Protocol for the development of a tool (INSPECT-SR) to identify problematic randomised controlled trials in systematic reviews of health interventions.

INTRODUCTION: Randomised controlled trials (RCTs) inform healthcare decisions. It is now apparent that some published RCTs contain false data and some appear to have been entirely fabricated. Systematic reviews are performed to identify and synthesise all RCTs that have been conducted on a given topic. While it is usual to assess methodological features of the RCTs in the process of undertaking a systematic review, it is not usual to consider whether the RCTs contain false data. Studies containing false data therefore go unnoticed and contribute to systematic review conclusions. The INveStigating ProblEmatic Clinical Trials in Systematic Reviews (INSPECT-SR) project will develop a tool to assess the trustworthiness of RCTs in systematic reviews of healthcare-related interventions. METHODS AND ANALYSIS: The INSPECT-SR tool will be developed using expert consensus in combination with empirical evidence, over five stages: (1) a survey of experts to assemble a comprehensive list of checks for detecting problematic RCTs, (2) an evaluation of the feasibility and impact of applying the checks to systematic reviews, (3) a Delphi survey to determine which of the checks are supported by expert consensus, culminating in, (4) a consensus meeting to select checks to be included in a draft tool and to determine its format and (5) prospective testing of the draft tool in the production of new health systematic reviews, to allow refinement based on user feedback. We anticipate that the INSPECT-SR tool will help researchers to identify problematic studies and will help patients by protecting them from the influence of false data on their healthcare. ETHICS AND DISSEMINATION: The University of Manchester ethics decision tool was used, and this returned the result that ethical approval was not required for this project (30 September 2022), which incorporates secondary research and surveys of professionals about subjects relating to their expertise. Informed consent will be obtained from all survey participants. All results will be published as open-access articles. The final tool will be made freely available.

Protocol for the development of a tool (INSPECT-SR) to identify problematic randomised controlled trials in systematic reviews of health interventions.

Introduction: Randomised controlled trials (RCTs) inform healthcare decisions. It is now apparent that some published RCTs contain false data and some appear to have been entirely fabricated. Systematic reviews are performed to identify and synthesise all RCTs that have been conducted on a given topic. While it is usual to assess methodological features of the RCTs in the process of undertaking a systematic review, it is not usual to consider whether the RCTs contain false data. Studies containing false data therefore go unnoticed and contribute to systematic review conclusions. The INSPECT-SR project will develop a tool to assess the trustworthiness of RCTs in systematic reviews of healthcare related interventions. Methods and analysis: The INSPECT-SR tool will be developed using expert consensus in combination with empirical evidence, over five stages: 1) a survey of experts to assemble a comprehensive list of checks for detecting problematic RCTs, 2) an evaluation of the feasibility and impact of applying the checks to systematic reviews, 3) a Delphi survey to determine which of the checks are supported by expert consensus, culminating in 4) a consensus meeting to select checks to be included in a draft tool and to determine its format, 5) prospective testing of the draft tool in the production of new health systematic reviews, to allow refinement based on user feedback. We anticipate that the INSPECT-SR tool will help researchers to identify problematic studies, and will help patients by protecting them from the influence of false data on their healthcare.

WITHDRAWN: Drugs for preventing postoperative nausea and vomiting.

