to have predictive value when tested on a set of 13 unrelated peptides known to bind DRB1*0401 with a wide range of apparent affinity. The database was tested further by analyzing myelin basic protein. All 13 amino acid peptides containing a hydrophobic amino acid at the third position were synthesized and assayed for binding purified DRB1*0401. In every case, the measured affinity correlated with the predictive values within the experimental error of the assays. Finally, the ability to predict peptide binding to MHC class II molecules was shown to help in identifying T cell determinants. The specificity of DRB1*0401-restricted T cell hybridomas against human serum albumin corresponded to two peptides, predicted and shown to bind the class II protein with high affinity.


The importance of maternal pregnancy vitamin D for offspring bone health: learnings from the MAVIDOS trial.
Optimisation of skeletal mineralisation in childhood is important to reduce childhood fracture and the long-term risk of osteoporosis and fracture in later life. One approach to achieving this is antenatal vitamin D supplementation. The Maternal Vitamin D Osteoporosis Study is a randomised placebo-controlled trial, the aim of which was to assess the effect of antenatal vitamin D supplementation (1000 IU/day cholecalciferol) on offspring bone mass at birth. The study has since extended the follow up into childhood and diversified to assess demographic, lifestyle and genetic factors that determine the biochemical response to antenatal vitamin D supplementation, and to understand the mechanisms underpinning the effects of vitamin D supplementation on offspring bone development, including epigenetics. The demonstration of positive effects of maternal pregnancy vitamin D supplementation on offspring bone development and the delineation of underlying biological mechanisms inform clinical care and future public-health policies.


Working memory in patients with mild traumatic brain injury: functional MR imaging analysis.
To analyze brain activation patterns in response to tests of working memory after a mild traumatic brain injury (MTBI). Research ethics committee approval and patient written informed consent were obtained. Brain activation patterns in response to n-back working memory tasks (n = 1, 2, 3) were assessed with functional magnetic resonance (MR) imaging in 20 patients with MTBI within 1 month after their injury and in 18 healthy control subjects. In n-back working memory tasks, participants monitored a series of number stimuli and were to indicate when the presented number was the same as that presented n back previously. Nine (45%) MTBI patients underwent follow-up functional MR imaging studies 6 weeks later. Digit span, a memory test for how many numbers a person can remember in sequence, and continuous performance test (CPT), a test that measures a person's sustained and selective attention and impulsivity, were also performed before functional MR imaging studies and outside the imager for each participant. Clinical data were analyzed by using t and χ(2) tests. Within-group, between-group, and initial and follow-up differences of functional MR imaging data were analyzed by using one-sample, two-sample, and paired t tests, respectively. Groups were similar for sex (P = .75), years of education (P = .069), digit span (P = .37 for total score), CPT (P = .31, .27, and .43 for omission error, commission error, and hit reaction time, respectively), and accuracy of n-back working memory performance (P = .90, .11, and .39 for one-, two-, and three-back tasks, respectively). Brain activation patterns differed between MTBI patients and controls in response to increasing working memory loads (P < .01, uncorrected). Control subjects maintained their ability to increase activation in the working memory circuitry with each increase in working memory load. In contrast, MTBI patients were impaired in their ability to increase activation in working memory circuitry under both moderate and high working memory load conditions. However, MTBI patients did show cerebral plasticity, as evidenced by more activation in some areas outside and inside the working memory circuitry as compared with control subjects (P < .01, uncorrected). In the 6-week follow-up study, compared with baseline, MTBI patients showed an improvement of activation in response to increasing working memory loads (P < .05, uncorrected). MTBI-induced differences in working memory functional activity were observed even though differences in behavioral performance between MTBI patients and controls were absent, which suggests that this approach may increase sensitivity to MTBI compared with neuropsychological evaluation alone.


Postapproval Outcomes: The Berlin Heart EXCOR Pediatric in North America.
The Berlin Heart EXCOR Pediatric Ventricular Assist Device (BH) was approved for use in the United States in December 2011, based on a prospective investigational device exemption (IDE) trial. Strict exclusion criteria for the trial selected a low-risk "ideal" cohort. We sought to determine whether postapproval usage of the BH in a "real world" cohort of recipients would result in similar outcomes. Preimplant diagnostic information was collected for all patients. Efficacy was evaluated by comparison of all children (efficacy group, n = 247) implanted between FDA approval and April 2015 to those in the IDE trial (IDE, n = 48), with regard to achievement of one of four end-states: transplanted, successful weaning, death/unsuccessful weaning, or still-on-device. Safety outcomes were compared between IDE patients and a subset of postapproval patients (safety group, n = 39) for whom adjudicated adverse events were tracked in a regulator-mandated dataset. Diagnostic categories were similar between groups: IDE (congenital 19%, dilated cardiomyopathy/myocarditis/other 81%) versus Efficacy Group (congenital 24%, dilated cardiomyopathy/myocarditis/other 75%). Patients in the IDE cohort were larger (median 14.8 kg, range 3.6-58.1 kg vs. 10.7 kg, 2.9-112.0 kg, p = 0.02). More IDE patients were successfully supported than in the efficacy group cohort (90% vs. 77%, p = 0.05). Proportions with bleeding and stroke were similar between the IDE and safety group cohorts (46% vs. 41%, p = 0.65; 29% vs. 33%, p = 0.68, respectively). With usage of the BH in a less-ideal population, rates of bridge to transplant and weaning have declined slightly, but remain encouragingly high. Bleeding and neurologic event rates have not increased.


[Spatiotemporal trends and the impact factors of acid rain in Anhui Province].
The observational data of acid rain at seven stations in Anhui province operated by China Meteorological Administration (CMA), as well as the coal consumptions in Anhui and some surrounding provinces along with satellite measured tropospheric NO2 columns, were used to analyze the spatiotemporal trends of acid rain in Anhui and the potential reasons of the increasing occurrence frequency of acid rain. In addition, the technique of back-trajectory-cluster analysis was used to examine the impacts of transport patterns on the precipitation acidity in Anhui. The occurrence frequency shows the lowest in summer and the highest in autumn, with 3-year average pH < 5.6 during 2006-2008 at all stations, hereinto, pH values are between 5.0 and 4.5 in Hefei, Anqing, Maanshan and Bengbu. In spatial, acid rain were the most severe in southern to middle Anhui and mitigated to north. The distributions of pH were concentrative at Fuyang, Tongling and Huangshan, with more than 75% occurred between 6.00-7.50 (Fuyang), 5.00-6.00 (Tongling) and 5.00-6.50 (Huangshan); quite dispersive at other stations, with the maximum at 4.00-4.50 (Hefei and Anqing), 5.00-5.50 (Maanshan) and 5.50-6.00 (Bengbu). The occurrence frequencies of acid rain increased evidently at all stations comparing with those in the end of 1990s. The results of back-trajectories-cluster analysis show that the acid rain is closely related with the regional-range transport of acid rain precursors at each station. The air-masses from southeast and northeast, especially those passing through Jiangsu and Zhejiang, associated with the highest frequencies of acid rain with pH < 5.0, indicating that the industrial emissions in the economy developed areas of Yangtze Delta play key roles in acid rain in Anhui province. In addition, statistics shows that the occurrence frequency of acid rain in Hefei was highly correlated with the trends of the provincial coal consumptions in Anhui, Jiangsu and Zhejiang, also tropospheric NO2 column content over Anhui province and surrounding areas with all correlation coefficients > 0.7, suggesting the close relationship between the quick increasing acid rain in Hefei and the regional pollutant emissions.


