Importance:Incidental meningiomas are common. There is a need for a validated clinical tool to stratify patients into early intervention, serial monitoring, or safe discharge from outpatient care. Objective:To externally validate the Incidental Meningioma: Prognostic Analysis Using Patient Comorbidity and Magnetic Resonance Imaging Tests (IMPACT) tool. Design, Setting, and Participants:This retrospective cohort study included 33 centers in 15 countries. Adult patients diagnosed with an incidental meningioma from January 2009 to December 2010 were included, up to the point of intervention, death, or last clinical encounter. Patients with radiation-induced meningioma and NF2-related schwannomatosis were excluded. Data collection was completed on December 31, 2023. Statistical analysis was conducted between March 2024 and December 2024. Main Outcomes and Measures:The primary outcome of the study was a composite end point comprising growth, symptom development, meningioma-related mortality, and end points related to loss of window of curability. Secondary end points included the occurrence of an intervention and nonmeningioma-related mortality. Results:Overall, 1248 patients were included. The median (IQR) age was 66 (55-77) years and 999 were female individuals (80%). There were 945 patients (75.7%) who had 1010 treatment-naive meningiomas. During follow-up (median [IQR], 61 [17-108] months), 114 tumors (11.3%) in 113 patients (12%) progressed, 132 tumors (13.1%) in 126 patients (13.3%) underwent an intervention, and 383 patients (40.5%) died without progression or intervention, from a nonmeningioma-related cause. The 5- and 10-year progression-free survival rates were 88.1% (95% CI, 85.8%-90.5%) and 85.7% (95% CI, 83.2%-88.2%), respectively. A low-risk meningioma had a disease progression risk of 3.9%, compared with 24.2% in medium-risk meningioma, and 51.6% in high-risk meningioma (χ2 test, P < .001). Measures of external validity were adequate (Brier score = 0.12; C-statistic = 0.80; 10-year area under the curve, 0.83) and the addition of other variables in a Cox regression analysis did not confound the statistical significance of the IMPACT tool. Patients with an age-adjusted Charlson Comorbidity Index score of 6 or higher (eg, a patient aged 80 years with type 2 diabetes and a previous myocardial infarction) and a performance status of 2 to 4 (unable to carry out any work activities or in a chair/bed for 50% or more of the day) were more likely to die of other causes than to receive intervention following diagnosis. Conclusions and Relevance:This cohort study found that the IMPACT tool accurately predicted the risk of incidental meningioma progression and can be used to stratify patients into early intervention, serial monitoring, or safe discharge from outpatient care.
Most genetic variants associated with complex diseases lie in non-coding regions1, complicating efforts to identify effector genes and relevant cell types. Here we map cis-expression quantitative trait loci (eQTLs) across 2.2 million single cells using intestinal biopsies and blood from 421 individuals, including 125 with inflammatory bowel disease (IBD). Cell-type-level eQTLs were more distal to transcription start sites, enriched in enhancers, less likely to regulate the nearest gene, and more than 3.5-fold more likely to colocalize with IBD loci detected in genome-wide association studies (GWASs) than eQTLs detected at tissue-level resolution. We nominate effector genes at more than half of known IBD loci, including MAML2, PSEN2 and ZMIZ1 in myeloid cells, implicating reduced Notch signalling in intestinal immune dysfunction. We also identify Wnt-regulated genes, including MYC, in epithelial stem and progenitor cells, suggesting that impaired renewal contributes to barrier breakdown. Our results provide a mechanistic map that links genetic risk to specific genes and cell types in IBD, and a generalized framework for interpretation of GWAS loci using single-cell eQTL mapping of disease-relevant tissues in complex diseases.
