Citations

Abstract Background: Currently known associations between common genetic variants and colorectal cancer explain less than half of its heritability of 25%. As alcohol consumption has a J-shape association with colorectal cancer risk, nondrinking and heavy drinking are both risk factors for colorectal cancer. Methods: Individual-level data was pooled from the Colon Cancer Family Registry, Colorectal Transdisciplinary Study, and Genetics and Epidemiology of Colorectal Cancer Consortium to compare nondrinkers (≤1 g/day) and heavy drinkers (>28 g/day) with light-to-moderate drinkers (1–28 g/day) in GxE analyses. To improve power, we implemented joint 2df and 3df tests and a novel two-step method that modifies the weighted hypothesis testing framework. We prioritized putative causal variants by predicting allelic effects using support vector machine models. Results: For nondrinking as compared with light-to-moderate drinking, the hybrid two-step approach identified 13 significant SNPs with pairwise r2 > 0.9 in the 10q24.2/COX15 region. When stratified by alcohol intake, the A allele of lead SNP rs2300985 has a dose–response increase in risk of colorectal cancer as compared with the G allele in light-to-moderate drinkers [OR for GA genotype = 1.11; 95% confidence interval (CI), 1.06–1.17; OR for AA genotype = 1.22; 95% CI, 1.14–1.31], but not in nondrinkers or heavy drinkers. Among the correlated candidate SNPs in the 10q24.2/COX15 region, rs1318920 was predicted to disrupt an HNF4 transcription factor binding motif. Conclusions: Our study suggests that the association with colorectal cancer in 10q24.2/COX15 observed in genome-wide association study is strongest in nondrinkers. We also identified rs1318920 as the putative causal regulatory variant for the region. Impact: The study identifies multifaceted evidence of a possible functional effect for rs1318920.

Abstract Objective Accurate extraction of breast cancer patients’ phenotypes is important for clinical decision support and clinical research. This study developed and evaluated cancer domain pretrained CancerBERT models for extracting breast cancer phenotypes from clinical texts. We also investigated the effect of customized cancer-related vocabulary on the performance of CancerBERT models. Materials and Methods A cancer-related corpus of breast cancer patients was extracted from the electronic health records of a local hospital. We annotated named entities in 200 pathology reports and 50 clinical notes for 8 cancer phenotypes for fine-tuning and evaluation. We kept pretraining the BlueBERT model on the cancer corpus with expanded vocabularies (using both term frequency-based and manually reviewed methods) to obtain CancerBERT models. The CancerBERT models were evaluated and compared with other baseline models on the cancer phenotype extraction task. Results All CancerBERT models outperformed all other models on the cancer phenotyping NER task. Both CancerBERT models with customized vocabularies outperformed the CancerBERT with the original BERT vocabulary. The CancerBERT model with manually reviewed customized vocabulary achieved the best performance with macro F1 scores equal to 0.876 (95% CI, 0.873–0.879) and 0.904 (95% CI, 0.902–0.906) for exact match and lenient match, respectively. Conclusions The CancerBERT models were developed to extract the cancer phenotypes in clinical notes and pathology reports. The results validated that using customized vocabulary may further improve the performances of domain specific BERT models in clinical NLP tasks. The CancerBERT models developed in the study would further help clinical decision support.

Abstract The methodological procedure for generating three-dimensional (3-D) finite element analysis (FEA) geometry models from CT or MRI medical imaging scan data was developed in this study. Medical images of a human scapula and a fifth proximal phalangeal bone were used to demonstrate the techniques of image processing and generation of 3-D FEA models. The biomedical imaging quality and its effects on the outcome of the FEA geometry model was also studied.

