Investigation of critical heat fluxes in vertical tubes internally cooled by Freon-12, Part I - critical heat flux experiments with axially uniform and non-uniform heating and comparisons of data with selected correlations.

Experiments have been performed using vertical heated tubes cooled internally by Freon-12 to determine critical heat fluxes (CHFs) for both a uniformly heated section and an exit region with a separately controlled power supply. Heated lengths of the main separately were 2870 mm (8.48 and 16.76 mm tube bores) and 3700 mm (for 21.34 mm tube bore); heated length of the exit section was 230 mm. Coolant pressures exit qualities and mass fluxes were in the range 0.9 to 1.3 MPa 0.19 to 0.86 and 380 to 2800 kg m -2 -1 respectively. The data have been compared with published empirical correlations specifically formulated to predict CHFs in Freon-cooled vertical tubes; relevant published CHF data have also been compared with these correlations. These comparisons show that even over the ranges of conditions for which the correlations were developed predicted values are only accurate to within +-20 per cent. Moreover as mass fluxes increase above 3500 kg m - 2 -1 the modified Groeneveld correlation becomes increasingly inadequate and the Bertoletti and modified Bertoletti correlations under-predict CHF values by increasing amounts. At mass fluxes below 750 kg m - 2 -1 the Bertoletti correlations exhibit increasing inaccuracy with a decrease in mass flux. For non-uniform heating the correlations are at variance with the experimental data

Vedolizumab for Treating Moderately to Severely Active Crohn’s Disease After Prior Therapy: An Evidence Review Group Perspective of a NICE Single Technology Appraisal

As part of its single technology appraisal process, the National Institute for Health and Care Excellence (NICE) invited the manufacturer of vedolizumab (Takeda UK) to submit evidence of the clinical effectiveness and cost effectiveness of vedolizumab for the treatment of patients with moderate-to-severe, active Crohn’s disease. The School of Health and Related Research (ScHARR) at the University of Sheffield was commissioned as the Evidence Review Group (ERG) and produced a critical review of the evidence of the clinical effectiveness and cost effectiveness of the technology, based upon the company’s submission to NICE. The GEMINI II and III trials formed the main supporting evidence for the intervention. Both studies were phase III, randomised, double-blind, placebo-controlled, multicentre trials designed to evaluate the efficacy and safety of vedolizumab. They included patients who were naïve to tumour necrosis factor alpha antagonist (anti-TNF-α) therapy and patients who had an inadequate response to, loss of response to or intolerance of immunomodulators or anti-TNF-α agents. GEMINI II was designed to evaluate the efficacy and safety of vedolizumab as an induction treatment (dosing at weeks 0 and 2, with assessment at week 6) and maintenance treatment (during weeks 6–52). In contrast, GEMINI III was designed to evaluate the efficacy and safety of vedolizumab as an induction treatment only, with doses at weeks 0, 2 and 6, and assessment at weeks 6 and 10. In the absence of any direct head-to-head, randomised, controlled trials comparing vedolizumab with other relevant biologic therapies (adalimumab and infliximab) for the treatment of moderate-to-severe Crohn’s disease, the company conducted a network meta-analysis, which compared vedolizumab, adalimumab, infliximab and placebo for the outcomes of clinical response, enhanced clinical response, clinical remission and discontinuation due to adverse events. The company model estimated the incremental cost-effectiveness ratio (ICER) for vedolizumab compared with the standard of care (consisting of 5-aminosalicylic acids, corticosteroids and immunosuppressants) to be £21,620 per quality-adjusted life-year (QALY) gained within the anti-TNF-α-failure population (which included a confidential patient access scheme for vedolizumab). The ICERs were above £30,000 per QALY gained for the mixed intention-to-treat population (including both anti-TNF-α-naïve and anti-TNF-α-failure populations) and in patients who were anti-TNF-α naïve only. The ERG identified a number of limitations that were believed to limit the robustness of the results presented by the company. These limitations could not be addressed by the ERG without major restructuring of the economic model. Therefore, the ERG concluded that the results from the company’s model needed to be interpreted with caution and that it was unclear whether the ICERs would increase or decrease following amendment of the identified structural issues

A drug-repositioning screen using splicing-sensitive fluorescent reporters identifies novel modulators of VEGF-A splicing with anti-angiogenic properties.

