Publications by authors named "Raphaël Porcher"

312 Publications

Free-Living Physical Activity and Sedentary Behaviour in Autoimmune Myasthenia Gravis: A Cross-Sectional Study.

J Neuromuscul Dis 2021 Apr 7. Epub 2021 Apr 7.

Bioingénierie, Tissus et Neuroplasticité, EA Université Paris-Est Créteil, Créteil, France.

Background: Muscle weakness and fatigability, the prominent symptoms of autoimmune myasthenia gravis (MG), impact negatively on daily function and quality of life (QoL). It is currently unclear as to what extent symptoms limit activity and whether physical activity (PA) behaviours are associated with reduced QoL.

Objectives: This study aimed to describe habitual PA patterns and explore relationships between PA metrics, clinical MG characteristics, and health-related QoL (HRQoL).

Methods: PA data from a trunk tri-axial accelerometer worn for seven days, was collected from females with generalized, stable MG and compared to control subjects. MG-specific evaluations, the six-minute walk test and knee extension strength were assessed in individuals with MG (IwMG). Mann-Whitney tests were used to study between-group differences. Spearman rank correlation coefficient was performed to explore relationships between variables.

Results: Thirty-three IwMG (mean (SD) age 45 (11) years) and 66 control subjects were included. IwMG perform less vigorous-intensity PA than control subjects (p = 0.001), spend more time sedentary (p = 0.02) and engage in less and shorter durations of moderate-vigorous-intensity PA (MVPA). For IwMG, habitual PA correlated positively with 6 min walking distance (rho = 0.387, p = 0.029) and negatively with body mass index (rho = -0.407, p = 0.019). We did not find any association between PA or sedentary behaviour and; HRQoL, symptom severity nor lower limb strength.

Conclusions: Individuals with stable MG perform less PA, at lower intensities, and are more inactive than controls individuals. Further research is warranted to understand factors influencing PA patterns in MG and whether interventions could be successful in increasing PA quantity and intensity in IwMG.
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http://dx.doi.org/10.3233/JND-210637DOI Listing
April 2021

Epidemiology and prognostic factors of pleural empyema.

Thorax 2021 Mar 30. Epub 2021 Mar 30.

Thoracic Surgery, Hopital Cochin, Assistance Publique-Hopitaux de Paris, Paris, France.

Background: Infection of the pleural cavity invariably leads to hospitalisation, and a fatal outcome is not uncommon. Our aim was to study the epidemiology of pleural empyema on a nationwide basis in the whole population and in three subgroups of patients, namely post-lung resection, associated cancer and those with no surgery and no cancer.

Methods: Data from patients aged ≥18 years hospitalised with a diagnosis of pleural infection in France between January 2013 and December 2017 were retrieved from the medical-administrative national hospitalisation database and retrospectively analysed. Mortality, length of stay and costs were assessed.

Results: There were 25 512 hospitalisations for pleural empyema. The annual rate was 7.15 cases per 100 000 habitants in 2013 and increased to 7.75 cases per 100 000 inhabitants in 2017. The mean age of patients was 62.4±15.6 years and 71.7% were men. Post-lung resection, associated cancer and no surgery-no cancer cases accounted for 9.8%, 30.1% and 60.1% of patients, respectively. These groups were significantly different in terms of clinical characteristics, mortality and risk factors for length of stay, costs and mortality. Mortality was 17.1% in the whole population, 29.5% in the associated cancer group, 17.7% in the post-lung resection group and 10.7% in the no surgery-no cancer group. In the whole population, age, presence of fistula, higher Charlson Comorbidity Index (3), alcohol abuse, arterial hypertension, hyperlipidaemia, atheroma, atrial fibrillation, performance status 3 and three subgroups of pleural empyema independently predicted mortality.

Conclusions: Empyema is increasing in incidence. Factors associated with mortality are recent lung resection and associated diagnosis of cancer.
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http://dx.doi.org/10.1136/thoraxjnl-2020-215267DOI Listing
March 2021

Ruxolitinib before allogeneic hematopoietic transplantation in patients with myelofibrosis on behalf SFGM-TC and FIM groups.

Bone Marrow Transplant 2021 Mar 25. Epub 2021 Mar 25.

Hôpital Saint-Louis, APHP, Centre d'investigation clinique, Paris, France.

This multicenter prospective phase 2 trial analyzed disease-free survival (DFS) in myelofibrosis patients receiving ruxolitinib for 6 months before transplantation. Seventy-six patients were recruited. Age-adjusted dynamic international prognostic scoring system was intermediate-1, intermediate-2, and high in 27 (36%), 31 (41%), and 18 (24%) patients. All patients received ruxolitinib from inclusion to conditioning regimen (fludarabine-melphalan) or to progression. A donor was found in 64 patients: 18 HLA-matched sibling donor (MSD), 32 HLA-matched unrelated (UD10/10), and 14 HLA mismatched unrelated donor (UD9/10. Among 64 patients with a donor, 20 (31%) achieved a partial response before transplantation and 59 (92%) could be transplanted after ruxolitinib therapy (18/18 MSD, 30/21 UD10/10, 11/34 UD9/10), of whom 19 (32%) were splenectomized. Overall survival from inclusion was 68% at 12 months. One-year DFS after transplantation was 55%: 83%, 40%, and 34% after MSD, UD10/10 or UD9/10, respectively. Cumulative incidence of grade 2-4 acute graft-versus-host disease (GVHD) was 66% and non-relapse-mortality was 42% at 12 months. Short course of ruxolitinib before transplantation is followed by a high rate of transplantation. With the platform used in this protocol, outcome was much better in patients transplanted with HLA-matched sibling donor as compared to unrelated donor.
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http://dx.doi.org/10.1038/s41409-021-01252-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992510PMC
March 2021

Association between prophylactic angiotensin-converting enzyme inhibitors and overall survival in Duchenne muscular dystrophy-analysis of registry data.

Eur Heart J 2021 Mar 22. Epub 2021 Mar 22.

APHP, Cochin Hospital, Cardiology Department, FILNEMUS, Paris-Descartes, Sorbonne Paris Cité University, Paris, France.

Aims: To estimate the effect of prophylactic angiotensin-converting enzyme inhibitors (ACEi) on survival in Duchenne muscular dystrophy (DMD).

