Faecal metabolome and its determinants in inflammatory bowel disease

OBJECTIVE: Inflammatory bowel disease (IBD) is a multifactorial immune-mediated inflammatory disease of the intestine, comprising Crohn's disease and ulcerative colitis. By characterising metabolites in faeces, combined with faecal metagenomics, host genetics and clinical characteristics, we aimed to unravel metabolic alterations in IBD.DESIGN: We measured 1684 different faecal metabolites and 8 short-chain and branched-chain fatty acids in stool samples of 424 patients with IBD and 255 non-IBD controls. Regression analyses were used to compare concentrations of metabolites between cases and controls and determine the relationship between metabolites and each participant's lifestyle, clinical characteristics and gut microbiota composition. Moreover, genome-wide association analysis was conducted on faecal metabolite levels.RESULTS: We identified over 300 molecules that were differentially abundant in the faeces of patients with IBD. The ratio between a sphingolipid and L-urobilin could discriminate between IBD and non-IBD samples (AUC=0.85). We found changes in the bile acid pool in patients with dysbiotic microbial communities and a strong association between faecal metabolome and gut microbiota. For example, the abundance of Ruminococcus gnavus was positively associated with tryptamine levels. In addition, we found 158 associations between metabolites and dietary patterns, and polymorphisms near NAT2 strongly associated with coffee metabolism.CONCLUSION: In this large-scale analysis, we identified alterations in the metabolome of patients with IBD that are independent of commonly overlooked confounders such as diet and surgical history. Considering the influence of the microbiome on faecal metabolites, our results pave the way for future interventions targeting intestinal inflammation.</p

Time to make a change:A call for more experimental research on key mechanisms in anorexia nervosa

Anorexia nervosa (AN) is a life‐threatening eating disorder, characterised by persistent pathological weight loss behaviours and an intense fear of weight gain and food consumption. Although there is an abundance of scientific theories on the neurobiological, psychological and sociocultural factors thought to be involved in the maintenance of AN, there is little experimental research testing these ideas. The need for theory firmly grounded in empirical evidence becomes strikingly clear when we consider that current treatments for patients with AN are limited in their effectiveness, and relapse after treatment is common

Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use.

Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders1. They are heritable2,3 and etiologically related4,5 behaviors that have been resistant to gene discovery efforts6-11. In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures

JWST NIRCam Photometry: A Study of Globular Clusters Surrounding Bright Elliptical Galaxy VV 191a at z=0.0513

James Webb Space Telescope NIRCam images have revealed 443 globular cluster (GC) candidates around the $z=0.0513$ elliptical galaxy VV 191a. NIRCam broadband observations are made at 0.9-4.5 $\mu$m using filters F090W, F150W, F356W, and F444W. Using photometry, the data is analyzed to present color-magnitude diagrams (CMDs) that suggest a fairly uniform population of GCs. Color histograms show a unimodal color distribution that is well fit by a single Gaussian, using color to primarily trace the metallicity. The findings show the sample's globular cluster luminosity function (GCLF) does not reach the turnover value and is, therefore, more luminous than what is typically expected, with an absolute AB magnitude, $M_{F090W} = -8.70$ mag, reaching within nearly one magnitude of the classical turnover value. We attribute this to the completeness in the sample. Models show that the mass estimate of the GCs detected tends to be more massive, reaching upward of $\simeq 10^7 M_{\odot}$. However, the results show that current GC models do not quite align with the data. We find that the models appear to be bluer than the JWST data in the reddest (F356W-F444W) filters and redder than the data in the bluest (F090W-F150W) filters and may need to be revised to improve the modeling of near-IR colors of old, metal-poor stellar populations.Comment: 11 pages, 7 figure

Biological and Clinical Implications of Gene-Expression Profiling in Diffuse Large B-Cell Lymphoma:A Proposal for a Targeted BLYM-777 Consortium Panel as Part of a Multilayered Analytical Approach

Gene-expression profiling (GEP) is used to study the molecular biology of lymphomas. Here, advancing insights from GEP studies in diffuse large B-cell lymphoma (DLBCL) lymphomagenesis are discussed. GEP studies elucidated subtypes based on cell-of-origin principles and profoundly changed the biological understanding of DLBCL with clinical relevance. Studies integrating GEP and next-generation DNA sequencing defined different molecular subtypes of DLBCL entities originating at specific anatomical localizations. With the emergence of high-throughput technologies, the tumor microenvironment (TME) has been recognized as a critical component in DLBCL pathogenesis. TME studies have characterized so-called “lymphoma microenvironments" and “ecotypes”. Despite gained insights, unexplained chemo-refractoriness in DLBCL remains. To further elucidate the complex biology of DLBCL, we propose a novel targeted GEP consortium panel, called BLYM-777. This knowledge-based biology-driven panel includes probes for 777 genes, covering many aspects regarding B-cell lymphomagenesis (f.e., MYC signature, TME, immune surveillance and resistance to CAR T-cell therapy). Regarding lymphomagenesis, upcoming DLBCL studies need to incorporate genomic and transcriptomic approaches with proteomic methods and correlate these multi-omics data with patient characteristics of well-defined and homogeneous cohorts. This multilayered methodology potentially enhances diagnostic classification of DLBCL subtypes, prognostication, and the development of novel targeted therapeutic strategies. Simple Summary: This review summarizes gene-expression profiling insights into the background and origination of diffuse large B-cell lymphomas (DLBCL). To further unravel the molecular biology of these lymphomas, a consortium panel called BLYM-777 was designed including genes important for subtype classifications, genetic pathways, tumor-microenvironment, immune response and resistance to targeted therapies. This review proposes to combine this transcriptomic method with genomics, proteomics, and patient characteristics to facilitate diagnostic classification, prognostication, and the development of new targeted therapeutic strategies in DLBCL

