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Background: Sézary syndrome is an extremely rare and fatal cutaneous T-cell lymphoma (CTCL). Mogamulizumab, an anti-CCR4 monoclonal antibody, has recently been associated with increased progression-free survival in a randomized clinical trial in CTCL. We aimed to evaluate OS and prognostic factors in Sézary syndrome, including treatment with mogamulizumab, in a real-life setting. Methods: Data from patients with Sézary (ISCL/EORTC stage IV) and pre-Sézary (stage IIIB) syndrome diagnosed from 2000 to 2020 were obtained from 24 centers in Europe. Age, disease stage, plasma lactate dehydrogenases levels, blood eosinophilia at diagnosis, large-cell transformation and treatment received were analyzed in a multivariable Cox proportional hazard ratio model. This study has been registered in ClinicalTrials (SURPASSe01 study: NCT05206045). Findings: Three hundred and thirty-nine patients were included (58% men, median age at diagnosis of 70 years, Q1-Q3, 61-79): 33 pre-Sézary (9.7% of 339), 296 Sézary syndrome (87.3%), of whom 10 (2.9%) had large-cell transformation. One hundred and ten patients received mogamulizumab. Median follow-up was 58 months (95% confidence interval [CI], 53-68). OS was 46.5% (95% CI, 40.6%-53.3%) at 5 years. Multivariable analysis showed that age ≥ 80 versus <50 (HR: 4.9, 95% CI, 2.1-11.2, p = 0.001), and large-cell transformation (HR: 2.8, 95% CI, 1.6-5.1, p = 0.001) were independent and significant factors associated with reduced OS. Mogamulizumab treatment was significantly associated with decreased mortality (HR: 0.34, 95% CI, 0.15-0.80, p = 0.013). Interpretation: Treatment with mogamulizumab was significantly and independently associated with decreased mortality in Sézary syndrome. Funding: French Society of Dermatology, Swiss National Science Foundation (IZLIZ3_200253/1) and SKINTEGRITY.CH collaborative research program.
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INTRODUCTION: In children, respiratory distress due to upper airway obstruction (UAO) is a common complication of extubation. The quantitative cuff-leak test (qtCLT) is a simple, rapid and non-invasive test that has not been extensively studied in children. The objective of the ongoing study whose protocol is reported here is to investigate how well the qtCLT predicts UAO-related postextubation respiratory distress in paediatric intensive care unit (PICU) patients. METHODS AND ANALYSIS: Air Leak Test in the Paediatric Intensive Care Unit is a multicentre, prospective, observational study that will recruit 900 patients who are aged 2 days post-term to 17 years and ventilated through a cuffed endotracheal tube for at least 24 hours in any of 19 French PICUs. Within an hour of planned extubation, the qtCLT will be performed as a sequence of six measurements of the tidal volume with the cuff inflated then deflated. The primary outcome is the occurrence within 48 hours after extubation of severe UAO defined as combining a requirement for intravenous corticosteroid therapy and/or ventilator support by high-flow nasal cannula and/or by non-invasive ventilation or repeat invasive mechanical ventilation with a Westley score ≥4 with at least one point for stridor at each initiation. The results of the study are expected to identify risk factors for UAO-related postextubation respiratory distress and extubation failure, thereby identifying patient subgroups most likely to require preventive interventions. It will also determine whether qtCLT appears to be a reliable method to predict an increased risk for postextubation adverse events as severe UAO. ETHICS AND DISSEMINATION: The study was approved by the Robert Debré University Hospital institutional review board (IRB) on September 2021 (approval #2021578). The report of Robert Debré University Hospital IRB is valid for all sites, given the nature of the study with respect to the French law. The results will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT05328206.
