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By 2030, early-onset colorectal cancer (EOCRC) is expected to become the leading cancer-related cause of death for people age 20 to 49. To improve understanding of this phenomenon, we analyzed the geographic determinants of EOCRC in Utah by examining county-level incidence and mortality. We linked data from the Utah Population Database to the Utah Cancer Registry to identify residents (age 18–49) diagnosed with EOCRC between 2000 and 2020, and we used spatial empirical Bayes smoothing to determine county-level hotspots. We identified 1,867 EOCRC diagnoses (52.7% in male patients, 69.2% in non-Hispanic White patients). Ten counties (34%) were classified as hotspots, with high EOCRC incidence or mortality. Hotspot status was unrelated to incidence rates, but non-Hispanic ethnic-minority men (incidence rate ratio, 1.49; 95% CI, 1.15–1.91), Hispanic White men and women (incidence rate ratio, 2.24; 95% CI, 2.00–2.51), and Hispanic ethnic-minority men and women (incidence rate ratio, 4.59; 95% CI, 3.50–5.91) were more likely to be diagnosed with EOCRC. After adjustment for income and obesity, adults living in hotspots had a 31% higher hazard for death (HR, 1.31; 95% CI, 1.02–1.69). Survival was poorest for adults with a late-stage diagnosis living in hotspots (chi square (1) = 4.0; p = .045). Adults who were married or who had a life partner had a lower hazard for death than single adults (HR, 0.73; 95% CI, 0.58–0.92). The risk for EOCRC is elevated in 34% of Utah counties, warranting future research and interventions aimed at increasing screening and survival in the population age 18 to 49.

One of Japan’s most versatile scholars of film, television, and manga (comic books), Yomota Inuhiko (1953–) made a deep impact on Manga Studies, where he engaged in a form of manga analysis commonly called “expression theory” (hyōgen-ron). In the present translated twin essays from Yomota’s now-classic study, The Principles of Manga (Manga Genron, 1994), he demonstrates his awareness of the possibilities of applying a linguistic lens to the study of Japanese comics. In Part One, Yomota explores the idea of onomatopoeia in manga, considering how they are very much cultural constructions that can be difficult to translate into other languages. In Part Two, Yomota delves deeper into the way onomatopoeia appear on the page, often creating impossible-to-utter expressions but ones easily understood nonetheless by readers. While there is already a great deal of research on onomatopoeia mimetics in spoken Japanese, Yomota here expounds on how manga artists have invented new ways of employing onomatopoeia outside of these established patterns in the spoken language. He gives clear examples of the evolution and representation of mimetics in manga, discusses several key features of comic-book mimetics, and makes a clear argument that they have spurred the evolution of modern-day manga.

Background Glaucoma is the leading cause of irreversible blindness globally. During the COVID-19 pandemic, an enforced reduction in capacity resulted in the deferral of routine outpatient appointments for glaucoma patients. Aim This study analyses patient outcomes following the establishment of a drive-through intra-ocular pressure (IOP) clinic during the COVID-19 pandemic to alleviate increased pressure on the tertiary glaucoma services at Royal Victoria Eye and Ear Hospital (RVEEH) and Mater Misericordiae University Hospital (MMUH) between August 2020 and June 2021. Methods A 1-lane driveway system was established in a marquee on the grounds of City West hotel. IOPs were measured in patients’ cars using a hand held iCare100 tonometer. Results were reviewed by a consultant ophthalmologist. At hospital follow-up clinic visits, IOP was measured using the Goldmann applanation tonometer (GAT). Results Three hundred one patients of a total of 672 who attended the drive-through clinic have subsequently attended a designated hospital follow-up appointment. In this cohort, the mean drive-through iCare IOP of 19.4 mmHg ± 6.0 was significantly higher (

Coding region variants that are shared by Family I affected members III:6 and III:7

Polymorphisms in DNA double-strand break repair gene XRCC2 may play an important role in colorectal cancer etiology, specifically in disease subtypes. Associations of XRCC2 variants and colorectal cancer were investigated by tumor site and tumor instability status in a four-center collaboration including three U.K. case-control studies (Sheffield, Leeds, and Dundee) and a U.S. case-control study of cases from high-risk Utah pedigrees (total: 1,252 cases and 1,422 controls). The 14 variants studied were tagging single nucleotide polymorphisms (SNP) selected from National Institute of Environmental Health Sciences/HapMap data supplemented with SNPs identified from sequencing of 125 cases chosen to represent multiple colorectal cancer groups (familial, metastatic disease, and tumor subsite). Monte Carlo significance testing using Genie software provided valid meta-analyses of the total resource that includes family-based data. Similar to reports of colorectal cancer and other cancer sites, the rs3218536 R188H allele was not associated with increased risk. However, we observed a novel, highly significant association of a common SNP, rs3218499G>C, with increased risk of rectal tumors (odds ratio, 2.1; 95% confidence interval, 1.3-3.3; Pχ2 = 0.0006) versus controls, with the largest risk found for female rectal cases (odds ratio, 3.1; 95% confidence interval, 1.6-6.1; Pχ2 = 0.0006). This difference was significantly different to that for proximal and distal colon cancers (Pχ2 = 0.02). Our investigation supports a role for XRCC2 in colorectal cancer tumorigenesis, conferring susceptibility to rectal tumors. (Cancer Epidemiol Biomarkers Prev 2009;18(9):2476–84)

PCA and gene based rare synonymous variant comparison analyses of European ancestry Multiple Myeloma cases and controls

