Publications by authors named "Carin Y Smith"

42 Publications

Risk of de novo severe carpal tunnel syndrome after bilateral oophorectomy: a population-based cohort study.

Menopause 2021 May 24;28(9):1026-1036. Epub 2021 May 24.

Women's Health Research Center, Mayo Clinic, Rochester, MN.

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, MN. 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 (nonsignificant 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.
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http://dx.doi.org/10.1097/GME.0000000000001804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8403136PMC
May 2021

Coronary Heart Disease Risk Associated with Primary Isolated Hypertriglyceridemia; a Population-Based Study.

J Am Heart Assoc 2021 06 25;10(11):e019343. Epub 2021 May 25.

Department of Cardiovascular Medicine Mayo Clinic Rochester MN.

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 <150 mg/dL. There were 3329 individuals with elevated triglyceride levels; after excluding those with concomitant hypercholesterolemia, a secondary cause of high triglycerides, age <18 years or an incomplete record, 517 patients (49.4±14.0 years, 72.0% men) had PIH (triglyceride 627.6±183.6 mg/dL). The age- and sex-adjusted prevalence of PIH in adults was 0.80% (0.72-0.87); the diagnosis was recorded in 60%, 46% were on a lipid-lowering medication for primary prevention and a triglyceride level <150 mg/dL was achieved in 24.1%. The association of PIH with coronary heart disease was attenuated but remained significant after adjustment for demographic, socioeconomic, and conventional cardiovascular risk factors (hazard ratio [HR], 1.53; 95% CI, 1.06-2.20; = 0.022). There was no statistically significant association between PIH and cerebrovascular disease (HR, 1.06; 95% CI, 0.65-1.73, = 0.813), peripheral artery disease (HR, 1.27; 95% CI, 0.43-3.75; = 0.668), or the composite end point of all 3 (HR, 1.28; 95% CI, 0.92-1.80; =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.
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http://dx.doi.org/10.1161/JAHA.120.019343DOI Listing
June 2021

Pneumococcal serotype-specific cut-offs based on antibody responses to pneumococcal polysaccharide vaccination in healthy adults.

Vaccine 2021 05 22;39(21):2850-2856. Epub 2021 Apr 22.

Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH, USA. Electronic address:

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-naïve 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.
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http://dx.doi.org/10.1016/j.vaccine.2021.04.015DOI Listing
May 2021

Survival outcomes in locally advanced cutaneous squamous cell carcinoma presenting with clinical perineural invasion alone.

Head Neck 2021 07 28;43(7):1995-2001. Epub 2021 Feb 28.

Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota, USA.

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.
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http://dx.doi.org/10.1002/hed.26661DOI Listing
July 2021

Association of Premenopausal Bilateral Oophorectomy With Restless Legs Syndrome.

JAMA Netw Open 2021 02 1;4(2):e2036058. Epub 2021 Feb 1.

Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota.

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 < .001), were more likely to have obesity (576 women [34.8%] vs 442 women [27.1%]; overall P < .001), and were more likely to have a history of anemia of any type (573 women [34.7%] vs 225 women [13.6%]; P < .001), iron deficiency anemia (347 women [21.0%] vs 135 women [8.2%]; P < .001), and restless legs syndrome before the index date (32 women [1.9%] vs 14 women [0.8%]; P = .008). Women who underwent bilateral oophorectomy prior to natural menopause had a higher risk of restless legs syndrome after the index date compared with women in the reference group (120 diagnoses vs 74 diagnoses), with an adjusted hazard ratio (HR) of 1.44 (95% CI, 1.08-1.92; P = .01). After stratification by indication for the bilateral oophorectomy, there was an increased risk of restless legs syndrome among women without a benign ovarian condition (HR, 1.52; 95% CI, 1.03-2.25; P = .04) but not among women with a benign condition (HR, 1.25; 95% CI, 0.80-1.96; P = .34). Treatment with estrogen therapy through the age of 46 years in women who underwent bilateral oophorectomy at younger ages was not associated with a difference in risk.

