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To determine early somatic changes in high-grade serous ovarian cancer (HGSOC), we performed whole genome sequencing on a rare collection of 16 low stage HGSOCs. The majority showed extensive structural alterations (one had an ultramutated profile), exhibited high levels of p53 immunoreactivity, and harboured a TP53 mutation, deletion or inactivation. BRCA1 and BRCA2 mutations were observed in two tumors, with nine showing evidence of a homologous recombination (HR) defect. Combined Analysis with The Cancer Genome Atlas (TCGA) indicated that low and late stage HGSOCs have similar mutation and copy number profiles. We also found evidence that deleterious TP53 mutations are the earliest events, followed by deletions or loss of heterozygosity (LOH) of chromosomes carrying TP53, BRCA1 or BRCA2. Inactivation of HR appears to be an early event, as 62.5% of tumours showed a LOH pattern suggestive of HR defects. Three tumours with the highest ploidy had little genome-wide LOH, yet one of these had a homozygous somatic frame-shift BRCA2 mutation, suggesting that some carcinomas begin as tetraploid then descend into diploidy accompanied by genome-wide LOH. Lastly, we found evidence that structural variants (SV) cluster in HGSOC, but are absent in one ultramutated tumor, providing insights into the pathogenesis of low stage HGSOC.

SummaryBackground The relationships between primary sclerosing cholangitis (PSC) and the environment are largely unknown. Aim To validate associations reported in previous studies and to identify novel environmental exposures among PSC patients. Methods We performed a multicenter, case–control analysis utilising self-administered questionnaires. Responses between cases (n = 1000) and controls (n = 663) were compared using multivariable logistic regression adjusted for age and gender. The model was further stratified based on inflammatory bowel disease (IBD) status (with IBD n = 741 without IBD n = 259). Results Smoking was associated with PSC only when IBD was present (OR, 0.5; 95% CI 0.4–0.7) but not among those PSC patients without IBD (OR, 0.9; 95% CI 0.7–1.2). Compared to controls, women with PSC (irrespective of the presence of IBD) were less likely to have received hormone replacement therapy (HRT; OR, 0.5; 95% CI 0.4–0.7) and were more likely to have recurrent urinary tract infections (OR, 1.6; 95% CI 1.2–2.3). PSC patients regardless of gender or IBD status were less likely to eat fish (OR, 0.4; 95% CI 0.3–0.6) and grilled/barbecued meat (OR, 0.8; 95% CI 0.7–0.9). In contrast, PSC patients with and without IBD were more likely to consume steak/burgers that were more well done (OR, 1.3; 95% CI 1.2–1.5). Conclusions IBD (rather than PSC) is associated with smoking. Women with PSC are more likely to have recurrent urinary tract infections and less likely to receive HRT. Dietary intake and methods of food preparation differ in PSC patients when compared to controls.

Aim Following defibrillation, ventricular fibrillation (VF) frequently recurs during out-of-hospital cardiac arrest (OHCA). Prior studies have reported conflicting results regarding its association with survival. The aim of this study was to examine the impact of recurrent VF in the presence of first responders before advanced life support (ALS) interventions. Methods Electrocardiographic data from first responder automated external defibrillators (AEDs) were analyzed. A successful shock was defined as termination of VF for 5 s or longer. Recurrent VF was defined as any VF that occurred after a successful shock. The primary outcome was neurologically intact survival to hospital discharge (CPC 1–2). Results 108 patients within our emergency system experienced a witnessed VF arrest. Of these, 73 (68%) had at least one recurrence of VF. Median time to recurrence of VF was 25 s [interquartile range (IQR) 11–66 s]. Median time in recurrent VF was 180 s (IQR 105–266 s). Survival was observed in 25 (71%) of patients with no recurrent VF and in 36 (49%) who had recurrence. Recurrent VF was associated with a lower odds of survival on univariate analysis (OR 0.39, 95% CI 0.16–0.92, p = 0.0325). After adjusting for bystander CPR, gender and age, recurrent VF had a similar direction of effect but was no longer significantly associated with neurologically intact survival (OR 0.44, 95% CI 0.17–1.11, p = 0.081). Conclusions In the presence of first responders, VF recurred in 68% of patients. Recurrent VF was associated with a lower odds of survival, though its prognostic significance appeared to be blunted when considered in light of confounding variables. Recurrent VF may have significant survival implications, and further studies to assess its prognostic significance should be performed.

