Clin Ther

Purpose Although quantitative benefit–risk models (qBRms) are indisputably valuable tools for gaining comprehensive assessments of health care interventions, they are not systematically used, probably because they lack an integrated framework that provides methodologic structure and harmonization. An alternative that allows all stakeholders to design operational models starting from a standardized framework was recently developed: the discretely integrated condition event (DICE) simulation. The aim of the present work was to assess the feasibility of implementing a qBRm in DICE, using the example of rotavirus vaccination. Methods A model of rotavirus vaccination was designed using DICE and implemented in spreadsheet software with 3 worksheets: Conditions, Events, and Outputs. Conditions held the information in the model; this information changed at Events, and Outputs were special Conditions that stored the results collected during the analysis. A hypothetical French birth cohort was simulated for the assessment of rotavirus vaccination over time. The benefits were estimated for up to 5 years, and the risks in the 7 days following rotavirus vaccination versus no vaccination were assessed, with the results expressed as benefit–risk ratios. Findings This qBRm model required 8 Events, 38 Conditions, and 9 Outputs. Two Events cyclically updated the rates of rotavirus gastroenteritis (RVGE) and intussusception (IS) according to age. Vaccination occurred at 2 additional Events, according to the vaccination scheme applied in France, and affected the occurrence of the other Events. Outputs were the numbers of hospitalizations related to RVGE and to IS, and related deaths. The entire model was specified in a small set of tables contained in a 445-KB electronic workbook. Analyses showed that for each IS-related hospitalization or death caused, 1613 (95% credible interval, 1001–2800) RVGE-related hospitalizations and 787 (95% credible interval, 246–2691) RVGE-related deaths would be prevented by vaccination. These results are consistent with those from a published French study using similar inputs but a very different modeling approach. Implications A limitation of the DICE approach was the extended run time needed for completing the sensitivity analyses when implemented in the electronic worksheets. DICE provided a user-friendly integrated framework for developing qBRms and should be considered in the development of structured approaches to facilitate benefit–risk assessment

CNS Drugs

BACKGROUND: Hepatotoxicity may be a concern when prescribing antidepressants. Nevertheless, this risk remains poorly understood for serotonin and noradrenaline reuptake inhibitors (SNRIs: venlafaxine, milnacipran, duloxetine) and 'other antidepressants' (mianserin, mirtazapine, tianeptine and agomelatine), particularly in comparison with selective serotonin reuptake inhibitors (SSRIs: fluoxetine, citalopram, paroxetine, sertraline, fluvoxamine, escitalopram), which are by far the most commonly prescribed antidepressants. OBJECTIVE: We quantified the risk of serious liver injury associated with new use of SNRIs and 'other antidepressants' compared with SSRIs in real-life practice. METHODS: Based on the French national health insurance database, this cohort study included 4,966,825 individuals aged 25 years and older with a first reimbursement of SSRIs, SNRIs or 'other antidepressants' between January 2010 and June 2015. We compared the risk of serious liver injury within the 6 months following antidepressant initiation according to antidepressant class, with SSRIs as the reference, using an inverse probability-of-treatment-weighted Cox proportional hazard model adjusted for demographic characteristics and risk factors of liver injury. RESULTS: We identified 382 serious liver injuries overall (none for milnacipran initiators). Age and gender standardized incidence rates per 100,000 person-years were 19.2 for SSRIs, 22.2 for venlafaxine, 12.6 for duloxetine, 21.5 for mianserin, 32.8 for mirtazapine, 31.6 for tianeptine and 24.6 for agomelatine initiators. Initiation of antidepressants of interest versus SSRIs was not associated with an increased risk of serious liver injury [adjusted hazard ratios (95% confidence interval): venlafaxine 1.17 (0.83-1.64), duloxetine 0.54 (0.28-1.02), mianserin 0.90 (0.58-1.41), mirtazapine 1.17 (0.67-2.02), tianeptine 1.35 (0.82-2.23) and agomelatine 1.07 (0.51-2.23)]. This finding was confirmed by the results of an additional study using a case-time-control design. CONCLUSION: These results do not provide evidence of an increased risk of serious liver injury following initiation of SNRIs or 'other antidepressants' compared with SSRIs in real-life practice. This could reflect an inherent lack of difference in risk between the drug classes, or the fact that individuals with higher susceptibility to drug-induced liver injury are not prescribed drugs considered to be more hepatotoxic