Conclusions And Relevance: This cohort study found that risk of restless legs syndrome was increased among women who underwent bilateral oophorectomy prior to menopause, especially those without a benign ovarian indication.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.36058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851733PMC
February 2021

Reproductive history and progressive multiple sclerosis risk in women.

Brain Commun 2020 17;2(2):fcaa185. Epub 2020 Nov 17.

Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA.

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 ( = 233). Menarche age was similar between multiple sclerosis and control females ( = 0.306). Females with multiple sclerosis had fewer full-term pregnancies than the controls ( < 0.001). Non-natural menopause was more common in multiple sclerosis (40.7%) than in controls (30.1%) ( = 0.030). Age at natural menopause was similar between multiple sclerosis (median, interquartile range: 50 years, 48-52) and controls (median, interquartile range: 51 years, 49-53) ( = 0.476). Nulliparous females had earlier age at progressive multiple sclerosis onset (mean ± standard deviation: 41.9 ± 12.5 years) than females with ≥1 full-term pregnancies (mean ± standard deviation: 47.1 ± 9.7 years) ( = 0.069) with a pregnancy-dose effect [para 0 (mean ± standard deviation: 41.9 ± 12.5 years), para 1-3 (mean ± standard deviation: 46.4 ± 9.2 years), para ≥4 (mean ± standard deviation: 52.6 ± 12.9 years) ( = 0.005)]. Menopause age was associated with progressive multiple sclerosis onset age (  = 0.359,  < 0.001). Duration from onset of relapses to onset of progressive multiple sclerosis was shorter for females with premature/early menopause ( = 26; mean ± standard deviation: 12.9 ± 9.0 years) than for females with normal menopause age ( = 39; mean ± standard deviation: 17.8 ± 10.3 years) but was longer than for males (mean  ±standard deviation: 10.0 ± 9.4 years) ( = 0.005). There was a pregnancy-dose effect of age at expanded disability status scale 6 (para 0: 43.0 ± 13.2 years, para 1-3: 51.7 ± 11.3 years, para ≥4: 53.5 ± 4.9 years) ( = 0.013). Age at menopause was associated with age at expanded disability status scale 6 (  = 0.229,  < 0.003). Premature/early menopause or nulliparity was associated with earlier onset of progressive multiple sclerosis with a 'dose effect' of pregnancies on delaying progressive multiple sclerosis and severe disability. Although causality remains uncertain, our results suggest a beneficial impact of oestrogen in delaying progressive multiple sclerosis. If confirmed in prospective studies, our findings have implications for counselling women with multiple sclerosis about pregnancy, surgical menopause and menopausal hormone therapy.
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http://dx.doi.org/10.1093/braincomms/fcaa185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772117PMC
November 2020

Salvage Therapy With Multikinase Inhibitors and Immunotherapy in Advanced Adrenal Cortical Carcinoma.

J Endocr Soc 2020 Jul 9;4(7):bvaa069. Epub 2020 Jun 9.

Division of Medical Oncology, Mayo Clinic, Rochester, MN, US.

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.
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http://dx.doi.org/10.1210/jendso/bvaa069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326479PMC
July 2020

Mental health conditions diagnosed before bilateral oophorectomy: a population-based case-control study.

Menopause 2019 12;26(12):1395-1404

Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, MN.

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 < 0.001).

Conclusions: We identified several mental health conditions that were associated with bilateral oophorectomy for nonmalignant indications. Awareness of these associations may guide women and physicians in future decision-making and limit unindicated bilateral oophorectomies. VIDEO SUMMARY:: http://links.lww.com/MENO/A458.
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http://dx.doi.org/10.1097/GME.0000000000001413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893116PMC
December 2019

Long-term risk of de novo mental health conditions after hysterectomy with ovarian conservation: a cohort study.

Menopause 2020 01;27(1):33-42

Department of Surgery, Mayo Clinic, Rochester, MN.

