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Compare the area under the receiver operating characteristic curve (AUC) vs. the area under the precision–recall curve (AUPRC) in summarizing the performance of a diagnostic biomarker according to the disease prevalence. A simulation study was performed considering different sizes of diseased and nondiseased groups. Values of a biomarker were sampled with various variances and differences in mean values between the two groups. The AUCs and the AUPRCs were examined regarding their agreement and vs. the positive predictive value (PPV) and the negative predictive value (NPV) of the biomarker. With a disease prevalence of 50%, the AUC and the AUPRC showed high correlations with the PPV and the NPV (ρ > 0.95). With a prevalence of 1%, small PPV and AUPRC values (<0.2) but high AUC values (>0.9) were found. The AUPRC reflected better than the AUC the discriminant ability of the biomarker; it had a higher correlation with the PPV (ρ = 0.995 vs. 0.724; P < 0.001). In uncommon and rare diseases, the AUPRC should be preferred to the AUC because it summarizes better the performance of a biomarker.

Longitudinal data are data in which each variable is measured repeatedly over time. One possibility for the analysis of such data is to cluster them. The majority of clustering methods group together individual that have close trajectories at given time points. These methods group trajectories that are locally close but not necessarily those that have similar shapes. However, in several circumstances, the progress of a phenomenon may be more important than the moment at which it occurs. One would thus like to achieve a partitioning where each group gathers individuals whose trajectories have similar shapes whatever the time lag between them. In this article, we present a longitudinal data partitioning algorithm based on the shapes of the trajectories rather than on classical distances. Because this algorithm is time consuming, we propose as well two data simplification procedures that make it applicable to high dimensional datasets. In an application to Alzheimer disease, this algorithm revealed a \"rapid decline\" patient group that was not found by the classical methods. In another application to the feminine menstrual cycle, the algorithm showed, contrarily to the current literature, that the luteinizing hormone presents two peaks in an important proportion of women (22%).

Since the 1990s, fluorouracil-based adjuvant chemotherapy has significantly reduced the risk of tumour recurrence in patients with stage III colon cancer. We aimed to assess whether the addition of cetuximab to standard adjuvant oxaliplatin, fluorouracil, and leucovorin chemotherapy (FOLFOX4) in patients with stage III colon cancer improved disease-free survival (DFS). For this open-label, randomised phase 3 study done in nine European countries, we enrolled patients through an interactive voice response system to the central randomisation centre, with a central stratified permuted block randomisation procedure. We randomly assigned patients with resected (R0) stage III disease (1:1) to receive 12 cycles of FOLFOX4 twice a week with or without cetuximab. Patients were stratified by N-status (N1 vs N2), T-status (T1-3 vs T4), and obstruction or perforation status (no obstruction and no perforation vs obstruction or perforation or both). A protocol amendment (applied in June, 2008, after 2096 patients had been randomly assigned to treatment-restricted enrolment to patients with tumours wild-type at codons 12 and 13 in exon 2 of the KRAS gene (KRAS exon 2 wild-type). The primary endpoint was DFS. Analysis was intention to treat in all patients with KRAS exon 2 wild-type tumours. The study is registered at EudraCT, number 2005-003463-23. Between Dec 22, 2005, and Nov 5, 2009, 2559 patients from 340 sites in Europe were randomly assigned. Of these patients, 1602 had KRAS exon 2 wild-type tumours (intention-to-treat population), 791 in the FOLFOX4 plus cetuximab group and 811 in the FOLFOX4 group. Median follow-up was 3·3 years (IQR 3·2–3·4). In the experimental and control groups, DFS was similar in the intention-to-treat population (hazard ratio [HR] 1·05; 95% CI 0·85–1·29; p=0·66), and in patients with KRAS exon 2/BRAF wild-type (n=984, HR 0·99; 95% CI 0·76–1·28) or KRAS exon 2-mutated tumours (n=742, HR 1·06; 95% CI 0·82–1·37). We noted heterogeneous responses to the addition of cetuximab in preplanned subgroup analyses. Grade 3 or 4 acne-like rash (in 209 of 785 patients [27%] vs four of 805 [<1%]), diarrhoea (113 [14%] vs 70 [9%]), mucositis (63 [8%] vs 10 [1%]), and infusion-related reactions (55 [7%] vs 30 [4%]) were more frequent in patients treated with FOLFOX4 plus cetuximab than in those patients who received FOLFOX4 alone. The addition of cetuximab to FOLFOX4 did not improve DFS compared with FOLFOX4 alone in patients with KRAS exon 2 wild-type resected stage III colon cancer. This trial cannot conclude on the benefit of cetuximab in the studied population, but the heterogeneity of response suggests that further investigation of the role of FOLFOX4 plus cetuximab in specific patient subgroups is warranted. Fédération Francophone de Cancérologie Digestive (FFCD), Merck KGaA, and Sanofi-Aventis.

