Methodological criteria for the assessment of moderators in systematic reviews of randomised controlled trials : a consensus study

Background: Current methodological guidelines provide advice about the assessment of sub-group analysis within RCTs, but do not specify explicit criteria for assessment. Our objective was to provide researchers with a set of criteria that will facilitate the grading of evidence for moderators, in systematic reviews. Method: We developed a set of criteria from methodological manuscripts (n = 18) using snowballing technique, and electronic database searches. Criteria were reviewed by an international Delphi panel (n = 21), comprising authors who have published methodological papers in this area, and researchers who have been active in the study of sub-group analysis in RCTs. We used the Research ANd Development/University of California Los Angeles appropriateness method to assess consensus on the quantitative data. Free responses were coded for consensus and disagreement. In a subsequent round additional criteria were extracted from the Cochrane Reviewers’ Handbook, and the process was repeated. Results: The recommendations are that meta-analysts report both confirmatory and exploratory findings for subgroups analysis. Confirmatory findings must only come from studies in which a specific theory/evidence based apriori statement is made. Exploratory findings may be used to inform future/subsequent trials. However, for inclusion in the meta-analysis of moderators, the following additional criteria should be applied to each study: Baseline factors should be measured prior to randomisation, measurement of baseline factors should be of adequate reliability and validity, and a specific test of the interaction between baseline factors and interventions must be presented. Conclusions: There is consensus from a group of 21 international experts that methodological criteria to assess moderators within systematic reviews of RCTs is both timely and necessary. The consensus from the experts resulted in five criteria divided into two groups when synthesising evidence: confirmatory findings to support hypotheses about moderators and exploratory findings to inform future research. These recommendations are discussed in reference to previous recommendations for evaluating and reporting moderator studies

Correlation functions quantify super-resolution images and estimate apparent clustering due to over-counting

We present an analytical method to quantify clustering in super-resolution localization images of static surfaces in two dimensions. The method also describes how over-counting of labeled molecules contributes to apparent self-clustering and how the effective lateral resolution of an image can be determined. This treatment applies to clustering of proteins and lipids in membranes, where there is significant interest in using super-resolution localization techniques to probe membrane heterogeneity. When images are quantified using pair correlation functions, the magnitude of apparent clustering due to over-counting will vary inversely with the surface density of labeled molecules and does not depend on the number of times an average molecule is counted. Over-counting does not yield apparent co-clustering in double label experiments when pair cross-correlation functions are measured. We apply our analytical method to quantify the distribution of the IgE receptor (Fc{\epsilon}RI) on the plasma membranes of chemically fixed RBL-2H3 mast cells from images acquired using stochastic optical reconstruction microscopy (STORM) and scanning electron microscopy (SEM). We find that apparent clustering of labeled IgE bound to Fc{\epsilon}RI detected with both methods arises from over-counting of individual complexes. Thus our results indicate that these receptors are randomly distributed within the resolution and sensitivity limits of these experiments.Comment: 22 pages, 5 figure

Gestational trophoblastic disease: does central nervous system chemoprophylaxis have a role?

In the UK there are standardized surveillance procedures for gestational trophoblastic disease. However, there are differences in practice between the two treatment centres in terms of definition of persistent gestational trophoblastic disease, prognostic risk assessment and chemotherapeutic regimens. The role of prophylactic chemotherapy for cerebral micrometastatic disease in persistent gestational trophoblastic disease is unclear. We have analysed the outcome of 69 patients with lung metastases who elsewhere might have received prophylactic intrathecal chemotherapy. Of the 69 patients, 67 received intravenous chemotherapy only. The other two patients had cerebral metastases at presentation. One patient who received only intravenous chemotherapy subsequently developed a cerebral metastasis, but this patient's initial treatment was compromised by non-compliance. This experience supports our current policy of not treating patients with pulmonary metastases, without clinical evidence of central nervous system (CNS) involvement, with prophylactic intrathecal therapy. © 1999 Cancer Research Campaig

