Effect of transcutaneous electrical nerve stimulation (TENS) on knee pain and physical function in patients with symptomatic knee osteoarthritis: the ETRELKA randomized clinical trial.

OBJECTIVE: To determine the effectiveness of TENS at relieving pain and improving physical function as compared to placebo TENS, and to determine its safety, in patients with knee osteoarthritis. METHODS: Multi-centre, parallel, 1:1 randomized, double-blind, placebo-controlled clinical trial conducted in six outpatient clinics in Switzerland. We included 220 participants with knee osteoarthritis recruited between October 15, 2012, and October 15, 2014. Patients were randomized to 3 weeks of treatment with TENS (n = 108) or placebo TENS (n = 112). Our pre-specified primary endpoint was knee pain at the end of 3-weeks treatment assessed with the WOMAC pain subscale. Secondary outcome measures included WOMAC physical function subscale and safety outcomes. RESULTS: There was no difference between TENS and placebo TENS in WOMAC pain at the end of treatment (mean difference -0.06; 95%CI -0.41 to 0.29; P = 0.74), nor throughout the trial duration (P = 0.98). Subgroup analyses did not indicate an interaction between patient/treatment characteristics and treatment effect on WOMAC pain at the end of treatment (P-interaction ≥0.22). The occurrence of adverse events was similar across groups, with 10.4% and 10.6% of patients reporting events in the TENS and placebo TENS groups, respectively (P = 0.95). No relevant differences were observed in secondary outcomes. CONCLUSIONS: TENS does not improve knee osteoarthritis pain when compared to placebo TENS. Therapists should consider other potentially more effective treatment modalities to decrease knee osteoarthritis pain and facilitate strengthening and aerobic exercise. Our findings are conclusive and further trials comparing TENS and placebo TENS in this patient population are not necessary.

Venous thromboembolism in cancer patients receiving neoadjuvant chemotherapy: a systematic review and meta-analysis.

Essentials Cancer patients are at risk for venous thromboembolism (VTE). The risk of VTE in less advanced stage cancer on neoadjuvant chemotherapy is unclear. In over 7800 patients, we found a 7% pooled incidence of VTE during neoadjuvant therapy. Highest VTE rates were observed in patients with bladder and esophageal cancer. SUMMARY: Background Venous thromboembolism (VTE) is a frequent complication in cancer patients receiving adjuvant treatment. The risk of VTE during neoadjuvant chemo-radiotherapy remains unclear. Objectives This systematic review evaluated the incidence of VTE in patients with cancer receiving neoadjuvant treatment. Methods MEDLINE and EMBASE databases were searched from inception to October 2017. Search results were supplemented with screening of conference proceedings of the American Society of Clinical Oncology (2009-2016) and the International Society of Thrombosis and Haemostasis (2003-2016). Two review authors independently screened titles and abstracts, and extracted data onto standardized forms. Results Twenty-eight cohort studies (7827 cancer patients, range 11 to 1398) were included. Twenty-five had a retrospective design. Eighteen cohorts included patients with gastrointestinal cancer, representing over two-thirds of the whole study population (n = 6002, 78%). In total, 508 of 7768 patients were diagnosed with at least one VTE during neoadjuvant treatment, for a pooled VTE incidence of 7% (95% CI, 5% to 10%) in the absence of substantial between-study heterogeneity. Heterogeneity was not explained by site of cancer or study design characteristics. VTE presented as pulmonary embolism in 22% to 96% of cases (16 cohorts), and it was symptomatic in 22% to 100% of patients (11 cohorts). The highest VTE rates were observed in patients with bladder (10.6%) or esophageal (8.4%) cancer. Conclusions This review found a relatively high incidence of VTE in cancer patients receiving neoadjuvant therapy in the presence of some between-study variation, which deserves further evaluation in prospective studies.

Non-O blood group and outcomes of in vitro fertilization.

