Ciclesonide versus other inhaled corticosteroids for chronic asthma in children

Background Inhaled corticosteroids (ICS) are the cornerstone of asthma maintenance treatment in children. Particularly among parents, there is concern about the safety of ICS as studies in children have shown reduced growth. Small-particle-size ICS targeting the smaller airways have improved lung deposition and effective asthma control might be achieved at lower daily doses. Ciclesonide is a relatively new ICS. This small-particle ICS is a pro-drug that is converted in the airways to an active metabolite and therefore with potentially less local (throat infection) and systemic (reduced growth) side effects. It can be inhaled once daily, thereby possibly improving adherence. Objectives To assess the efficacy and adverse effects of ciclesonide compared to other ICS in the management of chronic asthma in children. Search methods We searched the Cochrane Airways Group Register of trials with pre-defined terms. Additional searches of MEDLINE (via PubMed), EMBASE and Clinicalstudyresults. org were undertaken. Searches are up to date to 7 November 2012. Selection criteria Randomised controlled parallel or cross-over studies were eligible for the review. We included studies comparing ciclesonide with other corticosteroids both at nominally equivalent doses or lower doses of ciclesonide. Data collection and analysis Two review authors independently assessed trial quality and extracted data. Study authors were contacted for additional information. Adverse effects information was collected from the trials. Main results Six studies were included in this review (3256 children, 4 to 17 years of age). Two studies were published as conference abstracts only. Ciclesonide was compared to budesonide and fluticasone. Ciclesonide compared to budesonide (dose ratio 1: 2): asthma symptoms and adverse effect were similar in both groups. Pooled results showed no significant difference in children who experience an exacerbation (risk ratio (RR) 2.20, 95% confidence interval (CI) 0.75 to 6.43). Both studies reported that 24-hour urine cortisol levels showed a statistically significant decrease in the budesonide group compared to the ciclesonide group. Ciclesonide compared to fluticasone (dose ratio 1: 1): no significant differences were found for the outcome asthma symptoms. Pooled results showed no significant differences in number of patients with exacerbations (RR 1.37, 95% CI 0.58 to 3.21) and data from a study that could not be pooled in the meta-analysis reported similar numbers of patients with exacerbations in both groups. None of the studies found a difference in adverse effects. No significant difference was found for 24-hour urine cortisol levels between the groups (mean difference 0.54 nmol/mmol, 95% CI -5.92 to 7.00). Ciclesonide versus fluticasone (dose ratio 1: 2) was assessed in one study and showed similar results between the two corticosteroids for asthma symptoms. The number of children with exacerbations was significantly higher in the ciclesonide group (RR 3.57, 95% CI 1.35 to 9.47). No significant differences were found in adverse effects (RR 0.98, 95% CI 0.81 to 1.14) and 24-hour urine cortisol levels (mean difference 1.15 nmol/mmol, 95% CI 0.07 to 2.23). The quality of evidence was judged 'low' for the outcomes asthma symptoms and adverse events and 'very low' for the outcome exacerbations for ciclesonide versus budesonide (dose ratio 1: 1). The quality of evidence was graded 'moderate' for the outcome asthma symptoms, 'very low' for the outcome exacerbations and 'low' for the outcome adverse events for ciclesonide versus fluticasone (dose ratio 1: 1). For ciclesonide versus fluticasone (dose ratio 1: 2) the quality was rated 'low' for the outcome asthma symptoms and 'very low' for exacerbations and adverse events (dose ratio 1: 2). Authors' conclusions An improvement in asthma symptoms, exacerbations and side effects of ciclesonide versus budesonide and fluticasone could be neither demonstrated nor refuted and the trade-off between benefits and harms of using ciclesonide instead of budesonide or fluticasone is unclear. The resource use or costs of different ICS should therefore also be considered in final decision making. Longer-term superiority trials are needed to identify the usefulness and safety of ciclesonide compared to other ICS. Additionally these studies should be powered for patient relevant outcomes (exacerbations, asthma symptoms, quality of life and side effects). There is a need for studies comparing ciclesonide once daily with other ICS twice daily to assess the advantages of ciclesonide being a pro-drug that can be administered once daily with possibly increased adherence leading to increased control of asthma and fewer side effects

