Inflammatory bowel disease (IBD) presents specific clinical challenges for which AI may have solutions, including prediction of therapeutic response, novel subgroup classification, precise molecular ...diagnosis, complication risk stratification and endoscopic image analysis for scoring of severity of mucosal inflammation in both ulcerative colitis and Crohn’s disease.2 We are also moving to an era of big data in IBD research, with consortia collecting and collating large cohorts of patients with available genomic, and other multiomic, data.3 4 This resource presents an unrivalled opportunity to alter the landscape of disease prediction and classification in IBD, and usher in routine personalisation of diagnosis and treatment (figure 1). Lack of in-depth clinical data, systemic bias in data entry, lack of longitudinal outcomes and missing data all pose huge challenges to application of AI, with algorithms reliant on high-quality data input to give high-quality output.5 While this constitutes a challenge, it also creates an opportunity to develop robust systems to gather prospective and retrospective data, in structured ways and to use routinely collected data for alternative purposes. There are several defined avenues which need to be considered for optimisation of data collection and study management that will improve outcomes and ensure best practice is followed in application of AI and delivery of precision medicine.8 Stringent definitions for clinical variables and outcomes There is high variability in recording and defining disease, including the tools used, the data collected and the local guidelines followed.9 Standardising and defining basic clinical parameters including biochemical, endoscopic and histological data, alongside long-term measures of disease outcomes, would allow for reduction in the introduction of systemic bias and better utilisation of retrospective clinical data. The Gut Reaction collaboration is now starting to harness the power of ‘big’ clinical data and research opportunities of this repository may be significant.10 It is vital that high-quality data do not come at the cost of being overly burdensome on clinicians, and in some instances data collection directly from patients may prove highly relevant for outcomes not easily captured through medical records.
A crystal plasticity computational framework is developed and validated to investigate the microstructure sensitivity of crack initiation in fretting. Randomly distributed microstructure geometries ...are incorporated into a partial-slip finite element fretting model. The number of cycles to fretting crack initiation is shown to be sensitive to average grain size and microstructure morphology. Scatter in the number of cycles to crack initiation is shown to increase as the number of grains across the contact width decreases due to statistical size effects. Average number of cycles to crack initiation is shown to increase with decreasing number of grains in the contact. Microstructure morphology is shown to have a negligible influence on the effect of stroke for the partial slip cases considered here.
•A microstructure-sensitive study of fretting crack initiation is presented.•Fretting crack initiation is shown to be sensitive to average grain size.•Scatter is shown to increase as the number of grains across the contact decreases.•Average life is shown to increase as average grain size increases.
Abstract
The noradrenergic system shows pathological modifications in aging and neurodegenerative diseases and undergoes substantial neuronal loss in Alzheimer’s disease and Parkinson’s disease. ...While a coherent picture of structural decline in post-mortem and in vivo MRI measures seems to emerge, whether this translates into a consistent decline in available noradrenaline levels is unclear.
We conducted a meta-analysis of noradrenergic differences in Alzheimer’s disease dementia and Parkinson’s disease using CSF and PET biomarkers.
CSF noradrenaline and 3-methoxy-4-hydroxyphenylglycol levels as well as noradrenaline transporters availability, measured with PET, were summarized from 26 articles using a random-effects model meta-analysis.
Compared to controls, individuals with Parkinson’s disease showed significantly decreased levels of CSF noradrenaline and 3-methoxy-4-hydroxyphenylglycol, as well as noradrenaline transporters availability in the hypothalamus. In Alzheimer’s disease dementia, 3-methoxy-4-hydroxyphenylglycol but not noradrenaline levels were increased compared to controls.
Both CSF and PET biomarkers of noradrenergic dysfunction reveal significant alterations in Parkinson’s disease and Alzheimer’s disease dementia. However, further studies are required to understand how these biomarkers are associated to the clinical symptoms and pathology.
Lancini et al. showed that compared to controls, CSF and PET noradrenergic biomarkers are decreased in Parkinson’s disease, while in Alzheimer’s disease, only CSF noradrenaline metabolite 3-methoxy-4-hydroxyphenylglycol levels are significantly increased.
Further studies should determine how CSF measures of noradrenergic dysfunction are related to pathology and clinical symptoms.