Methods And Results: We analysed the data from the French multicentre DMD Heart Registry (ClinicalTrials.gov: NCT03443115). We estimated the association between the prophylactic prescription of ACEi and event-free survival in 668 patients aged 8 to 13 years, with normal left ventricular function, using (i) a Cox model with intervention as a time-dependent covariate, (ii) a propensity-based analysis comparing ACEi treatment vs. no treatment, and (iii) a set of sensitivity analyses. The study outcomes were overall survival and hospitalizations for heart failure (HF) or acute respiratory failure. Among the 668 patients included in the DMD Heart Registry, 576 (mean age 6.1 ± 2.8 years) were eligible for this study, of whom 390 were treated with ACEi prophylactically. Death occurred in 53 patients (13.5%) who were and 60 patients (32.3%) who were not treated prophylactically with ACEi, respectively. In a Cox model with intervention as a time-dependent variable, the hazard ratio (HR) associated with ACEi treatment was 0.49 [95% confidence interval (CI) 0.34-0.72] and 0.47 (95% CI 0.31-0.17) for overall mortality after adjustment for baseline variables. In the propensity-based analysis, 278 patients were included in the treatment group and 834 in the control group, with 18.5% and 30.4% 12-year estimated probability of death, respectively. ACEi were associated with a lower risk of death (HR 0.39; 95% CI 0.17-0.92) and hospitalization for HF (HR 0.16; 95% CI 0.04-0.62). All other sensitivity analyses yielded similar results.

Conclusion: Prophylactic ACEi treatment in DMD was associated with a significantly higher overall survival and lower rates of hospitalization for HF.
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http://dx.doi.org/10.1093/eurheartj/ehab054DOI Listing
March 2021

Characteristics and risk factors for poor outcome in patients with systemic vasculitis involving the gastrointestinal tract.

Semin Arthritis Rheum 2021 Mar 3;51(2):436-441. Epub 2021 Mar 3.

Department of Internal Medicine, Hôpital Cochin, AP-HP, Paris, France. Electronic address:

Background: Gastrointestinal (GI) involvement was described to be a poor prognostic factor in systemic necrotizing vasculitis. Its prognostic significance may vary according to clinical presentation and vasculitis subtype.

Aims: This study investigated risk-factors associated to poor outcome in GI-involvement of vasculitis.

Methods: Patients with systemic vasculitis as defined by the 2012 Chapel Hill Consensus Conference and presenting with GI involvement were retrospectively included. Baseline characteristics, treatments and outcome were recorded. Primary endpoint was a composite of admission to intensive care unit (ICU), emergency surgical procedure, or death.

Results: Two hundred and thirteen patients were included. Vasculitis were distributed as follows: 41% IgA vasculitis, 27% ANCA-associated vasculitis, 17% polyarteritis nodosa (PAN), and 15% other vasculitis. Eighty-three (39%) patients fulfilled the composite primary endpoint within 6 months. Predictive factors associated with the primary endpoint included PAN subtype (OR 3.08, 95% CI 1.29-7.34), performance status (OR 1.40, 1.05-1.87), use of morphine (OR 2.51, 0.87-7.24), abdominal guarding (OR 3.08, 1.01-9.37), ileus (OR 2.29, 0.98-5.32), melena (OR 2.74, 1.17-6.42), increased leukocytes (per G/L, OR 1.05, 1.00-1.10), low hemoglobin (per g/dL, OR 0.80, 0.71-0.91) and increased CRP (log mg/L, OR 1.21, 0.94-1.56). A risk prediction model for the achievement of primary endpoint had a very good performance [C-statistics 0.853 (0.810 to 0.895], and for overall survival as well.

Conclusions: Vasculitis presenting with GI involvement have a poor outcome in more than one third of cases. An easy-to-use risk prediction model had a very good performance to predict the admission to ICU, emergency surgical procedure, or death.
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http://dx.doi.org/10.1016/j.semarthrit.2021.03.002DOI Listing
March 2021

Editorial: What Readers and Clinician Scientists Need to Know About the "Other" EQUATOR.

Clin Orthop Relat Res 2021 Apr;479(4):643-647

S. S. Leopold, Editor-in-Chief, Clinical Orthopaedics and Related Research®, Philadelphia, PA, USA.

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http://dx.doi.org/10.1097/CORR.0000000000001708DOI Listing
April 2021

Valproic Acid as an Adjuvant Treatment for Generalized Convulsive Status Epilepticus in Adults Admitted to Intensive Care Units: Protocol for a Double-Blind, Multicenter Randomized Controlled Trial.

JMIR Res Protoc 2021 Feb 24;10(2):e22511. Epub 2021 Feb 24.

Centre Hospitalier Poissy Saint Germain en Laye, Poissy, France.

Background: Generalized convulsive status epilepticus (GCSE) is a frequent medical emergency. GCSE treatment focuses on the administration of benzodiazepines followed by a second-line antiepileptic drug (AED). Despite this stepwise strategy, GCSE is not controlled in one-quarter of patients and is associated with protracted hospitalization, high mortality, and long-term disability. Valproic acid (VPA) is an AED with good tolerability and neuroprotective properties.

Objective: This study aims to demonstrate that administration of VPA as an adjuvant for first- and second-line treatment in GCSE can improve outcomes.

Methods: A multicenter, double-blind, randomized controlled trial was conducted, comparing VPA with a placebo in adults admitted to intensive care units (ICUs) for GCSE in France. GCSE was diagnosed by specifically trained ICU physicians according to standard criteria. All patients received standard of care, including a benzodiazepine and a second-line AED (not VPA), at the discretion of the treating medical team. In the intervention arm, VPA was administered intravenously at a loading dose of 30 mg/kg over 15 minutes, followed by a continuous infusion of 1 mg/kg/hour over the next 12 hours. In the placebo group, an identical intravenous administration of 0.9% saline was used. The primary outcome was the proportion of patients discharged alive from the hospital by day 15. Secondary outcomes were frequency of refractory and super refractory GCSE, ICU-related morbidity, adverse events related to VPA, and cognitive dysfunction at 3 months. Statistical analyses will be performed according to the intent-to-treat principle.