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Extubação , Unidades de Terapia Intensiva Pediátrica , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Extubação/efeitos adversos , Obstrução das Vias Respiratórias/etiologia , França , Intubação Intratraqueal/efeitos adversos , Estudos Multicêntricos como Assunto , Estudos Observacionais como Assunto , Estudos Prospectivos , Respiração Artificial/efeitos adversos , Volume de Ventilação PulmonarRESUMO
PURPOSE: Suboptimal communication with clinicians, fragmented care and failure to align with patients' preferences are determinants of post intensive care unit (ICU) burden in family members. Our aim was to evaluate the impact of a nurse facilitator on family psychological burden. METHODS: We carried out a randomised controlled trial in five ICUs in France comparing standard communication by ICU clinicians to additional communication and support by nurse facilitators. We included patients > 18 years, with expected ICU length of stay > 2 days, chronic life-limiting illness, and their family members. Facilitators were trained to help families to secure care in line with patient's goals, beginning in ICU and continuing for 3 months. Assessments were made at baseline and 1, 3 and 6 months post-randomisation. Primary outcome was the evolution of family symptoms of depression over 6 months using a linear mixed effects model on the depression subscale of the Hospital Anxiety and Depression Scale (HADS). Secondary outcomes included HADS-Anxiety, Impact of Event Scale-6, goal-concordant care and experience of serious illness (QUAL-E). RESULTS: 385 patients and family members were enrolled. Follow-up at 1-, 3- and 6-month was completed by 284 (74%), 264 (68.6%) and 260 (67.5%) family members respectively. The intervention was associated with significantly more formal meetings between the ICU team and the family (1 [1-3] vs 2 [1-4]; p < 0.001). There was no significant difference between the intervention and control groups in evolution of symptoms of depression over 6 months (p = 0.91), nor in symptoms of depression at 6 months [0.53 95% CI (- 0.48; 1.55)]. There were no significant differences in secondary outcomes. CONCLUSION: This study does not support the use of facilitators for family members of ICU patients.
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Comunicação , Estado Terminal , Família , Unidades de Terapia Intensiva , Relações Profissional-Família , Humanos , Masculino , Feminino , Estado Terminal/psicologia , Estado Terminal/terapia , Pessoa de Meia-Idade , Família/psicologia , Unidades de Terapia Intensiva/organização & administração , Idoso , França , Adulto , Depressão/psicologiaAssuntos
COVID-19 , Influenza Humana , Síndrome do Desconforto Respiratório , Sobreviventes , Humanos , COVID-19/complicações , Síndrome do Desconforto Respiratório/terapia , Síndrome do Desconforto Respiratório/mortalidade , Influenza Humana/complicações , Sobreviventes/estatística & dados numéricos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , SARS-CoV-2 , PneumoniaRESUMO
The main objectives of multidisciplinary clinical investigation center (CIC-P) are to facilitate the availability of new drugs for patients, to enhance the visibility and attractiveness of French clinical research, to improve the quality of early phase trials, and to enhance the value of academic research by evaluating molecules in rare diseases. Since 2017, the CIC-P has been committed to a quality approach process, launching in 2018 its first satisfaction survey on patient care and clinical trial management of all its employees. A second satisfaction survey targeted by profession type was to be launched in 2020, in view of the requirements of the ISO 9001:2015 standard, but the process was interrupted following the coronavirus diseases 2019 (COVID-19) pandemic. The successful reorganization of the CIC-P activity during the first containment of the COVID-19 pandemic was driven by the implementation of a quality management system that promotes continuous improvement through the organization and involvement of all the staff. This voluntary and participative approach motivated the CIC-P to apply for the organizational sesame. The ISO 9001:2015 certification of CIC-P aims at increasing its performance, to satisfying its customers and to fully integrate its activities in a continuous improvement process, according to the requirements of this international standard, through the deployment of quality tools such as The Deming wheel (PDCA), an indispensable tool for transformation and reorganization; the analysis of the environment by the strengths, weakness, opportunities, threats (SWOT) analysis tool; the analysis and management of risks by the FMEA method, and all with performance indicators (SMART) and precise objectives at each stage of a project/process. The implementation of satisfaction questionnaires remains the essential tool for evaluating the expectations and needs of interested parties, but also for improving the quality of CIC-P activities and services. All these tools put in place have allowed us to continuously improve the means of production and to constantly improve our organization.
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BACKGROUND: Clinician-reported outcome (ClinRO) measures are emerging as useful contributors to assessments of treatment benefits. The objective of this study was to collect ClinRO measures of physical and cognitive impairments after convulsive status epilepticus (CSE) requiring intensive care unit admission. METHODS: We conducted a post hoc analysis of the data from HYBERNATUS, a multicenter open-label controlled trial that randomized 270 critically ill patients with CSE requiring mechanical ventilation in 11 French intensive care units to therapeutic hypothermia (32-34 °C for 24 h) plus standard care or standard care alone. We included all patients who attended a day 90 in-person neurologist visit with measurement of the functional independence measure (FIM) score (range from 18 [total assistance] to 126 [total independence]), Mini-Mental State Examination (MMSE) score (range 0-30), and Glasgow outcome scale (GOS) score (1, death; 2, vegetative state; 3, severe disability; 4, moderate disability; and 5, mild or no disability). These three scores were compared across groups defined by several patient and CSE characteristics. RESULTS: Of 229 patients with GOS scores ≥ 3 on day 90 (male sex, 58.2%; median age, 56 years [47-67]), 67 (29%) attended an in-person neurologist visit. Twenty-nine (43%) patients had a previous history of epilepsy, and 16 (24%) patients had a primary brain insult. CSE was refractory in 22 (33%) patients. On day 90 after CSE onset, median FIM and MMSE scores were 121 (112-125) and 26.0 (24.0-28.8), respectively. The GOS score was 3 in 16 (33.8%) patients, 4 in 9 (13.4%) patients, and 5 in 42 (62.7%) patients. Worse GOS score values were significantly associated with worse FIM and MMSE scores. CONCLUSIONS: In patients attending the in-person neurologist visit on day 90 after CSE onset, ClinRO measures indicated that the main impairments were cognitive. FIM and MMSE scores were associated with GOS scores. Further studies are needed to evaluate the possible impact of neuroprotective and rehabilitation strategies on disability and cognitive impairments in survivors of CSE. Clinical trial registration NCT01359332.