BACKGROUND: Drugs can prevent postoperative nausea and vomiting, but their relative efficacies and side effects have not been compared within one systematic review. OBJECTIVES: The objective of this review was to assess the prevention of postoperative nausea and vomiting by drugs and the development of any side effects. SEARCH METHODS: We searched The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 2, 2004), MEDLINE (January 1966 to May 2004), EMBASE (January 1985 to May 2004), CINAHL (1982 to May 2004), AMED (1985 to May 2004), SIGLE (to May 2004), ISI WOS (to May 2004), LILAC (to May 2004) and INGENTA bibliographies. SELECTION CRITERIA: We included randomized controlled trials that compared a drug with placebo or another drug, or compared doses or timing of administration, that reported postoperative nausea or vomiting as an outcome. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted outcome data. MAIN RESULTS: We included 737 studies involving 103,237 people. Compared to placebo, eight drugs prevented postoperative nausea and vomiting: droperidol, metoclopramide, ondansetron, tropisetron, dolasetron, dexamethasone, cyclizine and granisetron. Publication bias makes evidence for differences among these drugs unreliable. The relative risks (RR) versus placebo varied between 0.60 and 0.80, depending upon the drug and outcome. Evidence for side effects was sparse: droperidol was sedative (RR 1.32) and headache was more common after ondansetron (RR 1.16). AUTHORS' CONCLUSIONS: Either nausea or vomiting is reported to affect, at most, 80 out of 100 people after surgery. If all 100 of these people are given one of the listed drugs, about 28 would benefit and 72 would not. Nausea and vomiting are usually less common and, therefore, drugs are less useful. For 100 people, of whom 30 would vomit or feel sick after surgery if given placebo, 10 people would benefit from a drug and 90 would not. Between one to five patients out of every 100 people may experience a mild side effect, such as sedation or headache, when given an antiemetic drug. Collaborative research should focus on determining whether antiemetic drugs cause more severe, probably rare, side effects. Further comparison of the antiemetic effect of one drug versus another is not a research priority.

Diamond coated artificial cardiovascular devices.

Ultrananocrystalline diamond (UNCD), an extremely smooth, low cost diamond coating was successfully developed herein for antithrombogenic application which requires high biocompatibility, low wear, low friction, and chemical inertness. The substrate materials utilized in the Jarvik 2000 ventricular assist device (VAD), silicon carbide and titanium alloy, provide an excellent substrate match for UNCD integration. The paper addresses the development of medical-quality UNCD films to significantly improve the knowledge base regarding the defect mechanisms of UNCD films, to reduce or eliminate known wear-inducing imperfections in the film, and to thoroughly characterize and test the films as well as assembled UNCD-coated VADs. After the defect reduction and seeding experiments to improve film adhesion and coating quality, the best candidate deposition method has been down-selected for coating and assembly of VAD parts from Jarvik Heart. The coated and assembled devices have been tested with mechanical and blood-simulating fluid hydrodynamic testing at Jarvik Heart for full verification of the new coating technology. UNCD interface takes advantage of combining unmatched durability and antithrombogenicity.

Ultrananocrystalline Diamond Integration with Pyrolytic Carbon Components of Mechanical Heart Valves.

In this report, an idea of integrating ultrananocrystalline diamond (UNCD) with pyrolytic carbon (PyC) -based mechanical heart valves, has been demonstrated. The report addresses the strategies to avoid graphitization and film delamination during the diamond coating. Raman and scratch tests showed that a UNCD film with high purity could adhere to the PyC substrate strongly. A thrombin generation study demonstrated an excellent biocompatibility of UNCD towards fresh human platelets. These results suggest that UNCD could be a good candidate of surface material for next generation heart valves and other implantable devices.

The effect of electrode size and surface heterogeneity on electrochemical properties of ultrananocrystalline diamond microelectrode.

We report here the effect of electrode size on electrochemical properties of boron-doped ultrananocrystalline diamond (UNCD) microelectrodes using electrochemical impedance spectroscopy (EIS). By reducing microelectrode size from 250-µm to 10-µm diameter (D), the shape of impedance spectra changes from linear line to two-arcs. The fitting of experimental data to electrochemical circuit model suggests that each arc likely corresponds to UNCD grains and grain boundary phases. The two phases become separable as a result of microelectrode size reduction. In addition, for D ≤ 100-µm, microstructural and morphological defects/heterogeneities of grain boundaries and the presence of surface oxygen are also revealed in the spectra. The microelectrode size reduction specifically affect the impedance of the grain boundaries, e.g. for ultramicroelectrodes, UMEs (D ≤ 25-µm), as the grain boundary impedance increases by ~30-fold. Thus, at UMEs, the grain-grain boundary properties are revealed more sensitively in the spectra. Atomic force microscopy, scanning electron microscopy, Raman spectroscopy and surface profilometry measurements were performed to study the influence of microfabrication on surface properties. A significant increase in surface roughness after microfabrication shows that heterogeneities as observed in the spectra are not only due to intrinsic UNCD properties but also arises from microfabrication.

