Background
Few studies documented the potential association between vaccination and the risk of central demyelination (CD). Specifically, anti-hepatitis B and anti-human papillomavirus (HPV) vaccines ...have been the subject of distrust with regard to their implication to trigger CD.
Methods
From a systematic national registry, patients with first signs of CD (cases) were identified and documented for their exposure to vaccination up to 24 months before the first signs occurred. This exposure was compared to that of a representative sample of general practice patients without a history of CD, randomly selected from a national registry (referents). CD cases were 2:1 matched on age, sex, index date (ID), and region of residence. Vaccines against influenza, HPV, hepatitis B and diphtheria–tetanus–pertussis–poliomyelitis–haemophilus (DTPPHae) were considered. Associations between vaccination and CD were assessed using multivariate conditional logistic regressions, controlled for confounding factors.
Findings
564 CD cases were matched to 1,128 randomly selected referents (age range: 2–79 years old). Overall, 123 (22%) CD cases and 320 (28%) referents had received at least one vaccine within 24 months before ID. Adjusted odds ratios (ORs) for any vaccination were 0.69, 95% confidence interval (CI) 0.54–0.88 with respect to any CD first signs, 0.68 0.51–0.90 for myelitis and 0.70 0.42–1.17 for optic neuritis. Adjusted ORs for any CD first signs were 1.02 0.71–1.47 for influenza vaccine (administered in 9.6% of cases and 10.4% of referents) and 0.72 0.53–0.99 for DTPPHae vaccine (administered in 10.8% of cases and 14.5% of referents). Vaccines against hepatitis B and HPV were only administered in 1.1% and 1.2% of cases and in 2.9% and 3.2% of referents respectively, which statistically explained the point estimates < 1 (ORs of 0.39 0.16–0.94 and of 0.32 0.13–0.80).
Interpretation
No increased risk of CD incidence was observed amongst vaccinated patients. Lower rates of vaccination against hepatitis B and HPV observed in patients with CD compared to referents may be due to the reluctance of physicians to vaccinate patients considered at risk of CD.
Pharmacovigilance reports of cerebral and cardiovascular events in those who use decongestants have triggered alerts related to their use. We aimed to assess the risk of stroke and myocardial ...infarction (MI) associated with the use of decongestants. We conducted a nested case-crossover study of patients with incident stroke and MI identified in France between 2013 and 2016 in two systematic disease registries. Decongestant use in the three weeks preceding the event was assessed using a structured telephone interview. Conditional logistic multivariable models were used to estimate the odds of incident MI and stroke, also accounting for transient risk factors and comparing week 1 (index at-risk time window, immediately preceding the event) to week 3 (reference). Time-invariant risk factors were controlled by design. In total, 1394 patients with MI and 1403 patients with stroke, mainly 70 years old or younger, were interviewed, including 3.2% who used decongestants during the three weeks prior to the event (1.0% definite exposure in the index at-risk time window, 1.1% in the referent time window; adjusted odds ratio (aOR), 0.78; 95%CI, 0.43-1.42). Secondary analysis yielded similar results for individual events (MI/stroke). We observed no increased risk of MI or stroke for patients 70 years of age and younger without previous MI or stroke who used decongestants.
Abstract Background The concept of the “efficacy-effectiveness gap” (EEG) has started to challenge confidence in decisions made for drugs when based on randomized controlled trials alone. Launched by ...the Innovative Medicines Initiative, the GetReal project aims to improve understanding of how to reconcile evidence to support efficacy and effectiveness and at proposing operational solutions. Objectives The objectives of the present narrative review were 1) to understand the historical background in which the concept of the EEG has emerged and 2) to describe the conceptualization of EEG. Methods A focused literature review was conducted across the gray literature and articles published in English reporting insights on the EEG concept. The identification of different “paradigms” was performed by simple inductive analysis of the documents’ content. Results The literature on the EEG falls into three major paradigms, in which EEG is related to 1) real-life characteristics of the health care system; 2) the method used to measure the drug’s effect; and 3) a complex interaction between the drug’s biological effect and contextual factors. Conclusions The third paradigm provides an opportunity to look beyond any dichotomy between “standardized” versus “real-life” characteristics of the health care system and study designs. Namely, future research will determine whether the identification of these contextual factors can help to best design randomized controlled trials that provide better estimates of drugs’ effectiveness.
