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PURPOSE: We compared new cases detected per index case in familial hypercholesterolemia (FH) families with or without an identifiable monogenic etiology. METHODS: We enrolled 52 FH probands with a pathogenic variant (FH(g+)) in LDLR, APOB, or PCSK9 and 73 probands without such a variant (FH(g−)). After direct contact by the study team, family members (FMs) of FH(g+) probands could opt-in for genetic testing and FMs of FH(g−) probands were asked to provide a lipid profile. New cases were defined as presence of a pathogenic variant in FH(g+) families and as low-density lipoprotein cholesterol ≥155 mg/dL in FH(g−) families. RESULTS: Of 71 FH(g+) probands seen by a genetic counselor, 52 consented and identified 253 FMs (111 consented and were tested, yielding 48 new cases). Of 101 FH(g−) probands who received counseling, 73 consented and identified 295 FMs (63 consented and were tested, yielding 17 new cases). New case detection per index case was significantly greater in FH(g+) than in FH(g−) families (0.92 vs 0.23), a result of higher cascade testing uptake (43.9 vs 21.4%) and yield (43.2 vs 27.0%) in the former. CONCLUSION: New case detection rate was significantly higher in FH families with a monogenic etiology than in those without such an etiology owing to greater uptake and yield of cascade testing.

Vaccine nonresponse during the coronavirus disease 2019 (COVID-19) pandemic has considerable individual and societal risks.To investigate the clinical characteristics of patients with lack of seroconversion after vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).Demographic and clinical data were collected from 805 patients who had validated antibody assays against the SARS-CoV-2 spike protein at least 14 days after completion of their COVID-19 vaccination. Clinical characteristics from patients with a negative (0.4 U/mL) antibody response were assessed and summarized.A total of 622 (77.3%) patients attained seroconversion as defined by a titer of greater than or equal to 0.4 U/mL, whereas 183 out of 805 (22.7%) patients exhibited no seroconversion after vaccination against SARS-CoV-2. Univariately, older age (P = .02) and male sex were associated with a lower likelihood of seroconversion (P = .003). Therapy with immunosuppressive drugs was noted in 93 (50.8%) of seronegative patients with most (n = 83/93, 89.2%) receiving ongoing immunosuppressive therapy at the time of vaccination. Among the 134 (73.2%) seronegative patients with immunodeficiency, 110 (82.1%) had primary immunodeficiency. Cancer (n = 128, 69.9%), B cell depletion therapy (n = 90/115, 78.3%), and immunosuppressant steroid use (n = 71/93 on immunosuppressants, 76.3%) were the other common characteristics among the vaccine nonresponders. More importantly, our study did not evaluate the actual efficacy of COVID-19 vaccination.Vaccine responses vary by age and sex, with men showing lower rates of seroconversion as compared with women. Primary immunodeficiency along with active malignancy and ongoing immunosuppression with steroids or B cell depletion therapy appeared to be the most common characteristics for those with a lack of vaccine seroconversion after COVID-19 vaccination.

PDF file - 118KB, Supplementary Table 1. number of patients for each observed clusters with 4 autoantibodies. Supplementary Table 2. Number of patients for each observed clusters with 5 autoantibodies.

ImportanceThe association of premenopausal bilateral oophorectomy with parkinsonism and Parkinson disease (PD) remains controversial.ObjectiveTo assess whether women who underwent premenopausal bilateral oophorectomy were at increased risk of parkinsonism and PD and whether the associations varied by age at oophorectomy and by receipt of estrogen replacement therapy.Design, Setting, and ParticipantsThis cohort study used data from a combination of 2 independent cohort studies, the Mayo Clinic Cohort Study of Oophorectomy and Aging 1 and 2, which were based on the Rochester Epidemiology Project medical records–linkage system. A population-based sample of 5499 women from Olmsted County, Minnesota, were included; of those, 2750 women underwent bilateral oophorectomy for a benign indication before spontaneous menopause between January 1, 1950, and December 31, 2007 (oophorectomy cohort), and 2749 age-matched women who did not undergo bilateral oophorectomy were randomly sampled from the general population (reference cohort). Data were analyzed from March 1 to April 30, 2022. The date of oophorectomy was considered the index date for both groups.ExposuresMedical record documentation of bilateral oophorectomy abstracted from a medical records–linkage system (Rochester Epidemiology Project).Main Outcomes and MeasuresIncidence and risk of parkinsonism or PD, with diagnoses confirmed by in-person examination or medical record review.ResultsAmong 5499 participants (median [IQR] age, 45.0 [40.0-48.0] years; 5312 [96.6%] White), 2750 women (2679 White [97.4%]) underwent bilateral oophorectomy at a median age of 45.0 years (IQR, 40.0-48.0 years), and 2749 women (2633 White [95.8%]) with a median age of 45.0 years (IQR, 40.0-48.0 years) at the index date were included in the reference cohort. Bilateral oophorectomy was associated with an increased risk of parkinsonism overall (hazard ratio [HR], 1.59; 95% CI, 1.02-2.46) and in women younger than 43 years at oophorectomy (HR, 7.67; 95% CI, 1.77-33.27). There was a pattern of increasing risk with younger age at the time of oophorectomy using 4 age strata (≥50 years: HR, 1.43 [95% CI, 0.50-4.15]; 46-49 years: HR, 1.55 [95% CI, 0.79-3.07]; 40-45 years: HR, 1.36 [95% CI, 0.64-2.89]; P = .02 for trend). The number needed to harm was 53 women overall and 27 women younger than 43 years at the time of oophorectomy. Bilateral oophorectomy was also associated with an increased risk of PD in women younger than 43 years at oophorectomy (HR, 5.00; 95% CI, 1.10-22.70), with a number needed to harm of 48 women. Among women who underwent oophorectomy at 45 years and younger, the risk was lower in women who received estrogen after the procedure and through age 50 years compared with women who did not. For parkinsonism, the HRs were 1.72 (95% CI, 0.54-5.53) vs 2.05 (95% CI, 0.80-5.23); for PD, the HRs were 1.53 (95% CI, 0.29-8.23) vs 2.75 (95% CI, 0.84-9.04). However, the differences were not significant.Conclusions and RelevanceIn this study, premenopausal women who underwent bilateral oophorectomy before age 43 years had an increased risk of parkinsonism and PD compared with women who did not undergo bilateral oophorectomy. These findings suggest that a reduction in the practice of prophylactic bilateral oophorectomy in premenopausal women at average risk of ovarian cancer may have substantial benefit for reducing the risk of parkinsonism and PD.

OBJECTIVE: The incidence of carpal tunnel syndrome (CTS) is higher in women, and peaks around the age of menopause. Therefore, we investigated whether bilateral oophorectomy is associated with an increased risk of severe CTS. METHODS: We included all of the 1,653 premenopausal women who underwent bilateral oophorectomy for a nonmalignant indication between 1988 and 2007, and a random sample of 1,653 age-matched referent women who did not undergo bilateral oophorectomy in Olmsted County, Minnesota. Diagnoses of CTS assigned to women over their entire lifetime were identified in these two cohorts. The risk of de novo severe CTS after bilateral oophorectomy (or index date) was evaluated using Cox proportional hazards models adjusted for potential confounders. RESULTS: Bilateral oophorectomy was associated with an increased risk of severe CTS (adjusted hazard ratio 1.65, 95% confidence interval 1.20-2.25). The risk was suggestively greater in women with lower body mass index, nulliparity, and with a benign ovarian indication for oophorectomy (non-significant interactions). We did not observe a protective effect of estrogen therapy after the oophorectomy. The findings were similar in secondary analyses considering the incidence of CTS of any severity or idiopathic CTS. CONCLUSIONS: The risk of severe CTS, common in perimenopausal women, is increased after bilateral oophorectomy. The association may be causal or due to confounding. Therefore, the precise biological mechanisms explaining the association and the absence of a mitigating effect of estrogen therapy should be further investigated.