SUPPLEMENTAL TABLE: Effect of homozygosity at the three HLA class I loci -A, -B and -C and five HLA class I loci -DRB1, DQA1, DQB1, DPA1, and DPB1 on susceptibility to four NHL subtypes (DLBCL, FL, CLL/SLL, and MZL) stratified by GWAS platform (analyses adjusted for sex, age, and ancestry/principal components)

DNA repair enzymes function in major pathways to reverse DNA damage, including base excision repair (BER). Missense polymorphisms in BER repair genes may contribute to differences in DNA repair capacity, specific mutations, and susceptibility to cancer in the presence of exposure to carcinogens such as cigarette smoking. In a study of 1,604 incident colon cancer cases and 1,969 matched population-based controls genotyped for BER variants OGG1 (S326C) and XRCC1 (R194W, R280H, and R399Q), we found no associations with colon cancer overall. However, a 2-fold increased risk of BRAF V600E tumor mutation was observed in current and former cigarette smokers homozygous for the OGG1 polymorphism (odds ratio, 2.2; 95% confidence interval, 1.02-4.9, recessive model); similar associations were not observed for microsatellite instability, CpG island methylator phenotype, KRAS2 mutations, or TP53 mutations. The XRCC1 R194W polymorphism was associated with a modest increased risk of TP53 tumor mutations in those who regularly smoked cigarettes (odds ratio, 1.4; 95% confidence interval, 1.02-1.9). These findings point to the importance of studying tumor mutations when examining DNA repair polymorphisms and cigarette smoke exposure to identify potentially relevant associations with colorectal cancer. (Cancer Epidemiol Biomarkers Prev 2009;18(12):3384–8)

Supplementary Table 2 from Genetic Variants in XRCC2: New Insights Into Colorectal Cancer Tumorigenesis

Supplementary Table 1 from Assessing Tumor Mutations to Gain Insight into Base Excision Repair Sequence Polymorphisms and Smoking in Colon Cancer

A growing number of loci within the human leukocyte antigen (HLA) region have been implicated in non-Hodgkin lymphoma (NHL) etiology. Here, we test a complementary hypothesis of “heterozygote advantage” regarding the role of HLA and NHL, whereby HLA diversity is beneficial and homozygous HLA loci are associated with increased disease risk. HLA alleles at class I and II loci were imputed from genome-wide association studies (GWAS) using SNP2HLA for 3,617 diffuse large B-cell lymphomas (DLBCL), 2,686 follicular lymphomas (FL), 2,878 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLL), 741 marginal zone lymphomas (MZL), and 8,753 controls of European descent. Both DLBCL and MZL risk were elevated with homozygosity at class I HLA-B and -C loci (OR DLBCL = 1.31, 95% CI = 1.06–1.60; OR MZL = 1.45, 95% CI = 1.12–1.89) and class II HLA-DRB1 locus (OR DLBCL = 2.10, 95% CI = 1.24–3.55; OR MZL = 2.10, 95% CI = 0.99–4.45). Increased FL risk was observed with the overall increase in number of homozygous HLA class II loci (P trend < 0.0001, FDR = 0.0005). These results support a role for HLA zygosity in NHL etiology and suggests that distinct immune pathways may underly the etiology of the different NHL subtypes.Significance: HLA gene diversity reduces risk for non-Hodgkin lymphoma. Cancer Res; 78(14); 4086–96. ©2018 AACR.

Supplementary Table 3 from Genetic Variants in XRCC2: New Insights Into Colorectal Cancer Tumorigenesis

Supplementary Table 2 from Assessing Tumor Mutations to Gain Insight into Base Excision Repair Sequence Polymorphisms and Smoking in Colon Cancer

Supplementary Table 1 from Genetic Variants in XRCC2: New Insights Into Colorectal Cancer Tumorigenesis

Given the frequent and largely incurable occurrence of multiple myeloma, identification of germline genetic mutations that predispose cells to multiple myeloma may provide insight into disease etiology and the developmental mechanisms of its cell of origin, the plasma cell (PC). Here, we identified familial and early-onset multiple myeloma kindreds with truncating mutations in lysine-specific demethylase 1 (LSD1/KDM1A), an epigenetic transcriptional repressor that primarily demethylates histone H3 on lysine 4 and regulates hematopoietic stem cell self-renewal. In addition, we found higher rates of germline truncating and predicted deleterious missense KDM1A mutations in patients with multiple myeloma unselected for family history compared with controls. Both monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma cells have significantly lower KDM1A transcript levels compared with normal PCs. Transcriptome analysis of multiple myeloma cells from KDM1A mutation carriers shows enrichment of pathways and MYC target genes previously associated with myeloma pathogenesis. In mice, antigen challenge followed by pharmacologic inhibition of KDM1A promoted PC expansion, enhanced secondary immune response, elicited appearance of serum paraprotein, and mediated upregulation of MYC transcriptional targets. These changes are consistent with the development of MGUS. Collectively, our findings show that KDM1A is the first autosomal-dominant multiple myeloma germline predisposition gene providing new insights into its mechanistic roles as a tumor suppressor during post-germinal center B-cell differentiation.Significance: KDM1A is the first germline autosomal dominant predisposition gene identified in multiple myeloma and provides new insights into multiple myeloma etiology and the mechanistic role of KDM1A as a tumor suppressor during post-germinal center B-cell differentiation. Cancer Res; 78(10); 2747–59. ©2018 AACR.

Additional methods, statistical and resource information to assist readers about how experiments and analyses were conducted.

