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AbstractBackgroundPeriodontal disease is a prevalent, preventable, and highly treatable oral infection that is (1) stratified by sociodemographic, educational, and spatial factors and (2) is believed to impact cognitive impairment and ADRD risk. However, there is very little information from community‐based, population‐representative, longitudinal studies about the association between periodontal disease and midlife cognitive functioning net of early life confounders.MethodWe use data from the U.S. High School and Beyond (HSB) cohort study, which has followed a nationally representative sample of ∼25,500 people from high school in 1980 through midlife in 2021‐22. HSB data from the 1980s includes rich information about educational contexts, opportunities, and outcomes; early life socioeconomic and family circumstances; spatial location; and demographic group memberships. HSB data from 2021‐22 include indicators of periodontal disease diagnosis and multiple measures of cognitive functioning.ResultPeople who have been diagnosed with periodontal disease score worse on measures of memory, executive function, and other domains of cognitive functioning at midlife. These associations are only partly attributable to early life confounders. Some ─ but not all ─ of the association can be attributed to the mediating role of diabetes and CVD.ConclusionPeriodontal disease is a preventable and treatable risk factor for subsequent cognitive impairment. Because risk of periodontal disease is stratified by demographic, educational, and other social factors, periodontal disease may also be important in shaping sociodemographic gradients in midlife cognitive functioning. This is the first population‐representative study using data from a community‐based cohort that has been followed from adolescence through midlife. As such, this work provides important evidence about the role of periodontal disease in stratifying cognitive outcomes.

ABSTRACTBackgroundPeriodontal disease (PD) is a prevalent, preventable and treatable oral infection associated with substantial morbidity globally. There is little information from population‐representative cohort studies about the sociodemographic, educational and other early life factors that stratify PD risk.MethodsWe used data from the U.S. ‘High School and Beyond’ (HS&B:80) study, which has followed a nationally representative sample of 26,820 people from high school in 1980 through midlife in 2021. Data from the 1980s include information about education, early life circumstances, spatial location and demographic attributes. Data from 13,080 sample members who responded in 2021 include indicators of self‐reported PD diagnosis.ResultsPeople with higher degrees and course grades have a lower risk of midlife PD. Rural adolescents and those who attended private schools are also at lower risk. We find little evidence of heterogeneity in correlates of midlife PD by gender or race/ethnicity.ConclusionsThe quantity and characteristics of people's schooling and their location of residence are associated with midlife PD.

Background: There is limited data on the safety and efficacy of ventricular tachycardia (VT) ablation in patients with chronic kidney disease (CKD). We examined the outcomes of patients with CKD undergoing VT ablation in a nationally representative cohort of patients. Methods: The National Inpatient Sample Database (NIS) was analyzed from 2018 to 2021 to identify patients ≥18 years old with VT undergoing ablation. Patients with atrial fibrillation, atrial flutter, supraventricular tachycardia, or pre-excitation syndrome were excluded. Patients were divided into those with CKD and without CKD. A multivariable logistic regression model was utilized to assess the association of CKD with in-hospital mortality and outcomes after adjusting for confounders. Results: Our cohort included 1608 VT ablation procedures, of which 428 (27%) were performed on CKD patients. Mean age was 63 (±13) years, 318 (19%) were female, and 1194 (74%) were White. 1475 (92%) of the procedures were done at an urban teaching hospital, and 1240 (77%) at a private non-profit hospital. On multivariable analysis, CKD was associated with significantly higher odds of death (adjusted odds ration [aOR]: 3.43; 95% confidence interval [CI]: 1.79-6.5; p=0.0002), acute decompensated heart failure (aOR: 3.1; 95% CI 2.24-4.56; p<.0001), bleeding (aOR: 1.53; 95% CI1.02-2.28; p<.03), and acute kidney injury (aOR: 4.49; 95% CI3.42-5.9; p<.0001). There was no difference in the odds of acute myocardial infarction, stroke, cardiogenic shock, vasopressor use, mechanical ventilation, and pericardial tamponade or pericardial procedures Figure . Conclusion: Patients with CKD undergoing VT ablation have an increased risk of mortality and adverse in-hospital outcomes when compared to patients without CKD. These hypothesis-generating findings need validation in future prospective studies for optimal pre-procedural risk stratification.

Colorectal cancer (CRC) is the third most frequent neoplastic disorder and is a main cause of tumor-related mortality, as many patients progress to stage IV metastatic CRC. Standard care consists of combination chemotherapy (FOLFIRI or FOLFOX). Patients with WT KRAS typing are eligible to receive anti-EGFR therapy combined with chemotherapy. Unfortunately, predicting efficacy of CRC anti-EGFR therapy has remained challenging. Here we uncovered that the EGFR pathway component RasGRP1 acts as a CRC tumor suppressor in the context of aberrant Wnt signaling. We found that RasGRP1 suppresses EGF-driven proliferation of colonic epithelial organoids. Having established that RasGRP1 dosage levels impact biology, we next focused on CRC patients. Mining 5 different data platforms, we establish that RasGRP1 expression levels decrease with CRC progression and predict poor clinical outcome of patients. Last, deletion of 1 or 2 Rasgrp1 alleles made CRC spheroids more susceptible to EGFR inhibition. Retrospective analysis of the CALGB 80203 clinical trial showed that addition of anti-EGFR therapy to chemotherapy significantly improved outcome for CRC patients when tumors expressed low levels of RasGRP1 suppressor. In sum, our data support RasGRP1 as a biomarker in the EGFR pathway that has potential relevance to anti-EGFR therapy for CRC patients.

PurposeThe association of deficient DNA mismatch repair (dMMR) with prognosis in patients with colon cancer treated with adjuvant fluorouracil, leucovorin, and oxaliplatin (FOLFOX) chemotherapy remains unknown.Patients and MethodsResected, stage III colon carcinomas from patients (N = 2,686) randomly assigned to FOLFOX ± cetuximab (North Central Cancer Treatment Group N0147 trial) were analyzed for mismatch repair (MMR) protein expression and mutations in BRAFV600E(exon 15) and KRAS (codons 12 and 13). Association of biomarkers with disease-free survival (DFS) was determined using Cox models. A validation cohort (Cancer and Leukemia Group B 88903 trial) was used.ResultsdMMR was detected in 314 (12%) of 2,580 tumors, of which 49.3% and 10.6% had BRAFV600Eor KRAS mutations, respectively. MMR status was not prognostic overall (adjusted hazard ratio [HR], 0.82; 95% CI, 0.64 to 1.07; P = .14), yet significant interactions were found between MMR and primary tumor site (Pinteraction= .009) and lymph node category (N1 v N2; Pinteraction= .014). Favorable DFS was observed for dMMR versus proficient MMR proximal tumors (HR, 0.71; 95% CI, 0.53 to 0.94; P = .018) but not dMMR distal tumors (HR, 1.71; 95% CI, 0.99 to 2.95; P = .056), adjusting for mutations and covariates. Any survival benefit of dMMR was lost in N2 tumors. Mutations in BRAFV600E(HR, 1.37; 95% CI, 1.08 to 1.70; P = .009) or KRAS (HR, 1.44; 95% CI, 1.21 to 1.70; P < .001) were independently associated with worse DFS. The observed MMR by tumor site interaction was validated in an independent cohort of stage III colon cancers (Pinteraction= .037).ConclusionThe prognostic impact of MMR depended on tumor site, and this interaction was validated in an independent cohort. Among dMMR cancers, proximal tumors had favorable outcome, whereas distal or N2 tumors had poor outcome. BRAF or KRAS mutations were independently associated with adverse outcome.