Results: The first patient was randomized on February 18, 2013, and the last patient was randomized on July 7, 2018. Of 248 planned patients, 98.7% (245/248) were enrolled across 20 ICUs. At present, data management is still ongoing, and all parties involved in the trial remain blinded.

Conclusions: The Valproic Acid as an Adjuvant Treatment for Generalized Convulsive Status Epilepticus (VALSE) trial will evaluate whether the use of VPA as an adjuvant for first- and second-line treatment in GCSE improves outcomes.

Trial Registration: ClinicalTrials.gov NCT01791868; https://clinicaltrials.gov/ct2/show/NCT01791868.

International Registered Report Identifier (irrid): DERR1-10.2196/22511.
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http://dx.doi.org/10.2196/22511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946594PMC
February 2021

Randomised controlled trial in an experimental online supermarket testing the effects of front-of-pack nutrition labelling on food purchasing intentions in a low-income population.

BMJ Open 2021 Feb 8;11(2):e041196. Epub 2021 Feb 8.

Sorbonne Paris Nord University, Inserm, Inrae, Cnam, Nutritional Epidemiology Research Team (EREN), Epidemiology and Statistics Research Centre -University of Paris (CRESS), Bobigny, France.

Background: The Nutri-Score, a front-of-pack nutrition label, has been adopted in 2017 in France but its impact on low-income populations is unknown, and they are more at risk of having unhealthy diets. The present study assessed the effects of the Nutri-Score on the nutritional quality of purchasing intentions among low-income individuals, compared with the current French labelling situation: references intakes (RIs) and no label, using a three-arm parallel-group randomised controlled trial.

Methods: Low-income active adults from the NutriNet-Santé cohort (household income below €1200/month) were asked to perform a shopping task in an experimental online supermarket after being randomised in one of the three conditions (Nutri-Score, RIs or no labelling). The main outcome was the overall nutritional quality of the virtual shopping cart, assessed with the French-modified Food Standards Agency Nutrient Profiling System (FSAm-NPS), and secondary outcomes were the nutrient content of the shopping carts. 524 subjects were randomised, and 336 included in the analyses.

Results: The Nutri-Score resulted in the highest overall nutritional quality of the shopping cart, as reflected by a FSAm-NPS score (1.86 (SD 3.59) points) significantly lower (reflecting higher nutritional quality) than the RIs (3.21 (SD 4.14) points, p≤0.05) but not significantly lower than no label (2.60 (SD 3.09) points, p=0.3). The Nutri-Score also resulted into significantly lower contents in calories and saturated fatty acids in the shopping cart, compared with the RIs only (p≤0.05).

Conclusion: The implementation of the front of pack nutrition label Nutri-Score, adopted in France and in different European countries, appears to have the potential to encourage purchasing intentions of foods from higher nutritional quality among low-income individuals, compared with the RIs label promoted by food manufacturers. NCT02769455.
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http://dx.doi.org/10.1136/bmjopen-2020-041196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871692PMC
February 2021

Comparison of Corticosteroid Tapering Regimens in Myasthenia Gravis: A Randomized Clinical Trial.

JAMA Neurol 2021 Apr;78(4):426-433

General Intensive Care Unit, APHP, Raymond Poincaré Hospital, University of Versailles Saint-Quentin en Yvelines, Garches, France.

Importance: The tapering of prednisone therapy in generalized myasthenia gravis (MG) presents a therapeutic dilemma; however, the recommended regimen has not yet been validated.

Objective: To compare the efficacy of the standard slow-tapering regimen of prednisone therapy with a rapid-tapering regimen.

Design: From June 1, 2009, to July 31, 2013, a multicenter, parallel, single-blind randomized trial was conducted to compare 2 regimens of prednisone tapering. Data analysis was conducted from February 18, 2019, to January 23, 2020. A total of 2291 adults with a confirmed diagnosis of moderate to severe generalized MG at 7 specialized centers in France were assessed for eligibility.

Interventions: The slow-tapering arm included a gradual increase of the prednisone dose to 1.5 mg/kg every other day and a slow decrease once minimal manifestation status of MG was attained. The rapid-tapering arm consisted of immediate high-dose daily administration of prednisone, 0.75 mg/kg, followed by an earlier and rapid decrease once improved MG status was attained. Azathioprine, up to a maximum dose of 3 mg/kg/d, was prescribed for all participants.

Main Outcomes And Measures: The primary outcome was attainment of minimal manifestation status of MG without prednisone at 12 months and without clinical relapse at 15 months. Intention-to-treat analysis was conducted.

Results: Of the 2291 patients assessed, 2086 did not fulfill the inclusion criteria, 87 declined to participate, and 1 patient registered after trial closure. A total of 117 patients (58 in the slow-tapering arm and 59 in the rapid-tapering arm) were selected for inclusion by MG specialists and were randomized. The population included 62 men (53%); median age was 65 years (interquartile range, 35-69 years). The proportion of patients having met the primary outcome was higher in the rapid- vs slow-tapering arm (23 [39%] vs 5 [9%]), with a risk ratio of 3.61 (95% CI, 1.64-7.97; P < .001) after adjusting for center and thymectomy. The rapid-tapering regimen allowed sparing of a mean of 1898 mg (95% CI, -3121 to -461 mg) of prednisone over 1 year (ie, 5.3 mg/d per patient, P = .03). The number of serious adverse events did not differ significantly between the slow- vs rapid-tapering group (13 [22%] vs 21 [36%], P = .15).

Conclusions And Relevance: In patients with moderate to severe generalized MG who require high-dose prednisone with azathioprine therapy, rapid tapering of prednisone appears to be feasible, well tolerated, and associated with a good outcome.

Trial Registration: ClinicalTrials.gov Identifier: NCT00987116.
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http://dx.doi.org/10.1001/jamaneurol.2020.5407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871208PMC
April 2021

Remdesivir for COVID-19 in Europe: will it provide value for money?

Lancet Respir Med 2021 02 17;9(2):127-128. Epub 2020 Dec 17.

Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, Netherlands.

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http://dx.doi.org/10.1016/S2213-2600(20)30568-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836228PMC
February 2021

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Ann Rheum Dis 2020 Dec 16. Epub 2020 Dec 16.

