Using Interpretable Machine Learning to Identify Baseline Predictive Factors of Remission and Drug Durability in Crohn's Disease Patients on Ustekinumab.

Ustekinumab has shown efficacy in Crohn's Disease (CD) patients. To identify patient profiles of those who benefit the most from this treatment would help to position this drug in the therapeutic paradigm of CD and generate hypotheses for future trials. The objective of this analysis was to determine whether baseline patient characteristics are predictive of remission and the drug durability of ustekinumab, and whether its positioning with respect to prior use of biologics has a significant effect after correcting for disease severity and phenotype at baseline using interpretable machine learning. Patients' data from SUSTAIN, a retrospective multicenter single-arm cohort study, were used. Disease phenotype, baseline laboratory data, and prior treatment characteristics were documented. Clinical remission was defined as the Harvey Bradshaw Index ≤ 4 and was tracked longitudinally. Drug durability was defined as the time until a patient discontinued treatment. A total of 439 participants from 60 centers were included and a total of 20 baseline covariates considered. Less exposure to previous biologics had a positive effect on remission, even after controlling for baseline disease severity using a non-linear, additive, multivariable model. Additionally, age, body mass index, and fecal calprotectin at baseline were found to be statistically significant as independent negative risk factors for both remission and drug survival, with further risk factors identified for remission.

Monitoring the Anisotropy and Fluidity of the HDL Monolayer as Surrogates of HDL Functionality.

The fluidity of the biological lipid layers modulates processes involved in cardiovascular disease. High-density lipoprotein (HDL) monolayer fluidity is considered as a surrogate of HDL functionality. In particular, the more fluid the HDL monolayer is, the greater the cholesterol efflux (ChE) is observed. Fluidity depends on cholesterol and on the saturation and length of the fatty acids present in lipid layers. Specifically, low cholesterol and short-chain and/or low-saturated fatty acids content in the lipid layers increases fluidity. Lipid peroxidation is also involved in regulating the monolayers' fluidity. HDL oxidation decreases its fluidity and ChE capacity. Accordingly, the presence of antioxidants in biological membranes and in HDL increases fluidity. The fluidity is assessed in polarization studies that measures the steady-state anisotropy (r) using fluorescent probes (such as 1,6-diphenyl-1,3,5-hexatriene; DPH) that mimic the molecular movements of the sample analyzed. Since r refers to the rigidity and fluidity refers to the viscosity of lipid layers, the fluidity index is the inverse value of r (i.e., 1/r). This chapter describes a method for measuring HDL monolayer fluidity and r. The reproducibility of this method was excellent as the intra-assay coefficients of variation (CV) were <2.5 (20 replicates on the same day) and the interassay CV were <5% (60 replicates measured on 3 different days; 20 replicates/day). The method therefore represents a reproducible and useful tool to evaluate HDL functionality as an emerging cardiovascular risk factor.

Long-Term Real-World Effectiveness and Safety of Ustekinumab in Crohn's Disease Patients: The SUSTAIN Study.

BACKGROUND: Large real-world-evidence studies are required to confirm the durability of response, effectiveness, and safety of ustekinumab in Crohn's disease (CD) patients in real-world clinical practice. METHODS: A retrospective, multicentre study was conducted in Spain in patients with active CD who had received ≥1 intravenous dose of ustekinumab for ≥6 months. Primary outcome was ustekinumab retention rate; secondary outcomes were to identify predictive factors for drug retention, short-term remission (week 16), loss of response and predictive factors for short-term efficacy and loss of response, and ustekinumab safety. RESULTS: A total of 463 patients were included. Mean baseline Harvey-Bradshaw Index was 8.4. A total of 447 (96.5%) patients had received prior biologic therapy, 141 (30.5%) of whom had received ≥3 agents. In addition, 35.2% received concomitant immunosuppressants, and 47.1% had ≥1 abdominal surgery. At week 16, 56% had remission, 70% had response, and 26.1% required dose escalation or intensification; of these, 24.8% did not subsequently reduce dose. After a median follow-up of 15 months, 356 (77%) patients continued treatment. The incidence rate of ustekinumab discontinuation was 18% per patient-year of follow-up. Previous intestinal surgery and concomitant steroid treatment were associated with higher risk of ustekinumab discontinuation, while a maintenance schedule every 12 weeks had a lower risk; neither concomitant immunosuppressants nor the number of previous biologics were associated with ustekinumab discontinuation risk. Fifty adverse events were reported in 39 (8.4%) patients; 4 of them were severe (2 infections, 1 malignancy, and 1 fever). CONCLUSIONS: Ustekinumab is effective and safe as short- and long-term treatment in a refractory cohort of CD patients in real-world clinical practice.

This large retrospective study demonstrated the short- and long-term effectiveness and safety of ustekinumab in patients with Crohn's disease in real-world clinical practice, including those with refractory disease.

Effectiveness of a Motivational Nutritional Intervention through Social Networks 2.0 to Increase Adherence to the Mediterranean Diet and Improve Lung Function in Active Smokers: The DIET Study, a Randomized, Controlled and Parallel Clinical Trial in Primary Care.

BACKGROUND: Diet can help preserve lung function in smokers, as well as aid individuals who avoid smoking. This study aimed to evaluate the effectiveness of a nutritional intervention, using the Social Networks 2.0 tool, to increase adherence to the Mediterranean diet (MD) and improve lung function in smokers without prior respiratory disease. METHODS: A randomized controlled parallel design was used. The participants were assigned to either the intervention or control group. Data from representative smokers without respiratory disease (n = 77) aged 18-70 years were analyzed. The participants completed a validated semi-quantitative food-frequency questionnaire, and their adherence to the diet was evaluated by using the questionnaire called the Mediterranean Diet Adherence Score (MEDAS, with 14 items), which considers ≥9 points to indicate high adherence. The lung function was assessed by spirometry. Associations among variables were determined by logistic regression. RESULTS: A comparison of the variables at the end of the study between the control and intervention groups showed that the intervention significantly increased adherence to the MD based on the MEDAS questionnaire (0.69 (2.1) vs. 2.05 (2.03); p = 0.009). Specifically, the consumption of fruits was increased after two years in both groups; however, a more significant increase was detected in the intervention group (121 (178) vs. 12.7 (167) in the control group; p-value = 0.008). In the unadjusted analysis, the intervention only showed a statistical significant increase in the score of adherence to the MD (ß: 1.36; 95% CI 0.35; 2.3; p = 0.009), and this increase was maintained after adjusting for age and sex (ß: 1.15; 95% CI 0.05; 2.2; p = 0.040) and after adjusting for various sociodemographic, lifestyle and anthropometric variables (ß: 1.17; 95% CI 0.02; 2.31; p = 0.046). The pulmonary function parameters improved more in the intervention group; however, no significant differences were observed between the two groups. CONCLUSIONS: A nutritional intervention based on a dietetic-nutritional education program resulted in a significant increase in adherence to the MD. However, some evidence suggests that an MD dietary intervention can improve lung function, but in our study, we were not able to demonstrate this. Further research is needed to obtain more robust data and confirm a possible benefit of the program before it can be extended to general practice.