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Transgender and gender-diverse (TGD) individuals are at risk for discrimination and inequities across legal, social, and medical contexts. Population-level resources have rarely been used for TGD health research and, therefore, data is lacking about prevalences of a wide range of clinical conditions among TGD populations. To leverage the Utah Population Database's demographic, vital, and health records and examine population-level diagnostic prevalences in TGD individuals and an age-matched general cohort. 6,664 TGD individuals were identified using ICD codes for gender incongruence between 1995 and 2021; 64,124 age-matched individuals comprised the control cohort. Using Phecodes to collapse ICD codes, this study examined differences in the prevalence of medical, mental health, and neurodevelopmental clinical phenotypes in TGD and control cohorts using modified Poisson regression models. Affiliated healthcare systems within the state of Utah. We evaluated adjusted prevalence ratios of identified Phecodes. The TGD cohort showed broadly higher documented prevalences of medical, mental health, and neurodevelopmental conditions compared to controls. Medical diagnoses more common in the TGD cohort included sleep disorders and chronic pain. Disparities in diagnoses such as \"other endocrine disorders\" and \"need for hormone replacement therapy\" likely reflect gender-affirming treatments. Mental health conditions including mood, depression, anxiety, and personality disorders were significantly more prevalent in the TGD cohort. This study highlights diagnostic disparities for TGD individuals across multiple clinical categories. Our findings may be driven by: 1) discrimination and over-medicalization of TGD individuals, 2) differences in accessing and interacting with the healthcare system, and 3) variation in the true incidence of medical and mental health outcomes in the TGD vs control cohorts.

Introduction Acute extremity compartment syndrome (“CS”) is an under-researched, highly morbid condition affecting trauma populations. The purpose of this study was to analyze incidence rates and risk factors for extremity compartment syndrome using a high-quality population database. Additionally, we evaluated heritable risk for CS using available genealogic data. We hypothesized that diagnosis of extremity compartment syndrome would demonstrate heritability. Materials and methods Adult patients with fractures of the tibia, femur, and upper extremity were retrospectively identified by ICD-9, ICD-10, and CPT codes from 1996 to 2020 in a statewide hospital database. Exposed and unexposed cohorts were created based on a diagnosis of CS. Available demographic data were analyzed to determine risk factors for compartment syndrome using logistic regression. Mortality risk at the final follow-up was evaluated using Cox proportional hazard modeling. Patients with a diagnosis of CS were matched with those without a diagnosis for heritability analysis. Results Of 158,624 fractures, 931 patients were diagnosed with CS. Incidence of CS was 0.59% (tibia 0.83%, femur 0.31%, upper extremity 0.27%). Male sex (78.1% vs. 46.4%; p  < 0.001; RR = 3.24), younger age at fracture (38.8 vs. 48.0 years; p  < 0.001; RR = 0.74), Medicaid enrollment (13.2% vs. 9.3%; p  < 0.001; RR = 1.58), and smoking (41.1% vs. 31.1%; p  < 0.001; RR 1.67) were significant risk factors for CS. CS was associated with mortality (RR 1.61, p  < 0.001) at mean follow-up 8.9 years in the CS cohort. No significant heritable risk was found for diagnosis of CS. Conclusions Without isolating high-risk fractures, rates of CS are lower than previously reported in the literature. Male sex, younger age, smoking, and Medicaid enrollment were independent risk factors for CS. CS increased mortality risk at long-term follow-up. No heritable risk was found for CS. Level of evidence III.