Background: Comorbid chronic rhinosinusitis (CRS) of adulthood is increasing among patients with cystic fibrosis (CF) due to improved median survival. However, little is known about the natural history of endoscopic sinus surgery (ESS) in this cohort. The objective of this study was to evaluate the revision rate of ESS and associated risk factors among adults with CRS and CF (CRSwCF). Methods: The Utah Population Database was queried for patients age >18 with CRS who underwent at least one ESS between 1996 and 2018. Demographic information and ESS history were collected and compared for CRSwCF versus CRS without CF (CRSsCF) using chi-square and t-tests. Risk factors for revision were analyzed using Cox proportional hazard models and logistic regression analysis. Results: A total of 34 050 patients (33 639 CRSsCF and 411 CRSwCF) were included in the final analysis. The mean duration of follow-up was 9.3 and 9.3 years, respectively ( P = .98). Adult patients with CF were significantly more likely to undergo revision ESS (18.7%) than those without CF (13.4%; P

Several studies have suggested a possible relationship between exfoliation syndrome (XFS) and abdominal aortic aneurysm (AAA). A systematic literature review was undertaken to investigate this potential association. The systematic literature review was performed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Clear definitions of XFS and AAA were used to identify eligible studies via an unrestricted search of the PubMed interface from 1979 to October 31st, 2021. After review, 876 citations were gathered and evaluated for inclusion, from which 22 articles were included. Of these 22, 16 were excluded because they did not assess the relationship between AAA and XFS or provide primary data. Ultimately, six studies were included in this literature review. Half of the studies explored AAA prevalence in a population with or without XFS, and the other half explored the opposite. Three studies supported XFS as a risk factor for the development of AAA, and the other three found this relationship to be inconclusive. This systematic review revealed inconsistent results regarding an association between AAA and XFS. A large database study including XFS and AAA patients would be useful in further determining if an association does in fact exist.

A pilot study of electronic medical records (EMR) in Utah was undertaken to investigate exfoliation syndrome and exfoliation glaucoma (XFS/XFG) in abdominal aortic aneurysm (AAA) patients. In a subsequent retrospective cohort study of Utah XFS/XFG patients and population controls, the risk of AAA was examined.EMR of a statewide healthcare population were obtained from the Utah Population Database (UPDB) which links decades of medical records with Utah demographic and vital records data. In a pilot study, 7167 patients ages ≥40 years identified with AAA diagnosed from 1996 to 2015, based on International Classification of Diseases (ICD) version 9/10 codes, were included. A univariable hazards model was used to determine the risk of XFS/XFG in AAA patients. An XFS/XFG outcome based on ICD 9/10 codes in AAA patients and in 5:1 sex- and age-matched non-AAA controls was determined. A retrospective cohort of 3412 XFS/XFG patients ages ≥50 years diagnosed from 1996 to 2020 and 10 227 3:1 sex- and age-matched controls who underwent ≥1 dilated eye examination(s) were recently identified and updated diagnoses of AAA were obtained. Multivariable logistic regression was used to estimate AAA risk in XFS/XFG patients compared with controls. In a subset of XFS/XFG patients, chart reviews were conducted to confirm clinically diagnosed AAA.In the AAA pilot, 20 patients (0.3%) and 118 controls (0.3%) developed XFS/XFG, respectively. We observed no increased risk of XFS/XFG in AAA patients compared with non-AAA-matched controls (HR = 0.99, 95% CI 0.6-1.6). Among XFS/XFG study patients and controls, 122 patients (3.6%) and 376 controls (3.7%) had an AAA diagnosis. We likewise observed no increased risk of AAA in XFS/XFG patients (OR = 0.97, 95% CI 0.8-1.2). In 14 XFS/XFG patients with an ICD 9/10 diagnosis of AAA who underwent chart review, a clinical diagnosis of AAA was confirmed in 9 patients (64.3%).Our findings do not support an association between AAA and XFS/XFG.

Background: Mammographic density (MD) is strongly associated with breast cancer risk. We examined whether body mass index (BMI) partially explains racial and ethnic variation in MD. Methods: We used multivariable Poisson regression to estimate associations between BMI and binary MD [Breast Imaging Reporting and Database System (BI-RADS) A&B versus BI-RADS C&D] among 160,804 women in the Utah mammography cohort. We estimated associations overall and within racial and ethnic subgroups and calculated population attributable risk percents (PAR%). Results: We observed the lowest BMI and highest MD among Asian women, the highest BMI among Native Hawaiian and Pacific Islander women, and the lowest MD among American Indian and Alaska Native (AIAN) and Black women. BMI was inversely associated with MD [RRBMI≥30 vs. BMI Conclusions: While we observed substantial differences in the distributions of BMI and MD by race and ethnicity, associations between BMI and MD were generally similar across groups. Impact: Distributions of BMI and MD may be important contributors to breast cancer disparities.