Antibody responses to pneumococcal polysaccharide vaccination are frequently used as a diagnostic tool for humoral immunodeficiencies, part of the larger collection of inborn errors of immunity. Currently, arbitrary criteria, such as a serotype specific titer of >/= 1.3 µg/mL is most often used as a cut-off for interpretation of pneumococcal antibody responses. The magnitude of the antibody response to each of the 23 serotypes in Pneumovax®, and serotype-specific cut-offs in healthy pneumococcal vaccine-naive adults has not been previously characterized. IgG antibody concentrations were measured prospectively for 23 pneumococcal serotypes pre and 4–6 weeks post-Pneumovax® vaccination in 100 healthy adults, using a multiplex bead-based assay. Antibodies to 19 of 23 serotypes were informative for distinguishing subjects who responded to vaccination, and the serotype threshold was determined to be 9 of 19 serotypes, which characterized an antibody response to pneumococcal vaccination. While this study may facilitate classification of IgG serotype-specific antibody responses post-pneumococcal vaccination in adult patients undergoing diagnostic immunological evaluation for antibody immunodeficiencies or other relevant contexts, additional studies in healthy children and S. pneumoniae protein-conjugate-vaccinated healthy adults will need to be undertaken in the future.

OBJECTIVE: To determine trends in amputations and revascularizations for peripheral arterial disease in a well-defined population. PATIENTS AND METHODS: Population-based cohort study of Olmsted County, MN residents with peripheral arterial disease undergoing amputation or revascularization between January 1, 1990 and December 31, 2009. Population-level 5-year incidence trends for endovascular, open surgical and hybrid revascularizations and major and minor amputations were determined. Limb-specific outcomes following revascularization including major adverse limb events and amputation-free survival were compared between initial surgical and endovascular/hybrid revascularization groups using Kaplan-Meier analysis. RESULTS: We identified 773 residents who underwent 1906 limb-procedures, including 689 open revascularizations, 685 endovascular/hybrid revascularizations and 220 major amputations. Over the 20-year study period, the incidence of endovascular and hybrid revascularizations increased while the incidence of open surgical revascularizations and major amputations decreased. Incidence of revascularizations for chronic limb-threatening ischemia did not change. Among residents with chronic limb-threatening ischemia undergoing their first revascularization on a limb, endovascular revascularization was associated with more major adverse limb events and major amputations compared to surgical revascularization over the ensuing 15 years. CONCLUSIONS: A rising incidence of endovascular/hybrid revascularizations and decreasing incidence of open surgical revascularizations for peripheral arterial disease was associated with a decreasing incidence of major amputations in this population between 1990 and 2009, despite a stable incidence of revascularizations for chronic limb-threatening ischemia. With more major adverse limb events and major amputations following endovascular revascularization, these trends suggest that additional emphasis should be placed on improving limb salvage efforts beyond just mode of revascularization.

The associations of bilateral oophorectomy among premenopausal women, age at oophorectomy, and use of estrogen therapy after oophorectomy with cognitive performance later in life remain controversial.To investigate whether women who underwent premenopausal bilateral oophorectomy were at increased risk of mild cognitive impairment (MCI) and experienced decreased global or domain-specific cognitive performance.This case-control study and cross-sectional study were made possible by combining data from the Mayo Clinic Study of Aging (MCSA) and the Rochester Epidemiology Project (REP) medical record-linkage system. The studies were conducted among a population-based sample in Olmsted County, Minnesota, consisting of 2732 women aged 50 to 89 years who participated in the MCSA study from 2004 to 2019 and underwent a clinical evaluation and comprehensive cognitive testing. Data were analyzed from January to May 2021.Medical record documentation of bilateral oophorectomy abstracted from a medical record-linkage system (ie, REP).Odds of MCI and global or domain-specific z scores on cognitive tests were measured at the first MCSA visit. The median (IQR) lag time between bilateral oophorectomy performed before menopause and before age 50 years and cognitive evaluation was 30 (22-38) years.Among 2732 women aged 50 to 89 years (median [IQR] age at evaluation, 74 [66-81] years) who participated in the MCSA, the case-control study included 283 women with MCI (10.4%) and 2449 women without cognitive impairment (89.6%). Bilateral oophorectomy before menopause and before age 46 years was associated with clinically diagnosed MCI (adjusted odds ratio [aOR], 2.21; 95% CI, 1.41-3.45; P .001) compared with no bilateral oophorectomy. The presence of an association with MCI varied by surgical indication, with an association among 259 women with bilateral oophorectomy before menopause and before age 50 years for the indication of benign ovarian condition (aOR, 2.43; 95% CI, 1.36-4.33; P = .003) but not for cancer or no ovarian condition. The presence of an association did not vary by estrogen therapy after bilateral oophorectomy, with associations among women aged less than 46 years with estrogen therapy (aOR, 2.56; 95% CI, 1.24-5.31; P = .01) and without estrogen therapy (aOR, 2.05; 95% CI, 1.18-3.52; P = .01). The cross-sectional study included 625 women with a history of bilateral oophorectomy (median [IQR] age, 75 [70-82] years) and 2107 women without a history of bilateral oophorectomy (median [IQR] age, 73 [65-80] years). Premenopausal bilateral oophorectomy was performed before age 46 years among 161 women and was associated with decreased global cognition z score (β, -0.17; 95% CI, -0.32 to -0.03; P = .02), attention and executive domain z score (β, -0.21; 95% CI, -0.36 to -0.05; P = .009), and Short Test of Mental Status score (β, -0.51; 95% CI, -0.95 to -0.08; P = .02) compared with no bilateral oophorectomy.This study found that women who underwent bilateral oophorectomy before menopause had increased odds of MCI and poorer performance on cognitive tests approximately 30 years later compared with women who did not undergo bilateral oophorectomy.

To study the trajectories of metabolic parameters after bilateral oophorectomy.This population-based cohort study included a random sample of all premenopausal women who underwent bilateral oophorectomy at or before age 45 years from 1988 to 2007 in Olmsted County, Minnesota, and their age-matched (±1 year) referent women who did not undergo bilateral oophorectomy.The medical records of all women were reviewed to collect the metabolic parameters over a 10-year period. We compared three groups of women: 1) referent women (n = 270), 2) women who underwent bilateral oophorectomy and received estrogen therapy (n = 163), and 3) women who underwent bilateral oophorectomy and did not receive estrogen therapy (n = 107).Over 10 years of follow-up, the three groups had significantly different mean values of diastolic blood pressure, weight, body mass index (BMI), total cholesterol, triglycerides, and high-density lipoprotein cholesterol (HDL-C). However, women with and without bilateral oophorectomy were already different at baseline for hyperlipidemia, systolic blood pressure, weight, and BMI. Nevertheless, the trajectories of change over 10 years were significant for weight (group by time interaction p = 0.03), BMI (p = 0.03), and HDL-C (p = 0.004). The changes occurred primarily in the initial 4-5 years. Women who received estrogen therapy after bilateral oophorectomy were comparable to the referent women with respect to the weight and BMI trends, and they experienced an increase in HDL-C over time.Women who underwent bilateral oophorectomy before menopause experienced unfavorable changes in some metabolic parameters possibly increasing their cardiovascular risk.