PURPOSE: Retrospective and cross-sectional studies suggested that non-O blood group may be associated with failures of in vitro fertilization (IVF), but data remain controversial. The aim of this observational cohort study was to prospectively evaluate the effect of non-O blood type on clinical outcomes of IVF. METHODS: Women < 40 years who underwent IVF and had ABO blood type recorded as part of the routine workup were eligible. The primary study outcome was live birth. Secondary outcomes included spontaneous abortion, positive pregnancy test, and clinical pregnancy. RESULTS: A total of 497 women with a mean age of 34.6 (standard deviation 3.2) years were included. The mean number of embryos transferred was 2.3 (standard deviation 0.6). The most common ABO blood types were O (n = 213, 42.9%) and A (n = 203, 40.8%), while 63 (12.7%) and 18 (3.6%) women had the B and AB blood types, respectively. Differences in live birth (21.8 vs. 24.3%, odds ratio [OR] 1.17; 95% confidence intervals [CI], 0.76 to 1.78), positive pregnancy test (37.9 vs. 36.6%, OR 0.96; 95% CI, 0.66 to 1.38), clinical pregnancy (35.1 vs. 33.8%, OR 0.95; 95% CI, 0.66 to 1.39), and spontaneous abortion (12.3 vs. 9.2%, OR 0.72; 95% CI, 0.41 to 1.29) between women with O and non-O blood type were not statistically significant. CONCLUSIONS: In a prospective cohort study, we confirmed the lack of a significant association between non-O blood type and clinical outcomes of IVF. Further studies are needed to clarify whether non-O blood group has any prognostic relevance in women undergoing IVF.

Does cyclic guanosine monophosphate induce autophagy in thyroid malignant carcinoma through down-regulation of cyclic guanosine monophosphate phosphodiesterase?

The aim of this study was to evaluate whether or not the expression of cGMP- phosphodiesterases (cGMP-PDE) varies in different thyroid pathologies and to elucidate the relationship between the expression of cGMP-PDE, cGMP, and autophagy. Fifty-four thyroid biopsy samples, excised to perform the biopsy, were split into two parts and randomly assigned: one part was microscopically examined and histological classified, and the other was frozen and analysed in order to evaluate the cGMP-PDE activity. Intracellular cGMP was also measured. A strong expression of intracellular cGMP and cGMP-PDE activity was observed in carcinoma in respect to controls and benign pathologies. The level of cGMP-PDE in papillary carcinoma without lymph node involvement (N-) was approximately four-fold higher compared to those with lymph node invasion (N±). On the contrary, the cGMP was one and a half times higher in N± than N-. Our results are promising, although further epigenetical studies are needed to confirm this association. A correlation between the cGMP-degrading activity and the severity of thyroid pathology has been shown. The decrease of cGMP-PDE and the increase of cGMP in N± papillar carcinoma could be an autophagic stimulus, a defence mechanism of the body, against the cancer that is expanding and invading other tissues and organs.

Absorbable collagen membranes for periodontal regeneration: a systematic review.

Guided tissue regeneration (GTR) with bioabsorbable collagen membranes (CM) is commonly used for the treatment of periodontal defects. The objective of this systematic review of randomized clinical trials was to assess the clinical efficacy of GTR procedures with CM, with or without bone substitutes, in periodontal infrabony defects compared with that of open flap debridement (OFD) alone. Primary outcomes were tooth loss and gain in clinical attachment level (CAL). Screening of records, data extraction, and risk-of-bias assessments were performed by two reviewers. Weighted mean differences were estimated by random effects meta-analysis. We included 21 reports on 17 trials. Risk of bias was generally high. No data were available for the primary outcome tooth loss. The summary treatment effect for change in CAL for GTR with CM compared with OFD was 1.58 mm (95% CI, 1.27 to 1.88). Despite large between-trial heterogeneity (I2 = 75%, p < .001), all trials favored GTR over OFD. No differences in treatment effects were detected between trials of GTR with CM alone and trials of GTR with CM in combination with bone substitutes (p for interaction, .31). GTR with CM, with or without substitutes, may result in improved clinical outcomes compared with those achieved with OFD alone. Our findings support GTR with CM for the treatment of infrabony periodontal defects.