Purpose Exfoliation syndrome (XFS), the most common recognizable cause of open-angle glaucoma worldwide, is a systemic disorder with genetic predisposition due to variations in lysyl oxidase-like 1 (LOXL1) function, leading to altered elastin matrices in ocular and systemic tissues. Obstructive sleep apnea (OSA) is a highly prevalent disorder also involving elastic tissue dysfunction and is associated with glaucoma. Because of the similarities between the disorders, we sought to uncover any relationship in the prevalence of these diagnoses. Design Case-control, retrospective cohort study. Participants A cohort of 81 735 patients diagnosed with OSA at ages 50 to 90 years was identified from medical records from 1996 to 2017 in the Utah Population Database. Case subjects were matched to random controls on sex and birth year in a 4:1 ratio. Methods International Classification of Diseases, Ninth Revision (ICD-9) codes or their Tenth Revision equivalent were used to define a diagnosis of OSA (ICD-9 327.23) and a diagnosis of XFS (ICD-9 365.52 and 366.11). Conditional logistic regression odds ratios (ORs) accounting for individual matching on sex and birth year were used to estimate the risk of XFS in patients with OSA. Models included adjustment for race, obesity, tobacco use, hypertension (HTN), atrial fibrillation (AF), and chronic obstructive pulmonary disease (COPD). Main Outcome Measure Whether patients with OSA have an increased risk of diagnosis of XFS compared with controls without OSA. Results There was an increased risk of an XFS diagnosis in patients with OSA compared with non-OSA controls (OR, 1.27; 95% confidence interval [CI], 1.02–1.59; P = 0.03). In a stratification of patients by HTN diagnosis history, patients with OSA and HTN exhibited an increased risk of XFS compared with non-OSA controls with HTN (OR, 2.67; 95% CI, 2.06–3.46; P Conclusions Patients with OSA may be at an increased risk of XFS compared with patients without OSA, particularly in patients with a history of HTN.

Background Large epidemiologic studies have suggested that a history of tobacco use may be associated with an increased risk of developing chronic rhinosinusitis (CRS). The impact of tobacco use on revision rates of endoscopic sinus surgery (ESS), however, remains limited. Objective This study seeks to define the independent risk of tobacco use (active or prior) on revision rates of ESS among a large cohort of patients with CRS. Methods A state population database was queried for patients age ≥18 years with CRS who underwent at least one ESS between 1996 and 2018. Demographic characteristics, history of ESS, and tobacco use status were compared across patients with CRS, using t tests for continuous variables and χ2 tests for categorical variables. Unadjusted and adjusted logistic regression models were used to understand the impact of tobacco status on revision surgery. Results The final analysis included 34 350 patients (29 916 CRS with no revision surgery and 4434 CRS with revision surgery). Unadjusted regression analysis demonstrated an increased odds of undergoing revision ESS (OR 1.12, 95% CI: 1.00–1.25, P = .05) among males with a history of tobacco use and CRS. Adjusted regression analysis demonstrated that the risk of revision ESS among CRS patients with a history of asthma and tobacco use was 1.72-fold, while the risk among CRS patients who were tobacco users without asthma was 1.11-fold. Conclusion History of tobacco use is an independent risk factor for revision ESS among patients with CRS.

Introduction: Women with extremely dense breast tissue on mammography have a higher risk of breast cancer compared to similarly-aged women with less dense breast tissue. Tamoxifen therapy has been observed to reduce breast density among both pre- and postmenopausal women with HR+ breast cancer and may predict benefit of therapy. Studies of aromatase inhibitor (AI) therapy and breast density change, however, are limited and results inconclusive. Factors associated with breast density change with ET, and effect of duration of ET on breast density change, have not been well studied. Methods: Using the Utah Population Database, women were identified who underwent screening mammography in 2005-2016 and who had no personal history of breast cancer. Those who were subsequently diagnosed with HR+ breast cancer and treated in one of the major health care systems in Utah (Intermountain Healthcare or University of Utah Health) were included in the analysis. ET prescription information and duration of ET were obtained from provider records and the Utah All-Payer Claims Database. Women with mammography results in the electronic medical record both before and within 3 years after the breast cancer diagnosis were included. BI-RADS density classification from mammogram reports 6-12 months, 13-24 months, and 25-36 months after ET initiation were compared to pre-diagnosis BI-RADS density classification. Breast density reduction was defined as a decrease of ≥1 BI-RADS category compared to baseline. Fisher’s exact test was used to examine ET and breast density reduction among women ≥55y and Results: In total, 1328 women with HR+ breast cancer and baseline BI-RADS breast density categories B-D were included. Women with BI-RADS density category A(almost entirely fatty) were excluded. A majority (61%) were age ≥55y at diagnosis, were non-Hispanic white (90%), and had BMI ≥25 kg/m2 (56%); 15% had a first-degree family history of breast cancer. At baseline, 602 (44%) women had scattered fibroglandular densities (BI-RADS category B), 697 (50%) had heterogeneously dense breasts (BI-RADS category C), and 83 (6%) had extremely dense breasts (BI-RADS category D). Half were treated with AI only (49%), 21% with tamoxifen only, and 29% with both during follow-up. In both the age ≥55y and Conclusion: Baseline breast density is associated with a demonstrable reduction in breast density during ET. Our findings suggest that AI therapy can reduce breast density similar to that seen with tamoxifen therapy. Table 1 Breast Density (BD) changes among women who underwent mammography 6-12 months, 13-24 months, and 25-36 months after ET initiationBaseline BDN≥55 years oldPTotal Citation Format: Mei Wei, Lisa Pappas, Emily Guinto, Carol Sweeney, Nicola Camp, Phoebe Freer, Saundra Buys, N. Lynn Henry, Karen Curtin. Mammographic breast density changes with endocrine therapy (ET) in women with hormone receptor positive (HR+) breast cancer in a Utah population [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-08-10.