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Disfunção Cognitiva , Epilepsia , Hipotermia Induzida , Estado Epiléptico , Humanos , Masculino , Pessoa de Meia-Idade , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/terapia , Encéfalo , Resultado do TratamentoRESUMO
PURPOSE: To assess risk factors for arterial and venous thromboses (AVT) in patients hospitalized in general wards for COVID-19 pneumonia and requiring oxygen therapy. METHODS: Our study was based on three randomized studies conducted as part of the CORIMUNO-19 platform in France between 27 March and 26 April 2020. Adult inpatients with COVID-19 pneumonia requiring at least 3 l/min of oxygen but not ventilation were randomized to receive standard care alone or standard care plus biologics. Patients were followed up for 3 months, and adverse events were documented. Risk factor for AVT and bleeding was identified by analyzing clinical, laboratory, and treatment data at baseline among the 315 patients with complete datasets. A Fine and Gray model was used to take account of competing events. RESULTS: During the 3-month follow-up period, 39 AVT occurred in 38 (10%) of the 388 patients: 26 deep vein thromboses and/or pulmonary embolisms in 25 (6%) patients, and 14 arterial thrombotic events in 13 (3%) patients. A history of diabetes at inclusion [sHR (95% CI) = 2.65 (1.19-5.91), P = .017] and the C-reactive protein (CRP) level (sHR = 1 [1-1.01], P = .049) were significantly associated with an elevated risk of thrombosis. Obesity was not associated with a higher risk of thrombosis (sHR = 1.01 [0.4-2.57], P = .98). The CRP level and diabetes were not risk factors for hemorrhage. CONCLUSION: Among patients hospitalized in general wards for COVID-19 pneumonia during the first wave of the epidemic, diabetes (but not obesity) and a high CRP level were risk factors for AVT. The use of higher doses of anticoagulant in these high-risk patients could be considered.
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COVID-19 , Diabetes Mellitus , Tromboembolia , Trombose , Adulto , Humanos , COVID-19/complicações , COVID-19/terapia , SARS-CoV-2 , Oxigênio , Quartos de Pacientes , Tromboembolia/epidemiologia , Tromboembolia/etiologia , Hemorragia , Fatores de RiscoRESUMO
Background: The clinical outcome of COVID-19 pneumonia is highly variable. Few biological predictive factors have been identified. Genetic and immunological studies suggest that type 1 interferons (IFN) are essential to control SARS-CoV-2 infection. Objective: To study the link between change in blood IFN-α2 level and plasma SARS-Cov2 viral load over time and subsequent death in patients with severe and critical COVID-19. Methods: One hundred and forty patients from the CORIMUNO-19 cohort hospitalized with severe or critical COVID-19 pneumonia, all requiring oxygen or ventilation, were prospectively studied. Blood IFN-α2 was evaluated using the Single Molecule Array technology. Anti-IFN-α2 auto-Abs were determined with a reporter luciferase activity. Plasma SARS-Cov2 viral load was measured using droplet digital PCR targeting the Nucleocapsid gene of the SARS-CoV-2 positive-strand RNA genome. Results: Although the percentage of plasmacytoid dendritic cells was low, the blood IFN-α2 level was higher in patients than in healthy controls and was correlated to SARS-CoV-2 plasma viral load at entry. Neutralizing anti-IFN-α2 auto-antibodies were detected in 5% of patients, associated with a lower baseline level of blood IFN-α2. A longitudinal analysis found that a more rapid decline of blood IFN-α2 was observed in fatal versus surviving patients: mortality HR=3.15 (95% CI 1.14-8.66) in rapid versus slow decliners. Likewise, a high level of plasma SARS-CoV-2 RNA was associated with death risk in patients with severe COVID-19. Conclusion: These findings could suggest an interest in evaluating type 1 IFN treatment in patients with severe COVID-19 and type 1 IFN decline, eventually combined with anti-inflammatory drugs. Clinical trial registration: https://clinicaltrials.gov, identifiers NCT04324073, NCT04331808, NCT04341584.