Polysomy detected by fluorescence in situ hybridization (FISH) is associated with cholangiocarcinoma (CCA) in patients with primary sclerosing cholangitis (PSC). However, a subset of PSC patients with polysomy do not manifest CCA even after long-term follow-up. It is unknown if patients with chromosomal gains detected by FISH in multiple areas of the biliary tree (i.e., multifocal polysomy, MFP) are more likely to be diagnosed with CCA than patients with unifocal polysomy (UFP). Therefore, our aim is to determine whether patients with MFP are more likely to manifest CCA compared with patients with other chromosomal abnormalities including UFP and other FISH subtypes.We performed a retrospective review of PSC patients without a mass lesion who underwent FISH testing at our institution from 1 January 2005 to 1 July 2013.Three-hundred and seventy-one PSC patients were included. Compared with patients with UFP, those with MFP were more likely to have weight loss (32 vs. 9%), suspicious cytology (45 vs. 13%) and develop serial polysomy (91 vs. 35%). MFP was associated with CCA (hazard ratio (HR), 82.42; 95% confidence interval (CI), 24.50-277.31) and was the strongest predictor of cancer diagnosis. Suspicious cytology (HR, 26.31; 95% CI, 8.63-80.24) and UFP (HR, 13.27; 95% CI, 3.32-53.08) were also predictive of CCA. MFP, UFP and suspicious cytology remained associated with CCA in the multivariable model.Compared with other FISH subtypes, MFP is the strongest predictor of CCA. However, patients with UFP and suspicious cytology (regardless of FISH status) are also at an increased risk for CCA.

Background and aims Routine serologic testing for celiac disease (CD) may be useful in irritable bowel syndrome (IBS) patients, but this is controversial. We aimed to compare the prevalence of unrecognized CD in a large cohort of patients with and without IBS. Participants and methods This is a family case-control IBS study conducted at a single US academic medical center. Stored serum and DNA were available. Tissue transglutaminase (TTg) immunoglobulin A was performed, followed by indirect immunofluorescence testing for endomysial antibodies with positive or weakly positive TTg results. Individuals were considered to have CD if both results were positive. χ and Fisher's exact tests were used to compare prevalence between the two groups. Results Serum samples were studied from 533 cases and 531 controls. In all, 80% of participants were female, with a median age of 50 years; 65% of cases and 0% controls met the Rome criteria for IBS. Previous serological testing for CD had occurred in 142 (27%) cases and 13 (2%) controls, but none had CD on subsequent testing. Six (1.1%) cases versus five (0.9%) controls had positive or weakly positive TTg test. Six cases (1.1%) versus three (0.6%) controls were confirmed to have CD by endomysial antibody (P=0.51). Conclusion No difference in the prevalence of CD between patients with IBS and patients without IBS at a tertiary medical center was observed. Our findings do not support routine celiac serologic or genetic testing in patients with IBS in all US populations.