Benchmarking clinical management of spinal and non-spinal disorders using quality of life: results from the EPI3-LASER survey in primary care

Concerns have been raised regarding sub-optimal utilization of analgesics and psychotropic drugs in the treatment of patients with chronic musculoskeletal disorders (MSDs) and their associated co-morbidities. The objective of this study was to describe drug prescriptions for the management of spinal and non-spinal MSDs contrasted against a standardized measure of quality of life. A representative population sample of 1,756 MSDs patients [38.5% with spinal disorder (SD) and 61.5% with non-spinal MSDs (NS-MSD)] was drawn from the EPI3-LASER survey of 825 general practitioners (GPs) in France. Physicians recorded their diagnoses and prescriptions on that day. Patients provided information on socio-demographics, lifestyle and quality of life using the Short Form 12 (SF-12) questionnaire. Chronicity of MSDs was defined as more than 12 weeks duration of the current episode. Chronic SD and NS-MSD patients were prescribed less analgesics and non-steroidal anti-inflammatory drugs than their non-chronic counterpart [odds ratios (OR) and 95% confidence intervals (CI), respectively: 0.4, 0.2–0.7 and 0.5, 0.3–0.6]. They also had more anxio-depressive co-morbidities reported by their physicians (SD: 16.1 vs.7.4%; NS-MSD: 21.6 vs. 9.5%) who prescribed more antidepressants and anxiolytics with a difference that was statistically significant only for spinal disorder patients (OR, 95% CI: 2.0, 1.1–3.6). Psychotropic drugs were more often prescribed in patients in the lower quartile of SF-12 mental score and prescriptions of analgesics in the lower quartile of SF-12 physical score (P < 0.001). In conclusion, anxiety and depressive disorders were commonly reported by GPs among chronic MSD patients. Their prescriptions of psychotropic and analgesic drugs were consistent with patients’ self-rated mental and physical health

Drug Saf

Introduction Quantitative benefit-risk models (qBRm) applied to vaccines are increasingly used by public health authorities and pharmaceutical companies as an important tool to help decision makers with supporting benefit-risk assessment (BRA). However, many publications on vaccine qBRm provide insufficient details on the methodological approaches used. Incomplete and/or inadequate qBRm reporting may affect result interpretation and confidence in BRA, highlighting a need for the development of standard reporting guidance. Objectives Our objective was to provide an operational checklist for improved reporting of vaccine qBRm. Methods The consolidated standards of reporting quantitative Benefit-RIsk models applied to VACcines (BRIVAC) were designed as a checklist of key information to report in qBRm scientific publications regarding the assessed vaccines, the methodological considerations and the results and their interpretation. Results In total, 22 items and accompanying definitions, recommendations, explanations and examples were provided and divided into six main sections corresponding to the classic subdivisions of a scientific publication: title and abstract (items 1–2), introduction (items 3–4), methods (items 5–15), results (items 16–17), discussion (items 18–20) and other (items 21–22). Conclusions The BRIVAC checklist is the first initiative providing an operational checklist for improved reporting of qBRm applied to vaccines in scientific articles. It is intended to assist authors, peer-reviewers, editors and readers in their critical appraisal. Future initiatives are needed to provide methodological guidance to perform qBRm while taking into account the vaccine specificities