Alternative splicing of the vascular endothelial growth factor A (VEGF-A) terminal exon generates two protein families with differing functions. Pro-angiogenic VEGF-Axxxa isoforms are produced via selection of the proximal 3' splice site of the terminal exon. Use of an alternative distal splice site generates the anti-angiogenic VEGF-Axxxb proteins. A bichromatic splicing-sensitive reporter was designed to mimic VEGF-A alternative splicing and was used as a molecular tool to further investigate this alternative splicing event. Part of VEGF-A's terminal exon and preceding intron were inserted into a minigene construct followed by the coding sequences for two fluorescent proteins. A different fluorescent protein is expressed depending on which 3' splice site of the exon is used during splicing (dsRED denotes VEGF-Axxxa and EGFP denotes VEGF-Axxxb). The fluorescent output can be used to follow splicing decisions in vitro and in vivo. Following successful reporter validation in different cell lines and altering splicing using known modulators, a screen was performed using the LOPAC library of small molecules. Alterations to reporter splicing were measured using a fluorescent plate reader to detect dsRED and EGFP expression. Compounds of interest were further validated using flow cytometry and assessed for effects on endogenous VEGF-A alternative splicing at the mRNA and protein level. Ex vivo and in vitro angiogenesis assays were used to demonstrate the anti-angiogenic effect of the compounds. Furthermore, anti-angiogenic activity was investigated in a Matrigel in vivo model. To conclude, we have identified a set of compounds that have anti-angiogenic activity through modulation of VEGF-A terminal exon splicing

Measuring and Valuing Health-Related Quality of Life among Children and Adolescents in Mainland China - A Pilot Study

Background: The Child Health Utility 9D (CHU9D), a new generic preference-based health-related quality of life (HRQoL) instrument, has been validated for use in young people in both the UK and Australia. The main objectives of this study were to examine the feasibility of using a Chinese version of the CHU9D (CHU9D-CHN) to assess HRQoL and to investigate the association of physical activity, homework hours and sleep duration with HRQoL in children and adolescents in Mainland China. Methods: Data were collected using a multi-stage sampling method from grades 4–12 students in May 2013 in Nanjing, China. Consenting participants (N = 815) completed a self-administered questionnaire including the CHU9D-CHN instrument and information on physical activity, homework and sleep duration, self-reported health status, and socio-demographic characteristics. Descriptive and multivariate linear regression analyses were undertaken. CHU9D-CHN utility scores were generated by employing two scoring algorithms currently available for the instrument, the first derived from UK adults utilising the standard gamble (SG) valuation method and the second derived from Australian adolescents utilising the bestworst scaling (BWS) method. Results: It was found that CHU9D utility scores discriminated well in relation to self-reported health status and that better health status was significantly associated with higher utility scores regardless of which scoring algorithm was employed (both p,0.001). The adjusted mean utilities were significantly higher for physically active than inactive students (0.023 by SG, 0.029 by BWS scoring methods, p,0.05). An additional hour of doing homework and sleep duration were, separately, associated with mean utilities of 20.019 and 0.032 based on SG, and 20.021 and 0.040 according to BWS scoring algorithms (p,0.01). Conclusion: The CHU9D-CHN shows promise for measuring and valuing the HRQoL of children and adolescents in China. Levels of self-reported physical activity, homework and sleep time were important influencers of utility scores

A ‘quiet revolution’? The impact of Training Schools on initial teacher training partnerships

This paper discusses the impact on initial teacher training of a new policy initiative in England: the introduction of Training Schools. First, the Training School project is set in context by exploring the evolution of a partnership approach to initial teacher training in England. Ways in which Training Schools represent a break with established practice are considered together with their implications for the dominant mode of partnership led by higher education institutions (HEIs). The capacity of Training Schools to achieve their own policy objectives is examined, especially their efficacy as a strategy for managing innovation and the dissemination of innovation. The paper ends by focusing on a particular Training School project which has adopted an unusual approach to its work and enquires whether this alternative approach could offer a more profitable way forward. During the course of the paper, five different models of partnership are considered: collaborative, complementary, HEI-led, school-led and partnership within a partnership

