Publications by authors named "Christine Binquet"

136 Publications

Prediction of Cardiovascular Parameters With Supervised Machine Learning From Singapore "I" Vessel Assessment and OCT-Angiography: A Pilot Study.

Transl Vis Sci Technol 2021 Nov;10(13):20

Université Paris-Saclay, CNRS, Institut des Neurosciences Paris-Saclay, Gif-sur-Yvette, France.

Purpose: Assessment of cardiovascular risk is the keystone of prevention in cardiovascular disease. The objective of this pilot study was to estimate the cardiovascular risk score (American Hospital Association [AHA] risk score, Syntax risk, and SCORE risk score) with machine learning (ML) model based on retinal vascular quantitative parameters.

Methods: We proposed supervised ML algorithm to predict cardiovascular parameters in patients with cardiovascular diseases treated in Dijon University Hospital using quantitative retinal vascular characteristics measured with fundus photography and optical coherence tomography - angiography (OCT-A) scans (alone and combined). To describe retinal microvascular network, we used the Singapore "I" Vessel Assessment (SIVA), which extracts vessel parameters from fundus photography and quantitative OCT-A retinal metrics of superficial retinal capillary plexus.

Results: The retinal and cardiovascular data of 144 patients were included. This paper presented a high prediction rate of the cardiovascular risk score. By means of the Naïve Bayes algorithm and SIVA + OCT-A data, the AHA risk score was predicted with 81.25% accuracy, the SCORE risk with 75.64% accuracy, and the Syntax score with 96.53% of accuracy.

Conclusions: Performance of these algorithms demonstrated in this preliminary study that ML algorithms applied to quantitative retinal vascular parameters with SIVA software and OCT-A were able to predict cardiovascular scores with a robust rate. Quantitative retinal vascular biomarkers with the ML strategy might provide valuable data to implement predictive model for cardiovascular parameters.

Translational Relevance: Small data set of quantitative retinal vascular parameters with fundus and with OCT-A can be used with ML learning to predict cardiovascular parameters.
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http://dx.doi.org/10.1167/tvst.10.13.20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8590163PMC
November 2021

Cognitive assessment scale for stroke patients (CASP): A multicentric validation study.

Ann Phys Rehabil Med 2021 Nov 17;65(3):101594. Epub 2021 Nov 17.

Centre d'Investigation Clinique CIC 1432 and University of Bourgogne-Franche-Comté, France.

Background: The Mini Mental State Examination and Montreal Cognitive Assessment are commonly used as short screening batteries for assessing cognitive impairment after stroke. However, aphasia or hemispatial neglect may interfere with the results. For this reason, we developed the Cognitive Assessment scale for Stroke Patients (CASP), which takes these conditions into consideration and previously demonstrated its superiority over these scales in terms of feasibility.

Objectives: Our goal was to verify the psychometric properties of the (original) French version of the CASP.

Methods: We included 201 patients with a recent first hemispheric stroke and 50 controls. Stroke patients were examined 4 times (visit 1 [V1] to visit 4 [V4]) in the subacute post-stroke phase. The structural validity of the CASP was studied by principal factorial analysis, convergent validity by comparison with several variables including a comprehensive neuropsychological assessment, divergent validity by comparison with the total score between stroke patients and controls, and sub-scores between right and left stroke. Internal consistency, reproducibility and sensitivity to change were assessed. We propose the Minimal Clinically Important Difference (MCID) value and a pathological threshold as well as a threshold to predict cognitive change between V1 and V4.

Results: Of the 201 participants included (63% male; mean [SD] age 63 [13] years), CASP data were available for 199/150/133/93 at V1/V2/V3/V4, respectively. CASP has a one-dimensional structure. The hypotheses of convergent/divergent validities were confirmed. Internal consistency was good and reliability excellent. Responsiveness was small to moderate, but the MCID could still be estimated. We discuss the choice of a pathological threshold and a predictive threshold of V1 over V4.

Conclusions: CASP has good psychometric properties for screening cognitive impairment in the subacute post-stroke phase, which is consistent with its Italian and Korean versions. It can be used for patients with severe motor aphasia or left hemispatial neglect but not in case of severe oral comprehension or visual impairment.
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http://dx.doi.org/10.1016/j.rehab.2021.101594DOI Listing
November 2021

Analysis and quantification of female and male contributions to the first stages of embryonic kinetics: study from a time-lapse system.

J Assist Reprod Genet 2021 Oct 21. Epub 2021 Oct 21.

Laboratoire de Biologie de La Reproduction, Hôpital François Mitterrand, Université de Bourgogne, Dijon, France.

Purpose: The few studies that examined the effect of male and/or female features on early embryo development, notably using the time-lapse system (TL), reported conflicting results. This can be explained by the small number of studies using an adapted model.

Methods: We used two original designs to study the female and male effects on embryo development: (1) based on embryos from donor oocytes (TL-DO), and (2) from donor sperm (TL-DS). Firstly, we analyzed the female and male similarities using an ad hoc intraclass correlation coefficient (ICC), then we completed the analysis with a multivariable model to assess the association between both male and female factors, and early embryo kinetics. A total of 572 mature oocytes (TL-DO: 293; TL-DS: 279), fertilized by intracytoplasmic sperm injection (ICSI) and incubated in a TL (Embryoscope®) were included from March 2013 to April 2019; 429 fertilized oocytes (TL-DO: 212; TL-DS: 217) were assessed. The timings of the first 48 h have been analyzed.

Results: The similarities in the timings thought to be related to the female component were significant: (ICC in both DO-DS designs respectively: tPB2: 9-18%; tPNa: 16-21%; tPNf: 40-26%; t2: 38-24%; t3: 15-20%; t4: 21-32%). Comparatively, those related to male were lower. Surprisingly after multivariable analyses, no intrinsic female factors were clearly identified. However, in TL-DO design, oligozoospermia was associated with a tendency to longer timings, notably for tPB2 (p = 0.026).

Conclusion: This study quantifies the role of the oocyte in the first embryo cleavages, but without identified specific female factors. However, it also highlights that sperm may have an early embryonic effect.
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http://dx.doi.org/10.1007/s10815-021-02336-5DOI Listing
October 2021

Do frozen embryo transfers modify the epigenetic control of imprinted genes and transposable elements in newborns compared with fresh embryo transfers and natural conceptions?

Fertil Steril 2021 Dec 16;116(6):1468-1480. Epub 2021 Sep 16.

Université Bourgogne Franche-Comté-Equipe Génétique des Anomalies du Développement (GAD), INSERM UMR1231, Dijon, France; Centre Hospitalier Universitaire Dijon-Bourgogne, Laboratoire de Biologie de la Reproduction-CECOS, Dijon, France. Electronic address:

Objective: To determine whether the epigenetic control of imprinted genes (IGs) and transposable elements (TEs) differs at birth between fresh or frozen embryo transfers and natural conceptions.

Design: Prospective study.

Setting: University hospital.

Patient(s): A total of 202 singleton births were divided into three groups: 84 natural pregnancies (controls), 66 in vitro fertilization/intracytoplasmic sperm injection with fresh embryo transfers, and 52 vitro fertilization/intracytoplasmic sperm injection with frozen embryo transfers.

Intervention(s): None.

