Familial risk of epithelial ovarian cancer after accounting for gynaecological surgery: a population-based study.

BACKGROUND: Uptake of risk-reducing surgery has increased among women at high risk of epithelial ovarian cancer. We sought to characterise familial risk of epithelial ovarian cancer histotypes in a population-based study after accounting for gynaecological surgeries, including bilateral oophorectomy. METHODS: We compared risk of epithelial ovarian cancer in relatives of 3536 epithelial ovarian cancer cases diagnosed in 1966-2016 and relatives of 35 326 matched controls. We used Cox competing risk models, incorporating bilateral oophorectomy as a competing risk, to estimate the relative risk of ovarian cancer in first-degree (FDR), second-degree (SDR) and third-degree (TDR) relatives from 1966 to 2016. We also estimated relative risks in time periods before (1966-1994, 1995-2004) and after (2005-2016) formal recommendations were made for prophylactic oophorectomy among women with pathogenic variants in BRCA1/2. RESULTS: The relative risks of epithelial ovarian cancer in FDRs, SDRs and TDRs of cases versus controls were 1.68 (95% CI 1.39 to 2.04), 1.51 (95% CI 1.30 to 1.75) and 1.34 (95% CI 1.20 to 1.48), respectively. Relative risks were greatest for high-grade serous, mucinous and 'other epithelial' histotypes. Relative risks were attenuated for case FDRs, but not for SDRs or TDRs, from 2005 onwards, consistent with the timing of recommendations for prophylactic surgery. CONCLUSION: Familial risk of epithelial ovarian cancer extends to TDRs, especially for high-grade serous and mucinous histotypes. Distant relatives share genes but minimal environment, highlighting the importance of germline inherited genetics in ovarian cancer aetiology. Increased ovarian cancer risk in distant relatives has implications for counselling and recommendations for prophylactic surgeries that, from our data, appear only to reach FDRs.

Healthcare Burden and Resource Utilization After Pediatric Acute Respiratory Distress Syndrome: A Secondary Analysis of the Collaborative Pediatric Critical Care Research Network Acute Respiratory Distress Syndrome Study.

OBJECTIVES: To describe family healthcare burden and health resource utilization in pediatric survivors of acute respiratory distress syndrome (ARDS) at 3 and 9 months. DESIGN: Secondary analysis of a prospective multisite cohort study. SETTING: Eight academic PICUs in the United States (2019-2020). PATIENTS: Critically ill children with ARDS and follow-up survey data collected at 3 and/or 9 months after the event. INTERVENTIONS: None. METHODS AND MEASUREMENT: We evaluated family healthcare burden, a measure of healthcare provided by families at home, and child health resource use including medication use and emergency department (ED) and hospital readmissions during the initial 3- and 9-month post-ARDS using proxy-report. Using multivariable logistic regression, we evaluated patient characteristics associated with family healthcare burden at 3 months. MAIN RESULTS: Of 109 eligible patients, 74 (68%) and 63 patients (58%) had follow-up at 3- and 9-month post-ARDS. At 3 months, 46 families (62%) reported healthcare burden including (22%) with unmet care coordination needs. At 9 months, 33 families (52%) reported healthcare burden including 10 families (16%) with unmet care coordination needs. At month 3, 61 patients (82%) required prescription medications, 13 patients (18%) had ED visits and 16 patients (22%) required hospital readmission. At month 9, 41 patients (65%) required prescription medications, 19 patients (30%) had ED visits, and 16 (25%) required hospital readmission were reported. Medication use was associated with family healthcare burden at both 3 and 9 months. In a multivariable analysis, preillness functional status and chronic conditions were associated with healthcare burden at month 3 but illness characteristics were not. CONCLUSIONS: Pediatric ARDS survivors report high rates of healthcare burden and health resource utilization at 3- and 9-month post-ARDS. Future studies should assess the impact of improved care coordination to simplify care (e.g., medication management) and improve family burden.

Analysis of acute extremity compartment syndrome using a genealogic population database.

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.

Social inequities in neighborhood health amenities over time in the Wasatch Front Region of Utah: Historical inequities, population selection, or differential investment?