Permissive hypoxaemia versus normoxaemia for mechanically ventilated critically ill patients.

BACKGROUND: Permissive hypoxaemia describes a concept in which a lower level of arterial oxygenation (PaO2) than usual is accepted to avoid the detrimental effects of high fractional inspired oxygen and invasive mechanical ventilation. Currently however, no specific threshold is known that defines permissive hypoxaemia, and its use in adults remains formally untested. The importance of this systematic review is thus to determine whether any substantial evidence is available to support the notion that permissive hypoxaemia may improve clinical outcomes in mechanically ventilated critically ill patients. OBJECTIVES: We assessed whether permissive hypoxaemia (accepting a lower PaO2 than is current practice) in mechanically ventilated critically ill patients affects patient morbidity and mortality. We planned to conduct subgroup and sensitivity analyses and to examine the role of bias to determine the level of evidence provided. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) 2013, Issue 11, part of The Cochrane Library; MEDLINE (1954 to November 2013); EMBASE (1980 to November 2013); CINAHL (1982 to November 2013) and ISI Web of Science (1946 to November 2013). We combined the sensitive search strategies described in the Cochrane Handbook for Systematic Reviews of Interventions to search for randomized controlled trials (RCTs) in MEDLINE and EMBASE. For ongoing trials, we also searched the following databases: MetaRegister of ControlledTrials and the National Research Register. We applied no language restrictions. SELECTION CRITERIA: RCTs and quasi-RCTs that compared outcomes for mechanically ventilated critically ill participants, in which the intervention group was targeted to be hypoxaemic relative to the control group, and the control group was normoxaemic or was mildly hypoxaemic, were eligible for inclusion in this review. Exact values defining 'conventional' and 'permissive hypoxaemia' groupings were purposely not specified, and the manner in which these oxygenation goals were achieved also was not specified. We did state however that the intervention group required a target oxygenation level lower than that of the control group, and that the control group target levels should be in the range of normoxaemia or mild hypoxaemia (not hyperoxaemia). DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by The Cochrane Collaboration. Using the results of the above searches, two review authors (EG-K and KM) independently screened all titles and abstracts for eligibility and duplication. No discrepancies were encountered, nor was it necessary for review authors to contact the first author of any trial to ask for additional information. MAIN RESULTS: Our search strategy yielded a total of 2419 results. After exclusion of duplications, 1651 candidate studies were identified. Screening of titles and abstracts revealed that no studies met our inclusion criteria. AUTHORS' CONCLUSIONS: This comprehensive review failed to identify any relevant studies evaluating permissive hypoxaemia versus normoxaemia in mechanically ventilated critically ill participants. Therefore we are unable to support or refute the hypothesis that this treatment strategy is of benefit to patients.Given the substantial amount of provocative evidence derived from related clinical contexts (resuscitation, myocardial infarction, stroke), we believe that this review highlights an important unanswered question within critical care.  In the presence of two competing harms (hypoxia and hyperoxia), it will be important to carefully evaluate the safety and feasibility of permissive hypoxaemia before proceeding to efficacy and effectiveness trials.

Characterization of ultrananocrystalline diamond microsensors for in vivo dopamine detection.

