Numerical continuation in nonlinear experiments using local Gaussian process regression

Control-based continuation (CBC) is a general and systematic method to probe the dynamics of nonlinear experiments. In this paper, CBC is combined with a novel continuation algorithm that is robust to experimental noise and enables the tracking of geometric features of the response surface such as folds. The method uses Gaussian process regression to create a local model of the response surface on which standard numerical continuation algorithms can be applied. The local model evolves as continuation explores the experimental parameter space, exploiting previously captured data to actively select the next data points to collect such that they maximise the potential information gain about the feature of interest. The method is demonstrated experimentally on a nonlinear structure featuring harmonically coupled modes. Fold points present in the response surface of the system are followed and reveal the presence of an isola, i.e. a branch of periodic responses detached from the main resonance peak

Hirschsprung's disease in the newborn

The records of all patients with Hirschsprung's disease diagnosed and treated at our institution between 1 July 1974 and 31 August 1985 were reviewed. Of these 99 patients, 35 (35%) presented and were diagnosed within the first 30 days of life and constitute the basis of the present study group. Twenty-two infants (63%) had standard rectosigmoid disease with a male-to-female ratio of 2.2:1. Only one infant was premature. The spectrum of presenting signs included abdominal distension in 19 (54%), failure to pass meconium within the first 48 h of life in 16 (46%), “constipation” in 12 (34%), and vomiting in 9 (26%). Intestinal perforation was a presenting sign in 2 patients (6%) and enterocolitis occurred preoperatively in 4 (12%). Evaluation was facilitated by diagnostic barium enema in 60% of the patients. In those infants able to undergo elective evaluation, the definitive diagnosis was made by suction rectal biopsy, which was accurate in all cases. In addition to the high proportion of patients with long-segment disease (13 patients, 37%), there was a significant incidence of associated congenital anomalies (26%), including Down's syndrome in 5 (14%). Thirty-three of the 35 patients have undergone definitive treatment using the endorectal pull-through procedure, performed at an average age of 12 months, with no mortality related to the operation. In addition to highlighting the high incidence of congenital anomalies, the large proportion of neonates with long-segment disease, and the reliability of the diagnostic barium enema, this subgroup of patients with Hirschsprung's disease emphasizes the special diagnostic and management considerations required in the newborn infant who presents with sepsis of unknown etiology, intestinal obstruction, or constipation. A high index of suspicion, liberal use of suction rectal biopsy, early leveling colostomy, and definitive treatment by endorectal pull-through are important in achieving 0% operative mortality and excellent functional results.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47145/1/383_2004_Article_BF00166865.pd

Safety of long-term denosumab therapy: results from the open label extension phase of two phase 3 studies in patients with metastatic breast and prostate cancer

Purpose: Zoledronic acid (ZA) or denosumab treatment reduces skeletal-related events; however, the safety of prolonged therapy has not been adequately studied. Here, we describe safety results of extended denosumab therapy in patients with bone metastases from the open-label extension phase of two phase 3 trials. Methods: Patients with metastatic breast or prostate cancer received subcutaneous denosumab 120 mg Q4W or intravenous ZA 4 mg Q4W in a double-blinded fashion. Denosumab demonstrated superior efficacy in the blinded treatment phase; thus, patients were offered open-label denosumab for up to an additional 2 years. Results: Cumulative median (Q1, Q3) denosumab exposure was 19.1 (9.2, 32.2) months in the breast cancer trial (n = 1019) and 12.0 (5.6, 21.3) months in the prostate cancer trial (n = 942); 295 patients received denosumab for >3 years. No new safety signals were identified during the open-label phase, or among patients who switched from ZA to denosumab. During the blinded treatment phase, exposure-adjusted subject incidences of osteonecrosis of the jaw (ONJ) were 49 (1.9 %) and 31 (1.2 %) in the denosumab and ZA groups, respectively. In total, 32 (6.9 %) and 25 (5.5 %) new cases of ONJ (not adjusted for exposure) were reported for patients continuing and switching to denosumab, respectively. The incidences of hypocalcemia were 4.3 and 3.1 %, in patients continuing and switching to denosumab, respectively. Conclusion: These results describe the safety profile of denosumab after long-term exposure, or after switching to denosumab from ZA. No new safety signals were identified. Hypocalcemia rates were similar in the blinded treatment and open-label phases. ONJ rates increased with increasing exposure to antiresorptives, consistent with previous reports