Methods of Therapeutic Evaluation Of Chronic Diseases (METHODS) team, INSERM, UMR 1153, Epidemiology and Biostatistics Sorbonne Paris Cité Research Center (CRESS), Paris, France.

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http://dx.doi.org/10.1136/annrheumdis-2020-219568DOI Listing
December 2020

Thresholds of glycemia, insulin therapy, and risk for severe retinopathy in premature infants: A cohort study.

PLoS Med 2020 12 11;17(12):e1003477. Epub 2020 Dec 11.

Department of Neonatal Medicine, Nantes University Hospital, Nantes, France.

Background: Hyperglycemia in preterm infants may be associated with severe retinopathy of prematurity (ROP) and other morbidities. However, it is uncertain which concentration of blood glucose is associated with increased risk of tissue damage, with little consensus on the cutoff level to treat hyperglycemia. The objective of our study was to examine the association between hyperglycemia and severe ROP in premature infants.

Methods And Findings: In 2 independent, monocentric cohorts of preterm infants born at <30 weeks' gestation (Nantes University Hospital, 2006-2016, primary, and Lyon-HFME University Hospital, 2009-2017, validation), we first analyzed the association between severe (stage 3 or higher) ROP and 2 markers of glucose exposure between birth and day 21-maximum value of glycemia (MaxGly1-21) and mean of daily maximum values of glycemia (MeanMaxGly1-21)-using logistic regression models. In both the primary (n = 863 infants, mean gestational age 27.5 ± 1.4 weeks, boys 52.5%; 38 with severe ROP; 54,083 glucose measurements) and the validation cohort (n = 316 infants, mean gestational age 27.4 ± 1.4 weeks, boys 51.3%), MaxGly1-21 and MeanMaxGly1-21 were significantly associated with an increased risk of severe ROP: odds ratio (OR) 1.21 (95% CI 1.14-1.27, p < 0.001) and OR 1.70 (95% CI 1.48-1.94, p < 0.001), respectively, in the primary cohort and OR 1.17 (95% CI 1.05-1.32, p = 0.008) and OR 1.53 (95% CI 1.20-1.95, p < 0.001), respectively, in the validation cohort. These associations remained significant after adjustment for confounders in both cohorts. Second, we identified optimal cutoff values of duration of exposure above each concentration of glycemia between 7 and 13 mmol/l using receiver operating characteristic curve analyses in the primary cohort. Optimal cutoff values for predicting stage 3 or higher ROP were 9, 6, 5, 3, 2, 2, and 1 days above a glycemic threshold of 7, 8, 9, 10, 11, 12, and 13 mmol/l, respectively. Severe exposure was defined as at least 1 exposure above 1 of the optimal cutoffs. Severe ROP was significantly more common in infants with severe exposure in both the primary (10.9% versus 0.6%, p < 0.001) and validation (5.2% versus 0.9%, p = 0.030) cohorts. Finally, we analyzed the association between insulin therapy and severe ROP in a national population-based prospectively recruited cohort (EPIPAGE-2, 2011, n = 1,441, mean gestational age 27.3 ± 1.4, boys 52.5%) using propensity score weighting. Insulin use was significantly associated with severe ROP in overall cohort crude analyses (OR 2.51 [95% CI 1.13-5.58], p = 0.024). Adjustment for inverse propensity score (gestational age, sex, birth weight percentile, multiple birth, spontaneous preterm birth, main pregnancy complications, surfactant therapy, duration of oxygen exposure between birth and day 28, digestive state at day 7, caloric intake at day 7, and highest glycemia during the first week) and duration of oxygen therapy had a large but not significant effect on the association between insulin treatment and severe ROP (OR 0.40 [95% CI 0.13-1.24], p = 0.106). Limitations of this study include its observational nature and, despite the large number of patients included compared to earlier similar studies, the lack of power to analyze the association between insulin use and retinopathy.

Conclusions: In this study, we observed that exposure to high glucose concentration is an independent risk factor for severe ROP, and we identified cutoff levels that are significantly associated with increased risk. The clinical impact of avoiding exceeding these thresholds to prevent ROP deserves further evaluation.
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http://dx.doi.org/10.1371/journal.pmed.1003477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732100PMC
December 2020

Early abolition of cough reflex predicts mortality in deeply sedated brain-injured patients.

PeerJ 2020 26;8:e10326. Epub 2020 Nov 26.

Laboratory of Human Histopathology and Animal Models, Institut Pasteur, Paris, France.

Background: Deep sedation may hamper the detection of neurological deterioration in brain-injured patients. Impaired brainstem reflexes within the first 24 h of deep sedation are associated with increased mortality in non-brain-injured patients. Our objective was to confirm this association in brain-injured patients.

Methods: This was an observational prospective multicenter cohort study involving four neuro-intensive care units. We included acute brain-injured patients requiring deep sedation, defined by a Richmond Assessment Sedation Scale (RASS) < -3. Neurological assessment was performed at day 1 and included pupillary diameter, pupillary light, corneal and cough reflexes, and grimace and motor response to noxious stimuli. Pre-sedation Glasgow Coma Scale (GCS) and Simplified Acute Physiology Score (SAPS-II) were collected, as well as the cause of death in the Intensive Care Unit (ICU).

Results: A total of 137 brain-injured patients were recruited, including 70 (51%) traumatic brain-injured patients, 40 (29%) vascular (subarachnoid hemorrhage or intracerebral hemorrhage). Thirty patients (22%) died in the ICU. At day 1, the corneal (OR 2.69, = 0.034) and cough reflexes (OR 5.12, = 0.0003) were more frequently abolished in patients that died in the ICU. In a multivariate analysis, abolished cough reflex was associated with ICU mortality after adjustment to pre-sedation GCS, SAPS-II, RASS (OR: 5.19, 95% CI [1.92-14.1], = 0.001) or dose of sedatives (OR: 8.89, 95% CI [2.64-30.0], = 0.0004).

Conclusion: Early (day 1) cough reflex abolition is an independent predictor of mortality in deeply sedated brain-injured patients. Abolished cough reflex likely reflects a brainstem dysfunction that might result from the combination of primary and secondary neuro-inflammatory cerebral insults revealed and/or worsened by sedation.
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http://dx.doi.org/10.7717/peerj.10326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7700733PMC
November 2020

Ethical and Scientific Considerations Regarding the Early Approval and Deployment of a COVID-19 Vaccine.

