Meta-narrative and realist reviews: guidance, rules, publication standards and quality appraisal.

Recently, there has been an expansion of different forms of systematic review of research and the development of guidance and standards about particular types of review. These reviews can be best understood within a broad framework of the dimensions on which reviews differ, and how the review methodology relates to the methodology of primary research. Similarly, publication standards can be understood in terms of their relation to other standards such as guidance and rules for undertaking reviews and systems for appraising the quality of reviews. This commentary is written with special reference to the publication standards for meta-narrative and realist reviews being published in BMC Medicine.See related research articles http://www.biomedcentral.com/1741-7015/11/20 and http://www.biomedcentral.com/1741-7015/11/21.

Effects of solution concentration on the physicochemical properties of a polymeric anticancer therapeutic.

Poly(γ-glutamyl-glutamate) paclitaxel (PGG-PTX) is a series of eighteen semiflexible polymer-drug constructs varying in PTX loading fraction (f(PTX) of 0.18, 0.24, and 0.37) and spatial PTX arrangement (uniform, "even" and "random"; clustered, "clusters" and "ends"; concentrated, "ends" and "side"). Structural properties of PGG-PTX in dilute and concentrated conditions are determined from coarse-grained molecular dynamics (MD) simulations. Since PGG-PTX does not have a specific conformation, MD simulations were run until minimal structural deviations persisted. Root-mean-square deviation (RMSD) clustering was then used to determine the significant, unique characteristic conformations. Results show that dilute PGG-PTX undergoes a globule-to-filament transition with respect to increasingly denser PTX arrangements. While a similar transition is apparent in concentrated conditions, PGG-PTX tends to be more filamentous on the whole. PGG-PTX is also more rigid in concentrated conditions, and a higher PTX loading fraction leads to decreased flexibility. In general, the dilute "ends", "middle", and "side" PGG-PTX molecules at f(PTX) = 0.18 and 0.24 prove to be the most efficaciously promising and are recommended for future biological testing. This study demonstrates the practicality of molecular modeling toward understanding structural behavior of an anticancer therapeutic in different solution concentrations.

Aggregation properties of a polymeric anticancer therapeutic: a coarse-grained modeling study.

The effects of paclitaxel (PTX) loading fraction and spatial PTX arrangement on poly(γ-glutamyl-glutamate) paclitaxel (PGG-PTX) aggregation were explored using coarse-grained molecular dynamics. Results show that the PTX loading fraction does not significantly impact aggregation, and the spatial PTX arrangement only affects aggregation at more concentrated PTX arrangements. Overall, the f(PTX) = 0.37 'ends' and f(PTX) = 0.18 'even' PGG-PTX systems exhibit the highest aggregation and the 'middle' and 'side' systems the lowest.

A Compact Battery-Powered rTMS Prototype.

This paper describes the design and testing of a compact, battery-powered repetitive Transcranial Magnetic Stimulation (rTMS) prototype. This device generates a 10 Hz magnetic pulse train with peak flux density of 100 mT at 2 cm distance. Circuit component design, including the inductor, switched LC resonator, and boost converter, are discussed in the context of weight and size reduction, and performance optimization. The experimental approach and rationale together with acquired results validating the rTMS prototype design are presented. To the best of our knowledge, this is the first comprehensive feasibility demonstration of an inexpensive, lightweight, and portable rTMS device able to generate therapeutic levels of current, pulse rise time, and number of pulses. The generated magnetic field was kept to 0.1 Tesla for safety and testing considerations, but nevertheless was very close to therapeutic intensity, with driving circuitry scalable to support much stronger fields.Clinical Relevance- This feasibility study of a compact, battery-powered rTMS prototype test platform aims to enable broader and more convenient rTMS treatment at home, in a small clinic, vessel, or field hospital, and potentially, on an ambulatory basis.

Evidence Synthesis International (ESI): Position Statement.