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.
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http://dx.doi.org/10.1097/GME.0000000000001415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7089568PMC
January 2020

Association of Bilateral Salpingo-Oophorectomy Before Menopause Onset With Medial Temporal Lobe Neurodegeneration.

JAMA Neurol 2019 01;76(1):95-100

Department of Radiology, Mayo Clinic, Rochester, Minnesota.

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 < .001). The parahippocampal-entorhinal cortex was thinner in the BSO group (median [IQR], 3.91 [3.64-4.00] mm) than the control group (3.97 [3.89-4.28] mm; P = .046). Entorhinal white matter fractional anisotropy was lower in the BSO group (median [IQR], 0.19 [0.18-0.22]) than the control group (0.22 [0.20-0.23]; P = .03). Women were treated with estrogen in both groups (BSO, n = 22 of 23 [96%]; control, n = 10 of 19 [53%]). Global cognitive status test results did not differ between the groups.

Conclusions And Relevance: Abrupt hormonal changes associated with BSO in premenopausal women may lead to medial temporal lobe structural abnormalities later in life. Longitudinal evaluation is needed to determine whether cognitive decline follows.
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http://dx.doi.org/10.1001/jamaneurol.2018.3057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439881PMC
January 2019

Personal, reproductive, and familial characteristics associated with bilateral oophorectomy in premenopausal women: A population-based case-control study.

Maturitas 2018 Nov 14;117:64-77. Epub 2018 Sep 14.

Women's Health Research Center, Mayo Clinic, Rochester, MN, United States; Department of Surgery, Mayo Clinic, Rochester, MN, United States.

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.
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http://dx.doi.org/10.1016/j.maturitas.2018.09.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6231412PMC
November 2018

Loss of Ovarian Hormones and Accelerated Somatic and Mental Aging.

Physiology (Bethesda) 2018 11;33(6):374-383

Women's Health Research Center, Mayo Clinic , Rochester, Minnesota.

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.
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http://dx.doi.org/10.1152/physiol.00024.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6734081PMC
November 2018

In Reply.

Menopause 2019 01;26(1):112-114

Division of Gynecology, Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, MN Division of Biostatistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, MN Department of Health Sciences Research and Department of Neurology, Mayo Clinic, Rochester, MN.

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http://dx.doi.org/10.1097/GME.0000000000001242DOI Listing
January 2019

CKD in Patients with Bilateral Oophorectomy.

Clin J Am Soc Nephrol 2018 11 19;13(11):1649-1658. Epub 2018 Sep 19.

Epidemiology, Department of Health Sciences Research, and

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 (eGFR<60 ml/min per 1.73 m on two occasions >90 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.
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http://dx.doi.org/10.2215/CJN.03990318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6237067PMC
November 2018

Reference Values for Mid-Ascending Aorta Diameters by Transthoracic Echocardiography in Adults.

Am J Cardiol 2018 09 27;122(6):1068-1073. Epub 2018 Jun 27.

Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota. Electronic address:

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; p <0.001). 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.
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http://dx.doi.org/10.1016/j.amjcard.2018.06.006DOI Listing
September 2018

Venous Thromboembolism (VTE) Incidence and VTE-Associated Survival among Olmsted County Residents of Local Nursing Homes.

Thromb Haemost 2018 Jul 2;118(7):1316-1328. Epub 2018 Jul 2.

Division of Epidemiology, Department of Health Sciences Research, College of Medicine, Mayo Clinic, Rochester, Minnesota, United States.

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.
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http://dx.doi.org/10.1055/s-0038-1660436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6206861PMC
July 2018

Autoimmune encephalitis epidemiology and a comparison to infectious encephalitis.

Ann Neurol 2018 01;83(1):166-177

Departments of Neurology.

Objective: To evaluate the incidence and prevalence of autoimmune encephalitis and compare it to that of infectious encephalitis.