Background Prenatal exposure to maternal metabolic conditions associated with inflammation and steroid dysregulation has previously been linked to increased autism risk. Steroid-related maternal serum biomarkers have also provided insight into the in utero steroid environment for offspring who develop autism. Objective This study examines the link between autism among offspring and early second trimester maternal steroid-related serum biomarkers from pregnancies enriched for prenatal metabolic syndrome (PNMS) exposure. Study design Early second trimester maternal steroid-related serum biomarkers (i.e., estradiol, free testosterone, total testosterone, and sex hormone binding globulin) were compared between pregnancies corresponding to offspring with ( N  = 68) and without ( N  = 68) autism. Multiple logistic regression analyses were stratified by sex and gestational duration. One-way ANCOVA with post hoc tests was performed for groups defined by autism status and PNMS exposure. Results Increased estradiol was significantly associated with autism only in males (AOR = 1.13 per 100 pg/ml, 95% CI 1.01–1.27, p  = 0.036) and only term pregnancies (AOR = 1.17 per 100 pg/ml, 95% CI 1.04–1.32, p  = 0.010). Autism status was significantly associated with decreased sex hormone binding globulin (AOR = 0.65 per 50 nmol/L, 95% CI 0.55–0.78, p  < 0.001) overall and when stratified by sex and term pregnancy status. The inverse association between sex hormone binding globulin and autism was independent of PNMS exposure. Limitations The relative racial and ethnic homogeneity of Utah’s population limits the generalizability of study results. Although significant differences by autism status were identified in concentrations of sex hormone binding globulin overall and of estradiol in participant subgroups, differences by PNMS exposure failed to reach statistical significance, which may reflect insufficient statistical power. Conclusion Both elevated maternal serum estradiol in males only and low maternal serum sex hormone binding globulin in both sexes are associated with increased autism risk. Further investigation is merited to identify how steroid, metabolic, and inflammatory processes can interact to influence neurodevelopment in early second trimester.

Background Ovarian cancer is the fifth most common female cancer in the United States. There have been very few studies investigating mental health diagnoses among ovarian cancer survivors with long‐term follow up. The aim of this study is to examine the incidence of mental illness among ovarian cancer survivors compared to a general population cohort. A secondary aim is to investigate risk factors for mental illnesses among ovarian cancer survivors. Patients and methods Cohorts of 1689 ovarian cancer patients diagnosed between 1996 and 2012 and 7038 women without cancer matched by age and birth state from the general population were identified. Mental health diagnoses were identified from electronic medical records and statewide healthcare facilities data. Cox proportional hazard models were used to estimate hazard ratios (HRs). Results Ovarian cancer survivors experienced increased risks of mental illnesses within the first 2 years after cancer diagnosis (HR = 3.55, 95% CI = 3.04–4.14). The risks of depression among ovarian cancer survivors were nearly 3‐fold within the first 2 years of cancer diagnosis (HR = 2.59, 95% CI = 1.94–3.47), and 1.69‐fold at 2–5 years after cancer diagnosis (HR = 1.69, 95% CI = 1.18–2.42). Ovarian cancer survivors experienced an 80% increased risk of death with a mental illness diagnosis (HR = 1.80, 95% CI = 1.48–2.18) and a 94% increased risk of death with a depression diagnosis (HR = 1.94, 95% CI = 1.56–2.40). Conclusions Higher risks of mental illnesses were observed among ovarian cancer survivors throughout the follow‐up periods of 0–2 years and 2–5 years after cancer diagnosis. Multidisciplinary care is needed to monitor and treat mental illnesses among ovarian cancer survivors.

Background Genes associated with hereditary breast and ovarian cancer (HBOC) and colorectal cancer (CRC) predisposition have been shown to play a role in pancreatic cancer susceptibility. Growing evidence suggests that pancreatic cancer may be useful as a sentinel cancer to identify families that could benefit from HBOC or CRC surveillance, but to date pancreatic cancer is only considered an indication for genetic testing in the context of additional family history. Methods Preliminary data generated at the Huntsman Cancer Hospital (HCH) included variants identified on a custom 34-gene panel or 59-gene panel including both known HBOC and CRC genes for respective sets of 66 and 147 pancreatic cancer cases, unselected for family history. Given the strength of preliminary data and corresponding literature, 61 sequential pancreatic cancer cases underwent a custom 14-gene clinical panel. Sequencing data from HCH pancreatic cancer cases, pancreatic cancer cases of the Cancer Genome Atlas (TCGA), and an unselected pancreatic cancer screen from the Mayo Clinic were combined in a meta-analysis to estimate the proportion of carriers with pathogenic and high probability of pathogenic variants of uncertain significance (HiP-VUS). Results Approximately 8.6% of unselected pancreatic cancer cases at the HCH carried a variant with potential HBOC or CRC screening recommendations. A meta-analysis of unselected pancreatic cancer cases revealed that approximately 11.5% carry a pathogenic variant or HiP-VUS. Conclusion With the inclusion of both HBOC and CRC susceptibility genes in a panel test, unselected pancreatic cancer cases act as a useful sentinel cancer to identify asymptomatic at-risk relatives who could benefit from relevant HBOC and CRC surveillance measures.