Socially disadvantaged groups generally are more likely to reside in areas with less desirable conditions. We examined longitudinal relationships between neighborhood resident characteristics and amenities from 1990 to 2010 in an urban area of Utah, U.S. Four temporal patterns of social inequities are described using mixed-effects models: historical inequities; differential selection into amenity-rich tracts; differential investment in amenities; and simultaneous twenty-year change. Results indicate historical differences by neighborhood socioeconomic status, with lower status tracts having fewer green/natural amenities and higher air pollution in 1990 but also greater walkability and more food stores. Differences in amenities by neighborhood socioeconomic status widened over time as aggregate socioeconomic status disproportionately increased in tracts with more green/natural amenities, less air pollution, and lower walkability in 1990, consistent with differential selection. Tract percentage non-Hispanic White did not predict historical differences, but tracts that were less walkable and had fewer healthy food stores in 1990 experienced larger subsequent increases in racial/ethnic diversity. Tracts with higher relative to lower percentage non-Hispanic White in 1990 had larger decreases in air pollution but declining green/natural amenities. This study shows how social inequities in neighborhood amenities change over time, providing evidence of historical socioeconomic differences increasing from differential resident selection.

Long-term maternal mortality risk following spontaneous preterm birth: A retrospective cohort study.

OBJECTIVE: To determine whether women with spontaneous preterm birth (PTB) have increased risks for long-term mortality. DESIGN: Retrospective cohort. SETTING: Births in Utah between 1939 and 1977. POPULATION: We included women with a singleton live birth ≥20 weeks who survived at least 1 year following delivery. We excluded those who had never lived in Utah, had improbable birthweight/gestational age combinations, underwent induction (except for preterm membrane rupture) or had another diagnosis likely to cause PTB. METHODS: Exposed women had ≥1 spontaneous PTB between 20+0 weeks and 37+0 weeks. Women with >1 spontaneous PTB were included only once. Unexposed women had all deliveries at or beyond 38+0 weeks. Exposed women were matched to unexposed women by birth year, infant sex, maternal age group and infant birth order. Included women were followed up to 39 years after index delivery. MAIN OUTCOME MEASURES: Overall and cause-specific mortality risks were compared using Cox regression. RESULTS: We included 29 048 exposed and 57 992 matched unexposed women. There were 3551 deaths among exposed (12.2%) and 6013 deaths among unexposed women (10.4%). Spontaneous PTB was associated with all-cause mortality (adjusted hazard ratio [aHR] 1.26, 95% confidence interval [CI] 1.21-1.31), death from neoplasms (aHR 1.10, 95% CI 1.02-1.18), circulatory disease (aHR 1.35, 95% CI 1.25-1.46), respiratory disease (aHR 1.73, 95% CI 1.46-2.06), digestive disease (aHR 1.33, 95% CI 1.12-1.58), genito-urinary disease (aHR 1.60, 95% CI 1.15-2.23) and external causes (aHR 1.39, 95% CI 1.22-1.58). CONCLUSIONS: Spontaneous PTB is associated with modestly increased risks for all-cause and some cause-specific mortality.

Familial aggregation of stillbirth: A pedigree analysis of a matched case-control study.