Methods: We performed a population-based comparative study of the incidence and prevalence of autoimmune and infectious encephalitis in Olmsted County, Minnesota. Autoimmune encephalitis diagnosis and subgroups were defined by 2016 diagnostic criteria, and infectious encephalitis diagnosis required a confirmed infectious pathogen. Age- and sex-adjusted prevalence and incidence rates were calculated. Patients with encephalitis of uncertain etiology were excluded.

Results: The prevalence of autoimmune encephalitis on January 1, 2014 of 13.7/100,000 was not significantly different from that of all infectious encephalitides (11.6/100,000; p = 0.63) or the viral subcategory (8.3/100,000; p = 0.17). The incidence rates (1995-2015) of autoimmune and infectious encephalitis were 0.8/100,000 and 1.0/100,000 person-years, respectively (p = 0.58). The number of relapses or recurrent hospitalizations was higher for autoimmune than infectious encephalitis (p = 0.03). The incidence of autoimmune encephalitis increased over time from 0.4/100,000 person-years (1995-2005) to 1.2/100,000 person-years (2006-2015; p = 0.02), attributable to increased detection of autoantibody-positive cases. The incidence (2.8 vs 0.7/100,000 person-years, p = 0.01) and prevalence (38.3 vs 13.7/100,000, p = 0.04) of autoimmune encephalitis was higher among African Americans than Caucasians. The prevalence of specific neural autoantibodies was as follows: myelin oligodendrocyte glycoprotein, 1.9/100,000; glutamic acid decarboxylase 65, 1.9/100,000; unclassified neural autoantibody, 1.4/100,000; leucine-rich glioma-inactivated protein 1, 0.7/100,000; collapsin response-mediator protein 5, 0.7/100,000; N-methyl-D-aspartate receptor, 0.6/100,000; antineuronal nuclear antibody type 2, 0.6/100,000; and glial fibrillary acidic protein α, 0.6/100,000.

Interpretation: This study shows that the prevalence and incidence of autoimmune encephalitis are comparable to infectious encephalitis, and its detection is increasing over time. Ann Neurol 2018;83:166-177.
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http://dx.doi.org/10.1002/ana.25131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6011827PMC
January 2018

Cardiovascular and metabolic morbidity after hysterectomy with ovarian conservation: a cohort study.

Menopause 2018 05;25(5):483-492

Department of Surgery, Mayo Clinic, Rochester, MN.

Objective: The aim of the study was 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 y) 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 (HRs) and 95% CIs using Cox proportional hazards models adjusted for 20 preexisting 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 increased 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.
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http://dx.doi.org/10.1097/GME.0000000000001043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5898981PMC
May 2018

Cohort profile: the Mayo Clinic Cohort Study of Oophorectomy and Aging-2 (MOA-2) in Olmsted County, Minnesota (USA).

BMJ Open 2017 Nov 20;7(11):e018861. Epub 2017 Nov 20.

Women's Health Research Center, Mayo Clinic, Rochester, Minnesota, USA.

Purpose: This cohort study was established to investigate the effects of unilateral and bilateral oophorectomy on the ageing processes in women.

Participants: We 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 Date: An 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 Plans: We 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.
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http://dx.doi.org/10.1136/bmjopen-2017-018861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5719295PMC
November 2017

Nursing Home Use Across The Spectrum of Cognitive Decline: Merging Mayo Clinic Study of Aging With CMS MDS Assessments.

J Am Geriatr Soc 2017 Oct 11;65(10):2235-2243. Epub 2017 Sep 11.

Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota.

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.
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http://dx.doi.org/10.1111/jgs.15022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5657551PMC
October 2017

Adverse childhood experiences and adult abuse are predictors of hysterectomy and oophorectomy.

Maturitas 2017 12 3;106:95-96. Epub 2017 Aug 3.

Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA; Department of Neurology, Mayo Clinic, Rochester, MN, USA; Women's Health Research Center, Mayo Clinic, Rochester, MN, USA. Electronic address:

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http://dx.doi.org/10.1016/j.maturitas.2017.08.001DOI Listing
December 2017

Adverse childhood or adult experiences and risk of bilateral oophorectomy: a population-based case-control study.