Breast cancer diagnosed within 5 to 10 years after childbirth, called postpartum breast cancer (PPBC), is associated with increased risk for metastasis and death. Whether a postpartum diagnosis is an independent risk factor or a surrogate marker of cancer features associated with poor outcomes remains understudied. To determine whether diagnostic temporal proximity to childbirth is associated with features of breast cancer associated with poor outcomes, including tumor stage, estrogen receptor (ER) status, and risk for distant metastasis and breast cancer-specific mortality, using a population database from the state of Utah. This population-based cohort study using the Utah Population Database (UPDB) included individuals with stage I to III breast cancer diagnosed at age 45 years or younger between 1996 and 2017, followed-up until February 2020. Participant data were analyzed from November 2019 to August 2022. The primary exposures were no prior childbirth or time between most recent childbirth and breast cancer diagnosis. Patients were grouped by diagnoses within less than 5 years, 5 to less than 10 years, or 10 years or more since recent childbirth. The 2 primary outcomes were distant metastasis-free survival and breast cancer-specific death. Cox proportional hazard models were used to investigate associations between exposures and outcomes adjusting for diagnosis year, patient age, tumor stage, and estrogen receptor (ER) status. Of 2970 individuals with breast cancer diagnosed at age 45 years or younger (mean [SD] age, 39.3 [5.0] years; 12 Black individuals [0.4%], 2679 White individuals [90.2%]), breast cancer diagnosis within 5 years of recent childbirth was independently associated with approximately 1.5-fold elevated risk for metastasis (hazard ratio [HR], 1.5; 95% CI, 1.2-2.0) and breast cancer-specific death (HR, 1.5; 95% CI, 1.1-2.1) compared with nulliparous individuals. For cancers classically considered to have tumor features associated with good outcomes (ie, stage I or II and ER-positive), a postpartum diagnosis was a dominant feature associated with increased risk for metastasis and death (eg, for individuals with ER-positive disease diagnosed within <5 years of childbirth: age-adjusted metastasis HR, 1.5; 95% CI, 1.1-2.1; P = .01; age-adjusted death HR, 1.5; 95% CI, 1.0-2.1; P = .04) compared with nulliparous individuals. Furthermore, liver metastases were specifically increased in the group with diagnosis within 5 years postpartum and with positive ER expression (38 of 83 patients [45.8%]) compared with the nulliparous (28 of 77 patients [36.4%]), although the difference was not statistically significant. Overall, these data implicate parity-associated breast and liver biology in the observed poor outcomes of PPBC. In this cohort study of individuals with breast cancer diagnosed at age 45 years or younger, a postpartum breast cancer diagnosis was a risk factor associated with poor outcomes. Irrespective of ER status, clinical consideration of time between most recent childbirth and breast cancer diagnosis could increase accuracy of prognosis in patients with young-onset breast cancer.

Background Endometrial cancer is the second most common cancer among female cancer survivors in the US and is increasing in incidence. Rural endometrial cancer patients experience lower survival rates but the reasons for the lower survival are not known. The aim of this study is to examine whether prognostic factors are different for rural and urban patients in a population-based cohort. Methods Endometrial cancer patients diagnosed 1997-2012 were identified through the Utah Cancer Registry and Utah Population Database. The address at cancer diagnosis was used to classify patients in rural or urban residences. Demographic and cancer-specific characteristics were examined as prognostic factors for both all-cause and endometrial cancer-specific mortality using Cox proportional hazards models. Results There were 2,994 endometrial cancer patients and 14.1% of these patients lived in rural areas at diagnosis. Rural endometrial cancer patients were older at cancer diagnosis and did not appear to be different in terms of obesity or overweight at cancer diagnosis. There were no differences for treatment or stage at diagnosis although rural patients had higher proportions of higher grade. Age at diagnosis, poverty, education, and histology were significant prognostic factors for all-cause death. Rural patients with more advanced stages of cancer had significantly increased risks of all-cause and endometrial cancer-specific death than urban patients. Rural endometrial cancer patients diagnosed at advanced stage had a 17-fold increase in the risk of all-cause death compared to an 8-fold increase in death for urban patients. Conclusions Rural endometrial cancer patients in Utah were older at diagnosis, had higher grade and higher comorbidities. While urban and rural endometrial cancer patients shared many prognostic factors, the risk of mortality is greater among rural patients with advanced stage endometrial cancer. Future studies should examine where patients are receiving treatment and how that impacts their survival and how to reduce the mortality rates of high risk patients.

