Citations

AbstractBackground & AimsMachine learning (ML) provides new approaches for prognostication through the identification of novel subgroups of patients. We explored whether ML could support disease sub‐phenotyping and risk stratification in primary biliary cholangitis (PBC).MethodsML was applied to an international dataset of PBC patients. The dataset was split into a derivation cohort (training set) and a validation cohort (validation set), and key clinical features were analysed. The outcome was a composite of liver‐related death or liver transplantation. ML and standard survival analysis were performed.ResultsThe training set was composed of 11,819 subjects, while the validation set was composed of 1,069 subjects. ML identified four clusters of patients characterized by different phenotypes and long‐term prognosis. Cluster 1 (n = 3566) included patients with excellent prognosis, whereas Cluster 2 (n = 3966) consisted of individuals at worse prognosis differing from Cluster 1 only for albumin levels around the limit of normal. Cluster 3 (n = 2379) included young patients with florid cholestasis and Cluster 4 (n = 1908) comprised advanced cases. Further sub‐analyses on the dynamics of albumin within the normal range revealed that ursodeoxycholic acid‐induced increase of albumin >1.2 x lower limit of normal (LLN) is associated with improved transplant‐free survival.ConclusionsUnsupervised ML identified four novel groups of PBC patients with different phenotypes and prognosis and highlighted subtle variations of albumin within the normal range. Therapy‐induced increase of albumin >1.2 x LLN should be considered a treatment goal.

Abstract This international guideline proposes improving clozapine package inserts worldwide by using ancestry-based dosing and titration. Adverse drug reaction (ADR) databases suggest that clozapine is the third most toxic drug in the United States (US), and it produces four times higher worldwide pneumonia mortality than that by agranulocytosis or myocarditis. For trough steady-state clozapine serum concentrations, the therapeutic reference range is narrow, from 350 to 600 ng/mL with the potential for toxicity and ADRs as concentrations increase. Clozapine is mainly metabolized by CYP1A2 (female non-smokers, the lowest dose; male smokers, the highest dose). Poor metabolizer status through phenotypic conversion is associated with co-prescription of inhibitors (including oral contraceptives and valproate), obesity, or inflammation with C-reactive protein (CRP) elevations. The Asian population (Pakistan to Japan) or the Americas’ original inhabitants have lower CYP1A2 activity and require lower clozapine doses to reach concentrations of 350 ng/mL. In the US, daily doses of 300–600 mg/day are recommended. Slow personalized titration may prevent early ADRs (including syncope, myocarditis, and pneumonia). This guideline defines six personalized titration schedules for inpatients: 1) ancestry from Asia or the original people from the Americas with lower metabolism (obesity or valproate) needing minimum therapeutic dosages of 75–150 mg/day, 2) ancestry from Asia or the original people from the Americas with average metabolism needing 175–300 mg/day, 3) European/Western Asian ancestry with lower metabolism (obesity or valproate) needing 100–200 mg/day, 4) European/Western Asian ancestry with average metabolism needing 250–400 mg/day, 5) in the US with ancestries other than from Asia or the original people from the Americas with lower clozapine metabolism (obesity or valproate) needing 150–300 mg/day, and 6) in the US with ancestries other than from Asia or the original people from the Americas with average clozapine metabolism needing 300–600 mg/day. Baseline and weekly CRP monitoring for at least four weeks is required to identify any inflammation, including inflammation secondary to clozapine rapid titration.

AbstractWaldenström macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) is often differentiated from myeloma based on the presence of lytic bone lesions (LBL). However, WM/LPL can present with LBL, and management is poorly understood. We describe a case of an 81‐year‐old woman with LPL who presented with LBL and was successfully treated with chemoimmunotherapy.