The United Kingdom-Primary Biliary Cholangitis (UK-PBC) risk scores are a set of prognostic models that estimate the risk of end-stage liver disease in patients with PBC at 5-, 10- and 15-year intervals. They have not been externally validated outside the United Kingdom. In this retrospective, external validation study, data were abstracted from outpatient charts and discrimination and calibration of the UK-PBC risk scores were assessed. A total of 464 patients with PBC treated with ursodeoxycholic acid were included. The median diagnosis age was 52.4 years, and 88% were female patients. The cumulative incidence of events was 6%, 9%, and 15% at 5, 10, and 15 years, respectively. Concordance (c-statistic) was 0.88, 0.85, and 0.84 using the 5-, 10- and 15-year risk scores, respectively, which was slightly lower than values observed in the United Kingdom validation cohort. Using the 5-year risk score, more events were observed than predicted (25 versus 16.8; P = 0.046); using the 10-year risk score, there was no difference between the observed and predicted number of events (35 versus 44.9; P = 0.14); conversely, using the 15-year risk score, fewer events were observed than predicted (46 versus 67.5; P = 0.009). Limiting evaluation by the 15-year UK-PBC risk score to those with >10 years of follow-up demonstrated no difference between observed and predicted events. Using the 5-year risk score, patients within the highest quartile had statistically significant worse event-free survival compared to the rest of the cohort: 82% versus 98% at 5 years, 73% versus 97% at 10 years, and 58% versus 93% at 15 years. Conclusion: In patients assessed at a North American tertiary medical center, the UK-PBC risk score had excellent discrimination and was reasonably calibrated both in the short and long term. (Hepatology Communications 2018;2:676-682).

Summary A serum biomarker of biological versus chronological age would have significant impact on clinical care. It could be used to identify individuals at risk of early‐onset frailty or the multimorbidities associated with old age. It may also serve as a surrogate endpoint in clinical trials targeting mechanisms of aging. Here, we identified MCP‐1/CCL2, a chemokine responsible for recruiting monocytes, as a potential biomarker of biological age. Circulating monocyte chemoattractant protein‐1 (MCP‐1) levels increased in an age‐dependent manner in wild‐type (WT) mice. That age‐dependent increase was accelerated in Ercc1 −/Δ and Bubr1 H/H mouse models of progeria. Genetic and pharmacologic interventions that slow aging of Ercc1 −/Δ and WT mice lowered serum MCP‐1 levels significantly. Finally, in elderly humans with aortic stenosis, MCP‐1 levels were significantly higher in frail individuals compared to nonfrail. These data support the conclusion that MCP‐1 can be used as a measure of mammalian biological age that is responsive to interventions that extend healthy aging.

Background Compensatory stepping thresholds evaluate the response to postural disturbances. Although such fall-recovery measures are a promising indicator of fall risk, the relationships between stepping thresholds and other measures used to predict falls are not well established. Research Question We sought to quantify the relationships between stepping thresholds and other measurements used to assess fall risk in older women, a population at high risk for falls and related injuries, including fractures. Methods We studied 112 ambulatory, community-dwelling women, age 65 years or older. Using a treadmill to deliver standing postural disturbances, we determined anterior and posterior single-stepping and multiple-stepping thresholds. These thresholds represented the magnitude of the disturbance that elicited one step or more than one step, respectively. We also assessed balance confidence, functional reach, unipedal stance time, isometric strength, obstacle crossing, postural sway, and gait kinematics. Outcomes were normalized to body size. Results After accounting for age, stepping thresholds were, at most, moderately correlated (Pearson partial correlation coefficients r = 0.20 to 0.40 and r = -0.21 to -0.31) to several assessments of gait, postural control, and strength. Approximately 24–52% of the variance in stepping thresholds was explained by a combination of age and other fall risk assessments, which frequently consisted of balance confidence, unipedal stance time, obstacle crossing, the Romberg ratio of postural sway, and/or strength. Significance Our results suggest that anteroposterior fall-recovery ability, as assessed by stepping thresholds, can only be partially inferred from age and a combination of assessments of sway, strength, unipedal tasks, and balance confidence. Compensatory stepping thresholds may provide information on stability maintenance unique from other assessments of fall risk. Further investigation would be necessary to determine whether stepping thresholds are better predictors of falls in older women.

