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The recognition of dominantly inherited micro-satellite instable (MSI) cancers caused by pathogenic variants in one of the four mismatch repair (MMR) genes MSH2, MLH1, MSH6 and PMS2 has modified our understanding of carcinogenesis. Inherited loss of function variants in each of these MMR genes cause four dominantly inherited cancer syndromes with different penetrance and expressivities: the four Lynch syndromes. No person has an 'average sex 'or a pathogenic variant in an 'average Lynch syndrome gene' and results that are not stratified by gene and sex will be valid for no one. Carcinogenesis may be a linear process from increased cellular division to localized cancer to metastasis. In addition, in the Lynch syndromes (LS) we now recognize a dynamic balance between two stochastic processes: MSI producing abnormal cells, and the host's adaptive immune system's ability to remove them. The latter may explain why colonoscopy surveillance does not reduce the incidence of colorectal cancer in LS, while it may improve the prognosis. Most early onset colon, endometrial and ovarian cancers in LS are now cured and most cancer related deaths are after subsequent cancers in other organs. Aspirin reduces the incidence of colorectal and other cancers in LS. Immunotherapy increases the host immune system's capability to destroy MSI cancers. Colonoscopy surveillance, aspirin prevention and immunotherapy represent major steps forward in personalized precision medicine to prevent and cure inherited MSI cancer., Author(s): Pal Maller[sup.1], Toni T. Seppälä[sup.2,3,4], Aysel Ahadova[sup.5,6,7], Emma J. Crosbie[sup.8,9], Elke Holinski-Feder[sup.10,11], Rodney Scott[sup.12], Saskia Haupt[sup.13,14], Gabriela Möslein[sup.15], Ingrid Winship[sup.16,17], Sanne W. Bajwa-ten Broeke[sup.18], Kelly E. Kohut[sup.19], Neil Ryan[sup.20,21], [...]

Objective To compare colorectal cancer (CRC) incidences in carriers of pathogenic variants of the MMR genes in the PLSD and IMRC cohorts, of which only the former included mandatory colonoscopy surveillance for all participants. Methods CRC incidences were calculated in an intervention group comprising a cohort of confirmed carriers of pathogenic or likely pathogenic variants in mismatch repair genes (path_MMR) followed prospectively by the Prospective Lynch Syndrome Database (PLSD). All had colonoscopy surveillance, with polypectomy when polyps were identified. Comparison was made with a retrospective cohort reported by the International Mismatch Repair Consortium (IMRC). This comprised confirmed and inferred path_MMR carriers who were first- or second-degree relatives of Lynch syndrome probands. Results In the PLSD, 8,153 subjects had follow-up colonoscopy surveillance for a total of 67,604 years and 578 carriers had CRC diagnosed. Average cumulative incidences of CRC in path_MLH1 carriers at 70 years of age were 52% in males and 41% in females; for path_MSH2 50% and 39%; for path_MSH6 13% and 17% and for path_PMS2 11% and 8%. In contrast, in the IMRC cohort, corresponding cumulative incidences were 40% and 27%; 34% and 23%; 16% and 8% and 7% and 6%. Comparing just the European carriers in the two series gave similar findings. Numbers in the PLSD series did not allow comparisons of carriers from other continents separately. Cumulative incidences at 25 years were < 1% in all retrospective groups. Conclusions Prospectively observed CRC incidences (PLSD) in path_MLH1 and path_MSH2 carriers undergoing colonoscopy surveillance and polypectomy were higher than in the retrospective (IMRC) series, and were not reduced in path_MSH6 carriers. These findings were the opposite to those expected. CRC point incidence before 50 years of age was reduced in path_PMS2 carriers subjected to colonoscopy, but not significantly so. Keywords: Lynch Syndrome, Epidemiology, Prevention, Penetrance, Colorectal cancer, Segregation analysis, Prospective, Incidence, Over-diagnosis, Colonoscopy, Author(s): Pål Maller[sup.1], Toni Seppälä[sup.2,3,4], James G. Dowty[sup.5], Saskia Haupt[sup.6,7], Mev Dominguez-Valentin[sup.1], Lone Sunde[sup.8,9], Inge Bernstein[sup.10,11], Christoph Engel[sup.12], Stefan Aretz[sup.13], Maartje Nielsen[sup.14], Gabriel Capella[sup.15], Dafydd Gareth Evans[sup.16], John Burn[sup.17], Elke [...]