Current management of funguria.
Recent findings on the epidemiology and treatment of funguria are reviewed. Funguria, or candiduria, is a common nosocomial condition and may develop as early as the first two weeks of hospitalization. Risk factors include antibacterial therapy, an indwelling urinary catheter, urologic procedures, female sex, diabetes, and immunosuppressive therapy. Candida albicans is the species most commonly isolated from the urine of infected patients. Spontaneous resolution of funguria is relatively infrequent. Furthermore, although nonpharmacologic measures, such as removing unnecessary antibacterials and changing or removing indwelling urinary catheters, may be beneficial, they are often inadequate without additional, pharmacologic therapy. The most serious complication of untreated asymptomatic funguria is candidemia. Bladder irrigations with amphotericin B have been the standard of therapy for many years; recently, the optimal concentration and method of irrigation (continuous versus intermittent) have been debated. Studies indicate that intravesical amphotericin B and oral fluconazole therapy are each effective in clearing funguria. Intravesical amphotericin B appears to act more rapidly; however, the effect of systemic fluconazole therapy often persists longer than that of amphotericin B irrigation, and oral therapy is more convenient and less expensive. Oral fluconazole appears to have a more delayed but more lasting effect on funguria than amphotericin B bladder irrigation. Studies are needed to determine whether intravesical amphotericin B still has a role in the treatment of funguria and to refine strategies involving fluconazole.


Mentoring fathers of children newly diagnosed with T1DM.
To pilot test a social support intervention for fathers of children <13 years old newly diagnosed with type 1 diabetes mellitus (T1DM). The pilot study was part of a larger randomized, controlled clinical trial. Father participants (28 fathers of children newly diagnosed) were recruited from two pediatric diabetes centers. For 12 months fathers (n = 19) and their spouses in the experimental arm received social support (home visits and phone calls). Control group fathers (n = 9) and their spouses received the phone number of an experienced parent (but not formally educated to provide social support) to call as needed. Fathers in the intervention group had significantly greater confidence but scored higher on worry at 12 months than control group fathers. Fathers in the two groups did not differ significantly in disease-related concerns or perceived disease impact on the family, nor did they differ significantly in perceived amount and helpfulness of their daily management. However, mothers overall perceived fathers as contributing more care and help than fathers perceived themselves (p > .10). Fathers in the experimental arm identified parent mentors as individuals they would seek advice regarding day-to-day management and community agencies. Over this 4.5 year study, 6 of 28 father participants and two of the three father mentors dropped out. Nurses caring for families with young children newly diagnosed with T1DM should consider fathers social support needs and encourage their participation in day-to-day management.


The predicted influence of climate change on lesser prairie-chicken reproductive parameters.
The Southern High Plains is anticipated to experience significant changes in temperature and precipitation due to climate change. These changes may influence the lesser prairie-chicken (Tympanuchus pallidicinctus) in positive or negative ways. We assessed the potential changes in clutch size, incubation start date, and nest survival for lesser prairie-chickens for the years 2050 and 2080 based on modeled predictions of climate change and reproductive data for lesser prairie-chickens from 2001-2011 on the Southern High Plains of Texas and New Mexico. We developed 9 a priori models to assess the relationship between reproductive parameters and biologically relevant weather conditions. We selected weather variable(s) with the most model support and then obtained future predicted values from climatewizard.org. We conducted 1,000 simulations using each reproductive parameter's linear equation obtained from regression calculations, and the future predicted value for each weather variable to predict future reproductive parameter values for lesser prairie-chickens. There was a high degree of model uncertainty for each reproductive value. Winter temperature had the greatest effect size for all three parameters, suggesting a negative relationship between above-average winter temperature and reproductive output. The above-average winter temperatures are correlated to La Niña events, which negatively affect lesser prairie-chickens through resulting drought conditions. By 2050 and 2080, nest survival was predicted to be below levels considered viable for population persistence; however, our assessment did not consider annual survival of adults, chick survival, or the positive benefit of habitat management and conservation, which may ultimately offset the potentially negative effect of drought on nest survival.


Comparison of the effectiveness of microsatellites and SNP panels for genetic identification, traceability and assessment of parentage in an inbred Angus herd.
During the last decade, microsatellites (short tandem repeats or STRs) have been successfully used for animal genetic identification, traceability and paternity, although in recent year single nucleotide polymorphisms (SNPs) have been increasingly used for this purpose. An efficient SNP identification system requires a marker set with enough power to identify individuals and their parents. Genetic diagnostics generally include the analysis of related animals. In this work, the degree of information provided by SNPs for a consanguineous herd of cattle was compared with that provided by STRs. Thirty-six closely related Angus cattle were genotyped for 18 STRs and 116 SNPs. Cumulative SNPs exclusion power values (Q) for paternity and sample matching probability (MP) yielded values greater than 0.9998 and 4.32E(-42), respectively. Generally 2-3 SNPs per STR were needed to obtain an equivalent Q value. The MP showed that 24 SNPs were equivalent to the ISAG (International Society for Animal Genetics) minimal recommended set of 12 STRs (MP ∼ 10(-11)). These results provide valuable genetic data that support the consensus SNP panel for bovine genetic identification developed by the Parentage Recording Working Group of ICAR (International Committee for Animal Recording).


Polymorphism and divergence at a Drosophila pseudogene locus.
The larval cuticle protein (Lcp) cluster in Drosophila melanogaster contains four functional genes and a closely related pseudogene. A 630-bp fragment including the larval cuticle pseudogene locus (Lcp psi) was nucleotide sequenced in 10 strains of D. melanogaster and a 458-bp Lcp psi fragment from D. simulans was also sequenced. We used these data to test the hypotheses that the rates of synonymous and nonsynonymous substitution are equal, that the absolute levels of variation are higher than in functional genes, and that intraspecific polymorphism is correlated with interspecific divergence. As predicted, synonymous and nonsynonymous substitution rates were equivalent, and overall nucleotide divergence between D. melanogaster and D. simulans (Jukes-Cantor distance = 0.149 +/- 0.150) was extremely high. However, within-species DNA sequence comparisons at Lcp psi revealed lower levels of polymorphism (theta = 0.001 +/- 0.001) than at many functional loci in D. melanogaster. Using the HUDSON, KREITMAN, and AGUADE (HKA) test, we show that the level of polymorphism in Lcp psi within D. melanogaster is lower than expected given the amount of divergence between D. melanogaster and D. simulans when the pseudogene data are compared to the Adh 5' flanking region. Because the Lcp psi lies in a region of relatively infrequent recombination, we suggest that the low level of within-species polymorphism is the result of background selection.