Background: Prior data suggest an association between non-melanoma skin cancer, i.e., basal and squamous cell cancers most often located in areas of sun exposure, and pseudoexfoliation syndrome. This study aimed to evaluate the association between these conditions and UV exposure through a detailed questionnaire in a large and robust Utah population. Methods: The two arms of this study are a population-based study (evaluated via chart review) and a UV exposure study (evaluated via a questionnaire). Participants answered a questionnaire designed to assess lifelong UV exposure, including leisure and occupational sun exposure, likelihood to tan or burn in early life, eye and hair color, smoking behavior, vitamin D deficiency, skin cancer history, alcohol consumption, and caffeine intake. Conclusion: Descriptive findings suggest UV exposure over an adult’s lifespan may associate with a higher risk of non-melanoma skin cancer in Utah exfoliation patients vs. unaffected individuals. Patients with exfoliation glaucoma reside at higher elevations than non-glaucoma patients.

The purpose of the Utah Project on Exfoliation Syndrome (UPEXS) is to identify associations between exfoliation syndrome (XFS) and other diseases that share the commonality of abnormalities in elastin and Lysyl Oxidase-Like 1 gene regulation. The UPEXS is unique because it uses the Utah Population Database, which is linked to the Utah genealogy, that contains a compilation of large pedigrees of most families in the state of Utah that go back multiple generations (3 to ≥11). The health and medical records of these family members are linked to vital records and can be used effectively in studies focused on genetic disorders like XFS, where familial clustering of a disorder is a trend. There is increasing evidence that patients with XFS have a higher risk of certain systemic disorders that reflect the systemic tissue abnormalities of XFS. Epidemiological studies focused on patients with XFS have shown that there is an increased risk of these individuals developing other pathologies that have abnormalities in extracellular matrix metabolism and repair. UPEXS has focused on suspected comorbidities that involve abnormalities in elastin maintenance, a protein that plays a role in the makeup of the extracellular matrix. In this paper, the results from the analysis of chronic obstructive pulmonary disease, inguinal hernias, pelvic organ prolapse, obstructive sleep apnoea and atrial fibrillation are summarised along with the utility of using such a large dataset.

PURPOSE Exfoliation syndrome, a systemic disorder with ocular manifestations, is associated with lysyl oxidase-like gene variants. Along with transforming growth factor beta-1, lysyl oxidase-like 1 is a key enzyme in stabilizing extracellular matrix and remodelling collagen/elastin. Given the role that transforming growth factor beta-1, lysyl oxidase-like gene variants and fibrosis play in atrial fibrillation, an association with exfoliation syndrome was investigated. METHODS An exfoliation syndrome cohort of 2803 patients and an atrial fibrillation cohort of 43 694 patients aged 60-90 years at disease onset were identified using the Utah Population Database (1996-2015). Conditional logistic regression was used to estimate risk of atrial fibrillation in exfoliation syndrome patients and risk of exfoliation syndrome in atrial fibrillation patients compared with respective 5:1 sex- and age-matched control cohorts. Kaplan-Meier curves were examined to assess survival in atrial fibrillation patients by exfoliation syndrome status. RESULTS Exfoliation syndrome patients had a 21% greater risk (95% CI 1.06-1.37; p

Background: Incidence of small-intestine neuroendocrine tumors (SINT) has been increasing in the United States over the past 40 years, with higher incidence in Utah than elsewhere. As information about how these tumors arise is limited, elucidating lifestyle factors associated with SINT in a statewide cohort could potentially identify those at risk to help mitigate their effects. Methods: Cases of SINT with a carcinoid histology (8240 or 8241) diagnosed in Utah from 1996 to 2014 with no prior history of cancer within 5 years (n = 433) were matched to population controls (1:10 ratio). Tobacco and alcohol exposures before case diagnosis were identified from International Classification of Diseases codes in statewide medical records and from self-reported data captured at patient encounters beginning in 1996. Multivariate logistic regression was used to estimate risk of SINT associated with tobacco and alcohol in cases compared with controls. Results: An increased risk of SINT was observed in tobacco-exposed individuals compared with unexposed [OR, 1.44; 95% confidence interval (CI), 1.11–1.86; P = 0.006]. Those who were exposed to alcohol exhibited an increased risk of SINT (OR, 1.62; 95% CI, 1.05–2.49; P = 0.03). Conclusions: This study supports tobacco and alcohol use as risk factors for SINT, independent of family history. However, low rates of smoking and alcohol use in Utah coupled with higher rates of SINT suggest other factors may contribute to development of these tumors. Impact: Although tobacco and alcohol modestly contribute to risk, our study suggests in addition to greater detection of tumors, other as-of-yet undefined exposures may drive rising SINT incidence.