Preterm birth (PTB), defined as birth prior to a gestational age (GA) of 37 completed weeks, affects more than 10 % of births worldwide. PTB is the leading cause of neonatal mortality and is associated with a broad spectrum of lifelong morbidity in survivors. The etiology of spontaneous PTB (SPTB) is complex and has an important genetic component. Previous studies have compared monozygotic and dizygotic twin mothers and their families to estimate the heritability of SPTB, but these approaches cannot separate the relative contributions of the maternal and the fetal genomes to GA or SPTB. Using the Utah Population Database, we assessed the heritability of GA in more than 2 million post-1945 Utah births, the largest familial GA dataset ever assembled. We estimated a narrow-sense heritability of 13.3 % for GA and a broad-sense heritability of 24.5 %. A maternal effect (which includes the effect of the maternal genome) accounts for 15.2 % of the variance of GA, and the remaining 60.3 % is contributed by individual environmental effects. Given the relatively low heritability of GA and SPTB in the general population, multiplex SPTB pedigrees are likely to provide more power for gene detection than will samples of unrelated individuals. Furthermore, nongenetic factors provide important targets for therapeutic intervention.

Background Personal cancer diagnosis and family cancer history factor into which individuals should undergo genetic testing for hereditary breast and ovarian cancer (HBOC) syndrome. Family history is often determined in the research setting through kindreds with disease clusters, or clinically from self‐report. The population prevalence of individuals with diagnostic characteristics and/or family cancer history meeting criteria for HBOC testing is unknown. Methods Utilizing Surveillance, Epidemiology, and End Results (SEER) cancer registry data and a research resource linking registry records to genealogies, the Utah Population Database, the population‐based prevalence of diagnostic and family history characteristics meeting National Comprehensive Cancer Network (NCCN) criteria for HBOC testing was objectively assessed. Results Among Utah residents with an incident breast cancer diagnosis 2010‐2015 and evaluable for family history, 21.6% met criteria for testing based on diagnostic characteristics, but the proportion increased to 62.9% when family history was evaluated. The proportion of cases meeting testing criteria at diagnosis was 94% for ovarian cancer, 23% for prostate cancer, and 51.1% for pancreatic cancer. Among an unaffected Utah population of approximately 1.7 million evaluable for family history, 197,601 or 11.6% met testing criteria based on family history. Conclusions This study quantifies the population‐based prevalence of HBOC criteria using objectively determined genealogy and cancer incidence data. Sporadic breast cancer likely represents a portion of the high prevalence of family cancer history seen in this study. These results underline the importance of establishing presence of a deleterious mutation in an affected family member, per NCCN guidelines, before testing unaffected relatives. Using diagnostic and family history data, almost 63% of individuals with breast cancer diagnoses meet criteria for genetic testing based on diagnostic and family history. Utilizing the Utah Population Database, a research resource that links of four decades of cancer registry records to genealogies, almost 12% of the unaffected Utah population meets criteria for genetic testing. Given the high proportion of the population, targeting affected cases can maximize family impact while minimizing cost.

Introduction Women with hypertensive disorders of pregnancy (HDP) have an increased risk of cardiovascular disease. Whether HDP is also associated with later‐life dementia has not been fully explored. Methods Using the Utah Population Database, we performed an 80‐year retrospective cohort study of 59,668 parous women. Results Women with, versus without, HDP, had a 1.37 higher risk of all‐cause dementia (95% confidence interval [CI]: 1.26, 1.50) after adjustment for maternal age at index birth, birth year, and parity. HDP was associated with a 1.64 higher risk of vascular dementia (95% CI: 1.19, 2.26) and 1.49 higher risk of other dementia (95% CI: 1.34, 1.65) but not Alzheimer's disease dementia (adjusted hazard ratio = 1.04; 95% CI: 0.87, 1.24). Gestational hypertension and preeclampsia/eclampsia showed similar increased dementia risk. Nine mid‐life cardiometabolic and mental health conditions explained 61% of HDP's effect on subsequent dementia risk. Discussion Improved HDP and mid‐life care could reduce the risk of dementia.