INTRODUCTION: Efforts to model the cost-effectiveness of managing/modifying cognitive-impairment lack reliable, objective, baseline medical- and nursing-home-costs. METHODS: A stratified-random sample of Olmsted County, MN, residents age 70–89 years (N=3,545), well-characterized as cognitively-unimpaired, mild-cognitive-impairment, or dementia, were followed forward ≤1-year in provider-linked billing-data and Centers-for-Medicare-and-Medicaid-Services nursing-home assessments. Direct medical/nursing-home/medical+nursing-home costs were estimated. Costs were stratified by vital status and nursing-home-use intensity (nursing-home-days/follow-up-days [0%, 1–24%, 25–99%, and100%]). Between-category mean-annual-cost differences were adjusted for patient characteristics and follow-up-days. RESULTS: Costs/follow-up-day distributions differed significantly across cognitive categories. Mean costs/follow-up-day were 2.5–18 times higher for decedents vs survivors. Among all persons with mild-cognitive-impairment, the

ObjectivesPopulation-based epidemiologic data for paraneoplastic neurologic syndromes (PNSs) in the United States are lacking. Our objective was to evaluate the incidence, prevalence, and associated morbidity of PNS.MethodsWe performed a population-based epidemiology study in Olmsted County, Minnesota, with patients identified between January 1, 1987, and December 31, 2018, using the medical records linkage system of the Rochester Epidemiology Project (REP) who met the definite/probable 2021 PNS criteria and 2004 PNS criteria. Patients with dermatomyositis and myasthenia gravis with underlying tumors were included. Age- and sex-specific population counts were obtained from REP resources for January 1, 2014 (prevalence denominator) and annually for 1987–2018 (incidence denominator). Morbidity was estimated using disability-adjusted life years (DALYs; years lived with disability [YLD] plus years of life lost [YLL]).ResultsThere were 28 patients with PNS identified (50% female) residing in Olmsted County, Minnesota, with median age at diagnosis of 54.5 (IQR 46.5–69.0) years. All patients had a cancer diagnosis, and 18 (64%) patients were neural autoantibody positive including antineuronal nuclear autoantibody type 1 (ANNA-1/anti-Hu; n = 1), ANNA-2/anti-Ri (n = 1), muscle-type acetylcholine receptor (AChR; n = 6), Purkinje cell cytoplasmic antibody type 1 (PCA-1/anti-Yo; n = 1), kelch-like protein 11 (KLH11; n = 3), collapsin response mediator protein 5 (CRMP-5/anti-CV2; n = 2), α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (n = 1), neurofilament light chain (n = 1), leucine zipper 4 (LUZP4; n = 1), and unclassified neural antibodies (n = 1). PNS incidence was 0.6/100,000 person-years and increased over time from 0.4/100,000 person-years (1987–2002) to 0.8/100,000 person-years (2003–2018) (p = 0.06). Prevalence was 5.4/100,000 people. The median follow-up period after PNS diagnosis was 3.1 years (IQR, 1.1–9.9 years). Total disability-adjusted life years (DALYs) for 28 patients with PNS were 472.7 years, based on total years of life lost (YLL) for patients dying between 1987 and 2018 (n = 15) of 445.3 years plus years lived with disability (YLD) 27.4 years.DiscussionPNSs are rare neurologic disorders but are associated with severe morbidity and mortality. The estimated number of prevalent PNS cases in the United States is 17,099, and predicted DALY for all US PNS cases is 292,393 years. Their apparent increasing rate of detection is attributable to increasing physician awareness and availability of serologic testing.

Objective The aim of this research was to study the long-term risk of de novo mental health conditions in women who underwent hysterectomy with bilateral ovarian conservation compared with age-matched referent women. Methods Using the Rochester Epidemiology Project records-linkage system, we identified a historical cohort of 2,094 women who underwent hysterectomy with ovarian conservation for benign indications at age ≥18 years and with an index date between 1980 and 2002 in Olmsted County, Minnesota. Each woman was age-matched (±1 y) to a referent woman residing in the same county who had not undergone hysterectomy or any oophorectomy before the index date. These two cohorts were followed historically to identify de novo mental health conditions. We estimated hazard ratios (HRs) and 95% confidence intervals (95% CIs) using Cox proportional hazards models adjusted for 20 preexisting chronic conditions and other potential confounders. We also calculated absolute risk increases (ARIs) and reductions (ARRs) at 30 years of follow-up. Results Over a median follow-up of 21.9 years, women who underwent hysterectomy at any age experienced increased risks of de novo depression (adjusted HR 1.26; 95% CI, 1.12-1.41; ARI 6.6%) and anxiety (adjusted HR 1.22; 95% CI, 1.08-1.38; ARI 4.7%). The association for depression increased significantly with younger age at hysterectomy, but did not vary significantly by indication. Interactions were not significant for anxiety. Conclusions Hysterectomy, even with ovarian conservation, is associated with an increased long-term risk of de novo depression and anxiety, especially when performed in women who are younger. : Video Summary:http://links.lww.com/MENO/A465.

Background Hypertriglyceridemia is associated with increased risk of coronary heart disease but the association is often attributed to concomitant metabolic abnormalities. We investigated the epidemiology of primary isolated hypertriglyceridemia (PIH) and associated cardiovascular risk in a population‐based setting. Methods and Results We identified adults with at least one triglyceride level ≥500 mg/dL between 1998 and 2015 in Olmsted County, Minnesota. We also identified age‐ and sex‐matched controls with triglyceride levels P = 0.022). There was no statistically significant association between PIH and cerebrovascular disease (HR, 1.06; 95% CI, 0.65‐1.73, P = 0.813), peripheral artery disease (HR, 1.27; 95% CI, 0.43‐3.75; P = 0.668), or the composite end point of all 3 (HR, 1.28; 95% CI, 0.92‐1.80; P =0.148) in adjusted models. Conclusions PIH was associated with incident coronary heart disease events (although there was attenuation after adjustment for conventional risk factors), supporting a causal role for triglycerides in coronary heart disease. The condition is relatively prevalent but awareness and control are low.

Background Electronic health records (EHRs) are a rich source of longitudinal patient data. However, missing information due to clinical care that predated the implementation of EHR system(s) or care that occurred at different medical institutions impedes complete ascertainment of a patient’s medical history. Objective This study aimed to investigate information discrepancies and to quantify information gaps by comparing the gynecological surgical history extracted from an EHR of a single institution by using natural language processing (NLP) techniques with the manually curated surgical history information through chart review of records from multiple independent regional health care institutions. Methods To facilitate high-throughput evaluation, we developed a rule-based NLP algorithm to detect gynecological surgery history from the unstructured narrative of the Mayo Clinic EHR. These results were compared to a gold standard cohort of 3870 women with gynecological surgery status adjudicated using the Rochester Epidemiology Project medical records–linkage system. We quantified and characterized the information gaps observed that led to misclassification of the surgical status. Results The NLP algorithm achieved precision of 0.85, recall of 0.82, and F1-score of 0.83 in the test set (n=265) relative to outcomes abstracted from the Mayo EHR. This performance attenuated when directly compared to the gold standard (precision 0.79, recall 0.76, and F1-score 0.76), with the majority of misclassifications being false negatives in nature. We then applied the algorithm to the remaining patients (n=3340) and identified 2 types of information gaps through error analysis. First, 6% (199/3340) of women in this study had no recorded surgery information or partial information in the EHR. Second, 4.3% (144/3340) of women had inconsistent or inaccurate information within the clinical narrative owing to misinterpreted information, erroneous “copy and paste,” or incorrect information provided by patients. Additionally, the NLP algorithm misclassified the surgery status of 3.6% (121/3340) of women. Conclusions Although NLP techniques were able to adequately recreate the gynecologic surgical status from the clinical narrative, missing or inaccurately reported and recorded information resulted in much of the misclassification observed. Therefore, alternative approaches to collect or curate surgical history are needed.