Main Outcome Measure(s): Pyrosequencing was used to assess the DNA methylation profiles of three IGs (H19/IGF2:IG-DMR [two sequences], KCNQ1OT1:TSS-DMR, and SNURF:TSS-DMR) and two TEs (LINE-1 and HERV-FRD) in cord blood and placenta. The quantitative reverse transcriptase polymerase chain reaction was used to study the transcription of three IGs (H19, KCNQ1, and SNRPN) and two TEs (LINE-1 and ORF2).

Result(s): After adjustment, the placental DNA methylation levels of H19/IGF2 were lower in the fresh embryo transfer group than in the control (H19/IGF2-seq1) and frozen embryo transfer (H19/IGF2-seq2) groups. The DNA methylation rate for LINE-1 was lower in placentas from the fresh embryo transfer group than in placentas from the control and frozen embryo transfer groups and for HERV-FRD compared with controls. In cord blood, DNA methylation levels were not significantly associated with the mode of conception. The relative expression of LINE-1 and ORF2 was decreased in both cord blood and placental tissues from fresh embryo transfer conceptions compared with natural conceptions and frozen embryo transfer conceptions.

Conclusion(s): Compared with natural conceptions and frozen embryo transfers, fresh embryo transfers were associated with methylation and/or transcription changes in some TEs and IGs, mostly in placental samples, which could indicate altered placental epigenetic regulation resulting from ovarian stimulation protocols.
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http://dx.doi.org/10.1016/j.fertnstert.2021.08.014DOI Listing
December 2021

Specific Features of the Coagulopathy Signature in Severe COVID-19 Pneumonia.

Front Med (Lausanne) 2021 4;8:675191. Epub 2021 Aug 4.

Infectious Diseases Department, Dijon Bourgogne University Hospital, Dijon, France.

COVID-19 displays distinct characteristics that suggest a unique pathogenesis. The objective of this study was to compare biomarkers of coagulopathy and outcomes in COVID-19 and non-COVID-19 patients with severe pneumonia. Thirty-six non-COVID-19 and 27 COVID-19 non-immunocompromised patients with severe pneumonia were prospectively enrolled, most requiring intensive care. Clinical and biological characteristics (including plasma biomarkers of coagulopathy) were compared. At similar baseline severity, COVID-19 patients required mechanical ventilation (MV) for significantly longer than non-COVID-19 patients ( = 0.0049) and more frequently developed venous thrombotic complications ( = 0.031). COVID-19 patients had significantly higher plasma concentrations of soluble VCAM1 (sVCAM1) (5,739 ± 3,293 vs. 3,700 ± 2,124 ng/ml; = 0.009), but lower levels of D-dimers, vWF-A2, sICAM1, sTREM1, VEGF, and P-selectin, compared to non-COVID-19 patients. Principal component analysis identified two main patterns, with a clear distinction between non-COVID-19 and COVID-19 patients. Multivariable regression analysis confirmed that sVCAM1 rising levels were independently associated with a longer duration of MV. Finally, we identified close correlations between sVCAM1 and some features of COVID-19 immune dysregulation (ie. CXCL10, GM-CSF, and IL-10). We identified specific features of the coagulopathy signature in severe COVID-19 patients, with higher plasma sVCAM1 levels, that were independently associated with the longer duration of mechanical ventilation. ClinicalTrials.gov, identifier: NCT03505281.
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http://dx.doi.org/10.3389/fmed.2021.675191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8371474PMC
August 2021

10 years of CEMARA database in the AnDDI-Rares network: a unique resource facilitating research and epidemiology in developmental disorders in France.

Orphanet J Rare Dis 2021 08 4;16(1):345. Epub 2021 Aug 4.

Centre de Référence Anomalies du Développement et Syndromes Malformatifs, CHU de Dijon, Dijon, France.

Background: In France, the Ministry of Health has implemented a comprehensive program for rare diseases (RD) that includes an epidemiological program as well as the establishment of expert centers for the clinical care of patients with RD. Since 2007, most of these centers have entered the data for patients with developmental disorders into the CEMARA population-based registry, a national online data repository for all rare diseases. Through the CEMARA web portal, descriptive demographic data, clinical data, and the chronology of medical follow-up can be obtained for each center. We address the interest and ongoing challenges of this national data collection system 10 years after its implementation.

Methods: Since 2007, clinicians and researchers have reported the "minimum dataset (MDS)" for each patient presenting to their expert center. We retrospectively analyzed administrative data, demographic data, care organization and diagnoses.

Results: Over 10 years, 228,243 RD patients (including healthy carriers and family members for whom experts denied any suspicion of RD) have visited an expert center. Among them, 167,361 were patients affected by a RD (median age 11 years, 54% children, 46% adults, with a balanced sex ratio), and 60,882 were unaffected relatives (median age 37 years). The majority of patients (87%) were seen no more than once a year, and 52% of visits were for a diagnostic procedure. Among the 2,869 recorded rare disorders, 1,907 (66.5%) were recorded in less than 10 patients, 802 (28%) in 10 to 100 patients, 149 (5.2%) in 100 to 1,000 patients, and 11 (0.4%) in > 1,000 patients. Overall, 45.6% of individuals had no diagnosis and 6.7% had an uncertain diagnosis. Children were mainly referred by their pediatrician (46%; n = 55,755 among the 121,136 total children referrals) and adults by a medical specialist (34%; n = 14,053 among the 41,564 total adult referrals). Given the geographical coverage of the centers, the median distance from the patient's home was 25.1 km (IQR = 6.3 km-64.2 km).

Conclusions: CEMARA provides unprecedented support for epidemiological, clinical and therapeutic studies in the field of RD. Researchers can benefit from the national scope of CEMARA data, but also focus on specific diseases or patient subgroups. While this endeavor has been a major collective effort among French RD experts to gather large-scale data into a single database, it provides tremendous potential to improve patient care.
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http://dx.doi.org/10.1186/s13023-021-01957-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8335940PMC
August 2021

Care management in a French cohort with Down syndrome from the AnDDI-Rares/CNSA study.

Eur J Med Genet 2021 Oct 15;64(10):104290. Epub 2021 Jul 15.

Centre de Référence Anomalies du Développement et Syndromes Malformatifs Ile de France, APHP Robert Debré, Paris, France.

Down syndrome (DS) is a genetic neurodevelopmental disorder. In individuals with DS, a multidisciplinary approach to care is required to prevent multiple medical complications. The aim of this study was to describe the rehabilitation, medical care, and educational and social support provided to school-aged French DS patients with varying neuropsychological profiles. A mixed study was conducted. Quantitative data were obtained from a French multicentre study that included patients aged 4-20 years with diverse genetic syndromes. Qualitative data were collected by semi-structured face-to-face interviews and focus groups. Ninety-five DS subjects with a mean age of 10.9 years were included. Sixty-six per cent had a moderate intellectual disability (ID) and 18.9% had a severe ID. Medical supervision was generally multidisciplinary but access to medical specialists was often difficult. In terms of education, 94% of children under the age of six were in typical classes. After the age of 15, 75% were in medico-social institutions. Analysis of multidisciplinary rehabilitation conducted in the public and private sectors revealed failure to access physiotherapy, psychomotor therapy and occupational therapy, but not speech therapy. The main barrier encountered by patients was the difficulty accessing appropriate facilities due to a lack of space and long waiting lists. In conclusion, children and adolescents with DS generally received appropriate care. Though the management of children with DS has been improved considerably, access to health facilities remains inadequate.
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http://dx.doi.org/10.1016/j.ejmg.2021.104290DOI Listing
October 2021

Mental health and stress among ICU healthcare professionals in France according to intensity of the COVID-19 epidemic.