Accuracy of diagnostic tests for clinically suspected upper extremity deep vein thrombosis: a systematic review.

BACKGROUND: The best available test for the diagnosis of upper extremity deep venous thrombosis (UEDVT) is contrast venography. The aim of this systematic review was to assess whether the diagnostic accuracy of other tests for clinically suspected UEDVT is high enough to justify their use in clinical practise and to evaluate if any test can replace venography. METHODS: MEDLINE and EMBASE databases were searched from inception to June 2009. Two reviewers independently evaluated study eligibility, extracted data, and assessed study quality. RESULTS: We identified 17 papers, reporting on 793 patients. Overall, the methodological quality was poor, sample sizes were small, and large between-study differences were observed in spectrum and design. The summary estimates of sensitivity (95% confidence interval) were 97% (90-100%) for compression ultrasonography, 84% (72-97%) for Doppler ultrasonography, 91% (85-97%) for Doppler ultrasonography with compression, and 85% (72-99%) for phleboreography. The corresponding summary estimates of specificity were, respectively, 96% (87-100%), 94% (86-100%), 93% (80-100%), and 87% (71-100%). Clinical findings, a clinical score, D-dimer, magnetic resonance imaging, rheography and plethysmography were evaluated in one study each, involving a median number of 46 patients (range 21-214). Sensitivity and specificity ranged from 0% to 100% and from 14% to 100%. CONCLUSIONS: Methodological limitations, large between-study differences and small sample sizes limit the evidence of tests for clinically suspected UEDVT. Compression ultrasonography may be an acceptable alternative to venography. The addition of (color) Doppler does not seem to improve the accuracy. Adequately designed studies are warranted to confirm these findings.

Evaluation of diagnostic tests when there is no gold standard. A review of methods.

OBJECTIVE: To generate a classification of methods to evaluate medical tests when there is no gold standard. METHODS: Multiple search strategies were employed to obtain an overview of the different methods described in the literature, including searches of electronic databases, contacting experts for papers in personal archives, exploring databases from previous methodological projects and cross-checking of reference lists of useful papers already identified. RESULTS: All methods available were classified into four main groups. The first method group, impute or adjust for missing data on reference standard, needs careful attention to the pattern and fraction of missing values. The second group, correct imperfect reference standard, can be useful if there is reliable information about the degree of imperfection of the reference standard and about the correlation of the errors between the index test and the reference standard. The third group of methods, construct reference standard, have in common that they combine multiple test results to construct a reference standard outcome including deterministic predefined rules, consensus procedures and statistical modelling (latent class analysis). In the final group, validate index test results, the diagnostic test accuracy paradigm is abandoned and research examines, using a number of different methods, whether the results of an index test are meaningful in practice, for example by relating index test results to relevant other clinical characteristics and future clinical events. CONCLUSIONS: The majority of methods try to impute, adjust or construct a reference standard in an effort to obtain the familiar diagnostic accuracy statistics, such as sensitivity and specificity. In situations that deviate only marginally from the classical diagnostic accuracy paradigm, these are valuable methods. However, in situations where an acceptable reference standard does not exist, applying the concept of clinical test validation can provide a significant methodological advance. All methods summarised in this report need further development. Some methods, such as the construction of a reference standard using panel consensus methods and validation of tests outwith the accuracy paradigm, are particularly promising but are lacking in methodological research. These methods deserve particular attention in future research.

Diagnostic accuracy of D-dimer test for exclusion of venous thromboembolism: a systematic review.