Search filters to identify geriatric medicine in Medline

Objectives To create user-friendly search filters with high sensitivity, specificity, and precision to identify articles on geriatric medicine in Medline. Design A diagnostic test assessment framework was used. A reference set of 2255 articles was created by hand-searching 22 biomedical journals in Medline, and each article was labeled as 'relevant', 'not relevant', or 'possibly relevant' for geriatric medicine. From the relevant articles, search terms were identified to compile different search strategies. The articles retrieved by the various search strategies were compared with articles from the reference set as the index test to create the search filters. Measures Sensitivity, specificity, precision, accuracy, and number-needed-to-read (NNR) were calculated by comparing the results retrieved by the different search strategies with the reference set. Results The most sensitive search filter had a sensitivity of 94.8%, a specificity of 88.7%, a precision of 73.0%, and an accuracy of 90.2%. It had an NNR of 1.37. The most specific search filter had a specificity of 96.6%, a sensitivity of 69.1%, a precision of 86.6%, and an accuracy of 89.9%. It had an NNR of 1.15. Conclusion These geriatric search filters simplify searching for relevant literature and therefore contribute to better evidence-based practice. The filters are useful to both the clinician who wants to find a quick answer to a clinical question and the researcher who wants to find as many relevant articles as possible without retrieving too many irrelevant article

Data sources and methods used to determine pretest probabilities in a cohort of Cochrane diagnostic test accuracy reviews

BACKGROUND: A pretest probability must be selected to calculate data to help clinicians, guideline boards and policy makers interpret diagnostic accuracy parameters. When multiple analyses for the same target condition are compared, identical pretest probabilities might be selected to facilitate the comparison. Some pretest probabilities may lead to exaggerations of the patient harms or benefits, and guidance on how and why to select a specific pretest probability is minimally described. Therefore, the aim of this study was to assess the data sources and methods used in Cochrane diagnostic test accuracy (DTA) reviews for determining pretest probabilities to facilitate the interpretation of DTA parameters. A secondary aim was to assess the use of identical pretest probabilities to compare multiple meta-analyses within the same target condition. METHODS: Cochrane DTA reviews presenting at least one meta-analytic estimate of the sensitivity and/or specificity as a primary analysis published between 2008 and January 2018 were included. Study selection and data extraction were performed by one author and checked by other authors. Observed data sources (e.g. studies in the review, or external sources) and methods to select pretest probabilities (e.g. median) were categorized. RESULTS: Fifty-nine DTA reviews were included, comprising of 308 meta-analyses. A pretest probability was used in 148 analyses. Authors used included studies in the DTA review, external sources, and author consensus as data sources for the pretest probability. Measures of central tendency with or without a measure of dispersion were used to determine the pretest probabilities, with the median most commonly used. Thirty-two target conditions had at least one identical pretest probability for all of the meta-analyses within their target condition. About half of the used identical pretest probabilities were inside the prevalence ranges from all analyses within a target condition. CONCLUSIONS: Multiple sources and methods were used to determine (identical) pretest probabilities in Cochrane DTA reviews. Indirectness and severity of downstream consequences may influence the acceptability of the certainty in calculated data with pretest probabilities. Consider: whether to present normalized frequencies, the influence of pretest probabilities on normalized frequencies, and whether to use identical pretest probabilities for meta-analyses in a target condition

Prognostic value of radiological recurrence patterns in ovarian cancer

Objective: To study the prognostic value of CT assessed recurrence patterns on survival outcomes in women with epithelial ovarian cancer. Methods: CT scans were systematically re-evaluated on predefined anatomical sites for the presence of tumor in all 89 patients diagnosed with epithelial ovarian cancer between January 2008 and December 2013 who underwent cytoreductive surgery at our institution and developed a recurrence. A Cox proportional hazard analysis was used to test the effect of recurrence patterns on survival. Results: The median survival time for patients grouped as predominantly intraperitoneal (n = 62), hematogenous (n = 13) or lymphatic (n = 14) recurrence was 25.8 (95% CI 18.4–33.2), 27.6 (95% CI 18.5–36.6) and 52.9 months (95% CI 42.1–63.7), respectively. Univariate Cox regression analysis identified the following prognostic factors: lymphatic recurrence pattern (HR 0.42, 95% CI 0.21–0.85), ascites at diagnosis (HR 2.35, 95% CI 1.46–3.79), residual tumor at initial surgery (HR 2.16, 95% CI 1.36–3.44) and FIGO stage (I–IIIB: HR 0.59, 95% CI 0.33–1.06). The median time to recurrence was 19.5 month for patients after complete debulking surgery, 13.1 months for patients with residual disease ≤1 cm and 8.2 months for patients with residual disease >1 cm after surgery (P < 0.001). No differences in recurrence patterns between patients with complete and incomplete surgery were found. Conclusions: Prolonged survival rates were found in ovarian cancer patients with a predominantly lymphatic recurrence compared to patients with a predominantly peritoneal or hematogenous recurrence. Completeness of surgery was associated with time to recurrence. Classification of recurrence patterns can help counsel patients on their prognosis at the time of recurrence

Interventions for preventing falls and fall-related fractures in community-dwelling older adults: A systematic review and network meta-analysis.

