Pooling, meta-analysis, and the evaluation of drug safety

BACKGROUND: The "integrated safety report" of the drug registration files submitted to health authorities usually summarizes the rates of adverse events observed for a new drug, placebo or active control drugs by pooling the safety data across the trials. Pooling consists of adding the numbers of events observed in a given treatment group across the trials and dividing the results by the total number of patients included in this group. Because it considers treatment groups rather than studies, pooling ignores validity of the comparisons and is subject to a particular kind of bias, termed "Simpson's paradox." In contrast, meta-analysis and other stratified analyses are less susceptible to bias. METHODS: We use a hypothetical, but not atypical, application to demonstrate that the results of a meta-analysis can differ greatly from those obtained by pooling the same data. In our hypothetical model, a new drug is compared to 1) a placebo in 4 relatively small trials in patients at high risk for a certain adverse event and 2) an active reference drug in 2 larger trials of patients at low risk for this event. RESULTS: Using meta-analysis, the relative risk of experiencing the adverse event with the new drug was 1.78 (95% confidence interval [1.02; 3.12]) compared to placebo and 2.20 [0.76; 6.32] compared to active control. By pooling the data, the results were, respectively, 1.00 [0.59; 1.70] and 5.20 [2.07; 13.08]. CONCLUSIONS: Because these findings could mislead health authorities and doctors, regulatory agencies should require meta-analyses or stratified analyses of safety data in drug registration files

Superparamagnetic Bifunctional Bisphosphonates Nanoparticles: A Potential MRI Contrast Agent for Osteoporosis Therapy and Diagnostic

A bone targeting nanosystem is reported here which combined magnetic contrast agent for Magnetic Resonance Imaging (MRI) and a therapeutic agent (bisphosphonates) into one drug delivery system. This new targeting nanoplatform consists of superparamagnetic γFe2O3 nanoparticles conjugated to 1,5-dihydroxy-1,5,5-tris-phosphono-pentyl-phosphonic acid (di-HMBPs) molecules with a bisphosphonate function at the outer of the nanoparticle surface for bone targeting. The as-synthesized nanoparticles were evaluated as a specific MRI contrast agent by adsorption study onto hydroxyapatite and MRI measurment. The strong adsorption of the bisphosphonates nanoparticles to hydroxyapatite and their use as MRI T2∗ contrast agent were demonstrated. Cellular tests performed on human osteosarcoma cells (MG63) show that γFe2O3@di-HMBP hybrid nanomaterial has no citoxity effect in cell viability and may act as a diagnostic and therapeutic system

Towards a codification of practical knowledge

International audienceAs practical knowledge seems to have a central place in organisational issues, we focus on possibilities to study and formalize it. From an unusual theoretical perspective, we view practical knowledge as embodied knowing which only is only manifest through action in a particular situation. Although this knowledge is largely implicit, we try to make what is 'articulable' explicit. After highlighting the stakes involved in the codification of practices, we review the ontological and epistemological assumptions underlying the method developed. It is founded on participant observation, a video recording of a situated subjective perspective and an ex post interview using this perspective to aid an actor to make part of his/her practical knowledge explicit. We present its implementation within research on polar expeditions in order to understand how an experienced actor deals with risks. In conclusion, we point out (1) the importance of this kind of data in knowledge management, (2) some lines of further research

COVID-19 and cancer registries: Learning from the first peak of the SARS-CoV-2 pandemic

The SARS-Cov-2 pandemic in 2020 has caused oncology teams around the world to adapt their practice in the aim of protecting patients. Early evidence from China indicated that patients with cancer, and particularly those who had recently received chemotherapy or surgery, were at increased risk of adverse outcomes following SARS-Cov-2 infection. Many registries of cancer patients infected with SARS-Cov-2 emerged during the first wave. We collate the evidence from these national and international studies and focus on the risk factors for patients with solid cancers and the contribution of systemic anti-cancer treatments (SACT-chemotherapy, immunotherapy, targeted and hormone therapy) to outcomes following SARS-Cov-2 infection. Patients with cancer infected with SARS-Cov-2 have a higher probability of death compared with patients without cancer. Common risk factors for mortality following COVID-19 include age, male sex, smoking history, number of comorbidities and poor performance status. Oncological features that may predict for worse outcomes include tumour stage, disease trajectory and lung cancer. Most studies did not identify an association between SACT and adverse outcomes. Recent data suggest that the timing of receipt of SACT may be associated with risk of mortality. Ongoing recruitment to these registries will enable us to provide evidence-based care

Impact of the Specific Mutation in KRAS Codon 12 Mutated Tumors on Treatment Efficacy in Patients with Metastatic Colorectal Cancer Receiving Cetuximab-Based First-Line Therapy: A Pooled Analysis of Three Trials

