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•Liver-related prognosis in non-alcoholic fatty liver disease (NAFLD) is impaired in patients with advanced fibrosis.•FibroMeterVCTE is a new test combining blood markers and ...elastography.•FibroMeterVCTE outperforms other fibrosis tests for the diagnosis of advanced fibrosis in NAFLD.•Algorithms using FibroMeterVCTE as a second-line test provide 90% diagnostic accuracy.
Advanced liver fibrosis is an important diagnostic target in non-alcoholic fatty liver disease (NAFLD) as it defines the subgroup of patients with impaired prognosis. The non-invasive diagnosis of advanced fibrosis is currently limited by the suboptimal positive predictive value and the grey zone (representing indeterminate diagnosis) of fibrosis tests. Here, we aimed to determine the best combination of non-invasive tests for the diagnosis of advanced fibrosis in NAFLD.
A total of 938 patients with biopsy-proven NAFLD were randomized 2:1 into derivation and validation sets. All patients underwent liver stiffness measurement with vibration controlled transient elastography (VCTE) and blood fibrosis tests (NAFLD fibrosis score, Fibrosis-4 FIB4, Fibrotest, Hepascore, FibroMeter). FibroMeterVCTE, which combines VCTE results and FibroMeter markers in a single test, was also calculated in all patients.
For the diagnosis of advanced fibrosis, VCTE was significantly more accurate than the blood tests (area under the receiver operating characteristic curve AUROC: 0.840 ± 0.013, p ≤0.005). FibroMeter was the most accurate blood test (AUROC: 0.793 ± 0.015, p ≤0.017). The combinatory test FibroMeterVCTE outperformed VCTE and blood tests (AUROC: 0.866 ± 0.012, p ≤0.005). The sequential combination of FIB4 then FibroMeterVCTE (FIB4-FMVCTE algorithm) or VCTE then FibroMeterVCTE (VCTE-FMVCTE algorithm) provided an excellent diagnostic accuracy of 90% for advanced fibrosis, with liver biopsy only required to confirm the diagnosis in 20% of cases. The FIB4-FMVCTE and VCTE-FMVCTE algorithms were significantly more accurate than the pragmatic algorithms currently proposed.
The sequential combination of fibrosis tests in the FIB4-FMVCTE and VCTE-FMVCTE algorithms provides a highly accurate solution for the diagnosis of advanced fibrosis in NAFLD. These algorithms should now be validated for the diagnosis of advanced liver fibrosis in diabetology or primary care settings.
The evaluation of liver fibrosis is mandatory in non-alcoholic fatty liver disease (NAFLD), as advanced fibrosis identifies the subgroup of patients with impaired prognosis. FibroMeterVCTE is a new fibrosis test combining blood markers and the result of vibration controlled transient elastography (VCTE) into a single diagnostic test. Our results show that FibroMeterVCTE outperforms other blood fibrosis tests and VCTE alone for the diagnosis of advanced fibrosis in a large multi-centric cohort of 938 patients with biopsy-proven NAFLD. Sequential algorithms using a simple blood test or VCTE as a first-line procedure, then FibroMeterVCTE as a second-line test accurately classified 90% of patients.
The "Renal Risk Score" (RRS) and the histopathological classification have been proposed to predict the risk of end-stage kidney disease (ESKD) in ANCA-associated glomerulonephritis (ANCA-GN). ...Besides, factors associated with kidney function recovery after ANCA-GN onset remain to be more extensively studied. In the present study, we analyzed the value of the RRS and of the histopathological classification for ESKD prediction. Next, we analyzed factors associated with eGFR change within the first 2 years following ANCA-GN diagnosis.
We included patients from the Maine-Anjou ANCA-associated vasculitis registry with at least 6 months of follow-up. The values of ANCA-GN, histopathological classification, and RRS, and the factors associated with eGFR variations between ANCA-GN diagnosis and 2 years of follow-up were assessed.