Reliability and validity of the short questionnaire to assess health-enhancing physical activity (SQUASH) in patients after total hip arthroplasty

BACKGROUND: Despite recognized benefits of regular physical activity on musculoskeletal fitness as well as general health, little is known about the physical activity behavior of patients after Total Hip Arthroplasty (THA). So far, no physical activity questionnaire has been validated in this category of patients. As the Short Questionnaire to Assess Health-enhancing physical activity (SQUASH) has been shown to be a fairly reliable and valid tool to gauge the physical activity behavior of the general Dutch adult population, we measured the reliability and relative validity of this tool in patients after THA. METHODS: 44 patients (17 men and 27 women, mean age 71 +/- 8 years) completed the SQUASH twice with an in-between period of 2 to 6 weeks (mean 3.7). Reliability was determined by calculating the Spearman correlation coefficient between the activity scores of the separate questions as well as the total activity scores from both administrations. Additionally, a Bland & Altman analysis was performed for the total activity scores. Relative validity was determined using the Actigraphaccelerometer, worn by 39 patients (15 men and 24 women, mean age 70 +/- 8 years) for a 2-week period following the second questionnaire, as a criterion measure. RESULTS: Spearman's correlation coefficient for overall reliability was 0.57. It varied between 0.45 and 0.90 for the separate questions. No systematic biases between readings were found. The Spearman correlation between Actigraph readings and total activity score was 0.67. It was 0.56 for total minutes of activity, 0.20 for time spent in light intensity activity, 0.40 for moderate activity and 0.35 for vigorous activity. Systematic bias was found between the SQUASH and the Actigraph. CONCLUSION: The SQUASH can be considered to be a fairly reliable tool to assess the physical activity behavior of patients after THA. Validity was found to be comparable with those of other questionnaires, and as it is short and easy to fill in, it may prove to be a useful tool to assess physical activity in this particular subset of the population. However, the considerable systematic bias found in this study illustrates the need for further analysis of the validity of the SQUASH

Identifying Experimental Tool Use Through Confocal Microscopy

Characterizing use-wear traces quantitatively is a valid way to improve the capacity of use-wear analysis. This aim has been on specialists’ agenda since the beginning of the discipline. Micropolish quantification is especially important, as this type of trace allows the identification of worked materials. During the last decade, confocal microscopy has been used as a promising approach to address this question. Following previous efforts in plant microwear characterization (Ibáñez et al. Journal of Archaeological Science, 48, 96–103, 2014; Journal of Archaeological Science, 73, 62–81, 2016), here we test the capacity of the method for correctly grouping experimental tools used for working eight types of materials: bone, antler, wood, fresh hide, dry hide, wild cereals, domestic cereals, and reeds. We demonstrate, for the first time, that quantitative texture analysis of use-wear micropolish based on confocal microscopy can consistently identify tools used for working different contact materials. In this way, we are able to move toward using texture analysis as part of the standard functional analysis of prehistoric instruments.This study is part of the projects HAR2016-74999-P, HAR2015-68566-P, and HAR2016-81971-REDT funded by the Spanish Ministerio de Ciencia, Innovación y Universidades.Peer reviewe

The role of input noise in transcriptional regulation

Even under constant external conditions, the expression levels of genes fluctuate. Much emphasis has been placed on the components of this noise that are due to randomness in transcription and translation; here we analyze the role of noise associated with the inputs to transcriptional regulation, the random arrival and binding of transcription factors to their target sites along the genome. This noise sets a fundamental physical limit to the reliability of genetic control, and has clear signatures, but we show that these are easily obscured by experimental limitations and even by conventional methods for plotting the variance vs. mean expression level. We argue that simple, global models of noise dominated by transcription and translation are inconsistent with the embedding of gene expression in a network of regulatory interactions. Analysis of recent experiments on transcriptional control in the early Drosophila embryo shows that these results are quantitatively consistent with the predicted signatures of input noise, and we discuss the experiments needed to test the importance of input noise more generally.Comment: 11 pages, 5 figures minor correction