Ann Intern Med 2021 02 20;174(2):258-260. Epub 2020 Nov 20.

Université de Paris, Centre of Research in Epidemiology and Statistics (CRESS-UMR1153), Institut National de la Santé et de la Recherche Médicale, Paris, France (R.P.).

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http://dx.doi.org/10.7326/M20-7357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713906PMC
February 2021

Key stakeholders' perspectives and experiences with defining, identifying and displaying gaps in health research: a qualitative study.

BMJ Open 2020 11 10;10(11):e039932. Epub 2020 Nov 10.

University of Split Faculty of Humanities and Social Sciences, Split, Croatia.

Introduction: Mapping the current body of evidence including what is missing helps provide a better understanding of what research is available, ongoing and needed and should be prioritised. Identifying research gaps can inform the design and conduct of health research by providing additional context information about the body of evidence in a given topic area. Despite the commonly used term 'research gap' in scientific literature, little is written on how to find a 'research gap' in the first place. Moreover, there is no clear methodological guidance to identify and display gaps.

Objective: This study aimed to explore how key stakeholders define research gaps and characterise methods/practices used to identify and display gaps in health research to further advance efforts in this area.

Design: This was an exploratory qualitative study using semistructured in-depth interviews. The study sample included the following stakeholder groups: researchers, funders, healthcare providers, patients/public and policy-makers. Interview transcripts were subjected to thematic analysis.

Results: Among the 20 interviews conducted (20 participants), a variety of research gap definitions were expressed (ie, five main themes, including gaps in information, knowledge/evidence gaps, uncertainties, quality and patient perspective). We identified three main themes for methods used to identify gaps (primary, secondary and both primary and secondary) and finally six main themes for the methods to display gaps (forest plots, diagrams/illustrations, evidence maps, mega maps, 3IE gap maps and info graphics).

Conclusion: This study provides insights into issues related to defining research gaps and methods used to identify and display gaps in health research from the perspectives of key stakeholders involved in the process. Findings will be used to inform methodological guidance on identifying research gaps.
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http://dx.doi.org/10.1136/bmjopen-2020-039932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7656956PMC
November 2020

A Markov chain approach for ranking treatments in network meta-analysis.

Stat Med 2021 Jan 26;40(2):451-464. Epub 2020 Oct 26.

Université de Paris, Research Center of Epidemiology and Statistics (CRESS-U1153), INSERM, Paris, France.

When interpreting the relative effects from a network meta-analysis (NMA), researchers are usually aware of the potential limitations that may render the results for some comparisons less useful or meaningless. In the presence of sufficient and appropriate data, some of these limitations (eg, risk of bias, small-study effects, publication bias) can be taken into account in the statistical analysis. Very often, though, the necessary data for applying these methods are missing and data limitations cannot be formally integrated into ranking. In addition, there are other important characteristics of the treatment comparisons that cannot be addressed within a statistical model but only through qualitative judgments; for example, the relevance of data to the research question, the plausibility of the assumptions, and so on. Here, we propose a new measure for treatment ranking called the Probability of Selecting a Treatment to Recommend (POST-R). We suggest that the order of treatments should represent the process of considering treatments for selection in clinical practice and we assign to each treatment a probability of being selected. This process can be considered as a Markov chain model that allows the end-users of NMA to select the most appropriate treatments based not only on the NMA results but also to information external to the NMA. In this way, we obtain rankings that can inform decision-making more efficiently as they represent not only the relative effects but also their potential limitations. We illustrate our approach using a NMA comparing treatments for chronic plaque psoriasis and we provide the Stata commands.
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http://dx.doi.org/10.1002/sim.8784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821202PMC
January 2021

Effect of Tocilizumab vs Usual Care in Adults Hospitalized With COVID-19 and Moderate or Severe Pneumonia: A Randomized Clinical Trial.

JAMA Intern Med 2021 01;181(1):32-40

Université de Paris, Centre of Research Epidemiology and Statistics (CRESS), INSERM U1153, Paris, France.

Importance: Severe pneumonia with hyperinflammation and elevated interleukin-6 is a common presentation of coronavirus disease 2019 (COVID-19).

Objective: To determine whether tocilizumab (TCZ) improves outcomes of patients hospitalized with moderate-to-severe COVID-19 pneumonia.

Design, Setting, And Particpants: This cohort-embedded, investigator-initiated, multicenter, open-label, bayesian randomized clinical trial investigating patients with COVID-19 and moderate or severe pneumonia requiring at least 3 L/min of oxygen but without ventilation or admission to the intensive care unit was conducted between March 31, 2020, to April 18, 2020, with follow-up through 28 days. Patients were recruited from 9 university hospitals in France. Analyses were performed on an intention-to-treat basis with no correction for multiplicity for secondary outcomes.

Interventions: Patients were randomly assigned to receive TCZ, 8 mg/kg, intravenously plus usual care on day 1 and on day 3 if clinically indicated (TCZ group) or to receive usual care alone (UC group). Usual care included antibiotic agents, antiviral agents, corticosteroids, vasopressor support, and anticoagulants.

Main Outcomes And Measures: Primary outcomes were scores higher than 5 on the World Health Organization 10-point Clinical Progression Scale (WHO-CPS) on day 4 and survival without need of ventilation (including noninvasive ventilation) at day 14. Secondary outcomes were clinical status assessed with the WHO-CPS scores at day 7 and day 14, overall survival, time to discharge, time to oxygen supply independency, biological factors such as C-reactive protein level, and adverse events.

