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Refined genotype-phenotype correlations in neurofibromatosis type 1 patients with NF1 point variants
No full textBackground Neurofibromatosis type 1 (NF1) is one of the most frequent genetic disorders. NF1 is caused by dominant loss-of-function pathogenic variants (PVs) of the tumour-suppressor gene NF1, which encodes neurofibromin, a negative regulator of rat sarcoma proteins. NF1 is an autosomal dominant disorder with complete penetrance, but a highly variable expression. Identification of genotype–phenotype correlations is challenging because of the wide clinical variability, the progressive nature of the disorder and the extreme diversity of the mutation spectrum. Only a few NF1 point variants have been associated with a specific phenotype in NF1 patients. Methods We investigated a large, well-phenotyped NF1 cohort. Results We report analyses of genotype-phenotype correlations in 112 NF1 patients with specific NF1 point variants: p.Arg1809 missense variants were associated with a mild form of NF1 (n=24), while a more severe phenotype was associated with codons 844–848 (n=27), p.Arg1276 (n=25) and p.Lys1423 (n=35) missense variants. We describe a new correlation for p.Arg1204 missense variants (n=11), with no neurofibroma observed in patients. Functional studies will be critical for drawing conclusions on the potential hypomorphic or dominant-negative effects of these variants. Conclusion The current data confirms several genotype-phenotype correlations in NF1, which may be relevant to the management and surveillance of NF1 patients with specific NF1 PVs.</p
Detection of genome-wide methylation changes in bladder cancer by long-read sequencing of urinary DNA
No full textBACKGROUND: Non-invasive urine tests for bladder cancer (BC) could reduce dependence on flexible cystoscopy for diagnosis and surveillance. Most recent developments in urine testing are based on targeted detection of genomic and/or epigenomic markers. We hypothesised that long-read whole-genome sequencing of urinary DNA with direct methylation profiling may allow accurate BC detection and insights into disease biology. However, the feasibility of such an approach has not yet been reported. METHODS: We applied long-read whole-genome sequencing with direct methylation detection to urine cell pellet DNA (ucpDNA) from 21 haematuria clinic patients: 13 BCs and 8 non-BCs. The modkit Hidden Markov Model algorithm was used to define differentially methylated regions across the genome. The ability to discriminate between BC and non-BC, and the cellular pathways affected were tested using PCA, h-clust and GSEA. RESULTS: We observed global hypomethylation and cancer-specific patterns of promoter hypermethylation in urine from BC patients. Sequencing of a single ucpDNA sample per flow cell yielded read depths of 18-34x; furthermore, BC methylation patterns were also evident with 2-5x multiplex sequencing. Copy number changes were also evident in ucpDNAs from BC patients. A limitation of the study is the small number of samples analysed; however, the detection of cancer-specific events demonstrates the feasibility of the approach, both in single and multiplexed flow-cell runs. CONCLUSIONS: Even at low-read depths, genome-wide methylation patterns in urinary DNA reflect the presence of BC, potentially permitting rapid, non-invasive and cost-effective BC detection
Liver transplantation indications and strategies in polycystic liver disease:A european survey
No full textBACKGROUND AIMS: Liver transplantation (LT) remains the only cure for severe polycystic liver disease (PLD). However, LT indications and strategies vary across Europe, resulting in (unwanted) practice variation and unequal access to care for patients with PLD. This study aimed to (1) identify existing PLD-specific LT criteria across European countries, (2) assess which criteria are considered relevant by specialist, and (3) map the variation in liver-kidney transplant strategies among patients with autosomal dominant polycystic kidney disease (ADPKD). METHODS: National PLD-specific LT criteria were collected, and if unavailable ERN RARE-Liver representatives from that country were asked to provide information. An online survey was conducted amongst hepatologists, LT surgeons, and nephrologists managing patients with PLD. The survey assessed relevant LT indications/listing requirements, clinical case evaluations, and explored preferences for liver-kidney transplantation in patients with ADPKD. RESULTS: Defined LT criteria for patients with PLD were available in only 8 of the 17 assessed countries and showed substantial variation. Sixty-nine clinicians (43 hepatologists, 15 surgeons, 11 nephrologists), predominantly from LT centers (75.4%), completed the survey. Key LT indications were recurrent liver cyst infections (78.3%), significant impaired quality of life (75.4%), and severe malnutrition (75.4%). In ADPKD simultaneous liver-kidney transplantation (SLK) was preferred by 40.4% of respondents, primarily due the favorable immunological profile (47.6%) and prevention of renal failure (33.3%). In contrast, those favoring a liver-first approach (30.8%), followed by sequential kidney transplant, highlighted the potential harm to the kidney graft during SLK (62.5%). CONCLUSIONS: Uniform PLD-specific LT criteria in Europe are lacking. While recurrent liver cyst infections, decreased quality of life, and malnutrition are widely recognized as crucial LT indications, they are insufficiently reflected in existing criteria, contributing to unequal access to LT. Moreover, considerable variation exists in liver-kidney transplantation for ADPKD patients, with a current lack of evidence to support one approach over another