Osteopontin Impairs Host Defense during Established Gram-Negative Sepsis Caused by Burkholderia pseudomallei (Melioidosis)

Melioidosis is a severe tropical disease caused by infection with the bacterium Burkholderia (B.) pseudomallei. In northeast Thailand infection with this bacterium is the major cause of community-acquired septicemia with a mortality rate up to 40%. Extending the knowledge on the mechanisms of host defense against B. pseudomallei infection would be helpful to improve treatment of this severe illness. Osteopontin (OPN) is a cytokine that is involved in several immune responses that occur during bacterial infection. In this study, we investigated levels of OPN in patients with melioidosis, and studied the function of OPN during experimental melioidosis in mice. We found that OPN concentrations were elevated in patients with severe melioidosis, and that high OPN concentrations are associated with poor outcome in patients with melioidosis. In experimental melioidosis in mice plasma and lung OPN levels were also increased. Moreover, mice with melioidosis that were deficient for OPN demonstrated reduced bacterial numbers in their lungs, diminished pulmonary tissue injury, and decreased neutrophil infiltration into the lungs during established melioidosis. Moreover, these mice displayed a delayed mortality as compared to control mice. In conclusion, sustained production of OPN impairs host defense during melioidosis

Reliability of two behavioral tools to assess pain in preterm neonates

CONTEXT: One of the main difficulties in adequately treating the pain of neonatal patients is the scarcity of validated pain evaluation methods for this population. OBJECTIVE: To analyze the reliability of two behavioral pain scales in neonates. TYPE OF STUDY: Cross-sectional. SETTING: University hospital neonatal intensive care unit. PARTICIPANTS: 22 preterm neonates were studied, with gestational age of 34 ± 2 weeks, birth weight of 1804 ± 584 g, 68% female, 30 ± 12 hours of life, and 30% intubated. PROCEDURES: Two neonatologists (A and B) observed the patients at the bedside and on video films for 10 minutes. The Neonatal Facial Coding System and the Clinical Scoring System were scored at 1, 5, and 10 minutes. The final score was the median of the three values for each observer and scale. A and B were blinded to each other. Video assessments were made three months after bedside evaluations. MAIN MEASUREMENTS: End scores were compared between the observers using the intraclass correlation coefficient and bias analysis (paired t test and signal test). RESULTS: For the Neonatal Facial Coding System, at the bedside and on video, A and B showed a significant correlation of scores (intraclass correlation score: 0.62), without bias between them (t test and signal test: p > 0.05). For the Clinical Scoring System bedside assessment, A and B showed correlation of scores (intraclass correlation score: 0.55), but bias was also detected between them: A scored on average two points higher than B (paired t test and signal test: p 0,05). Para a Escala de Conforto Clínico à beira do leito, os escores obtidos por A e B mostraram uma correlação significante (0,55), foi detectado: o escore obtido por A foi, em média, dois pontos superior ao de B (teste t e do sinal: p < 0,05). Para a mesma escala aplicada em vídeo, os escores obtidos por A e B não mostraram correlação (0,25) e detectou-se viés (teste t e do sinal: p < 0,05). CONCLUSÃO: Os resultados reforçam a confiabilidade do Sistema de Codificação da Atividade Facial Neonatal aplicado à beira do leito para a avaliação da dor no recém-nascido pré-termo.Universidade Federal de São Paulo (UNIFESP) Escola Paulista de MedicinaUniversidade Federal de São Paulo (UNIFESP) Escola Paulista de Medicina Neonatal DivisionUniversidade Federal de São Paulo (UNIFESP) Escola Paulista de Medicina Department of EpidemiologyUNIFESP, EPM, Neonatal DivisionUNIFESP, EPM, Department of EpidemiologySciEL