This prospective observational cohort study aimed to explore the clinical features of incident immune thrombocytopenia in adults and predictors of outcome, while determining if a family history of ...autoimmune disorder is a risk factor for immune thrombocytopenia. All adults, 18 years of age or older, recently diagnosed with immune thrombocytopenia were consecutively recruited across 21 hospital centers in France. Data were collected at diagnosis and after 12 months. Predictors of chronicity at 12 months were explored using logistic regression models. The association between family history of autoimmune disorder and the risk of developing immune thrombocytopenia was explored using a conditional logistic regression model after matching each case to 10 controls. One hundred and forty-three patients were included: 63% female, mean age 48 years old (Standard Deviation=19), and 84% presented with bleeding symptoms. Median platelet count was 10×10(9)/L. Initial treatment was required in 82% of patients. After 12 months, only 37% of patients not subject to disease-modifying interventions achieved cure. The sole possible predictor of chronicity at 12 months was a higher platelet count at baseline Odds Ratio 1.03; 95%CI: 1.00, 1.06. No association was found between outcome and any of the following features: age, sex, presence of either bleeding symptoms or antinuclear antibodies at diagnosis. Likewise, family history of autoimmune disorder was not associated with incident immune thrombocytopenia. Immune thrombocytopenia in adults has been shown to progress to a chronic form in the majority of patients. A lower platelet count could be indicative of a more favorable outcome.
Type 2 diabetes mellitus (T2DM) and atrial fibrillation are risk factors for stroke. The potential preventive effects of cardiovascular and antidiabetic treatments on stroke risk in patients with ...these diseases remain insufficiently documented. Sulfonylureas have also been reported to be associated with stroke. This study aimed to assess the risk of stroke according to the use of drugs (anticoagulants, antiplatelet agents, and oral antidiabetic drugs OADs) in patients with T2DM and nonvalvular atrial fibrillation (NVAF).
Patients with a history of T2DM and NVAF were identified from two systematic registries: a registry of patients with stroke and a registry of patients with atrial fibrillation. Patients with stroke were randomly matched to patients without prior stroke events based on age, sex, body mass index, and index date. All treatments administered 12 months before the index date were documented. The associations between anticoagulants, antiplatelet agents, and OADs and stroke were assessed using multivariate conditional logistic models that yielded adjusted odds ratios (aORs) and 95 % confidence intervals, controlling for risk factors identified in the univariate comparison of cases and matched referents.
Three-hundred and fifteen patients with stroke with both diabetes and NVAF were matched to 523 referents with both diabetes and NVAF but no history of stroke. The aORs for the use of drugs and stroke were 0.24 0.15–0.40 for direct oral anticoagulants (DOACs), 0.42 0.27–0.67 for vitamin K agonists (VKA), 0.80 0.52–1.24 for antiplatelet agents, and 0.68 0.45–1.02 for OADs. No significant associations were found between individual OAD use and stroke risk. Similar results were obtained for ischemic stroke. Only VKAs were significantly associated with hemorrhagic stroke (odds ratio = 4.25 1.16–15.64).
Anticoagulant use was associated with a protective effect against the risk of stroke in patients with diabetes and NVAF, with no increase in the risk of hemorrhagic stroke for DOAC. No increased risk of stroke was observed because of any OAD, including sulfonylureas.
•Unlike other oral antidiabetic drugs, an increased risk of stroke has been suggested for sulfonylureas•First study assessing stroke’ risk according to the use of anticoagulants, antiplatelet and oral antidiabetic drugs (OADs).•Anticoagulants and OADs were associated with a protective effect against stroke risk in patients with diabetes and NVAF.•Antiplatelet agents were associated with a favorable, but limited, trend for reduced risk of stroke•No increase in the risk of stroke was observed in the users of OADs, including sulfonylureas
Prescribing of antibiotics for upper respiratory tract infections (URTI) varies substantially in primary care.
To describe and compare antibiotic and antipyretic/anti-inflammatory drugs use, URTI ...symptoms' resolution and occurrence of potentially-associated infections in patients seeking care from general practitioners (GPs) who exclusively prescribe conventional medications (GP-CM), regularly prescribe homeopathy within a mixed practice (GP-Mx), or are certified homeopathic GPs (GP-Ho).
The EPI3 survey was a nationwide population-based study of a representative sample of 825 GPs and their patients in France (2007-2008). GP recruitment was stratified by self-declared homeopathic prescribing preferences. Adults and children with confirmed URTI were asked to participate in a standardized telephone interview at inclusion, one-, three- and twelve-month follow up. Study outcomes included medication consumption, URTI symptoms' resolution and potentially-associated infections (sinusitis or otitis media/externa) as reported by patients. Analyses included calibration to account for non-respondents and groups were compared using multivate analyses adjusting for baseline differences with a propensity score.