This cohort study assesses whether bilateral oophorectomy for a benign indication prior to natural menopause is associated with risk of restless legs syndrome., Key Points Question Is bilateral oophorectomy for a benign indication prior to natural menopause associated with risk of restless legs syndrome? Findings In this cohort study of 3306 women, those who underwent bilateral oophorectomy prior to natural menopause had a higher risk of restless legs syndrome than those who did not undergo such surgery. The increased risk was independent of multiple chronic conditions present at baseline, was greater among women without a benign ovarian condition, and did not differ by estrogen therapy. Meaning This study found that undergoing bilateral oophorectomy for a benign indication prior to natural menopause was associated with an increased risk of restless legs syndrome., Importance Restless legs syndrome is a common neurologic disorder that is more prevalent in women than in men, and it has been suggested that female hormones may be involved in the disorder’s pathophysiology. Objective To determine whether women who underwent premenopausal bilateral oophorectomy were at increased risk of restless legs syndrome. Design, Setting, and Participants This cohort study was performed using data from the Mayo Clinic Cohort Study of Oophorectomy and Aging–2 for a population in Olmsted County, Minnesota. There were 1653 women who underwent premenopausal bilateral oophorectomy before the age of 50 years for a benign indication between 1988 and 2007 and 1653 age-matched women (of same age plus or minus 1 year) in a reference group. Follow-up was conducted until the end of the study period (ie, December 31, 2014). Data were analyzed from January to July 2020. Exposures Undergoing bilateral oophorectomy, as shown in medical record documentation. Main Outcomes and Measures Diagnosis of restless legs syndrome, as defined using Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) criteria, was recorded. Results Among 3306 women, the median (interquartile range) age at baseline was 44.0 (40.0-47.0) years. Women who underwent bilateral oophorectomy, compared with women who did not undergo this procedure, had a greater number of chronic conditions at the index date (eg, 300 women [18.1%] vs 171 women [10.3%] with ≥3 chronic conditions; overall P

Background Cutaneous squamous cell carcinomas (CSCC) involving the head and neck are common, but initial presentation or recurrence limited to the cranial nerves is rare. Methods We conducted a retrospective study of 21 patients with clinical perineural invasion (PNI) from CSCC and no measurable disease by RECIST 1.1. Patients treated with radiotherapy or chemoradiotherapy were included. Results The median time from symptom onset until diagnosis was 13.0 months (2.6-83.1). All patients received radiotherapy. Fourteen received concurrent systemic therapy. The median follow-up time was 30.5 months (1.1-106.0). Ten patients recurred, with the majority being locoregional. The 2-year overall survival rate was 85%. The median progression-free survival (PFS) was 21.5 months with an estimated 2-year PFS of 44.5% (95%CI: 22.3-66.8). Conclusions CSCCs with clinical PNI alone are difficult to diagnose and can have a long interval between appearance of symptoms and diagnosis. They can successfully be treated with chemoradiotherapy. However, many patients still suffer from locoregional recurrences.

Hysterectomy is one of the most frequent gynecologic surgeries in the United States. Women undergoing hysterectomy are commonly offered bilateral oophorectomy for ovarian and breast cancer prevention. Although bilateral oophorectomy may dramatically reduce the risk of gynecologic cancers, some studies suggested that bilateral oophorectomy may be associated with an increased risk of other types of cancer, such as lung cancer and colorectal cancer. However, the results are conflicting.To study the association between bilateral oophorectomy and the risk of subsequent cancer of any type.This population-based cohort study included all premenopausal women who underwent bilateral oophorectomy for a nonmalignant indication before the age of 50, between January 1, 1988 and December 31, 2007 in Olmsted County, Minnesota, and a random sample of age-matched (±1 year) referent women who did not undergo bilateral oophorectomy. Women with cancer before oophorectomy (or index date) or within 6 months after the index date were excluded. Time-to-event analyses were performed to assess the risk of de novo cancer. Cancer diagnosis and type were confirmed using medical record review.Over a median follow-up of 18 years, the risk of any cancer did not significantly differ between the 1562 women who underwent bilateral oophorectomy before natural menopause and the 1610 referent women (adjusted hazard ratio, 0.82; 95% confidence interval, 0.66-1.03). However, women who underwent bilateral oophorectomy had a decreased risk of gynecologic cancers (adjusted hazard ratio, 0.15; 95% confidence interval, 0.06-0.34) but not of nongynecologic cancers (adjusted hazard ratio, 0.99; 95% confidence interval, 0.78-1.26). In particular, the risk of breast cancer, gastrointestinal cancer, and lung cancer did not differ between these 2 cohorts. Use of estrogen therapy through the age of 50 years in women who underwent bilateral oophorectomy did not modify the results.Women who underwent bilateral oophorectomy before menopause have a reduced risk of gynecologic cancer but not of other types of cancer including breast cancer. Women at average risk of ovarian cancer should not consider bilateral oophorectomy for the prevention of breast cancer or other nongynecologic cancers.

Background Median overall survival is 12 to 15 months in patients with metastatic adrenal cortical carcinoma (ACC). Etoposide, doxorubicin, and cisplatin with or without the adrenolytic agent mitotane is considered the best first-line approach in this context, but has limited activity and no curative potential; additional salvage therapeutic options are needed. Methods Fifteen total patients with recurrent/metastatic ACC were treated with single-agent multikinase inhibitors (MKI) (n = 8), single-agent PD-1 inhibition (n = 8), or cytotoxic chemotherapy plus PD-1 inhibition (n = 4) at our institution as later-line systemic therapies in efforts to palliate disease and attempt to achieve a therapeutic response when not otherwise possible using standard approaches. Results Two of 8 patients (25%) treated with single-agent MKI achieved a partial response (PR), including 1 PR lasting 23.5 months. Another 3 patients (38%) had stable disease (SD); median progression-free survival (PFS) with single-agent MKI was 6.4 months (95% confidence interval [CI] 0.8—not reached). On the other hand, 2 of 12 patients (17%) treated with PD-1 inhibitors (either alone or in combination with cytotoxic chemotherapy) attained SD or better, with 1 patient (8%) achieving a PR; median PFS was 1.4 months (95% CI 0.6-2.7). Conclusions Our single-institution experience suggests that select ACC patients respond to late-line MKI or checkpoint inhibition despite resistance to cytotoxic agents. These treatments may be attractive to ACC patients with limited other therapeutic options. The use of MKI and immunotherapy in ACC warrants prospective investigation emphasizing parallel correlative studies to identify biomarkers that predict for response.

Being a woman is one of the strongest risk factors for multiple sclerosis. The natural reproductive period from menarche to natural menopause corresponds to the active inflammatory disease period in multiple sclerosis. The fifth decade marks both the peri-menopausal transition in the reproductive aging and a transition from the relapsing-remitting to the progressive phase in multiple sclerosis. A short reproductive period with premature/early menopause and/or low number of pregnancies may be associated with an earlier onset of the progressive multiple sclerosis phase. A cross-sectional study of survey-based reproductive history in a multiple sclerosis clinical series enriched for patients with progressive disease, and a case–control study of multiple sclerosis and age/sex matched controls from a population-based cohort were conducted. Menarche age, number of complete/incomplete pregnancies, menopause type and menopause age were compared between 137 cases and 396 control females. Onset of relapsing-remitting phase of multiple sclerosis, progressive disease onset and reaching severe disability (expanded disability status scale 6) were studied as multiple sclerosis-related outcomes (n = 233). Menarche age was similar between multiple sclerosis and control females (P = 0.306). Females with multiple sclerosis had fewer full-term pregnancies than the controls (P, Premature/early menopause or nulliparity was associated with earlier progressive multiple sclerosis onset with a ‘dose effect’ of pregnancies on delaying progressive multiple sclerosis and severe disability. Zeydan et al.’s findings suggest a beneficial impact of oestrogen in delaying progressive multiple sclerosis and may have implications for counselling women on reproductive health., Graphical Abstract