Delirium in older COVID-19 patients:Evaluating risk factors and outcomes

Objectives: A high incidence of delirium has been reported in older patients with Coronavirus disease 2019 (COVID-19). We aimed to identify determinants of delirium, including the Clinical Frailty Scale, in hospitalized older patients with COVID-19. Furthermore, we aimed to study the association of delirium independent of frailty with in-hospital outcomes in older COVID-19 patients. Methods: This study was performed within the framework of the multi-center COVID-OLD cohort study and included patients aged ≥60 years who were admitted to the general ward because of COVID-19 in the Netherlands between February and May 2020. Data were collected on demographics, co-morbidity, disease severity, and geriatric parameters. Prevalence of delirium during hospital admission was recorded based on delirium screening using the Delirium Observation Screening Scale (DOSS) which was scored three times daily. A DOSS score ≥3 was followed by a delirium assessment by the ward physician In-hospital outcomes included length of stay, discharge destination, and mortality. Results: A total of 412 patients were included (median age 76, 58% male). Delirium was present in 82 patients. In multivariable analysis, previous episode of delirium (Odds ratio [OR] 8.9 [95% CI 2.3–33.6] p = 0.001), and pre-existent memory problems (OR 7.6 [95% CI 3.1–22.5] p < 0.001) were associated with increased delirium risk. Clinical Frailty Scale was associated with increased delirium risk (OR 1.63 [95%CI 1.40–1.90] p < 0.001) in univariable analysis, but not in multivariable analysis. Patients who developed delirium had a shorter symptom duration and lower levels of C-reactive protein upon presentation, whereas vital parameters did not differ. Patients who developed a delirium had a longer hospital stay and were more often discharged to a nursing home. Delirium was associated with mortality (OR 2.84 [95% CI1.71–4.72] p < 0.001), but not in multivariable analyses. Conclusions: A previous delirium and pre-existent memory problems were associated with delirium risk in COVID-19. Delirium was not an independent predictor of mortality after adjustment for frailty

Performance Measures Based on How Adults With Cancer Feel and Function: Stakeholder Recommendations and Feasibility Testing in Six Cancer Centers

PURPOSE Patient-reported outcome measures (PROMs) that assess how patients feel and function have potential for evaluating quality of care. Stakeholder recommendations for PRO-based performance measures (PMs) were elicited, and feasibility testing was conducted at six cancer centers. METHODS Interviews were conducted with 124 stakeholders to determine priority symptoms and risk adjustment variables for PRO-PMs and perceived acceptability. Stakeholders included patients and advocates, caregivers, clinicians, administrators, and thought leaders. Feasibility testing was conducted in six cancer centers. Patients completed PROMs at home 5-15 days into a chemotherapy cycle. Feasibility was operationalized as $75$ 75% patient acceptability. RESULTS Stakeholder priority PRO-PMs for systemic therapy were GI symptoms (diarrhea, constipation, nausea, vomiting), depression/anxiety, pain, insomnia, fatigue, dyspnea, physical function, and neuropathy. Recommended risk adjusters included demographics, insurance type, cancer type, comorbidities, emetic risk, and difficulty paying bills. In feasibility testing, 653 patients enrolled (approximately 110 per site), and 607 (93%) completed PROMs, which indicated high feasibility for home collection. The majority of patients (470 of 607; 77%) completed PROMs without a reminder call, and 137 (23%) of 607 completed them after a reminder call. Most patients (72%) completed PROMs through web, 17% paper, or 2% interactive voice response (automated call that verbally asked patient questions). For acceptability, . 95% of patients found PROM items to be easy to understand and complete. CONCLUSION Clinicians, patients, and other stakeholders agree that PMs that are based on how patients feel and function would be an important addition to quality measurement. This study also shows that PRO-PMs can be feasibly captured at home during systemic therapy and are acceptable to patients. PRO-PMs may add value to the portfolio of PMs as oncology transitions from fee-for-service payment models to performance-based care that emphasizes outcome measures