White matter microstructural recovery with abstinence and decline with relapse in alcohol dependence interacts with normal ageing: a controlled longitudinal DTI study.
Alcohol dependence exacts a toll on brain white matter microstructure, which has the potential of repair with prolonged sobriety. Diffusion tensor imaging (DTI) enables in-vivo quantification of tissue constituents and localisation of tracts potentially affected in alcohol dependence and its recovery. We did an extended longitudinal study of alcoholism's trajectory of effect on selective fibre bundles with sustained sobriety or decline with relapse. Participants were drawn from a longitudinal, 1·5T DTI database of 841 scans of individuals with various medical or neuropsychiatric conditions and normal ageing. Participants diagnosed with alcohol dependence had to meet the criteria from DSM-IV for alcohol dependence. Controls were screened and free of any DSM-IV axis I diagnosis, including being without history of alcohol or drug abuse or dependence. Tract-based spatial statistics (TBSS) quantified white matter integrity throughout the brain in 47 alcohol-dependent individuals and 56 controls examined 2-5 times over 1-8 year intervals. We identified regions showing group differences with a white matter atlas. For macrostructural comparison, we measured corpus callosum and centrum semiovale volumes on MRI. This study took place in the USA, between June 23, 2000, and Sept 6, 2011. TBSS identified a large cluster (threshold p<0·001), where controls showed significant fractional anisotropy (FA) decrease with ageing and alcohol-dependent individuals had significantly lower FA than controls regardless of age. Over the examination interval, 27 (57%) alcohol-dependent individuals abstained, ten (21%) relapsed into light drinking, and ten (21%) relapsed into heavy drinking (>5 kg of alcohol/year). Despite abnormally low FA, age trajectories of the abstainers were positive and progressing toward normality, whereas those of the relapsers and controls were negative. Axial diffusivity (lower values indexing myelin integrity) was abnormally high in the total alcohol-dependent group; however, the abstainers' slopes paralleled those of controls, whereas the heavy-drinking relapsers' slopes showed accelerated ageing. Callosal genu and body microstructure but not macrostructure showed untoward alcohol-related effects. Affected projection and association tracts had an anterior and superior neuroanatomical distribution. Return to heavy drinking resulted in accelerating microstructural white matter damage. Despite evidence for damage, alcohol-dependent individuals maintaining sobriety over extended periods showed improvement in brain fibre tract integrity reflective of fibre reorganisation and myelin restoration, indicative of a neural mechanism explaining recovery. US National Institute on Alcohol Abuse and Alcoholism (AA012388, AA017168, AA005965, AA013521-INIA).


Sexual ornaments, body morphology, and swimming performance in naturally hybridizing swordtails (teleostei: xiphophorus).
Determining the costs of sexual ornaments is complicated by the fact that ornaments are often integrated with other, non-sexual traits, making it difficult to dissect the effect of ornaments independent of other aspects of the phenotype. Hybridization can produce reduced phenotypic integration, allowing one to evaluate performance across a broad range of multivariate trait values. Here we assess the relationship between morphology and performance in the swordtails Xiphophorus malinche and X. birchmanni, two naturally-hybridizing fish species that differ extensively in non-sexual as well as sexual traits. We took advantage of novel trait variation in hybrids to determine if sexual ornaments incur a cost in terms of locomotor ability. For both fast-start and endurance swimming, hybrids performed at least as well as the two parental species. The sexually-dimorphic sword did not impair swimming performance per se. Rather, the sword negatively affected performance only when paired with a sub-optimal body shape. Studies seeking to quantify the costs of ornaments should consider that covariance with non-sexual traits may create the spurious appearance of costs.


Bone health and deterioration in quality of life among participants from the Hertfordshire cohort study.
We utilised the Hertfordshire cohort study to examine relationships between bone density at baseline and SF-36 status 4 years later. We found deterioration in the mental health domain over follow-up in osteoporotic men (but not women) compared with other groups (relative rate ratio=5.78, 95% confidence interval (CI) 1.78-19.2). Osteoporosis is associated with decreased quality of life, although it has been difficult to evaluate the confounding effects of fracture and co-morbidity. Having previously shown that male osteoporotics have poorer health than counterparts with normal bone mineral density, even after adjustment for co-morbidity and prior fracture, we assessed quality of life in both groups 4 years apart. Four hundred and ninety-eight men and 468 women completed questionnaires detailing lifestyle factors, co-morbidities and quality of life (SF-36) before undergoing bone density measurements at the lumbar spine and total femur. At follow-up 4 years later, 322 men and 320 women were reassessed. Multinomial logistic regression confirmed deterioration in mental health over follow-up in osteoporotic men compared with other groups (relative rate ratio=5.78, 95% CI 1.78-19.2). These patterns were not apparent among women. Men with lower bone density at baseline had poorer quality of life some 4 years later, even after adjustment for co-morbidity and fracture. This may reflect secondary osteoporosis in men (due to alcohol or hypogonadism).


Investigating sorption on iron-oxyhydroxide soil minerals by solid-state NMR spectroscopy: a 6Li MAS NMR study of adsorption and absorption on goethite.
High-resolution 2H MAS NMR spectra can be obtained for nanocrystalline particles of goethite (alpha-FeOOH, particle size approximately 4-10 nm) at room temperature, facilitating NMR studies of sorption under environmentally relevant conditions. Li sorption was investigated as a function of pH, the system representing an ideal model system for NMR studies. 6Li resonances with large hyperfine shifts (approximately 145 ppm) were observed above the goethite point of zero charge, providing clear evidence for the presence of Li-O-Fe connectivities, and thus the formation of an inner sphere Li+ complex on the goethite surface. Even larger Li hyperfine shifts (289 ppm) were observed for Li+-exchanged goethite, which contains lithium ions in the tunnels of the goethite structure, confirming the Li assignment of the 145 ppm Li resonance to the surface sites.


Expanding the genetic and phenotypic spectrum of popliteal pterygium disorders.
The popliteal pterygia syndromes are a distinct subset of the hundreds of Mendelian orofacial clefting syndromes. Popliteal pterygia syndromes have considerable variability in severity and in the associated phenotypic features but are all characterized by cutaneous webbing across one or more major joints, cleft lip and/or palate, syndactyly, and genital malformations. Heterozygous mutations in IRF6 cause popliteal pterygium syndrome (PPS) while homozygous mutations in RIPK4 or CHUK (IKKA) cause the more severe Bartsocas-Papas syndrome (BPS) and Cocoon syndrome, respectively. In this study, we report mutations in six pedigrees with children affected with PPS or BPS. Using a combination of Sanger and exome sequencing, we report the first case of an autosomal recessive popliteal pterygium syndrome caused by homozygous mutation of IRF6 and the first case of uniparental disomy of chromosome 21 leading to a recessive disorder. We also demonstrate that mutations in RIPK4 can cause features with a range of severity along the PPS-BPS spectrum and that mutations in IKKA can cause a range of features along the BPS-Cocoon spectrum. Our findings have clinical implications for genetic counseling of families with pterygia syndromes and further implicate IRF6, RIPK4, and CHUK (IKKA) in potentially interconnected pathways governing epidermal and craniofacial development.


Control of the gain of visual-motor transmission occurs in visual coordinates for smooth pursuit eye movements.
Sensory inputs control motor behavior with a strength, or gain, that can be modulated according to the movement conditions. In smooth pursuit eye movements, the response to a brief perturbation of target motion is larger during pursuit of a moving target than during fixation of a stationary target. As a step toward identifying the locus and mechanism of gain modulation, we test whether it acts on signals that are in visual or motor coordinates. Monkeys tracked targets that moved at 15°/s in one of eight directions, including left, right, up, down, and the four oblique directions. In eight-ninths of the trials, the target underwent a brief perturbation that consisted of a single cycle of a 10 Hz sine wave of amplitude ±5°/s in one of the same eight directions. Even for oblique directions of baseline target motion, the magnitude of the eye velocity response to the perturbation was largest for a perturbation near the axis of target motion and smallest for a perturbation along the orthogonal axis. Computational modeling reveals that our data are reproduced when the strength of visual-motor transmission is modulated in sensory coordinates, and there is a static motor bias that favors horizontal eye movements. A network model shows how the output from the smooth eye movement region of the frontal eye fields (FEF(SEM)) could implement gain control by shifting the peak of a visual population response along the axes of preferred image speed and direction.