Objectives We investigated the association of personal, reproductive, and familial characteristics with bilateral oophorectomy performed for nonmalignant indications in a US population. Study design In an established cohort study, we used the records-linkage system of the Rochester Epidemiology Project (REP http://www.rochesterproject.org ) to identify 1653 premenopausal women who underwent bilateral oophorectomy in Olmsted County, Minnesota between 1988 and 2007 for a nonmalignant indication. Each woman was matched by age (±1 year) to a population-based referent woman who had not undergone bilateral oophorectomy as of the index date. We used case-control analyses to investigate several characteristics associated with bilateral oophorectomy. Odds ratios and their 95% confidence intervals were adjusted for race, education, and income. Results In the overall analyses, infertility was more common in women who underwent bilateral oophorectomy than in the controls, whereas use of oral contraceptives, a history of breast feeding, and fibrocystic breast disease were less common. The women who underwent bilateral oophorectomy weighed more than controls, had a higher body mass index and were younger at menarche. The associations were more pronounced for women who underwent the bilateral oophorectomy before age 46 years, and some associations were different for women with or without a benign ovarian indication. Reported family histories of uterine and other cancers were more common in women without a benign ovarian indication. Conclusions We identified a number of personal, reproductive, and familial characteristics that were associated with bilateral oophorectomy over a 20-year period. Our historical findings may help inform decision-making about oophorectomy in the future.

Bilateral oophorectomy in premenopausal women is a unique condition causing the abrupt and premature loss of ovarian hormones, primarily estrogen. Bilateral oophorectomy causes an alteration of several fundamental aging processes at the cellular, tissue, organ, and system levels, leading to multimorbidity, frailty, and reduced survival. However, many questions remain unanswered.

We sought to characterize mid-ascending aorta diameter reference values by age, sex, and body surface area (BSA) in a large echocardiography laboratory practice-based cohort. All subjects with transthoracic echocardiograms with mid-ascending aorta diameter measure from January 2004 to December 2009 were identified, and medical records were reviewed for medical history and anthropometric data. Those with aortic valve disease or replacement, congenital heart disease, any connective tissue or inflammatory disease that may affect the aorta, or known aortic aneurysm (55 mm) were excluded. Mid-ascending aorta diameter was measured in a standardized manner using "leading edge to leading edge" technique at end-diastole. Of 27,839 eligible subjects, 16,620 did not have history of hypertension and were included in the analysis (56.3% female; mean age 52.0 ± 15.8 years), mean mid-ascending aorta diameter 31.7 ± 4.1 mm. Females had smaller diameter than males (30.5 ± 3.7 mm vs 33.3 ± 4.0 mm; p0.001). Subjects with history of hypertension (n = 11,219; not included in the analysis) had larger mid-ascending aorta diameter compared with normotensive subjects (33.9 ± 3.8 mm vs 31.7 ± 4.1 mm; p 0.001). Age had the greatest correlation with aortic size (r = 0.55), followed by sex (r = 0.35) and BSA (r = 0.35). Nomograms for predicted mid-ascending aorta diameter were generated at the 95th percentile using quantile regression for subjects without hypertension stratified by age, sex, and BSA. In conclusion, mid-ascending aorta diameter is predominantly associated with sex, age, and BSA. The nomograms established by this study may serve as useful reference values for echocardiographic screening and surveillance.

Objectives We evaluate incidence and prevalence of autoimmune encephalitis and compare the epidemiology of autoimmune and infectious encephalitis.

Background/objectives Objective, complete estimates of nursing home (NH) use across the spectrum of cognitive decline are needed to help predict future care needs and inform economic models constructed to assess interventions to reduce care needs. Design Retrospective longitudinal study. Setting Olmsted County, MN. Participants Mayo Clinic Study of Aging participants assessed as cognitively normal (CN), mild cognitive impairment (MCI), previously unrecognized dementia, or prevalent dementia (age = 70–89 years; N = 3,545). Measurements Participants were followed in Centers for Medicare and Medicaid Services (CMS) Minimum Data Set (MDS) NH records and in Rochester Epidemiology Project provider-linked medical records for 1-year after assessment of cognition for days of observation, NH use (yes/no), NH days, NH days/days of observation, and mortality. Results In the year after cognition was assessed, for persons categorized as CN, MCI, previously unrecognized dementia, and prevalent dementia respectively, the percentages who died were 1.0%, 2.6%, 4.2%, 21%; the percentages with any NH use were 3.8%, 8.7%, 19%, 40%; for persons with any NH use, median NH days were 27, 38, 120, 305, and median percentages of NH days/days of observation were 7.8%, 12%, 33%, 100%. The year after assessment, among persons with prevalent dementia and any NH use, >50% were a NH resident all days of observation. Pairwise comparisons revealed that each increase in cognitive impairment category exhibited significantly higher proportions with any NH use. One-year mortality was especially high for persons with prevalent dementia and any NH use (30% vs 13% for those with no NH use); 58% of all deaths among persons with prevalent dementia occurred while a NH resident. Conclusions Findings suggest reductions in NH use could result from quality alternatives to NH admission, both among persons with MCI and persons with dementia, together with suitable options for end-of-life care among persons with prevalent dementia.

OBJECTIVE We studied eight mental health conditions diagnosed before bilateral oophorectomy performed for nonmalignant indications. METHODS We identified 1,653 premenopausal women who underwent bilateral oophorectomy for a nonmalignant indication in Olmsted County, Minnesota, during a 20-year period (1988-2007). Each woman was matched by age (±1 year) to one population-based control who had not undergone bilateral oophorectomy before the index date (age range: 21-49 years). Both cases and controls were identified using the records-linkage system of the Rochester Epidemiology Project (REP http://www.rochesterproject.org). For eight mental health conditions, we calculated odds ratios (ORs) and their 95% confidence intervals (95% CIs) adjusted for race, education, and income using conditional logistic regression. RESULTS Pre-existing mood disorders, anxiety disorders, and somatoform disorders were associated with increased risk of bilateral oophorectomy in overall analyses. These associations were also significant in women ≤45 years of age at index date. Personality disorders were associated with increased risk only in overall analyses and adjustment disorders only in women 46 to 49 years of age. Some of the associations were significantly different across strata by age at index date and by indication. There was also a linear trend of increasing adjusted ORs from 1.55 (95% CI 1.31-1.83) for one mental health condition to 2.19 (95% CI 1.40-3.41) for three or more conditions (trend P

Objective To study the association between bilateral oophorectomy and the rate of accumulation of multimorbidity. Patients and Methods In this historical cohort study, the Rochester Epidemiology Project records-linkage system was used to identify all premenopausal women who underwent bilateral oophorectomy before age 50 years between January 1, 1988, and December 31, 2007, in Olmsted County, Minnesota. Each woman was randomly matched to a referent woman born in the same year (± 1 year) who had not undergone bilateral oophorectomy. We studied the rate of accumulation of 18 common chronic conditions over a median of approximately 14 years of follow-up. Results Although women who underwent bilateral oophorectomy already had a higher multimorbidity burden at the time of oophorectomy, they also experienced a significantly increased risk of subsequent multimorbidity (P=.XX). After adjustments for 18 chronic conditions present at baseline, race/ethnicity, education, body mass index, smoking, age at baseline, and calendar year at baseline, women who underwent oophorectomy before age 46 years experienced an increased risk of depression, hyperlipidemia, cardiac arrhythmias, coronary artery disease, arthritis, asthma, chronic obstructive pulmonary disease, and osteoporosis. In addition, they experienced an accelerated rate of accumulation of the 18 chronic conditions considered together (hazard ratio, 1.22; 95% CI, 1.14–1.31; P