Ann Intensive Care 2021 Jun 4;11(1):90. Epub 2021 Jun 4.

Service de Médecine Intensive Réanimation-Unité de Sevrage Ventilatoire et Réhabilitation, CH de Bethune, Bethune, France.

Background: We investigated the impact of the COVID-19 crisis on mental health of professionals working in the intensive care unit (ICU) according to the intensity of the epidemic in France.

Methods: This cross-sectional survey was conducted in 77 French hospitals from April 22 to May 13 2020. All ICU frontline healthcare workers were eligible. The primary endpoint was the mental health, assessed using the 12-item General Health Questionnaire. Sources of stress during the crisis were assessed using the Perceived Stressors in Intensive Care Units (PS-ICU) scale. Epidemic intensity was defined as high or low for each region based on publicly available data from Santé Publique France. Effects were assessed using linear mixed models, moderation and mediation analyses.

Results: In total, 2643 health professionals participated; 64.36% in high-intensity zones. Professionals in areas with greater epidemic intensity were at higher risk of mental health issues (p < 0.001), and higher levels of overall perceived stress (p < 0.001), compared to low-intensity zones. Factors associated with higher overall perceived stress were female sex (B = 0.13; 95% confidence interval [CI] = 0.08-0.17), having a relative at risk of COVID-19 (B = 0.14; 95%-CI = 0.09-0.18) and working in high-intensity zones (B = 0.11; 95%-CI = 0.02-0.20). Perceived stress mediated the impact of the crisis context on mental health (B = 0.23, 95%-CI = 0.05, 0.41) and the impact of stress on mental health was moderated by positive thinking, b = - 0.32, 95% CI = - 0.54, - 0.11.

Conclusion: COVID-19 negatively impacted the mental health of ICU professionals. Professionals working in zones where the epidemic was of high intensity were significantly more affected, with higher levels of perceived stress. This study is supported by a grant from the French Ministry of Health (PHRC-COVID 2020).
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http://dx.doi.org/10.1186/s13613-021-00880-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8177250PMC
June 2021

Are adipokines the missing link between obesity, immune response, and outcomes in severe COVID-19?

Int J Obes (Lond) 2021 09 31;45(9):2126-2131. Epub 2021 May 31.

Infectious Diseases Department, Dijon Bourgogne University Hospital, Dijon, France.

Introduction: Obesity is commonly reported in COVID-19 patients and is associated with poorer outcomes. It is suggested that leptin could be the missing link between obesity and severe COVID-19. Our study aimed to unravel the link between adipokines, COVID-19 status, immune response, and outcomes in severe pneumonia.

Methods: In this prospective observational single-center study, 63 immunocompetent patients with severe pneumonia (36 non-COVID-19 and 27 COVID-19) were enrolled, most required intensive care. Clinical and biological characteristics (glucose metabolism, plasma adipokines, and cytokine concentrations) and outcomes were compared.

Results: At similar baseline severity, COVID-19 patients required mechanical ventilation for significantly longer than non-COVID-19 patients (p = 0.0049). Plasma concentrations of leptin and adiponectin were respectively positively and negatively correlated with BMI and glucose metabolism (glycemia and insulinemia), but not significantly different between the two groups. Leptin levels were negatively correlated with IL-1β and IL-6, but the adipokines were not correlated with most other inflammatory mediators, baseline severity (SOFA score), or the duration of mechanical ventilation.

Conclusion: Adipokine levels were correlated with BMI but not with most inflammatory mediators, severity, or outcomes in severe pneumonia, regardless of the origin. The link between obesity, dysregulated immune response, and life-threatening COVID-19 requires further investigation.

Clinical Trial: ClinicalTrials.gov: NCT03505281.
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http://dx.doi.org/10.1038/s41366-021-00868-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166380PMC
September 2021

High plasma concentration of non-esterified polyunsaturated fatty acids is a specific feature of severe COVID-19 pneumonia.

Sci Rep 2021 05 24;11(1):10824. Epub 2021 May 24.

Univ. Bourgogne Franche-Comté, LNC UMR1231, 21000, Dijon, France.

COVID-19 pneumonia has specific features and outcomes that suggests a unique immunopathogenesis. Severe forms of COVID-19 appear to be more frequent in obese patients, but an association with metabolic disorders is not established. Here, we focused on lipoprotein metabolism in patients hospitalized for severe pneumonia, depending on COVID-19 status. Thirty-four non-COVID-19 and 27 COVID-19 patients with severe pneumonia were enrolled. Most of them required intensive care. Plasma lipid levels, lipoprotein metabolism, and clinical and biological (including plasma cytokines) features were assessed. Despite similar initial metabolic comorbidities and respiratory severity, COVID-19 patients displayed a lower acute phase response but higher plasmatic concentrations of non-esterified fatty acids (NEFAs). NEFA profiling was characterised by higher level of polyunsaturated NEFAs (mainly linoleic and arachidonic acids) in COVID-19 patients. Multivariable analysis showed that among severe pneumonia, COVID-19-associated pneumonia was associated with higher NEFAs, lower apolipoprotein E and lower high-density lipoprotein cholesterol concentrations, independently of body mass index, sequential organ failure (SOFA) score, and C-reactive protein levels. NEFAs and PUFAs concentrations were negatively correlated with the number of ventilator-free days. Among hospitalized patients with severe pneumonia, COVID-19 is independently associated with higher NEFAs (mainly linoleic and arachidonic acids) and lower apolipoprotein E and HDL concentrations. These features might act as mediators in COVID-19 pathogenesis and emerge as new therapeutic targets. Further investigations are required to define the role of NEFAs in the pathogenesis and the dysregulated immune response associated with COVID-19.Trial registration: NCT04435223.
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http://dx.doi.org/10.1038/s41598-021-90362-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144366PMC
May 2021

Pancreatoduodenectomy for Neuroendocrine Tumors in Patients with Multiple Endocrine Neoplasia Type 1: An AFCE (Association Francophone de Chirurgie Endocrinienne) and GTE (Groupe d'étude des Tumeurs Endocrines) Study.

World J Surg 2021 06 1;45(6):1794-1802. Epub 2021 Mar 1.

Department of Digestive and Endocrine Surgery, Dijon University Hospital, University of Burgundy, Dijon, France.

Aim: To assess postoperative complications and control of hormone secretions following pancreatoduodenectomy (PD) performed on multiple endocrine neoplasia type 1 (MEN1) patients with duodenopancreatic neuroendocrine tumors (DP-NETs).

Background: The use of PD to treat MEN1 remains controversial, and evaluating the right place of PD in MEN1 disease makes sense.

Methods: Thirty-one MEN1 patients from the Groupe d'étude des Tumeurs Endocrines MEN1 cohort who underwent PD for DP-NETs between 1971 and 2013 were included. Early and late postoperative complications, secretory control and overall survival were analyzed.