BMJ Open 2017 06 7;7(5):e016045. Epub 2017 Jun 7.

Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA.

Objectives: Bilateral oophorectomy has commonly been performed in conjunction with hysterectomy even in women without a clear ovarian indication; however, oophorectomy may have long-term deleterious consequences. To better understand this surgical practice from the woman's perspective, we studied the possible association of adverse childhood or adult experiences with the subsequent occurrence of bilateral oophorectomy.

Design: Population-based case-control study.

Setting: Olmsted County, Minnesota (USA).

Participants: From an established population-based cohort study, we sampled 128 women who underwent bilateral oophorectomy before age 46 years for a non-cancerous condition in 1988-2007 (cases) and 128 age-matched controls (±1 year).

Methods: Information about adverse experiences was abstracted from the medical records dating back to age 15 years or earlier archived in the Rochester Epidemiology Project (REP) records-linkage system. Adverse childhood experiences were summarised using the Adverse Childhood Experience (ACE) score.

Results: We observed an association of bilateral oophorectomy performed before age 46 years with verbal or emotional abuse, physical abuse, any abuse, substance abuse in the household, and with an ACE score ≥1 experienced before age 19 years (OR=3.23; 95% CI 1.73 to 6.02; p<0.001). In women who underwent the oophorectomy before age 40 years, we also observed a strong association with physical abuse experienced during adulthood (OR=4.33; 95% CI 1.23 to 15.21; p=0.02). Several of the associations were higher in women who underwent oophorectomy at a younger age (<40 years) and in women without an ovarian indication for the surgery. None of the psychosocial or medical variables explored as potential confounders or intervening variables changed the results noticeably.

Conclusions: Women who suffered adverse childhood experiences or adult abuse are at increased risk of undergoing bilateral oophorectomy before menopause. We suggest that the association may be explained by a series of biological, emotional, and psychodynamic mechanisms.
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http://dx.doi.org/10.1136/bmjopen-2017-016045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5623400PMC
June 2017

Bilateral Oophorectomy and Accelerated Aging: Cause or Effect?

J Gerontol A Biol Sci Med Sci 2017 Sep;72(9):1213-1217

Women's Health Research Center.

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.
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http://dx.doi.org/10.1093/gerona/glx026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5777385PMC
September 2017

Expression of PD-1 and PD-L1 in Anaplastic Thyroid Cancer Patients Treated With Multimodal Therapy: Results From a Retrospective Study.

J Clin Endocrinol Metab 2017 06;102(6):1943-1950

Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota 55905.

Context: Anaplastic thyroid cancer (ATC) is rare and a highly fatal malignancy. The role of programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) as prognostic and/or predictive markers in ATC is unknown.

Objective: Multimodal therapy offers the best chance at tumor control. The objective of this study was to detect potential associations of PD-1/PD-L1 axis variables with outcome data in ATC.

Design: Retrospective study of a uniformly treated cohort.

Setting: Single institution retrospective cohort study.

Patients Or Other Participants: Sixteen patients who received intensity-modulated radiation therapy (15 had preceding surgery) were studied.

Main Outcome Measure: Patients treated with multimodal therapy were followed and assessed for overall survival (OS) and progression-free survival (PFS).

Results: All samples demonstrated PD-1 expression in inflammatory cells whereas tumor cells were primarily negative. PD-L1 was expressed on ATC tumor cells in most samples and showed mainly membranous staining. High PD-1 expression (>40% staining) in inflammatory cells was associated with worse overall survival (OS; hazard ratio, 3.36; 95% confidence interval, 1.00 to 12.96; P < 0.05) and trended toward worse PFS, whereas high PD-L1 expression in tumor cells (>33% staining) trended toward worse PFS and OS.

Conclusion: PD-1/PD-L1 pathway proteins are highly expressed in ATC tumor samples and appear to represent predictive markers of PFS and OS in multimodality-treated ATC patients.
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http://dx.doi.org/10.1210/jc.2016-3756DOI Listing
June 2017

Accelerated Accumulation of Multimorbidity After Bilateral Oophorectomy: A Population-Based Cohort Study.

