Citations

AbstractBackgroundUnderstanding whether specific histopathologic features on skin biopsy are predictive of systemic associations in dermatomyositis (DM) would be useful to guide clinical screening.MethodsThrough retrospective medical record search, clinical and laboratory findings of patients with DM were documented. Existing skin biopsy slides were re‐reviewed blindly.ResultsOf all biopsy specimens (n = 42), the most frequent histopathological finding was vacuolar interface dermatitis (95%). Other features included perivascular lymphocytic infiltrate (71%), increased dermal mucin (40%), vessel wall thickening (12%), follicular plugging (9.5%), and dermal sclerosis (7%). Neutrophilic infiltrate was observed in three biopsies from a patient with adalimumab‐associated DM. Vasculitis was not observed. There was no statistically significant difference in the presence of any histopathological feature and that of various systemic manifestations (i.e., myopathy, interstitial lung disease [ILD] and malignancy). However, we observed that dense lichenoid infiltrate rather than pauci‐inflammatory changes correlated with severe itching (p < 0.001). Patients with MDA‐5 antibodies were significantly more likely to have vasculopathy than those without (p = 0.029*).ConclusionsNo dermatopathologic feature was reliably predictive of myopathy, ILD, or malignancy. This finding implies that, regardless of histopathologic findings, patients should be screened for associated conditions as clinically indicated.

SummaryBackgroundEpithelial barrier dysfunction contributes to a dysregulated intestinal immune response in ulcerative colitis (UC). GB004 is an orally administered, small molecule, gut‐targeted stabiliser of hypoxia‐inducible factor‐1α, a transcription factor with protective roles at the epithelial layer of the inflamed gut.AimsTo evaluate safety, pharmacokinetics, pharmacodynamics and efficacy of GB004 in patients with active UC.MethodsThis double‐blind, placebo‐controlled study randomised patients 2:1 to receive an oral solution of GB004 120 mg or placebo once daily for 28 days. Eligible patients had a Robarts Histopathology Index score ≥4 with neutrophils in the epithelium, total Mayo Clinic score 3‐12, Mayo Clinic endoscopic subscore ≥1, and blood in the stool, despite treatment with 5‐aminosalicylates, corticosteroids or immunosuppressants.ResultsThirty‐four patients were randomised. GB004 120 mg for 28 days was generally well‐tolerated. Adverse events occurred in 27.3% (3/11) and 39.1% (9/23) of patients in the placebo and GB004 groups respectively. Nausea and dysgeusia were most commonly reported in the GB004 group (0% for placebo and 21.7% [5/23] and 13.0% [3/23] respectively for GB004). There were no treatment‐related serious adverse events or deaths. GB004 exhibited minimal accumulation, with higher colonic concentrations relative to plasma. Exploratory pharmacodynamic and efficacy analyses demonstrated GB004 target engagement and numerically higher proportions of patients achieving improvement in multiple measures of disease activity, respectively, at day 28 for GB004 compared to placebo.ConclusionResults from this phase 1b trial support evaluation of the full therapeutic potential of GB004 for the treatment of UC. A phase 2 study (NCT04556383) is ongoing. Clinicaltrials.gov NCT03860896.

AbstractBackgroundAfrican Americans (AA) remain underrepresented in Alzheimer’s disease (AD) research, despite the prevalence of AD being ∼2X higher in this population compared to non‐Hispanic whites. To address this disparity, our group has established the Florida Consortium for African American Alzheimer’s Disease Studies (FCA3DS), focusing primarily on the identification of genetic risk factors and novel plasma biomarkers.MethodUtilizing plasma samples from FCA3DS AD cases (n=158) and cognitively unimpaired elderly controls (n=272), we have performed differential gene expression (DEG) and expression quantitative trait locus (eQTL) analyses on 50 transcripts measured with a custom NanoString® panel that we have designed to measure transcript levels in plasma of genes relevant to AD. Transcript counts were determined using the NanoString® nCounter system, following manufacturer’s protocols. Transcript counts from 43 of the 50 customs assays passed pre‐established quality control thresholds and were utilized for the DEG and eQTL analyses. Our published FCA3DS whole exome sequence (WES) data was utilized for the eQTL analyses. Linear mixed models adjusted for relevant biological and technical covariates were implemented with the lme4 package in R software (v3.6.2) for the DEG and eQTL analyses.ResultAn association with higher plasma CLU in controls compared to AD remained significant after Bonferroni correction for the 43 transcripts tested. The eQTL analysis revealed significant association (FDR q‐value<0.05) with 105 WES variants in cis with 22 of 43 genes tested, including variants in genes previously associated with AD risk in AA. ConclusionThe results from this AA plasma eQTL analysis revealed ABCA7 variants that are significantly associated with lower plasma ABCA7 transcript levels. One of the significant plasma ABCA7 eQTLs was previously shown by our group to be associated with increased AD risk in AA, suggesting that this may be a functional eQTL underlying the risk of AD in AA. The association of higher levels of CLU transcript in plasma from controls compared to AD is in line with results published by others which showed that higher baseline concentration of clusterin protein in plasma was associated with slower rates of brain atrophy. These results support plasma transcripts as novel endophenotypes in AD biomarker studies.

