Citations

Abstract Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium's possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N=2,367) and replicated in the combined PsyCourse (N=89) and BipoLife (N=102) studies. The associations of Li+PGS and lithium treatment response — defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P<����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������

AbstractObjectiveIn this observational study on a cohort of biopsy‐proven central nervous system demyelinating disease consistent with MS, we examined the relationship between early‐active demyelinating lesion immunopattern (IP) with subsequent clinical course, radiographic progression, and cognitive function.MethodsSeventy‐five patients had at least one early‐active lesion on biopsy and were pathologically classified into three immunopatterns based on published criteria. The median time from biopsy at follow‐up was 11 years, median age at biopsy ‐ 41, EDSS ‐ 4.0. At last follow‐up, the median age was 50, EDSS ‐ 3.0. Clinical examination, cognitive assessment (CogState battery), and 3‐Tesla‐MRI (MPRAGE/FLAIR/T2/DIR/PSIR/DTI) were obtained.ResultsIP‐I was identified in 14/75 (19%), IP‐II was identified in 41/75 (56%), and IP‐III was identified in 18/75 (25%) patients. Patients did not differ significantly by immunopattern in clinical measures at onset or last follow‐up. The proportions of disease courses after a median of 11 years were similar across immunopatterns, relapsing–remitting being most common (63%), followed by monophasic (32%). No differences in volumetric or DTI measures were found. CogState performance was similar for most tasks. A slight yet statistically significant difference was identified for episodic memory scores, with IP‐III patients recalling one word less on average.InterpretationIn this study, immunopathological heterogeneity of early‐active MS lesions identified at biopsy does not correlate with different long‐term clinical, neuroimaging or cognitive outcomes. This could be explained by the fact that while active white matter lesions are pathological substrates for relapses, MS progression is driven by mechanisms converging across immunopatterns, regardless of pathogenic mechanisms driving the acute demyelinated plaque.

Abstract Objective COVID-19 vaccines have a favorable safety profile in patients with autoimmune rheumatic diseases (AIRDs) such as idiopathic inflammatory myopathies (IIMs); however, hesitancy continues to persist among these patients. Therefore, we studied the prevalence, predictors and reasons for hesitancy in patients with IIMs, other AIRDs, non-rheumatic autoimmune diseases (nrAIDs) and healthy controls (HCs), using data from the two international COVID-19 Vaccination in Autoimmune Diseases (COVAD) e-surveys. Methods The first and second COVAD patient self-reported e-surveys were circulated from March to December 2021, and February to June 2022 (ongoing). We collected data on demographics, comorbidities, COVID-19 infection and vaccination history, reasons for hesitancy, and patient reported outcomes. Predictors of hesitancy were analysed using regression models in different groups. Results We analysed data from 18 882 (COVAD-1) and 7666 (COVAD-2) respondents. Reassuringly, hesitancy decreased from 2021 (16.5%) to 2022 (5.1%) (OR: 0.26; 95% CI: 0.24, 0.30, P &lt; 0.001). However, concerns/fear over long-term safety had increased (OR: 3.6; 95% CI: 2.9, 4.6, P &lt; 0.01). We noted with concern greater skepticism over vaccine science among patients with IIMs than AIRDs (OR: 1.8; 95% CI: 1.08, 3.2, P = 0.023) and HCs (OR: 4; 95% CI: 1.9, 8.1, P &lt; 0.001), as well as more long-term safety concerns/fear (IIMs vs AIRDs – OR: 1.9; 95% CI: 1.2, 2.9, P = 0.001; IIMs vs HCs – OR: 5.4 95% CI: 3, 9.6, P &lt; 0.001). Caucasians [OR 4.2 (1.7–10.3)] were likely to be more hesitant, while those with better PROMIS physical health score were less hesitant [OR 0.9 (0.8–0.97)]. Conclusion Vaccine hesitancy has decreased from 2021 to 2022, long-term safety concerns remain among patients with IIMs, particularly in Caucasians and those with poor physical function.