Purpose: This study investigated the impact of specific mutations in codon 12 of the Kirsten-ras (KRAS) gene on treatment efficacy in patients with metastatic colorectal cancer (mCRC). Patients: Overall, 119 patients bearing a KRAS mutation in codon 12 were evaluated. All patients received cetuximab-based first-line chemotherapy within the Central European Cooperative Oncology Group (CECOG), AIO KRK-0104 or AIO KRK-0306 trials. Results: Patients with KRAS codon 12 mutant mCRC showed a broad range of outcome when treated with cetuximab-based first-line regimens. Patients with tumors bearing a KRAS p.G12D mutation showed a strong trend to a more favorable outcome compared to other mutations (overall survival 23.3 vs. 14-18 months; hazard ratio 0.66, range 0.43-1.03). An interaction model illustrated that KRAS p.G12C was associated with unfavorable outcome when treated with oxaliplatin plus cetuximab. Conclusion: The present analysis suggests that KRAS codon 12 mutation may not represent a homogeneous entity in mCRC when treated with cetuximab-based first-line therapy. Copyright (C) 2012 S. Karger AG, Base

Heteroglossia n°16. Langues et cultures dans l'internationalisation de l'enseignement supérieur au XXIe siècle. Volume 2. Analyser les politiques linguistiques: études de cas sur le plurilinguisme et l'anglais.

Secondo volume degli atti selezionati del convegno internazionale "Le plurilinguisme, le pluriculturalisme et l'angalis dans la mondialisation: dispositifs, pratiques et problématiques de l'internationalisation dans l'enseignement supérieur européen" organizzato all'Università di Angers (Francia). M. ANquetil è stata membro del comitato internazionale scientifico e organizzativo, e co-editrice della selezione di atti del convegno per il primo volume edito presso Peter Lang (Berne, Svizzera) e del secondo volume presso Heteroglossia

Exploring Perceptions of Group Processes in Ice Hockey Officiating

This is an Original Manuscript of an article published by Taylor & Francis in Journal of Applied Sport Psychology on 10 July 2017, available online: http://www.tandfonline.com/10.1080/10413200.2017.1349208.Understanding factors that influence sport officials’ performance is vital to ensuring fair sport competition. Through semi-structured interviews (N = 17), we explored officials’ perceptions of group processes that occurred among ice hockey officiating teams. Participant responses revealed numerous ways that group processes were present within officials’ interactions, and two unique characteristics involved the transient nature of officiating groups (frequently performing with different officials) and intra-team competition pertaining to post-season assignments. In the discussion, we expand on the unique nature of officiating groups, synthesize activities in which officials seek to enhance groupness, and provide insights for future interventions and researchers

TP53 mutations predict disease control in metastatic colorectal cancer treated with cetuximab-based chemotherapy

Recent studies have suggested that activation of the EGFR pathway leads to malignant transformation only if the p53 protein is inactivated. Therefore, we evaluated the impact of TP53 mutations on cetuximab-based chemotherapy (CT) sensitivity in combination with KRAS mutations that have been associated with cetuximab resistance. KRAS and TP53 status were assessed in tumours from 64 metastatic colorectal cancer patients treated with cetuximab-based CT and correlated to clinical response using the Fisher's exact test. Times to progression (TTPs) according to gene status were calculated using the Kaplan–Meier method and compared with log-rank test. TP53 mutations were found in 41 patients and were significantly associated with controlled disease (CD), as defined as complete response, partial response or stable disease (P=0.037) and higher TTP (20 vs 12 weeks, P=0.004). Remarkably, in the subgroup of 46 patients without KRAS mutation, but not in patients with KRAS mutation, TP53 mutations were also associated with CD (P=0.008) and higher TTP (24 vs 12 weeks, P=0.0007). This study suggests that TP53 mutations are predictive of cetuximab sensitivity, particularly in patients without KRAS mutation, and that TP53 genotyping could have a clinical interest to select patients who should benefit from cetuximab-based CT

Putative contribution of CD56 positive cells in cetuximab treatment efficacy in first-line metastatic colorectal cancer patients

Activity of cetuximab, a chimeric monoclonal antibody targeting the epidermal growth factor receptor, is largely attributed to its direct antiproliferative and proapoptotic effects. Antibody-dependent cell-mediated cytotoxicity (ADCC) could be another possible mechanism of cetuximab antitumor effects and its specific contribution on the clinical activity of cetuximab is unknown.Journal ArticleSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Molecular and cellular mechanisms underlying the evolution of form and function in the amniote jaw.

The amniote jaw complex is a remarkable amalgamation of derivatives from distinct embryonic cell lineages. During development, the cells in these lineages experience concerted movements, migrations, and signaling interactions that take them from their initial origins to their final destinations and imbue their derivatives with aspects of form including their axial orientation, anatomical identity, size, and shape. Perturbations along the way can produce defects and disease, but also generate the variation necessary for jaw evolution and adaptation. We focus on molecular and cellular mechanisms that regulate form in the amniote jaw complex, and that enable structural and functional integration. Special emphasis is placed on the role of cranial neural crest mesenchyme (NCM) during the species-specific patterning of bone, cartilage, tendon, muscle, and other jaw tissues. We also address the effects of biomechanical forces during jaw development and discuss ways in which certain molecular and cellular responses add adaptive and evolutionary plasticity to jaw morphology. Overall, we highlight how variation in molecular and cellular programs can promote the phenomenal diversity and functional morphology achieved during amniote jaw evolution or lead to the range of jaw defects and disease that affect the human condition