BACKGROUND Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder, diagnosed on symptom-based criteria. Many have reported discrepancies between formal Rome criteria and diagnoses made in clinical practice. The aim of the study was to explore whether a quantitative version of the Rome criteria would better represent a clinical diagnosis of IBS than the current dichotomous criteria for symptom measure. METHODS As part of a large, case-control study, participants completed a validated bowel disease questionnaire. Rome criteria were analyzed based on 15 individual symptoms. Penalized logistic regression model with stepwise selection was used to identify significant symptoms of IBS which were independently associated with case-control status. KEY RESULTS In cases with a clinical diagnosis of IBS, 347 (70%) met Rome criteria for IBS. Increasing number of Rome symptoms were found related to the odds of being diagnosed with IBS. Nearly half of the Rome-negative case group experienced infrequent symptoms suggesting milder disease. Five of 15 Rome symptoms were associated with predicting case-control status in the final model, with 96% correctly classified among Rome-positive cases, 76% for Rome-negative cases, and 91% for controls. CONCLUSIONS AND INFERENCES Irritable bowel syndrome appears to be a spectrum disorder. Quantifying individual symptoms of Rome criteria has greater utility than the current application in representing the degree of IBS affectedness and appears to better reflect a clinical diagnosis of IBS applied by physicians. The use of a quantitative diagnostic Rome "score" may be helpful in clinical practice and research studies to better reflect the degree an individual is affected with IBS.

Background In the busy clinic, identifying individuals at high fracture (fx) risk who warrant intervention can be a challenge. There are several medical conditions that increase the risk for bone loss and falls which are recorded in the electronic medical record (EMR). Objectives We explored whether we could exploit data available in the EMR to estimate FRAX treatment thresholds to help passively identify patients who would benefit from further bone mineral density screening and management. Methods We studied 912 women and men, previously recruited for our bone health studies, in whom FRAX scores (with and without BMD) had been determined and comprehensive medical diagnoses were available through the medical linkage system of the Rochester Epidemiology Project. All diagnoses were categorized by the Clinical Classification Software (CCS) system whereby over 14,000 ICD-9-CM diagnoses are reduced to 568 clinically meaningful categories. If a subject had at least two diagnoses in a CCS category that were at least 30 days apart and within 5 years of their FRAX assessment, the subject was treated as having that CCS code. We used Gradient Boosting Machine (GBM) to create models that would predict the treatment thresholds for the FRAX 10-year risk for major osteoporotic (OP) fx (>20%) and hip fx (>3%), based on available diagnoses. Models were fit using age, sex and CCS category from 80% of the data, retaining 20% for validation. Results Of the 564 (62%) women and 348 (38%) men, the mean ± SD age was 61±16 yrs. There were no significant differences in subject characteristics used for FRAX calculation or FRAX scores between the training and validation sets. The c-statistic for GBM models predicting treatment thresholds for FRAX, calculated with BMD, for major OP fx and hip fx were 0.95 and 0.96, respectively, for the training set, and 0.88 and 0.94 for the validation set. Similar results were observed for FRAX scores without BMD. Conclusions FRAX treatment thresholds may be reasonably estimated from data available in the EMR to help identify to the clinician those at highest risk for fracture who would warrant further evaluation. Further work to implement and validate these findings in the EMR system would be necessary. Disclosure of Interest None declared

Numerous studies have examined the association of body composition with bone development in children and adolescents, but none have used micro-finite element (μFE) analysis of high-resolution peripheral quantitative computed tomography images to assess bone strength.This study sought to examine the relations of appendicular lean mass (ALM) and total body fat mass (TBFM) to bone strength (failure load) at the distal radius and tibia.This was a cross-sectional study of 198 healthy 8- to15-year-old boys (n = 109) and girls (n = 89) performed in a Clinical Research Unit.After adjusting for bone age, height, fracture history, ALM, and TBFM, multiple linear regression analyses in boys and girls, separately, showed robust positive associations between ALM and failure loads at both the distal radius (boys: β = 0.92, P.001; girls: β = 0.66, P = .001) and tibia (boys: β = 0.96, P.001; girls: β = 0.66, P.001). By contrast, in both boys and girls the relationship between TBFM and failure load at the distal radius was virtually nonexistent (boys: β = -0.07; P = .284; girls: β = -0.03; P = .729). At the distal tibia, positive, albeit weak, associations were observed between TBFM and failure load in both boys (β = 0.09, P = .075) and girls (β = 0.17, P = .033).Our data highlight the importance of lean mass for optimizing bone strength during growth, and suggest that fat mass may have differential relations to bone strength at weight-bearing vs non-weight-bearing sites in children and adolescents. These observations suggest that the strength of the distal radius does not commensurately increase with excess gains in adiposity during growth, which may result in a mismatch between bone strength and the load experienced by the distal forearm during a fall. These findings may explain, in part, why obese children are over-represented among distal forearm fracture cases.

