Atkinson, Elizabeth J.

Abstract Background: Primary sclerosing cholangitis (PSC) is a rare, chronic cholestatic liver disease that often progresses to end-stage liver disease and/or the development of hepatobiliary neoplasia. Lack of prognostic tools and treatment options for PSC is driven in part by our poor understanding of its pathogenesis, which is thought to be complex, the interaction of genetic variants, environmental influences and biological response throughout the course of disease. The PSC Scientific Community Resource (PSC-SCR) seeks to overcome previous shortcomings by facilitating novel research in PSC with the ultimate goals of individualizing patient care and improving patient outcomes.Methods: PSC patients who receive their health care at Mayo Clinic or a collaborating site are identified by chart review and invited in person or by mail to participate. Non-Mayo patients are offered enrollment if they provide sufficient access to their medical records to evaluate inclusion/exclusion criteria. Controls without liver disease are identified with assistance of the Mayo Clinic Biobank. Participant consent is obtained at the beginning of the recruitment process by mail-in, electronic or face-to-face protocols. Clinical data is extracted from the medical record by qualified physicians and entered in a custom designed database. Participants fill out a custom-designed, comprehensive questionnaire, which collects scientifically relevant demographic and clinical information. Biospecimens are collected using mail-in kitsthar are returned via overnight carrier service and processed by the biospecimen accessioning and processing facility at Mayo Clinic, which coordinates sample transfers and provides required sample preparation services.The resource is currently being utilized to perform omics-scale projects investigating the exposome, metabolome, methylome, immunome and microbiome in PSC. Datasets and residual biospecimens will be shared with researchers proposing scientifically sound PSC-focused research with approval of the appropriate review boards.Discussion:Patient-based studies leveraging the latest technologies for targeted and wide-scale interrogation of multiple omics layers offer promise to accelerate PSC research through discovery of unappreciated aspects of disease pathogenesis. However, the rarity of PSC severely limits such studies. Here we describe our effort to overcome this limitation, the PSC-SCR, a repository of patient biospecimens coupled with clinical and omics data for use by the broader PSC research community.

Abstract Context While adrenal adenomas have been linked with cardiovascular morbidity in convenience samples of patients from specialized referral centers, large-scale population-based data are lacking. Objective To determine the prevalence and incidence of cardiometabolic disease and assess mortality in a population-based cohort of patients with adrenal adenomas. Design Population-based cohort study. Setting Olmsted County, Minnesota, USA. Patients Patients diagnosed with adrenal adenomas without overt hormone excess and age- and sex-matched referent subjects without adrenal adenomas. Main outcome measure Prevalence, incidence of cardiometabolic outcomes, mortality. Results (Adrenal adenomas were diagnosed in 1004 patients (58% women, median age 63 years) from 1/01/1995 to 12/31/2017. At baseline, patients with adrenal adenomas were more likely to have hypertension [adjusted odds ratio (aOR) 1.96, 95% CI 1.58-2.44], dysglycemia (aOR 1.63, 95% CI 1.33-2.00), peripheral vascular disease (aOR 1.59, 95% CI 1.32-2.06), heart failure (aOR 1.64, 95% CI 1.15-2.33), and myocardial infarction (aOR 1.50, 95% CI 1.02-2.22) compared to referent subjects. During median follow-up of 6.8 years, patients with adrenal adenomas were more likely than referent subjects to develop de novo chronic kidney disease [adjusted hazard ratio (aHR) 1.46, 95% CI 1.14-1.86], cardiac arrhythmia (aHR 1.31, 95% CI 1.08-1.58), peripheral vascular disease (aHR 1.28, 95% CI 1.05-1.55), cardiovascular events (aHR 1.33, 95% CI 1.01-1.73), and venous thromboembolic events (aHR 2.15, 95% CI 1.48-3.13). Adjusted mortality was similar between the 2 groups. Conclusion Adrenal adenomas are associated with an increased prevalence and incidence of adverse cardiometabolic outcomes in a population-based cohort.