BACKGROUND The effect of diabetes type on the risk of periprosthetic joint infection is not well documented. We hypothesized that patients with diabetes mellitus type 1 would be at greater risk for periprosthetic joint infection than those with diabetes mellitus type 2 and that a history of diabetic complications would be associated with an increased risk of periprosthetic joint infection. METHODS We performed a retrospective cohort study, within a statewide database, on all adult patients who underwent hip or knee arthroplasty, with follow-up of ≥2 years, from 1996 to 2013. Of the 75,478 patients included, 1,668 had type-1 diabetes and 18,186 had type-2 diabetes. Risk factors were calculated using Cox regression, adjusting for siblings and stratified by age. Logistic regression was used to analyze the effect of diabetic complications on the risk of periprosthetic joint infection, controlling for other known risks for periprosthetic joint infection. RESULTS There was no difference in age or sex between groups (p > 0.05). The frequency of periprosthetic joint infection in patients without diabetes was 2.6% compared with 4.3% in all patients with diabetes (relative risk, 1.47; p < 0.001). Patients with type-1 diabetes were at a 1.8 times greater risk for periprosthetic joint infection than patients with type-2 diabetes (7% compared with 4%; p < 0.001). The following diabetic complications increased the risk of periprosthetic joint infection: peripheral circulatory disorders (odds ratio [OR], 2.59 [95% confidence interval (CI), 1.70 to 3.94]), ketoacidosis (OR, 2.52 [95% CI, 1.51 to 4.19]), neurological manifestations (OR, 2.33 [95% CI, 1.96 to 2.78]), renal manifestations (OR, 2.15 [95% CI, 1.66 to 2.79]), and ophthalmic manifestations (OR, 1.76 [95% CI, 1.24 to 2.51]). The odds of periprosthetic joint infection increased with each added complication and patients with ≥4 complications were 9 times more likely to have a periprosthetic joint infection than patients with uncomplicated diabetes (OR, 9.47 [95% CI, 4.97 to 18.03]). Overweight and obese patients with type-2 diabetes and underweight patients with type-1 diabetes were at greater risk for periprosthetic joint infection compared with the general population (all p < 0.05). CONCLUSIONS Our data showed an increased risk of periprosthetic joint infection in patients with type-1 diabetes compared with those with type-2 diabetes, along with an increasing risk associated with additional diabetic complications. These findings emphasize the need to better understand the medical history of patients with diabetes for more appropriate risk management. LEVEL OF EVIDENCE Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

BACKGROUND. The link between hypertensive disorders of pregnancy (HDP) and short-term adverse outcomes has long been recognized. However, there is now evidence that survivors of HDP remain at risk of adverse biological events long after giving birth, including ocular complications. We sought to determine whether HDP is associated with development of the choroidal neovascular (CNV) form of age-related macular degeneration (AMD), a leading cause of blindness. METHODS. We identified women who experienced HDP (preeclampsia/eclampsia, HELLP syndrome, and gestational hypertension) as recorded in Utah birth certificates from 1939-2013. Exposed subjects were matched 1:2 to unexposed women on: mother’s age at delivery, and on child’s birth year, sex, and birth order. An AMD outcome from 1992-2015 was determined from electronic medical records. Risk of CNV AMD was estimated using stratified Cox regression with a competing risk of death. FINDINGS. We included 31,454 HDP-exposed and 62,908 unexposed women for study. Of 681 exposed and 1,355 unexposed with subsequent AMD, 158 and 284 developed choroidal neovascularization, respectively. Women with HDP exhibited an 80% higher risk for early-onset CNV AMD before age 70 [adjusted hazard ratio (aHR) 1.8, 95%CI 1.23-2.58; p

Abnormal serum immunoglobulin (Ig) free light chains (FLC) are established biomarkers of early disease in multiple B-cell lymphoid malignancies, including chronic lymphocytic leukemia (CLL). Heavy chains have also been shown to be biomarkers in plasma cell disorders. An unanswered question is whether these Ig biomarkers are heritable, i.e., influenced by germline factors. CLL is heritable but highly heterogeneous. Heritable biomarkers could elucidate steps of disease pathogenesis that are affected by germline factors, and may help partition heterogeneity and identify genetic pleiotropies across malignancies. Relatives in CLL pedigrees present an opportunity to identify heritable biomarkers. We compared FLCs and heavy chains between relatives in 23 high-risk CLL pedigrees and population controls. Elevated IgM (eIgM) and abnormal FLC (aFLC) ratio was significantly increased in relatives, suggesting that these Ig biomarkers are heritable and could offer risk stratification in pedigree relatives. Within high-risk CLL pedigrees, B-cell lymphoid malignancies were five times more prevalent in close relatives of individuals with eIgM, prostate cancer was three times more prevalent in relatives of individuals with aFLC, and monoclonal B-cell lymphocytosis increased surrounding individuals with normal Ig levels. These different clustering patterns suggest Ig biomarkers have the potential to partition genetic heterogeneity in CLL and provide insight into distinct heritable pleiotropies associated with CLL.

Purpose Exfoliation syndrome (XFS) is associated with genetic variants of lysyl oxidase–like 1 (LOXL1), a key enzyme in the stabilization of extracellular matrix (ECM) and elastin, and in connective tissue repair. Because patients with chronic obstructive pulmonary disease (COPD) have increased and altered elastin degradation, an association between XFS and COPD was hypothesized and analyzed. Impact of XFS on survival in patients with COPD was evaluated. Design Case-case and case-control comparison with 5:1 age- and sex-matched controls. Subjects Total of 2943 patients with XFS, 20 589 patients with COPD, and 162 patients with both disorders seen between 1996 and 2015 were identified from Utah Population Database–linked medical records. Controls were selected and matched by sex and birth year to patients in a 5:1 ratio. Methods Unconditional logistic regression, using International Classification of Diseases, Ninth Revision codes (365.52 and 366.11) to define XFS and an outcome of COPD (496.0), was used to calculate the odds ratio (OR) to estimate risk of COPD in patients with XFS, adjusting for age and sex. Model covariates included race, obesity, and tobacco use. Main Outcome Measures Whether XFS patients have an increased risk of developing COPD; whether COPD patients have an increased risk of XFS; and, in COPD patients, whether survival differs between those with XFS and those without. Results In XFS patients, risk of a COPD diagnosis was increased compared with that of non-XFS controls (OR = 1.41; 95% confidence interval [CI], 1.17–1.70; P Conclusions XFS patients may have an increased risk of a COPD diagnosis compared with non-XFS individuals. In COPD patients, risk of XFS was not increased compared with those with no COPD history. In COPD patients with XFS, survival is significantly improved compared with COPD patients with no XFS history.