c-Met is a receptor tyrosine kinase shown to be overexpressed in malignant pleural mesothelioma (MPM). Whereas MET mutations have been identified in 3%-16% of MPMs, MET amplification has recently been reported in a single epithelioid MPM. We studied c-Met expression and MET amplification in a large MPM cohort and correlated results with morphologic and clinical features. We report the first case of MET amplification in sarcomatoid MPM. MPMs from surgical pathology files (1989-2014) were reviewed. c-Met immunohistochemistry was performed. Staining intensity and distribution were multiplied (H-score). Staining localization (cytoplasmic and/or membranous) was noted. Fluorescence in situ hybridization was performed using probes for MET and centromere 7. One hundred forty-nine patients (median age, 68.0years; interquartile range, 61-75) had epithelioid (n=97), biphasic (n=18), or sarcomatoid (n=34) MPM. Median follow-up was 10.1months (range, 0.1-222.5). One hundred thirty patients died of disease; 2 were alive with disease. c-Met was expressed in 147 MPMs. c-Met staining intensity, distribution, and H-score differed among the histologic subtypes (P=.015; P=.0001, and P=.0005, respectively), but none were predictive of survival. Epithelioid subtype had greater c-Met expression. MET amplification was identified in 1 sarcomatoid MPM and MET duplication in 1 epithelioid MPM; both had poor outcomes. Chromosome 7 aneusomy was observed in 54 of 144 (37.5%) MPMs and associated with decreased overall survival in sarcomatoid MPMs (hazard ratio=2.81; 95% confidence interval, 1.21-6.51; P=.01). In conclusion, c-Met is expressed in MPM, with significant differences in expression among histologic subtypes. MET amplification is a rare event in MPM, making it an unlikely common pathogenesis for c-Met expression.

Restless legs syndrome (RLS), a common neurologic disorder, is more prevalent in women than in men. Evidence indicates the potential role of female hormones in the pathophysiology of RLS. However, few studies have examined the relationship between premenopausal bilateral oophorectomy (BSO) and the risk of RLS. The Mayo Clinic Cohort Study of Oophorectomy and Aging-2 (MOA-2) includes all women residents of Olmsted County, Minnesota, who underwent premenopausal BSO before the age of 50 years for a non-cancer reason between 1988 and 2007 (n=1,653). In addition, 1,653 age-matched (± 1 year) referent women who did not undergo BSO prior to index-date were included. Survival analyses were used to examine the association between BSO and risk of RLS (defined by DSM-IV criteria) after adjustments using inverse probability weighting. The median (IQR) age at index-date was 40.0 (40.0-47.0) years for the BSO and 40.0 (40.0-47.0) for the non-BSO cohorts. Women who underwent BSO before menopause had a higher risk of RLS (HR,1.47; 95% CI, 1.08-2.01). In addition, women who underwent BSO before 46 years (HR:1.53, 95% CI, 1.03-2.28) or received BSO without benign ovarian indications (e.g., cysts, endometriosis, HR: 1.69, 95% CI, 1.11-2.56) were at greater risk of RLS. Estrogen use after BSO did not affect the risk of RLS. Premenopausal women who underwent BSO had an increased risk of RLS, especially those younger than 46 years and without benign medical indication. Women considering BSO for ovarian cancer prevention should be informed of the increased risk of neurological disorder including RLS.

ObjectiveTo investigate whether aquaporin-4–immunoglobulin G (AQP4-IgG) titers and measures of complement-mediated cell killing are clinically useful to predict the occurrence of relapse, relapse severity, and/or disability in neuromyelitis optica spectrum disorder (NMOSD).MethodsWe studied 336 serial serum specimens from 82 AQP4-lgG–seropositive patients. NMOSD activity at blood draw was defined as preattack (24 [7.1%], drawn within 30 days preceding an attack), attack (108 [32.1%], drawn on attack onset or within 30 days after), or remission (199 [59.2%], drawn >90 days after attack onset and >30 days preceding a relapse). For each specimen, we documented the attack type and severity and immunotherapy status. Complement-mediated cell killing was quantitated by flow cytometry using an M23-AQP4 cell-based assay.ResultsThe estimated logarithmic means of AQP4-IgG titers in preattack, attack, and remission samples were 3.302, 3.657, and 3.458, respectively, p = 0.21. Analyses of 81 attack/remission pairs in 42 patients showed no significant titer differences (3.736 vs 3.472, p = 0.15). Analyses of 13 preattack/attack pairs in 9 patients showed no significant titer differences (3.994 vs 3.889, p = 0.67). Of 5 patients who converted to seronegative status, 2 continued to have attacks. Titers for major and minor attacks (n = 70) were not significantly different (3.905 vs 3.676, p = 0.47). Similarly, measures (titers) of complement-mediated cell killing were not significantly associated with disease course, attack severity, or disability at 5 years.Conclusions and relevanceAQP4-IgG titer and complement-mediated cell killing lack significant prognostic or predictive utility in NMOSD. Although titers may drop in the setting of immunotherapy, seroconversion to negative status does not preclude ongoing clinical attacks.Classification of evidenceThis study provides Class II evidence that in patients with NMOSD, AQP4-IgG titers and measures of complement-mediated cell killing activity do not predict relapses, relapse severity, or disability.

Key Points Question Do women who underwent bilateral salpingo-oophorectomy before menopause show greater medial temporal lobe structural changes, β-amyloid accumulation, and white matter lesion load on neuroimaging later in life compared with a control group? Findings In this case-control study, women with bilateral salpingo-oophorectomy before menopause had smaller amygdala volumes, thinner parahippocampal-entorhinal cortices, and lower entorhinal white matter fractional anisotropy values compared with control participants. Meaning Abrupt hormonal changes associated with bilateral salpingo-oophorectomy in premenopausal women may lead to medial temporal lobe structural abnormalities later in life; because alterations in structural imaging biomarkers of the medial temporal lobe neurodegeneration may precede clinical symptoms of dementia, longitudinal follow-up of this cohort with cognitive testing is necessary., This case-control study combines portions of 2 existing cohorts to investigate medial temporal lobe structure, white matter lesion load, and β-amyloid deposition in older women who underwent bilateral salpingo-oophorectomy before age 50 years and before reaching natural menopause, compared with a group of female control participants., Importance There is an increased risk of cognitive impairment or dementia in women who undergo bilateral salpingo-oophorectomy (BSO) before menopause. However, data are lacking on the association of BSO before menopause with imaging biomarkers that indicate medial temporal lobe neurodegeneration and Alzheimer disease pathophysiology. Objective To investigate medial temporal lobe structure, white matter lesion load, and β-amyloid deposition in women who underwent BSO before age 50 years and before reaching natural menopause. Design, Setting, and Participants This nested case-control study of women in the population-based Mayo Clinic Cohort Study of Oophorectomy and Aging-2 (MOA-2) and in the Mayo Clinic Study of Aging (MCSA) in Olmsted County, Minnesota, included women who underwent BSO from 1988 through 2007 and a control group from the intersection of the 2 cohorts. Women who underwent BSO and control participants who underwent a neuropsychological evaluation, magnetic resonance imaging (MRI), and Pittsburgh compound B positron emission tomography (PiB-PET) were included in the analysis. Data analysis was performed from November 2017 to August 2018. Exposure Bilateral salpingo-oophorectomy in premenopausal women who were younger than 50 years. Main Outcomes and Measures Cortical β-amyloid deposition on PiB-PET scan was calculated using the standard uptake value ratio. White matter hyperintensity volume and biomarkers for medial temporal lobe neurodegeneration (eg, amygdala volume, hippocampal volume, and parahippocampal-entorhinal cortical thickness) on structural MRI and entorhinal white matter fractional anisotropy on diffusion tensor MRI were also measured. Results Forty-one women who underwent BSO and 49 control participants were recruited. One woman was excluded from the BSO group after diagnosis of an ovarian malignant condition, and 6 women were excluded from the control group after undergoing BSO after enrollment. Twenty control participants and 23 women who had undergone BSO completed all examinations. The median (interquartile range [IQR]) age at imaging was 65 (62-68) years in the BSO group and 63 (60-66) years in the control group. Amygdala volume was smaller in the BSO group (median [IQR], 1.74 [1.59-1.91] cm3) than the control group (2.15 [2.05-2.37] cm3; P