Results: Of 131 patients, 64 patients were randomly assigned to the TCZ group and 67 to UC group; 1 patient in the TCZ group withdrew consent and was not included in the analysis. Of the 130 patients, 42 were women (32%), and median (interquartile range) age was 64 (57.1-74.3) years. In the TCZ group, 12 patients had a WHO-CPS score greater than 5 at day 4 vs 19 in the UC group (median posterior absolute risk difference [ARD] -9.0%; 90% credible interval [CrI], -21.0 to 3.1), with a posterior probability of negative ARD of 89.0% not achieving the 95% predefined efficacy threshold. At day 14, 12% (95% CI -28% to 4%) fewer patients needed noninvasive ventilation (NIV) or mechanical ventilation (MV) or died in the TCZ group than in the UC group (24% vs 36%, median posterior hazard ratio [HR] 0.58; 90% CrI, 0.33-1.00), with a posterior probability of HR less than 1 of 95.0%, achieving the predefined efficacy threshold. The HR for MV or death was 0.58 (90% CrI, 0.30 to 1.09). At day 28, 7 patients had died in the TCZ group and 8 in the UC group (adjusted HR, 0.92; 95% CI 0.33-2.53). Serious adverse events occurred in 20 (32%) patients in the TCZ group and 29 (43%) in the UC group (P = .21).

Conclusions And Relevance: In this randomized clinical trial of patients with COVID-19 and pneumonia requiring oxygen support but not admitted to the intensive care unit, TCZ did not reduce WHO-CPS scores lower than 5 at day 4 but might have reduced the risk of NIV, MV, or death by day 14. No difference on day 28 mortality was found. Further studies are necessary for confirming these preliminary results.

Trial Registration: ClinicalTrials.gov Identifier: NCT04331808.
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http://dx.doi.org/10.1001/jamainternmed.2020.6820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577198PMC
January 2021

A Multicenter Phase II Study of Pazopanib in Patients with Unresectable Dermatofibrosarcoma Protuberans.

J Invest Dermatol 2021 Apr 18;141(4):761-769.e2. Epub 2020 Sep 18.

Team 1, HIPI, INSERM U976, Université de Paris, Paris, France; Department of Dermatology, Hôpital Saint-Louis AP-HP, Paris, France.

Dermatofibrosarcoma protuberans (DFSP) is a soft-tissue sarcoma characterized by a high risk of local infiltration. The identification of the COL1A1-PDGFB t(17;22) translocation activating the PDGF pathway led to the use of imatinib in unresectable DFSP, with a response rate of 36-80%. Pazopanib is a multitarget tyrosine kinase inhibitor approved for soft-tissue sarcomas. We conducted a phase II study of patients with unresectable DFSP to evaluate the efficacy and safety of pazopanib. Patients received 800 mg of pazopanib daily. The primary endpoint was the objective response rate defined as the reduction of the largest diameter of the tumor by ≥30% at 6 months or at surgery. A total of 23 patients, including one pretreated with imatinib, were enrolled. With a median follow-up of 6.2 months (interquartile range = 5.6-7.8 months), five patients (22%, 95% confidence interval = 7-22%) had a partial response to pazopanib. The best objective response rate was 30% (95% confidence interval = 13-53%) using Response Evaluation Criteria in Solid Tumors. One patient with metastatic DFSP previously treated with imatinib died after 2.4 months. Nine patients (39%) discontinued the treatment owing to adverse events. Pharmacodynamics analyses of tumor samples were conducted: the enrichment of EGF and the EGFR-associated gene panel was associated with resistance, suggesting that EGFR-targeted therapies could be a therapeutic option to explore in DFSP. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01059656.
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http://dx.doi.org/10.1016/j.jid.2020.06.039DOI Listing
April 2021

Association Between Anxiety and New Organ Failure, Independently of Critical Illness Severity and Respiratory Status: A Prospective Multicentric Cohort Study.

Crit Care Med 2020 10;48(10):1471-1479

1General Intensive Care Unit, APHP, Raymond Poincaré Hospital, University of Versailles Saint-Quentin en Yvelines, Garches, France. 2Perception and Memory Laboratory, Neuroscience Department, Institut Pasteur, Paris, France. 3General Intensive Care Unit, Sud-Essonne Hospital, Étampes, France. 4Centre d'Epidémiologie Clinique, Assistance Publique Hôpitaux de Paris, Hôtel Dieu Hospital, University Paris Descartes, Paris, France. 5General Intensive Care Unit, Institut Gustave Roussy Hospital, Villejuif, France. 6Department of Psychiatry, Sainte-Anne Hospital, Paris-Descartes University, Paris, France. 7Centre Hospitalier Sainte-Anne, Service Hospitalo-Universitaire, Faculté de Médecine Paris Descartes, Paris, France. 8Université Paris Descartes, Inserm Centre de Psychiatrie et Neurosciences, Laboratoire de Physiopathologie des maladies Psychiatriques, Paris, France. 9CNRS, GDR 3557, Institut de Psychiatrie, Paris, France. 10Department of Neuropathology, Sainte-Anne Hospital, Université de Paris, Paris, France. 11Laboratory of Critical Care, National Institute of Infectious Disease Evandro Chagas, Oswaldo Cruz Foundation, Ministry of Health, Rio de Janeiro, Brazil. 12D'Or Institute of Research and Education (IDOR), Rio de Janeiro, Brazil.

Objectives: Anxiety results from the anticipation of a threat and might be associated with poor outcome in the critically ill. This study aims at showing that anxiety at admission in critically ill patients is associated with new organ failure over the first 7 days of ICU hospitalization independently of baseline organ failure at admission.

Design: Prospective multicenter cohort study.

Setting: Three mixed ICU from April 2014 to December 2017.

Patients: Coma-, delirium-, and invasive mechanical ventilation-free patients admitted to the ICU were included.

Interventions: None.

Measurements And Main Results: "State anxiety" was assessed using the state component of the State-Trait Anxiety Inventory State. Severity of illness was measured using Simplified Acute Physiology Score II and Sequential Organ Failure Assessment scores. Primary endpoint was a composite of occurrence of death or new organ failure in the first 7 days after admission. Three hundred ninety-one patients were included; 159 of 391 women (40.7%); median age 63 years (49-74 yr); median Simplified Acute Physiology Score II 28 (19-37). Two hundred three out of 391 patients (51.9%) reported moderate to severe anxiety (State-Trait Anxiety Inventory State ≥ 40). One hundred two out of 391 patients (26.1%) developed a new organ failure. After adjustment to Simplified Acute Physiology Score II and Sequential Organ Failure Assessment, State-Trait Anxiety Inventory State greater than or equal to 40 was associated with the primary endpoint (odds ratio, 1.94; 95% CI, 1.18-3.18; p = 0.009) and respiratory failure. In post hoc analysis, State-Trait Anxiety Inventory State greater than or equal to 40 was associated with new organ failure independently and notably of respiratory status at admission (dyspnea-Visual Analogic Scale and PaCO2 ≥ 45 mm Hg).