Differential roles of FOXO transcription factors on insulin action in brown and white adipose tissue.
Insulin and IGF-1 are essential for adipocyte differentiation and function. Mice lacking insulin and IGF-1 receptors in fat (FIGIR-KO, fat-specific IGF-1 receptor and insulin receptor-KO) exhibit complete loss of white and brown adipose tissue (WAT and BAT), glucose intolerance, insulin resistance, hepatosteatosis, and cold intolerance. To determine the role of FOXO transcription factors in the altered adipose phenotype, we generated FIGIR-KO mice with fat-specific KO of fat-expressed Foxos [Foxo1, Foxo3, Foxo4] (F-Quint-KO). Unlike FIGIR-KO mice, F-Quint-KO mice had normal BAT, glucose tolerance, insulin-regulated hepatic glucose production, and cold tolerance. However, loss of FOXOs only partially rescued subcutaneous WAT and hepatosteatosis, did not rescue perigonadal WAT or systemic insulin resistance, and led to even more marked hyperinsulinemia. Thus, FOXOs play different roles in insulin/IGF-1 action in different adipose depots, being most important in BAT, followed by subcutaneous WAT and then by visceral WAT. Disruption of FOXOs in fat also led to a reversal of insulin resistance in liver, but not in skeletal muscle, and an exacerbation of hyperinsulinemia. Thus, adipose FOXOs play a unique role in regulating crosstalk between adipose depots, liver, and β cells.


Bee venom phospholipase A2 prevents prion peptide induced-cell death in neuronal cells.
Bee venom phospholipase A2 (bvPLA2) is a prototypic group III enzyme which consists of unique N-terminal and C-terminal domains and a central secretory PLA2 (sPLA2) domain. This sPLA2 domain is highly homologous with human group III sPLA2. Current evidence suggests that group III sPLA2 may affect some neuronal functions, such as neuritogenesis, neurotransmitter release and neuronal survival. The prion diseases are neurodegenerative disorders characterized by the conversion of the normal cellular prion (PrPC) to the misfolded isoform scrapie prion protein (PrPSc). PrPSc accumulation in the central nervous system (CNS) leads to neurotoxicity by inhibition of the PI3K/AKT pathway or activation of p38 mitogen-activated protein kinase (MAPK) pathways. In the present study, we found that bvPLA2 inhibited prion protein (PrP) fragment (106-126)-induced neuronal cell death. PrP(106-126)-mediated increase of p-p38 MAPK and cleaved caspases and decrease of p-AKT were blocked by bvPLA2 treatment. These results indicate that increasing PLA2, including the group III sPLA2 is key to regulating PrP(106-126)-mediated neurotoxicity. Taken together, the results of this study suggest that specific modulation of PLA2 appears to prevent neuronal cell death caused by prion peptides.


Selective inhibitory effects of zinc on cell proliferation in esophageal squamous cell carcinoma through Orai1.
Zinc, an essential micronutrient, has a cancer preventive role. Zinc deficiency has been shown to contribute to the progression of esophageal cancer. Orai1, a store-operated Ca2+ entry (SOCE) channel, was previously reported to be highly expressed in tumor tissues removed from patients with esophageal squamous cell carcinoma (ESCC) with poor prognosis, and elevation of its expression contributes to both hyperactive intracellular Ca2+ oscillations and fast cell proliferation in human ESCC cells. However, the molecular basis of cancer preventive functions of zinc and its association with Orai1-mediated cell proliferation remains unknown. The present study shows that zinc supplementation significantly inhibits proliferation of ESCC cell lines and that the effect of zinc is reversible with N,N,N',N'-tetrakis (2-pyridylmethyl) ethylenediamine, a specific Zn2+ chelator, whereas nontumorigenic esophageal epithelial cells are significantly less sensitive to zinc treatment. Fluorescence live cell imaging revealed that extracellular Zn2+ exerted rapid inhibitory effects on Orai1-mediated SOCE and on intracellular Ca2+ oscillations in the ESCC cells. Knockdown of Orai1 or expression of Orai1 mutants with compromised zinc binding significantly diminished sensitivity of the cancer cells to zinc treatment in both SOCE and cell proliferation analyses. These data suggest that zinc may inhibit cell proliferation of esophageal cancer cells through Orai1-mediated intracellular Ca2+ oscillations and reveal a possible molecular basis for zinc-induced cancer prevention and Orai1-SOCE signaling pathway in cancer cells.-Choi, S., Cui, C., Luo, Y., Kim, S.-H., Ko, J.-K., Huo, X., Ma, J., Fu, L.-W., Souza, R. F., Korichneva, I., Pan, Z. Selective inhibitory effects of zinc on cell proliferation in esophageal squamous cell carcinoma through Orai1.


MetaPSICOV: combining coevolution methods for accurate prediction of contacts and long range hydrogen bonding in proteins.
Recent developments of statistical techniques to infer direct evolutionary couplings between residue pairs have rendered covariation-based contact prediction a viable means for accurate 3D modelling of proteins, with no information other than the sequence required. To extend the usefulness of contact prediction, we have designed a new meta-predictor (MetaPSICOV) which combines three distinct approaches for inferring covariation signals from multiple sequence alignments, considers a broad range of other sequence-derived features and, uniquely, a range of metrics which describe both the local and global quality of the input multiple sequence alignment. Finally, we use a two-stage predictor, where the second stage filters the output of the first stage. This two-stage predictor is additionally evaluated on its ability to accurately predict the long range network of hydrogen bonds, including correctly assigning the donor and acceptor residues. Using the original PSICOV benchmark set of 150 protein families, MetaPSICOV achieves a mean precision of 0.54 for top-L predicted long range contacts-around 60% higher than PSICOV, and around 40% better than CCMpred. In de novo protein structure prediction using FRAGFOLD, MetaPSICOV is able to improve the TM-scores of models by a median of 0.05 compared with PSICOV. Lastly, for predicting long range hydrogen bonding, MetaPSICOV-HB achieves a precision of 0.69 for the top-L/10 hydrogen bonds compared with just 0.26 for the baseline MetaPSICOV. MetaPSICOV is available as a freely available web server at http://bioinf.cs.ucl.ac.uk/MetaPSICOV. Raw data (predicted contact lists and 3D models) and source code can be downloaded from http://bioinf.cs.ucl.ac.uk/downloads/MetaPSICOV. Supplementary data are available at Bioinformatics online.


Participation of adults with visual and severe or profound intellectual disabilities: Definition and operationalization.
The available opinions regarding participation do not appear to be applicable to adults with visual and severe or profound intellectual disabilities (VSPID). Because a clear definition and operationalization are lacking, it is difficult for support professionals to give meaning to participation for adults with VSPID. The purpose of the present study was to develop a definition and operationalization of the concept of participation of adults with VSPID. Parents or family members, professionals, and experts participated in an online concept mapping procedure. This procedure includes generating statements, clustering them, and rating their importance. The data were analyzed quantitatively using multidimensional scaling and qualitatively with triangulation. A total of 53 participants generated 319 statements of which 125 were clustered and rated. The final cluster map of the statements contained seven clusters: (1) Experience and discover; (2) Inclusion; (3) Involvement; (4) Leisure and recreation; (5) Communication and being understood; (6) Social relations; and (7) Self-management and autonomy. The average importance rating of the statements varied from 6.49 to 8.95. A definition of participation of this population was developed which included these seven clusters. The combination of the developed definition, the clusters, and the statements in these clusters, derived from the perceptions of parents or family members, professionals, and experts, can be employed to operationalize the construct of participation of adults with VSPID. This operationalization supports professionals in their ability to give meaning to participation in these adults. Future research will focus on using the operationalization as a checklist of participation for adults with VSPID.