Graphical Abstract
Graphical abstract
Mildly elevated circulating unconjugated bilirubin (UCB) is associated with protection against hypertension and ischemic heart disease. We assessed whether endogenously elevated bilirubin in Gunn ...rats modifies cardiovascular function and resistance to ischemic insult. Hearts were assessed ex vivo (Langendorff perfusion) and in vivo (Millar catheterization and echocardiography), and left ventricular myocardial gene expression was measured via quantitative real-time PCR. Ex vivo analysis revealed reduced intrinsic contractility in the Gunn myocardium (+dP/dt: 1,976 ± 622 vs. 2,907 ± 334 mmHg/s, P < 0.01; -dP/dt: -1,435 ± 372 vs. -2,234 ± 478 mmHg/s, P < 0.01), which correlated positively with myocardial UCB concentration (P < 0.05). In vivo analyses showed no changes in left ventricular contractile parameters and ejection (fractional shortening and ejection fraction). However, Gunn rats exhibited reductions in the rate of aortic pressure development (3,008 ± 461 vs. 4,452 ± 644 mmHg/s, P < 0.02), mean aortic velocity (439 ± 64 vs. 644 ± 62 mm/s, P < 0.01), and aortic volume time integral pressure gradient (2.32 ± 0.65 vs. 5.72 ± 0.74 mmHg, P < 0.01), in association with significant aortic dilatation (12-24% increase in aortic diameter, P < 0.05). Ex vivo Gunn hearts exhibited improved ventricular function after 35 min of ischemia and 90 min of reperfusion (63 ± 14 vs. 35 ± 12%, P < 0.01). These effects were accompanied by increased glutathione peroxidase and reduced superoxide dismutase and phospholamban gene expression in Gunn rat myocardium (P < 0.05). These data collectively indicate that hyperbilirubinemia in Gunn rats 1) reduces intrinsic cardiac contractility, which is compensated for in vivo; 2) induces aortic dilatation, which may beneficially influence aortic ejection velocities and pressures; and 3) may improve myocardial stress resistance in association with beneficial transcriptional changes. These effects may contribute to protection from cardiovascular disease with elevated bilirubin.
Purpose: The causes of childhood brain tumors (CBT) are largely unknown, but gestational diet may influence this risk. The aim of this analysis was to investigate whether maternal coffee or tea ...consumption during pregnancy was associated with the risk of CBT. Methods: The Australian Study of the Causes of Childhood Brain Tumours was a population-based, Australian case–control study conducted between 2005 and 2010. Case children were recruited from 10 pediatric oncology centers and control children by nationwide random-digit dialing, frequency matched to cases on the basis of age, sex and state of residence. Coffee and tea intake were assessed using a food frequency questionnaire. Results: Data on coffee and tea consumption during pregnancy were available from 293 case mothers and 726 control mothers. Odds ratios (ORs) and confidence intervals (CIs) were calculated using multivariable unconditional logistic regression. There was little evidence of an association between gestational consumption of any coffee (OR 1.23, 95 % CI 0.92, 1.64) or tea (OR 1.00, 95 % CI 0.74, 1.36) and CBT risk. Among children aged under 5 years, the OR for any coffee consumption during pregnancy was 1.76 (95 % CI 1.09, 2.84) and for ≥2 cups per day during pregnancy was 2.52 (95 % CI 1.26, 5.04). There was little evidence that associations with coffee or tea intake differed by parental smoking status. Conclusions: These results suggest a positive association between coffee intake ≥2 cups per day and risk of CBT in younger children, although some estimates are imprecise. There was no association between maternal tea drinking and risk of CBT.