BACKGROUND: The reported diagnostic accuracy of the D-dimer test for exclusion of deep vein thrombosis (DVT) and pulmonary embolism (PE) varies. It is unknown to what extent this is due to differences in study design or patient groups, or to genuine differences between D-dimer assays. METHODS: Studies evaluating the diagnostic accuracy of the D-dimer test in the diagnosis of venous thromboembolism were systematically searched for in the MEDLINE and EMBASE databases up to March 2005. Reference lists of all included studies and of reviews related to the topic of the present meta-analysis were manually searched for other additional potentially eligible studies. Two reviewers independently extracted study characteristics using standardized forms. RESULTS: In total, 217 D-dimer test evaluations for DVT and 111 for PE were analyzed. Several study design characteristics were associated with systematic differences in diagnostic accuracy. After adjustment for these features, the sensitivities of the D-dimer enzyme-linked immunofluorescence assay (ELFA) (DVT 96%; PE 97%), microplate enzyme-linked immunosorbent assay (ELISA) (DVT 94%; PE 95%), and latex quantitative assay (DVT 93%; PE 95%) were superior to those of the whole-blood D-dimer assay (DVT 83%; PE 87%), latex semiquantitative assay (DVT 85%; PE 88%) and latex qualitative assay (DVT 69%; PE 75%). The latex qualitative and whole-blood D-dimer assays had the highest specificities (DVT 99%, 71%; PE 99%, 69%). CONCLUSIONS: Compared to other D-dimer assays, the ELFA, microplate ELISA and latex quantitative assays have higher sensitivity but lower specificity, resulting in a more confident exclusion of the disease at the expense of more additional imaging testing. These conclusions are based on the most up-to-date and extensive systematic review of the topic area, including 184 articles, with 328 D-dimer test evaluations.

The quality of diagnostic accuracy studies since the STARD statement: has it improved?

OBJECTIVE: To assess whether the quality of reporting of diagnostic accuracy studies has improved since the publication of the Standards for the Reporting of Diagnostic Accuracy studies (STARD statement). METHODS: The quality of reporting of diagnostic accuracy studies published in 12 medical journals in 2000 (pre-STARD) and 2004 (post-STARD) was evaluated by two reviewers independently. For each article, the number of reported STARD items was counted (range 0 to 25). Differences in completeness of reporting between articles published in 2000 and 2004 were analyzed, using multilevel analyses. RESULTS: We included 124 articles published in 2000 and 141 articles published in 2004. Mean number of reported STARD items was 11.9 (range 3.5 to 19.5) in 2000 and 13.6 (range 4.0 to 21.0) in 2004, an increase of 1.81 items (95% CI: 0.61 to 3.01). Articles published in 2004 reported the following significantly more often: methods for calculating test reproducibility of the index test (16% vs 35%); distribution of the severity of disease and other diagnoses (23% vs 53%); estimates of variability of diagnostic accuracy between subgroups (39% vs 60%); and a flow diagram (2% vs 12%). CONCLUSIONS: The quality of reporting of diagnostic accuracy studies has improved slightly over time, without a more pronounced effect in journals that adopted the STARD statement. As there is still room for improvement, editors should mention the use of the STARD statement as a requirement in their guidelines for authors, and instruct reviewers to check the STARD items. Authors should include a flow diagram in their manuscript.

Use of methodological search filters to identify diagnostic accuracy studies can lead to the omission of relevant studies.

OBJECTIVE: To determine the usefulness of methodological filters in search strategies for diagnostic studies in systematic reviews. STUDY DESIGN AND SETTING: We made an inventory of existing methodological search filters for diagnostic accuracy studies and applied them in PubMed to a reference set derived from 27 published systematic reviews in a broad range of clinical fields. Outcome measures were the fraction of not identified relevant studies and the reduction in the number of studies to read. RESULTS: We tested 12 search filters. Of the studies included in the systematic reviews, 2%-28% did not pass the sensitive search filters, 4%-24% did not pass the accurate filters, and 39%-42% did not pass the specific filters. Decrease in number-needed-to-read when a search filter was used in a search strategy for a diagnostic systematic review varied from 0% to 77%. CONCLUSION: The use of methodological filters to identify diagnostic accuracy studies can lead to omission of a considerable number of relevant studies that would otherwise be included. When preparing a systematic review, it may be preferable to avoid using methodological filters.

