Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial

Background Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. Methods In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH,non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2–F3, or F1 with at least oneaccompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpointsfor the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2–F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. Findings Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1–F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2–F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1–F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). Interpretation Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Diagnostic Performance of Height-Estimated Baseline Creatinine in Diagnosing Acute Kidney Injury in Children with Type 1 Diabetes Mellitus Onset

At type 1 diabetes mellitus (T1DM) onset, acute kidney injury (AKI) is very common. To diagnose AKI, the availability of a baseline serum creatinine (bSCr) is pivotal. However, in most hospitalized children the bSCr is unknown. We aimed to test whether the bSCr estimated on the basis of height (ebSCr) could be a reliable surrogate for AKI diagnosis compared with the measured bSCr (mbSCr). As the mbSCr, we considered the creatinine measured 14 days after T1DM onset while ebSCr (mg/dL) = (k x height [cm])/120 mL/min/1.73 m(2), where k = 0.55 for children and adolescent girls and k = 0.7 for adolescent boys. AKI was defined as serum creatinine values >1.5 times the baseline creatinine. Kappa statistics and the percentage of agreement in AKI classification by ebSCr-AKI versus mbSCr-AKI definition methods were calculated. Bland-Altman plots were used to show the agreement between the creatinine ratio (highest/baseline creatinine; HC/BC) calculated with mbSCr and ebSCr. The number of 163 patients with T1DM onset were included. On the basis of mbSCr, 66/163 (40.5%) presented AKI while, on the basis of ebSCr, 50/163 (30.7%) accomplished AKI definition. ebSCr showed good correlation with mbSCr using both the Spearman test (rho = 0.67; p < 0.001) and regression analysis (r = 0.68; p < 0.001). Moreover, at the Bland-Altman plots, the bias of the highest/baseline creatinine ratio calculated on the basis of the mbSCr compared to ebSCr was minimal (bias = -0.08 mg/dL; 95% limits of agreement = -0.23/0.39). AKI determined using ebSCr showed 90% agreement with AKI determined using mbSCr (kappa = 0.66; p < 0.001). Finally, we compared the area under a receiver-operating characteristic curve (AUROC) of HC/BC ratio calculated on the basis of ebSCr with AUROC of the gold standard HC/BC ratio calculated on the basis of mbSCr. As expected, the gold standard had an AUROC = 1.00 with a 95% confidence interval (CI) between 0.98 and 1.00, p < 0.001. The HC/BC ratio calculated on the basis of ebSCr also had significant AUROC (AUROC = 0.94; 95% CI: 0.90-0.97; p < 0.001). The comparison of the two ROC curves showed a p < 0.001. In conclusion, when mbSCr is unknown in patients with T1DM onset, the ebSCr calculated on the basis of height could be an alternative to orientate clinicians toward AKI diagnosis

Early-in-Life Serum Aldosterone Levels Could Predict Surgery in Patients with Obstructive Congenital Anomalies of the Kidney and Urinary Tract: A Pilot Study

The aim of the study was to evaluate whether serum aldosterone levels or plasmatic renin activity (PRA) measured early in life (1-3 months) could predict a future surgical intervention for obstructive congenital anomalies of kidney and urinary tract (CAKUT). Twenty babies aged 1-3 months of life with suspected obstructive CAKUT were prospectively enrolled. The patients underwent a 2-year follow-up and were classified as patients needing or not needing surgery. In all of the enrolled patients, PRA and serum aldosterone levels were measured at 1-3 months of life and were evaluated as predictors of surgery by receiver-operating characteristic (ROC) curve analysis. Patients undergoing surgery during follow-up showed significantly higher levels of aldosterone at 1-3 months of life compared to those who did not require surgery (p = 0.006). The ROC curve analysis of the aldosterone for obstructive CAKUT needing surgery showed an area under the ROC curve of 0.88 (95%CI = 0.71-0.95; p = 0.001). The aldosterone cut-off of 100 ng/dL presented 100% sensitivity and 64.3% specificity and predicted surgery in 100% of cases. The PRA at 1-3 months of life was not a predictor of surgery. In conclusion, serum aldosterone levels at 1-3 months could predict the need for surgery during obstructive CAKUT follow-up

Effects of Lockdown for COVID-19 Pandemic on Chronic Kidney Disease Progression in Children with Congenital Anomalies of the Kidney and Urinary Tract: A Retrospective Pilot Study

The coronavirus disease 2019 (COVID-19) pandemic changed adults and children’s lifestyle. We focused our attention on children affected by chronic kidney disease (CKD) due to congenital abnormalities of kidney and urinary tract (CAKUT) and their behavior during the lockdown. Our aims were to evaluate the incidence of CKD progression within 6 months after the end of the first Italian lockdown and the factors associated to it. CKD progression was defined by the transition to higher CKD stage or by the drop in estimated glomerular filtration rate by a 25% or more for patients belonging to CKD stages 1 and 2. We retrospectively selected 21 children with CAKUT and CKD ≥ stage 1 observed within 3 months before and 6 months after the first Italian lockdown. We called them by phone and asked them about their lifestyle before and during lockdown focusing on physical activity, screen time, sweet/candies/sugar-sweetened beverages eaten/drunk and adherence to the Mediterranean diet (MD) (through KIDMED questionnaire). We calculated and analyzed the delta between the pre- and post- lockdown observation of all collected parameters (clinical and biochemical parameters and questionnaires scores). Analyzing the overall cohort, we found significantly increased mean BMI and mean screen time and significantly lower mean physical activity time in post- compared with pre-lockdown observations. Eleven out of twenty-one patients (52.4%) had a worsening of CKD. These patients presented higher delta of levels of uric acid and microalbuminuria and showed minor adherence to the MD and declared to have consumed more sweets or candies or sugar-sweetened beverages/week during the lockdown with a tendentially major increment of BMI compared with patients not presenting CKD progression. In conclusion, the lockdown for COVID-19 pandemic determined increase of BMI in all enrolled patients due to a “forced” negative lifestyle. About half of these patients presented CKD progression. This progression was associated to less adherence to the MD and major consumption of sweets or candies or sugar-sweetened beverages

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical science. © The Author(s) 2019. Published by Oxford University Press