OBJECTIVE: To determine whether stillbirth aggregates in families and quantify its familial risk using extended pedigrees. DESIGN: State-wide matched case-control study. SETTING: Utah, United States. POPULATION: Stillbirth cases (n = 9404) and live birth controls (18 808) between 1978 and 2019. METHODS: Using the Utah Population Database, a population-based genealogical resource linked with state fetal death and birth records, we identified high-risk pedigrees with excess familial aggregation of stillbirth using the Familial Standardised Incidence Ratio (FSIR). Stillbirth odds ratio (OR) for first-degree relatives (FDR), second-degree relatives (SDR) and third-degree relatives (TDR) of parents with a stillbirth (affected) and live birth (unaffected) were estimated using logistic regression models. MAIN OUTCOME MEASURES: Familial aggregation estimated using FSIR, and stillbirth OR estimated for FDR, SDR and TDR of affected and unaffected parents using logistic regression models. RESULTS: We identified 390 high-risk pedigrees with evidence for excess familial aggregation (FSIR ≥2.00; P-value <0.05). FDRs, SDRs and TDRs of affected parents had 1.14-fold (95% confidence interval [CI]: 1.04-1.26), 1.22-fold (95% CI 1.11-1.33) and 1.15-fold (95% CI 1.08-1.21) higher stillbirth odds compared with FDRs, SDRs and TDRs of unaffected parents, respectively. Parental sex-specific analyses showed male FDRs, SDRs and TDRs of affected fathers had 1.22-fold (95% CI 1.02-1.47), 1.38-fold (95% CI 1.17-1.62) and 1.17-fold (95% CI 1.05-1.30) higher stillbirth odds compared with those of unaffected fathers, respectively. FDRs, SDRs and TDRs of affected mothers had 1.12-fold (95% CI 0.98-1.28), 1.09-fold (95% CI 0.96-1.24) and 1.15-fold (95% CI 1.06-1.24) higher stillbirth odds compared with those of unaffected mothers, respectively. CONCLUSIONS: We provide evidence for familial aggregation of stillbirth. Our findings warrant investigation into genes associated with stillbirth and underscore the need to design large-scale studies to determine the genetic architecture of stillbirth.

Interpregnancy Body Mass Index Change and Offspring Mortality Risk following the Second Pregnancy.

OBJECTIVE: The aim of the study is to examine the impact of maternal interpregnancy body mass index (BMI) change on subsequent offspring mortality risk. STUDY DESIGN: This is a retrospective cohort study of women who had two consecutive live singleton deliveries of at least 20 weeks' gestation from the Utah Population Database. Our exposure was defined as interpregnancy BMI change from the date of first delivery to the conception date of subsequent pregnancy. We categorized BMI change as: < - 1, -1 to 0, 0 to <1 (reference), 1 to 2, 2 to 4, ≥4 kg/m2. Our primary outcome was all-cause age-specific mortality during four time periods: neonatal (≤28 days), infant (29 days to <1 year old), childhood ((≥1 to <5 years old), and late childhood (5 to <18 years old). We also examined mortality specifically attributed to congenital anomalies. Analyses used Cox proportional hazard models stratified by full term (≥37 weeks) and preterm (<37 weeks) deliveries. All models were adjusted for relevant confounders. RESULTS: Of 266,752 women, among full-term deliveries, women with a BMI increase of 4 kg/m2 or more had an increased risk of neonatal mortality in their subsequent pregnancy (hazard ratio or HR = 1.72, 95% confidence interval or CI: 1.23-2.41) Women who lost 1 kg/m2 or more between deliveries also had increased neonatal mortality (HR = 1.46, 95% CI: 1.04-2.05). There were no differences in infant, early, or late childhood mortality by interpregnancy BMI change. Maternal interpregnancy interval weight loss of 1 kg/m2 or more and weight gain of ≥4 kg/m2 also had increased risk of mortality associated with congenital anomalies or conditions arising during the neonatal period following their subsequent delivery. CONCLUSION: Women with significant interpregnancy weight gain and modest weight loss have a significant increased risk of neonatal mortality following their subsequent pregnancy. KEY POINTS: · Significant weight gain between deliveries increases the risk of neonatal death.. · Modest weight loss between deliveries increases the risk of neonatal death.. · This risk may be partially explained by increased risk of congenital malformations..

Lean legacy, heavy heritage: family history of diabetes and its association with young adult body mass index.