Outlived by a lesser shamelessness:The inscrutable Subject and Sensuality before the Law in Augustine, Dostoevsky and Kafka
Get PDFThis essay sets up a constellation of Augustine, Dostoevsky and Kafka. The paper will demonstrate how for these figures, self-knowledge is compromised in related, but differing ways. How can the subject maintain their identity as categorically different from its impressions, and what is the role of law therein? For Augustine, self-knowledge becomes a problem due to the structure of time, but also because of the way in which God perceives us. Between Dostoevsky and Kafka, there is a development wherein the role of God is usurped by that of a secular law, and God’s judgement is deferred. If for Dostoevsky, secular law can be an instrument of divine law, for Kafka the distinction, and more importantly the hierarchy between them, seems unsustainable. The evidence to examine these hypotheses by has to do with sensuality and sensory perception: how does the subject navigate the world? The trajectory moves from the Augustinian Christian opacity, to Dostoevsky’s Raskolnikov and Kafka’s The Trial, drawing an arc from a religious and phenomenological ontology to a modern imaginary of an existence increasingly irredeemable. Indeed, this essay joins the contemporary discussions of critically engaging with subjectivity, as a bio- and psycho-political liability
Prediction of Hepatocellular Carcinoma and Other Liver-Related Events in Chronic Hepatitis B Patients With Metabolic Dysfunction or Metabolic Dysfunction-Associated Steatotic Liver Disease
No full textIntroduction: Metabolic dysfunction and metabolic dysfunction-associated steatotic liver disease (MASLD) are associated with an increased risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). We aimed to study risk factors for HCC and to assess the performance of the PAGE-B score in this population. Methods: We included CHB patients with ≥ 1 metabolic comorbidity from nine centres. Steatosis was diagnosed by ultrasound, CAP, or histology. Risk factors were analysed by Cox regression, and the performance of the PAGE-B score was assessed in the overall population and across relevant subgroups. Results: We included 1922 patients. 1730 (90.0%) were overweight, 434 (22.6%) had hypertension, 254 (13.2%) dyslipidemia, 230 (12.0%) diabetes and 732 (38.1%) MASLD. Presence of cirrhosis, older age, lower platelets and lower albumin were independent risk factors for HCC. The 5-year HCC risk was 0.1%/2.0%/12.4% patients with low/intermediate/high PAGE-B scores (p < 0.001). Consistent results were obtained in patients with MASLD (0/2.8/11.1% for low, intermediate and high PAGE-B scores (p < 0.001)). PAGE-B stratified risk in patients without cirrhosis (0% vs. 1.2% and 1.8%, p < 0.001). Among the subset of patients with cirrhosis, risks were 4.2% (low), 6.9% (intermediate) and 27.3% (high) (p < 0.001). Conclusions: CHB patients with metabolic dysfunction and/or MASLD are at significant risk of HCC. The PAGE-B score can be used to stratify HCC risk in this population, with negligible 5-year HCC incidence in those without cirrhosis and low PAGE-B scores. However, caution should be exercised in patients with cirrhosis in whom HCC risk remains significant even among those with a low PAGE-B score.</p
Light does not phase shift the circadian clock of subcutaneous adipose tissue in vitro
No full textThe retinal photopigment melanopsin is also expressed in subcutaneous white adipose tissue (scWAT). Through melanopsin, light can modulate scWAT metabolism, but its impact on circadian phase is unclear. In vitro exposure of murine scWAT to bright light at different times over 24 h did not elicit phase shifts, unlike the response to corticosterone. This finding suggests that the direct impact of bright light on scWAT metabolism occurs in a circadian-independent manner
Associations of Biomarkers of Kidney Tubule Health with Retinal Microvascular Signs:The Multi-Ethnic Study of Atherosclerosis (MESA)
