René Spijker

Search filters for finding prognostic and diagnostic prediction studies in Medline to enhance systematic reviews.

Background The interest in prognostic reviews is increasing, but to properly review existing evidence an accurate search filer for finding prediction research is needed. The aim of this paper was to validate and update two previously introduced search filters for finding prediction research in Medline: the Ingui filter and the Haynes Broad filter. Methodology/Principal Findings Based on a hand search of 6 general journals in 2008 we constructed two sets of papers. Set 1 consisted of prediction research papers (n = 71), and set 2 consisted of the remaining papers (n = 1133). Both search filters were validated in two ways, using diagnostic accuracy measures as performance measures. First, we compared studies in set 1 (reference) with studies retrieved by the search strategies as applied in Medline. Second, we compared studies from 4 published systematic reviews (reference) with studies retrieved by the search filter as applied in Medline. Next – using word frequency methods – we constructed an additional search string for finding prediction research. Both search filters were good in identifying clinical prediction models: sensitivity ranged from 0.94 to 1.0 using our hand search as reference, and 0.78 to 0.89 using the systematic reviews as reference. This latter performance measure even increased to around 0.95 (range 0.90 to 0.97) when either search filter was combined with the additional string that we developed. Retrieval rate of explorative prediction research was poor, both using our hand search or our systematic review as reference, and even combined with our additional search string: sensitivity ranged from 0.44 to 0.85. Conclusions/Significance Explorative prediction research is difficult to find in Medline, using any of the currently available search filters. Yet, application of either the Ingui filter or the Haynes broad filter results in a very low number missed clinical prediction model studies.

Enhanced formation and survival of CD4+ CD25hi Foxp3+ T-cells in chronic lymphocytic leukemia

Recently, it has been described that patients with chronic lymphocytic leukemia (CLL) have increased numbers of regulatory T (Treg) cells. In the present study, we analysed the mechanism behind Treg cells expansion in CLL. Neither analysis of the T-cell receptor repertoire nor CD45 isoform expression of Treg cells from patients with CLL provided evidence for chronic (tumor) antigenic stimulation as a possible cause for Treg cells expansion in CLL. We found evidence however for increased formation of Treg cells via CD70 costimulation, because we observed that CD40 ligand activated CLL cells (which might be considered a model of lymph node CLL cells) strongly induced CD70-dependent formation of Treg cells. Reverse transcription-multiplex ligation-dependent probe amplification assay expression analysis of 34 apoptosis-regulating genes showed that in comparison with other CD4+ T-cells, Treg cells from both healthy individuals (HD) and patients with CLL had a high expression of pro-apoptotic Noxa and a low expression of anti-apoptotic Bcl-2. Strikingly, Bcl-2 levels of Treg cells in patients with CLL were significantly higher than in HD. Finally, the different apoptotic profile resulted in differences at the functional level, because Treg cells from patients with CLL were more resistant to drug-induced apoptosis than Treg cells from HD. In conclusion, Treg cells in CLL may accumulate both by increased formation, facilitated by CD27-CD70 interaction in the lymph node proliferation centres, and decreased sensitivity to apoptosis because of a shifted Noxa-Bcl-2 balance.

Diagnostic accuracy of minimally invasive markers for detection of airway eosinophilia in asthma: a systematic review and meta-analysis

BACKGROUND Eosinophilic airway inflammation is associated with increased corticosteroid responsiveness in asthma, but direct airway sampling methods are invasive or laborious. Minimally invasive markers for airway eosinophilia could present an alternative method, but estimates of their accuracy vary. METHODS We did a systematic review and searched Medline, Embase, and PubMed for studies assessing the diagnostic accuracy of markers against a reference standard of induced sputum, bronchoalveolar lavage, or endobronchial biopsy in patients with asthma or suspected asthma (for inception to Aug 1, 2014). Unpublished results were obtained by contacting authors of studies that did not report on diagnostic accuracy, but had data from which estimates could be calculated. We assessed risk of bias with QUADAS-2. We used meta-analysis to produce summary estimates of accuracy. FINDINGS We included 32 studies: 24 in adults and eight in children. Of these, 26 (81%) showed risk of bias in at least one domain. In adults, three markers had extensively been investigated: fraction of exhaled nitric oxide (FeNO) (17 studies; 3216 patients; summary area under the receiver operator curve [AUC] 0·75 [95% CI 0·72-0·78]); blood eosinophils (14 studies; 2405 patients; 0·78 [0·74-0·82]); total IgE (seven studies; 942 patients; 0·65 [0·61-0·69]). In children, only FeNO (six studies; 349 patients; summary AUC 0·81 [0·72-0·89]) and blood eosinophils (three studies; 192 patients; 0·78 [0·71-0·85]) had been investigated in more than one study. Induced sputum was most frequently used as the reference standard. Summary estimates of sensitivity and specificity in detecting sputum eosinophils of 3% or more in adults were: 0·66 (0·57-0·75) and 0·76 (0·65-0·85) for FeNO; 0·71 (0·65-0·76) and 0·77 (0·70-0·83) for blood eosinophils; and 0·64 (0·42-0·81) and 0·71 (0·42-0·89) for IgE. INTERPRETATION FeNO, blood eosinophils, and IgE have moderate diagnostic accuracy. Their use as a single surrogate marker for airway eosinophilia in patients with asthma will lead to a substantial number of false positives or false negatives. FUNDING None.

