Drug-specific in vitro release of IL-2, IL-5, IL-13 and IFN-gamma in patients with delayed-type drug hypersensitivity

BACKGROUND: The most prevalent drug hypersensitivity reactions are T-cell mediated. The only established in vitro test for detecting T-cell sensitization to drugs is the lymphocyte transformation test, which is of limited practicability. To find an alternative in vitro method to detect drug-sensitized T cells, we screened the in vitro secretion of 17 cytokines/chemokines by peripheral blood mononuclear cells (PBMC) of patients with well-documented drug allergies, in order to identify the most promising cytokines/chemokines for detection of T-cell sensitization to drugs. METHODS: Peripheral blood mononuclear cell of 10 patients, five allergic to beta-lactams and five to sulfanilamides, and of five healthy controls were incubated for 3 days with the drug antigen. Cytokine concentrations were measured in the supernatants using commercially available 17-plex bead-based immunoassay kits. RESULTS: Among the 17 cytokines/chemokines analysed, interleukin-2 (IL-2), IL-5, IL-13 and interferon-gamma (IFN-gamma) secretion in response to the drugs were significantly increased in patients when compared with healthy controls. No difference in cytokine secretion patterns between sulfonamide- and beta-lactam-reactive PBMC could be observed. The secretion of other cytokines/chemokines showed a high variability among patients. CONCLUSION: The measurement of IL-2, IL-5, IL-13 or IFN-gamma or a combination thereof might be a useful in vitro tool for detection of T-cell sensitization to drugs. Secretion of these cytokines seems independent of the type of drug antigen and the phenotype of the drug reaction. A study including a higher number of patients and controls will be needed to determine the exact sensitivity and specificity of this test.

Delayed development of pneumothorax after pulmonary radiofrequency ablation

Acute pneumothorax is a frequent complication after percutaneous pulmonary radiofrequency (RF) ablation. In this study we present three cases showing delayed development of pneumothorax after pulmonary RF ablation in 34 patients. Our purpose is to draw attention to this delayed complication and to propose a possible approach to avoid this major complication. These three cases occurred subsequent to 44 CT-guided pulmonary RF ablation procedures (6.8%) using either internally cooled or multitined expandable RF electrodes. In two patients, the pneumothorax, being initially absent at the end of the intervention, developed without symptoms. One of these patients required chest drain placement 32 h after RF ablation, and in the second patient therapy remained conservative. In the third patient, a slight pneumothorax at the end of the intervention gradually increased and led into tension pneumothorax 5 days after ablation procedure. Underlying bronchopleural fistula along the coagulated former electrode track was diagnosed in two patients. In conclusion, delayed development of pneumothorax after pulmonary RF ablation can occur and is probably due to underlying bronchopleural fistula, potentially leading to tension pneumothorax. Patients and interventionalists should be prepared for delayed onset of this complication, and extensive track ablation following pulmonary RF ablation should be avoided.

Early- and delayed antipsychotic response and prediction of outcome in 528 severely impaired patients with schizophrenia treated with amisulpride

'Early-onset' studies have shown that symptomatic response often occurs early and that early symptomatic response is predictive for later outcome. Limiting factors of these studies include the restriction on symptomatic outcome, the inclusion of mostly moderately ill patients, and the use of various antipsychotics.

Cohort study of trials submitted to ethics committee identified discrepant reporting of outcomes in publications

OBJECTIVES To identify factors associated with discrepant outcome reporting in randomized drug trials. STUDY DESIGN AND SETTING Cohort study of protocols submitted to a Swiss ethics committee 1988-1998: 227 protocols and amendments were compared with 333 matching articles published during 1990-2008. Discrepant reporting was defined as addition, omission, or reclassification of outcomes. RESULTS Overall, 870 of 2,966 unique outcomes were reported discrepantly (29.3%). Among protocol-defined primary outcomes, 6.9% were not reported (19 of 274), whereas 10.4% of reported outcomes (30 of 288) were not defined in the protocol. Corresponding percentages for secondary outcomes were 19.0% (284 of 1,495) and 14.1% (334 of 2,375). Discrepant reporting was more likely if P values were <0.05 compared with P ≥ 0.05 [adjusted odds ratio (aOR): 1.38; 95% confidence interval (CI): 1.07, 1.78], more likely for efficacy compared with harm outcomes (aOR: 2.99; 95% CI: 2.08, 4.30) and more likely for composite than for single outcomes (aOR: 1.48; 95% CI: 1.00, 2.20). Cardiology (aOR: 2.34; 95% CI: 1.44, 3.79) and infectious diseases (aOR: 1.77; 95% CI: 1.01, 3.13) had more discrepancies compared with all specialties combined. CONCLUSION Discrepant reporting was associated with statistical significance of results, type of outcome, and specialty area. Trial protocols should be made freely available, and the publications should describe and justify any changes made to protocol-defined outcomes.

