Interpretation of the Expected Value of Perfect Information and Research Recommendations:A Systematic Review and Empirical Investigation

calculations are increasingly performed to guide and underpin research recommendations. An EVPI value that exceeds the estimated cost of research forms a necessary (although not sufficient) condition for further research to be considered worthwhile. However, it is unclear what factors affect researchers ’ recommendations and whether there is a notional threshold of positive returns below which research is not recommended. The objectives of this study were to explore whether EVPI and other factors have a bearing on research recommendations and to assess whether there exists a threshold EVPI below which research is typically not recommended. Methods. A systematic lit-erature review was undertaken to identify applied EVPI calculations in the health care field. Study characteris-tics were extracted, including funder, location, diseas

Building solids inside nano-space: from confined amorphous through confined solvate to confined ‘metastable’ polymorph

The nanocrystallisation of complex molecules inside mesoporous hosts and control over the resulting structure is a significant challenge. To date the largest organic molecule crystallised inside the nano-pores is a known pharmaceutical intermediate – ROY (259.3 g mol1). In this work we demonstrate smart manipulation of the phase of a larger confined pharmaceutical – indomethacin (IMC, 357.8 g mol1), a substance with known conformational flexibility and complex polymorphic behaviour. We show the detailed structural analysis and the control of solid state transformations of encapsulated molecules inside the pores of mesoscopic cellular foam (MCF, pore size ca. 29 nm) and controlled pore glass (CPG, pore size ca. 55 nm). Starting from confined amorphous IMC we drive crystallisation into a confined methanol solvate, which upon vacuum drying leads to the stabilised rare form V of IMC inside the MCF host. In contrast to the pure form, encapsulated form V does not transform into a more stable polymorph upon heating. The size of the constraining pores and the drug concentration within the pores determine whether the amorphous state of the drug is stabilised or it recrystallises into confined nanocrystals. The work presents, in a critical manner, an application of complementary techniques (DSC, PXRD, solid-state NMR, N2 adsorption) to confirm unambiguously the phase transitions under confinement and offers a comprehensive strategy towards the formation and control of nano-crystalline encapsulated organic solids

Are acceptance and mindfulness-based interventions 'value for money'? : evidence from a systematic literature review

Objectives: Acceptance and mindfulness‐based interventions (A/MBIs) are recommended for people with mental health conditions. Although there is a growing evidence base supporting the effectiveness of different A/MBIs for mental health conditions, the economic case for these interventions has not been fully explored. The aim of this systematic review was to identify and appraise all available economic evidence of A/MBIs for the management of mental health conditions. Methods: Eight electronic bibliographic databases (MEDLINE, MEDLINE In‐Process & Other Non‐Indexed Citations, EMBASE, Web of Science, NHS Economic Evaluation Database (EED), Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment (HTA) database, and EconLit) were searched for relevant economic evaluations published from each database's inception date until November 2017. Study selection, quality assessment, and data extraction were carried out according to published guidelines. Results: Ten relevant economic evaluations presented in 11 papers were identified. Seven of the included studies were full economic evaluations (i.e., costs and effects assessed), and three studies were partial economic evaluations (i.e., only costs were considered in the analysis). The A/MBIs that had been subjected to economic evaluation were acceptance and commitment therapy (ACT), dialectical behaviour therapy (DBT), mindfulness‐based cognitive therapy (MBCT), and mindfulness‐based stress reduction (MBSR). In terms of clinical presentations, the evaluation of cost‐effectiveness of A/MBIs has been more focused on depression and emotional unstable personality disorder with three and four economic evaluations, respectively. Three out of seven full economic evaluations observed that A/MBIs were cost‐effective for the management of mental health conditions. Nevertheless, the heterogeneity of included populations, interventions, and economic evaluation study types limits the extent to which firm conclusions can currently be made. Conclusion: This first substantive review of economic evaluations of A/MBIs indicates that more research is needed before firm conclusions can be reached on the cost‐effectiveness of A/MBIs for mental health conditions

Intrathecal drug delivery systems for the management of chronic non-cancer pain : a systematic review of economic evaluations