Results: Indication for surgery was: Zollinger-Ellison syndrome (n = 18; 58%), nonfunctioning tumor (n = 9; 29%), insulinoma (n = 2; 7%), VIPoma (n = 1; 3%) and glucagonoma (n = 1; 3%). Mean follow-up was 141 months (range 0-433). Pancreatic fistulas occurred in 5 patients (16.1%), distant metastases in 6 (mean onset of 43 months; range 13-110 months), postoperative diabetes mellitus in 7 (22%), and pancreatic exocrine insufficiency in 6 (19%). Five-year overall survival was 93.3% [CI 75.8-98.3] and ten-year overall survival was 89.1% [CI 69.6-96.4]. After a mean follow-up of 151 months (range 0-433), the biochemical cure rate for MEN-1 related gastrinomas was 61%.

Conclusion: In MEN1 patients, pancreatoduodenectomy can be used to control hormone secretions (gastrin, glucagon, VIP) and to remove large NETs. PD was found to control gastrin secretions in about 60% of cases.
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http://dx.doi.org/10.1007/s00268-021-06005-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093175PMC
June 2021

Impact of time-varying cumulative bevacizumab exposures on survival: re-analysis of data from randomized clinical trial in patients with metastatic colo-rectal cancer.

BMC Med Res Methodol 2021 01 9;21(1):14. Epub 2021 Jan 9.

INSERM, U1231, EPICAD team, Equipe EPICAD, 7, Bld Jeanne d'Arc, Dijon, France.

Background: As cancer treatment, biotherapies can be as effective as chemotherapy while reducing the risk of secondary effects, so that they can be taken over longer periods than conventional chemotherapy. Thus, some trials aimed at assessing the benefit of maintaining biotherapies during chemotherapy-free intervals (CFI). For example, the recent PRODIGE9 trial assessed the effect of maintaining bevacizumab during CFI in metastatic colorectal cancer (mCRC) patients. However, its analysis was hindered by a small difference of exposure to the treatment between the randomized groups and by a large proportion of early drop outs, leading to a potentially unbalanced distribution of confounding factors among the trial completers. To address these limitations, we re-analyzed the PRODIGE9 data to assess the effects of different exposure metrics on all-cause mortality of patients with mCRC using methods originally developed for observational studies.

Methods: To account for the actual patterns of drug use by individual patients and for possible cumulative effects, we used five alternative time-varying exposure metrics: (i) cumulative dose, (ii) quantiles of the cumulative dose, (iii) standardized cumulative dose, (iv) Theoretical Blood Concentration (TBC), and (v) Weighted Cumulative Exposure (WCE). The last two metrics account for the timing of drug use. Treatment effects were estimated using adjusted Hazard Ratio from multivariable Cox proportional hazards models.

Results: After excluding 112 patients who died during the induction period, we analyzed data on 382 patients, among whom 320 (83.8%) died. All time-varying exposures improved substantially the model's fit to data, relative to using only the time-invariant randomization group. All exposures indicated a protective effect for higher cumulative bevacizumab doses. The best-fitting WCE and TBC models accounted for both the cumulative effects and the different impact of doses taken at different times.

Conclusions: All time-varying analyses, regardless of the exposure metric used, consistently suggested protective effects of higher cumulative bevacizumab doses. However, the results may partly reflect the presence of a confusion bias. Complementing the main ITT analysis of maintenance trials with an analysis of potential cumulative effects of treatment actually taken can provide new insights, but the results must be interpreted with caution because they do not benefit from the randomization.

Trial Registration: clinicaltrials.gov, NCT00952029 . Registered 8 August 2009.
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http://dx.doi.org/10.1186/s12874-020-01202-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796644PMC
January 2021

The dysregulated innate immune response in severe COVID-19 pneumonia that could drive poorer outcome.

J Transl Med 2020 12 3;18(1):457. Epub 2020 Dec 3.

Infectious Diseases Department, Dijon Bourgogne University Hospital , 14 rue Paul Gaffarel, 21079, Dijon, France.

Background: Although immune modulation is a promising therapeutic avenue in coronavirus disease 2019 (COVID-19), the most relevant targets remain to be found. COVID-19 has peculiar characteristics and outcomes, suggesting a unique immunopathogenesis.

Methods: Thirty-six immunocompetent non-COVID-19 and 27 COVID-19 patients with severe pneumonia were prospectively enrolled in a single center, most requiring intensive care. Clinical and biological characteristics (including T cell phenotype and function and plasma concentrations of 30 cytokines) and outcomes were compared.

Results: At similar baseline respiratory severity, COVID-19 patients required mechanical ventilation for significantly longer than non-COVID-19 patients (15 [7-22] vs. 4 (0-15) days; p = 0.0049). COVID-19 patients had lower levels of most classical inflammatory cytokines (G-CSF, CCL20, IL-1β, IL-2, IL-6, IL-8, IL-15, TNF-α, TGF-β), but higher plasma concentrations of CXCL10, GM-CSF and CCL5, compared to non-COVID-19 patients. COVID-19 patients displayed similar T-cell exhaustion to non-COVID-19 patients, but with a more unbalanced inflammatory/anti-inflammatory cytokine response (IL-6/IL-10 and TNF-α/IL-10 ratios). Principal component analysis identified two main patterns, with a clear distinction between non-COVID-19 and COVID-19 patients. Multivariate regression analysis confirmed that GM-CSF, CXCL10 and IL-10 levels were independently associated with the duration of mechanical ventilation.

Conclusion: We identified a unique cytokine response, with higher plasma GM-CSF and CXCL10 in COVID-19 patients that were independently associated with the longer duration of mechanical ventilation. These cytokines could represent the dysregulated immune response in severe COVID-19, as well as promising therapeutic targets. ClinicalTrials.gov: NCT03505281.
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http://dx.doi.org/10.1186/s12967-020-02646-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711269PMC
December 2020

CXCL10 could drive longer duration of mechanical ventilation during COVID-19 ARDS.

Crit Care 2020 11 2;24(1):632. Epub 2020 Nov 2.

INSERM, LNC UMR 1231, FCS Bourgogne-Franche Comté, LipSTIC LabEx, F-21000, Dijon, France.

Background: COVID-19-related ARDS has unique features when compared with ARDS from other origins, suggesting a distinctive inflammatory pathogenesis. Data regarding the host response within the lung are sparse. The objective is to compare alveolar and systemic inflammation response patterns, mitochondrial alarmin release, and outcomes according to ARDS etiology (i.e., COVID-19 vs. non-COVID-19).

Methods: Bronchoalveolar lavage fluid and plasma were obtained from 7 control, 7 non-COVID-19 ARDS, and 14 COVID-19 ARDS patients. Clinical data, plasma, and epithelial lining fluid (ELF) concentrations of 45 inflammatory mediators and cell-free mitochondrial DNA were measured and compared.

Results: COVID-19 ARDS patients required mechanical ventilation (MV) for significantly longer, even after adjustment for potential confounders. There was a trend toward higher concentrations of plasma CCL5, CXCL2, CXCL10, CD40 ligand, IL-10, and GM-CSF, and ELF concentrations of CXCL1, CXCL10, granzyme B, TRAIL, and EGF in the COVID-19 ARDS group compared with the non-COVID-19 ARDS group. Plasma and ELF CXCL10 concentrations were independently associated with the number of ventilator-free days, without correlation between ELF CXCL-10 and viral load. Mitochondrial DNA plasma and ELF concentrations were elevated in all ARDS patients, with no differences between the two groups. ELF concentrations of mitochondrial DNA were correlated with alveolar cell counts, as well as IL-8 and IL-1β concentrations.