Conclusions: Moderate to severe anxiety at ICU admission is associated with early occurrence of new organ failure in critically ill patients, independently of respiratory status and severity of critical illness. The causality link could be addressed in an interventional trial.
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http://dx.doi.org/10.1097/CCM.0000000000004495DOI Listing
October 2020

COVID-19 clinical trials: Ethical and scientific consequences of the RECOVERY trial results.

Basic Clin Pharmacol Toxicol 2020 Dec 30;127(6):445-447. Epub 2020 Sep 30.

The Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

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http://dx.doi.org/10.1111/bcpt.13489DOI Listing
December 2020

Editorial: Opposites Attract at CORR®-Machine Learning and Qualitative Research.

Clin Orthop Relat Res 2020 10;478(10):2193-2196

M. D. Wongworawat, Senior Editor, Clinical Orthopaedics and Related Research®, Philadelphia, PA, USA.

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http://dx.doi.org/10.1097/CORR.0000000000001466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7491879PMC
October 2020

Liver Resection for Early Hepatocellular Carcinoma: Preoperative Predictors of Non Transplantable Recurrence and Implications for Treatment Allocation.

Ann Surg 2020 11;272(5):820-826

Hepatobiliary Center Paul Brousse Hospital, APHP-Université Paris Saclay, Villejuif, France.

Background And Aims: LR and LT are the standard curative options for early HCC. LT provides best long-term survival but is limited by organ shortage. LR, readily available, is hampered by high recurrence rates. Salvage liver transplantation is an efficient treatment of recurrences within criteria. The aim of the study was to identify preoperative predictors of non transplantable recurrence (NTR) to improve patient selection for upfront LR or LT at initial diagnosis.

Study Design: Consecutive LR for transplantable HCC between 2000 and 2015 were studied. A prediction model for NTR based on preoperative variables was developed using sub-distribution hazard ratio after multiple imputation and internal validation by bootstrapping. Model performance was evaluated by the concordance index after correction for optimism.

Results: A total of 148 patients were included. Five-year overall survival and recurrence free survival were 73.6% and 29.3%, respectively (median follow-up 45.8 months). Recurrence rate was 54.8%. NTR rate was 38.2%. Preoperative model for NTR identified >1 nodule [sub-distribution hazard ratio 2.35 95% confidence interval (CI) 1.35-4.09], AFP >100 ng/mL (2.14 95% CI 1.17-3.93), and F4 fibrosis (1.93 95% CI 1.03-3.62). The apparent concordance index of the model was 0.664 after correction for optimism. In the presence of 0, 1, and ≥2 factors, NTR rates were 2.6%, 22.7%, and 40.9%, respectively. The number of prognostic factors was significantly associated with the pattern of recurrence (P = 0.001) and 5-year recurrence free survival (P < 0.001).

Conclusions: Cirrhosis, >1 nodule, and AFP >100 ng/mL were identified as preoperative predictors of NTR. In the presence of 2 factors or more upfront transplantation should be probably preferred to resection in regard of organ availability. Other patients are good candidates for LR and salvage liver transplantation should be encouraged in eligible patients with recurrence.
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http://dx.doi.org/10.1097/SLA.0000000000004259DOI Listing
November 2020

CORR Insights®: Does Artificial Intelligence Outperform Natural Intelligence in Interpretation of Musculoskeletal Radiological Studies? A Systematic Review.

Authors:
Raphaël Porcher

Clin Orthop Relat Res 2020 Dec;478(12):2765-2767

R. Porcher, Université de Paris, CRESS UMR1153, INSERM, INRA, F-75004 Paris, France; Centre d'Epidémiologie Clinique, AP-HP, Hôtel-Dieu, F-75004 Paris, France.

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http://dx.doi.org/10.1097/CORR.0000000000001415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7899408PMC
December 2020

Methotrexate and rheumatoid arthritis associated interstitial lung disease.

Eur Respir J 2021 Feb 11;57(2). Epub 2021 Feb 11.

Dept of Rheumatology, DMU Locomotion, INSERM UMR1152, Hôpital Bichat-Claude Bernard, APHP, Université de Paris, Paris, France.

Question Addressed By The Study: Methotrexate (MTX) is a key anchor drug for rheumatoid arthritis (RA) management. Fibrotic interstitial lung disease (ILD) is a common complication of RA. Whether MTX exposure increases the risk of ILD in patients with RA is disputed. We aimed to evaluate the association of prior MTX use with development of RA-ILD.

Methods: Through a case-control study design with discovery and international replication samples, we examined the association of MTX exposure with ILD in 410 patients with chronic fibrotic ILD associated with RA (RA-ILD) and 673 patients with RA without ILD. Estimates were pooled over the different samples using meta-analysis techniques.

Results: Analysis of the discovery sample revealed an inverse relationship between MTX exposure and RA-ILD (adjusted OR 0.46, 95% CI 0.24-0.90; p=0.022), which was confirmed in the replication samples (pooled adjusted OR 0.39, 95% CI 0.19-0.79; p=0.009). The combined estimate using both the derivation and validation samples revealed an adjusted OR of 0.43 (95% CI 0.26-0.69; p=0.0006). MTX ever-users were less frequent among patients with RA-ILD compared to those without ILD, irrespective of chest high-resolution computed tomography pattern. In patients with RA-ILD, ILD detection was significantly delayed in MTX ever-users compared to never-users (11.4±10.4 years and 4.0±7.4 years, respectively; p<0.001).

Answer To The Question: Our results suggest that MTX use is not associated with an increased risk of RA-ILD in patients with RA, and that ILD was detected later in MTX-treated patients.
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http://dx.doi.org/10.1183/13993003.00337-2020DOI Listing
February 2021

Fold-stratified cross-validation for unbiased and privacy-preserving federated learning.