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COVID-19 , Interferon Tipo I , Humanos , Plasma , RNA Viral , SARS-CoV-2RESUMO
Objective: To evaluate the efficacy of covid-19 convalescent plasma to treat patients admitted to hospital for moderate covid-19 disease with or without underlying immunodeficiency (CORIPLASM trial). Design: Open label, randomised clinical trial. Setting: CORIMUNO-19 cohort (publicly supported platform of open label, randomised controlled trials of immune modulatory drugs in patients admitted to hospital with moderate or severe covid-19 disease) based on 19 university and general hospitals across France, from 16 April 2020 to 21 April 2021. Participants: 120 adults (n=60 in the covid-19 convalescent plasma group, n=60 in the usual care group) admitted to hospital with a positive SARS-CoV2 test result, duration of symptoms <9 days, and World Health Organization score of 4 or 5. 49 patients (n=22, n=27) had underlying immunosuppression. Interventions: Open label randomisation to usual care or four units (200-220 mL/unit, 2 units/day over two consecutive days) of covid-19 convalescent plasma with a seroneutralisation titre >40. Main outcome measures: Primary outcomes were proportion of patients with a WHO Clinical Progression Scale score of ≥6 on the 10 point scale on day 4 (higher values indicate a worse outcome), and survival without assisted ventilation or additional immunomodulatory treatment by day 14. Secondary outcomes were changes in WHO Clinical Progression Scale scores, overall survival, time to discharge, and time to end of dependence on oxygen supply. Predefined subgroups analyses included immunosuppression status, duration of symptoms before randomisation, and use of steroids. Results: 120 patients were recruited and assigned to covid-19 convalescent plasma (n=60) or usual care (n=60), including 22 (covid-19 convalescent plasma) and 27 (usual care) patients who were immunocompromised. 13 (22%) patients who received convalescent plasma had a WHO Clinical Progression Scale score of ≥6 at day 4 versus eight (13%) patients who received usual care (adjusted odds ratio 1.88, 95% credible interval 0.71 to 5.24). By day 14, 19 (31.6%) patients in the convalescent plasma group and 20 (33.3%) patients in the usual care group needed ventilation, additional immunomodulatory treatment, or had died. For cumulative incidence of death, three (5%) patients in the convalescent plasma group and eight (13%) in the usual care group died by day 14 (adjusted hazard ratio 0.40, 95% confidence interval 0.10 to 1.53), and seven (12%) patients in the convalescent plasma group and 12 (20%) in the usual care group by day 28 (adjusted hazard ratio 0.51, 0.20 to 1.32). In a subgroup analysis performed in patients who were immunocompromised, transfusion of covid-19 convalescent plasma was associated with mortality (hazard ratio 0.39, 95% confidence interval 0.14 to 1.10). Conclusions: In this study, covid-19 convalescent plasma did not improve early outcomes in patients with moderate covid-19 disease. The efficacy of convalescent plasma in patients who are immunocompromised should be investigated further. Trial registration: ClinicalTrials.gov NCT04345991.
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OBJECTIVE: Previous studies suggested that distinct phenotypes of eosinophilic granulomatosis with polyangiitis (EGPA; formerly known as Churg-Strauss syndrome) could be determined by the presence or absence of antineutrophil cytoplasmic antibodies (ANCA), reflecting predominant vasculitic or eosinophilic processes, respectively. This study explored whether ANCA-based clusters or other clusters can be identified in EGPA. METHODS: This study used standardized data of 15 European centers for patients with EGPA fulfilling widely accepted classification criteria. We used multiple correspondence analysis, hierarchical cluster analysis, and a decision tree model. The main model included 10 clinical variables (musculoskeletal [MSK], mucocutaneous, ophthalmological, ENT, cardiovascular, pulmonary, gastrointestinal, renal, central, or peripheral neurological involvement); a second model also included ANCA results. RESULTS: The analyses included 489 patients diagnosed between 1984 and 2015. ANCA were detected in 37.2% of patients, mostly perinuclear ANCA (85.4%) and/or antimyeloperoxidase (87%). Compared with ANCA-negative patients, those with ANCA had more renal (P < 0.001) and peripheral neurological involvement (P = 0.04), fewer cardiovascular signs (P < 0.001), and fewer biopsies with eosinophilic tissue infiltrates (P = 0.001). The cluster analyses generated 4 (model without ANCA) and 5 clusters (model with ANCA). Both models identified 3 identical clusters of 34, 39, and 40 patients according to the presence or absence of ENT, central nervous system, and ophthalmological involvement. Peripheral neurological and cardiovascular involvement were not predictive characteristics. CONCLUSION: Although reinforcing the known association of ANCA status with clinical manifestations, cluster analysis does not support a complete separation of EGPA in ANCA-positive and -negative subsets. Collectively, these data indicate that EGPA should be regarded as a phenotypic spectrum rather than a dichotomous disease.