Abstract The purpose of this pilot study was to explore the efficacy, safety, and tolerability of vidofludimus calcium (VC) in the treatment of primary sclerosing cholangitis (PSC). This was a single‐arm open‐label pilot study with a cohort of 18 patients with PSC. Study patients received VC for a period of 6 months. The study was undertaken at two sites, Mayo Clinic, Rochester, MN, and Mayo Clinic, Phoenix, AZ. The primary endpoint of the study was improvement of serum alkaline phosphatase (ALP) at the end of the study. Secondary endpoints included assessment of other liver biomarkers (bilirubin, alanine aminotransferase, and aspartate aminotransferase). Of 18 patients enrolled, 11 completed the 6 months of study treatment. Patients who completed treatment versus those who did not were similar other than a significantly higher direct bilirubin at baseline in the group that completed treatment (mean ± SD, 0.4 ± 0.3 versus 0.1 ± 0.1, p = 0.04). By intent to treat analysis, the primary outcome was met in 16.7% (3/18) of patients. By per‐protocol analysis, including only patients who completed treatment, normalization of ALP occurred in 27.7% (3/11) at week 24 (95% confidence interval, 6.0% to 61.0%). VC was well tolerated with no drug‐related serious adverse events. Conclusion: This proof of concept study provides support for further exploration of VC in patients with PSC.

ObjectivesThis study was designed to evaluate significant differences in treatment and survival outcomes between patients with T1a and T1b glottic cancer.MethodsPatients within the SEER Research Plus, 18 Registries dataset who were diagnosed with Stage I T1a or T1b cancer of the glottis between 2004 and 2015 were included in this study. Data prior to 2004 could not be included, as the SEER database did not distinguish between T1a and T1b glottic cancer until that year.ResultsThe 5‐year disease‐specific survival for T1a patients was significantly better than that of patients diagnosed with T1b glottic cancer. Age and year of diagnosis were also independent factors that impacted mortality. More patients who were diagnosed with T1b glottic cancer underwent external beam radiation than those diagnosed with T1a glottic cancer.ConclusionOur data shows that there are several independent factors effecting mortality including T classification, age at time of diagnosis, and year of diagnosis. T1a glottic cancers also show a significantly better prognosis compared with T1b. T1b glottic cancers are much more likely to be treated with primary radiotherapy compared with surgery.Level of Evidence4 Laryngoscope, 132:2187–2193, 2022

ABSTRACT. The clinical epidemiology of adults admitted with reduced level of consciousness (LOC) in sub-Saharan Africa (SSA) and the impact of HIV infection on the risk of mortality in this population is unknown. We secondarily analyzed data from a cohort study that enrolled 359 consecutive adults with reduced LOC presenting to Mbarara Regional Hospital in Uganda with the aim of comparing the prognostic utility of the Full Outline of Unresponsiveness (FOUR) score to the Glasgow Coma Scale (GCS) Score. For this analysis, we included 336 individuals with known HIV serostatus, obtaining clinical, laboratory, and follow-up data. We recorded investigations and treatments deemed critical by clinicians for patient care but were unavailable. We computed mortality rates and used logistic regression to determine predictors of 30-day mortality. The median GCS was 10. Persons living with HIV infection (PLWH) accounted for 97 of 336 (29%) of the cohort. The 30-day mortality rate in the total cohort was 148 of 329 (45%), and this was significantly higher in PLWH (57% versus 40%, adjusted odds ratio [aOR] 2.39: 95% confidence interval [CI]: 1.31–4.35, P = 0.0046). Other predictors of mortality were presence of any unmet clinical need (aOR 1.72; 95% CIL 1.04–2.84, P = 0.0346), anemia (aOR 1.68; 95% CI: 1.01–2.81, P = 0.047), and admission FOUR score < 12 [aOR 4.26; 95% CI: 2.36–7.7, P < 0.0001). Presentation with reduced LOC in Uganda is associated with high mortality rates, with worse outcomes in PLWH. Improvement of existing acute care services is likely to improve outcomes.