Conclusion: CXCL10 could be one key mediator involved in the dysregulated immune response. It should be evaluated as a candidate biomarker that may predict the duration of MV in COVID-19 ARDS patients. Targeting the CXCL10-CXCR3 axis could also be considered as a new therapeutic approach.

Trial Registration: ClinicalTrials.gov, NCT03955887.
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http://dx.doi.org/10.1186/s13054-020-03328-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604548PMC
November 2020

Association between the retinal vascular network and retinal nerve fiber layer in the elderly: The Montrachet study.

PLoS One 2020 21;15(10):e0241055. Epub 2020 Oct 21.

Department of Ophthalmology, University Hospital, Dijon, France.

Purpose: To investigate the association between the characteristics of the retinal vascular network in the elderly and retinal nerve fiber layer (RNFL) thickness in a population-based study.

Methods: We conducted a population-based study, the Montrachet study (Maculopathy Optic Nerve, nuTRition neurovAsCular, and HEarT disease), in participants aged ≥ 75 years. RNFL thickness was assessed with spectral-domain optical coherence tomography (SD-OCT). Analysis of the retinal vascular network was performed by means of the Singapore "I" Vessel Assessment (SIVA) software based on fundus photography.

Results: Data from 970 participants were suitable for analysis. Patients with optic neuropathy were excluded. In multivariable analysis, each standard deviation (SD) decrease in the caliber of the six largest arterioles and veins in zone B and the six largest arterioles and veins in zone C was associated with a decrease in global RNFL thickness (β = -1.62 μm, P = 0.001; β = -2.39 μm, P < 0.001; β = -1.56 μm, P = 0.002; and β = -2.64 μm, P < 0.001, respectively).

Conclusions: Our study found that decreased retinal vessels caliber were associated with a decreased RNFL thickness in the elderly without optic neuropathy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0241055PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577490PMC
December 2020

Home Treatment of Older People with Symptomatic SARS-CoV-2 Infection (COVID-19): A structured Summary of a Study Protocol for a Multi-Arm Multi-Stage (MAMS) Randomized Trial to Evaluate the Efficacy and Tolerability of Several Experimental Treatments to Reduce the Risk of Hospitalisation or Death in outpatients aged 65 years or older (COVERAGE trial).

Trials 2020 Oct 13;21(1):846. Epub 2020 Oct 13.

CHU Bordeaux, Department of Infectious Diseases and Tropical Medicine, Division of Tropical Medicine and Clinical International Health, F-33000, Bordeaux, France.

Objectives: To assess the efficacy of several repurposed drugs to prevent hospitalisation or death in patients aged 65 or more with recent symptomatic SARS-CoV-2 infection (COVID-19) and no criteria for hospitalisation.

Trial Design: Phase III, multi-arm (5) and multi-stage (MAMS), randomized, open-label controlled superiority trial. Participants will be randomly allocated 1:1:1:1:1 to the following strategies: Arm 1: Control arm Arms 2 to 5: Experimental treatment arms Planned interim analyses will be conducted at regular intervals. Their results will be reviewed by an Independent Data and Safety Monitoring Board. Experimental arms may be terminated for futility, efficacy or toxicity before the end of the trial. New experimental arms may be added if new evidence suggests that other treatments should be tested. A feasibility and acceptability substudy as well as an immunological substudy will be conducted alongside the trial.

Participants: Inclusion criteria are: 65-year-old or more; Positive test for SARS-CoV-2 on a nasopharyngeal swab; Symptoms onset within 3 days before diagnosis; No hospitalisation criteria; Signed informed consent; Health insurance. Exclusion criteria are: Inability to make an informed decision to participate (e.g.: dementia, guardianship); Rockwood Clinical Frailty Scale ≥7; Long QT syndrome; QTc interval > 500 ms; Heart rate <50/min; Kalaemia >5.5 mmol/L or <3.5 mmol/L; Ongoing treatment with piperaquine, halofantrine, dasatinib, nilotinib, hydroxyzine, domperidone, citalopram, escitalopram, potent inhibitors or inducers of cytochrome P450 CYP3A4 isoenzyme, repaglinide, azathioprine, 6-mercaptopurine, theophylline, pyrazinamide, warfarin; Known hypersensitivity to any of the trial drugs or to chloroquine and other 4-aminoquinolines, amodiaquine, mefloquine, glafenine, floctafenine, antrafenine, ARB; Hepatic porphyria; Liver failure (Child-Pugh stage ≥B); Stage 4 or 5 chronic kidney disease (GFR <30 mL/min/1.73 m²); Dialysis; Hypersentivity to lactose; Lactase deficiency; Abnormalities in galactose metabolism; Malabsorption syndrome; Glucose-6-phosphate dehydrogenase deficiency; Symptomatic hyperuricemia; Ileus; Colitis; Enterocolitis; Chronic hepatitis B virus disease. The trial is being conducted in France in the Bordeaux, Corse, Dijon, Nancy, Paris and Toulouse areas as well as in the Grand Duchy of Luxembourg. Participants are recruited either at home, nursing homes, general practices, primary care centres or hospital outpatient consultations.

Intervention And Comparator: The four experimental treatments planned in protocol version 1.2 (April 8, 2020) are: (1) Hydroxychloroquine 200 mg, 2 tablets BID on day 0, 2 tablets QD from day 1 to 9; (2) Imatinib 400 mg, 1 tablet QD from day 0 to 9; (3) Favipiravir 200 mg, 12 tablets BID on day 0, 6 tablets BID from day 1 to 9; (4) Telmisartan 20 mg, 1 tablet QD from day 0 to 9. The comparator is a complex of vitamins and trace elements (AZINC Forme et Vitalité®), 1 capsule BID for 10 days, for which there is no reason to believe that they are active on the virus. In protocol version 1.2 (April 8th, 2020): People in the control arm will receive a combination of vitamins and trace elements; people in the experimental arms will receive hydroxychloroquine, or favipiravir, or imatinib, or telmisartan.

Main Outcome: The primary outcome is the proportion of participants with an incidence of hospitalisation and/or death between inclusion and day 14 in each arm.

Randomisation: Participants are randomized in a 1:1:1:1:1 ratio to each arm using a web-based randomisation tool. Participants not treated with an ARB or ACEI prior to enrolment are randomized to receive the comparator or one of the four experimental drugs. Participants already treated with an ARB or ACEI are randomized to receive the comparator or one of the experimental drugs except telmisartan (i.e.: hydroxychloroquine, imatinib, or favipiravir). Randomisation is stratified on ACEI or ARBs treatment at inclusion and on the type of residence (personal home vs. nursing home).

Blinding (masking): This is an open-label trial. Participants, caregivers, investigators and statisticians are not blinded to group assignment.

Numbers To Be Randomised (sample Size): A total of 1057 participants will be enrolled if all arms are maintained until the final analysis and no additional arm is added. Three successive futility interim analyses are planned, when the number of participants reaches 30, 60 and 102 in the control arm. Two efficacy analyses (interim n°3 and final) will be performed successively.

Trial Status: This describes the Version 1.2 (April 8, 2020) of the COVERAGE protocol that was approved by the French regulatory authority and ethics committee. The trial was opened for enrolment on April 15, 2020 in the Nouvelle Aquitaine region (South-West France). Given the current decline of the COVID-19 pandemic in France and its unforeseeable dynamic in the coming months, new trial sites in 5 other French regions and in Luxembourg are currently being opened. A revised version of the protocol was submitted to the regulatory authority and ethics committee on June 15, 2020. It contains the following amendments: (i) Inclusion criteria: age ≥65 replaced by age ≥60; time since first symptoms <3 days replaced by time since first symptoms <5 days; (ii) Withdrawal of the hydroxychloroquine arm (due to external data); (iii) increase in the number of trial sites.