518 adults and children with URTI (79.3% rhinopharyngitis) were included (36.9% response rate comparable between groups). As opposed to GP-CM patients, patients in the GP-Ho group showed significantly lower consumption of antibiotics (Odds ratio (OR) = 0.43, 95% confidence interval (CI): 0.27-0.68) and antipyretic/anti-inflammatory drugs (OR = 0.54, 95% CI: 0.38-0.76) with similar evolution in related symptoms (OR = 1.16, 95% CI: 0.64-2.10). An excess of potentially-associated infections (OR = 1.70, 95% CI: 0.90-3.20) was observed in the GP-Ho group (not statistically significant). No difference was found between GP-CM and GP-Mx patients.
Patients who chose to consult GPs certified in homeopathy used less antibiotics and antipyretic/anti-inflammatory drugs for URTI than those seen by GPs prescribing conventional medications. No difference was observed in patients consulting GPs within mixed-practice. A non-statistically significant excess was estimated through modelling for associated infections in the GP-Ho group and needs to be further studied.
Purpose Based on contemporary epidemiological and pathological characteristics of prostate cancer we explain the rationale for and concerns about focal therapy for low risk prostate cancer, review ...potential methods of delivery and propose study design parameters. Materials and Methods Articles regarding the epidemiology, diagnosis, imaging, treatment and pathology of localized prostate cancer were reviewed with a particular emphasis on technologies applicable for focal therapy, defined as targeted ablation of a limited area of the prostate expected to contain the dominant or only focus of cancer. A consensus summary was constructed by a multidisciplinary international task force of prostate cancer experts, forming the basis of the current review. Results In regions with a high prevalence of prostate specific antigen screening the over detection and subsequent overtreatment of prostate cancer is common. The incidence of unifocal cancers in radical prostatectomy specimens is 13% to 38%. In many others there is an index lesion with secondary foci containing pathological features similar to those found incidentally at autopsy. Because biopsy strategies and imaging techniques can provide more precise tumor localization and characterization, there is growing interest in focal therapy targeting unifocal or biologically unifocal tumors. The major arguments against focal therapy are multifocality, limited accuracy of staging, the unpredictable aggressiveness of secondary foci and the lack of established technology for focal ablation. Emerging technologies with the potential for focal therapy include high intensity focused ultrasound, cryotherapy, radio frequency ablation and photodynamic therapy. Conclusions Early detection of prostate cancer has led to concerns that while many cancers now diagnosed pose too little a threat for radical therapy, many men are reluctant to accept watchful waiting or active surveillance. Several emerging technologies seem capable of focal destruction of prostate tissue with minimal morbidity. We encourage the investigation of focal therapy in select men with low risk prostate cancer in prospective clinical trials that carefully document safety, functional outcomes and cancer control.
Objective: The purpose of this study was to develop a practical and scientifically rigorous, patient-reported outcome measure to evaluate quality of life and symptoms across the range of conditions ...(eg, telangiectasias, varicose veins, edema, skin changes, leg ulcers) in chronic venous disorders of the leg (CVDL).
Methods: This study was a psychometric study within the VEnous INsufficiency Epidemiological and Economic Study (VEINES), an international, prospective cohort study to evaluate clinical outcomes, quality of life, costs, and use of health services in CVDL. The study was set in the 166 general practices and 116 specialist clinics in Belgium, France, Italy, and Canada (Quebec) that participated in the VEINES study plus in additional specialist clinics in Ottawa and Montreal. Field testing was carried out in three samples of patients in four countries (Belgium, France, Italy, Canada), including participants in the VEINES study (n † 1531) and patients recruited in additional samples of 88 English-speaking patients (Canada) and 53 French-speaking patients (Belgium, France). The reliability and validity sample (n = 615) included 527 VEINES patients and 88 patients from the supplementary English-speaking sample. The test-retest sample (n = 135) included 53 French-speaking and 82 English-speaking patients from the supplementary samples. The responsiveness sample included 1516 VEINES patients. The 26-item VEINES-QOL/Sym is a new, patient-reported questionnaire to evaluate symptoms and quality of life and is available in four language versions (English, French, Italian, French Canadian).