Substantial intergenerational transmission of diabetes mellitus (DM) risk exists. However, less is known regarding whether parental DM and DM among extended family members relate to adult offspring's body mass index (BMI), and whether any of these associations vary by sex. Using data from the National Longitudinal Study of Youth 1997 cohort (NLSY97), we assess the sex-specific relationship between DM present in first-degree parents and second-degree relatives and BMI among the parents' young adult offspring.Multivariate regressions reveal a positive relationship between parental DM and young adults' BMI for both daughters and sons, and the magnitude of coefficients is somewhat larger for the same-sex parent. Further, we observe that the link between parental DM and young adults' BMI is strongest when both parents have diagnosed diabetes. In contrast, the relationship between second-degree relatives with DM and the respondent's BMI is weaker and appears to be sex-specific, through same-sex parent and respondent. Logistic regressions show the association is especially strong when assessing how parental DM status relates to young adults' obesity risk. These results generally persist when controlling for parental BMI. The findings of this study point to the need to better distinguish the role of shared family environments (e.g., eating and physical activity patterns) from shared genes in order to understand factors that may influence young adults' BMI. Young adult offspring of parents with diabetes should be targeted for obesity prevention efforts in order to reduce their risks of obesity and perhaps diabetes.

Disparities and determinants of place of death: Insights from the Utah Population Database.

To better understand determinants and potential disparities in end of life, we model decedents' place of death with explanatory variables describing familial, social, and economic resources. A retrospective cohort of 204,041 decedents and their family members are drawn from the Utah Population Database family caregiving dataset. Using multinomial regression, we model place of death, categorized as at home, in a hospital, in another location, or unknown. The model includes family relationship variables, sex, race and ethnicity, and a socioeconomic status score, with control variables for age at death and death year. We identified the effect of a family network of multiple caregivers, with 3+ daughters decreasing odds of a hospital death by 17 percent (OR: 0.83 [0.79, 0.87], p < 0.001). Place of death also varies significantly by race and ethnicity, with most nonwhite groups more likely to die in a hospital. These determinants may contribute to disparities in end of life.

Tobacco use increases the risk of chronic rhinosinusitis among patients undergoing endoscopic sinus surgery.

BACKGROUND: Although it has been postulated that tobacco use, as well as other environmental exposures, may contribute to chronic rhinosinusitis (CRS), the data remain limited. Here, we utilised a large state population database to assess the association between tobacco use and CRS prevalence among patients undergoing endoscopic sinus surgery (ESS). METHODS: Employing a case-control study design, the Utah Population Database was queried for patients age >18 with a diagnosis of CRS and tobacco use who underwent ESS between 1996 and 2018. Smoking status was compared between patients with CRS (n = 34 350) and random population controls matched 5:1 on sex, birth year, birthplace, time residing in Utah, and pedigree (i.e., familial) information (n = 166 020). Conditional logistic regression models were used for comparisons between CRS patients and their matched controls. All analyses were repeated, additionally adjusting for race, ethnicity, tobacco use, asthma history, and interaction between tobacco use and asthma history. RESULTS: A total of 200 370 patients were included in the final analysis. Patients with CRS were significantly more likely to demonstrate a history of tobacco use than controls (19.6% vs. 15.0%; p < .001), with an adjusted odds ratio (aOR) of 1.42, 95% confidence interval 1.37-1.47; p < .001. More patients with CRS and comorbid asthma used tobacco (19.5%) than controls with asthma (15.0%; p < .001). CONCLUSION: History of tobacco use may portend increased risk for the development of CRS among patients undergoing ESS compared to healthy controls.

Lower female partner live birth rate in male cancer survivors: An age-matched cohort analysis of the Utah Population Database.

We determine the time to first live birth for female partners of males after a cancer diagnosis. Our group performed a retrospective, population-based, age-matched cohort study of Utah male residents diagnosed with cancer at age 18 years or later between 1956 and 2013 (exposed) matched to male Utah residents without cancer diagnosis (unexposed). Using stratified Cox proportional hazard models, we adjusted for race, ethnicity and number of live births prior to cancer diagnosis, to estimate the effect of time to a partner live birth following cancer diagnosis. Our study cohort included 19,303 men diagnosed with cancer (exposed) and 93,608 age-matched men without cancer diagnoses (unexposed). Exposed men were less likely to have a live birth prior to first cancer diagnosis (60.7% vs. 65.4%, p < 0.001) and after first cancer diagnosis (10.9% vs. 12.2%, p < 0.001) compared to unexposed men. Exposed men had a fertility hazard rate that was 31% lower after cancer diagnosis date than unexposed men (HR: 0.69; 95% CI: 0.65-0.72). This was most profound for men aged 18-30 years (HR: 0.59, 95% CI: 0.55-0.63). Male cancer survivors have a 31% lower female partner live birth rate after cancer diagnosis. These findings are important for patient counselling regarding fertility preservation at the time of cancer diagnosis.