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Síndrome de Churg-Strauss , Granulomatose com Poliangiite , Humanos , Síndrome de Churg-Strauss/diagnóstico , Granulomatose com Poliangiite/diagnóstico , Anticorpos Anticitoplasma de Neutrófilos , Fenótipo , Análise por ConglomeradosRESUMO
BACKGROUND: Cardiac surgery-associated acute kidney injury (CSA-AKI) is frequent. While two network meta-analyses assessed the impact of pharmacological interventions to prevent CSA-AKI, none focused on non-pharmacological interventions. We aim to assess the effectiveness of non-pharmacological interventions to reduce the incidence of CSA-AKI. METHODS: We searched PubMed, Embase, Central and clinical trial registries from January 1, 2004 (first consensus definition of AKI) to July 1, 2023. Additionally, we conducted manual screening of abstracts of major anesthesia and intensive care conferences over the last 5 years and reference lists of relevant studies. We selected all randomized controlled trials (RCTs) assessing a non-pharmacological intervention to reduce the incidence of CSA-AKI, without language restriction. We excluded RCTs of heart transplantation or involving a pediatric population. The primary outcome variable was CSA-AKI. Two reviewers independently identified trials, extracted data and assessed risk of bias. Random-effects meta-analyses were conducted to calculate risk ratios (RRs) with 95% confidence intervals (CIs). We used the Grading of Recommendations Assessment, Development, and Evaluation to assess the quality of evidence. RESULTS: We included 86 trials (25,855 patients) evaluating 10 non-pharmacological interventions to reduce the incidence of CSA-AKI. No intervention had high-quality evidence to reduce CSA-AKI. Two interventions were associated with a significant reduction in CSA-AKI incidence, with moderate quality of evidence: goal-directed perfusion (RR, 0.55 [95% CI 0.40-0.76], I2 = 0%; Phet = 0.44) and remote ischemic preconditioning (RR, 0.86 [0.78-0.95]; I2 = 23%; Phet = 0.07). Pulsatile flow during cardiopulmonary bypass was associated with a significant reduction in CSA-AKI incidence but with very low quality of evidence (RR = 0.69 [0.48; 0.99]; I2 = 53%; Phet < 0.01). We found high quality of evidence for lack of effect of restrictive transfusion strategy (RR, 1.02 [95% CI 0.92; 1.12; Phet = 0.67; I2 = 3%) and tight glycemic control (RR, 0.86 [95% CI 0.55; 1.35]; Phet = 0.25; I2 = 26%). CONCLUSIONS: Two non-pharmacological interventions are likely to reduce CSA-AKI incidence, with moderate quality of evidence: goal-directed perfusion and remote ischemic preconditioning.
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Injúria Renal Aguda , Anestesia , Anestesiologia , Procedimentos Cirúrgicos Cardíacos , Criança , Humanos , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/prevenção & controle , Ponte CardiopulmonarRESUMO
This study compares data on the symptoms of posttraumatic stress disorder (PTSD) among family members of patients with acute respiratory distress syndrome (ARDS) caused by COVID-19 vs nonCOVID-19 ARDS.