We show the technical feasibility of coating and micro patterning boron-doped ultrananocrystalline diamond (UNCD®) on metal microwires and of applying them as microsensors for the detection of dopamine in vivo using fast-scan cyclic voltammetry. UNCD electrode surface consistently generated electrochemical signals with high signal-to-noise ratio of >800 using potassium ferrocyanide-ferricyanide redox couple. Parylene patterned UNCD microelectrodes were effectively applied to detect dopamine reliably in vitro using flow injection analysis with a detection limit of 27 nM and in the striatum of the anesthetized rat during electrical stimulation of dopamine neurons.

Joint space predicts THA after hip arthroscopy in patients 50 years and older.

BACKGROUND: All patients considering joint-preserving hip arthroscopy should be educated on the risk of THA after arthroscopy. The degree of radiographic osteoarthritis predicts subsequent THA. To provide patients with the best information, the best radiographic measure that predicts THA after hip arthroscopy should be identified. QUESTIONS/PURPOSES: We therefore determined if Tönnis grade, Kellgren-Lawrence grade, or joint space narrowing was superior in predicting THA after hip arthroscopy. METHODS: We retrospectively reviewed 203 patients 50 years of age or older treated with hip arthroscopy between March 2007 and October 2010. Of these, 96 patients met the study inclusion criteria. Sixty-five did not undergo THAs during the followup time (non-THA group) and 31 patients did (THA group). We determined Tönnis grade, Kellgren-Lawrence grade, and/or joint space narrowing before arthroscopy. The median followup for the non-THA group was 54 months (95% confidence interval, 49.9-58.9 months). RESULTS: In 81% of the patients, joint space accurately predicted THA or non-THA, whereas Kellgren-Lawrence was accurate in 73% and Tönnis grade was accurate in 65%. On binary logistic regression, the only predictor (r(2) = 0.45) of THA was joint space of 2 mm or less. CONCLUSIONS: Measuring joint space by determining if any measurement is 2 mm or less predicts patients progressing to THA after hip arthroscopy approximately 80% of the time. At this early time point, joint space measurements were the most accurate predictor of THA and should be used in patient education to define the risk of early failure from hip arthroscopy.

Association between preoperative haemoglobin concentration and cardiopulmonary exercise variables: a multicentre study.

BACKGROUND: Preoperative anaemia and low exertional oxygen uptake are both associated with greater postoperative morbidity and mortality. This study reports the association among haemoglobin concentration ([Hb]), peak oxygen uptake (V˙O2 peak) and anaerobic threshold (AT) in elective surgical patients. METHODS: Between 1999 and 2011, preoperative [Hb] and cardiopulmonary exercise tests were recorded in 1,777 preoperative patients in four hospitals. The associations between [Hb], V˙O2 peak and AT were analysed by linear regression and covariance. RESULTS: In 436 (24.5%) patients, [Hb] was <12 g dl-1 and, in 83 of these, <10 g dl-1. Both AT and V˙O2 peak rose modestly with increasing [Hb] (r2 = 0.24, P <0.0001 and r2 = 0.30, P <0.0001, respectively). After covariate adjustment, an increase in [Hb] of one standard deviation was associated with a 6.7 to 9.7% increase in V˙O2 peak, and a rise of 4.4 to 6.0% in AT. Haemoglobin concentration accounted for 9% and 6% of the variation in V˙O2 peak and AT respectively. CONCLUSIONS: To a modest extent, lower haemoglobin concentrations are independently associated with lower oxygen uptake during preoperative cardiopulmonary exercise testing. It is unknown whether this association is causative.

Ultrananocrystalline diamond tip integrated onto a heated atomic force microscope cantilever.

We report a wear-resistant ultrananocrystalline (UNCD) diamond tip integrated onto a heated atomic force microscope (AFM) cantilever and UNCD tips integrated into arrays of heated AFM cantilevers. The UNCD tips are batch-fabricated and have apex radii of approximately 10 nm and heights up to 7 µm. The solid-state heater can reach temperatures above 600 °C and is also a resistive temperature sensor. The tips were shown to be wear resistant throughout 1.2 m of scanning on a single-crystal silicon grating at a force of 200 nN and a speed of 10 µm s(-1). Under the same conditions, a silicon tip was completely blunted. We demonstrate the use of these heated cantilevers for thermal imaging in both contact mode and intermittent contact mode, with a vertical imaging resolution of 1.9 nm. The potential application to nanolithography was also demonstrated, as the tip wrote hundreds of polyethylene nanostructures.