The predictive values of the histopathological classification and RRS were analyzed in 123 patients. After a median follow-up of 42 months, 33.3% patients developed ESKD. The predictive value of RRS for ESKD was greater than that of the histopathological classification. Determinants of eGFR variation were assessed in 80/123 patients with complete eGFR measurement. The median eGFR increased from ANCA-GN diagnosis to month 6 and stabilized thereafter. The only factor associated with eGFR variation in our study was eGFR at ANCA-GN diagnosis, with higher eGFR at diagnosis being associated with eGFR loss (p<0.001).
The RRS has a better predictive value for ESKD than the histopathological classification. The main determinant of eGFR variation at 2 years was eGFR at ANCA-GN diagnosis. Thus, this study suggests that eGFR recovery is poorly predicted by histological damage at ANCA-GN diagnosis.
IntroductionPatients with lower limb trauma requiring orthopaedic immobilisation may be at risk of venous thromboembolism but opinions differ about who may benefit from thromboprophylactic ...anticoagulant treatment.The aim of this CASTING study is to demonstrate the safety of thromboprophylaxis based on the Thrombosis Risk Prediction for patients with cast immobilisation (TRiP(cast) score with regards to the 3-month incidence of symptomatic venous thromboembolism events in low-risk patients not receiving thromboprophylaxis, as well as the usefulness of this strategy on the rate of patients receiving anticoagulant treatment in comparison to current practice.Methods and analysisCASTING will be a stepped-wedge cluster randomised controlled clinical trial, performed in 15 emergency departments in France and Belgium. With their informed consent, outpatients admitted to one of the participating emergency departments for a lower limb trauma requiring orthopaedic immobilisation without surgery will be included. All centres will begin the trial with the ‘observational period’ and, every 2 weeks, 1 centre will be randomly assigned to switch to the ‘interventional period’ and to apply the TRiP(cast) score, in which only patients with a score ≥7 will receive thromboprophylactic anticoagulant treatment. The primary endpoint is the rate of clinical thromboembolic events within 90 days following the inclusion of low-risk patients not receiving thromboprophylaxis.Ethics and disseminationThe protocol has been approved by the Comité de Protection des Personnes Sud I (Ethics Review ID-RCB: 2019-A01829-48) for France and the Comité d’éthique hôpital-facultaire Saint Luc (N° B403201941338) for Belgium. It is carried out in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. The findings of this study will be disseminated in peer-reviewed journals and at scientific conferences.Trial registration numberNCT04064489.
IntroductionIn the context of the COVID-19 pandemic, early identification of patients who are likely to get worse is a major concern. Severity mainly depends on the development of acute respiratory ...distress syndrome (ARDS) with a predominance of subpleural lesions. Lung point-of-care ultrasonography (L-POCUS) is highly effective in detecting pulmonary peripheral patterns and may be appropriate for examining patients with COVID-19. We suggest that L-POCUS performed during the initial examination may identify patients with COVID-19 who are at a high risk of complicated treatment or unfavourable evolution.Methods and analysisPoint-of-care ultrasonography for risk stratification of non-critical COVID-19 patients on admission is a prospective, multicentre study. Adult patients visiting the emergency department (ED) of participating centres for suspected or confirmed COVID-19 are assessed for inclusion. Included patients have L-POCUS performed within 48 hours following ED admission. The severity of lung damage is assessed using the L-POCUS score based on 36 points for ARDS. Apart from the L-POCUS score assessment, patients are treated as recommended by the WHO. For hospitalised patients, a second L-POCUS is performed at day 5±3. A follow-up is carried out on day 14, and the patient’s status according to the Ordinal Scale for Clinical Improvement for COVID-19 from the WHO is recorded.The primary outcome is the rate of patients requiring intubation or who are dead from any cause during the 14 days following inclusion. We will determine the area under the ROC curve of L-POCUS.Ethics and disseminationThe protocol has been approved by the French and Belgian Ethics Committees and is carried out in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. The study is funding by a grant from the French Health Ministry, and its findings will be disseminated in peer-reviewed journals and at scientific conferences.Trial registration numberNCT04338100.
Vitamin D supplementation has been proposed as a treatment for Coronavirus Disease 2019 (COVID-19) based on experimental data and data from small and uncontrolled observational studies. The COvid19 ...and VITamin d TRIAL (COVIT-TRIAL) study was conducted to test whether a single oral high dose of cholecalciferol (vitamin D3) administered within 72 hours after the diagnosis of COVID-19 improves, compared to standard-dose cholecalciferol, the 14-day overall survival among at-risk older adults infected with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2).