Genome-wide signatures of convergent evolution in echolocating mammals

Evolution is typically thought to proceed through divergence of genes, proteins, and ultimately phenotypes(1-3). However, similar traits might also evolve convergently in unrelated taxa due to similar selection pressures(4,5). Adaptive phenotypic convergence is widespread in nature, and recent results from a handful of genes have suggested that this phenomenon is powerful enough to also drive recurrent evolution at the sequence level(6-9). Where homoplasious substitutions do occur these have long been considered the result of neutral processes. However, recent studies have demonstrated that adaptive convergent sequence evolution can be detected in vertebrates using statistical methods that model parallel evolution(9,10) although the extent to which sequence convergence between genera occurs across genomes is unknown. Here we analyse genomic sequence data in mammals that have independently evolved echolocation and show for the first time that convergence is not a rare process restricted to a handful of loci but is instead widespread, continuously distributed and commonly driven by natural selection acting on a small number of sites per locus. Systematic analyses of convergent sequence evolution in 805,053 amino acids within 2,326 orthologous coding gene sequences compared across 22 mammals (including four new bat genomes) revealed signatures consistent with convergence in nearly 200 loci. Strong and significant support for convergence among bats and the dolphin was seen in numerous genes linked to hearing or deafness, consistent with an involvement in echolocation. Surprisingly we also found convergence in many genes linked to vision: the convergent signal of many sensory genes was robustly correlated with the strength of natural selection. This first attempt to detect genome-wide convergent sequence evolution across divergent taxa reveals the phenomenon to be much more pervasive than previously recognised

Improving Health and Building Human Capital Through an Effective Primary Care System

To improve population health, one must put emphasis on reducing health inequities and enhancing health protection and disease prevention, and early diagnosis and treatment of diseases by tackling the determinants of health at the downstream, midstream, and upstream levels. There is strong theoretical and empirical evidence for the association between strong national primary care systems and improved health indicators. The setting approach to promote health such as healthy schools, healthy cities also aims to address the determinants of health and build the capacity of individuals, families, and communities to create strong human and social capitals. The notion of human and social capitals begins to offer explanations why certain communities are unable to achieve better health than other communities with similar demography. In this paper, a review of studies conducted in different countries illustrate how a well-developed primary health care system would reduce all causes of mortalities, improve health status, reduce hospitalization, and be cost saving despite a disparity in socioeconomic conditions. The intervention strategy recommended in this paper is developing a model of comprehensive primary health care system by joining up different settings integrating the efforts of different parties within and outside the health sector. Different components of primary health care team would then work more closely with individuals and families and different healthy settings. This synergistic effect would help to strengthen human and social capital development. The model can then combine the efforts of upstream, midstream, and downstream approaches to improve population health and reduce health inequity. Otherwise, health would easily be jeopardized as a result of rapid urbanization

High-dose chemotherapy and peripheral blood stem cell support in refractory gestational trophoblastic neoplasia

We present retrospectively our experience in the use of high-dose chemotherapy and haematopoietic stem cell support (HSCS) for refractory gestational trophoblastic neoplasia (GTN) in the largest series so far reported. In all, 11 patients have been treated at three Trophoblast Centres between 1993 and 2004. The conditioning regimens comprised either Carbop-EC-T (carboplatin, etoposide, cyclophosphamide, paclitaxel and prednisolone) or CEM (carboplatin, etoposide and melphalan) or ICE (ifosfamide, carboplatin, etoposide). Two patients had complete human chorionic gonadotrophin responses, one for 4 and the other for 12 months. Three patients had partial tumour marker responses for 1–2 months. High-dose chemotherapy and HSCS for GTN is still unproven. Further studies are needed, perhaps in high-risk patients who fail their first salvage treatment

Assessment of terrain elevation estimates from ICESat-2 and GEDI spaceborne LiDAR missions across different land cover and forest types