Combined use of clinical pretest probability and D-dimer test in cancer patients with clinically suspected deep venous thrombosis.

BACKGROUND: The value of the D-dimer (DD) test in combination with the clinical pretest probability (PTP) has not been evaluated in cancer patients with suspected deep vein thrombosis (DVT), whereas this group of patients usually accounts for 10-25% of clinically suspected DVT. METHODS: A cohort of 2066 consecutive patients with clinically suspected DVT was investigated. Patients were judged to be positive or negative for DVT according to the outcomes of serial compression ultrasound and a 3-month follow-up period with imaging test verification of the symptomatic cases. Diagnostic accuracy indices of the DD test according to the PTP score were assessed in patients with and without cancer. RESULTS: Of the cohort, 244 (11%) were known to have cancer at presentation. A venous thromboembolic event was diagnosed in 41% of the patients with cancer and in 22% of the patients without malignancy. Among the cancer patients, 17% were considered to have a low PTP, 35% a moderate and 41% a high PTP. The negative predictive value (NPV) of the DD test was 100% (95% CI, 85-100) and 97% (95% CI, 88-99) among cancer patients with low PTP or low-moderate PTP. In the absence of malignancy, the corresponding NPV were 98% and 97%, respectively. The specificity of the DD test progressively decreased moving from the low to the higher PTP. CONCLUSIONS: In cancer patients with clinically suspected DVT, a negative DD might be useful in excluding the diagnosis within the low or low-moderate PTP groups. More studies are warranted to confirm these findings.

Development and validation of methods for assessing the quality of diagnostic accuracy studies.

OBJECTIVES: To develop a quality assessment tool which will be used in systematic reviews to assess the quality of primary studies of diagnostic accuracy. DATA SOURCES: Electronic databases including MEDLINE, EMBASE, BIOSIS and the methodological databases of both CRD and the Cochrane Collaboration. REVIEW METHODS: Three systematic reviews were conducted to provide an evidence base for the development of the quality assessment tool. A Delphi procedure was used to develop the quality assessment tool and the information provided by the reviews was incorporated into this. A panel of nine experts in the area of diagnostic accuracy studies took part in the Delphi procedure to agree on the items to be included in the tool. Panel members were also asked to provide feedback on various other items and whether they would like to see the development of additional topic and design specific items. The Delphi procedure produced the quality assessment tool, named the QUADAS tool, which consisted of 14 items. A background document was produced describing each item included in the tool and how each of the items should be scored. RESULTS: The reviews produced 28 possible items for inclusion in the quality assessment tool. It was found that the sources of bias supported by the most empirical evidence were variation by clinical and demographic subgroups, disease prevalence/severity, partial verification bias, clinical review bias and observer/instrument variation. There was also some evidence of bias for the effects of distorted selection of participants, absent or inappropriate reference standard, differential verification bias and review bias. The evidence for the effects of other sources of bias was insufficient to draw conclusions. The third review found that only one item, the avoidance of review bias, was included in more than 75% of tools. Spectrum composition, population recruitment, absent or inappropriate reference standard and verification bias were each included in 50-75% of tools. Other items were included in less than 50% of tools. The second review found that the quality assessment tool should have the potential to be discussed narratively, reported in a tabular summary, used as recommendations for future research, used to conduct sensitivity or regression analyses and used as criteria for inclusion in the review or a primary analysis. This suggested that some distinction is needed between high- and low-quality studies. Component analysis was considered the best approach to incorporate quality into systematic reviews of diagnostic studies and this was taken into consideration when developing the tool. CONCLUSIONS: This project produced an evidence-based quality assessment tool to be used in systematic reviews of diagnostic accuracy studies. Through the various stages of the project the current lack of such a tool and the need for a systematically developed validated tool were demonstrated. Further work to validate the tool continues beyond the scope of this project. The further development of the tool by the addition of design- and topic-specific criteria is proposed.