OBJECTIVE To compare the effectiveness of single, multiple, and multifactorial interventions to prevent falls and fall-related fractures in community-dwelling older persons. METHODS MEDLINE, Embase, and Cochrane Central Register of Controlled Trials were systematically searched for randomized controlled trials (RCTs) evaluating the effectiveness of fall prevention interventions in community-dwelling adults aged ≥65 years, from inception until February 27, 2019. Two large RCTs (published in 2020 after the search closed) were included in post hoc analyses. Pairwise meta-analysis and network meta-analysis (NMA) were conducted. RESULTS NMA including 192 studies revealed that the following single interventions, compared with usual care, were associated with reductions in number of fallers: exercise (risk ratio [RR] 0.83; 95% confidence interval [CI] 0.77-0.89) and quality improvement strategies (e.g., patient education) (RR 0.90; 95% CI 0.83-0.98). Exercise as a single intervention was associated with a reduction in falls rate (RR 0.79; 95% CI 0.73-0.86). Common components of multiple interventions significantly associated with a reduction in number of fallers and falls rate were exercise, assistive technology, environmental assessment and modifications, quality improvement strategies, and basic falls risk assessment (e.g., medication review). Multifactorial interventions were associated with a reduction in falls rate (RR 0.87; 95% CI 0.80-0.95), but not with a reduction in number of fallers (RR 0.95; 95% CI 0.89-1.01). The following single interventions, compared with usual care, were associated with reductions in number of fall-related fractures: basic falls risk assessment (RR 0.60; 95% CI 0.39-0.94) and exercise (RR 0.62; 95% CI 0.42-0.90). CONCLUSIONS In keeping with Tricco et al. (2017), several single and multiple fall prevention interventions are associated with fewer falls. In addition to Tricco, we observe a benefit at the NMA-level of some single interventions on preventing fall-related fractures

Meta-Analyses Proved Inconsistent in How Missing Data Were Handled Across Their Included Primary Trials: A Methodological Survey

Background: How systematic review authors address missing data among eligible primary studies remains uncertain. Objective: To assess whether systematic review authors are consistent in the way they handle missing data, both across trials included in the same meta-analysis, and with their reported methods. Methods: We first identified 100 eligible systematic reviews that included a statistically significant meta-analysis of a patient-important dichotomous efficacy outcome. Then, we successfully retrieved 638 of the 653 trials included in these systematic reviews' meta-analyses. From each trial report, we extracted statistical data used in the analysis of the outcome of interest to compare with the data used in the meta-analysis. First, we used these comparisons to classify the "analytical method actually used" for handling missing data by the systematic review authors for each included trial. Second, we assessed whether systematic reviews explicitly reported their analytical method of handling missing data. Third, we calculated the proportion of systematic reviews that were consistent in their "analytical method actually used" across trials included in the same meta-analysis. Fourth, among systematic reviews that were consistent in the "analytical method actually used" across trials and explicitly reported on a method for handling missing data, we assessed whether the "analytical method actually used" and the reported methods were consistent. Results: We were unable to determine the "analytical method reviews actually used" for handling missing outcome data among 397 trials. Among the remaining 241, systematic review authors most commonly conducted "complete case analysis" (n=128, 53%) or assumed "none of the participants with missing data had the event of interest" (n=58, 24%). Only eight of 100 systematic reviews were consistent in their approach to handling missing data across included trials, but none of these reported methods for handling missing data. Among seven reviews that did explicitly report their analytical method of handling missing data, only one was consistent in their approach across included trials (using complete case analysis), and their approach was inconsistent with their reported methods (assumed all participants with missing data had the event). Conclusion: The majority of systematic review authors were inconsistent in their approach towards reporting and handling missing outcome data across eligible primary trials, and most did not explicitly report their methods to handle missing data. Systematic review authors should clearly identify missing outcome data among their eligible trials, specify an approach for handling missing data in their analyses, and apply their approach consistently across all primary trials

Splinting or surgery for carpal tunnel syndrome? Design of a randomized controlled trial [ISRCTN18853827]