Importance Sport-related concussion (SRC), a form of mild traumatic brain injury, is a prevalent occurrence in collision sports. There are no well-established approaches for tracking neurobiologic ...recovery after SRC. Objective To examine the levels of serum glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) in Australian football athletes who experience SRC. Design, Setting, and Participants A cohort study recruiting from April 10, 2021, to September 17, 2022, was conducted through the Victorian Amateur Football Association, Melbourne, Australia. Participants included adult Australian football players with or without SRC. Data analysis was performed from May 26, 2023, to March 27, 2024. Exposure Sport-related concussion, defined as at least 1 observable sign and/or 2 or more symptoms. Main Outcomes and Measures Primary outcomes were serum GFAP and NfL levels at 24 hours, and 1, 2, 4, 6, 8, 12, and 26 weeks. Secondary outcomes were symptoms, cognitive performance, and return to training times. Results Eighty-one individuals with SRC (median age, 22.8 IQR, 21.3-26.0 years; 89% male) and 56 control individuals (median age, 24.6 IQR, 22.4-27.3 years; 96% male) completed a total of 945 of 1057 eligible testing sessions. Compared with control participants, those with SRC exhibited higher GFAP levels at 24 hours (mean difference MD in natural log, pg/mL, 0.66 95% CI, 0.50-0.82) and 4 weeks (MD, 0.17 95% CI, 0.02-0.32), and NfL from 1 to 12 weeks (1-week MD, 0.31 95% CI, 0.12-0.51; 2-week MD, 0.38 95% CI, 0.19-0.58; 4-week MD, 0.31 95% CI, 0.12-0.51; 6-week MD, 0.27 95% CI, 0.07-0.47; 8-week MD, 0.36 95% CI, 0.15-0.56; and 12-week MD, 0.25 95% CI, 0.04-0.46). Growth mixture modeling identified 2 GFAP subgroups: extreme prolonged (16%) and moderate transient (84%). For NfL, 3 subgroups were identified: extreme prolonged (7%), moderate prolonged (15%), and minimal or no change (78%). Individuals with SRC who reported loss of consciousness (LOC) (33% of SRC cases) had higher GFAP at 24 hours (MD, 1.01 95% CI, 0.77-1.24), 1 week (MD, 0.27 95% CI, 0.06-0.49), 2 weeks (MD, 0.21 95% CI, 0.004-0.42) and 4 weeks (MD, 0.34 95% CI, 0.13-0.55), and higher NfL from 1 week to 12 weeks (1-week MD, 0.73 95% CI, 0.42-1.03; 2-week MD, 0.91 95% CI, 0.61-1.21; 4-week MD, 0.90 95% CI, 0.59-1.20; 6-week MD, 0.81 95% CI, 0.50-1.13; 8-week MD, 0.73 95% CI, 0.42-1.04; and 12-week MD, 0.54 95% CI, 0.22-0.85) compared with SRC participants without LOC. Return to training times were longer in the GFAP extreme compared with moderate subgroup (incident rate ratio IRR, 1.99 95% CI, 1.69-2.34; NfL extreme (IRR, 3.24 95% CI, 2.63-3.97) and moderate (IRR, 1.43 95% CI, 1.18-1.72) subgroups compared with the minimal subgroup, and for individuals with LOC compared with those without LOC (IRR, 1.65 95% CI, 1.41-1.93). Conclusions and Relevance In this cohort study, a subset of SRC cases, particularly those with LOC, showed heightened and prolonged increases in GFAP and NfL levels, that persisted for at least 4 weeks. These findings suggest that serial biomarker measurement could identify such cases, guiding return to play decisions based on neurobiologic recovery. While further investigation is warranted, the association between prolonged biomarker elevations and LOC may support the use of more conservative return to play timelines for athletes with this clinical feature.
Monogenic inflammatory bowel disease (IBD) comprises rare Mendelian causes of gut inflammation, often presenting in infants with severe and atypical disease. This study aimed to identify clinically ...relevant variants within 68 monogenic IBD genes in an unselected pediatric IBD cohort.
Whole exome sequencing was performed on patients with pediatric-onset disease. Variants fulfilling the American College of Medical Genetics criteria as "pathogenic" or "likely pathogenic" were assessed against phenotype at diagnosis and follow-up. Individual patient variants were assessed and processed to generate a per-gene, per-individual, deleteriousness score.
Four hundred one patients were included, and the median age of disease-onset was 11.92 years. In total, 11.5% of patients harbored a monogenic variant. TRIM22-related disease was implicated in 5 patients. A pathogenic mutation in the Wiskott-Aldrich syndrome (WAS) gene was confirmed in 2 male children with severe pancolonic inflammation and primary sclerosing cholangitis. In total, 7.3% of patients with Crohn's disease had apparent autosomal recessive, monogenic NOD2-related disease. Compared with non-NOD2 Crohn's disease, these patients had a marked stricturing phenotype (odds ratio 11.52, significant after correction for disease location) and had undergone significantly more intestinal resections (odds ratio 10.75). Variants in ADA, FERMT1, and LRBA did not meet the criteria for monogenic disease in any patients; however, case-control analysis of mutation burden significantly implicated these genes in disease etiology.
Routine whole exome sequencing in pediatric patients with IBD results in a precise molecular diagnosis for a subset of patients with IBD, providing the opportunity to personalize therapy. NOD2 status informs risk of stricturing disease requiring surgery, allowing clinicians to direct prognosis and intervention.
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