Reporting quality of diagnostic accuracy studies: a systematic review and meta-analysis of investigations on adherence to STARD

Background Poor reporting of diagnostic accuracy studies impedes an objective appraisal of the clinical performance of diagnostic tests. The Standards for Reporting of Diagnostic Accuracy Studies (STARD) statement, first published in 2003, aims to improve the reporting quality of such studies. Objective To investigate to which extent published diagnostic accuracy studies adhere to the 25-item STARD checklist, whether the reporting quality has improved after STARDs launch and whether there are any factors associated with adherence. Study selection We performed a systematic review and searched MEDLINE, EMBASE and the Methodology Register of the Cochrane Library for studies that primarily aimed to examine the reporting quality of articles on diagnostic accuracy studies in humans by evaluating adherence to STARD. Study selection was performed in duplicate; data were extracted by one author and verified by the second author. Findings We included 16 studies, analysing 1496 articles in total. Three studies investigated adherence in a general sample of diagnostic accuracy studies; the others did so in a specific field of research. The overall mean number of items reported varied from 9.1 to 14.3 between 13 evaluations that evaluated all 25 STARD items. Six studies quantitatively compared post-STARD with pre-STARD articles. Combining these results in a random-effects meta-analysis revealed a modest but significant increase in adherence after STARDs introduction (mean difference 1.41 items (95% CI 0.65 to 2.18)). Conclusions The reporting quality of diagnostic accuracy studies was consistently moderate, at least through halfway the 2000s. Our results suggest a small improvement in the years after the introduction of STARD. Adherence to STARD should be further promoted among researchers, editors and peer reviewers.

Is there a rural/urban gradient in the prevalence of eczema? A systematic review.

Background  Eczema affects approximately 10% of all schoolchildren in the western world and has shown an increase over the past decades in ‘developing’ countries. Numerous factors have been suggested that might contribute to the increasing prevalence of eczema. A plausible explanation is the role of environmental factors. As part of the ‘hygiene hypothesis’ it has been thought that eczema is more common in urban than in rural communities, but such a notion has never been assessed systematically.

Crosstalk among Bcl-2 family members in B-CLL: seliciclib acts via the Mcl-1/Noxa axis and gradual exhaustion of Bcl-2 protection.

Seliciclib (R-roscovitine) is a cyclin-dependent kinase inhibitor in clinical development. It triggers apoptosis by inhibiting de novo transcription of the short-lived Mcl-1 protein, but it is unknown how this leads to Bax/Bak activation that is required for most forms of cell death. Here, we studied the effects of seliciclib in B-cell chronic lymphocytic leukemia (B-CLL), a malignancy with aberrant expression of apoptosis regulators. Although seliciclib-induced Mcl-1 degradation within 4 h, Bax/Bak activation occurred between 16 and 20 h. During this period, no transcriptional changes in apoptosis-related genes occurred. In untreated cells, prosurvival Mcl-1 was engaged by the proapoptotic proteins Noxa and Bim. Upon drug treatment, Bim was quickly released. The contribution of Noxa and Bim as a specific mediator of seliciclib-induced apoptosis was demonstrated via RNAi. Significantly, 16 h after seliciclib treatment, there was accumulation of Bcl-2, Bim and Bax in the ‘mitochondria-rich’ insoluble fraction of the cell. This suggests that after Mcl-1 degradation, the remaining apoptosis neutralizing capacity of Bcl-2 is gradually overwhelmed, until Bax forms large multimeric pores in the mitochondria. These data demonstrate in primary leukemic cells hierarchical binding and crosstalk among Bcl-2 members, and suggest that their functional interdependence can be exploited therapeutically.