Objective: We examined the effect of relapses—before and after progression onset—on the rate of postprogression disability accrual in a progressive multiple sclerosis (MS) cohort. Methods: We studied patients with primary progressive MS (n = 322) and bout-onset progressive MS (BOPMS) including single-attack progressive MS (n = 112) and secondary progressive MS (n = 421). The effect of relapses on time to Expanded Disability Status Scale (EDSS) score of 6 was studied using multivariate Cox regression analysis (sex, age at progression, and immunomodulation modeled as covariates). Kaplan-Meier analysis was performed using EDSS 6 as endpoint. Results: Preprogression relapses (hazard ratio [HR]: 1.63; 95% confidence interval [CI]: 1.34–1.98), postprogression relapses (HR: 1.37; 95% CI: 1.11–1.70), female sex (HR: 1.19; 95% CI: 1.00–1.43), and progression onset after age 50 years (HR: 1.47; 95% CI: 1.21–1.78) were associated with shorter time to EDSS 6. Postprogression relapses occurred in 29.5% of secondary progressive MS, 10.7% of single-attack progressive MS, and 3.1% of primary progressive MS. Most occurred within 5 years (91.6%) after progressive disease onset and/or before age 55 (95.2%). Immunomodulation after onset of progressive disease course (HR: 0.64; 95% CI: 0.52–0.78) seemingly lengthened time to EDSS 6 (for BOPMS with ongoing relapses) when analyzed as a dichotomous variable, but not as a time-dependent variable. Conclusions: Pre- and postprogression relapses accelerate time to severe disability in progressive MS. Continuing immunomodulation for 5 years after the onset of progressive disease or until 55 years of age may be reasonable to consider in patients with BOPMS who have ongoing relapses.

Children and adolescents who sustain a distal forearm fracture (DFF) owing to mild, but not moderate, trauma have reduced bone strength and cortical thinning at the distal radius and tibia. Whether these skeletal deficits track into adulthood is unknown. Therefore, we studied 75 women and 75 men (age range, 20 to 40 years) with a childhood (age < 18 years) DFF and 150 sex-matched controls with no history of fracture using high-resolution peripheral quantitative computed tomography (HRpQCT) to examine bone strength (ie, failure load) by micro-finite element (µFE) analysis, as well as cortical and trabecular bone parameters at the distal radius and tibia. Level of trauma (mild versus moderate) was assigned using a validated classification scheme, blind to imaging results. When compared to sex-matched, nonfracture controls, women and men with a mild trauma childhood DFF (eg, fall from standing height) had significant reductions in failure load (p < 0.05) of the distal radius, whereas women and men with a moderate trauma childhood DFF (eg, fall while riding a bicycle) had values similar to controls. Consistent findings were observed at the distal tibia. Furthermore, women and men with a mild trauma childhood DFF had significant deficits in distal radius cortical area (p < 0.05), and significantly lower dual-energy X-ray absorptiometry (DXA)-derived bone density at the radius, hip, and total body regions compared to controls (all p < 0.05). By contrast, women and men with a moderate trauma childhood DFF had bone density, structure, and strength that did not differ significantly from controls. These findings in young adults are consistent with our observations in children/adolescents with DFF, and they suggest that a mild trauma childhood DFF may presage suboptimal peak bone density, structure, and strength in young adulthood. Children and adolescents who suffer mild trauma DFFs may need to be targeted for lifestyle interventions to help achieve improved skeletal health.