Aims/hypothesisPostprandial glucagon-like peptide-1 (GLP-1) secretion by enteroendocrine L cells of the gut plays an important role in glucose homeostasis, thus representing a therapeutic option of ever-growing significance for type 2 diabetes. However, the precise mechanisms linking nutrient sensing and GLP-1 secretion are incompletely understood. In this study, we focused on a potential new role for endoplasmic reticulum (ER)-mitochondria contact sites, called mitochondria-associated membranes (MAMs), in nutrient-induced GLP-1 secretion by L cells, as they are dynamically regulated by nutrients, they influence cellular calcium homeostasis crucial for hormone secretion, and their miscommunication has been implicated in alterations of glucose homeostasis in several tissues.MethodsWe combined biochemical and imaging approaches to investigate nutrient-induced GLP-1 secretion, and ER-mitochondria interaction and calcium exchange in the STC-1 cell line, ex vivo ileal mouse organoids, and/or in vivo in gut enteroendocrine cells from Glu-Venus mice, both in acute conditions and after diet-induced obesity and type 2 diabetes.ResultsWe show here that ER-mitochondria interactions are dynamically induced by two GLP-1 secretagogues, glucose and deoxycholic acid (DCA), in STC-1 cells (1.8- and 2.1-fold, respectively), ileal mouse organoids (1.7- and 1.3-fold, respectively), and in vivo in colonic L cells of Glu-Venus mice (1.3- and 1.2-fold, respectively). In addition, glucose increased ER-mitochondria calcium exchange in STC-1 cells (1.2-fold). A paracrine action of secreted GLP-1 was also involved in the regulation of MAMs by glucose and DCA in STC-1 cells. Dynamic reinforcement of MAMs by glucose and DCA played a causal role in GLP-1 release, as both pharmacological and genetic disruption of organelle communication blocked L cell secretory response to the two stimuli in STC-1 cells. In agreement, depleting ER calcium levels or inhibiting mitochondrial calcium entry decreased glucose-induced GLP-1 secretion (-37.5% and -30.9%, respectively), whereas inducing ER or mitochondrial stress prevented it (-47.9% and -51.8%, respectively). Mechanistically, glucose induces ER-mitochondria communication through a sodium-glucose cotransporter 1-mediated electrogenic effect, whereas DCA acts through a Takeda G protein-coupled receptor 5 (TGR5)-cAMP-protein kinase A (PKA) pathway. Finally, we demonstrated in C57Bl/6J mice and in Glu-Venus mice that diet-induced obesity reinforced basal ER-mitochondria interactions in colonic L cells and blocked their ability to respond to oral glucose in terms of both GLP-1 secretion and MAM upregulation.Conclusions/interpretationThese results point to a new role for ER-mitochondria calcium coupling in glucose-induced GLP-1 secretion in L cells of the gut, which is impaired in obesity and type 2 diabetes, providing a novel target for the modulation of GLP-1 secretion. Therefore, these data reinforce the potential targeting of MAMs to improve glycaemic outcomes in metabolic diseases.
OBJECTIVE:To assess prostate volume (PV) changes with age in symptomatic and asymptomatic men with and without clinically significant prostate cancer (csPCa). In symptomatic patients, we additionally analysed the effect of age and csPCa on PSA and PSA-density (PSA-D) and compared these to current National Institute for Health and Care Excellence (NICE) recommended PSA age-range thresholds. Patients and Methods This single-centre retrospective cross-sectional study included 2512 men: 760 asymptomatic, disease-free men and 1752 patients referred on a PCa diagnostic pathway. Magnetic resonance imaging-derived whole-gland PV was recorded for all patients. A machine-learning pipeline with k-fold cross validation modelled relationships between PV and age. RESULTS:In asymptomatic men (median PV 25.4 mL), the mean PV per age-group increased non-linearly with age, from 18.7 mL at an increase of 0.10 mL/year aged 18 years, to 41.3 mL at 0.68 mL/year aged 89 years, with increased rate of change from the age of 48.9 years. Significant positive relationships were shown between PSA and age in patients with and without csPCa (r2 = 0.09 vs 0.13, respectively), with PSA increasing by mean 0.17 ng/mL/year across groups. Patients with csPCa had consistently higher PSA levels. PSA-D showed significant age-related linear increases in patients with csPCa but remained consistently lower in those without csPCa at all ages (0.10-0.11 ng/mL2), allowing differentiation at a threshold of >0.15 ng/mL2. CONCLUSION:In asymptomatic men, PV changed non-linearly with age. Age-related PSA thresholds are supported; however, a static PSA-D threshold of 0.15 ng/mL2 can be applied across all age ranges.