Stem Cell Plasticity and Niche Dynamics in Cancer Progression.
Cancer stem cells (CSCs) have been hypothesized to initiate and drive tumor growth and recurrence due to their self-renewal ability. If correct, this hypothesis implies that successful therapy must focus primarily on eradication of this CSC fraction. However, recent evidence suggests stemness is niche dependent and may represent one of many phenotypic states that can be accessed by many cancer genotypes when presented with specific environmental cues. A better understanding of the relationship of stemness to niche-related phenotypic plasticity could lead to alternative treatment strategies. Here, we investigate the role of environmental context in the expression of stem-like cell properties through in-silico simulation of ductal carcinoma. We develop a two-dimensional hybrid discrete-continuum cellular automata model to describe the single-cell scale dynamics of multicellular tissue formation. Through a suite of simulations, we investigate interactions between a phenotypically heterogeneous cancer cell population and a dynamic environment. We generate homeostatic ductal structures that consist of a mixture of stem and differentiated cells governed by both intracellular and environmental dynamics. We demonstrate that a wide spectrum of tumor-like histologies can result from these structures by varying microenvironmental parameters. Niche driven phenotypic plasticity offers a simple first-principle explanation for the diverse ductal structures observed in histological sections from breast cancer. Conventional models of carcinogenesis largely focus on mutational events. We demonstrate that variations in the environmental niche can produce intraductal cancers independent of genetic changes in the resident cells. Therapies targeting the microenvironmental niche may offer an alternative cancer prevention strategy.


Validation of the Inflammatory Bowel Disease Disability Index in a population-based cohort.
IBDs are chronic destructive disorders that negatively affect the functional status of patients. Recently, the Inflammatory Bowel Disease Disability Index (IBD-DI) was developed according to standard WHO processes. The aims of the current study were to validate the IBD-DI in an independent patient cohort, to develop an index-specific scoring system and to describe the disability status of a well-defined population-based cohort of French patients with IBD. From February 2012 to March 2014, the IBD-DI questionnaire was administered to a random sample of adult patients with an established diagnosis of IBD issued from a French population-based registry. The IBD-DI consists of 28 items that evaluate the four domains of body functions, activity participation, body structures and environmental factors. Validation included item reduction and data structure, construct validity, internal consistency, interobserver and intraobserver reliability evaluations. 150 patients with Crohn's disease (CD) and 50 patients with UC completed the IBD-DI validation phase. The intraclass correlation coefficient for interobserver reliability was 0.91 and 0.54 for intraobserver reliability. Cronbach's α of internal consistency was 0.86. IBD-DI scores varied from 0 to 100 with a mean of 35.3 (Q1=19.6; Q3=51.8). IBD-DI scores were highly correlated with Inflammatory Bowel Disease Questionnaire (-0.82; p<0.001) and SF-36 (-0.61; p<0.05) scores. Female gender (p<0.001), clinical disease activity (p<0.0001) and disease duration (p=0.02) were associated with higher IBD-DI scores. The IBD-DI has been validated for use in clinical trials and epidemiological studies. The IBD-DI showed high internal consistency, interobserver reliability and construct validity, and a moderate intraobserver reliability. It comprises 14 questions and ranges from 0 to 100. The mean IBD-DI score was 35.3 and was associated with gender, clinical disease activity and disease duration. Further research is needed to confirm the structural validity and to assess the responsiveness of IBD-DI. 2011-A00877-34.


Learning AND-OR templates for object recognition and detection.
This paper presents a framework for unsupervised learning of a hierarchical reconfigurable image template--the AND-OR Template (AOT) for visual objects. The AOT includes: 1) hierarchical composition as "AND" nodes, 2) deformation and articulation of parts as geometric "OR" nodes, and 3) multiple ways of composition as structural "OR" nodes. The terminal nodes are hybrid image templates (HIT) [17] that are fully generative to the pixels. We show that both the structures and parameters of the AOT model can be learned in an unsupervised way from images using an information projection principle. The learning algorithm consists of two steps: 1) a recursive block pursuit procedure to learn the hierarchical dictionary of primitives, parts, and objects, and 2) a graph compression procedure to minimize model structure for better generalizability. We investigate the factors that influence how well the learning algorithm can identify the underlying AOT. And we propose a number of ways to evaluate the performance of the learned AOTs through both synthesized examples and real-world images. Our model advances the state of the art for object detection by improving the accuracy of template matching.


Impact of epilepsy surgery on seizure control and quality of life: a 26-year follow-up study.
The short-term efficacy and safety of epilepsy surgery relative to medical therapy has been established, but it remains underutilized. There is a lack of data regarding the long-term seizure-control rates and quality of life outcomes after epilepsy surgery. This study represents the longest follow-up study to date, with a mean follow-up duration of 26 years. We studied the seizure and health-related quality of life outcomes of patients who underwent epilepsy surgery by Dr. Sidney Goldring from 1967 to 1990. Retrospective clinical chart reviews gathered perioperative data and surveys obtained follow-up data. Seizure outcome was evaluated using the Engel classification system. Of 361 patients, 117 (32.4%) completed follow-up interviews. Fifty-six patients (48%) were Engel class I. Mean overall Quality of Life in Epilepsy (QOLIE-31) questionnaire score for the cohort was 68.2 ± 16. Eighty percent of patients reported their overall quality of life now as being better than before surgery. Seizure freedom was associated with better quality of life. We did not observe a statistically significant association between postoperative complications and long-term outcome. Patients who underwent temporal lobe resection achieved better seizure outcomes than those who underwent other types of procedures. Astatic seizures and bilateral surgery were associated with a worse Engel class outcome. Our study demonstrates that the beneficial effects of epilepsy surgery are sustained over decades, and that these beneficial effects are correlated with an improved quality of life. The confirmation of its durability makes us optimistic that the outcomes from modern epilepsy surgery will be even better and that our present enthusiasm for this treatment modality is not misplaced.


Three new toxins from the scorpion Pandinus imperator selectively block certain voltage-gated K+ channels.
Three 35-amino acid peptide K+ channel toxins (pandinotoxins) were purified from the venom of the scorpion Pandinus imperaton the toxins are designated pandinotoxin (PiTX)-K alpha, PiTX-K beta, and PiTX-K gamma. In an 86Rb tracer flux assay on rat brain synaptosomes, all three toxins selectively blocked the component of the K(+)-stimulated 86Rb efflux that corresponds to a voltage-gated, rapidly inactivating (A-type) K+ current (IC50 = 6, 42, and 100 nM, respectively). These toxins blocked neither the noninactivating component of the K(+)-stimulated 86Rb efflux (corresponding to a delayed rectifier) nor the Ca(2+)-dependent component of the 86Rb efflux (i.e., a Ca(2+)-activated K+ current) in these terminals. PiTX-K alpha, which was expressed by recombinant methods, also blocked the Kv1.2 channel expressed in fibroblasts (IC50 = 32 pM). PiTX-K alpha and PiTX-K beta have identical amino acid sequences except for the seventh amino acid: a proline in PiTX-K alpha, and a glutamic acid in PiTX-K beta. They have substantial sequence homology, especially at the carboxyl termini, with another scorpion toxin, charybdotoxin (ChTX), which blocks both the Ca(2+)-activated and the rapidly inactivating. K(+)-stimulated 86Rb efflux components in synaptosomes and the Kv 1.2 channel PiTX-K gamma, however, has much less sequence homology. Conserved in all four toxins are three identically positioned disulfide bridges; an asparagine at position 30; and positive charges at positions 27, 31, and 34 (based on ChTX numbering). PiTX-K gamma is novel in that it has a fourth pair of cysteines. The PiTX structures were computer simulated, using ChTX as a model. We speculate that the three-dimensional structures of all three PiTXs resemble that of ChTX: a beta-sheet at the carboxyl terminus, containing three cysteines, is linked to the central alpha-helix by two disulfide bridges (C17-C35 and C13-C33) and to an extended amino-terminal fragment by the third disulfide bridge (C7-C28). Further analysis of the three-dimensional structures reveals differences that may help to explain the selectivity and affinity differences of these toxins.