A quantitative study of detection mechanism of a label-free impedance biosensor using ultrananocrystalline diamond microelectrode array.

It is well recognized that label-free biosensors are the only class of sensors that can rapidly detect antigens in real-time and provide remote environmental monitoring and point-of-care diagnosis that is low-cost, specific, and sensitive. Electrical impedance spectroscopy (EIS) based label-free biosensors have been used to detect a wide variety of antigens including bacteria, viruses, DNA, and proteins due to the simplicity of their detection technique. However, their commercial development has been hindered due to difficulty in interpreting the change in impedance upon antigen binding and poor signal reproducibility as a result of surface fouling and non-specific binding. In this study, we develop a circuit model to adequately describe the physical changes at bio functionalized surface and provide an understanding of the detection mechanism based on electron exchange between electrolyte and surface through pores surrounding antibody-antigen. The model was successfully applied to extract quantitative information about the bio surface at different stages of surface functionalization. Further, we demonstrate boron-doped ultrananocrystalline diamond (UNCD) microelectrode array (3 × 3 format, 200 µm diameter) improves signal reproducibility significantly and increases sensitivity by four orders of magnitude. This study marks the first demonstration of UNCD array based biosensor that can reliably detect a model Escherichia coli K12 bacterium using EIS, positioning this technology for rapid adoption in point-of-use applications.

Reliability of various observers in determining common radiographic parameters of adult hip structural anatomy.

BACKGROUND: Radiographic evaluation of the hip is extremely important in the diagnosis and treatment decisionmaking process for pre-arthritic hip disease. Many different radiographic measurements have been described as indicators of underlying structural hip deformity. The purpose of this study was to determine the interobserver and intraobserver reliability of various musculoskeletal physicians in performing selected measurements of adult structural hip anatomy. METHODS: A blinded review of 45 sets of radiographs from patients with developmental dysplasia, femoro-acetabular impingement, and normal anatomy was performed. Data points included the lateral center-edge angle (LCEA), vertical-center-anterior angle (VCA), head-neck offset ratio (UNO), alpha angle, Tönnis angle, Tönnis osteoarthritis grade and a radiographic diagnosis. One orthopaedic fellow, two orthopaedic residents, and two attending musculoskeletal physiatrists analyzed radiographs on two separate occasions. One sports medicine orthopaedic attending physician completed a single analysis of the image sets. Intraobserver and interobserver reliability was established using intra-class correlation coefficients (ICC) for continuous variables. Agreement regarding categorical variables was performed using the kappa coefficient RESULTS: Excellent intraobserver reliability was found for the following: LCEA (ICC = 0.88), VCA (0.88), Tönnis angle (0.83), HNO on the frog lateral (0.78), alpha angle on the frog lateral (0.76), HNO on the cross-table lateral (0.75), and angle alpha on the cross-table lateral (0.76). Intraobserver reliability for osteoarthritis grade was poor (weighted kappa = 0.57). For all data points, interobserver reliability was considerably worse, with 95% confidence intervals spanning below 0.55. CONCLUSIONS: While the described measurements of adult structural hip anatomy provide excellent reliability for a given reader, these measurements are less reliable across readers. Taken in isolation, these measurements, as performed by observers with varied clinical experience and clinical backgrounds, are limited in determining a consistent radiographic diagnosis.

Control of Nanoscale Environment to Improve Stability of Immobilized Proteins on Diamond Surfaces.