This paper is the initial Position Statement of Evidence Synthesis International, a new partnership of organizations that produce, support and use evidence synthesis around the world. The paper (i) argues for the importance of synthesis as a research exercise to clarify what is known from research evidence to inform policy, practice and personal decision making; (ii) discusses core issues for research synthesis such as the role of research evidence in decision making, the role of perspectives, participation and democracy in research and synthesis as a core component of evidence ecosystems; (iii) argues for 9 core principles for ESI on the nature and role of research synthesis; and (iv) lists the 5 main goals of ESI as a coordinating partnership for promoting and enabling the production and use of research synthesis.

Outcome study of lower pole heminephrectomy in children.

OBJECTIVE: This study assessed the role and long-term outcome of lower pole heminephrectomy in the treatments of non-functioning lower renal moieties in children with duplex kidneys. MATERIAL AND METHODS: In a period of 10 years 31 lower pole heminephrectomies were performed in 30 patients with duplex systems. Eight patients were diagnosed prenatally, 24 patients (80%) presented with urinary tract infection and three (10%) with vomiting and failure to thrive, and five patients also had other symptoms. The indication for lower pole heminephroureterectomy was reflux nephropathy in non-functioning lower pole in 28 patients (93%), pelviureteric junction obstruction in one patient (3%) and cystic dysplasia in one patient (3%). The surgical technique used was a combination of anterolateral loin incision plus right or left inguinal incision in 28 patients (90%). RESULTS: The operative course was uneventful, no blood transfusion were required, and no damage to the upper pole moiety or upper pole ureter was observed. Four patients (13%) had immediate postoperative complications and three (10%) had late postoperative complications. Long-term follow-up revealed no complications in 27 patients (90%) and three patients (10%) with increased urinary frequency. CONCLUSIONS: The results indicate that lower pole heminephrectomy is the treatment of choice in cases of non-functioning dilated lower segments of duplicated kidneys. The use of two incisions in this procedure is effective in preventing the need for further surgical treatment secondary to complications of the stump.

Cardiac myxoma showing extramedullary hematopoiesis in a patient with beta thalassemia.

A 52-year-old woman presented with recurrent episodes of chest pain, shortness of breath, palpitations, and fatigue for three months. Her past medical history was significant for chronic anemia. Physical examination revealed a pansystolic murmur radiating to the left axilla. Her admission workup showed microcytic anemia. Her serum creatinine and iron studies were within normal limits and her hemoglobin electrophoresis pattern was that of beta thalassemia minor. Two-dimensional echocardiography showed a multilobulated mobile mass attached to the mitral annulus at the base of the anterior mitral valve leaflet. The patient underwent surgical resection of the mass. Pathology examination revealed a cardiac myxoma with conspicuous foci of extramedullary hematopoiesis.

Clarifying differences between reviews within evidence ecosystems.

This paper builds on a 2012 paper by the same authors which argued that the types and brands of systematic review do not sufficiently differentiate between the many dimensions of different review questions and review methods (Gough et al., Syst Rev 1:28, 2012). The current paper extends this argument by considering the dynamic contexts, or 'evidence ecosystems', within which reviews are undertaken; the fact that these ecosystems are constantly changing; and the relevance of this broader context for understanding 'dimensions of difference' in the unfolding development and refinement of review methods.The concept of an evidence ecosystem is used to consider particular issues within the three key dimensions of difference outlined in the 2012 paper of (1) review aims and approach, (2) structure and components of reviews, and (3) breadth, depth, and 'work done' by reviews.

Blood glucose dynamics.

Measurement of blood glucose concentration is central to the diagnosis and treatment of diabetes. Although there are large numbers of historic glucose measurements in individuals with diabetes, until recently there have been very few data sets that were recorded continuously or sampled frequently enough to reveal intrinsic blood glucose dynamics, or the change in blood glucose with time. There have even fewer such recordings from individuals not having diabetes to serve as a therapeutic target. As a result, blood glucose dynamics have generally not been used in the diagnosis or treatment of the disease. Although present blood glucose monitoring is based largely on discrete measurements, future monitoring will likely focus on analysis of blood glucose excursions. New measurements are now being obtained, and there is a need for new methods of analysis to extract the maximal information from the data. Several approaches are demonstrated here for characterization of blood glucose dynamics, and a patient profiling system is proposed. An example of new insights is the observation that there are four time scales of blood glucose variations in individuals without diabetes, and these time scales are modified or lost in diabetes.