Familial Clustering and Genetic Analysis of Severe Thumb Carpometacarpal Joint Osteoarthritis in a Large Statewide Cohort.

PURPOSE: Our goals were to identify individuals who required surgery for thumb carpometacarpal (CMC) joint osteoarthritis (OA), determine if CMC joint OA clusters in families, define the magnitude of familial risk of CMC joint OA, identify risk factors associated with CMC joint OA, and identify rare genetic variants that segregate with familial CMC joint OA. METHODS: We searched the Utah Population Database to identify a cohort of CMC joint OA patients who required surgery. Affected individuals were mapped to pedigrees to identify high-risk families with excess clustering of CMC joint OA. Cox regression models were used to calculate familial risk of CMC joint OA in related individuals. Risk factors were evaluated using logistic regression models. Whole exome sequencing was used to identify rare coding variants associated with familial CMC joint OA. RESULTS: We identified 550 pedigrees with excess clustering of severe CMC joint OA. The relative risk of CMC joint OA requiring surgical treatment was elevated significantly in first- and third-degree relatives of affected individuals, and significant associations with advanced age, female sex, obesity, and tobacco use were observed. We discovered candidate genes that dominantly segregate with severe CMC joint OA in 4 independent families, including a rare variant in Chondroitin Sulfate Synthase 3 (CHSY3). CONCLUSIONS: Familial clustering of severe CMC joint OA was observed in a statewide population. Our data indicate that genetic and environmental factors contribute to the disease process, further highlighting the multifactorial nature of the disease. Genomic analyses suggest distinct biological processes are involved in CMC joint OA pathogenesis. CLINICAL RELEVANCE: Awareness of associated comorbidities may guide the diagnosis of CMC joint OA in at-risk populations and help identify individuals who may not do well with nonoperative treatment. Further pursuit of the genes associated with severe CMC joint OA may lead to assays for detection of early stages of disease and have therapeutic potential.

Lower total motile count is associated with smaller historic intergenerational family size: a pedigree analysis from the Utah Population Database.

PURPOSE: To describe the association between contemporary total motile count (TMC), a measure of male factor infertility, and historic intergenerational family size. METHODS: This is a retrospective, population-based, cohort study of men who underwent semen analysis for infertility workup at University of Utah, with at least a single measure of TMC, who were linked to extensive genealogical data. Two thousand one hundred eighty-two pedigree branches of men with a measure of TMC within the UPDB were identified. We identified the average number of generations and offspring within each generation. Conditional logistic regression models were used to assess the association between the risk of having a TMC in the 5th or 25th percentile and intergenerational family size. Generalized estimating equations (GEE) were used to assess the association between interval-level TMC and the number of ancestral offspring. RESULTS: We found no association between intergenerational size and TMC within the 5th percentile (TMC < 4 million; RR = 0.97, 95% CI 0.93-1.01) or the 25th percentile (TMC < 62 million; RR = 1.00, 95% CI 0.97-1.03). When TMC was analyzed as a continuous variable, we found that lower TMC is associated with smaller intergenerational family size. For every additional child in their ancestral pedigree, we observed an increase in TMC of 1.88 million (p = 0.03). Men in the top quartile for intergenerational family size had a TMC that was 48 million higher than men in the bottom quartile (p = 0.047). CONCLUSIONS: We found an association between TMC and ancestral family size, suggesting that lower TMC is associated with smaller intergenerational family size.

Risks of cause-specific mortality in offspring of pregnancies complicated by hypertensive disease of pregnancy.