Patients with serrated polyposis syndrome (SPS) and their first-degree relatives (FDRs) have increased colorectal cancer (CRC) risk. Patients with sporadic sessile serrated lesion (SSL) have risk for progression to CRC. Yet familial risks of common extracolonic cancers and even CRC in these cohorts are poorly understood. Our aim was to examine cancer risk for patients with SPS and sporadic SSL and their close and more distant relatives using a large population database.Patients with SPS (n = 59) from hereditary patient registries were eligible for study. Sporadic SSL (n = 754) and sex- and age-matched normal colonoscopy controls (n = 1,624) were selected from clinical data linked to the Utah Population Database. Cox models adjusting for the number of relatives, degree of relatedness, and person-years at risk were used to estimate CRC, extracolonic, and any-site adenocarcinoma/carcinoma cancer risk in patients and their relatives.Compared with controls, CRC risk was elevated 10-fold in patients with SPS (P = 0.04) and 5-fold in their FDRs (P = 0.001). Any-site adenoma/carcinoma risk was increased 2.6-fold in FDRs of patients with SPS. No elevated risks of other common extracolonic cancers were observed in SPS and family members. The FDRs, second-degree relatives, and third-degree relatives of patients with both SSL and adenomatous polyps exhibited a 50% increased CRC risk.Patients with SPS and their FDRs have an increased CRC risk, confirming other reports. Interestingly, patients with SSL were noted to have an increased risk of prostate cancer. Relatives of individuals with both sporadic SSL and adenomas, irrespective of size or dysplasia on examination, may have an elevated CRC risk, suggesting closer colonoscopy surveillance in this population.

Chronic lymphocytic lymphoma (CLL) has one of the highest familial risks among cancers. Monoclonal B-cell lymphocytosis (MBL), the precursor to CLL, has a higher prevalence (13%-18%) in families with 2 or more members with CLL compared with the general population (5%-12%). Although, the rate of progression to CLL for high-count MBLs (clonal B-cell count ≥500/µL) is ∼1% to 5%/y, no low-count MBLs have been reported to progress to date. We report the incidence and natural history of MBL in relatives from CLL families. In 310 CLL families, we screened 1045 relatives for MBL using highly sensitive flow cytometry and prospectively followed 449 of them. MBL incidence was directly age- and sex-adjusted to the 2010 US population. CLL cumulative incidence was estimated using Kaplan-Meier survival curves. At baseline, the prevalence of MBL was 22% (235/1045 relatives). After a median follow-up of 8.1 years among 449 relatives, 12 individuals progressed to CLL with a 5-year cumulative incidence of 1.8%. When considering just the 139 relatives with low-count MBL, the 5-year cumulative incidence increased to 5.7%. Finally, 264 had no MBL at baseline, of whom 60 individuals subsequently developed MBL (2 high-count and 58 low-count MBLs) with an age- and sex-adjusted incidence of 3.5% after a median of 6 years of follow-up. In a screening cohort of relatives from CLL families, we reported progression from normal-count to low-count MBL to high-count MBL to CLL, demonstrating that low-count MBL precedes progression to CLL. We estimated a 1.1% annual rate of progression from low-count MBL, which is in excess of that in the general population.

Neuroendocrine tumors (NETs) of the small intestine undergo large chromosomal and methylation changes. The objective of this study was to identify methylation differences in NETs and consider how the differentially methylated genes may impact patient survival. Genome-wide methylation and chromosomal copy number variation (CNV) of NETs from the small intestine and appendix were measured. Tumors were divided into three molecular subtypes according to CNV results: chromosome 18 loss (18LOH), Multiple CNV, and No CNV. Comparison of 18LOH tumors with MultiCNV and NoCNV tumors identified 901 differentially methylated genes. Genes from the G-protein coupled receptor (GPCR) pathways are statistically overrepresented in the differentially methylated genes. One of the highlighted genes from the GPCR pathway is somatostatin (SST), a clinical target for NETs. Patient survival based on low versus high methylation in all samples identified four significant genes (p OR2S2, SMILR, RNU6-653P, and AC010543.1. Within the 18LOH molecular subtype tumors, survival differences were identified in high versus low methylation of 24 genes. The most significant is TRHR (p

BACKGROUND Chronic rhinosinusitis with asthma (CRS-A) has a significant impact on patient morbidity and quality of life. Nevertheless, little is known about the natural history of endoscopic sinus surgery (ESS) in this cohort. The objective of this study was to evaluate revision rates of ESS in CRS-A and identify risk factors associated with increased likelihood for revision surgery compared to those with CRS without asthma (CRS-alone). METHODS The Utah Population Database was queried for patients age >18 years with CRS who underwent at least 1 ESS between 1996 and 2018. Demographic information and history of ESS were collected and compared between CRS-A and CRS-alone using chi-square tests for categorical variables and t tests for continuous variables. Risk factors for revision surgery were analyzed using Cox proportional hazard models. RESULTS A total of 33,090 patients (7693 CRS-A and 25,397 CRS-alone) were included in the final analysis. Mean follow up was 9.8 years in CRS-A and 9.1 years in CRS-alone (p < 0.001). The revision rate among patients with CRS-A (21.5%) was twice that of CRS-alone (10.8%) (p < 0.001). Among patients with CRS, a history of allergy (p < 0.001), asthma (p < 0.001), and nasal polyposis (p < 0.001) was independently associated with increased risk of revision ESS. Patients with CRS-A and nasal polyposis were 6 times more likely to require revision surgery than those with CRS-alone (p < 0.010). CONCLUSION The rate of revision ESS in CRS-A was twice that of CRS-alone; patients with CRS-A and nasal polyposis were 6 times more likely to require revision than those with CRS-alone. ©2021 ARSAAOA, LLC.