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COVID-19 , Família , Síndrome do Desconforto Respiratório , Transtornos de Estresse Pós-Traumáticos , Humanos , COVID-19/complicações , Família/psicologia , Qualidade de Vida , Síndrome do Desconforto Respiratório/etiologia , Transtornos de Estresse Pós-Traumáticos/psicologiaRESUMO
RECIST 1.1 criteria are commonly used with computed tomography (CT) to evaluate the efficacy of systemic treatments in patients with neuroendocrine tumors (NETs) and liver metastases (LMs), but their relevance is questioned in this setting. We aimed to explore alternative criteria using different numbers of measured LMs and thresholds of size and density variation. We retrospectively studied patients with advanced pancreatic or small intestine NETs with LMs, treated with systemic treatment in the first-and/or second-line, without early progression, in 14 European expert centers. We compared time to treatment failure (TTF) between responders and non-responders according to various criteria defined by 0%, 10%, 20% or 30% decrease in the sum of LM size, and/or by 10%, 15% or 20% decrease in LM density, measured on two, three or five LMs, on baseline (≤1 month before treatment initiation) and first revaluation (≤6 months) contrast-enhanced CT scans. Multivariable Cox proportional hazard models were performed to adjust the association between response criteria and TTF on prognostic factors. We included 129 systemic treatments (long-acting somatostatin analogs 41.9%, chemotherapy 26.4%, targeted therapies 31.8%), administered as first-line (53.5%) or second-line therapies (46.5%) in 91 patients. A decrease ≥10% in the size of three LMs was the response criterion that best predicted prolonged TTF, with significance at multivariable analysis (HR 1.90; 95% CI: 1.06-3.40; p = .03). Conversely, response defined by RECIST 1.1 did not predict prolonged TTF (p = .91), and neither did criteria based on changes in LM density. A ≥10% decrease in size of three LMs could be a more clinically relevant criterion than the current 30% threshold utilized by RECIST 1.1 for the evaluation of treatment efficacy in patients with advanced NETs. Its implementation in clinical trials is mandatory for prospective validation. Criteria based on changes in LM density were not predictive of treatment efficacy. CLINICAL TRIAL REGISTRATION: Registered at CNIL-CERB, Assistance publique hopitaux de Paris as "E-NETNET-L-E-CT" July 2018. No number was assigned. Approved by the Medical Ethics Review Board of University Medical Center Groningen.
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Neoplasias Hepáticas , Tumores Neuroendócrinos , Humanos , Critérios de Avaliação de Resposta em Tumores Sólidos , Tumores Neuroendócrinos/diagnóstico por imagem , Tumores Neuroendócrinos/tratamento farmacológico , Estudos Retrospectivos , Tomografia Computadorizada por Raios X , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/tratamento farmacológicoRESUMO
OBJECTIVES: To investigate whether the lactate dehydrogenase D (LDHD) gene deficiency causes juvenile-onset gout. METHODS: We used whole-exome sequencing for two families and a targeted gene-sequencing panel for an isolated patient. d-lactate dosages were analysed using ELISA. RESULTS: We demonstrated linkage of juvenile-onset gout to homozygous carriage of three rare distinct LDHD variants in three different ethnicities. In a Melanesian family, the variant was (NM_153486.3: c.206C>T; rs1035398551) and, as compared with non-homozygotes, homozygotes had higher hyperuricaemia (P = 0.02), lower fractional clearance of urate (P = 0.002), and higher levels of d-lactate in blood (P = 0.04) and urine (P = 0.06). In a second, Vietnamese, family, very severe juvenile-onset gout was linked to homozygote carriage of an undescribed LDHD variant (NM_153486.3: c.1363dupG) leading to a frameshift followed by a stop codon, p.(AlaGly432fsTer58). Finally, a Moroccan man, with early-onset and high d-lactaturia, whose family was unavailable for testing, was homozygous for another rare LDHD variant [NM_153486.3: c.752C>T, p.(Thr251Met)]. CONCLUSION: Rare, damaging LDHD variants can cause autosomal recessive early-onset gout, the diagnosis of which can be suspected by measuring high d-lactate levels in the blood and/or urine.