BackgroundTarget trial emulation (TTE) offers a formal framework for causal inference using observational data, but its validity must be evaluated in each research domain by replicating randomised clinical trials (RCTs). We aimed to replicate eight RCTs evaluating the efficacy of disease-modifying therapies (DMTs) in multiple sclerosis (MS) using French registry data.MethodsThis multicentre, retrospective, observational study was conducted using data extracted in December 2023 from the Observatoire Français de la Sclérose en Plaques (OFSEP) database. For each emulated trial, patients were included when they initiated one of the DMT evaluated in the corresponding RCT and met its inclusion criteria. Clinical outcomes were the annualised relapse rate and 3-month confirmed Expanded Disability Status Scale progression. Radiological outcomes were new/enlarged T2-lesions and new gadolinium-enhanced T1-lesions on a brain MRI. A targeted maximum likelihood estimator was used to estimate the treatment effect adjusted for confounding factors between groups and corrected for censoring and missing outcome assessment.Results14 111 patients were included in eight emulated trials: ASSESS (fingolimod vs glatiramer acetate), BEYOND (interferon beta vs glatiramer acetate), CONFIRM (dimethyl fumarate (DMF) vs glatiramer acetate), OPERA (ocrelizumab vs interferon beta), REGARD (interferon beta vs glatiramer acetate), RIFUND-MS (rituximab vs DMF), TENERE (teriflunomide vs interferon beta) and TRANSFORMS (fingolimod vs interferon beta). Treatment effects estimated in emulated trials were concordant with RCT findings in seven of eight trials for relapse rate, and in all six trials assessing disability progression. Radiological outcomes were more challenging to replicate; concordance was achieved in three of five trials for new T2-lesions, and one of four trials for new gadolinium-enhanced T1-lesions.ConclusionThe combined use of a TTE methodology and high-quality registry data is a valid tool to evaluate treatment effectiveness in MS.

INTRODUCTION:When initial resection of rectal neuroendocrine tumors (r-NETs) is not R0, persistence of local residue could lead to disease recurrence. This study aimed to evaluate the interest of systematic resection of non-R0 r-NET scars.METHODS:Retrospective analysis of all the consecutive endoscopic revisions and resections of the scar after non-R0 resections of r-NETs.RESULTS:A total of 100 patients were included. Salvage endoscopic procedure using endoscopic submucosal dissection or endoscopic full-thickness resection showed an R0 rate of near 100%. Residual r-NET was found in 43% of cases.DISCUSSION:In case of non-R0 resected r-NET, systematic scar resection by endoscopic full-thickness resection or endoscopic submucosal dissection seems necessary.