Historical Biogeography Using Species Geographical Ranges.
Spatial variation in biodiversity is the result of complex interactions between evolutionary history and ecological factors. Methods in historical biogeography combine phylogenetic information with current species locations to infer the evolutionary history of a clade through space and time. A major limitation of most methods for historical biogeographic inference is the requirement of single locations for terminal lineages, reducing contemporary species geographical ranges to a point in two-dimensional space. In reality, geographic ranges usually show complex geographic patterns, irregular shapes, or discontinuities. In this article, we describe a method for phylogeographic analysis using polygonal species geographic ranges of arbitrary complexity. By integrating the geographic diversification process across species ranges, we provide a method to infer the geographic location of ancestors in a Bayesian framework. By modeling migration conditioned on a phylogenetic tree, this approach permits reconstructing the geographic location of ancestors through time. We apply this new method to the diversification of two neotropical bird genera, Trumpeters (Psophia) and Cinclodes ovenbirds. We demonstrate the usefulness of our method (called rase) in phylogeographic reconstruction of species ancestral locations and contrast our results with previous methods that compel researchers to reduce the distribution of species to one point in space. We discuss model extensions to enable a more general, spatially explicit framework for historical biogeographic analysis.


Ascorbic acid decreases the binding affinity of the AT1 receptor for angiotensin II.
Ascorbic acid is an essential vitamin and a powerful antioxidant. Many studies have highlighted the benefits of ascorbic acid for chronic cardiovascular diseases such as hypertension in which angiotensin II (Ang II) plays an significant role. We therefore hypothesized that ascorbic acid could modify the pharmacological properties of the AT(1) receptor for Ang II. Binding studies and Ca(2+) mobilization studies were performed with HEK293 cells stably expressing the AT(1) receptor for Ang II. Smooth muscle contraction studies were performed with rabbit aorta strips that endogenously express the AT(1) receptor. Scatchard analysis revealed that ascorbic acid decreased the binding affinity of the AT(1) receptor without modifying its maximal binding capacity. Ascorbic acid did not modify the binding affinity of the AT(2) receptor for Ang II or of the UT receptor for urotensin II. In single-cell Ca(2+) imaging assays, ascorbic acid reduced the frequency of intracellular Ca(2+) oscillations induced by a low dose of Ang II. In functional assays, ascorbic acid significantly diminished the contraction of rabbit aorta pre-contracted with Ang II but not those pre-contracted with urotensin II. Ascorbic acid decreases the binding affinity of the AT(1) receptor. These results offer a mechanistic explanation for the reported blood pressure lowering effect of ascorbic acid.


Pattern and correlates of out-of-pocket payment (OOP) on female sterilization in India, 1990-2014.
Large scale public investment in family welfare programme has made female sterilization a free service in public health centers in India. Besides, it also provides financial compensation to acceptors. Despite these interventions, the use of contraception from private health centers has increased over time, across states and socio-economic groups in India. Though many studies have examined trends, patterns, and determinants of female sterilization services, studies on out-of-pocket payment (OOP) and compensations on sterilisation are limited in India. This paper examines the trends and variations in out-of-pocket payment (OOP) and compensations associated with female sterilization in India. Data from the National Family Health Survey - 4, 2015-16 was used for the analyses. A composite variable based on compensation received and amount paid by users was computed and categorized into four distinct groups. Multivariate analyses were used to understand the significant predictors of OOP of female sterilization. Public health centers continued to be the major providers of female sterilization services; nearly 77.8% had availed themselves of free sterilization and 61.6% had received compensation for female sterilization. About two-fifths of the women in the economically well-off state like Kerala and one-third of the women in a poor state like Bihar had paid but did not receive any compensation for female sterilization. The OOP on female sterilization varies from 70 to 79% across India. The OOP on female sterilization was significantly higher among the educated and women belonging to the higher wealth quintile linking OOP to ability to pay for better quality of care. Public sector investment in family planning is required to provide free or subsidized provision of family welfare services, especially to women from a poor household. Improving the quality of female sterilization services in public health centers and rationalizing the compensation may extend the reach of family planning services in India.


Linking well-tempered metadynamics simulations with experiments.
Linking experiments with the atomistic resolution provided by molecular dynamics simulations can shed light on the structure and dynamics of protein-disordered states. The sampling limitations of classical molecular dynamics can be overcome using metadynamics, which is based on the introduction of a history-dependent bias on a small number of suitably chosen collective variables. Even if such bias distorts the probability distribution of the other degrees of freedom, the equilibrium Boltzmann distribution can be reconstructed using a recently developed reweighting algorithm. Quantitative comparison with experimental data is thus possible. Here we show the potential of this combined approach by characterizing the conformational ensemble explored by a 13-residue helix-forming peptide by means of a well-tempered metadynamics/parallel tempering approach and comparing the reconstructed nuclear magnetic resonance scalar couplings with experimental data.


[Factors associated with household and family in leprosy transmission in Rio de Janeiro, Brazil].
A cross-sectional study was carried out to characterize the contribution of several household characteristics to the transmission of leprosy. Households with diagnosed cases of illness were compared to two healthy groups. All randomly selected households were located in the municipality of Sao Goncalo, in the State of Rio de Janeiro. Using an aerial map with the description of the census tract, 2,412 cases were marked. Three groups were established, while the household was the analytical unit: group I - households with cases; group II - neighboring households; and group III - households located in tracts with no reported case of illness, that is, outside disease foci. Group I was compared with that of neighboring households using a multiple logistic regression model by conditional methods. Unconditional methods were used to compare groups I and III. Group I as compared to Group II showed an association with age and educational level for households and heads of families. Comparison of characteristics of the heads of families and households with cases of leprosy with those located outside the focus showed that the differential factors were age, type of dwelling, and availability of running water. This is probably due to more recent settlement in a peripheral region where water resources are not available yet. Households are the basic ecological unit, and age and educational level are determinant factors for leprosy morbidity in this area.


Simultaneous multislice inversion contrast imaging using power independent of the number of slices (PINS) and delays alternating with nutation for tailored excitation (DANTE) radio frequency pulses.
A method for simultaneous multislice (SMS) inversion contrast imaging is presented using a combination of the delays alternating with nutation for tailored excitation (DANTE) and the power independent of the number of slices (PINS) techniques. In SMS imaging, simultaneously excited slices result in an aliased image that is disentangled using parallel imaging reconstruction techniques. At high-magnetic field strengths, the peak amplitude and specific absorption rate of conventional (summed) SMS radio frequency pulses can be prohibitively high. Using the PINS approach, specific absorption rate is independent of the number of slices allowing high SMS acceleration factors even at high fields. Using DANTE, adiabatic SMS radio frequency pulses can be created to be combined with PINS. This allows 2D imaging protocols that employ adiabatic pulses to also reap the benefits of low specific absorption rate SMS acceleration. As a proof-of-concept, simulations and measurements using hyperbolic secant inversion pulses are shown.


Detailed characterization of, and clinical correlations in, 10 patients with distal deletions of chromosome 9p.
Deletions of distal 9p are associated with trigonocephaly, mental retardation, dysmorphic facial features, cardiac anomalies, and abnormal genitalia. Previous studies identified a proposed critical region for the consensus phenotype in band 9p23, between 11.8 Mb and 16 Mb from the 9p telomere. Here we report 10 new patients with 9p deletions; 9 patients have clinical features consistent with 9p- syndrome, but possess terminal deletions smaller than most reported cases, whereas one individual lacks the 9p- phenotype and shows a 140-kb interstitial telomeric deletion inherited from his mother. We combined fluorescence in situ hybridization and microarray analyses to delineate the size of each deletion. The deletion sizes vary from 800 kb to 12.4 Mb in our patients with clinically relevant phenotypes. Clinical evaluation and comparison showed little difference in physical features with regard to the deletion sizes. Severe speech and language impairment were observed in all patients with clinically relevant phenotypes. The smallest deleted region common to our patients who demonstrate a phenotype consistent with 9p- is <2 Mb of 9pter, which contains six known genes. These genes may contribute to some of the cardinal features of 9p deletion syndrome.