Immunoassays for detection of bacterial pathogens rely on the selectivity and stability of bio-recognition elements such as antibodies tethered to sensor surfaces. The search for novel surfaces that improve the stability of biomolecules and assay performance has been pursued for a long time. However, the anticipated improvements in stability have not been realized in practice under physiological conditions because the surface functionalization layers on commonly used substrates, silica and gold, are themselves unstable on time scales of days. In this paper, we show that covalent linking of antibodies to diamond surfaces leads to substantial improvements in biological activity of proteins as measured by the ability to selectively capture cells of the pathogenic bacterium Escherichia coli O157:H7 even after exposure to buffer solutions at 37 °C for extended periods of time, approaching 2 weeks. Our results from ELISA, XPS, fluorescence microscopy, and MD simulations suggest that by using highly stable surface chemistry and controlling the nanoscale organization of the antibodies on the surface, it is possible to achieve significant improvements in biological activity and stability. Our findings can be easily extended to functionalization of micro and nanodimensional sensors and structures of biomedical diagnostic and therapeutic interest.

Preoperative evaluation of the adult patient undergoing non-cardiac surgery: guidelines from the European Society of Anaesthesiology.

The purpose of these guidelines on the preoperative evaluation of the adult non-cardiac surgery patient is to present recommendations based on available relevant clinical evidence. The ultimate aims of preoperative evaluation are two-fold. First, we aim to identify those patients for whom the perioperative period may constitute an increased risk of morbidity and mortality, aside from the risks associated with the underlying disease. Second, this should help us to design perioperative strategies that aim to reduce additional perioperative risks. Very few well performed randomised studies on the topic are available and many recommendations rely heavily on expert opinion and are adapted specifically to the healthcare systems in individual countries. This report aims to provide an overview of current knowledge on the subject with an assessment of the quality of the evidence in order to allow anaesthetists all over Europe to integrate - wherever possible - this knowledge into daily patient care. The Guidelines Committee of the European Society of Anaesthesiology (ESA) formed a task force with members of subcommittees of scientific subcommittees and individual members of the ESA. Electronic databases were searched from the year 2000 until July 2010 without language restrictions. These searches produced 15 425 abstracts. Relevant systematic reviews with meta-analyses, randomised controlled trials, cohort studies, case-control studies and cross-sectional surveys were selected. The Scottish Intercollegiate Guidelines Network grading system was used to assess the level of evidence and to grade recommendations. The final draft guideline was posted on the ESA website for 4 weeks and the link was sent to all ESA members, individual or national (thus including most European national anaesthesia societies). Comments were collated and the guidelines amended as appropriate. When the final draft was complete, the Guidelines Committee and ESA Board ratified the guidelines.

Comparative systematic review of the open dislocation, mini-open, and arthroscopic surgeries for femoroacetabular impingement.

PURPOSE: To analyze the current approaches to the surgical management of symptomatic femoroacetabular impingement (FAI). METHODS: Thirteen relevant queries were used in four search engines (PubMed, EMBASE, Ovid, and the Cochrane Review) with a resultant 5,856 articles. Eighteen peer-reviewed treatment outcome studies met the inclusion criteria with minimum 1-year follow-up of the surgical treatment of skeletal pathoanatomy and associated chondrolabral pathology in skeletally mature patients with FAI. RESULTS: There were 6 open surgical dislocation, 4 mini-open, and 8 arthroscopic studies, all with Levels of Evidence III or IV. The only prospective studies were in the arthroscopic category. Outcome data were extracted and analyzed with respect to surgical efficacy, failure rates, and complications. CONCLUSIONS: The open dislocation, mini-open, and arthroscopic methods for treating symptomatic FAI are effective in improving pain and function in short-term to midterm studies and are relatively safe procedures. The historical gold standard of open dislocation surgery had a comparatively high major complication rate primarily because of trochanteric osteotomy-related issues. The mini-open method showed comparable efficacy but a significant incidence of iatrogenic injury to the lateral femoral cutaneous nerve in some studies. The arthroscopic method had surgical outcomes equal to or better than the other methods with a lower rate of major complications when performed by experienced surgeons.