Unsupervised Context-Sensitive Spelling Correction of English and Dutch Clinical Free-Text with Word and Character N-Gram Embeddings

We present an unsupervised context-sensitive spelling correction method for clinical free-text that uses word and character n-gram embeddings. Our method generates misspelling replacement candidates and ranks them according to their semantic fit, by calculating a weighted cosine similarity between the vectorized representation of a candidate and the misspelling context. To tune the parameters of this model, we generate self-induced spelling error corpora. We perform our experiments for two languages. For English, we greatly outperform off-the-shelf spelling correction tools on a manually annotated MIMIC-III test set, and counter the frequency bias of a noisy channel model, showing that neural embeddings can be successfully exploited to improve upon the state-of-the-art. For Dutch, we also outperform an off-the-shelf spelling correction tool on manually annotated clinical records from the Antwerp University Hospital, but can offer no empirical evidence that our method counters the frequency bias of a noisy channel model in this case as well. However, both our context-sensitive model and our implementation of the noisy channel model obtain high scores on the test set, establishing a state-of-the-art for Dutch clinical spelling correction with the noisy channel model.Comment: Appears in volume 7 of the CLIN Journal, http://www.clinjournal.org/biblio/volum

Impact of withholding early parenteral nutrition completing enteral nutrition in pediatric critically ill patients (PEPaNIC trial): Study protocol for a randomized controlled trial

Background: The state-of-the-art nutrition used for critically ill children is based essentially on expert opinion and extrapolations from adult studies or on studies in non-critically ill children. In critically ill adults, withholding parenteral nutrition (PN) during the first week in ICU improved outcome, as compared with early supplementation of insufficient enteral nutrition (EN) with PN. We hypothesized that withholding PN in children early during critical illness reduces the incidence of new infections and accelerates recovery. Methods/Design: The Pediatric Early versus Late Parenteral Nutrition in Intensive Care Unit (PEPaNIC) study is an investigator-initiated, international, multicenter, randomized controlled trial (RCT) in three tertiary referral pediatric intensive care units (PICUs) in three countries on two continents. This study compares early versus late initiation of PN when EN fails to reach preset caloric targets in critically ill children. In the early-PN (control, standard of care) group, PN comprising glucose, lipids and amino acids is administered within the first days to reach the caloric target. In the late-PN (intervention) group, PN completing EN is only initiated beyond PICU-day 7, when EN fails. For both study groups, an early EN protocol is applied and micronutrients are administered intravenously. The primary assessor-blinded outcome measures are the incidence of new infections during PICU-stay and the duration of intensive care dependency. The sample size (n = 1,440, 720 per arm) was determined in order to detect a 5% absolute reduction in PICU infections, with at least 80% 1-tailed power (70% 2-tailed) and an alpha error rate of 5%. Based on the actual incidence of new PICU infections in the control group, the required sample size was confirmed at the time of an a priori- planned interim-analysis focusing on the incidence of new infections in the control group only. Discussion: Clinical evidence in favor of early administration of PN in critically ill children is currently lacking, despite potential benefit but also known side effects. This large international RCT will help physicians to gain more insight in the clinical effects of omitting PN during the first week of critical illness in children

Effect of anti-interleukin drugs in patients with COVID-19 and signs of cytokine release syndrome (COV-AID): a factorial, randomised, controlled trial.

BACKGROUND: Infections with SARS-CoV-2 continue to cause significant morbidity and mortality. Interleukin (IL)-1 and IL-6 blockade have been proposed as therapeutic strategies in COVID-19, but study outcomes have been conflicting. We sought to study whether blockade of the IL-6 or IL-1 pathway shortened the time to clinical improvement in patients with COVID-19, hypoxic respiratory failure, and signs of systemic cytokine release syndrome. METHODS: We did a prospective, multicentre, open-label, randomised, controlled trial, in hospitalised patients with COVID-19, hypoxia, and signs of a cytokine release syndrome across 16 hospitals in Belgium. Eligible patients had a proven diagnosis of COVID-19 with symptoms between 6 and 16 days, a ratio of the partial pressure of oxygen to the fraction of inspired oxygen (PaO(2):FiO(2)) of less than 350 mm Hg on room air or less than 280 mm Hg on supplemental oxygen, and signs of a cytokine release syndrome in their serum (either a single ferritin measurement of more than 2000 μg/L and immediately requiring high flow oxygen or mechanical ventilation, or a ferritin concentration of more than 1000 μg/L, which had been increasing over the previous 24 h, or lymphopenia below 800/mL with two of the following criteria: an increasing ferritin concentration of more than 700 μg/L, an increasing lactate dehydrogenase concentration of more than 300 international units per L, an increasing C-reactive protein concentration of more than 70 mg/L, or an increasing D-dimers concentration of more than 1000 ng/mL). The COV-AID trial has a 2 × 2 factorial design to evaluate IL-1 blockade versus no IL-1 blockade and IL-6 blockade versus no IL-6 blockade. Patients were randomly assigned by means of permuted block randomisation with varying block size and stratification by centre. In a first randomisation, patients were assigned to receive subcutaneous anakinra once daily (100 mg) for 28 days or until discharge, or to receive no IL-1 blockade (1:2). In a second randomisation step, patients were allocated to receive a single dose of siltuximab (11 mg/kg) intravenously, or a single dose of tocilizumab (8 mg/kg) intravenously, or to receive no IL-6 blockade (1:1:1). The primary outcome was the time to clinical improvement, defined as time from randomisation to an increase of at least two points on a 6-category ordinal scale or to discharge from hospital alive. The primary and supportive efficacy endpoints were assessed in the intention-to-treat population. Safety was assessed in the safety population. This study is registered online with ClinicalTrials.gov (NCT04330638) and EudraCT (2020-001500-41) and is complete. FINDINGS: Between April 4, and Dec 6, 2020, 342 patients were randomly assigned to IL-1 blockade (n=112) or no IL-1 blockade (n=230) and simultaneously randomly assigned to IL-6 blockade (n=227; 114 for tocilizumab and 113 for siltuximab) or no IL-6 blockade (n=115). Most patients were male (265 [77%] of 342), median age was 65 years (IQR 54-73), and median Systematic Organ Failure Assessment (SOFA) score at randomisation was 3 (2-4). All 342 patients were included in the primary intention-to-treat analysis. The estimated median time to clinical improvement was 12 days (95% CI 10-16) in the IL-1 blockade group versus 12 days (10-15) in the no IL-1 blockade group (hazard ratio [HR] 0·94 [95% CI 0·73-1·21]). For the IL-6 blockade group, the estimated median time to clinical improvement was 11 days (95% CI 10-16) versus 12 days (11-16) in the no IL-6 blockade group (HR 1·00 [0·78-1·29]). 55 patients died during the study, but no evidence for differences in mortality between treatment groups was found. The incidence of serious adverse events and serious infections was similar across study groups. INTERPRETATION: Drugs targeting IL-1 or IL-6 did not shorten the time to clinical improvement in this sample of patients with COVID-19, hypoxic respiratory failure, low SOFA score, and low baseline mortality risk. FUNDING: Belgian Health Care Knowledge Center and VIB Grand Challenges program