Clinical decision-making: physicians' preferences and experiences

BACKGROUND: Shared decision-making has been advocated; however there are relatively few studies on physician preferences for, and experiences of, different styles of clinical decision-making as most research has focused on patient preferences and experiences. The objectives of this study were to determine 1) physician preferences for different styles of clinical decision-making; 2) styles of clinical decision-making physicians perceive themselves as practicing; and 3) the congruence between preferred and perceived style. In addition we sought to determine physician perceptions of the availability of time in visits, and their role in encouraging patients to look for health information. METHODS: Cross-sectional survey of a nationally representative sample of U.S. physicians. RESULTS: 1,050 (53% response rate) physicians responded to the survey. Of these, 780 (75%) preferred to share decision-making with their patients, 142 (14%) preferred paternalism, and 118 (11%) preferred consumerism. 87% of physicians perceived themselves as practicing their preferred style. Physicians who preferred their patients to play an active role in decision-making were more likely to report encouraging patients to look for information, and to report having enough time in visits. CONCLUSION: Physicians tend to perceive themselves as practicing their preferred role in clinical decision-making. The direction of the association cannot be inferred from these data; however, we suggest that interventions aimed at promoting shared decision-making need to target physicians as well as patients

Sharpin Contributes to TNFα Dependent NFκB Activation and Anti-Apoptotic Signalling in Hepatocytes

TNFα stimulates both pro- and anti-apoptotic signalling in hepatocytes. Anti-apoptotic signalling depends on a cascade of ubiquitylation steps leading to NFκB activation. Using Sharpin-deficient mice, we show that the ubiquitin binding protein Sharpin interacts with Hoip, an E3 ligase which generates linear ubiquitin chains. Sharpin-deficiency sensitized hepatocytes to induction of apoptosis by TNFα even in the absence of transcriptional inhibition. TNFα induced activation of NFκB was strongly reduced in hepatocytes from Sharpin-deficient mice, due to reduced and delayed phosphorylation and degradation of IκBα. Injection of TNFα-inducing lipopolysaccharides led to strongly exacerbated liver damage and premature death in Sharpin-deficient mice. Our findings point to an essential role of Sharpin in linear ubiquitin chain formation, NFκB activation, and protection of the liver against inflammatory damaging signals

Readability estimates for commonly used health-related quality of life surveys

To estimate readability of seven commonly used health-related quality of life instruments: SF-36, HUI, EQ-5D, QWB-SA, HALex, Minnesota Living with Heart Failure Questionnaire (MLHFQ), and the NEI-VFQ-25. The Flesch–Kincaid (F–K) and Flesch Reading Ease (FRE) formulae were used to estimate readability for every item in each measure. The percentage of items that require more than 5 years of formal schooling according to F–K was 50 for the EQ-5D, 53 for the SF-36, 80 for the VFQ-25, 85 for the QWB-SA, 100 for the HUI, HALex, and the MLHFQ. The percentage of items deemed harder than “easy” according to FRE was 50 for the SF-36, 67 for the EQ-5D, 79 for the QWB-SA, 80 for the VFQ-25, 100 for the HUI, HALex, and the MLHFQ. All seven surveys have a substantial number of items with high readability levels that may not be appropriate for the general population

Measuring health-related quality of life for child maltreatment: a systematic literature review

<p>Abstract</p> <p>Background</p> <p>Child maltreatment causes substantial morbidity and mortality in the U.S. Morbidity associated with child maltreatment can reduce health-related quality of life. Accurately measuring the reduction in quality of life associated with child maltreatment is essential to the economic evaluation of educational programs and interventions to reduce the incidence of child maltreatment. The objective of this study was to review the literature for existing approaches and instruments for measuring quality-of-life for child maltreatment outcomes.</p> <p>Methods</p> <p>We reviewed the current literature to identify current approaches to valuing child maltreatment outcomes for economic evaluations. We also reviewed available preference-based generic QOL instruments (EQ-5D, HUI, QWB, SF-6D) for appropriateness in measuring change in quality of life due to child maltreatment.</p> <p>Results</p> <p>We did not identify any studies that directly evaluated quality-of-life in maltreated children. We identified 4 studies that evaluated quality of life for adult survivors of child maltreatment and 8 studies that measured quality-of-life for pediatric injury not related to child maltreatment. No study reported quality-of-life values for children younger than age 3.</p> <p>Currently available preference-based QOL instruments (EQ-5D, HUI, QWB, SF-6D) have been developed primarily for adults with the exception of the Health Utilities Index. These instruments do not include many of the domains identified as being important in capturing changes in quality of life for child maltreatment, such as potential for growth and development or psychological sequelae specific to maltreatment.</p> <p>Conclusion</p> <p>Recommendations for valuing preference-based quality-of-life for child maltreatment will vary by developmental level and type of maltreatment. In the short-term, available multi-attribute utility instruments should be considered in the context of the type of child maltreatment being measured. However, if relevant domains are not included in existing instruments or if valuing health for children less than 6 years of age, direct valuation with a proxy respondent is recommended. The choice of a proxy respondent is not clear in the case of child maltreatment since the parent may not be a suitable proxy. Adult survivors should be considered as appropriate proxies. Longer-term research should focus on identifying the key domains for measuring child health and the development of preference-based quality-of-life instruments that are appropriate for valuing child maltreatment outcomes.</p