Background/Objectives: Degenerative cervical myelopathy (DCM) is the leading cause of functional disabilities of spinal origin in people over 50 years old. The objective of the present study was to establish a multi-parametric weighted scoring system that is easy to use in daily practice, based on the most significant MRI signs and correlated as strongly as possible with the clinical presentation (mJOA)—we call this system the SIMS or Severity on Imaging Myelopathy Score. Methods: Ninety-nine patients who underwent clinical and radiological evaluation by mJOA and MRI between January 2015 and March 2021 were retrospectively included. The variables included in the score were the Fujiwara ratio, the T2-weighted intramedullary hyperintensity, the aspect of the peri-medullary fluid cisterns, the Torg–Pavlov ratio, the local kyphosis and the number of stenotic levels. Each variable was first correlated to the mJOA score for each patient, making it possible to construct the final SIMS at the end, and validate it by comparison with mJOA scores. Results: The variables that were significantly correlated with one another were the T2-weighted intramedullary hyperintensity, the reduction in peri-medullary fluid spaces and the number of stenotic levels (p < 0.05). Then, points were assigned to each variable according to their relative importance and made it possible to construct the definitive SIMS. The final Spearman correlation coefficient between the SIMS and the mJOA score was −0.747. Conclusions: This work showed that this new multi-parametric MRI-based scoring system represents a consistent means to characterize the degree of severity of degenerative cervical myelopathy.

The prevalence of Ebola virus infection among people who have been in contact with patients with Ebola virus disease remains unclear, but is essential to understand the dynamics of transmission. This study aimed to identify risk factors for seropositivity and to estimate the prevalence of Ebola virus infection in unvaccinated contact persons. In this retrospective, cross-sectional observational study, we recruited individuals between May 12, 2016, and Sept 8, 2017, who had been in physical contact with a patient with Ebola virus disease, from four medical centres in Guinea (Conakry, Macenta, N'zérékoré, and Forécariah). Contact persons had to be 7 years or older and not diagnosed with Ebola virus disease. Participants were selected through the Postebogui survivors' cohort. We collected self-reported information on exposure and occurrence of symptoms after exposure using a questionnaire, and tested antibody response against glycoprotein, nucleoprotein, and 40-kDa viral protein of Zaire Ebola virus by taking a blood sample. The prevalence of Ebola virus infection was estimated with a latent class model. 1721 contact persons were interviewed and given blood tests, 331 of whom reported a history of vaccination so were excluded, resulting in a study population of 1390. Symptoms were reported by 216 (16%) contact persons. The median age of participants was 26 years (range 7–88) and 682 (49%) were male. Seropositivity was identified in 18 (8·33%, 95% CI 5·01–12·80) of 216 paucisymptomatic contact persons and 39 (3·32%, 5·01–12·80) of 1174 (2–4) asymptomatic individuals (p=0·0021). Seropositivity increased with participation in burial rituals (adjusted odds ratio [aOR] 2·30, 95% CI 1·21–4·17; p=0·0079) and exposure to blood or vomit (aOR 2·15, 1·23–3·91; p=0·0090). Frequency of Ebola virus infection varied from 3·06% (95% CI 1·84–5·05) in asymptomatic contact persons who did not participate in burial rituals to 5·98% (2·81–8·18) in those who did, and from 7·17% (3·94–9·09) in paucisymptomatic contact persons who did not participate in burial rituals to 17·16% (12·42–22·31) among those who did. This study provides a new assessment of the prevalence of Ebola virus infection among contact persons according to exposure, provides evidence for the occurrence of paucisymptomatic cases, and reinforces the importance of closely monitoring at-risk contact persons. Institut National de la Santé et de la Recherche Médicale, Reacting, the French Ebola Task Force, Institut de Recherche pour le Développement, and Montpellier University Of Excellence-University of Montpellier.