An insight into vaginal surgery in a severely masculinized CAH patient.

Reconstruction and exteriorization of the "high" vagina in girls with congenital adrenal hyperplasia (CAH) is technically challenging. Although current surgical thinking favors correction in infancy the evidence from several long-term studies indicates that many patients will require further surgery in adolescence or adult life. Deferred vaginoplasty has been advocated because the procedure may be technically easier as a consequence of changes in the characteristics of the genital tissues and vaginal anatomy. The role of urogenital mobilization is as yet undetermined but carries promise for the short, high vagina. We describe a patient where the radiological and clinical findings support the argument for deferred vaginoplasty.

Glucose Monitoring in Individuals With Diabetes Using a Long-Term Implanted Sensor/Telemetry System and Model.

OBJECTIVE: The use of a fully implanted first-generation prototype sensor/telemetry system is described for long-term monitoring of subcutaneous tissue glucose in a small cohort of people with diabetes. METHODS: Sensors are based on a membrane containing immobilized glucose oxidase and catalase coupled to oxygen electrodes and a telemetry system, integrated as an implant. The devices remained implanted for up to 180 days, with signals transmitted every 2 min to external receivers. RESULTS: The data include signal recordings from glucose clamps and spontaneous glucose excursions, matched, respectively, to reference blood glucose and finger-stick values. The sensor signals indicate dynamic tissue glucose, for which there is no independent standard, and a model describing the relationship between blood glucose and the signal is, therefore, included. The values of all model parameters have been estimated, including the permeability of adjacent tissues to glucose, and equated to conventional mass transfer parameters. As a group, the sensor calibration varied randomly at an average rate of -2.6%/week. Statistical correlation indicated strong association between the sensor signals and reference glucose values. CONCLUSION: Continuous long-term glucose monitoring in individuals with diabetes is feasible with this system. SIGNIFICANCE: All therapies for diabetes are based on glucose control, and therefore, require glucose monitoring. This fully implanted long-term sensor/telemetry system may facilitate a new era of management of the disease.

Reverse takotsubo cardiomyopathy with use of male enhancers.

Reverse takotsubo cardiomyopathy is a rare heart failure condition characterized by systolic dysfunction of the basal segments of the left ventricle in the absence of obstructive coronary artery disease. We present a case of a 54-year-old man with an overdose of Extenze (a male enhancer pill containing yohimbine) who was hospitalized with heart failure due to reverse takotsubo cardiomyopathy.

School-based violence prevention programs: systematic review of secondary prevention trials.

OBJECTIVE: To quantify the effectiveness of school-based violence prevention programs for children identified as at risk for aggressive behavior. DESIGN: Systematic review and meta-analysis of randomized controlled trials. Electronic databases and bibliographies were systematically searched and authors and organizations were contacted to identify randomized controlled trials. Standardized, weighted mean effect sizes were assessed by meta-analysis. SETTING: Elementary, middle, and high schools. PARTICIPANTS: Children at risk for aggressive behavior. MAIN OUTCOME MEASURES: Violent injuries, observed or reported aggressive or violent behaviors, and school or agency responses to aggressive behaviors. RESULTS: Of the 44 trials identified, none reported data on violent injuries. For the 28 trials that assessed aggressive behaviors, the pooled difference between study groups was -0.36 (95% confidence interval, -0.54 to -0.19) in favor of a reduction in aggression with intervention. For the 9 trials that reported data on school or agency responses to aggression, the pooled difference was -0.59 (95% confidence interval, -1.18 to 0.01). Subgroup analyses suggested greater effectiveness in older students and when administered to mixed-sex groups rather than to boys alone. CONCLUSIONS: School-based violence prevention programs may produce reductions in aggressive and violent behaviors in children who already exhibit such behavior. These results, however, need to be confirmed in large, high-quality trials.

Permeability of subcutaneous tissues surrounding long-term implants to oxygen.