AbstractBackgroundAlthough parkinsonism is a core feature of Parkinson’s Disease Dementia (PDD) and Dementia with Lewy bodies (DLB), its evolution is less delineated. We aimed to assess differences in severity and progression of parkinsonian motor symptoms and signs in a community autopsy cohort with clinicopathologic diagnosis of DLB, PDD or Alzheimer’s Disease (AD).MethodData included were from 194 participants in the Arizona study of Aging and Neurodegenerative Disorders with clinicopathologic diagnosis of DLB (n=48), PDD (n=98) (±AD co‐pathology) or pure AD (n=48), and at least two movement exams performed by movement disorders subspecialists who classified PD and parkinsonism according to MDS‐UPDRS criteria. DLB was subgrouped by presence or absence of parkinsonism at final exam (DLB+Park and DLB–Park). Between group trajectory of UPDRS‐II and UPDRS‐III scores were explored using piecewise‐linear and non‐linear MMRM multivariate analysis.ResultOver 1435 participant‐years of longitudinal data were included in the analyses (Figure 1). Mean±SD age at baseline movement exam and death were 76.0±7.5 and 83.4±6.8 years, respectively. At baseline, most participants did not have dementia or substantial motor abnormalities (except motor abnormalities in PDD). DLB (73.9%) and PDD (69.2%) groups had more males than AD (33.3%). Parkinsonism was present in 65.6% of DLB at last exam. Piecewise‐linear MMRM analysis showed baseline UPDRS‐II and UPDRS‐III scores were highest (p<0.001) for PDD (mean±SE: 14.3±0.78 and 27.4±1.64), followed by DLB+Park (5.0±1.05 and 17.4±3.10), DLB‐Park (3.7±2.54 and 3.8±1.35) and AD (3.2±0.88 and 8.0±1.94). Annual rate of increase in UPDRS‐II was greatest for DLB+Park (1.44±0.20) and PDD (1.04±0.08), followed by DLB‐Park (0.89±0.18) and AD (0.30±0.11). Annual rate of increase in UPDRS‐III was highest for PDD and DLB+Park (2.12±0.20 vs 2.64±0.42), followed by DLB‐Park and AD (1.31 ± 0.38 and 0.64 ± 0.22). Preliminary non‐linear MMRM models (Figure 2) further supported substantial between group/subgroup differences in motor trajectories, and progression in DLB‐Park.ConclusionThese preliminary results in a large, well‐characterized clinicopathological community‐based autopsy cohort support that DLB+Park experience comparable, or greater, parkinsonian motor progression to PDD. Future modeling/sensitivity analyses will better delineate expected trajectories of motor progression to add prognostication value in clinic and design of DLB clinical trials.

AbstractBackgroundThe association between mid‐life cardiovascular diseases or risk factors and cognition decline has been reported. However, sex differences in these associations have rarely been examined.MethodWe included 2,351 participants enrolled in the population‐based Mayo Clinic Study of Aging who were aged 30‐69 years at baseline. Participants were evaluated every 15 months by a coordinator, neurologic evaluation, and neuropsychological testing. The neuropsychological testing used nine tests to calculate global cognitive and domain‐specific (memory, language, executive function, and visuospatial skills) z‐scores. Nurse abstractors reviewed participant medical records to determine the presence and age at onset of cardiovascular diseases and risk factors. Linear mixed‐effect models evaluated the association between baseline cardiovascular conditions (coronary heart disease, myocardial infarction, atrial fibrillation, angina) or risk factors (hypertension, diabetes, dyslipidemia) and global and domain‐specific cognitive decline. Multivariable models adjusted for demographics, APOE, depression, and other medical conditions. Interactions between sex and each cardiovascular conditions or risk factors were examined; results were stratified by sex if the interaction was p<0.05.ResultOverall, 1651 (70.3%) participants had at least one cardiovascular condition or risk factor; the proportion of men was higher than women (875 (74.9%) vs.777 (65.7%), p<0.0001). Cross‐sectionally, baseline cardiovascular conditions and risk factors were not associated with cognitive performance in multivariable analyses and there were no sex differences. Longitudinally, several cardiovascular conditions and risk factors were associated with declines in global and/or domain‐specific z scores, with the exception of visual spatial z‐scores. Most cardiovascular conditions were more strongly associated with cognition among women: coronary heart disease, myocardial infraction, and angina were associated with global cognition decline only in women. Additionally, diabetes, dyslipidemia, and coronary heart disease were associated with language z‐score decline only in women.ConclusionMiddle aged cardiovascular conditions and risk factors are associated with mid‐life cognitive decline. Moreover, some specific cardiovascular conditions and risk factors, such as coronary artery disease, myocardial infraction, and angina have stronger associations with cognition decline among women.