AKT1 Inhibits Epithelial-to-Mesenchymal Transition in Breast Cancer through Phosphorylation-Dependent Twist1 Degradation.
Epithelial-to-mesenchymal transition (EMT) is an essential physiologic process that promotes cancer cell migration, invasion, and metastasis. Several lines of evidence from both cellular and genetic studies suggest that AKT1/PKBα, but not AKT2 or AKT3, serves as a negative regulator of EMT and breast cancer metastasis. However, the underlying mechanism by which AKT1 suppresses EMT remains poorly defined. Here, we demonstrate that phosphorylation of Twist1 by AKT1 is required for β-TrCP-mediated Twist1 ubiquitination and degradation. The clinically used AKT inhibitor MK-2206, which possesses higher specificity toward AKT1, stabilized Twist1 and enhanced EMT in breast cancer cells. However, we discovered that resveratrol, a naturally occurring compound, induced β-TrCP-mediated Twist1 degradation to attenuate MK-2206-induced EMT in breast cancer cells. Taken together, our findings demonstrate that resveratrol counteracts the unexpected metastatic potential induced by anti-AKT therapy and therefore suggest that the addition of resveratrol to an anti-AKT therapeutic regimen may provide extra support for limiting EMT.


1% permethrin cream rinse vs 1% lindane shampoo in treating pediculosis capitis.
The therapeutic efficacy and tolerance of a single application of 1% permethrin cream rinse, applied for ten minutes, and a single application of 1% lindane shampoo applied, as recommended by the manufacturer, for four minutes, against the head louse Pediculus humanus var capitis were compared in a single-blinded, randomized, controlled clinical trial. Of 573 patients enrolled at eight centers, 559 were assessable for tolerance and 508 for efficacy. Of the 257 patients treated with 1% permethrin cream rinse, 99% were lice free at 14 days; of the 251 patients treated with 1% lindane shampoo, 85% were lice free at 14 days. The difference is statistically significant. For both treatments, adverse experiences were infrequent, mild, and usually difficult to distinguish from the symptoms of head lice infestation. A single ten-minute application of 1% permethrin cream rinse was well tolerated, highly effective, and therapeutically superior to a single four-minute application of 1% lindane shampoo.


Synchronized retrovirus fusion in cells expressing alternative receptor isoforms releases the viral core into distinct sub-cellular compartments.
Disparate enveloped viruses initiate infection by fusing with endosomes. However, the highly diverse and dynamic nature of endosomes impairs mechanistic studies of fusion and identification of sub-cellular sites supporting the nucleocapsid release. We took advantage of the extreme stability of avian retrovirus-receptor complexes at neutral pH and of acid-dependence of virus-endosome fusion to isolate the latter step from preceding asynchronous internalization/trafficking steps. Viruses were trapped within endosomes in the presence of NH₄Cl. Removal of NH₄Cl resulted in a quick and uniform acidification of all subcellular compartments, thereby initiating synchronous viral fusion. Single virus imaging demonstrated that fusion was initiated within seconds after acidification and often culminated in the release of the viral core from an endosome. Comparative studies of cells expressing either the transmembrane or GPI-anchored receptor isoform revealed that the transmembrane receptor delivered the virus to more fusion-permissive compartments. Thus the identity of endosomal compartments, in addition to their acidity, appears to modulate viral fusion. A more striking manifestation of the virus delivery to distinct compartments in the presence of NH₄Cl was the viral core release into the cytosol of cells expressing the transmembrane receptor and into endosomes of cells expressing the GPI-anchored isoform. In the latter cells, the newly released cores exhibited restricted mobility and were exposed to a more acidic environment than the cytoplasm. These cores appear to enter into the cytosol after an additional slow temperature-dependent step. We conclude that the NH₄Cl block traps the virus within intralumenal vesicles of late endosomes in cells expressing the GPI-anchored receptor. Viruses surrounded by more than one endosomal membrane release their core into the cytoplasm in two steps--fusion with an intralumenal vesicle followed by a yet unknown temperature-dependent step that liberates the core from late endosomes.


NIOSH Manual of Analytical Methods 5th Edition and Harmonization of Occupational Exposure Monitoring.
The NIOSH Manual of Analytical Methods (NMAM: www.cdc.gov/niosh/nmam) is a collection of methods for sampling and analysis of contaminants in workplace air (or surfaces) and in the blood and urine of workers who are occupationally exposed. NIOSH methods are used worldwide for occupational exposure assessment to chemical and biological agents. These methods have been developed or adapted by NIOSH and/or its partners and have been evaluated according to established experimental protocols and performance criteria. NMAM also includes associated chapters on quality assurance, sampling guidance, instrumentation, aerosol measurement, gas and vapor monitoring, portable monitoring devices, and so forth. Often NIOSH methods are developed in coordination with voluntary consensus standards organizations such as ASTM International, the Comité Européen de Normalisation (European Committee for Standardization, CEN) and the International Organization for Standardization (ISO). Efforts to harmonize NIOSH methods with relevant consensus standards procedures are of particular interest and are highlighted. NIOSH also has a formal Memorandum of Understanding (MOU) with the Institut für Arbeitsschutz der Deutschen Geseltzlichen Unfallversicherung (Institute for Occupational Safety and Health of the German Social Accident Insurances, IFA), whereby NIOSH is adopting selected IFA methods and vice-versa. An overview of recent research and technology transfer activities relating to NMAM methods is provided, with selected examples in applications to exposure science, notably workplace air monitoring. Included in the discussion are newly approved methods and those under development, as well as needs for new methods and updates. Of particular interest are recent NIOSH recommendations and associated research on air samplers used for sampling and analysis of airborne particles.


Lipid metabolism of rumen ciliates and bacteria. II. Uptake of fatty acids and lipid analysis of Isotricha intestinalis and rumen bacteria with further information on Entodinium simplex.
The total lipid and free fatty acid contents of Isotricha intestinalis, Entodinium simplex, and the rumen bacterial flora of the respective protozoa were determined. Warburg manometric data showed that the sodium salts of tributyrin, oleic, and acetic acids stimulated gas production in I. intestinalis, whereas tributyrin was stimulatory with E. simplex and less active with oleic and acetic acids. Rumen bacteria provided fatty acids produced lower manometric gaseous increases when compared with the protozoa. Volatile fatty acids were produced by I. intestinalis and rumen bacteria with tributyrin, but not with tripalmitin. Sodium oleate gave little volatile fatty acid response with I. intestinalis or rumen bacteria. Washed suspensions of I. intestinalis and rumen bacteria concentrated C(14)-labeled oleic, palmitic, stearic, and linoleic acids within the cells during short incubation periods. Autoradiographs demonstrated the conversion of C(14)-labeled oleic, palmitic, stearic, linoleic, and acetic acids in the rumen protozoa and bacterial cells.