Background: Intrathecal drug delivery (ITDD) systems are one of a limited number of management options for chronic non-cancer pain, cancer pain and spasticity. Concerns over their effectiveness and high initial costs led NHS England to decommission ITDD for patients with chronic non-cancer pain. However, the extent to which this decision is in line with existing economic evidence is unclear. The aim of this systematic review is to identify and review the existing evidence on the cost-effectiveness of ITDD for chronic non-cancer pain. Methods: Full and partial economic evaluations on ITDD were identified through systematic searches in MEDLINE, EMBASE, Web of Science and the National Health Service Centre for Reviews and Dissemination databases. Database searches were complemented by hand searching of reference lists of relevant studies and searches of grey literature. Study selection was carried out by two assessors, independently. Study quality assessment was performed to inform critical appraisal of health economics studies. Data were extracted using a data extraction form developed for this study. Results: 4464 unique studies were identified, of which seven met the inclusion criteria. With the exception of one study, the studies found ITDD to be either cost-saving or cost-effective compared to conventional medical management. ITDD becomes cost-ineffective in one further study following price year adjustment to 2016. Conclusions: Study findings show ITDD as not cost-effective only in extremely conservative scenarios. There is limited evidence on the effectiveness of ITDD in non-cancer pain; however, the available economic evidence controverts arguments to refute the treatment on economic grounds

Site-directed mutagenesis of the D2 protein in the green alga 'Chlamydomonas reinhardtii'

The D2 polypeptide together with the D1 polypeptide are key components of the photosystem II (PS II) complex which is involved in photosynthetic oxygen evolution. This thesis describes the use of site-directed mutagenesis to introduce specific amino acid changes in the D2 protein of Chlamydomonas reinhardtii. The mutations were constructed at positions D2-Leu205 and D2-Thr2. Plasmids carrying mutated copies of the psbD gene (which encodes D2) were introduced into the chloroplast genome of C. reinhardtii by means of a particle gun. In order to identify the transformants, a selectable marker encoding resistance to spectinomycin, was inserted either upstream or downstream of the psbD gene. Genetic characterisation of the mutants was carried out using Southern blotting, PCR and DNA sequencing. D2-Leu205 is thought to be analogous to residue Tyr210 of the M subunit of the reaction centre (RC) of the purple photosynthetic bacterium Rhodobacter sphaeroides. Previous mutagenesis experiments have shown that the replacement of M-Tyr210 by leucine reduces the rate of the primary charge separation in purple bacterial RCs. Urns, the mutation Leu205Tyr was constructed in order to study whether the rate of primary charge separation is increased in this mutant. The Leu205Tyr mutant could grow photoautotrophically at wild type rates. However, its light-saturated PS II activity was reduced to ~62% compared to the wild type. PS II RCs isolated from a "wild type” control transformant and from the Leu205Tyr mutant showed in ultrafast transient absorption measurements that the rate of formation of the radical pair was slowed down in the mutant (lifetime of 40±7 ps compared to 21±2 ps for the wild type PS II RCs). Also the quantum yield of charge separation was reduced by about 50%. Fluorescence and thermoluminescence measurements in whole cells were also consistent with a reduced quantum yield of charge separation in PS II. Mutations Thr2Ala and Thr2Ser were constructed in order to study the role of D2 phosphorylation in C. reinhardtii. Biochemical characterisation of the Thr2Ala and Thr2Ser mutants indicated that both strains could grow photoautotrophically at wild type rates. Moreover, oxygen evolution, fluorescence and thermoluminescence measurements suggested that these site-directed mutations have only minor effects on PS II function. In addition to these experiments, attempts were carried out to find out whether D2 can be phosphorylated in C. reinhardtii. These attempts included in vivo labelling of whole cells with [32P]-orthophosphate, in vitro labelling of thylakoid membranes with [y-32P]-ATP, pulse-chase labelling of cells with [uC]-acetate and the use of a monospecific antibody against phosphothreonine. The data obtained from these experiments did not provide any indication that D2 can be phosphorylated in C. reinhardtii.Open acces

Proteome analysis of Phytophthora cinnamomi, the causal agent of Dieback

Phytophthora cinnamomi is a nasty pathogen that causes significant environmental and agricultural destruction. In this thesis, proteomic analysis was used to obtain a biochemical snapshot of the organism to understand its contributors to pathogenicity. The mode of action of phosphite, the only chemical used to combat dieback disease was also elucidated as there is a growing pressure of chemical resistance

Radiographers supporting radiologists in the interpretation of screening mammography: a viable strategy to meet the shortage in the number of radiologists.