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Gota , Hiperuricemia , Masculino , Humanos , Gota/genética , Hiperuricemia/genética , Homozigoto , Ácido Láctico , Lactato Desidrogenases/genéticaRESUMO
BACKGROUND: The combination of infliximab and immunosuppressant therapy is a standard management strategy for patients with Crohn's disease. Concerns regarding the implications of long-term combination therapy provided the rationale for a formal clinical trial of treatment de-escalation. Our aim was to compare the relapse rate and the time spent in remission over 2 years between patients continuing combination therapy and those stopping infliximab or immunosuppressant therapy. METHODS: This multicentre, open-label, randomised controlled trial was performed in 64 hospitals in seven countries in Europe and Australia. Adult patients with Crohn's disease in steroid-free clinical remission for more than 6 months, on combination therapy of infliximab and immunosuppressant therapy for at least 8 months were randomly assigned (1:1:1) to either continue combination therapy (combination group), discontinue infliximab (infliximab withdrawal group), or discontinue immunosuppressant therapy (immunosuppressant withdrawal group). Randomisation was stratified according to disease duration before start of first anti-TNF treatment (≤2 or >2 years), failure of immunosuppressant therapy before start of infliximab, and presence of ulcers at baseline endoscopy. The patient number and group of each stratum were assigned by a central online randomisation website. Treatment was optimised or resumed in case of relapse in all groups. Participants, those assessing outcomes, and those analysing the data were not masked to group assignment. The coprimary endpoints were the relapse rate (superiority analysis) and time in remission over 2 years (non-inferiority analysis, non-inferiority margin 35 days). Analyses were done on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, NCT02177071, and with EU Clinical Trials Register, EUDRACT 2014-002311-41. The trial was completed in April, 2021. FINDINGS: Between Nov 2, 2015, and April 24, 2019, 254 patients were screened. Of these, 211 were randomised and 207 were included in the final analysis (n=67 in the combination group, n=71 in the infliximab withdrawal group, and n=69 in the immunosuppressant withdrawal group). 39 patients had a relapse (eight [12%] of 67 in the combination group, 25 [35%] of 71 in the infliximab withdrawal group, six [9%] of 69 in the immunosuppressant withdrawal group). 2-year relapse rates were 14% (95% CI 4-23) in the combination group, 36% (24-47) in the infliximab withdrawal group, and 10% (2-18) in the immunosuppressant withdrawal group (hazard ratio [HR] 3·45 [95% CI 1·56-7·69], p=0·003, for infliximab withdrawal vs combination, and 4·76 [1·92-11·11], p=0·0004, for infliximab withdrawal vs immunosuppressant withdrawal). Of 28 patients who had a relapse and were retreated or optimised according to protocol, remission was achieved in 25 patients (one of two in the combination group, 22 of 23 in the infliximab withdrawal group, and two of three in the immunosuppressant withdrawal group). The mean time spent in remission over 2 years was 698 days (95% CI 668-727) in the combination group, 684 days (651-717) in the infliximab withdrawal group, and 706 days (682-730) in the immunosuppressant withdrawal group. The difference in restricted mean survival time in remission was -14 days (95% CI -56 to 27) between the infliximab withdrawal group and the combination group and -22 days (-62 to 16) between the infliximab withdrawal group and the immunosuppressant withdrawal group. The 95% CIs contained the non-inferiority threshold (-35 days). We recorded 31 serious adverse events, in 20 patients, with no difference in frequency between groups. The most frequent serious adverse events were infections (four in the combination group, two in the infliximab withdrawal group, and one in the immunosuppressant withdrawal group) and Crohn's disease exacerbation (three in the combination group, four in the infliximab withdrawal group, and one in the immunosuppressant withdrawal group). No death nor malignancy was recorded. INTERPRETATION: In patients with Crohn's disease in sustained steroid-free remission under combination therapy with infliximab and immunosuppressant therapy, withdrawal of infliximab should only be considered after careful assessment of risks and benefits for each patient, whereas withdrawal of immunosuppressant therapy could generally represent a preferable strategy when considering treatment de-escalation. FUNDING: European Union's Horizon 2020.
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Doença de Crohn , Imunossupressores , Adulto , Humanos , Imunossupressores/efeitos adversos , Infliximab/efeitos adversos , Doença de Crohn/tratamento farmacológico , Doença de Crohn/induzido quimicamente , Azatioprina/efeitos adversos , Inibidores do Fator de Necrose Tumoral/uso terapêutico , RecidivaRESUMO
OBJECTIVES: To compare machine learning (ML) to traditional models to predict radiographic progression in patients with early axial spondyloarthritis (axSpA). METHODS: We carried out a prospective French multicentric DESIR cohort study with 5 years of follow-up that included patients with chronic back pain for <3 years, suggestive of axSpA. Radiographic progression was defined as progression at the spine (increase of at least 1 point of mSASSS scores/2 years) or at the sacroiliac joint (worsening of at least one grade of the mNY score between 2 visits). Statistical analyses were based on patients without any missing data regarding the outcome and variables of interest (295 patients).Traditional modelling: we performed a multivariate logistic regression model (M1); then variable selection with stepwise selection based on Akaike Information Criterion (stepAIC) method (M2), and Least Absolute Shrinkage and Selection Operator (LASSO) method (M3).ML modelling: using "SuperLearner" package on R, we modelled radiographic progression with stepAIC, LASSO, random forest, Discrete Bayesian Additive Regression Trees Samplers (DBARTS), Generalized Additive Models (GAM), multivariate adaptive polynomial spline regression (polymars), Recursive Partitioning And Regression Trees (RPART) and Super Learner. Accuracy of these models was compared based on their 10-fold cross-validated AUC (cv-AUC). RESULTS: 10-fold cv-AUC for traditional models were 0.79 and 0.78 for M2 and M3, respectively. The three best models in the ML algorithms were the GAM, the DBARTS and the Super Learner models, with 10-fold cv-AUC of: 0.77, 0.76 and 0.74, respectively. CONCLUSIONS: Two traditional models predicted radiographic progression as good as the eight ML models tested in this population.