Mayo Clin Proc 2016 Nov 29;91(11):1577-1589. Epub 2016 Sep 29.

Women's Health Research Center, Mayo Clinic, Rochester, MN; Department of Surgery, Mayo Clinic, Rochester, MN.

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 an increased risk of subsequent multimorbidity. 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<.001). Several of these associations were reduced in women who received estrogen therapy.

Conclusion: Bilateral oophorectomy is associated with a higher risk of multimorbidity, even after adjustment for conditions present at baseline and for several possible confounders. However, several of these associations were reduced in women who received estrogen therapy.
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http://dx.doi.org/10.1016/j.mayocp.2016.08.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5097693PMC
November 2016

c-Met expression and MET amplification in malignant pleural mesothelioma.

Ann Diagn Pathol 2016 Aug 30;23:1-7. Epub 2016 Apr 30.

Department of Laboratory Medicine and Pathology, Rochester, MN, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.anndiagpath.2016.04.007DOI Listing
August 2016

Diagnostic accuracy and clinical relevance of an inflammatory biomarker panel for sepsis in adult critically ill patients.

Diagn Microbiol Infect Dis 2016 Feb 9;84(2):175-80. Epub 2015 Oct 9.

Cellular and Molecular Immunology Laboratory, Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN. Electronic address:

The objective of this study was to assess the diagnostic accuracy of C-reactive protein (CRP), procalcitonin (PCT), and cellular immune markers levels in sepsis. This was a prospective observational study in adult intensive care unit (ICU) patients, between 2012 and 2014. The 8-color flow cytometric biomarker panel included CD64, CD163, and HLA-DR. Index test results were compared with sepsis, using receiver operating characteristic curve analyses. Multivariate logistic regression assessed the relationship of sets of markers with the probability of sepsis. Of 219 enrolled patients, 120 had sepsis. C-statistic was the highest for CRP (0.86) followed by neutrophil CD64 expression (0.83), procalcitonin (0.82), and Acute Physiology and Chronic Health Evaluation (APACHE) IV (0.72). After adjustment for APACHE IV, the combination of CRP, PCT, and neutrophil CD64 measure remained a significant predictor of sepsis with an excellent AUC (0.90). In a targeted ICU population at increased risk of sepsis, CRP, PCT, and neutrophil CD64 combined improve the diagnostic accuracy of sepsis.
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http://dx.doi.org/10.1016/j.diagmicrobio.2015.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4716883PMC
February 2016

Trends in Coronary Atherosclerosis: A Tale of Two Population Subgroups.

Am J Med 2016 Mar 6;129(3):307-14. Epub 2015 Nov 6.

Department of Health Sciences Research, Mayo Clinic, Rochester, Minn. Electronic address:

Background: We previously investigated trends in subclinical coronary artery disease and associated risk factors among autopsied non-elderly adults who died from nonnatural causes. Although grade of atherosclerosis declined from 1981 through 2009, the trend was nonlinear, ending in 1995, concurrent with increasing obesity/diabetes in this population. The previous study used linear regression and examined trends for all 4 major epicardial coronary arteries combined. The present investigation of coronary artery disease trends for the period 1995 through 2012 was prompted by a desire for more detailed examination of more recent coronary artery disease trends in light of reports that the epidemics of obesity and diabetes have slowed and are perhaps ending.

Methods: This population-based series of cross-sectional investigations identified all Olmsted County, Minnesota residents aged 16-64 years who died 1995 through 2012 (N = 2931). For decedents with nonnatural manner of death, pathology reports were reviewed for grade of atherosclerosis assigned each major epicardial coronary artery. Using logistic regression, we estimated calendar-year trends in grade (unadjusted and age- and sex-adjusted) for each artery, initially as an ordinal measure (range, 0-4); then, based on evidence of nonproportional odds, as a dichotomous variable (any atherosclerosis, yes/no) and as an ordinal measure for persons with atherosclerosis (range, 1-4).