Reporting quality of systematic review abstracts in leading oral implantology journals

OBJECTIVES Abstracts of systematic reviews are of critical importance, as consumers of research often do not access the full text. This study aimed to assess the reporting quality of systematic review (SR) abstracts in leading oral implantology journals. METHODS Six specialty journals were screened for SRs between 2008 and 2012. A 16-item checklist, based on the PRISMA statement, was used to examine the completeness of abstract reporting. RESULTS Ninety-three SR abstracts were included in this study. The majority were published in Clinical Oral Implants Research (43%). The mean overall reporting quality score was 72.5% (95% CI: 70.8-74.2). Most abstracts were structured (97.9%), adequately reporting objectives (97.9%) and conclusions (93.6%). Conversely, inadequate reporting of methods of the study, background (79.6%), appraisal (65.6%), and data synthesis (65.6%) were observed. Registration of reviews was not reported in any of the included abstracts. Multivariate analysis revealed no difference in reporting quality with respect to continent, number of authors, or meta-analysis conduct. CONCLUSIONS The results of this study suggest that the reporting quality of systematic review abstracts in implantology journals requires further improvement. CLINICAL SIGNIFICANCE Better reporting of SR abstracts is particularly important in ensuring the reliability of research findings, ultimately promoting the practice of evidence-based dentistry. Optimal reporting of SR abstracts should be encouraged, preferably by endorsing the PRISMA for abstracts guidelines.

Reporting completeness of abstracts of systematic reviews published in leading dental specialty journals

The aim of this study was to investigate the reporting completeness of systematic review (SR) abstracts in leading dental specialty journals. Electronic and supplementary hand searching were undertaken to identify SRs published in seven dental specialty journals and in the Cochrane Database of Systematic Reviews. Abstract reporting completeness was evaluated using a checklist derived from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (prisma) guidelines. Descriptive statistics followed by univariate and multivariate analyses were conducted. Two-hundred and eighteen SR abstracts were identified. Reporting of interventions (94%), objectives (96%), data sources (81%), eligibility criteria (77%), and conclusions (97%) was adequate in the majority of reviews. However, inadequate reporting of participants (18%), results (42%), effect size (14%), level of significance (60%), and trial registration (100%) was commonplace. The mean overall reporting score was 79.1% (95% CI, 77.6-80.6). Only journal of publication was a significant predictor of overall reporting, with inferior results for all journals relative to Cochrane reviews, with scores ranging from -4.3% (95% CI, -8.74 to 0.08) to -35.6% (95% CI, -42.0 to -24.3) for the International Journal of Prosthodontics and the British Journal of Oral and Maxillofacial Surgery, respectively. Improved reporting of dental SR abstracts is needed and should be encouraged, as these abstracts may underpin influential clinical decisions.

Reporting quality of abstracts of randomized controlled trials published in dental specialty journals

OBJECTIVES A widespread assessment of the reporting of RCT abstracts published in dental journals is lacking. Our aim was to investigate the quality of reporting of abstracts published in leading dental specialty journals using, as a guide, the CONSORT for abstracts checklist. METHODS Electronic and supplementary hand searching were undertaken to identify RCTs published in seven dental specialty journals. The quality of abstract reporting was evaluated using a modified checklist based on the CONSORT for abstracts checklist. Descriptive statistics followed by univariate and multivariate analyses were conducted. RESULTS 228 RCT abstracts were identified. Reporting of interventions, objectives and conclusions within abstracts were adequate. Inadequately reported items included: title, participants, outcomes, random number generation, numbers randomized and effect size estimate. Randomization restrictions, allocation concealment, blinding, numbers analyzed, confidence intervals, intention-to-treat analysis, harms, registration and funding were rarely described. CONCLUSIONS The mean overall reporting quality score was suboptimal at 62.5% (95% CI: 61.9, 63.0). Significantly better abstract reporting was noted in certain specialty journals and in multicenter trials.

Cluster randomized clinical trials in orthodontics: design, analysis and reporting issues

Cluster randomized trials (CRTs) use as the unit of randomization clusters, which are usually defined as a collection of individuals sharing some common characteristics. Common examples of clusters include entire dental practices, hospitals, schools, school classes, villages, and towns. Additionally, several measurements (repeated measurements) taken on the same individual at different time points are also considered to be clusters. In dentistry, CRTs are applicable as patients may be treated as clusters containing several individual teeth. CRTs require certain methodological procedures during sample calculation, randomization, data analysis, and reporting, which are often ignored in dental research publications. In general, due to similarity of the observations within clusters, each individual within a cluster provides less information compared with an individual in a non-clustered trial. Therefore, clustered designs require larger sample sizes compared with non-clustered randomized designs, and special statistical analyses that account for the fact that observations within clusters are correlated. It is the purpose of this article to highlight with relevant examples the important methodological characteristics of cluster randomized designs as they may be applied in orthodontics and to explain the problems that may arise if clustered observations are erroneously treated and analysed as independent (non-clustered).