Assuntos
Espondiloartrite Axial , Espondilartrite , Humanos , Espondilartrite/diagnóstico por imagem , Estudos de Coortes , Estudos Prospectivos , Teorema de Bayes , AlgoritmosRESUMO
BACKGROUND: Survival after meningioma surgery is often reported with inadequate allowance for competing causes of death. METHODS: We processed the Système National des Données de Santé, the French administrative medical database to retrieve appropriate patients' case of surgically treated meningiomas. The Pohar Perme relative survival (RS) method was implement. RESULTS: A total of 28,778 patients were identified between 2007 and 2017 of which 75% were female. Median age at surgery 59 years. Cranial convexity was the most common (24.7%) location and, benign meningioma represented 91.5% of all meningioma. Median follow-up was 3.5 years interquartile range [3.4-3.5]. At data collection, 2,232 patients were dead. The five-year survival relative to the expected survival of an age- and gender-matched French standard population was 96.2% 95% confidence interval (CI)[95.7-96.8]. Meningioma absolute excess risk of death was 973/100,000 person-years 95%CI[887-1068] (p< .001). The related standardised mortality ratio was 1.8 95%CI[1.7-1.9] (p< .001). In the adjusted model, male gender (hazard ratio [HR] =1.39, 95%CI[1.27-1.54], p< .001), age at surgery (HR=0.97, 95%CI[0.97-0.97], p < .001), type 2 neurofibromatosis (HR=2.95, 95%CI[1.95-4.46], p < .001), comorbidities HR=1.39, 95%CI[1.36-1.42], p < .001), location (HR=0.8, 95%CI[0.67-0.95], p= .0111), pre-operative embolization, (HR=1.3, 95%CI[1.08-1.56], p= .00507), cerebro-spinal fluid shunt, (HR=2.48, 95%CI[2.04-3.01], p < .001), atypical (HR=1.3, 95%CI [1.09-1.54], p= .00307) or malignant histology (HR=1.86, 95%CI[1.56-2.22], p< .001), redo surgery (HR=1.19, 95%CI[1.04-1.36], p= .0122) and radiotherapy (HR=1.43, 95%CI[1.26-1.62], p < .001) were established as independent predictors of RS. CONCLUSION: This unique study highlights the excess mortality associated with meningioma disease. Many factors such as gender, age, location, histopathological grading, redo surgery influence the RS.
Assuntos
COVID-19 , Adulto , Estado Terminal , Humanos , Hidroxicloroquina/uso terapêutico , Receptores de Interleucina-6 , SARS-CoV-2RESUMO
Computed tomography (CT) is used increasingly for the emergency assessment of caustic injuries and the need for emergency endoscopy has been challenged. The study evaluates outcomes of caustic ingestion in the modern era and the feasibility of abandoning emergency endoscopy. Between 2013 and 2019, 414 patients (197 men, median age 42 years) were admitted for caustic ingestion. Emergency and long-term outcomes of patients managed by CT and endoscopy (n = 120) and by CT alone (n = 294) were compared. Propensity score-based analysis was performed to limit bias of between-group comparison. A standard mortality ratio (SMR) was used to compare the observed mortality with the expected mortality in the general French population. Complications occurred in 97 (23%) patients and 17 (4.1%) patients died within 90 days of ingestion. Among 359 patients who underwent nonoperative management, 51 (14%) experienced complications and 7 (2%) died. Of 55 patients who underwent emergency surgery, 46 (84%) experienced complications and 10 (18%) died. The SMR was 8.4 for whole cohort, 5.5 after nonoperative management, and 19.3 after emergency surgery. On multivariate analysis, intentional ingestion (P < 0.016), age (P < 0.0001) and the CT grade of esophageal injuries (P < 0.0001) were independent predictors of survival. The CT grade of esophageal injuries was the only independent predictor of success (P < 0.0001). Crude and propensity match analysis showed similar survival in patients managed with and without endoscopy. CT evaluation alone can be safely used for the emergency management of caustic ingestion.