This multicenter, randomized, controlled, open-label, superiority trial involved collaboration of 9 medical centers in France. Patients admitted to the hospital units or living in nursing homes adjacent to the investigator centers were eligible if they were ≥65 years, had SARS-CoV-2 infection of less than 3 days, and at least 1 COVID-19 worsening risk factor (among age ≥75 years, SpO2 ≤94%, or PaO2/FiO2 ≤300 mm Hg). Main noninclusion criteria were organ failure requiring ICU, SpO2 ≤92% despite 5 L/min oxygen, life expectancy <3 months, vitamin D supplementation >800 IU/day during the preceding month, and contraindications to vitamin D supplements. Eligible and consenting patients were randomly allocated to either a single oral high-dose (400,000 IU) or standard-dose (50,000 IU) cholecalciferol administered under medical supervision within 72 hours after the diagnosis of COVID-19. Participants and local study staff were not masked to the allocated treatment, but the Steering Committee and the Data and Safety Monitoring Board were masked to the randomization group and outcome data during the trial. The primary outcome was 14-day overall mortality. Between April 15 and December 17, 2020, of 1,207 patients who were assessed for eligibility in the COVIT-TRIAL study, 254 met eligibility criteria and formed the intention-to-treat population. The median age was 88 (IQR, 82 to 92) years, and 148 patients (58%) were women. Overall, 8 (6%) of 127 patients allocated to high-dose cholecalciferol, and 14 (11%) of 127 patients allocated to standard-dose cholecalciferol died within 14 days (adjusted hazard ratio = 0.39 95% confidence interval CI, 0.16 to 0.99, P = 0.049, after controlling for randomization strata i.e., age, oxygen requirement, hospitalization, use of antibiotics, anti-infective drugs, and/or corticosteroids and baseline imbalances in important prognostic factors i.e., sex, ongoing cancers, profuse diarrhea, and delirium at baseline). The number needed to treat for one person to benefit (NNTB) was 21 NNTB 9 to ∞ to number needed to treat for one person to harm (NNTH) 46. Apparent benefits were also found on 14-day mortality due to COVID-19 (7 (6%) deaths in high-dose group and 14 (11%) deaths in standard-dose group; adjusted hazard ratio = 0.33 95% CI, 0.12 to 0.86, P = 0.02). The protective effect of the single oral high-dose administration was not sustained at 28 days (19 (15%) deaths in high-dose group and 21 (17%) deaths in standard-dose group; adjusted hazard ratio = 0.70 95% CI, 0.36 to 1.36, P = 0.29). High-dose cholecalciferol did not result in more frequent adverse effects compared to the standard dose. The open-label design and limited study power are the main limitations of the study.
In this randomized controlled trial (RCT), we observed that the early administration of high-dose versus standard-dose vitamin D3 to at-risk older patients with COVID-19 improved overall mortality at day 14. The effect was no longer observed after 28 days.
ClinicalTrials.gov NCT04344041.
With the development of personalized medicine, the study of individual prognosis appears to be a major contemporary scientific issue. Dynamic models are particularly well adapted to such studies by ...allowing some potential changes in the follow-up to be taken into account. In particular, this leads to more accurate predictions by updating the available information throughout the patient monitoring. Some mathematical tools have been developed to quantify and compare the effectiveness of dynamic predictions using dynamic versions of the area under the receiver operating characteristic curve and the Brier score in the competing risks setting. Nevertheless, only two predictive abilities can be compared. This may be too restrictive in a clinical context where more and more information can be collected during patient follow-up thanks to recent technological advances. Here we propose a new procedure that allows multiple comparisons of the predictive abilities of different biomarkers, based on the dynamic area under the receiver operating characteristic curve or Brier score. Performances of our testing procedure were assessed by simulations. Moreover, a motivating application in hepatology will be presented. Finally, this work compares more than two dynamic predictive abilities of biomarkers and is available via R functions on GitHub.