Abstract Cellular senescence has emerged as a significant and potentially tractable mechanism of aging and multiple aging‐related conditions. Biomarkers of senescent cell burden, including molecular signals in circulating immune cells and the abundance of circulating senescence‐related proteins, have been associated with chronological age and clinical parameters of biological age in humans. The extent to which senescence biomarkers are affected by interventions that enhance health and function has not yet been examined. Here, we report that a 12‐week structured exercise program drives significant improvements in several performance‐based and self‐reported measures of physical function in older adults. Impressively, the expression of key markers of the senescence program, including p16, p21, cGAS , and TNFα , were significantly lowered in CD3 + T cells in response to the intervention, as were the circulating concentrations of multiple senescence‐related proteins. Moreover, partial least squares discriminant analysis showed levels of senescence‐related proteins at baseline were predictive of changes in physical function in response to the exercise intervention. Our study provides first‐in‐human evidence that biomarkers of senescent cell burden are significantly lowered by a structured exercise program and predictive of the adaptive response to exercise.

Senescent cells exacerbate COVID-19 Cellular senescence is a state elicited in response to stress signals and is associated with a damaging secretory phenotype. The number of senescent cells increases with advanced age and this in turn drives age-related diseases. Camell et al. show that senescent cells have an amplified inflammatory response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (see the Perspective by Cox and Lord). This response is communicated to nonsenescent cells, suppressing viral defense mechanisms and increasing the expression of viral entry proteins. In old mice infected with a SARS-CoV-2–related virus, treatment with senolytics to reduce the senolytic cell burden reduced mortality and increased antiviral antibodies. Science , abe4832, this issue p. eabe4832 ; see also abi4474, p. 281

AbstractBackgroundFailure of immunologic homeostasis and resultant hepatocyte destruction in autoimmune hepatitis (AIH) is likely the result of environmental triggers within a permissive genetic architecture.AimsWe aimed to identify risk factors associated with AIH in a well‐phenotyped AIH cohort.MethodsWe prospectively collected environmental questionnaires from 358 AIH cases and 563 healthy controls. Response frequencies were compared using logistic regression, adjusting for age at recruitment, sex and education.ResultsAIH cases were more likely to ever have a urinary tract infection (UTI) (53.6% vs 33.9%, P < .001) and recurrent UTI (more than 1 per year) (23.5% vs 15.9%, P = .002) compared to controls. Female cases more frequently had ever used oral contraceptives (83.0% vs 73.7%, P = .006), fewer pregnancies (median = 1 vs 3, P < .001) and less often used hormone replacement therapy compared to controls (28.5% vs 60.1%, P < .001). Current smoking was more prevalent in cases (18.9% vs 7.4%, P = .022), yet no difference according to historical smoking behaviours was observed. Finally, cases were less likely to have history of mumps (32.4% vs 53.1%, P = .011) and rheumatic fever (1.1% vs 4.4%, P = .028), but reported higher vaccination frequency to chicken pox (38% vs 28.1%), measles (66.5% vs 39.3%), mumps (58.7% vs 34.6%), rubella (55.3% vs 32.7%), pertussis (59.8% vs 40.1%) and pneumococcus (47.2% VS 39.4%) (P < .002).ConclusionsEnvironmental factors are important in AIH pathogenesis. Replication of these findings and prospective examination may provide new insight into AIH onset and outcomes.