AbstractBackgroundRepetitive head impacts from American football have been associated with long‐term cognitive symptoms. The late neuropsychological profiles of this population is not well‐characterized. Research has relied on retrospective informant reports and/or has been small samples of former professional players. We describe objective neuropsychological test performance in former college and professional American football players.MethodsMale (45‐74 years) former National Football League (n=107) and college football players (n=59) from the DIAGNOSE‐CTE Research Project completed a neuropsychological test battery, Functional Activities Questionnaire (FAQ) and Quick Dementia Rating Scale (QDRS). Neuropsychological test scores were converted to T‐scores using age, sex, and/or education‐adjusted normative data. T‐scores<35 defined impairment. Participants were enrolled across the spectrum of symptom severity (asymptomatic to dementia). Individuals without decisional capacity were excluded. Participants with missing data (n=4) and who scored <45 on Test of Memory Malingering Trial 2 (n=10) were excluded.Results108 (65.1%) identified as White and 53 (31.9%) as Black. Mean education years was 16.76 (SD=1.48). Fourteen (8.4%) and 6 (3.6%) reported diagnostic history of ADHD and learning disability, respectively. Average Montreal Cognitive Assessment score was 24.96 (SD=3.17); 85 (51.2%) scored <26. Impairment rates were highest for learning and episodic memory. On Neuropsychological Assessment Battery List Learning, 29.5% were impaired on Immediate recall, 36.1% on Short Delay, and 44.0% on Long Delay Recall. Impairment rates for Craft Story Immediate and Delayed Recall (Paraphrase) were 15.7% and 18.7%, respectively. 19.9% and 15.7% were impaired on learning and delayed recall of the Brief Visuospatial Memory Test‐Revised. Impairments were frequent on the Multilingual Naming Test (20.5%), Trail Making Test Parts B (19.3%) and A (18.1%), Animal Fluency (15.7%), and Number Span Backward (15.1%). Impairments were less common (<10%) for phonemic fluency, planning, basic attention, and visual‐perceptual abilities, Mean FAQ was 3.11 (SD=5.14); 23 (13.9%) had an FAQ >9. Based on QDRS scores, 66 (39.8%) had mild cognitive impairment, 44 (26.5%) mild dementia, and 6 (3.6%) moderate dementia.ConclusionsIn these former American football players, neuropsychological impairments were most frequent in episodic memory, followed by confrontation naming and executive function. Further research is needed to delineate this population’s unique neuropsychological profile.

Patients with decompensated cirrhosis, particularly those with acute‐on‐chronic liver failure (ACLF), show profound alterations in plasma metabolomics. The aim of this study was to investigate the effect of treatment with simvastatin and rifaximin on plasma metabolites of patients with decompensated cirrhosis, specifically on compounds characteristic of the ACLF plasma metabolomic profile. Two cohorts of patients were investigated. The first was a descriptive cohort of patients with decompensated cirrhosis (n = 42), with and without ACLF. The second was an intervention cohort from the LIVERHOPE‐SAFETY randomized, double‐blind, placebo‐controlled trial treated with simvastatin 20 mg/day plus rifaximin 1,200 mg/day (n = 12) or matching placebo (n = 13) for 3 months. Plasma samples were analyzed using ultrahigh performance liquid chromatography–tandem mass spectroscopy for plasma metabolomics characterization. ACLF was characterized by intense proteolysis and lipid alterations, specifically in pathways associated with inflammation and mitochondrial dysfunction, such as the tryptophan–kynurenine and carnitine beta‐oxidation pathways. An ACLF‐specific signature was identified. Treatment with simvastatin and rifaximin was associated with changes in 161 of 985 metabolites in comparison to treatment with placebo. A remarkable reduction in levels of metabolites from the tryptophan–kynurenine and carnitine pathways was found. Notably, 18 of the 32 metabolites of the ACLF signature were affected by the treatment. Conclusion: Treatment with simvastatin and rifaximin modulates some of the pathways that appear to be key in ACLF development. This study unveils some of the mechanisms involved in the effects of treatment with simvastatin and rifaximin in decompensated cirrhosis and sets the stage for the use of metabolomics to investigate new targeted therapies in cirrhosis to prevent ACLF development.