BACKGROUND: Fetal environment has a substantial influence on an individual's health throughout their life course. Animal models of hypertensive disease of pregnancy have demonstrated adverse health outcomes among offspring exposed to hypertensive disease of pregnancy in utero. Although there are numerous descriptions of the neonatal, infant, and pediatric outcomes of human offspring affected by hypertensive disease of pregnancy, there are few data in US populations on later life outcomes, including mortality. OBJECTIVE: To assess risk for early mortality among offspring of pregnancies complicated by hypertensive disease of pregnancy. STUDY DESIGN: This is a retrospective cohort study of offspring born to women with singleton or twin pregnancies between 1947 and 1967 with birth certificate information in the Utah Population Database. We identified offspring from delivery diagnoses of gestational hypertension, preeclampsia, or eclampsia. Offspring from these pregnancies (exposed) were matched to offspring of pregnancies without hypertensive disease of pregnancy (unexposed) by maternal age at delivery, birth year, sex, and multiple gestation. We also identified unexposed siblings of exposed offspring for a separate sibling analysis. Mortality follow-up of all offspring continued through 2016, at which time they would have been 49-69 years old. Adjusted hazard ratios for cause-specific mortality comparing exposed with unexposed offspring were estimated using Cox proportional hazard models. RESULTS: We compared mortality risks for 4050 exposed offspring and 6989 matched unexposed offspring from the general population and 7496 unexposed siblings. Mortality risks due to metabolic, respiratory, digestive, nervous, and external causes of death did not differ between exposed and unexposed groups. Mortality risks from cardiovascular disease were greater in exposed offspring compared with unexposed offspring (adjusted hazard ratio, 1.57; 95% confidence interval, 1.16-2.12). In sex-specific models among the general population, cardiovascular disease mortality was significantly associated with exposure among male patients (adjusted hazard ratio, 1.92; 95% confidence interval, 1.27-2.88) but not among female patients (adjusted hazard ratio, 0.97; 95% confidence interval, 0.81-1.94). An interaction between hypertensive disease of pregnancy exposure and birth order on cardiovascular disease mortality was significant (P=.047), suggesting that the effect of hypertensive disease of pregnancy on cardiovascular disease mortality increased with higher birth order. Among siblings, the association between hypertensive disease of pregnancy exposure and cardiovascular disease mortality was not significant (adjusted hazard ratio, 1.39; 95% confidence interval, 0.99-1.95), and this was also true for sex-specific analyses of males (adjusted hazard ratio, 1.26; 95% confidence interval, 0.81-1.94) and females (adjusted hazard ratio, 1.71; 95% confidence interval, 0.96-3.04). As in the general population, there was a significant interaction between hypertensive disease of pregnancy exposure and birth order on cardiovascular disease mortality (P=.011). CONCLUSION: In a US population, overall mortality risks are greater for offspring of pregnancies complicated by hypertensive disease of pregnancy compared with unexposed offspring. Among siblings, there was not a significant association between hypertensive disease of pregnancy exposure and cardiovascular disease mortality.

Male survival advantage on the Baja California peninsula.

A consistent finding from contemporary Western societies is that women outlive men. However, what is unclear is whether sex differences in survival are constant across varying socio-ecological conditions. We test the universality of the female survival advantage with mortality data from a nineteenth century population in the Baja California peninsula of Mexico. When examined simply, we find evidence for a male-biased survival advantage. However, results from Cox regression clearly show the importance of age intervals for variable survival patterns by sex. Our key findings are that males: (i) experience significantly lower mortality risk than females during the ages 15-30 (RR = 0.69), (ii) are at a significantly increased risk of dying in the 61+ category (RR = 1.30) and (iii) do not experience significantly different mortality risk at any other age interval (0-14, 31-45, 46-60). We interpret our results to stem from differing intrinsic and extrinsic risk factors for sex-biased mortality across age intervals, highlighting the relevance of a lifecourse approach to the study of survival advantage. Ultimately, our results make clear the need to more broadly consider variability in mortality risk factors across time and place to allow for a clearer understanding of human survival differences.

Socioeconomic Status May Not Be a Risk Factor for Periprosthetic Joint Infection.