(1) Background: Spontaneous bacterial peritonitis (SBP) is a feared complication of liver cirrhosis. We investigated the prevalence of SBP, positive ascitic fluid cultures, and risk factors for mortality. (2) Methods: A retrospective analysis of all patients with cirrhosis hospitalized or in follow-up in a single center between 1996 and 2020. The clinical data, long-term complications, and mortality of SBP patients were compared with those of non-SBP patients. Ascitic fluid positive culture was compared with those without growth. (3) Results: We included 1035 cirrhotic patients, of which 173 (16.7%) developed SBP. Ascitic fluid culture growth was found in 47.4% of the SBP cases, with Escherichia coli bacteria detected in 38%, 24.4% grew ESBL-producing bacteria, and 14.5% displayed multidrug resistance. In a Cox regression model, SBP, male sex, prolonged INR at diagnosis, and hepatocellular carcinoma were found to be risk factors for mortality in cirrhotic patients. The long-term all-cause mortality was 60% in non-SBP and 90% in SBP patients. (4) Conclusions: Only a minority of cirrhotic patients developed SBP, 47.4% of which had positive ascitic fluid cultures with high antibiotic resistance. Growth of ESBL and multidrug resistant organisms is becoming more frequent in the clinical setting, reaching SBP mortality of 90%. [ABSTRACT FROM AUTHOR]

Aim: Nuclear factor kappa B (NF-κB) is known to play an important role in the inflammatory process which takes place after ischemic stroke. The major objective of the present study was to examine the effects of MEDS-23, a potent inhibitor of NF-κB, on clinical outcomes and brain inflammatory markers in post-ischemic stroke rats. Main methods: Initially, a Toxicity Experiment was performed to determine the appropriate dose of MEDS-23 for use in animals, as MEDS-23 was analyzed in vivo for the first time. We used the middle cerebral artery occlusion (MCAO) model for inducing ischemic stroke in rats. The effects of MEDS-23 (at 10 mg/kg, ip) on post-stroke outcomes (brain inflammation, fever, neurological deficits, mortality, and depression- and anxiety-like behaviours) was tested in several efficacy experiments. Key findings: MEDS-23 was found to be safe and significantly reduced the severity of some adverse post-stroke outcomes such as fever and neurological deficits. Moreover, MEDS-23 significantly decreased prostaglandin E2 levels in the hypothalamus and hippocampus of post-stroke rats, but did not prominently alter the levels of interleukin-6 and tumor necrosis factor-α. Significance: These results suggest that NF-κB inhibition is a potential therapeutic strategy for the treatment of ischemic stroke. [ABSTRACT FROM AUTHOR]

Background/Objectives : Terminal ileitis (TI) is often identified on CT scans in emergency settings. Diagnosing Crohn's disease (CD) as a cause of TI is crucial due to its significant long-term implications. This study aimed to differentiate CD from other causes of acute TI and develop a predictive model for CD diagnosis. Methods : A retrospective case-control study was conducted at Shamir Medical Center including adults diagnosed with acute TI from January 2012 to December 2020. Patients with a history of inflammatory bowel disease or prior intestinal surgery were excluded. Patients were categorized into CD and non-CD groups based on their subsequent clinical course. A logistic regression model was developed and subsequently validated with additional patients hospitalized between 2021 and 2023. Results : Among 135 patients, 37 (27.4%) were diagnosed with CD. CD patients were younger (median age 27 vs. 39 years, p = 0.003), predominantly male (83.8% vs. 51%, p = 0.001), and had higher rates of chronic abdominal pain, diarrhea, anemia, and weight loss prior to hospitalization. Significant laboratory differences included higher platelet counts ( p = 0.006) and lower mean corpuscular volume (MCV) ( p = 0.001) in CD patients. Radiologic signs of complicated disease were more common in CD (35.1% vs. 4.1%, p < 0.001). The predictive model incorporating gender, abdominal pain history, and MCV showed an area under the curve (AUC) of 0.87, with a sensitivity of 100% and specificity of 63.6% in the validation group of 18 patients. Conclusions : This study identified key predictors of CD in patients presenting with acute TI and developed a predictive model with a substantial diagnostic capability. Use of this model for early identification and treatment of CD may potentially improve patient outcomes. Further prospective validation of this model is warranted.