Certain types of implanted medical devices depend on oxygen supplied from surrounding tissues for their function. However, there is a concern that the tissue associated with the foreign body response to implants may become impermeable to oxygen over the long term and render the implant nonfunctional. We report oxygen flux recordings from electrochemical oxygen sensor devices with wireless telemetry implanted in subcutaneous porcine tissues. The devices remained implanted for up to 13 weeks and were removed with adjacent tissues at specified times for histologic examination. There are four main observations: (1) In the first few weeks after implantation, the oxygen flux to the sensors, or current density, declined to a sustained mean value, having unsynchronized cyclic variations around the mean; (2) The oxygen mass transfer resistance of the sensor membrane was negligible compared to that of the tissue, allowing for a sensitive estimate of the tissue permeability; (3) The effective diffusion coefficient of oxygen in tissues was found to be approximately one order of magnitude lower than in water; and (4) Quantitative histologic analysis of the tissues showed a mild foreign body response to the PDMS sensor membrane material, with capillaries positioned close to the implant surface. Continuous recordings of oxygen flux indicate that the tissue permeability changes predictably with time, and suggest that oxygen delivery can be sustained over the long term.

A research and development agenda for systematic reviews that ask complex questions about complex interventions.

OBJECTIVES: This article outlines a research and development agenda for systematic reviews that ask complex questions about interventions varying in degree and type of complexity. STUDY DESIGN AND SETTING: Consensus development by key authors of articles on methodological challenges in systematic reviews of complex interventions, based on a 2-day workshop in Montebello, Canada, January 2012. RESULTS: There is an urgent need for a more precise and consistently applied lexicon and language to disaggregate several conceptually distinct dimensions of "complexity." Selected current evidence synthesis methods have potential application in reviews where complexity is important. There is a lack of evaluation of methods to better understand the nature of complex interventions and the optimal processes of synthesizing and interpreting evidence from these systematic reviews. Gaps in methods, knowledge, and know-how exist, and there is a need for additional guidance. CONCLUSION: Understanding how complexity can impact on findings of systematic reviews is critical. Experience in applying methods that have been developed to facilitate this understanding is limited, and the degree to which these approaches improve the systematic review process or transparency is only partially understood. Future research should concentrate on the impact of complexity on the systematic review process and findings and on further methodological development.

Clarifying differences between review designs and methods.

This paper argues that the current proliferation of types of systematic reviews creates challenges for the terminology for describing such reviews. Terminology is necessary for planning, describing, appraising, and using reviews, building infrastructure to enable the conduct and use of reviews, and for further developing review methodology. There is insufficient consensus on terminology for a typology of reviews to be produced and any such attempt is likely to be limited by the overlapping nature of the dimensions along which reviews vary. It is therefore proposed that the most useful strategy for the field is to develop terminology for the main dimensions of variation. Three such main dimensions are proposed: (1) aims and approaches (including what the review is aiming to achieve, the theoretical and ideological assumptions, and the use of theory and logics of aggregation and configuration in synthesis); (2) structure and components (including the number and type of mapping and synthesis components and how they relate); and (3) breadth and depth and the extent of 'work done' in addressing a research issue (including the breadth of review questions, the detail with which they are addressed, and the amount the review progresses a research agenda). This then provides an overarching strategy to encompass more detailed descriptions of methodology and may lead in time to a more overarching system of terminology for systematic reviews.

Hitting is contagious in baseball: evidence from long hitting streaks.

Data analysis is used to test the hypothesis that "hitting is contagious". A statistical model is described to study the effect of a hot hitter upon his teammates' batting during a consecutive game hitting streak. Box score data for entire seasons comprising [Formula: see text] streaks of length [Formula: see text] games, including a total [Formula: see text] observations were compiled. Treatment and control sample groups ([Formula: see text]) were constructed from core lineups of players on the streaking batter's team. The percentile method bootstrap was used to calculate [Formula: see text] confidence intervals for statistics representing differences in the mean distributions of two batting statistics between groups. Batters in the treatment group (hot streak active) showed statistically significant improvements in hitting performance, as compared against the control. Mean [Formula: see text] for the treatment group was found to be [Formula: see text] to [Formula: see text] percentage points higher during hot streaks (mean difference increased [Formula: see text] points), while the batting heat index [Formula: see text] introduced here was observed to increase by [Formula: see text] points. For each performance statistic, the null hypothesis was rejected at the [Formula: see text] significance level. We conclude that the evidence suggests the potential existence of a "statistical contagion effect". Psychological mechanisms essential to the empirical results are suggested, as several studies from the scientific literature lend credence to contagious phenomena in sports. Causal inference from these results is difficult, but we suggest and discuss several latent variables that may contribute to the observed results, and offer possible directions for future research.