Trial Registration: The trial was registered on Clinical Trials.gov on April 22, 2020 (Identifier: NCT04356495): and on EudraCT on April 10, 2020 (Identifier: 2020-001435-27).

Full Protocol: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).
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http://dx.doi.org/10.1186/s13063-020-04619-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7552584PMC
October 2020

Vascular density with optical coherence tomography angiography and systemic biomarkers in low and high cardiovascular risk patients.

Sci Rep 2020 10 7;10(1):16718. Epub 2020 Oct 7.

Laboratoire de Physiopathologie et Epidémiologie Cérébro-Cardiovasculaires (EA7460, PEC2), UFR Des Sciences de Santé, Bourgogne Franche-Comté University, Dijon, France.

We aimed to compare retinal vascular density in Optical Coherence Tomography Angiography (OCT-A) between patients hospitalized for acute coronary syndrome (ACS) and control patients and to investigate correlation with angiogenesis biomarkers. Patients hospitalized for an acute coronary syndrome (ACS) in the Intensive Care Unit were included in the "high cardiovascular risk" group while patients without cardiovascular risk presenting in the Ophthalmology department were included as "control". Both groups had blood sampling and OCT-A imaging. Retina microvascularization density in the superficial capillary plexus was measured on 3 × 3 mm angiograms centered on the macula. Angiopoietin-2, TGF-β1, osteoprotegerin, GDF-15 and ST-2 were explored with ELISA or multiplex method. Overall, 62 eyes of ACS patients and 42 eyes of controls were included. ACS patients had significantly lower inner vessel length density than control patients (p = 0.004). A ROC curve found that an inner vessel length density threshold below 20.05 mm was moderately associated with ACS. Significant correlation was found between serum levels of angiopoietin-2 and osteoprotegerin, and retinal microvascularization in OCT-A (R = - 0.293, p = 0.003; R = - 0.310, p = 0.001). Lower inner vessel length density measured with OCT-A was associated with ACS event and was also correlated with higher concentrations of angiopoietin-2 and osteoprotegerin.
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http://dx.doi.org/10.1038/s41598-020-73861-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542456PMC
October 2020

Associations between cognitive performance and the rehabilitation, medical care and social support provided to French children with Prader-Willi syndrome.

Eur J Med Genet 2020 Dec 28;63(12):104064. Epub 2020 Sep 28.

Clinical Investigation Centre, INSERM 1432 - Clinical Epidemiology, Faculty of Medicine, Dijon University Hospital, France.

Prader-Willi syndrome (PWS) is a rare genetic neurodevelopmental disorder with a characteristic behavioural phenotype. A multidisciplinary approach to care is required to prevent multiple medical complications in individuals affected by PWS. The aim of this study was to describe the rehabilitation, medical care, educational and social support provided to school-aged French PWS patients with varying neuropsychological profiles. Data were obtained from a French multicentre study that included patients aged 4-20 years with diverse genetic syndromes. Nineteen PWS subjects with a mean age of 9.2 years were included. The mean full-scale intellectual quotient (IQ) was 58 (Wechsler scale). There were frequent dissociations between verbal and performance IQ that were not associated with a specific profile. We also observed lower autonomy and communication scores (5.3 years and 5.9 years equivalent, respectively, Vineland scale), the absence of hyperactivity (Conners scale), and the presence of behavioural abnormalities (CBCL scale). Multidisciplinary medical supervision was generally coordinated by the paediatric endocrinologist and did not always include follow-up with all of the recommended specialists, in particular with a paediatric psychiatrist. Analysis of multidisciplinary rehabilitation conducted in public and private-sector establishment revealed failings in psychological support, occupational therapy and dietary follow-up. Regarding education, most children younger than 10 years were in normal schools, while older individuals were often cared for in medico-social institutions. In conclusion, children and adolescents with PWS generally received appropriate care. Though there have been considerable improvements in the management of children with PWS, reference centres should continue reinforcing the coordination of multidisciplinary supervision.
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http://dx.doi.org/10.1016/j.ejmg.2020.104064DOI Listing
December 2020

Is IL-6 the Right Target in COVID-19 Severe Pneumonia?

Am J Respir Crit Care Med 2021 01;203(1):139-140

Infectious Diseases Department University Hospital Dijon, France.

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http://dx.doi.org/10.1164/rccm.202007-2924LEDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781133PMC
January 2021

Monitoring HSP70 exosomes in cancer patients' follow up: a clinical prospective pilot study.

J Extracell Vesicles 2020 20;9(1):1766192. Epub 2020 May 20.

Centre d'investigation Clinique INSERM 1432, CHU Dijon-Bourgogne, Dijon, France.

Exosomes are nanovesicles released by all cells that can be found in the blood. A key point for their use as potential biomarkers in cancer is to differentiate tumour-derived exosomes from other circulating nanovesicles. Heat shock protein-70 (HSP70) has been shown to be abundantly expressed by cancer cells and to be associated with bad prognosis. We previously showed that exosomes derived from cancer cells carried HSP70 in the membrane while those from non-cancerous cells did not. In this work, we opened a prospective clinical pilot study including breast and lung cancer patients to determine whether it was possible to detect and quantify HSP70 exosomes in the blood of patients with solid cancers. We found that circulating exosomal HSP70 levels, but not soluble HSP70, reflected HSP70 content within the tumour biopsies. Circulating HSP70 exosomes increased in metastatic patients compared to non-metastatic patients or healthy volunteers. Further, we demonstrated that HSP70-exosome levels correlated with the disease status and, when compared with circulating tumour cells, were more sensitive tumour dissemination predictors. Finally, our case studies indicated that HSP70-exosome levels inversely correlated with response to the therapy and that, therefore, monitoring changes in circulating exosomal HSP70 might be useful to predict tumour response and clinical outcome.
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http://dx.doi.org/10.1080/20013078.2020.1766192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7301715PMC
May 2020

Toxoplasmosis screening during pregnancy in France: Opinion of an expert panel for the CNGOF.

J Gynecol Obstet Hum Reprod 2020 Sep 16;49(7):101814. Epub 2020 May 16.

Université Reims Champagne -Ardenne, EA7510 et Centre National de Référence de la Toxoplasmose, Centre de Ressources Biologiques Toxoplasma, Service de Parasitologie-Mycologie, Centre Hospitalier Universitaire de Reims, Reims, France.