LBA661 Background: Liposomal irinotecan administered with 5-fluorouracil/leucovorin (5-FU/LV) is approved in the USA and Europe for mPDAC following progression with gemcitabine-based therapy. A phase 1/2 study (Wainberg et al. Eur J Cancer 2021;151:14–24; NCT02551991) demonstrated promising anti-tumor activity in patients with mPDAC who received first-line liposomal irinotecan 50 mg/m2 + 5-FU 2400 mg/m2 + LV 400 mg/m2 + oxaliplatin 60 mg/m2 (NALIRIFOX). Herein, we present results from NAPOLI-3 (NCT04083235), a randomized, open-label, phase 3 study investigating the efficacy and safety of NALIRIFOX compared with nab-paclitaxel + gemcitabine as first-line therapy in patients with mPDAC. Methods: Eligible patients with histopathologically/cytologically confirmed untreated metastatic PDAC were randomized (1:1) to receive NALIRIFOX on days 1 and 15 of a 28-day cycle or nab-paclitaxel 125 mg/m2 + gemcitabine 1000 mg/m2 (Gem+NabP) on days 1, 8 and 15 of a 28-day cycle. Randomization was stratified by ECOG performance status, geographic region and presence or absence of liver metastases. The primary endpoint was overall survival (OS); secondary endpoints were progression-free survival (PFS), overall response rate (ORR) and safety. OS was evaluated when ≥ 543 events were observed using a stratified log-rank test with an overall 1-sided significance level of 0.025. Results: Overall, 770 patients (NALIRIFOX, n = 383; Gem+NabP, n = 387) were included. Baseline characteristics were well balanced between arms. At a median follow-up of 16.1 months, 544 events had occurred. The median OS was 11.1 months in the NALIFIROX arm as compared with 9.2 months in the Gem+NabP arm (HR 0.84 [95% CI 0.71–0.99]; p = 0.04); PFS was also significantly improved (7.4 months vs 5.6 months; HR 0.70 [0.59–0.84]; p = 0.0001). Grade 3/4 treatment-emergent adverse events (TEAEs) with ≥ 10% frequency in patients receiving NALIRIFOX versus Gem+NabP included diarrhea (20.3% vs 4.5%), nausea (11.9% vs 2.6%), hypokalemia (15.1% vs 4.0%), anemia (10.5% vs 17.4%) and neutropenia (14.1% vs 24.5%). Conclusions: First-line NALIRIFOX demonstrated clinically meaningful and statistically significant improvement in OS and PFS compared with Gem+NabP in treatment-naïve patients with mPDAC. The safety profile of NALIRIFOX was manageable and consistent with the profiles of the treatment components. Funding: Funded by Ipsen. Clinical trial information: NCT04083235 .[Table: see text]

Vitamin C remains an important, yet frequently unassessed, component of a healthy immune system though it may prove useful in alleviating the chronic inflammatory processes underlying chronic diseases such as coronary artery disease (CAD). Recent research identified a sizeable proportion of the United States population with insufficient vitamin C plasma levels and significant associations to both acute and chronic inflammation. This cross-sectional study used the 2003–2006 NHANES surveys data to extrapolate associations between plasma vitamin C levels (deficiency, hypovitaminosis, inadequate, adequate, and saturating) and CAD through inflammation (C-reactive protein and red cell distribution width). Increased reports of CAD diagnosis were identified in participants with vitamin C deficiency (OR: 2.31, CI: 1.49–3.58) and inadequate plasma levels (OR: 1.39, CI: 1.03–1.87). No significant correlation was identified between any other plasma vitamin C quintiles and CAD. When inflammation was controlled, previous associations in the deficient level of plasma vitamin C were no longer significant in association with CAD and participants with inadequate plasma vitamin C showed a reduced association to CAD diagnoses (OR: 0.33, CI: 0.13-0.86). Most chronic inflammation and vitamin C plasma statuses do not demonstrate specific signs or symptoms until the deficient level of vitamin C and/or disease. Thus, increased surveillance of both, and healthy nutritional habits remain crucial modifiable risk factors for disease prevention.