Aim: Recessive genetic variation is thought to play a role in non-Hodgkin lymphoma (NHL) etiology. Runs of homozygosity (ROH), defined based on long, continuous segments of homozygous SNPs, can be used to estimate both measured and unmeasured recessive genetic variation. We sought to examine genome-wide homozygosity and NHL risk.Methods: We used data from eight genome-wide association studies of four common NHL subtypes: 3061 chronic lymphocytic leukemia (CLL), 3814 diffuse large B-cell lymphoma (DLBCL), 2784 follicular lymphoma (FL), and 808 marginal zone lymphoma (MZL) cases, as well as 9374 controls. We examined the effect of homozygous variation on risk by: (1) estimating the fraction of the autosome containing runs of homozygosity (FROH); (2) calculating an inbreeding coefficient derived from the correlation among uniting gametes (F3); and (3) examining specific autosomal regions containing ROH. For each, we calculated beta coefficients and standard errors using logistic regression and combined estimates across studies using random-effects meta-analysis.Results: We discovered positive associations between FROH and CLL (β = 21.1, SE = 4.41, P = 1.6 × 10 -6) and FL (β = 11.4, SE = 5.82, P = 0.02) but not DLBCL ( P = 1.0) or MZL ( P = 0.91). For F3, we observed an association with CLL (β = 27.5, SE = 6.51, P = 2.4 × 10 -5). We did not find evidence of associations with specific ROH, suggesting that the associations observed with FROH and F3 for CLL and FL risk were not driven by a single region of homozygosity. Conclusion: Our findings support the role of recessive genetic variation in the etiology of CLL and FL; additional research is needed to identify the specific loci associated with NHL risk.

Inherited genetic risk factors play a role in multiple myeloma (MM), yet considerable missing heritability exists. Rare risk variants at genome-wide association study (GWAS) loci are a new avenue to explore. Pleiotropy between lymphoid neoplasms (LNs) has been suggested in family history and genetic studies, but no studies have interrogated sequencing for pleiotropic genes or rare risk variants. Sequencing genetically enriched cases can help discover rarer variants. We analyzed exome sequencing in familial or early-onset MM cases to identify rare, functionally relevant variants near GWAS loci for a range of LNs. A total of 149 distinct and significant LN GWAS loci have been published. We identified six recurrent, rare, potentially deleterious variants within 5 kb of significant GWAS single nucleotide polymorphisms in 75 MM cases. Mutations were observed in BTNL2, EOMES, TNFRSF13B, IRF8, ACOXL and TSPAN32. All six genes replicated in an independent set of 255 early-onset MM or familial MM or precursor cases. Expansion of our analyses to the full length of these six genes resulted in a list of 39 rare and deleterious variants, seven of which segregated in MM families. Three genes also had significant rare variant burden in 733 sporadic MM cases compared with 935 control individuals: IRF8 (P = 1.0 × 10−6), EOMES (P = 6.0 × 10−6) and BTNL2 (P = 2.1 × 10−3). Together, our results implicate six genes in MM risk, provide support for genetic pleiotropy between LN subtypes and demonstrate the utility of sequencing genetically enriched cases to identify functionally relevant variants near GWAS loci.

PURPOSE: Exfoliation syndrome (XFS), the most common recognizable cause of open-angle glaucoma worldwide, is a systemic disorder with genetic predisposition due to variations in lysyl oxidase-like 1 (LOXL1) function, leading to altered elastin matrices in ocular and systemic tissues. Obstructive sleep apnea (OSA) is a highly prevalent disorder also involving elastic tissue dysfunction and has been found to be associated with glaucoma. Due to similarities between the disorders, we sought to uncover any relationship in the prevalence of these diagnoses. DESIGN: Case-control retrospective cohort study. SUBJECTS: A cohort of 81,735 patients diagnosed with OSA at ages 50–90 years were identified from medical records from 1996 to 2017 in the Utah Population Database. Case subjects were matched to random controls on to sex and birth year in a 4:1 ratio. METHODS: International Classification of Diseases, Ninth Revision (ICD-9) codes or their ICD-10 equivalent were used to define a diagnosis of OSA (ICD-9 327.23) and a diagnosis of XFS (ICD-9 365.52 and 366.11). Conditional logistic regression odds ratios accounting for individual matching on sex and birth year was used to estimate the risk of XFS in OSA patients. Models included adjustment for race, obesity, tobacco use, hypertension, atrial fibrillation, and chronic obstructive pulmonary disease. OUTCOME: Whether OSA patients have an increased risk of diagnosis of XFS compared with non-OSA population controls. RESULTS: There was an increased risk of an XFS diagnosis in OSA patients compared with non-OSA controls (OR = 1.27; 95% CI, 1.02–1.59; P = 0.03). In a stratification of patients by hypertension diagnosis history, OSA patients with hypertension exhibited an increased risk of XFS compared to non OSA controls with hypertension (OR = 2.67; 95% CI, 2.06–3.46; P