Prenatal screening to prevent congenital toxoplasmosis as performed in France for several decades has been questioned in view of the decreasing incidence of this infection and the cost of testing. The French College of Obstetrics and Gynecology mandated a multidisciplinary panel of experts to perform a reassessment of the screening program in accordance with international good practice. In France, about 70% of pregnant women are not immune to T. gondii, and 0.2-0.25% become infected during pregnancy. The risk of maternal-fetal transmission of infection is on average 25-29% and depends greatly on the gestational age at seroconversion. In case of fetal transmission, the outcome is livebirth in 95% of cases, with latent congenital toxoplasmosis in 90% of cases and symptomatic forms in 10% of cases, of which 1/3 are severe and 2/3 moderate. Biological techniques have satisfactory performance regarding serologies for the diagnosis of maternal infections and PCR on amniotic fluid for the prenatal diagnosis of congenital toxoplasmosis. Primary prevention of toxoplasmosis is based on hygiene measures that are relatively simple, but poorly implemented. In case of maternal seroconversion, there is a strong case for prenatal prophylactic treatment as soon as possible (ideally within 3 weeks of seroconversion), spiramycin before 14 weeks of gestation (WG), and with a tendency to superiority of the pyrimethamine/sulfadiazine association over spiramycin beyond 14 W G, in order to reduce the risk of symptomatic congenital toxoplasmosis. In case of congenital toxoplasmosis, prompt initiation of treatment reduces the occurrence of cerebral signs and symptoms, as well as retinal lesions. Several medico-economic evaluations of the French toxoplasmosis screening program have been conducted including an individual cost-effectiveness approach with decision analysis which concluded on the profitability of prenatal screening as carried out in France (monthly surveillance of seronegative women, prenatal treatment in case of seroconversion, termination of pregnancy in severe forms). Though most international societies do not recommend systematic screening for mainly financial reasons, if congenital toxoplasmosis appears benign in France today, it is probably thanks to screening and the possibility of early treatment of fetuses and/or newborns. Thus, the panel recommends continuing for now the program in France for prevention of congenital toxoplasmosis.
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http://dx.doi.org/10.1016/j.jogoh.2020.101814DOI Listing
September 2020

Diagnostic ability of spectral-domain optical coherence tomography peripapillary retinal nerve fiber layer thickness to discriminate glaucoma patients from controls in an elderly population (The MONTRACHET study).

Acta Ophthalmol 2020 Dec 24;98(8):e1009-e1016. Epub 2020 Apr 24.

Department of Ophthalmology, University Hospital, Dijon, France.

Purpose: To evaluate the capacity of retinal nerve fibre layer (RNFL) thickness measured by SD-OCT to discriminate glaucoma patients from controls in an elderly population.

Methods: The MONTRACHET (Maculopathy, Optic Nerve, nuTRition, neurovAsCular and HEarT diseases) Study is a population-based study including participants aged 75 years and over. All participants underwent a complete eye examination with optic nerve photographs, visual field testing and OCT peripapillary RNFL thickness measurement. Glaucoma was defined according to the ISGEO (International Society for Epidemiologic and Geographical Ophthalmology) classification. Performance indicators were calculated including area under the receiver operating characteristics curves (AUC), likelihood ratios (LR) and diagnostic odds ratios (DOR).

Results: In total, 1061 participants were included in the study, of whom 89 were classified as having glaucoma and 972 were classified as normal. The mean (SD) age of the population was 82.3 (3.7) years. The average RNFL thickness was significantly lower in the glaucoma group than in controls 64.0 (14.9) µm versus 88.9 (12.4) µm, respectively, p < 0.001) and in all sectors compared with controls. The average RNFL thickness had the highest AUC (0.901) followed by the temporal-inferior (0.879) and temporal-superior sectors (0.862). When RNFL thickness was classified as abnormal by SD-OCT, the average RNFL thickness had the best sensitivity (83.75%) followed by the temporal-inferior sector (75.64%). The specificity for these two parameters was 87.34% and 91.08%, respectively. The highest DOR was 28.70 for average RNFL thickness and reached 34.84 when using the reference database of the OCT manufacturer.

Conclusion: This study confirms that SD-OCT could be useful as an additional test to discriminate glaucoma patients from controls in an elderly population.
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http://dx.doi.org/10.1111/aos.14448DOI Listing
December 2020

Recurrence after elective incisional hernia repair is more frequent than you think: An international prospective cohort from the French Society of Surgery.

Surgery 2020 07 15;168(1):125-134. Epub 2020 Apr 15.

Service de Chirurgie Générale et Digestive, Centre Hospitalier Universitaire de Dijon, Dijon, France; INSERM 1231, Dijon, France.

Background: The French Society of Surgery has endorsed a cohort aiming to prospectively assess the frequency of recurrence after incisional hernia repair and to identify the risk factors.

Methods: Consecutive patients undergoing incisional hernia repair in the participating centers were included in the prospective French Society of Surgery cohort over a 6-month period. Patients were followed up with a computed tomography scan at 1 y and a clinical assessment by the surgeon at 2 years.

Results: A total of 1,075 patients undergoing incisional hernia repair were included in 61 participating centers. The median follow-up was 24.0 months (interquartile range: 14.0-25.3). The follow-up rates were 83.0% and 68.5% at 1 and 2 years, respectively. The recurrence rates were 18.1% at 1 year and 27.7% at 2 years. Recurrence risk factors at 2 years were a history of hernia (odds ratio = 1.57, 95% confidence interval = 1.05-2.35, P = .028), a lateral hernia (odds ratio = 1.84, 95% confidence interval = 1.19-2.86, P = .007), a concomitant digestive operation (odds ratio = 1.97, 95% confidence interval = 1.20-3.22, P = .007), and the occurrence of early surgical site complications (odds ratio = 1,90, 95% confidence interval = 1.06-3.38, P = .030). The use of surgical mesh was strongly associated with a lower risk of recurrence at 2 years (P < .001).

Conclusion: After incisional hernia repair, the 2-year recurrence rate is as high as 27.7%. History of hernia, lateral hernia, concomitant digestive operation, the onset of surgical site complications, and the absence of mesh are strong risk factors for recurrence.
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http://dx.doi.org/10.1016/j.surg.2020.02.016DOI Listing
July 2020

EPIDEMIOLOGY OF VITREOMACULAR INTERFACE ABNORMALITIES USING MACULAR SPECTRAL-DOMAIN OPTICAL COHERENCE TOMOGRAPHY IN AN ELDERLY POPULATION (THE MONTRACHET STUDY).

Retina 2021 Jan;41(1):60-67

Ophthalmology Department, Dijon-Bourgogne University Hospital, Dijon, France.

Purpose: The aim of this study was to investigate the prevalence of vitreomacular interface abnormalities (VMIAs) and to identify associated factors in an elderly population in Europe.

Methods: The MONTRACHET (Maculopathy Optic Nerve nuTRition neurovAsCular and HEarT diseases) Study is a population-based study, conducted in subjects older than 75 years. Vitreomacular adhesions, vitreomacular tractions, macular holes, epiretinal membranes, and macular cysts were assessed on spectral-domain optical coherence tomography examinations. The prevalence of VMIAs was estimated. We studied the association of demographic and clinical factors with VMIAs.

Results: The mean age of the participants was 82.3 (SD, 3.8) years, and 37.3% were men. The prevalence rates of VMIAs were vitreomacular adhesions (17.7%), vitreomacular tractions (1.4%), lamellar macular holes (1.0%), full-thickness macular holes (0.2%), macular pseudoholes (0.4%), epiretinal membranes (38.9%), and macular cysts (5.8%). In multivariate analysis, vitreomacular adhesions were positively associated with male sex (P < 0.001) and negatively associated with older age (P < 0.001) and cataract extraction (P < 0.001). Epiretinal membranes were positively associated with older age (P < 0.001) and cataract extraction (P < 0.001).

Conclusion: The prevalence of VMIAs based on spectral-domain optical coherence tomography analysis was high in subjects older than 75 years.
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http://dx.doi.org/10.1097/IAE.0000000000002802DOI Listing
January 2021

Excess of de novo variants in genes involved in chromatin remodelling in patients with marfanoid habitus and intellectual disability.