Abstract Background: Adrenal adenomas have been linked with cardiovascular morbidity in selected patient populations from specialized referral centers. Population-based data examining the association of adrenal adenomas with cardiometabolic outcomes are lacking. Aim: To determine the incidence of cardiometabolic outcomes in a population-based cohort of patients with adrenal adenomas. Methods: We conducted a population-based cohort study of patients diagnosed with adrenal adenomas while living in a defined community from 1995–2017. Eligible patients were retrospectively identified by a medical records linkage system and confirmed on chart review. Adenomas were classified as mild autonomous cortisol secretion (MACS) if the serum cortisol concentration was &gt;1.8 mcg/dL after 1 mg overnight dexamethasone suppression test (DST), nonfunctioning adrenal tumor (NFAT) if serum cortisol after DST was ≤1.8 mcg/dL, and adenoma with unknown cortisol secretion (AUCS) if DST was not performed. Patients with overt hormone excess were excluded. Cardiometabolic outcomes were assessed at the time of adrenal adenoma diagnosis. Patients were then followed until death, migration out of the community, or through December 31, 2017. Incident outcomes were assessed starting at 1 year following the diagnosis and excluded those with the outcome of interest at baseline, except for myocardial infarction (MI) and coronary intervention, which were adjusted for in the analysis. Results: were compared to 1:1 age and sex-matched referent subjects without adrenal adenomas from the same community. Results: Adrenal adenomas were diagnosed in 1004 patients with 141 (14%) NFAT, 81 (8%) MACS, and 782 (78%) AUCS. The median age of diagnosis was 63 years (range, 20–96), and 582 (58%) were women. The baseline data was previously presented and showed higher prevalence of hypertension, diabetes, peripheral vascular disease (PVD), and heart failure (HF) in the adenoma group, after adjusting for BMI and tobacco use. During a median follow-up of 6.8 years (range, 0–22), patients with adrenal adenomas were more likely than referent subjects to develop new-onset dyslipidemia (HR 1.31, 95% CI 1.03–1.67), diabetes (HR 1.68, 95% CI 1.28–2.22), chronic kidney disease (HR 1.77, 95% CI 1.39–2.25), atrial fibrillation (HR 1.32 (1.03–1.70), PVD (HR 1.61, 95% CI 1.24–2.09), and HF (HR 1.46, 95% CI 1.15–1.85). In addition, the adenoma group had higher risk for incident MI (HR 1.62, 95% CI 1.16–2.25) and coronary intervention (HR 1.70, 95% CI 1.25–2.31). Conclusions: Adrenal adenomas are associated with increased incidence of adverse cardiometabolic outcomes in this population-based cohort study. While these results are potentially explained by different degrees of cortisol excess, the majority of patients received suboptimal hormone evaluation, suggesting a knowledge gap in the workup of adrenal adenomas in the broader medical community.

Abstract Background: Adrenal adenomas are incidentally diagnosed in 7% of adults undergoing abdominal imaging. Mild autonomous cortisol secretion is present in 50% of adrenal adenomas, and even “nonfunctioning” adrenal adenomas demonstrate abnormal steroid profile. We aimed to 1) investigate the prevalence of mental and sleep disorders in patients with adrenal adenomas and to 2) determine the risk of mental and sleep disorders after the diagnosis of adrenal adenoma in patients compared to the referent subjects from the same population Methods: Using a medical records linkage system, we identified adult patients living in the Olmsted County, MN diagnosed with an adrenal adenoma during 1995–2017. Patients with overt hormone excess were excluded. Every patient with adenoma was matched by sex and age to a referent subject from the same population. Subjects were followed until death or end of the study. Mental health related comorbidities and sleep disorders were assessed at baseline and during follow up. Results: Our cohort included 1004 patients with adrenal adenomas and 1004 referent subjects (58% women, median age of 63 years). Patients were more likely to smoke (70% vs 54%, p &lt;0.001) and had a higher BMI (30 kg/m2 vs 28 kg/m2, p &lt; 0.001). Within 5 years prior to the index date (diagnosis of adenoma), and after adjusting for BMI and smoking, patients demonstrated a higher prevalence of depression (Odds ratio, OR of 1.3 (CI95% 1.1–1.6), p=0.02), anxiety (OR of 1.4 (CI95% 1.1–1.8, p=0.003), substance abuse disorders (OR of 2.4 (CI 95% 1.7–3.4), p&lt;0.001), but not insomnia (OR of 1.2 (CI95% 0.9–1.7) and sleep related breathing disorders (OR of 1.3 (CI 95% 0.9–1.7). During follow-up, starting 1 year after the diagnosis, patients demonstrated a higher risk of new onset depression (HR of 1.9, CI95%1.5–2.4), anxiety (HR of 1.5,CI95% 1.2–1.9), schizophrenia (HR of 1.7, CI95% 1.2–2.4), and substance abuse disorders (HR of 1.6, CI95% 1.2–2.0). Risk of sleep disorders 1 year after diagnosis was also high for insomnia (HR of 1.4, CI95% 1.1–1.9), sleep-related breathing disorders (HR of 1.8, CI95% 1.4–2.3), hypersomnias of central origin (HR of 2.0, CI95%1.04–3.96), parasomnias (HR of 2.4, CI95%1.2–4.7), and sleep-related movement disorders(HR of 1.9, CI95%1.3–2.6). Conclusion: Patients with adenomas are at increased risk for mental and sleep disorders, possibly explained by the underlying subtle cortisol secretion. Further prospective studies with an in-depth characterization of both hormonal secretion and mental/sleep disorders are needed. Reversibility or improvement of mental health and sleep disorders with adrenalectomy should be investigated.