In medical research, explanatory continuous variables are frequently transformed or converted into categorical variables. If the coding is unknown, many tests can be used to identify the "optimal" ...transformation. This common process, involving the problems of multiple testing, requires a correction of the significance level. Liquet and Commenges proposed an asymptotic correction of significance level in the context of generalized linear models (GLM) (Liquet and Commenges, Stat Probab Lett 71:33-38, 2005). This procedure has been developed for dichotomous and Box-Cox transformations. Furthermore, Liquet and Riou suggested the use of resampling methods to estimate the significance level for transformations into categorical variables with more than two levels (Liquet and Riou, BMC Med Res Methodol 13:75, 2013).
CPMCGLM provides to users both methods of p-value adjustment. Futhermore, they are available for a large set of transformations. This paper aims to provide insight the user an overview of the methodological context, and explain in detail the use of the CPMCGLM R package through its application to a real epidemiological dataset.
We present here the CPMCGLMR package providing efficient methods for the correction of type-I error rate in the context of generalized linear models. This is the first and the only available package in R providing such methods applied to this context. This package is designed to help researchers, who work principally in the field of biostatistics and epidemiology, to analyze their data in the context of optimal cutoff point determination.
We aimed to identify patients at low risk of bloodstream infection (BSI) in the ED.
We derived and validated a prediction model to rule out BSI in the ED without the need for laboratory testing by ...determining variables associated with a positive blood culture (BC) and assigned points according to regression coefficients. This retrospective study included adult patients suspected of having BSI (defined by at least one BC collection) from two European ED between 1 January 2017 and 31 December 2019. The primary end point was the BSI rate in the validation cohort for patients with a negative Bacteremia Rule Out Criteria (BAROC) score. The effect of adding laboratory variables to the model was evaluated as a second step in a two-step diagnostic strategy.
We analysed 2580 patients with a mean age of 64 years±21, of whom 46.1% were women. The derived BAROC score comprises 12 categorical clinical variables. In the validation cohort, it safely ruled out BSI without BCs in 9% (58/648) of patients with a sensitivity of 100% (95% CI 95% to 100%), a specificity of 10% (95% CI 8% to 13%) and a negative predictive value of 100% (95% CI 94% to 100%). Adding laboratory variables (creatinine ≥177 µmol/L (2.0 mg/dL), platelet count ≤150 000/mm
and neutrophil count ≥12 000/mm
) to the model, ruled out BSI in 10.2% (58/570) of remaining patients who had been positive on the BAROC score. The BAROC score with laboratory results had a sensitivity of 100% (95% CI 94% to 100%), specificity of 11% (95% CI 9% to 14%) and negative predictive value of 100% (95% CI 94 to 100%). In the validation cohort, there was no evidence of a difference in discrimination between the area under the receiver operating characteristic for BAROC score with versus without laboratory testing (p=0.6).
The BAROC score safely identified patients at low risk of BSI and may reduce BC collection in the ED without the need for laboratory testing.
Myelofibrosis is a myeloproliferative neoplasm associated with constitutional symptoms, increasing splenomegaly, and worsening cytopenias. Janus kinase (JAK) inhibitors have been used for the ...treatment of myelofibrosis for several years, but there is a lack of comparative information between those treatments. A systematic review and network meta-analysis was performed on randomized controlled trials in patients with myelofibrosis receiving JAK inhibitor or placebo or control. Primary outcomes were efficacy on spleen volume reduction and total symptom score reduction. Additional analyses were conducted on anemia and thrombopenia events. Seven studies were included in the network meta-analysis including 1953 patients randomly assigned to four JAK inhibitors-ruxolitinib, fedratinib, pacritinib, momelotinib-or control. In first-line therapy, momelotinib and fedratinib were associated with comparable efficacy to ruxolitinib, and with less toxicity on erythrocytes and platelets, respectively. Pacritinib was less effective on splenomegaly than ruxolitinib as a first-line treatment but seemed effective in second line, after ruxolitinib exposure. Fedratinib and ruxolitinib that are FDA approved in myelofibrosis have both confirmed being valuable option to treat splenomegaly and constitutional symptoms, and their slightly different tolerance-profiles can guide therapeutic choice for first-line treatment, according to patient profile. Momelotinib could be another option especially due to its positive effect on anemia.
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