Sensorineural hearing loss in patients with head and neck cancer after chemoradiotherapy and radiotherapy: a systematic review of the literature

Both radiotherapy (RT) and cisplatin‐based chemoradiotherapy (CRT) in patients with head and neck cancer may cause sensorineural hearing loss (SNHL). The purpose of this review was to provide more insight into SNHL because of CRT compared to RT.

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 articles.

Should we search Chinese biomedical databases when performing systematic reviews

BackgroundChinese biomedical databases contain a large number of publications available to systematic reviewers, but it is unclear whether they are used for synthesizing the available evidence.MethodsWe report a case of two systematic reviews on the accuracy of anti-cyclic citrullinated peptide for diagnosing rheumatoid arthritis. In one of these, the authors did not search Chinese databases; in the other, they did. We additionally assessed the extent to which Cochrane reviewers have searched Chinese databases in a systematic overview of the Cochrane Library (inception to 2014).ResultsThe two diagnostic reviews included a total of 269 unique studies, but only 4 studies were included in both reviews. The first review included five studies published in the Chinese language (out of 151) while the second included 114 (out of 118). The summary accuracy estimates from the two reviews were comparable. Only 243 of the published 8,680 Cochrane reviews (less than 3%) searched one or more of the five major Chinese databases. These Chinese databases index about 2,500 journals, of which less than 6% are also indexed in MEDLINE. All 243 Cochrane reviews evaluated an intervention, 179 (74%) had at least one author with a Chinese affiliation; 118 (49%) addressed a topic in complementary or alternative medicine.Discussion and conclusionsAlthough searching Chinese databases may lead to the identification of a large amount of additional clinical evidence, Cochrane reviewers have rarely included them in their search strategy. We encourage future initiatives to evaluate more systematically the relevance of searching Chinese databases, as well as collaborative efforts to allow better incorporation of Chinese resources in systematic reviews.

Added value of combined endobronchial and oesophageal endosonography for mediastinal nodal staging in lung cancer: a systematic review and meta-analysis

BACKGROUND Guidelines recommend endosonography with fine-needle aspiration for mediastinal nodal staging in non-small-cell lung cancer, but most do not specify whether this should be through endobronchial endoscopy (EBUS), oesophageal endoscopy (EUS), or both. We assessed the added value and diagnostic accuracy of the combined use of EBUS and EUS. METHODS For this systematic review and random effects meta-analysis, we searched MEDLINE, Embase, BIOSIS Previews, and Web of Science, without language restrictions, for studies published between Jan 1, 2000, and Feb 25, 2016. We included studies that assessed the accuracy of the combined use of EBUS and EUS in detecting mediastinal nodal metastases (N2/N3 disease) in patients with lung cancer. For each included study, we extracted data on the age and sex of participants, inclusion criteria regarding tumour stage on imaging, details of the endoscopic testing protocol, duration of each endoscopic procedure, number of lymph nodes sampled, serious adverse events occurring during the endoscopic procedures, the reference standard, and 2 × 2 tables for EBUS, EUS, and the combined approach. We evaluated the added value (absolute increase in sensitivity and in detection rate) of the combined use of EBUS and EUS in detecting mediastinal nodal metastases over either test alone, and the diagnostic accuracy (sensitivity and negative predictive value) of the combined approach. This study is registered with PROSPERO, number CRD42015019249. FINDINGS We identified 2567 unique manuscripts by database search, of which 13 studies (including 2395 patients) were included in the analysis. Median prevalence of N2/N3 disease was 34% (range 23-71). On average, addition of EUS to EBUS increased sensitivity by 0·12 (95% CI 0·08-0·18) and addition of EBUS to EUS increased sensitivity by 0·22 (0·16-0·29). Mean sensitivity of the combined approach was 0·86 (0·81-0·90), and the mean negative predictive value was 0·92 (0·89-0·93). The mean negative predictive value was significantly higher in studies with a prevalence of 34% or less (0·93 [95% CI 0·91-0·95]) compared with studies with a prevalence of more than 34% (0·89 [0·85-0·91]; p=0·013). We found no significant differences in mean sensitivity and negative predictive value between studies that did EBUS first or EUS first, or between studies that used an EBUS-scope or a regular echoendoscope to do EUS. INTERPRETATION The combined use of EBUS and EUS significantly improves sensitivity in detecting mediastinal nodal metastases, reducing the need for surgical staging procedures. FUNDING No external funding.