Results: Standard psychometric tests confirmed the acceptability (missing data, item endorsement frequencies, floor and ceiling effects), reliability (internal consistency, item-total, inter-item correlations) and validity (content, construct, convergent, discriminant, known groups) of the four language versions of the VEINES-QOL/Sym and the test-retest reliability of the English and French versions and provided preliminary evidence of responsiveness in a pooled language sample.
Conclusion: The VEINES-QOL/Sym is a practical and scientifically sound, patient-reported measure of outcomes in CVDL that has been developed with rigorous methods. As the only fully validated measure of quality of life and symptoms that is appropriate for use across the full spectrum of CVDL-related conditions, that is quick and easy to administer, and that is available in four languages, the VEINES-QOL/Sym provides a rigorous tool for improving the evaluation of outcomes in clinical trials, epidemiologic studies, and audit. (J Vasc Surg 2003;37:410-9.)
Objectives
Nationwide prospective cohort study exploring (i) the factors associated with treatment initiation (vs. watchful waiting) in children with primary immune thrombocytopenia (ITP) followed in ...routine clinical practice and (ii) the predictors of chronicity at 12 months.
Procedure
Between 2008 and 2013, 23 centers throughout France consecutively included 257 children aged 6 months–18 years and diagnosed with primary ITP over a 5‐year period. Data on ITP clinical features along with medical management were collected at baseline and 12 months. Multivariate logistic regressions were used to determine (i) and (ii) as defined above, providing odds ratio (OR) with 95% confidence interval (95% CI).
Results
One hundred thirty‐seven (53%) children were males, median age was 4.6 years, median platelet count was 7 × 109/l, and 214 (81%) patients initiated medication. Factors independently associated with treatment initiation included platelet counts <10 × 109/l (P < 0.0001) and mucocutaneous bleeding symptoms at baseline (P < 0.001). At 12 months, data were available for 211 (82%) children, of whom 160 (74%) had recovered. Predictors of chronicity included female gender (OR = 2.2; 95% CI = 1.0–4.8), age ≥10 years (OR = 2.6; 95% CI = 1.1–6.0), and platelet counts ≥10 × 109/l (OR = 3.2; 95% CI = 1.5–6.9).
Conclusions
In routine clinical practice, the decision to apply a watchful waiting strategy seems to be driven by platelet counts even in the absence of bleeding symptoms, resulting in treatment being initiated in more than 80% of the children surveyed. Overall, younger children with ITP showed good prognosis, with lower platelet counts and, to a lesser extent, male gender predicting more favorable outcomes.
Phase III randomized controlled trials (RCT) typically exclude certain patient subgroups, thereby potentially jeopardizing estimation of a drug's effects when prescribed to wider populations and ...under routine care ("effectiveness"). Conversely, enrolling heterogeneous populations in RCTs can increase endpoint variability and compromise detection of a drug's effect. We developed the "RCT augmentation" method to quantitatively support RCT design in the identification of exclusion criteria to relax to address both of these considerations. In the present manuscript, we describe the method and a case study in schizophrenia.
We applied typical RCT exclusion criteria in a real-world dataset (cohort) of schizophrenia patients to define the "RCT population" subgroup, and assessed the impact of re-including each of the following patient subgroups: (1) illness duration 1-3 years; (2) suicide attempt; (3) alcohol abuse; (4) substance abuse; and (5) private practice management. Predictive models were built using data from different "augmented RCT populations" (i.e., subgroups where patients with one or two of such characteristics were re-included) to estimate the absolute effectiveness of the two most prevalent antipsychotics against real-world results from the entire cohort. Concurrently, the impact on RCT results of relaxing exclusion criteria was evaluated by calculating the comparative efficacy of those two antipsychotics in virtual RCTs drawing on different "augmented RCT populations".
Data from the "RCT population", which was defined with typical exclusion criteria, allowed for a prediction of effectiveness with a bias < 2% and mean squared error (MSE) = 5.8-6.8%. Compared to this typical RCT, RCTs using augmented populations provided improved effectiveness predictions (bias < 2%, MSE = 5.3-6.7%), while returning more variable comparative effects. The impact of augmentation depended on the exclusion criterion relaxed. Furthermore, half of the benefit of relaxing each criterion was gained from re-including the first 10-20% of patients with the corresponding real-world characteristic.
Simulating the inclusion of real-world subpopulations into an RCT before running it allows for quantification of the impact of each re-inclusion upon effect detection (statistical power) and generalizability of trial results, thereby explicating this trade-off and enabling a controlled increase in population heterogeneity in the RCT design.
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