Integration of merged delayed-enhanced magnetic resonance imaging and multidetector computed tomography for the guidance of ventricular tachycardia ablation: a pilot study

BACKGROUND Delayed enhancement (DE) MRI can assess the fibrotic substrate of scar-related VT. MDCT has the advantage of inframillimetric spatial resolution and better 3D reconstructions. We sought to evaluate the feasibility and usefulness of integrating merged MDCT/MRI data in 3D-mapping systems for structure-function assessment and multimodal guidance of VT mapping and ablation. METHODS Nine patients, including 3 ischemic cardiomyopathy (ICM), 3 nonischemic cardiomyopathy (NICM), 2 myocarditis, and 1 redo procedure for idiopathic VT, underwent MRI and MDCT before VT ablation. Merged MRI/MDCT data were integrated in 3D-mapping systems and registered to high-density endocardial and epicardial maps. Low-voltage areas (<1.5 mV) and local abnormal ventricular activities (LAVA) during sinus rhythm were correlated to DE at MRI, and wall-thinning (WT) at MDCT. RESULTS Endocardium and epicardium were mapped with 391 ± 388 and 1098 ± 734 points per map, respectively. Registration of MDCT allowed visualization of coronary arteries during epicardial mapping/ablation. In the idiopathic patient, integration of MRI data identified previously ablated regions. In ICM patients, both DE at MRI and WT at MDCT matched areas of low voltage (overlap 94 ± 6% and 79 ± 5%, respectively). In NICM patients, wall-thinning areas matched areas of low voltage (overlap 63 ± 21%). In patients with myocarditis, subepicardial DE matched areas of epicardial low voltage (overlap 92 ± 12%). A total number of 266 LAVA sites were found in 7/9 patients. All LAVA sites were associated to structural substrate at imaging (90% inside, 100% within 18 mm). CONCLUSION The integration of merged MDCT and DEMRI data is feasible and allows combining substrate assessment with high-spatial resolution to better define structure-function relationship in scar-related VT.

Time courses and quantitative analysis of atrial fibrillation episode number and duration after circular plus linear left atrial lesions: trigger elimination or substrate modification: early or delayed cure?

OBJECTIVES We sought to analyze the time course of atrial fibrillation (AF) episodes before and after circular plus linear left atrial ablation and the percentage of patients with complete freedom from AF after ablation by using serial seven-day electrocardiograms (ECGs). BACKGROUND The curative treatment of AF targets the pathophysiological corner stones of AF (i.e., the initiating triggers and/or the perpetuation of AF). The pathophysiological complexity of both may not result in an "all-or-nothing" response but may modify number and duration of AF episodes. METHODS In patients with highly symptomatic AF, circular plus linear ablation lesions were placed around the left and right pulmonary veins, between the two circles, and from the left circle to the mitral annulus using the electroanatomic mapping system. Repetitive continuous 7-day ECGs administered before and after catheter ablation were used for rhythm follow-up. RESULTS In 100 patients with paroxysmal (n = 80) and persistent (n = 20) AF, relative duration of time spent in AF significantly decreased over time (35 +/- 37% before ablation, 26 +/- 41% directly after ablation, and 10 +/- 22% after 12 months). Freedom from AF stepwise increased in patients with paroxysmal AF and after 12 months measured at 88% or 74% depending on whether 24-h ECG or 7-day ECG was used. Complete pulmonary vein isolation was demonstrated in <20% of the circular lesions. CONCLUSIONS The results obtained in patients with AF treated with circular plus linear left atrial lesions strongly indicate that substrate modification is the main underlying pathophysiologic mechanism and that it results in a delayed cure instead of an immediate cure.

Epoetin and Darbepoetin for Managing Anemia in Patients Undergoing Cancer Treatment: Comparative Effectiveness Update