AbstractBackgroundCurrently, there is no biologically based rationale for drug selection in migraine prophylactic treatment.MethodsTo investigate the genetic variation underlying treatment response to verapamil prophylaxis, we selected 225 patients from a longitudinally established, deeply phenotyped migraine database (N = 5983), and collected uninterrupted quantitated verapamil treatment response data and DNA for these 225 cases. We recorded the number of headache days in the four weeks preceding treatment with verapamil and for four weeks, following completion of a treatment period with verapamil lasting at least five weeks. Whole‐exome sequencing (WES) was applied to a discovery cohort consisting of 21 definitive responders and 14 definitive non‐responders, and the identified single nucleotide polymorphisms (SNPs) showing significant association were genotyped in a separate confirmation cohort (185 verapamil treated patients). Statistical analysis of the WES data from the discovery cohort identified 524 SNPs associated with verapamil responsiveness (p < 0.01); among them, 39 SNPs were validated in the confirmatory cohort (n = 185) which included the full range of response to verapamil from highly responsive to not responsive.ResultsFourteen SNPs were confirmed by both percentage and arithmetic statistical approaches. Pathway and protein network analysis implicated myo‐inositol biosynthetic and phospholipase‐C second messenger pathways in verapamil responsiveness, emphasizing the earlier pathogenic understanding of migraine. No association was found between genetic variation in verapamil metabolic enzymes and treatment response.ConclusionOur findings demonstrate that genetic analysis in well‐characterized subpopulations can yield important pharmacogenetic information pertaining to the mechanism of anti‐migraine prophylactic medications.

Objective Several small studies reported increased prevalence and incidence of asymptomatic vertebral fractures in patients with non-functioning adrenal adenomas and adenomas with mild autonomous cortisol secretion. However, the risk of symptomatic fractures at vertebrae, and at other sites remains unknown. Our objective was to determine the prevalence and incidence of symptomatic site-specific fractures in patients with adrenal adenomas. Design Population-based cohort study, Olmsted County, Minnesota, USA, 1995–2017. Methods Participants were the patients with adrenal adenoma and age/sex-matched referent subjects. Patients with overt hormone excess were excluded. Main outcomes measures were prevalence and incidence of bone fractures. Results Of 1004 patients with adrenal adenomas, 582 (58%) were women, and median age at diagnosis was 63 years (20–96). At the time of diagnosis, patients had a higher prevalence of previous fractures than referent subjects (any fracture: 47.9% vs 41.3%, P = 0.003, vertebral fracture: 6.4% vs 3.6%, P = 0.004, combined osteoporotic sites: 16.6% vs 13.3%, P = 0.04). Median duration of follow-up was 6.8 years (range: 0–21.9 years). After adjusting for age, sex, BMI, tobacco use, prior history of fracture, and common causes of secondary osteoporosis, patients with adenoma had hazard ratio of 1.27 (95% CI: 1.07–1.52) for developing a new fracture during follow up when compared to referent subjects. Conclusions Patients with adrenal adenomas have higher prevalence of fractures at the time of diagnosis and increased risk to develop new fractures when compared to referent subjects.

AbstractBeing 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 &lt; 0.001). Non-natural menopause was more common in multiple sclerosis (40.7%) than in controls (30.1%) (P = 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) (P = 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) (P = 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) (P = 0.005)]. Menopause age was associated with progressive multiple sclerosis onset age (R2 = 0.359, P &lt; 0.001). Duration from onset of relapses to onset of progressive multiple sclerosis was shorter for females with premature/early menopause (n = 26; mean ± standard deviation: 12.9 ± 9.0 years) than for females with normal menopause age (n = 39; mean ± standard deviation: 17.8 ± 10.3 years) but was longer than for males (mean ±standard deviation: 10.0 ± 9.4 years) (P = 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) (P = 0.013). Age at menopause was associated with age at expanded disability status scale 6 (R2 = 0.229, P &lt; 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.