Hypothyroidism Presenting as Psychosis: Myxedema Madness Revisited.
Hypothyroidism is a medical condition commonly encountered in a variety of clinical settings. The clinical presentations of thyroid hormone deficiency are diverse, complicated, and often overlooked. Hypothyroidism is a potential etiology for multiple somatic complaints and a variety of psychological disturbances. The physical complaints are primarily related to metabolic slowing secondary to lack of thyroid hormone. Psychiatric presentations include cognitive dysfunction, affective disorders, and psychosis. The realization that hypothyroidism might be the potential etiology of an assortment of symptoms is critical in the identification and treatment of the hypothyroid patient. Once hypothyroidism is identified, symptoms usually respond to appropriate thyroid hormone supplementation. This article presents a case of clinical hypothyroidism that came to clinical attention due to psychotic symptoms consisting of auditory and visual hallucinations. The case is followed by a brief discussion of the literature describing the relationship of hypothyroidism and psychiatric symptomatology. References were identified with an English language-based MEDLINE search (1966-2003) using the terms thyroid, hypothyroid, depression, dementia, delirium, mania, bipolar disorder, psychosis, and myxedema and utilization of referenced articles.


Interventions to improve district-level routine health data in low-income and middle-income countries: a systematic review.
Routine health information system(s) (RHIS) facilitate the collection of health data at all levels of the health system allowing estimates of disease prevalence, treatment and preventive intervention coverage, and risk factors to guide disease control strategies. This core health system pillar remains underdeveloped in many low-income and middle-income countries. Efforts to improve RHIS data coverage, quality and timeliness were launched over 10 years ago. A systematic review was performed across 12 databases and literature search engines for both peer-reviewed articles and grey literature reports on RHIS interventions. Studies were analysed in three stages: (1) categorisation of RHIS intervention components and processes; (2) comparison of intervention component effectiveness and (3) whether the post-intervention outcome improved above the WHO integrated disease surveillance response framework data quality standard of 80% or above. 5294 references were screened, resulting in 56 studies. Three key performance determinants-technical, organisational and behavioural-were proposed as critical to RHIS strengthening. Seventy-seven per cent [77%] of studies identified addressed all three determinants. The most frequently implemented intervention components were 'providing training' and 'using an electronic health management information systems'. Ninety-three per cent [93%] of pre-post or controlled trial studies showed improvements in one or more data quality outputs, but after applying a standard threshold of >80% post-intervention, this number reduced to 68%. There was an observed benefit of multi-component interventions that either conducted data quality training or that addressed improvement across multiple processes and determinants of RHIS. Holistic data quality interventions that address multiple determinants should be continuously practised for strengthening RHIS. Studies with clearly defined and pragmatic outcomes are required for future RHIS improvement interventions. These should be accompanied by qualitative studies and cost analyses to understand which investments are needed to sustain high-quality RHIS in low-income and middle-income countries.


The regularized iteratively reweighted MAD method for change detection in multi- and hyperspectral data.
This paper describes new extensions to the previously published multivariate alteration detection (MAD) method for change detection in bi-temporal, multi- and hypervariate data such as remote sensing imagery. Much like boosting methods often applied in data mining work, the iteratively reweighted (IR) MAD method in a series of iterations places increasing focus on "difficult" observations, here observations whose change status over time is uncertain. The MAD method is based on the established technique of canonical correlation analysis: for the multivariate data acquired at two points in time and covering the same geographical region, we calculate the canonical variates and subtract them from each other. These orthogonal differences contain maximum information on joint change in all variables (spectral bands). The change detected in this fashion is invariant to separate linear (affine) transformations in the originally measured variables at the two points in time, such as 1) changes in gain and offset in the measuring device used to acquire the data, 2) data normalization or calibration schemes that are linear (affine) in the gray values of the original variables, or 3) orthogonal or other affine transformations, such as principal component (PC) or maximum autocorrelation factor (MAF) transformations. The IR-MAD method first calculates ordinary canonical and original MAD variates. In the following iterations we apply different weights to the observations, large weights being assigned to observations that show little change, i.e., for which the sum of squared, standardized MAD variates is small, and small weights being assigned to observations for which the sum is large. Like the original MAD method, the iterative extension is invariant to linear (affine) transformations of the original variables. To stabilize solutions to the (IR-)MAD problem, some form of regularization may be needed. This is especially useful for work on hyperspectral data. This paper describes ordinary two-set canonical correlation analysis, the MAD transformation, the iterative extension, and three regularization schemes. A simple case with real Landsat Thematic Mapper (TM) data at one point in time and (partly) constructed data at the other point in time that demonstrates the superiority of the iterative scheme over the original MAD method is shown. Also, examples with SPOT High Resolution Visible data from an agricultural region in Kenya, and hyperspectral airborne HyMap data from a small rural area in southeastern Germany are given. The latter case demonstrates the need for regularization.


Autophagy and endosomal trafficking inhibition by Vibrio cholerae MARTX toxin phosphatidylinositol-3-phosphate-specific phospholipase A1 activity.
Vibrio cholerae, responsible for acute gastroenteritis secretes a large multifunctional-autoprocessing repeat-in-toxin (MARTX) toxin linked to evasion of host immune system, facilitating colonization of small intestine. Unlike other effector domains of the multifunctional toxin that target cytoskeleton, the function of alpha-beta hydrolase (ABH) remained elusive. This study demonstrates that ABH is an esterase/lipase with catalytic Ser-His-Asp triad. ABH binds with high affinity to phosphatidylinositol-3-phosphate (PtdIns3P) and cleaves the fatty acid in PtdIns3P at the sn1 position in vitro making it the first PtdIns3P-specific phospholipase A1 (PLA1). Expression of ABH in vivo reduces intracellular PtdIns3P levels and its PtdIns3P-specific PLA1 activity blocks endosomal and autophagic pathways. In accordance with recent studies acknowledging the potential of extracellular pathogens to evade or exploit autophagy to prevent their clearance and facilitate survival, this is the first report highlighting the role of ABH in inhibiting autophagy and endosomal trafficking induced by extracellular V. cholerae.


Occupational balance in health professionals in Sweden.
Health care employees are often women, a group that has high degrees of sick leave and perhaps problems attaining occupational balance. However, people think differently about their everyday activities and it is therefore important to take their perceptions into account but occupational balance has not yet been measured in health professionals. The aim was to describe occupational balance in three different samples of health professionals in Sweden. A further aim was to investigate whether occupational therapists (OTs) rate their occupational balance differently from other health professionals. Four hundred and eighty-two health professionals, employees in public dentistry, mental health care and OTs, aged 21-70 years participated. The participants' occupational balance was measured using the occupational balance questionnaire (OBQ). The ratings of occupational balance were similar to earlier studies and did not differ significantly between the samples. The OTs' occupational balance was also similar to that of the other health professionals. The similarities in occupational balance indicate the same difficulties in attaining it. The result highlights the possibility that working people face similar difficulties in achieving occupational balance. Further research is warranted about how to attain it.


Evidence-based translation for the genomic responses of murine models for the study of human immunity.
Murine models are an essential tool to study human immune responses and related diseases. However, the use of traditional murine models has been challenged by recent systemic surveys that show discordance between human and model immune responses in their gene expression. This is a significant problem in translational biomedical research for human immunity. Here, we describe evidence-based translation (EBT) to improve the analysis of genomic responses of murine models in the translation to human immune responses. Based on evidences from prior experiments, EBT introduces pseudo variances, penalizes gene expression changes in a model experiment, and finally detects false positive translations of model genomic responses that poorly correlate with human responses. Demonstrated over multiple data sets, EBT significantly improves the agreement of overall responses (up to 56%), experiment-specific responses (up to 143%), and enriched biological contexts (up to 100%) between human and model systems. In addition, we provide the category of genes specifically benefiting from EBT and the factors affecting the performance of EBT. The overall result indicates the usefulness of the proposed computational translation in biomedical research for human immunity using murine models.