Nursing home (NH) residency is an independent risk factor for venous thromboembolism (VTE), but the VTE burden within the NH population is uncertain. This study estimates VTE incidence and VTE-associated mortality among NH residents. We identified all NH residents in any NH in Olmsted County, Minnesota, United States, 1 October 1998 to 31 December 2005 and all first lifetime VTE among county residents to estimate VTE incidence while resident of local NHs (NHVTE), using Centers for Medicare and Medicaid Services Minimum Data Set and Rochester Epidemiology Project resources. We tested associations between NHVTE and age, sex and time since each NH admission using Poisson modelling. Additionally, we tested incident NHVTE as a potential predictor of survival using Cox proportional hazards, adjusting for age, sex and NH residency. Between 1 October 1998 and 31 December 2005, 3,465 Olmsted County residents with ≥1 admission to a local NH, contributed 4,762 NH stays. Of the 3,465 NH residents, 111 experienced incident NHVTE (2.3% of all eligible stays), for an overall rate of 3,653/100,000 NH person-years (NH-PY). VTE incidence was inversely associated with time since each NH admission, and was highest in the first 7 days after each NH admission (18,764/100,000 NH-PY). The adjusted hazard of death for incident NHVTE was 1.90 (95% confidence interval [CI]: 1.38–2.62). In conclusion, VTE incidence among NH residents was nearly 30-fold higher than published incidence rates for the general Olmsted County population. VTE incidence was highest within 7 days after NH admission, and NHVTE was associated with significantly reduced survival. These data can inform future research and construction of clinical trials regarding short-term prophylaxis.

OBJECTIVE: To determine the long-term risk of cardiovascular disease and metabolic conditions in women undergoing hysterectomy with bilateral ovarian conservation compared with age-matched referent women. METHODS: Using the Rochester Epidemiology Project records-linkage system, we identified 2,094 women who underwent hysterectomy with ovarian conservation for benign indications between 1980 and 2002 in Olmsted County, Minnesota. Each woman was age-matched (±1 year) to a referent woman residing in the same county who had not undergone prior hysterectomy or any oophorectomy. These two cohorts were followed historically to identify de novo cardiovascular or metabolic diagnoses. We estimated hazard ratios and 95% confidence intervals using Cox proportional hazards models adjusted for 20 pre-existing chronic conditions and other potential confounders. We also calculated absolute risk increases and reductions from Kaplan-Meier estimates. RESULTS: Over a median follow-up of 21.9 years, women who underwent hysterectomy experienced increased risks of de novo hyperlipidemia (HR 1.14; 95% CI 1.05-1.25), hypertension (HR 1.13; 95% CI 1.03-1.25), obesity (HR 1.18; 95% CI 1.04-1.35), cardiac arrhythmias (HR 1.17; 95% CI 1.05-1.32), and coronary artery disease (HR 1.33; 95% CI 1.12-1.58). Women who underwent hysterectomy at age ≤35 years had a 4.6-fold increased risk of congestive heart failure and a 2.5-fold risk of coronary artery disease. CONCLUSIONS: Even with ovarian conservation, hysterectomy is associated with an increased long-term risk of cardiovascular and metabolic conditions, especially in women who undergo hysterectomy at age ≤35 years. If these associations are causal, alternatives to hysterectomy should be considered to treat benign gynecologic conditions.

BACKGROUND AND OBJECTIVES: Premenopausal women who undergo bilateral oophorectomy are at a higher risk of morbidity and mortality. Given the potential benefits of estrogen on kidney function, we hypothesized that women who undergo bilateral oophorectomy are at higher risk of CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We performed a population-based cohort study of 1653 women residing in Olmsted County, Minnesota who underwent bilateral oophorectomy before age 50 years old and before the onset of menopause from 1988 to 2007. These women were matched by age (±1 year) to 1653 referent women who did not undergo oophorectomy. Women were followed over a median of 14 years to assess the incidence of CKD. CKD was primarily defined using eGFR (eGFR90 days apart). Hazard ratios were derived using Cox proportional hazards models, and absolute risk increases were derived using Kaplan–Meier curves at 20 years. All analyses were adjusted for 17 chronic conditions present at index date, race, education, body mass index, smoking, age, and calendar year. RESULTS: Women who underwent bilateral oophorectomy had a higher risk of eGFR-based CKD (211 events for oophorectomy and 131 for referent women; adjusted hazard ratio, 1.42; 95% confidence interval, 1.14 to 1.77; absolute risk increase, 6.6%). The risk was higher in women who underwent oophorectomy at age ≤45 years old (110 events for oophorectomy and 60 for referent women; adjusted hazard ratio, 1.59; 95% confidence interval, 1.15 to 2.19; absolute risk increase, 7.5%). CONCLUSIONS: Premenopausal women who undergo bilateral oophorectomy, particularly those ≤45 years old, are at higher risk of developing CKD, even after adjusting for multiple chronic conditions and other possible confounders present at index date. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2018_10_11_CJASNPodcast_18_1

Reduced monocyte HLA-DR expression and increased neutrophil CD64 expression have been proposed as biomarkers of infection. From 2009–2011, blood samples from neonatal intensive care unit (NICU) and pediatric intensive care unit (ICU) patients

Background Objective cost estimates and source of cost differences are needed across the spectrum of cognition, including cognitively normal (CN), mild cognitive impairment (MCI), newly discovered dementia, and prevalent dementia. Methods Subjects were a subset of the Mayo Clinic Study of Aging stratified-random sampling of Olmsted County, MN, residents aged 70 to 89 years. A neurologist reviewed provider-linked medical records to identify prevalent dementia (review date = index). Remaining subjects were invited to participate in prospective clinical/neuropsychological assessments; participants were categorized as CN, MCI, or newly discovered dementia (assessment date = index). Costs for medical services/procedures 1-year pre-index (excluding indirect and long-term care costs) were estimated using line-item provider-linked administrative data. We estimated contributions of care-delivery site and comorbid conditions (including and excluding neuropsychiatric diagnoses) to between-category cost differences. Results Annual mean medical costs for CN, MCI, newly discovered dementia, and prevalent dementia were $6042, $6784, $9431, $11,678, respectively. Hospital inpatient costs contributed 70% of total costs for prevalent dementia and accounted for differences between CN and both prevalent and newly discovered dementia. Ambulatory costs accounted for differences between CN and MCI. Age-, sex-, education-adjusted differences reached significance for CN versus newly discovered and prevalent dementia and for MCI versus prevalent dementia. After considering all comorbid diagnoses, between-category differences were reduced (e.g., prevalent dementia minus MCI (from $4842 to $3575); newly discovered dementia minus CN (from $3578 to $711)). Following the exclusion of neuropsychiatric diagnoses from comorbidity adjustment, between-category differences tended to revert to greater differences. Conclusions Cost estimates did not differ significantly between CN and MCI. Substantial differences between MCI and prevalent dementia reflected high inpatient costs for dementia and appear partly related to co-occurring mental disorders. Such comparisons can help inform models aimed at identifying where, when, and for which individuals proposed interventions might be cost-effective.