Accurate measurements of terrain elevation are crucial for many ecological applications. In this study, we sought to assess new global three-dimensional Earth observation data acquired by the spaceborne Light Detection and Ranging (LiDAR) missions Ice, Cloud, and Land Elevation Satellite-2 (ICESat-2) and Global Ecosystem Dynamics Investigation (GEDI). For this, we examined the “ATLAS/ICESat-2 L3A Land and Vegetation Height”, version 5 (20 × 14 m and 100 × 14 m segments) and the “GEDI Level 2A Footprint Elevation and Height Metrics”, version 2 (25 m circle). We conducted our analysis across four land cover classes (bare soil, herbaceous, forest, savanna), and six forest types (temperate broad-leaved, temperate needle-leaved, temperate mixed, tropical upland, tropical floodplain, and tropical secondary forest). For assessment of terrain elevation estimates from spaceborne LiDAR data we used high resolution airborne data. Our results indicate that both LiDAR missions provide accurate terrain elevation estimates across different land cover classes and forest types with mean error less than 1 m, except in tropical forests. However, using a GEDI algorithm with a lower signal end threshold (e.g., algorithm 5) can improve the accuracy of terrain elevation estimates for tropical upland forests. Specific environmental parameters (terrain slope, canopy height and canopy cover) and sensor parameters (GEDI degrade flags, terrain estimation algorithm; ICESat-2 number of terrain photons, terrain uncertainty) can be applied to improve the accuracy of ICESat-2 and GEDI-based terrain estimates. Although the goodness-of-fit statistics from the two spaceborne LiDARs are not directly comparable since they possess different footprint sizes (100 × 14 m segment or 20 × 14 m segment vs. 25 m circle), we observed similar trends on the impact of terrain slope, canopy cover and canopy height for both sensors. Terrain slope strongly impacts the accuracy of both ICESat-2 and GEDI terrain elevation estimates for both forested and non-forested areas. In the case of GEDI the impact of slope is, however, partly caused by horizontal geolocation error. Moreover, dense canopies (i.e., canopy cover higher than 90%) affect the accuracy of spaceborne LiDAR terrain estimates, while canopy height does not, when considering samples over flat terrains. Our analysis of the accuracy and precision of current versions of spaceborne LiDAR products for different vegetation types and environmental conditions provides insights on parameter selection and estimated uncertainty to inform users of these key global datasets

Study of lone working magnetic resonance technologists in Western Australia

Objectives: It is recommended that magnetic resonance (MR) technologists should not work alone due to potential occupational health risks although lone working is legally acceptable. The objective of this study was to investigate the current situation of lone working of MR technologists in Western Australia (WA) and any issue against the regulations. Materials and Methods: A questionnaire regarding the issues of occupational health of lone MR technologists was developed based on relevant literature and distributed to WA MR technologists. Descriptive (percentage of frequency, mean and standard deviation) and inferential statistics (Fisher’s exact, chi-square and t tests, and analysis of variance) were used to analyse the responses of the yes/no, multiple choice and 5 point scale questions from the returned questionnaires.Results: The questionnaire response rate was 65.6% (59/90). It was found that about half of the MR technologists (45.8%, 27/59) experienced lone working. The private magnetic resonance imaging (MRI) centres were more likely to arrange technologists to work alone (p <0.05). The respondents expressed positive views on issues of adequacy of training and arrangement, confidence and comfort towards lone working except immediate assistance for emergency (mean: 3). Factors of existence of MRI safety officer (p < 0.05) and nature of lone working (p < 0.001-0.05) affected MR technologists’ concerns. Conclusions: Lone working of MR technologists is common in WA especially private centres. The training and arrangement provided seem to be adequate for meeting the legal requirements. However, several areas should be improved by the workplaces including enhancement on immediate assistance for emergency and concern relief

Observation of an Exotic Baryon with S=+1 in Photoproduction from the Proton

The reaction $\gamma p \to \pi^+K^-K^+n$ was studied at Jefferson Lab using a tagged photon beam with an energy range of 3-5.47 GeV. A narrow baryon state with strangeness S=+1 and mass $M=1555\pm 10$ MeV/c$^2$ was observed in the $nK^+$ invariant mass spectrum. The peak's width is consistent with the CLAS resolution (FWHM=26 MeV/c$^2$), and its statistical significance is 7.8 $\pm$ 1.0 ~$\sigma$. A baryon with positive strangeness has exotic structure and cannot be described in the framework of the naive constituent quark model. The mass of the observed state is consistent with the mass predicted by a chiral soliton model for the $\Theta^+$ baryon. In addition, the $pK^+$ invariant mass distribution was analyzed in the reaction $\gamma p\to K^-K^+p$ with high statistics in search of doubly-charged exotic baryon states. No resonance structures were found in this spectrum.Comment: 5 pages, 5 figures, add reference

Tunable thermal expansion in framework materials through redox intercalation

Thermal expansion properties of solids are of fundamental interest and control of thermal expansion is important for practical applications but can be difficult to achieve. Many framework-type materials show negative thermal expansion when internal cages are empty but positive thermal expansion when additional atoms or molecules fill internal voids present. Here we show that redox intercalation offers an effective method to control thermal expansion from positive to zero to negative by insertion of Li ions into the simple negative thermal expansion framework material ScF3, doped with 10% Fe to enable reduction. The small concentration of intercalated Li ions has a strong influence through steric hindrance of transverse fluoride ion vibrations, which directly controls the thermal expansion. Redox intercalation of guest ions is thus likely to be a general and effective method for controlling thermal expansion in the many known framework materials with phonon-driven negative thermal expansion