BACKGROUND: Periprosthetic joint infection (PJI) is a devastating complication after total joint arthroplasty, carrying significant economic and personal burden. The goal of this study is to use an established database to analyze socioeconomic variables and assess their relationship to PJI. Additionally, we sought to evaluate whether socioeconomic factors, along with other known risk factors of PJI, when controlled for in a statistical model affected the familial risk of PJI. METHODS: With approval from our Institutional Review Board we performed a population-based retrospective cohort study on all primary total joint arthroplasty cases of the hip or knee (n = 85,332), within a statewide database, between January 1996 and December 2013. We excluded 9854 patients due to age <18 years, missing data, history of PJI prior to index procedure, and no evidence of 2-year follow-up (excluding those with PJI). Cases that developed PJI following the index procedure (n = 2282) were compared to those that did not (n = 73,196). RESULTS: After adjusting for covariates, patients with Medicaid as a primary payer were at greater risk for experiencing PJI (relative risk 1.40, 95% confidence interval [CI] 1.08-1.82, P = .01). There was no difference in risk between the groups associated with education level or median household income (all, P > .05). First-degree relatives of patients who develop PJI (hazard ratio 1.66, 95% CI 1.23-2.24, P = .001) and first-degree and second-degree relatives combined (hazard ratio 1.39, 95% CI 1.09-1.77, P = .007) were at greater risk despite controlling for the above socioeconomic factors. CONCLUSION: Our study provides further support that genetic factors may underlie PJI as we did observe significant familial risk even after accounting for socioeconomic factors and payer status. We did not find a correlation between education level or household income and PJI; however, Medicaid payees were at increased risk. Continued study is needed to define a possible heritable disposition to PJI in an effort to optimize treatment and possibly prevent this complication.

The BRCA1 c. 5096G>A p.Arg1699Gln (R1699Q) intermediate risk variant: breast and ovarian cancer risk estimation and recommendations for clinical management from the ENIGMA consortium.

BACKGROUND: We previously showed that the BRCA1 variant c.5096G>A p.Arg1699Gln (R1699Q) was associated with an intermediate risk of breast cancer (BC) and ovarian cancer (OC). This study aimed to assess these cancer risks for R1699Q carriers in a larger cohort, including follow-up of previously studied families, to further define cancer risks and to propose adjusted clinical management of female BRCA1*R1699Q carriers. METHODS: Data were collected from 129 BRCA1*R1699Q families ascertained internationally by ENIGMA (Evidence-based Network for the Interpretation of Germline Mutant Alleles) consortium members. A modified segregation analysis was used to calculate BC and OC risks. Relative risks were calculated under both monogenic model and major gene plus polygenic model assumptions. RESULTS: In this cohort the cumulative risk of BC and OC by age 70 years was 20% and 6%, respectively. The relative risk for developing cancer was higher when using a model that included the effects of both the R1699Q variant and a residual polygenic component compared with monogenic model (for BC 3.67 vs 2.83, and for OC 6.41 vs 5.83). CONCLUSION: Our results confirm that BRCA1*R1699Q confers an intermediate risk for BC and OC. Breast surveillance for female carriers based on mammogram annually from age 40 is advised. Bilateral salpingo-oophorectomy should be considered based on family history.

Examining validity of body mass index calculated using height and weight data from the US driver license.

BACKGROUND: Driver license departments in many US states collect data on individuals' height and weight. These data can be useful to researchers in epidemiological and public health studies. As height and weight on driver license are self-reported, they may be prone to reporting bias. We compare height and weight obtained from driver license records and clinically measured height and weight, as well as body mass index (BMI) values calculated using the two data sources for the same individual. METHODS: We linked individual height and weight records obtained from the Driver License Division (DLD) in the Utah Department of Public Safety to clinical records from one of the largest healthcare providers in the state of Utah. We then calculated average differences between height, weight and BMI values separately for women and men in the sample, as well as discrepancies between the two sets of measures by age and BMI category. We examined how well self-reported height and weight from the driver licenses classify individuals into specific BMI categories based on clinical measures. Finally, we used two sets of BMI values to estimate individuals' relative risk of type II diabetes. RESULTS: Individuals, on average, tend to overestimate their height and underestimate their weight. Consequently, the value of BMI calculated using driver license records is lower than BMI calculated using clinical measurements. The discrepancy varies by age and by BMI category. Despite the discrepancy, BMI based on self-reported height and weight allows for accurate categorization of individuals at the higher end of the BMI scale, such as the obese. When used as predictors of relative risk of type II diabetes, both sets of BMI values yield similar risk estimates. CONCLUSIONS: Data on height and weight from driver license data can be a useful asset for monitoring population health in states where such information is collected, despite the degree of misreporting associated with self-report.