J Med Genet 2020 07 10;57(7):466-474. Epub 2020 Apr 10.

Centre de Compétence Anomalies du Développement et Syndromes Malformatifs Sud-Est, CHI de Toulon - La Seyne-sur-Mer, France.

Purpose: Marfanoid habitus (MH) combined with intellectual disability (ID) (MHID) is a clinically and genetically heterogeneous presentation. The combination of array CGH and targeted sequencing of genes responsible for Marfan or Lujan-Fryns syndrome explain no more than 20% of subjects.

Methods: To further decipher the genetic basis of MHID, we performed exome sequencing on a combination of trio-based (33 subjects) or single probands (31 subjects), of which 61 were sporadic.

Results: We identified eight genes with de novo variants (DNVs) in at least two unrelated individuals ( and ). Using simulation models, we showed that five genes ( and ) met conservative Bonferroni genomewide significance for an excess of the observed de novo point variants. Overall, at least one pathogenic or likely pathogenic variant was identified in 54.7% of subjects (35/64). These variants fell within 27 genes previously associated with Mendelian disorders, including and , which are known to be mutated in overgrowth syndromes.

Conclusion: We demonstrated that DNVs were enriched in chromatin remodelling (p=2×10) and genes regulated by the fragile X mental retardation protein (p=3×10), highlighting overlapping genetic mechanisms between MHID and related neurodevelopmental disorders.
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http://dx.doi.org/10.1136/jmedgenet-2019-106425DOI Listing
July 2020

Social deprivation among socio-economic contrasted french areas: Using item response theory analysis to assess differential item functioning of the EPICES questionnaire in stroke patients.

PLoS One 2020 2;15(4):e0230661. Epub 2020 Apr 2.

Clinical Epidemiology Unit, INSERM, CIC 1432, University Hospital of Dijon, Epidemiology and infection control unit, Bourgogne-Franche-Comté University, Dijon, France.

Background: Multiple approaches have been proposed to measure low socio-economic status. In France the concept of precariousness, akin to social deprivation, was developed and is widely used. EPICES is a short questionnaire that was developed to measure this concept. This study aimed to evaluate Differential Item Functioning (DIF) in the EPICES questionnaire between contrasted areas: mainland France, French West Indies (FWI) and French Guiana (FG).

Methods: The population was taken from the INDIA study, which aimed to evaluate the impact of social inequalities on stroke characteristics and prognosis. Eligible people were patients referred to neurology or emergency departments for a suspicion of stroke. We assessed the DIF using hybrid ordinal logistic regression method, derived from item response theory.

Results: We analysed 1 553 stroke patients, including 768 from FWI (49.5%), 289 from FG (18.6%) and 496 from mainland (31.9%). We identified five items with a moderate to large DIF in area comparisons: "meeting with a social worker", "complementary health insurance", "home-owning", "financial difficulties" and "sport activities". Correlation between EPICES score and the latent variable was strong (r = 0.84).

Conclusion: This is the first attempt to assess the DIF of the EPICES score between different French populations. We found several items with DIF, which can be explained by individual interpretation or local context. However, the DIFs did not lead to a large difference between the latent variable and the EPICES score, which indicates that it can be used to assess precariousness and social deprivation between contrasted areas.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0230661PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7117693PMC
July 2020

Influence of deprivation on initial severity and prognosis of patients admitted to the ICU: the prospective, multicentre, observational IVOIRE cohort study.

Ann Intensive Care 2020 Feb 11;10(1):20. Epub 2020 Feb 11.

INSERM, CIC 1432, Module Epidémiologie Clinique, Dijon, France.

Background: The influence of socioeconomic status on patient outcomes is unclear. We assessed the impact of socioeconomic deprivation on severity of illness at intensive care unit (ICU) admission, and on the risk of death at 3 months after ICU admission.

Methods: The IVOIRE study was a prospective, observational, multicentre cohort study in the ICU of 8 participating hospitals in France, including patients aged ≥ 18 years admitted to the ICU and receiving at least one life support therapy for organ failure. The primary outcomes were severity at admission (assessed by SAPSII score), and mortality at 3 months. Socioeconomic data were obtained from interviews with patients or family. Deprivation was assessed using the EPICES score.

Results: Among 1294 patents included between 2013 and 2016, 629 (48.6%) were classed as deprived and differed significantly from non-deprived subjects in terms of sociodemographic characteristics and pre-existing conditions. The mean SAPS II score at admission was 50.1 ± 19.4 in deprived patients and 52.3 ± 17.3 in non-deprived patients, with no significant difference by multivariable analysis (β = - 1.85 [95% CI - 3.86; + 0.16, p = 0.072]). The proportion of death was 31.1% at 3 months, without significant differences between deprived and non-deprived patients, even after adjustment for confounders.

Conclusions: Deprivation is frequent in patients admitted to the ICU and is not associated with disease severity at admission, or with mortality at 3 months between deprived and non-deprived patients. Trial registration The IVOIRE cohort is registered with ClinicalTrials.gov under the identifier NCT01907581, registration date 17/7/2013.
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http://dx.doi.org/10.1186/s13613-020-0637-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7013026PMC
February 2020

Is the Pelvis-Thorax Coordination a Valuable Outcome Instrument to Assess Patients With Hip Osteoarthritis?

Front Bioeng Biotechnol 2019 23;7:457. Epub 2020 Jan 23.

INSERM, CIC 1432, Module Plurithematique, Plateforme d'Investigation Technologique, Dijon, France; CHU Dijon-Bourgogne, Centre d'Investigation Clinique, Module Plurithématique, Plateforme d'Investigation Technologique, Dijon, France.

The evaluation of the disease severity in hip osteoarthritis (OA) patients being currently based on subjective instruments. It would be of interest to develop more objective instruments, for example based on gait analysis. The aims of this study were to explore if pelvis-thorax coordination parameters could be valuable instrument outcomes to achieve this evaluation by assessing their reliability, discriminant capacity and responsiveness. Three groups of subjects; healthy, hip OA patients with severe disease (defined as indication to surgery), hip OA patients with less severe disease (no indication to surgery) were included. Hip OA patients with severe disease were evaluated before and 6 months after surgery. Subjects had to perform a gait analysis at comfortable speed, and pelvis-thorax coordination was evaluated. The correlations with clinical and structural parameters, as well as reliability, discriminant capacities and responsiveness, were assessed. The pelvis-thorax coordination in the coronal plane during walking was correlated to clinical and to structural severity in hip OA patients ( = 0.13). The coronal plane coordination allowed to discriminate healthy subjects from all hip OA patients (sensibility = 0.86; specificity = 0.59). Moreover, when comparing OA patients only, coronal plane coordination allows to discriminate patients with indication of surgery from those with no indication of surgery (sensibility = 0.72; specificity = 0.72). Moreover, the pelvis-thorax coordination demonstrated an excellent reliability and a good responsiveness. Changes in the pelvis-thorax coordination might refer to different mechanisms, from analgesia to motor control plasticity, and might be a possible explanation for the weak correlation between structure and symptoms in hip OA patients. Moreover, such parameter might be used as an objective outcome in hip OA clinical trials. www.ClinicalTrials.gov, identifier: NCT02042586 and NCT01907503.
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http://dx.doi.org/10.3389/fbioe.2019.00457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990408PMC
January 2020
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