BACKGROUND: Carpal tunnel syndrome is a common disorder, which can be treated with surgery or conservative options. However, there is insufficient evidence and no consensus among physicians with regard to the preferred treatment for carpal tunnel syndrome. Therefore, a randomized controlled trial is conducted to compare the short- and long-term efficacy of surgery and splinting in patients with carpal tunnel syndrome. An attempt is also made to avoid the (methodological) limitations encountered in earlier trials on the efficacy of various treatment options for carpal tunnel syndrome. METHODS: Patients of 18 years and older, with clinically and electrophysiologically confirmed idiopathic carpal tunnel syndrome, are recruited by neurologists in 13 hospitals. Patients included in the study are randomly allocated to either open carpal tunnel release or wrist splinting during the night for at least 6 weeks. The primary outcomes are general improvement, waking up at night and severity of symptoms (main complaint, night and daytime pain, paraesthesia and hypoesthesia). Outcomes are assessed up to 18 months after randomization

Ubiquitination of CXCR7 Controls Receptor Trafficking

The chemokine receptor CXCR7 binds CXCL11 and CXCL12 with high affinity, chemokines that were previously thought to bind exclusively to CXCR4 and CXCR3, respectively. Expression of CXCR7 has been associated with cardiac development as well as with tumor growth and progression. Despite having all the canonical features of G protein-coupled receptors (GPCRs), the signalling pathways following CXCR7 activation remain controversial, since unlike typical chemokine receptors, CXCR7 fails to activate Gαi-proteins. CXCR7 has recently been shown to interact with β-arrestins and such interaction has been suggested to be responsible for G protein-independent signals through ERK-1/2 phosphorylation. Signal transduction by CXCR7 is controlled at the membrane by the process of GPCR trafficking. In the present study we investigated the regulatory processes triggered by CXCR7 activation as well as the molecular interactions that participate in such processes. We show that, CXCR7 internalizes and recycles back to the cell surface after agonist exposure, and that internalization is not only β-arrestin-mediated but also dependent on the Serine/Threonine residues at the C-terminus of the receptor. Furthermore we describe, for the first time, the constitutive ubiquitination of CXCR7. Such ubiquitination is a key modification responsible for the correct trafficking of CXCR7 from and to the plasma membrane. Moreover, we found that CXCR7 is reversibly de-ubiquitinated upon treatment with CXCL12. Finally, we have also identified the Lysine residues at the C-terminus of CXCR7 to be essential for receptor cell surface delivery. Together these data demonstrate the differential regulation of CXCR7 compared to the related CXCR3 and CXCR4 receptors, and highlight the importance of understanding the molecular determinants responsible for this process

Erratum to: Methods for evaluating medical tests and biomarkers

[This corrects the article DOI: 10.1186/s41512-016-0001-y.]

Evidence synthesis to inform model-based cost-effectiveness evaluations of diagnostic tests: a methodological systematic review of health technology assessments

Background: Evaluations of diagnostic tests are challenging because of the indirect nature of their impact on patient outcomes. Model-based health economic evaluations of tests allow different types of evidence from various sources to be incorporated and enable cost-effectiveness estimates to be made beyond the duration of available study data. To parameterize a health-economic model fully, all the ways a test impacts on patient health must be quantified, including but not limited to diagnostic test accuracy. Methods: We assessed all UK NIHR HTA reports published May 2009-July 2015. Reports were included if they evaluated a diagnostic test, included a model-based health economic evaluation and included a systematic review and meta-analysis of test accuracy. From each eligible report we extracted information on the following topics: 1) what evidence aside from test accuracy was searched for and synthesised, 2) which methods were used to synthesise test accuracy evidence and how did the results inform the economic model, 3) how/whether threshold effects were explored, 4) how the potential dependency between multiple tests in a pathway was accounted for, and 5) for evaluations of tests targeted at the primary care setting, how evidence from differing healthcare settings was incorporated. Results: The bivariate or HSROC model was implemented in 20/22 reports that met all inclusion criteria. Test accuracy data for health economic modelling was obtained from meta-analyses completely in four reports, partially in fourteen reports and not at all in four reports. Only 2/7 reports that used a quantitative test gave clear threshold recommendations. All 22 reports explored the effect of uncertainty in accuracy parameters but most of those that used multiple tests did not allow for dependence between test results. 7/22 tests were potentially suitable for primary care but the majority found limited evidence on test accuracy in primary care settings. Conclusions: The uptake of appropriate meta-analysis methods for synthesising evidence on diagnostic test accuracy in UK NIHR HTAs has improved in recent years. Future research should focus on other evidence requirements for cost-effectiveness assessment, threshold effects for quantitative tests and the impact of multiple diagnostic tests