The BRCA2 c.68-7T > A variant is not pathogenic: A model for clinical calibration of spliceogenicity.

Although the spliceogenic nature of the BRCA2 c.68-7T > A variant has been demonstrated, its association with cancer risk remains controversial. In this study, we accurately quantified by real-time PCR and digital PCR (dPCR), the BRCA2 isoforms retaining or missing exon 3. In addition, the combined odds ratio for causality of the variant was estimated using genetic and clinical data, and its associated cancer risk was estimated by case-control analysis in 83,636 individuals. Co-occurrence in trans with pathogenic BRCA2 variants was assessed in 5,382 families. Exon 3 exclusion rate was 4.5-fold higher in variant carriers (13%) than controls (3%), indicating an exclusion rate for the c.68-7T > A allele of approximately 20%. The posterior probability of pathogenicity was 7.44 × 10-115 . There was neither evidence for increased risk of breast cancer (OR 1.03; 95% CI 0.86-1.24) nor for a deleterious effect of the variant when co-occurring with pathogenic variants. Our data provide for the first time robust evidence of the nonpathogenicity of the BRCA2 c.68-7T > A. Genetic and quantitative transcript analyses together inform the threshold for the ratio between functional and altered BRCA2 isoforms compatible with normal cell function. These findings might be exploited to assess the relevance for cancer risk of other BRCA2 spliceogenic variants.

Long-term mortality risk and life expectancy following recurrent hypertensive disease of pregnancy.

BACKGROUND: Women with a history of hypertensive disease of pregnancy have increased risks for early mortality from multiple causes. The effect of recurrent hypertensive disease of pregnancy on mortality risk and life expectancy is unknown. OBJECTIVE: We sought to determine whether recurrent hypertensive disease of pregnancy is associated with increased mortality risks. STUDY DESIGN: In this retrospective cohort study, we used birth certificate data to determine the number of pregnancies affected by hypertensive disease of pregnancy for each woman delivering in Utah from 1939 through 2012. We assigned women to 1 of 3 groups based on number of affected pregnancies: 0, 1, or ≥2. Exposed women had ≥1 affected singleton pregnancy and lived in Utah for ≥1 year postpartum. Exposed women were matched 1:2 to unexposed women by age, year of childbirth, and parity. Underlying cause of death was determined from death certificates. Mortality risks by underlying cause of death were compared between exposed and unexposed women as a function of number of affected pregnancies. Cox regressions controlled for infant sex, gestational age, parental education, ethnicity, and marital status. RESULTS: We identified 57,384 women with ≥1 affected pregnancy (49,598 women with 1 affected pregnancy and 7786 women with ≥2 affected pregnancies). These women were matched to 114,768 unexposed women. As of 2016, 11,894 women were deceased: 4722 (8.2%) exposed and 7172 (6.3%) unexposed. Women with ≥2 affected pregnancies had increased mortality from all causes (adjusted hazard ratio, 2.04; 95% confidence interval, 1.76-2.36), diabetes (adjusted hazard ratio, 4.33; 95% confidence interval, 2.21-8.47), ischemic heart disease (adjusted hazard ratio, 3.30; 95% confidence interval, 2.02-5.40), and stroke (adjusted hazard ratio, 5.10; 95% confidence interval, 2.62-9.92). For women whose index pregnancy delivered from 1939 through 1959 (n = 10,488), those with ≥2 affected pregnancies had shorter additional life expectancies than mothers who had only 1 or 0 hypertensive pregnancies (48.92 vs 51.91 vs 55.48 years, respectively). CONCLUSION: Hypertensive diseases of pregnancy are associated with excess risks for early all-cause mortality and some cause-specific mortality, and these risks increase further with recurrent disease.