BackgroundAn alternative approach to the traditional model of radiologists interpreting screening mammography is necessary due to the shortage of radiologists to interpret screening mammograms in many countries.MethodsWe evaluated the performance of 15 Mexican radiographers, also known as radiologic technologists, in the interpretation of screening mammography after a 6 months training period in a screening setting. Fifteen radiographers received 6 months standardized training with radiologists in the interpretation of screening mammography using the Breast Imaging Reporting and Data System (BI-RADS) system. A challenging test set of 110 cases developed by the Breast Cancer Surveillance Consortium was used to evaluate their performance. We estimated sensitivity, specificity, false positive rates, likelihood ratio of a positive test (LR+) and the area under the subject-specific Receiver Operating Characteristic (ROC) curve (AUC) for diagnostic accuracy. A mathematical model simulating the consequences in costs and performance of two hypothetical scenarios compared to the status quo in which a radiologist reads all screening mammograms was also performed.ResultsRadiographer's sensitivity was comparable to the sensitivity scores achieved by U.S. radiologists who took the test but their false-positive rate was higher. Median sensitivity was 73.3 % (Interquartile range, IQR: 46.7-86.7 %) and the median false positive rate was 49.5 % (IQR: 34.7-57.9 %). The median LR+ was 1.4 (IQR: 1.3-1.7 %) and the median AUC was 0.6 (IQR: 0.6-0.7). A scenario in which a radiographer reads all mammograms first, and a radiologist reads only those that were difficult for the radiographer, was more cost-effective than a scenario in which either the radiographer or radiologist reads all mammograms.ConclusionsGiven the comparable sensitivity achieved by Mexican radiographers and U.S. radiologists on a test set, screening mammography interpretation by radiographers appears to be a possible adjunct to radiologists in countries with shortages of radiologists. Further studies are required to assess the effectiveness of different training programs in order to obtain acceptable screening accuracy, as well as the best approaches for the use of non-physician readers to interpret screening mammography

Validation of the Bluebelle Wound Healing questionnaire (WHQ) for assessment of surgical site infection in primary surgical wounds after hospital discharge

Background Accurate assessment of surgical‐site infection (SSI) is crucial for surveillance and research. Self‐reporting patient measures are needed because current SSI tools are limited for assessing patients after leaving hospital. The Bluebelle Wound Healing Questionnaire (WHQ) was developed for patient or observer completion; this study tested its acceptability, scale structure, reliability and validity in patients with closed primary wounds after abdominal surgery. Methods Patients completed the WHQ (self‐assessment) within 30 days after leaving hospital and returned it by post. Healthcare professionals completed the WHQ (observer assessment) by telephone or face‐to‐face. Questionnaire response rates and patient acceptability were assessed. Factor analysis and Cronbach's α examined scale structure and internal consistency. Test–retest and self‐ versus observer reliability assessments were performed. Sensitivity and specificity for SSI discrimination against a face‐to‐face reference diagnosis (using Centers for Disease Control and Prevention criteria) were examined. Results Some 561 of 792 self‐assessments (70·8 per cent) and 597 of 791 observer assessments (75·5 per cent) were completed, with few missing data or problems reported. Data supported a single‐scale structure with strong internal consistency (α greater than 0·8). Reliability between test–retest and self‐ versus observer assessments was good (κ 0·6 or above for the majority of items). Sensitivity and specificity for SSI discrimination was high (area under the receiver operating characteristic (ROC) curve 0·91). Conclusion The Bluebelle WHQ is acceptable, reliable and valid with a single‐scale structure for postdischarge patient or observer assessment of SSI in closed primary wounds

The HY5-PIF regulatory module coordinates light and temperature control of photosynthetic gene transcription

The ability to interpret daily and seasonal alterations in light and temperature signals is essential for plant survival. This is particularly important during seedling establishment when the phytochrome photoreceptors activate photosynthetic pigment production for photoautotrophic growth. Phytochromes accomplish this partly through the suppression of phytochrome interacting factors (PIFs), negative regulators of chlorophyll and carotenoid biosynthesis. While the bZIP transcription factor long hypocotyl 5 (HY5), a potent PIF antagonist, promotes photosynthetic pigment accumulation in response to light. Here we demonstrate that by directly targeting a common promoter cis-element (G-box), HY5 and PIFs form a dynamic activation-suppression transcriptional module responsive to light and temperature cues. This antagonistic regulatory module provides a simple, direct mechanism through which environmental change can redirect transcriptional control of genes required for photosynthesis and photoprotection. In the regulation of photopigment biosynthesis genes, HY5 and PIFs do not operate alone, but with the circadian clock. However, sudden changes in light or temperature conditions can trigger changes in HY5 and PIFs abundance that adjust the expression of common target genes to optimise photosynthetic performance and growth