Background Cutaneous malignancy is associated with worse outcomes in patients with chronic lymphocytic leukemia (CLL). Objective We sought to identify the incidence and recurrence rate of nonmelanoma skin cancer (NMSC) in patients with non-Hodgkin lymphoma (NHL). Methods NMSC incidence was calculated and Cox proportional hazards models were used to evaluate associations with risk of recurrence for patients with NHL between 1976 and 2005 who were in the Rochester Epidemiology Project research infrastructure. Results We identified 282 patients with CLL or small lymphocytic lymphoma and 435 with non-CLL NHL. The incidence of basal cell carcinoma and squamous cell carcinoma was 1829.3 (95% confidence interval [CI] 1306.7-2491.1) and 2224.9 (95% CI 1645.9-2941.6), respectively, in patients with CLL. The cumulative recurrence rate at 8 years after treatment with Mohs micrographic surgery was 8.3% (95% CI 0.0%-22.7%) for basal cell carcinoma and 13.4% (95% CI 0.0%-25.5%) for squamous cell carcinoma in patients with CLL. Limitations This was a retrospective cohort study. Conclusions After Mohs micrographic surgery and standard excision of NMSC, patients with NHL had a skin cancer recurrence rate that was higher than expected. Careful treatment and monitoring of patients with NHL and NMSC are warranted.

PurposeThis cohort study was established to investigate the effects of unilateral and bilateral oophorectomy on the ageing processes in women.ParticipantsWe used the records-linkage system of the Rochester Epidemiology Project (REP,http://www.rochesterproject.org) to identify 570 women who underwent unilateral oophorectomy and 1653 women who underwent bilateral oophorectomy in Olmsted County, Minnesota from 1988 through 2007 (20 years). Each woman was matched by age (±1 year) to a population-based referent woman who had not undergone any oophorectomy (570 referent women) or bilateral oophorectomy (1653 referent women). These four cohorts are being followed to assess morbidity and mortality and to study imaging and biological markers related to ageing.Findings to dateAn extensive medical record abstraction using the REP has been completed for each woman to obtain demographic, reproductive and adult life characteristics and extensive clinical information about the surgical procedure and subsequent oestrogen replacement therapy (or other sex steroid therapy). The cohorts have been used to date to study the accumulation of multiple chronic conditions following bilateral oophorectomy in women with or without chronic conditions at the time of the oophorectomy (or index date). From the cohorts, we have also derived a sample of 128 pairs of women for a case–control study linking adverse childhood or adult experiences to the risk of bilateral oophorectomy.Future plansWe hypothesise that the abrupt hormonal changes caused by bilateral oophorectomy in younger women have a major effect on the ageing processes across the full body. Therefore, we plan to investigate the risk of a wide range of chronic conditions following bilateral oophorectomy. Specific studies are underway for kidney diseases, psychiatric diseases and neurological diseases. In addition, we plan to invite a subsample of women from the bilateral oophorectomy cohort to participate in an in-person study involving brain imaging and the collection of biomarkers.

Background The cause-effect relationship between bilateral oophorectomy and accelerated aging remains controversial. We conducted new analyses to further address this controversy. Methods The Rochester Epidemiology Project records-linkage system was used to identify all premenopausal women who underwent bilateral oophorectomy for a noncancerous condition before age 50 years between 1988 and 2007 in Olmsted County, MN. Each woman was randomly matched to a referent woman born in the same year (±1 year) who had not undergone bilateral oophorectomy. We studied the rate of accumulation of 18 common chronic conditions over a median of approximately 14 years of follow-up (historical cohort study). Analyses were restricted to women free of any of the 18 chronic conditions at the time of oophorectomy (or index date). Results After adjustments for race/ethnicity, education, body mass index, smoking, and age and calendar year at the index date, women who underwent oophorectomy before age 46 years experienced an accelerated rate of accumulation of the 18 chronic conditions considered together (hazard ratio = 1.24; 95% confidence interval: 1.12, 1.37; p < .001). The single-year incidence rate of new conditions was most different in the first 6 years after oophorectomy but the difference attenuated thereafter. Findings did not vary by surgical indication for the oophorectomy. Conclusions Bilateral oophorectomy is associated with a higher risk of multimorbidity among women who did not have any of the 18 selected conditions at baseline. The association did not vary by surgical indication for oophorectomy. Our findings suggest that bilateral oophorectomy is causally linked to accelerated aging.

BACKGROUND Nursing home (NH) residents are at increased risk for both VTE and bleeding from pharmacologic prophylaxis. Construction of prophylaxis guidelines is hampered by NH-specific limitations with VTE case identification and characterization of risk. We addressed these limitations by merging detailed provider-linked Rochester Epidemiology Project (REP) medical records with Centers for Medicare and Medicaid Services Minimum Data Set (MDS) NH assessments. METHODS This population-based nested case-control study identified all Olmsted County, Minnesota, residents with first-lifetime VTE October 1, 1998, through December 31, 2005, while a resident of an NH (N = 91) and one to two age-, sex-, and calendar year-matched NH non-VTE control subjects. For each NH case without hospitalization 3 months before VTE (n = 23), we additionally identified three to four nonhospitalized NH control subjects. REP and MDS records were reviewed before index date (VTE date for cases; respective REP encounter date for control subjects) for numerous characteristics previously associated with VTE in non-NH populations. Data were modeled using conditional logistic regression. RESULTS The multivariate model consisting of all cases and control subjects identified only three characteristics independently associated with VTE: respiratory infection vs no infection (OR, 5.9; 95% CI, 2.6-13.1), extensive or total assistance with walking in room (5.6, 2.5-12.6), and general surgery (3.3, 1.0-10.8). In analyses limited to nonhospitalized cases and control subjects, only nonrespiratory infection vs no infection was independently associated with VTE (8.8, 2.7-29.2). CONCLUSIONS Contrary to previous assumptions, most VTE risk factors identified in non-NH populations do not apply to the NH population. NH residents with infection, substantial mobility limitations, or recent general surgery should be considered potential candidates for VTE prophylaxis.

Purpose: Clustering of neural autoantibodies in patients with paraneoplastic neurologic disorders may predict tumor type. A mathematical analysis of neural autoantibody clusters was performed in 78,889 patients undergoing evaluation for a suspected paraneoplastic autoimmune neurologic disorder. Tumor predictive autoantibody profiles were confirmed in sera from patients with histologically proven tonsillar cancer, thymoma, and lung cancer. Patients and Methods: Of note, 78,889 patient sera were tested for 15 defined neural autoantibodies (1.2 million tests). The observed and hypothesized frequencies of autoantibody clusters were compared and their tumor associations defined. A tumor validation study comprised serum from 368 patients with a variety of tumors (thymoma, lung, or tonsil). Results: Informative oncological associations included (i) thymoma in 85% of patients with muscle striational, acetylcholine receptor antibodies plus CRMP5 autoantibodies; (ii) lung carcinoma in 80% with both P/Q-type and N-type calcium channel antibodies plus SOX1-IgG; and (iii) in men, prostate carcinoma frequency more than doubled when striational and muscle AChR specificities were accompanied by ganglionic AChR antibody. In women, amphiphysin-IgG alone was associated commonly with breast carcinoma, but amphiphysin-IgG, coexisting with antineuronal nuclear autoantibody-type 1 or CRMP5-IgG, was associated with lung cancer (P < 0.0001). In the validation cohorts, many tumor-associated profiles were encountered that matched the clusters identified in the screening study (e.g., 15% of thymoma patients had striational, acetylcholine receptor antibodies plus collapsin response-mediator protein-5 autoantibodies). Conclusions: Neural autoantibodies commonly coexist in specific clusters that are identifiable by comprehensive screening. Signature autoantibody clusters may predict a patient's cancer risk and type. Clin Cancer Res; 20(14); 3862–9. ©2014 AACR.