Abstract Background We evaluated the health-related quality of life (HRQoL) benefits of upadacitinib (UPA) induction and maintenance treatment in a phase 3 study of patients with ulcerative colitis (UC) across a broad range of patient-centered outcomes. Methods Patients received UPA 45 mg once daily or placebo as induction treatment for 8 weeks. Patients who achieved clinical response were rerandomized to receive once daily UPA 15 mg, 30 mg, or placebo as maintenance treatment for 52 weeks. The percentages of patients reporting a clinically meaningful within-person change from baseline in the Ulcerative Colitis Symptoms Questionnaire, Inflammatory Bowel Disease Questionnaire, Work Productivity and Impairment Questionnaire, 36-Item Short Form Survey, and European Quality of Life-5 Dimension 5 Levels were evaluated at weeks 2 and 8 of induction and at weeks 0 and 52 of maintenance. Results Significant improvements from baseline in all HRQoL measures except the Work Productivity and Impairment Questionnaire–absenteeism were achieved with UPA (P &lt; .001) vs placebo as early as week 2 of induction. These improvements were sustained at week 52 with significantly more patients treated with either 15 mg or 30 mg UPA vs placebo achieving meaningful within-person change in the Ulcerative Colitis Symptoms Questionnaire; Inflammatory Bowel Disease Questionnaire; overall work impairment, presenteeism, and activity impairment; both 36-Item Short Form Survey Physical and Mental Component Summaries; and European Quality of Life-5 Dimension 5 Levels (P &lt; .001). Conclusions Induction treatment with UPA 45 mg significantly improved HRQoL measures. A significantly higher percentage of patients who responded to induction treatment with UPA maintained clinically meaningful improvements consistently across a wide range of HRQoL outcomes after 52 weeks of maintenance therapy with UPA (15 mg and 30 mg) compared with placebo. (ClinicalTrials.gov, Numbers: NCT02819635, NCT03653026).

BACKGROUND: Decompression of the injured spinal cord confers neuroprotection. Compared with timing of surgery, verification of surgical decompression is understudied. OBJECTIVE: To compare the judgment of cervical spinal cord decompression using real-time intraoperative ultrasound (IOUS) following laminectomy with postoperative MRI and CT myelography. METHODS: Fifty-one patients were retrospectively reviewed. Completeness of decompression was evaluated by real-time IOUS and compared with postoperative MRI (47 cases) and CT myelography (4 cases). RESULTS: Five cases (9.8%) underwent additional laminectomy after initial IOUS evaluation to yield a final judgment of adequate decompression using IOUS in all 51 cases (100%). Postoperative MRI/CT myelography showed adequate decompression in 43 cases (84.31%). Six cases had insufficient bony decompression, of which 3 (50%) had cerebrospinal fluid effacement at >1 level. Two cases had severe circumferential intradural swelling despite adequate bony decompression. Between groups with and without adequate decompression on postoperative MRI/CT myelography, there were significant differences for American Spinal Injury Association motor score, American Spinal Injury Association Impairment Scale grade, AO Spine injury morphology, and intramedullary lesion length (IMLL). Multivariate analysis using stepwise variable selection and logistic regression showed that preoperative IMLL was the most significant predictor of inadequate decompression on postoperative imaging ( P = .024). CONCLUSION: Patients with severe clinical injury and large IMLL were more likely to have inadequate decompression on postoperative MRI/CT myelography. IOUS can serve as a supplement to postoperative MRI/CT myelography for the assessment of spinal cord decompression. However, further investigation, additional surgeon experience, and anticipation of prolonged swelling after surgery are required.

Abstract Mixed model repeated measures (MMRM) is the most common analysis approach used in clinical trials for Alzheimer's disease and other progressive diseases measured with continuous outcomes over time. The model treats time as a categorical variable, which allows an unconstrained estimate of the mean for each study visit in each randomized group. Categorizing time in this way can be problematic when assessments occur off‐schedule, as including off‐schedule visits can induce bias, and excluding them ignores valuable information and violates the intention to treat principle. This problem has been exacerbated by clinical trial visits which have been delayed due to the COVID19 pandemic. As an alternative to MMRM, we propose a constrained longitudinal data analysis with natural cubic splines that treats time as continuous and uses test version effects to model the mean over time. Compared to categorical‐time models like MMRM and models that assume a proportional treatment effect, the spline model is shown to be more parsimonious and precise in real clinical trial datasets, and has better power and Type I error in a variety of simulation scenarios.