Background: Inflammatory bowel disease (IBD) prevalence is increasing among Bedouin Arabs in Israel. This population is known to have a high rate of consanguinity. NOD2/CARD15 mutations are well-studied in IBD., Objectives: To investigate the frequency of NOD2/CARD15 mutations in IBD Bedouin patients and their relevance to disease phenotype., Methods: The IBD-Arab cohort in southern Israel included 68 patients, of which 25 Crohn's disease (CD) patients and 25 ulcerative colitis (UC) patients consented to participate (72%). Blood samples were obtained from all participants who were genotyped for NOD2/CARD15 variants Arg702Trp, Gly908Arg, and Leu1007fsinsC., Results: The NOD2/CARD15 mutation frequency was higher in Crohn's disease than in ulcerative colitis patients. Carrier frequency for the Gly908Arg mutation in CD and UC patients was 8/25 (32%) and 3/25 (12%), respectively (P = 0.08). Neither the Arg702Trp nor Leu1007fsinsC mutation was found in our cohort. No homozygous/compound heterozygote mutations were found. Genotype-phenotype analysis revealed that CD patients carrying the Gly908Arg mutation were younger at diagnosis, 22.8 ± 4.5 vs. 28.82 ± 9.1 years (P = 0.04). All carriers were males, compared with 41.2% in non-carriers (P = 0.005). NOD2/CARD15 mutation carriers with UC were older, 67.0 ± 24.5 years compared with 41.2 ± 12.3 years (P = 0.006). No other associations regarding disease localization or other clinical parameter were found., Conclusions: The frequency of NOD2/CARD15 gene mutations is high in CD and UC among Bedouin Arab IBD patients and is associated with younger age at onset in CD and male gender.

Background: The impact of admission glycated hemoglobin (HbA1c) on hospital outcome is controversial., Objectives: To evaluate the association between admission glucose and HbA1c levels and mortality 1 year after hospitalization in the internal medicine ward., Methods: HbA1c level of consecutive patients was measured during the first 24 hours of admission to the internal medicine ward and divided at the cutoff point of 6.5%. Three groups of patients were prospectively identified: patients with preexisting diabetes mellitus (DM), patients with glucose > 140 mg/dl (hyperglycemia) on admission and no known diabetes (H), and patients without diabetes or hyperglycemia (NDM). The primary end-point was 1 year all-cause mortality., Results: A total of 1024 patients were enrolled, 592 (57.8%) belonged to the DM group, 119 (11.6/6) to the H group and 313 (30.6%) to the NDM group. At 1 year, death occurred in 70 (11.9%) in the DM group, 12 (10.0%) in the H group and 15 (4.8%) in the NDM group (P = 0.002). Elevated admission glucose levels did not influence outcome in any of the groups. HbA1c levels were similar for survivors and non-survivors (P = 0.60). Within-group multivariate analysis adjusted for comorbidities and age showed that in the H group HbA1C levels of 6.5% or above were associated with increased mortality risk [hazard ratio (HR) 8.25, 95% confidence interval (CI) 1.93-35.21]. In the DM group, HbA1c levels below 6.5% were associated with increased mortality risk (HR = 2.05, 95% CI 1.25-3.36)., Conclusions: Glucose levels upon admission did not affect mortality. However, HbA1c levels below 6.5% had opposite effects on 1 year mortality in diabetes patients and patients with hyperglycemia.