Rationale Central neuropathic pain resulting from spinal cord injury is notoriously debilitating and difficult to treat with few currently available treatments. A novel molecule with intrathecal administration: Ziconotide has been approved for treatment of refractory neuropathic pain in general . It acts as a presynaptic calcium channel blocker. A pilot study has shown its potential in SCI neuropathic pain patients. Objective The aim of this study is to determine the long-term (6 months) efficacy of chronic intrathecal ziconotide for the treatment of neuropathic SCI pain. Study design Multicenter, Randomized, Comparative, Placebo controlled, Double blind clinical trial, with a crossover of random alternated periods of 6 months (placebo or ITZ) for a total of 15 months including a total of 44 patients. Study population • Patients with SCI of various etiologies exhibiting neuropathic pain refractory to non-invasive treatments. • > 18 years. Intervention Intrathecal administration of ziconotide via an implanted pump. Study outcomes Primary study outcome Difference in pain intensity for all patients between effective treatment and placebo periods. Secondary study outcomes 1. Continuous evaluation of pain intensity. 2. Percentage of patients with at least 30% of pain reduction. 3. Satisfaction level of the patient pain relief. 4. Declarations of serious adverse events. 5. Duration and intensity of spontaneous and provoked pain. 6. Quality of life. 7. Patient global impression of change. 8. Quantification of daily dosages of analgesic drug intake. 9. Long term memory and neurocognitive effects. 10. Assessment of the patient’s physical and emotional distress. Nature and extent of the burden and risks associated with participation, benefit, and group relatedness Participation in this study is in accordance with current treatment protocols for SCI neuropathic pain in France therefore it proposes a treatment that would currently be considered regular practice even though no RCT evidence is yet available. The study gives patients the advantage of directly testing versus placebo a treatment that otherwise entails significant constraints. A Data Safety Monitoring board (DSMB) will be created for continuous safety analysis. Furthermore, patients will be followed in specialized pain centers offering the possibility of continuing their treatment after the study period.

Background Attention-deficit/hyperactivity disorder (ADHD) affects approximately 5% of children globally, with symptoms often persisting into adulthood. While pharmacological interventions are commonly employed for management, understanding the optimal dosing for efficacy and tolerability remains crucial. This study aims to conduct a dose–response network meta-analysis to estimate the efficacy of pharmacological treatments across different doses, aiming to inform clinical decision-making and improve treatment outcomes. Methods This updated systematic review will include randomized controlled trials evaluating ADHD medication efficacy in children, adolescents, and adults. An updated search from a 2018 NMA will be conducted across multiple electronic databases with no language restrictions, using specific eligibility criteria focused on randomized controlled trials. The primary outcome will assess the severity of ADHD core symptoms, while secondary outcomes will consider treatment tolerability. A dose–response Bayesian hierarchical model will be used to estimate dose–response curves for each medication, identifying optimal dosing strategies. Discussion With this dose–response network meta-analysis, we aim to better understand the dose–response relationship of pharmacological treatment in ADHD, which could help clinician to the identification of optimal doses. Systematic review registration OSF https://doi.org/10.17605/OSF.IO/3MY4A .

TGF-β signaling is involved in pancreatic ductal adenocarcinoma (PDAC) tumorigenesis, representing one of the four major pathways genetically altered in 100% of PDAC cases. TGF-β exerts complex and pleiotropic effects in cancers, notably via the activation of SMAD pathways, predominantly SMAD2/3/4. Though SMAD2 and 3 are rarely mutated in cancers, SMAD4 is lost in about 50% of PDAC, and the role of SMAD2/3 in a SMAD4-null context remains understudied. We herein provide evidence of a SMAD2/3 oncogenic effect in response to TGF-β1 in SMAD4-null human PDAC cancer cells. We report that inactivation of SMAD2/3 in SMAD4-negative PDAC cells compromises TGF-β-driven collective migration mediated by FAK and Rho/Rac signaling. Moreover, RNA-sequencing analyses highlight a TGF-β gene signature related to aggressiveness mediated by SMAD2/3 in the absence of SMAD4. Using a PDAC patient cohort, we reveal that SMAD4-negative tumors with high levels of phospho-SMAD2 are more aggressive and have a poorer prognosis. Thus, loss of SMAD4 tumor suppressive activity in PDAC leads to an oncogenic gain-of-function of SMAD2/3, and to the onset of associated deleterious effects. In pancreatic ductal adenocarcinoma cells and patient tissue, SMAD2/3 is shown to mediate oncogenic effects of TGF-β in the absence of SMAD4.