Objectives: To update the 2006 systematic review of the comparative benefits and harms of erythropoiesis-stimulating agent (ESA) strategies and non-ESA strategies to manage anemia in patients undergoing chemotherapy and/or radiation for malignancy (excluding myelodysplastic syndrome and acute leukemia), including the impact of alternative thresholds for initiating treatment and optimal duration of therapy. Data sources: Literature searches were updated in electronic databases (n=3), conference proceedings (n=3), and Food and Drug Administration transcripts. Multiple sources (n=13) were searched for potential gray literature. A primary source for current survival evidence was a recently published individual patient data meta-analysis. In that meta-analysis, patient data were obtained from investigators for studies enrolling more than 50 patients per arm. Because those data constitute the most currently available data for this update, as well as the source for on-study (active treatment) mortality data, we limited inclusion in the current report to studies enrolling more than 50 patients per arm to avoid potential differential endpoint ascertainment in smaller studies. Review methods: Title and abstract screening was performed by one or two (to resolve uncertainty) reviewers; potentially included publications were reviewed in full text. Two or three (to resolve disagreements) reviewers assessed trial quality. Results were independently verified and pooled for outcomes of interest. The balance of benefits and harms was examined in a decision model. Results: We evaluated evidence from 5 trials directly comparing darbepoetin with epoetin, 41 trials comparing epoetin with control, and 8 trials comparing darbepoetin with control; 5 trials evaluated early versus late (delay until Hb ≤9 to 11 g/dL) treatment. Trials varied according to duration, tumor types, cancer therapy, trial quality, iron supplementation, baseline hemoglobin, ESA dosing frequency (and therefore amount per dose), and dose escalation. ESAs decreased the risk of transfusion (pooled relative risk [RR], 0.58; 95% confidence interval [CI], 0.53 to 0.64; I2 = 51%; 38 trials) without evidence of meaningful difference between epoetin and darbepoetin. Thromboembolic event rates were higher in ESA-treated patients (pooled RR, 1.51; 95% CI, 1.30 to 1.74; I2 = 0%; 37 trials) without difference between epoetin and darbepoetin. In 14 trials reporting the Functional Assessment of Cancer Therapy (FACT)-Fatigue subscale, the most common patient-reported outcome, scores decreased by −0.6 in control arms (95% CI, −6.4 to 5.2; I2 = 0%) and increased by 2.1 in ESA arms (95% CI, −3.9 to 8.1; I2 = 0%). There were fewer thromboembolic and on-study mortality adverse events when ESA treatment was delayed until baseline Hb was less than 10 g/dL, in keeping with current treatment practice, but the difference in effect from early treatment was not significant, and the evidence was limited and insufficient for conclusions. No evidence informed optimal duration of therapy. Mortality was increased during the on-study period (pooled hazard ratio [HR], 1.17; 95% CI, 1.04 to 1.31; I2 = 0%; 37 trials). There was one additional death for every 59 treated patients when the control arm on-study mortality was 10 percent and one additional death for every 588 treated patients when the control-arm on-study mortality was 1 percent. A cohort decision model yielded a consistent result—greater loss of life-years when control arm on-study mortality was higher. There was no discernible increase in mortality with ESA use over the longest available followup (pooled HR, 1.04; 95% CI, 0.99 to 1.10; I2 = 38%; 44 trials), but many trials did not include an overall survival endpoint and potential time-dependent confounding was not considered. Conclusions: Results of this update were consistent with the 2006 review. ESAs reduced the need for transfusions and increased the risk of thromboembolism. FACT-Fatigue scores were better with ESA use but the magnitude was less than the minimal clinically important difference. An increase in mortality accompanied the use of ESAs. An important unanswered question is whether dosing practices and overall ESA exposure might influence harms.

Cancer, meta-analysis and reporting biases: the case of erythropoiesis-stimulating agents.

Reporting and publication bias is a well-known problem in meta-analysis and healthcare research. In 2002 we conducted a meta-analysis on the effects of erythropoiesis-stimulating agents (ESAs) on overall survival in cancer patients, which suggested some evidence for improved survival in patients receiving ESAs compared with controls. However, a meta-analysis of individual patient data conducted several years later showed the opposite of our first meta-analysis, that is, evidence for increased on-study mortality and reduced overall survival in cancer patients receiving ESAs. We aimed to determine whether the results of our first meta-analysis could have been affected by publication and reporting biases and, if so, whether timely access to clinical study reports and individual patient data could have prevented this. We conducted a hypothetical meta-analysis for overall survival including all studies and study data that could have been available in 2002, at the time when we conducted our first meta-analysis. Compared with our original meta-analysis, which suggested an overall survival benefit for cancer patients receiving ESAs [hazard ratio (HR) 0.81, 95% confidence interval (CI) 0.67‒0.99], our hypothetical meta-analysis based on the results of all studies conducted at the time of the first analysis did not show evidence for a beneficial effect of ESAs on overall survival (HR 0.97, 95% CI 0.83‒1.12). Thus we have to conclude that our first meta-analysis showed misleading overall survival benefits due to publication and reporting biases, which could have been prevented by timely access to clinical study reports and individual patient data. Unrestricted access to clinical study protocols including amendments, clinical study reports and individual patient data is needed to ensure timely detection of both beneficial and harmful effects of healthcare interventions.