TLR-4 signalling accelerates colon cancer cell adhesion via NF-κB mediated transcriptional up-regulation of Nox-1.

Surgery induced inflammation is a potent promoter of tumour recurrence and metastasis in colorectal cancer. The recently discovered family of Nox enzymes represent a major source of endogenous reactive oxygen species (ROS) and are now heavily implicated in tumour cell metastasis. Interestingly, Nox enzymes can be 'purposefully' activated by inflammatory cytokines and growth factors which are present in abundance in the peri-operative window. As colon cancer cells express Nox enzymes and Toll-like receptor 4 (TLR-4), we hypothesised that LPS may potentiate the ability of colon cancer cells to metastasise via Nox enzyme mediated redox signalling. In support of this hypothesis, this paper demonstrates that LPS induces a significant, transient increase of endogenous ROS in SW480, SW620 and CT-26 colon cancer cells. This increase in LPS-induced ROS activity is completely abrogated by a Nox inhibitor, diphenyleneiodonium (DPI), Nox1 siRNA and an NF-κB inhibitor, Dihydrochloride. A significant increase in Nox1 and Nox2 protein expression occurs following LPS treatment. Inhibition of NF-κB also attenuates the increase of Nox1 and Nox2 protein expression. The sub-cellular location of LPS-induced ROS generation lies mainly in the endoplasmic reticulum. LPS activates the PI3K/Akt pathway via Nox generated ROS and this signal is inhibited by DPI. This LPS activated Nox mechanism facilitates a significant increase in SW480 colon cancer cell adhesion to collagen I, which is inhibited by DPI, Nox1 siRNA and a PI3K inhibitor. Altogether, these data suggest that the LPS-Nox1 redox signalling axis plays a crucial role in facilitation of colon cancer cell adhesion, thus increasing the metastatic potential of colon cancer cells. Nox1 may represent a valuable target in which to prevent colon cancer metastasis.

H2O2 production downstream of FLT3 is mediated by p22phox in the endoplasmic reticulum and is required for STAT5 signalling.

The internal tandem duplication (ITD) of the juxtamembrane region of the FLT3 receptor has been associated with increased reactive oxygen species (ROS) generation in acute myeloid leukemia (AML). How this elevated level of ROS contributes to the leukemic phenotype, however, remains poorly understood. In this work we show that ROS in the FLT3-ITD expressing AML cell line MV4-11 is reduced by treatment with PKC412, an inhibitor of FLT3, DPI, a flavoprotein inhibitor, and VAS2870, a Nox specific inhibitor, suggesting that ROS production is both FLT3 and NADPH oxidase dependent. The majority of these ROS co-localize to the endoplasmic reticulum (ER), as determined with the H(2)O(2)-specific aryl-boronate dye Peroxyorange 1, which also corresponds to co-localization of p22phox. Moreover, knocking down p22phox dramatically reduces H(2)O(2) after 24 hours in the ER, without affecting mitochondrial ROS. Significantly, the FLT3 inhibitor PKC412 reduces H(2)O(2) in FLT3-ITD expressing cell lines (MV4-11, MOLM-13) through reduction of p22phox over 24 hours. Reduced p22phox is achieved by proteasomal degradation and is prevented upon GSK3-ß inhibition. Knockdown of p22phox resulted in reduced STAT5 signalling and reduced Pim-1 levels in the cells after 24 hours. Thus, we have shown that FLT3 driven H(2)O(2) production in AML cells is mediated by p22phox and is critical for STAT5 signalling.