Results: Of 474 nonnatural deaths, 453 (96%) were autopsied; 426 (90%) had coronary stenosis graded. In the ordinal-logistic model for trends in coronary artery disease grade (range, 0-4), the proportional odds assumption did not hold. In subsequent analysis as a dichotomous outcome (grades 0 vs 1-4), each artery exhibited a significant temporal decline in the proportion with any atherosclerosis. Conversely, for subjects with coronary artery disease grade 1-4, age- and sex-adjusted ordinal regression revealed no change over time in 2 arteries and statistically significant temporal increases in severity in 2 arteries.

Conclusions: Findings suggest that efforts to prevent coronary artery disease onset have been relatively successful. However, statistically significant increases in the grade of atherosclerosis in 2 arteries among persons with coronary artery disease may be indicative of a major public health challenge.
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http://dx.doi.org/10.1016/j.amjmed.2015.10.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4755914PMC
March 2016

Monocyte HLA-DR expression and neutrophil CD64 expression as biomarkers of infection in critically ill neonates and infants.

Pediatr Res 2015 Dec 31;78(6):683-90. Epub 2015 Aug 31.

Division of Pediatric Infectious Diseases, Mayo Clinic, Rochester, Minnesota.

Background: Reduced monocyte HLA-DR expression and increased neutrophil CD64 expression have been proposed as biomarkers of infection.

Methods: From 2009-2011, blood samples from neonatal intensive care unit (NICU) and pediatric intensive care unit (ICU) patients <1 y of age were collected at enrollment and during subsequent evaluation for suspected infection, if it occurred. Samples were analyzed for monocyte HLA-DR and neutrophil CD64 expression levels by flow cytometry.

Results: Forty-seven infants had study samples collected at enrollment; 26 infants had study samples collected at the time of a suspected infection. At enrollment, there was an inverse relationship between neutrophil CD64 expression and age (P ≤ 0.047). At the time of suspected infection, infants with an infection demonstrated a lower percentage of HLA-DR+ monocytes (P = 0.02, area under the curve (AUC) 0.78), higher percentage of CD64+ neutrophils (P = 0.009, AUC 0.81), and higher neutrophil CD64 expression levels (P = 0.04, AUC 0.75).

Conclusion: Monocyte HLA-DR and neutrophil CD64 expression in critically ill infants are related to age and infection.
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http://dx.doi.org/10.1038/pr.2015.164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4689644PMC
December 2015

Monocyte HLA-DR expression and neutrophil CD64 expression as biomarkers of infection in critically ill neonates and infants.

Pediatr Res 2015 Dec 31;78(6):683-90. Epub 2015 Aug 31.

Division of Pediatric Infectious Diseases, Mayo Clinic, Rochester, Minnesota.

Background: Reduced monocyte HLA-DR expression and increased neutrophil CD64 expression have been proposed as biomarkers of infection.

Methods: From 2009-2011, blood samples from neonatal intensive care unit (NICU) and pediatric intensive care unit (ICU) patients <1 y of age were collected at enrollment and during subsequent evaluation for suspected infection, if it occurred. Samples were analyzed for monocyte HLA-DR and neutrophil CD64 expression levels by flow cytometry.

Results: Forty-seven infants had study samples collected at enrollment; 26 infants had study samples collected at the time of a suspected infection. At enrollment, there was an inverse relationship between neutrophil CD64 expression and age (P ≤ 0.047). At the time of suspected infection, infants with an infection demonstrated a lower percentage of HLA-DR+ monocytes (P = 0.02, area under the curve (AUC) 0.78), higher percentage of CD64+ neutrophils (P = 0.009, AUC 0.81), and higher neutrophil CD64 expression levels (P = 0.04, AUC 0.75).

Conclusion: Monocyte HLA-DR and neutrophil CD64 expression in critically ill infants are related to age and infection.
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http://dx.doi.org/10.1038/pr.2015.164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4689644PMC
December 2015
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