J Am Med Inform Assoc 2020 08;27(8):1244-1251

Centre of Research in Epidemiology and Statistics (CRESS), Université de Paris, French Institute of Health and Medical Research (INSERM), National Institute of Agricultural Research (INRA), Paris, France.

Objective: We introduce fold-stratified cross-validation, a validation methodology that is compatible with privacy-preserving federated learning and that prevents data leakage caused by duplicates of electronic health records (EHRs).

Materials And Methods: Fold-stratified cross-validation complements cross-validation with an initial stratification of EHRs in folds containing patients with similar characteristics, thus ensuring that duplicates of a record are jointly present either in training or in validation folds. Monte Carlo simulations are performed to investigate the properties of fold-stratified cross-validation in the case of a model data analysis using both synthetic data and MIMIC-III (Medical Information Mart for Intensive Care-III) medical records.

Results: In situations in which duplicated EHRs could induce overoptimistic estimations of accuracy, applying fold-stratified cross-validation prevented this bias, while not requiring full deduplication. However, a pessimistic bias might appear if the covariate used for the stratification was strongly associated with the outcome.

Discussion: Although fold-stratified cross-validation presents low computational overhead, to be efficient it requires the preliminary identification of a covariate that is both shared by duplicated records and weakly associated with the outcome. When available, the hash of a personal identifier or a patient's date of birth provides such a covariate. On the contrary, pseudonymization interferes with fold-stratified cross-validation, as it may break the equality of the stratifying covariate among duplicates.

Conclusion: Fold-stratified cross-validation is an easy-to-implement methodology that prevents data leakage when a model is trained on distributed EHRs that contain duplicates, while preserving privacy.
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http://dx.doi.org/10.1093/jamia/ocaa096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7647321PMC
August 2020

Handgrip strength is a comorbidity marker in systemic necrotizing vasculitides and predicts the risk of fracture and serious adverse events.

Rheumatology (Oxford) 2020 09;59(9):2581-2590

Department of Internal MedicineHôpital Cochin, Paris, France.

Objective: Sarcopenia has been associated with poor outcomes in various medical and surgical conditions. However, its impact in systemic necrotizing vasculitides (SNV) had never been characterized. We aimed to assess the prevalence, associated factors and prognostic impact of sarcopenia in SNV.

Methods: Patients with SNV were successively included in a prospective longitudinal study assessing comorbidities. At inclusion, we evaluated sarcopenia by assessing skeletal muscle mass index using DXA and muscle strength using handgrip strength. Vasculitis and treatments-related events were recorded and analysed using Cox models.

Results: One hundred and twenty patients were included. At inclusion, low handgrip strength (<30 kg for men and 20 kg for women) was identified in 28 (23%) patients, while no patient exhibited low skeletal muscle mass index (<7.23 kg/m2 for men and 5.67 kg/m2 for women). Low handgrip strength was associated with age (P <0.0001), type of vasculitis (P =0.01), vasculitis damage index (P =0.01), history of falls (P =0.0002), osteoporosis (P =0.04), low serum albumin (P =0.003) and prealbumin (P =0.0007), high CRP (P =0.001), high FRAX® tool (P =0.002) and low bone mineral density at femoral neck (P =0.0002). After median follow-up of 42 months, low handgrip strength was associated with higher risk of bone fracture [HR 4.25 (1.37-13.2), P =0.01] and serious adverse events [HR 2.80 (1.35-5.81), P =0.006].

Conclusion: Handgrip strength is associated in SNV with nutritional status and comorbidities such as bone disease, and seems to predict, as in other medical conditions, the risk of fracture and serious adverse events during follow-up. In contrast, assessment of skeletal muscle mass index in this population remains uncertain.
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http://dx.doi.org/10.1093/rheumatology/kez680DOI Listing
September 2020

Reply to comments on the Rigal et al. (2019) Bacloville trial.

Addiction 2020 11 13;115(11):2186-2187. Epub 2020 Jun 13.

Université de Paris, Faculté de Santé, UFR de Médecine,Département de Médecine Générale, Paris, France.

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http://dx.doi.org/10.1111/add.15104DOI Listing
November 2020

Early treatment with FCR versus watch and wait in patients with stage Binet A high-risk chronic lymphocytic leukemia (CLL): a randomized phase 3 trial.

Leukemia 2020 08 18;34(8):2038-2050. Epub 2020 Feb 18.

Unite de Recherche Clinique, Hopital Avicenne, Bobigny, France.

We report a randomized prospective phase 3 study (CLL7), designed to evaluate the efficacy of fludarabine, cyclophosphamide, and rituximab (FCR) in patients with an early-stage high-risk chronic lymphocytic leukemia (CLL). Eight hundred patients with untreated-stage Binet A disease were enrolled as intent-to-treat population and assessed for four prognostic markers: lymphocyte doubling time <12 months, serum thymidine kinase >10 U/L, unmutated IGHV genes, and unfavorable cytogenetics (del(11q)/del(17p)/trisomy 12). Two hundred and one patients with ≥2 risk features were classified as high-risk CLL and 1:1 randomized to receive either immediate therapy with 6xFCR (Hi-FCR, 100 patients), or to be observed according to standard of care (Hi-W&W, 101 patients). The overall response rate after early FCR was 92.7%. Common adverse events were hematological toxicities and infections (61.0%/41.5% of patients, respectively). After median observation time of 55.6 (0-99.2) months, event-free survival was significantly prolonged in Hi-FCR compared with Hi-W&W patients (median not reached vs. 18.5 months, p < 0.001). There was no significant overall survival benefit for high-risk patients receiving early FCR therapy (5-year OS 82.9% in Hi-FCR vs. 79.9% in Hi-W&W, p = 0.864). In conclusion, although FCR is efficient to induce remissions in the Binet A high-risk CLL, our data do not provide evidence that alters the current standard of care "watch and wait" for these patients.
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http://dx.doi.org/10.1038/s41375-020-0747-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387319PMC
August 2020

Application of Basic Epidemiologic Principles and Electronic Health Records in a Deep Learning Prediction Model.

JAMA Dermatol 2020 04;156(4):472-473

Université de Paris, Epidemiology and Statistics Research Center (CRESS), Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA), F-75004, Paris, France.

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http://dx.doi.org/10.1001/jamadermatol.2019.4919DOI Listing
April 2020