A school-based physical activity program to improve health and fitness in children aged 6–13 years ("Kinder-Sportstudie KISS"): study design of a randomized controlled trial [ISRCTN15360785]

BACKGROUND: Childhood obesity is the result of a long lasting imbalance between energy intake and energy expenditure. A major contributing factor is physical inactivity which is closely linked to bone health, cardiovascular disease risk, fitness and psychological factors. The school seems to provide an excellent setting to enhance levels of physical activity (PA). However, there is insufficient data from previous school-based intervention trials on how to enhance overall PA. It is also unknown whether an intervention aimed at increasing PA is effective in improving the children's health. The purpose of this paper is to outline the design of a school-based randomized, controlled trial (RCT) aiming to increase overall PA and to improve fitness and health in 6- to 13-year-old children. METHODS/DESIGN: 15 schools were randomized to the intervention (n = 9) or the control (n = 6) group, stratified by geographic region (urban vs. rural) and by age (1(st )and 5(th )grade). Participation was given for all children in the intervention group since in this group the intervention was part of the normal school curriculum. The intervention during one academic year consisted of: 1. two additional physical education classes per week given by trained physical education teachers adding up to a total of five PA classes per week, 2. short PA breaks (2–5 min each) during academic lessons, 3. PA home work, and 4. adaptation of recreational areas around the school. All children underwent anthropometric measurements, blood pressure assessment, fitness testing, measurement of PA and they filled out questionnaires. At least 70% of all children agreed to blood sampling and measurements of body composition and bone mineral measurements by dual energy x-ray absorptiometry. The primary endpoints of the study after one year were an increase in total PA by accelerometry, an increase in aerobic fitness measured by the 20 m shuttle run, a decrease in percent body fat derived from skinfold measurements and an increase in quality of life as assessed by the child health questionnaire in the intervention group compared to the control group. Secondary outcomes were overall fitness, differences in body composition including body fat distribution, cardiovascular risk factors, psychosocial health, bone mineral content and density of femur, lumbar spine and total body and food intake. DISCUSSION: Our preliminary data suggest that the children were representative of Swiss children with respect to sex, socio-demographic status, and body mass index. Short-term results can be expected by the beginning of 2007. We hypothesized that our intervention will lead to an increase in PA, fitness and overall health. Based on our data, we aim to provide important information regarding the influence of such an intervention on these outcome measures in school-aged children and to provide nationwide guidelines to improve PA in children

Dissection of the Complex Phenotype in Cuticular Mutants of Arabidopsis Reveals a Role of SERRATE as a Mediator

Mutations in LACERATA (LCR), FIDDLEHEAD (FDH), and BODYGUARD (BDG) cause a complex developmental syndrome that is consistent with an important role for these Arabidopsis genes in cuticle biogenesis. The genesis of their pleiotropic phenotypes is, however, poorly understood. We provide evidence that neither distorted depositions of cutin, nor deficiencies in the chemical composition of cuticular lipids, account for these features, instead suggesting that the mutants alleviate the functional disorder of the cuticle by reinforcing their defenses. To better understand how plants adapt to these mutations, we performed a genome-wide gene expression analysis. We found that apparent compensatory transcriptional responses in these mutants involve the induction of wax, cutin, cell wall, and defense genes. To gain greater insight into the mechanism by which cuticular mutations trigger this response in the plants, we performed an overlap meta-analysis, which is termed MASTA (MicroArray overlap Search Tool and Analysis), of differentially expressed genes. This suggested that different cell integrity pathways are recruited in cesA cellulose synthase and cuticular mutants. Using MASTA for an in silico suppressor/enhancer screen, we identified SERRATE (SE), which encodes a protein of RNA–processing multi-protein complexes, as a likely enhancer. In confirmation of this notion, the se lcr and se bdg double mutants eradicate severe leaf deformations as well as the organ fusions that are typical of lcr and bdg and other cuticular mutants. Also, lcr does not confer resistance to Botrytis cinerea in a se mutant background. We propose that there is a role for SERRATE-mediated RNA signaling in the cuticle integrity pathway