Abstract Background Severe coronavirus disease 2019 (COVID-19) often results from the immune-mediated cytokine storm, triggered by granulocyte macrophage-colony stimulating factor (GM-CSF), potentially leading to respiratory failure and death. Lenzilumab, a novel anti-human GM-CSF monoclonal antibody, neutralizes GM-CSF and demonstrated potential to improve clinical outcomes in a matched case-cohort study of patients with severe COVID-19 pneumonia. This Phase 3 randomized, double-blind, placebo-controlled trial investigated the efficacy and safety of lenzilumab to improve the likelihood of survival without invasive mechanical ventilation (SWOV), beyond available treatments. Methods Hypoxic patients, hospitalized with COVID-19 (n=520), requiring supplemental oxygen, but not invasive mechanical ventilation, were randomized on Day 0 to receive lenzilumab (1800mg, n=261) or placebo (n=259), and available treatments, including remdesivir and/or corticosteroids; and were followed through Day 28. Results Baseline demographics were comparable between groups: male, 64.7%; mean age, 60.5 years; median CRP, 79.0 mg/L. Patients across both groups received steroids (93.7%), remdesivir (72.4%), or both (69.1%). Lenzilumab improved the primary endpoint, likelihood of SWOV in the mITT population, by 1.54-fold (HR: 1.54; 95%CI: 1.02-2.32, p=0.0403). Lenzilumab improved SWOV by 1.91-fold (nominal p=0.0073) and 1.92-fold (nominal p=0.0067) in patients receiving remdesivir or remdesivir and corticosteroids, respectively. A key secondary endpoint of incidence of IMV, ECMO or death was also improved in patients receiving remdesivir (p=0.020) or remdesivir and corticosteroids (p=0.0180). Treatment-emergent serious adverse events were similar across both groups. Conclusion Lenzilumab significantly improved SWOV in hypoxic COVID-19 patients upon hospitalization, with the greatest benefit observed in patients receiving treatment with remdesivir and corticosteroids. NCT04351152 Disclosures Zelalem Temesgem, MD, Humanigen, Inc (Grant/Research Support) Jason Baker, MD, Humanigen, Inc (Grant/Research Support) Christopher Polk, MD, Atea (Research Grant or Support)Gilead (Advisor or Review Panel member, Research Grant or Support)Humanigen (Research Grant or Support)Regeneron (Research Grant or Support) Claudia R. Libertin, MD, Gilead (Grant/Research Support) Colleen F. Kelley, MD, MPH, Gilead Sciences (Individual(s) Involved: Self): Grant/Research Support; Moderna (Individual(s) Involved: Self): Grant/Research Support; Novavax (Individual(s) Involved: Self): Grant/Research Support; Viiv (Individual(s) Involved: Self): Grant/Research Support Vincent Marconi, MD, Bayer (Consultant, Scientific Research Study Investigator)Eli Lilly (Consultant, Scientific Research Study Investigator)Gilead Sciences (Consultant, Scientific Research Study Investigator)ViiV (Consultant, Scientific Research Study Investigator) Victoria Catterson, PhD, Humanigen, Inc (Consultant) William Aronstein, MD, PhD, Humanigen, Inc (Consultant) Cameron Durrant, MD, Humanigen, Inc (Employee) Dale Chappell, MD, Humanigen, Inc (Employee) Omar Ahmed, PharmD, Humanigen, Inc (Employee) Gabrielle Chappell, MSc, Humanigen, Inc (Consultant) Andrew Badley, M.D., AbbVie (Consultant) for the LIVE-AIR Study Group, n/a, Humanigen, Inc (Grant/Research Support)

Nutritional deficiencies following endoscopic sleeve gastroplasty (ESG) are unknown. We retrospectively studied nutritional deficiencies in 20 patients who underwent ESG at our institution. No subjects had preprocedural anemia, whereas 22.2% (N = 2/9) developed anemia at 12 months. Vitamin D deficiency developed in one subject post-ESG. Vitamin A, E, C and magnesium deficiencies developed in 8.3% (N = 1/12), 18.2% (N = 2/11), 14.3% (N = 1/7) and 10% (N = 1/10) of subjects, respectively, at 12 months. Vitamin B12 and B6 deficiencies were detected in 12.5 and 14.3% of the subjects at baseline, however, resolved at 12 months. There were no pre- or postprocedural deficiencies in zinc, selenium, copper, folate, thiamine, phosphorus or calcium. In this study, nutritional deficiencies were observed in a very small subset of patients at various time points after ESG.

AbstractAs prevention trials advance with autosomal dominant Alzheimer disease (ADAD) participants, understanding the similarities and differences between ADAD and “sporadic” late‐onset AD (LOAD) is critical to determine generalizability of findings between these cohorts. Cognitive trajectories of ADAD mutation carriers (MCs) and autopsy‐confirmed LOAD individuals were compared to address this question. Longitudinal rates of change on cognitive measures were compared in ADAD MCs (n = 310) and autopsy‐confirmed LOAD participants (n = 163) before and after symptom onset (estimated/observed). LOAD participants declined more rapidly in the presymptomatic (preclinical) period and performed more poorly at symptom onset than ADAD participants on a cognitive composite. After symptom onset, however, the younger ADAD MCs declined more rapidly. The similar but not identical cognitive trajectories (declining but at different rates) for ADAD and LOAD suggest common AD pathologies but with some differences.