No full textBackground: CKD is strongly associated with cardiovascular disease (CVD), yet the etiology responsible for this link remains elusive. Novel blood and urine biomarkers reflecting kidney tubule dysfunction and injury may provide novel insights to mechanisms linking the kidney to CVD. Methods: In 470 participants of the Multi-Ethnic Study of Atherosclerosis (MESA) without type 2 diabetes, CVD or CKD, we measured six plasma (kidney injury molecule-1 [KIM-1], monocyte chemoattractant protein-1 [MCP-1], soluble urokinase plasminogen activator receptor [suPAR], tumor necrosis factor receptor [TNFR] 1 and 2, and anti-chitinase-3-like protein 1 [YKL-40]) and six urinary (alpha 1 microglobulin [A-1M], epidermal growth factor [EGF], KIM-1, MCP-1, YKL-40 and uromodulin [UMOD]) kidney tubule health biomarkers. To assess microvascular health, we used retinal microvascular measurements assessed from fundus photography: central retinal arteriolar and venular equivalents (CRAE and CRVE, respectively). Multivariable linear regression evaluated associations of tubule biomarkers and kidney function with CRAE and CRVE. Results: The mean participant age was 60 ± 10 years with 52% female. The racial/ethnic distribution was 46% White, 24% African American, 18% Hispanic, and 11% Chinese. The mean eGFR was 92.1 ± 13.3 mL/min/1.73m 2, and the median urine ACR was 4.7 mg/g (IQR 3.0, 9.4). Higher plasma KIM-1 (β -5.14, 95% confidence interval [95% CI], -9.84 to -0.45), and urine KIM-1 (β -5.68, 95% CI, -10.15 to -1.22) concentrations were individually associated with narrower CRAE, while plasma suPAR concentrations were individually associated with wider CRAE (β 9.15, 95% CI, 0.89 to 17.4) and CRVE (β 21.49, 95% CI, 9.39 to 33.59). There were no significant associations between the remaining tubule health biomarkers and CRAE or CRVE, nor were there associations between eGFR or urine ACR with CRAE and CRVE. Conclusions: In this study of community-living individuals without CKD, diabetes, or CVD, selected kidney tubule health markers are associated with retinal microvascular changes. These findings suggest that kidney tubules biomarkers may reflect or contribute to systemic microvascular dysfunction, above and beyond glomerular damage. Tubular biomarkers may help elucidate the shared microvascular mechanisms linking CKD and CVD.</p
Plaque Magnetic Resonance Imaging Based Decision Rule for the Selection of Symptomatic Patients for Carotid Revascularisation:Clinician Perspectives on Acceptability and Implementation Barriers in the Netherlands
No full textObjective: At present, selection of patients for carotid revascularisation is mainly based on neurological symptoms and the degree of carotid artery stenosis. Individualised MRI based PRediction scOre using plaque Vulnerability for symptomatic carotid artEry disease patients (IMPROVE) can identify high risk patients who may benefit from carotid revascularisation, based on intraplaque haemorrhage, stenosis severity, cerebral symptoms, sex, and age. For use in clinical trials and eventual practice, the decision rule must be acceptable to clinicians. The level of acceptance and possible barriers to implementation of the IMPROVE decision rule were assessed among clinicians in the Netherlands. Methods: Qualitative semi-structured individual interviews were conducted with 40 clinicians involved in stroke care: 18 working in the department of neurology, 12 in vascular surgery, and 10 in radiology across 10 Dutch academic and non-academic medical centres. After an introduction to the IMPROVE decision rule, clinicians were queried regarding their stance on the proposition: “the IMPROVE clinical decision rule meets my approval”. Next, clinicians were queried about potential barriers expected in implementing this model in clinical practice. All interviews were transcribed and systematically coded to identify barriers to acceptability. Results: Twenty-nine (72%) clinicians agreed, five (13%) clinicians (three neurologists and two radiologists) completely agreed, and another six (15%) clinicians (three neurologists and three vascular surgeons) neither disagreed nor agreed with the proposition. This analysis identified 12 barriers to acceptability for the IMPROVE decision rule that could be grouped into four categories: lack of evidence, limited clinical practicability, insufficient familiarity, and healthcare burden. Conclusion: Most clinicians accepted IMPROVE but emphasised the need for clinical evaluation. A feasibility study is required to evaluate the clinical applicability of IMPROVE and its impact on healthcare burden. Additionally, a clinical trial comparing IMPROVE based revascularisation selection with current clinical practice is necessary to demonstrate beneficial patient outcomes.</p
Evaluation of legal scholarship - experience from abroad
No full textAbstract: The evaluation of legal scholarship and its outputs is a complex task with far-reaching consequences. Such evaluations can affect the academic careers of individuals, the reputation of research institutions, the overall quality of academic work, and the development of law as a discipline. This article examines how legal scholarship and its outputs are evaluated abroad. It maps evaluation practices from the perspective of relevant institutions in six selected countries (Italy, Belgium, Spain, Sweden, the Netherlands, and France). It then discusses in detail the internal debates on quality assessment at the Faculty of Law of Maastricht University. The aim of the article is not only to present experiences from abroad but also to stimulate discussion on how the outputs of legal scholarship should and could be evaluated in the Czech Republic