J Neurol Neurosurg Psychiatry

BACKGROUND: Previous studies have shown associations between the use of anticholinergics (AC) and cognitive performance in the elderly, considering AC as a homogeneous set of drugs. The present study aims to assess the relationship between exposure to AC drugs and cognitive performance in middle-aged adults according to AC potency and drug class. METHODS: Our cross-sectional study used baseline data of 34 267 participants aged 45-70 from the Consultants des centres d'examen de sante de la securite sociale (CONSTANCES) cohort. The cumulative exposure to AC was measured using national reimbursement databases over the 3-year period preceding assessment of cognitive performance. Eight classes of AC drugs were differentiated. Episodic verbal memory, language abilities and executive functions were evaluated by validated neuropsychological tests. Analyses were controlled on lifestyle and health status variables. RESULTS: This study showed a negative association between overall cumulative AC exposure and cognitive performances after adjustment. The use of drugs with possible AC effect according to the Anticholinergic Cognitive Burden scale (ACB-1 score) was only associated with executive functions. Analyses of AC exposure across drug classes showed a negative association between the use of AC antipsychotics and all cognitive functions assessed. Heterogeneous associations were found for the use of AC anxiolytics, AC opioids and AC drugs targeting the gastrointestinal tract or metabolism. We did not find significant associations between the use of antihistamines, antidepressants, cardiovascular system or other AC medications and cognitive function. CONCLUSION: Association between AC drugs and cognitive performance was highly heterogeneous across drug classes; this heterogeneity will have to be considered by future studies

CD26/dipeptidyl peptidase IV (CD26/DPPIV) is highly expressed in peripheral blood of HIV-1 exposed uninfected Female sex workers

<p>Abstract</p> <p>Background</p> <p>Design of effective vaccines against the human immunodeficiency virus (HIV-1) continues to present formidable challenges. However, individuals who are exposed HIV-1 but do not get infected may reveal correlates of protection that may inform on effective vaccine design. A preliminary gene expression analysis of HIV resistant female sex workers (HIV-R) suggested a high expression CD26/DPPIV gene. Previous studies have indicated an anti-HIV effect of high CD26/DPPIV expressing cells in vitro. Similarly, high CD26/DPPIV protein levels in vivo have been shown to be a risk factor for type 2 diabetes. We carried out a study to confirm if the high CD26/DPPIV gene expression among the HIV-R were concordant with high blood protein levels and its correlation with clinical type 2 diabetes and other perturbations in the insulin signaling pathway.</p> <p>Results</p> <p>A quantitative CD26/DPPIV plasma analysis from 100 HIV-R, 100 HIV infected (HIV +) and 100 HIV negative controls (HIV Neg) showed a significantly elevated CD26/DPPIV concentration among the HIV-R group (mean 1315 ng/ml) than the HIV Neg (910 ng/ml) and HIV + (870 ng/ml, p < 0.001). Similarly a FACs analysis of cell associated DPPIV (CD26) revealed a higher CD26/DPPIV expression on CD4+ T-cells derived from HIV-R than from the HIV+ (90.30% vs 80.90 p = 0.002) and HIV Neg controls (90.30% vs 82.30 p < 0.001) respectively. A further comparison of the mean fluorescent intensity (MFI) of CD26/DPPIV expression showed a higher DPP4 MFI on HIV-R CD4+ T cells (median 118 vs 91 for HIV-Neg, p = 0.0003). An evaluation for hyperglycemia, did not confirm Type 2 diabetes but an impaired fasting glucose condition (5.775 mmol/L). A follow-up quantitative PCR analysis of the insulin signaling pathway genes showed a down expression of NFκB, a central mediator of the immune response and activator of HIV-1 transcription.</p> <p>Conclusion</p> <p>HIV resistant sex workers have a high expression of CD26/DPPIV in tandem with lowered immune activation markers. This may suggest a novel role for CD26/DPPIV in protection against HIV infection in vivo.</p

Therapie

Pharmacoepidemiology, in the sense of the study of the reciprocal interactions between drugs and populations, was probably conceived far before being named so. However, the modern era started in 1985 with the birth of the International society of pharmacoepidemiology and the development of specific methodological approaches and large databases. This advent of pharmacoepidemiology resulted from a long period where the actual target of medicines, i.e., patients in real-life settings, was not considered, the truth being provided solely by pre-approval or peri-approval clinical trials. The methodological advances made during the last three decades are unprecedented. The challenge is now to avoid focusing excessively on the method to the detriment of pharmacological and public health objectives