Background & Aims Coffee consumption has been associated with decreased risk of liver disease and related outcomes. However, coffee drinking has not been investigated among patients with cholestatic autoimmune liver diseases, primary biliary cirrhosis (PBC), or primary sclerosing cholangitis (PSC). We investigated the relationship between coffee consumption and risk of PBC and PSC in a large North American cohort. Methods Lifetime coffee drinking habits were determined from responses to questionnaires from 606 patients with PBC, 480 with PSC, and 564 healthy volunteers (controls). Patients (those with PBC or PSC) were compared with controls by using the Wilcoxon rank sum test for continuous variables and c 2 method for discrete variables. Logistic regression was used to analyze the estimate of the effects of different coffee parameters (time, frequency, and type of coffee consumption) after adjusting for age, sex, smoking status, and education level. Results Patients with PBC and controls did not differ in coffee parameters. However, 24% of patients with PSC had never drunk coffee compared with 16% of controls ( P P P P P Conclusions Coffee consumption is lower among patients with PSC, but not PBC, compared with controls.

To determine the extent to which excess mortality after fractures attributable to particular causes at specific skeletal sites can be predicted using data about all medical diagnoses, we conducted a historical cohort study among 1991 Olmsted County, Minnesota, residents aged ≥ 50 years who experienced any fracture in 1989 to 1991 and who were followed passively for up to 22 years for death from any cause. We used a machine learning approach, gradient boosting machine (GBM) modeling, to determine whether the comorbid conditions present at the time of fracture and those that arose subsequently could, in aggregate, identify patients at the greatest increased risk of death. During 21,867 person-years of follow-up, 1245 deaths were observed when 1061 were expected (standardized mortality ratio, 1.2; 95% confidence interval [CI] 1.1-1.2). Patients presented with a median history of 26 comorbid conditions each as assessed by the Clinical Classification Software system and 57 each over the total duration of follow-up. Using all available information, the excess deaths could be predicted with good accuracy (c-index ≥ 0.80) in 89% of the GBM models built for patients with different types of fracture; in one-third of the models, the c-index was ≥ 0.90. The conditions most prominent in the GBM prediction models were also reflected in the specific causes of death that were elevated, suggesting the influence of confounding on the relationship. However, the predominant comorbid conditions were mainly those responsible for mortality in the general population, rather than the specific diseases most closely associated with secondary osteoporosis. To reduce long-term deaths in the fracture population as a whole, a more general approach to the fracture patient is indicated.

Most fragility fractures arise among the many women with osteopenia, not the smaller number with osteoporosis at high risk for fracture. Thus, most women at risk for fracture assessed only by measuring areal bone mineral density (aBMD) will remain untreated. We measured cortical porosity and trabecular bone volume/total volume (BV/TV) of the ultradistal radius (UDR) using high-resolution peripheral quantitative computed tomography, aBMD using densitometry, and 10-year fracture probability using the country-specific fracture risk assessment tool (FRAX) in 68 postmenopausal women with forearm fractures and 70 age-matched community controls in Olmsted County, MN, USA. Women with forearm fractures had 0.4 standard deviations (SD) higher cortical porosity and 0.6 SD lower trabecular BV/TV. Compact-appearing cortical porosity predicted fracture independent of aBMD; odds ratio (OR) = 1.92 (95% confidence interval [CI] 1.10–3.33). In women with osteoporosis at the UDR, cortical porosity did not distinguish those with fractures from those without because high porosity was present in 92% and 86% of each group, respectively. By contrast, in women with osteopenia at the UDR, high porosity of the compact-appearing cortex conferred an OR for fracture of 4.00 (95% CI 1.15–13.90). In women with osteoporosis, porosity is captured by aBMD, so measuring UDR cortical porosity does not improve diagnostic sensitivity. However, in women with osteopenia, cortical porosity was associated with forearm fractures.

Background The etiology of irritable bowel syndrome (IBS) is not been fully elucidated, but childhood trauma may disturb the brain–gut axis and therefore be important. Thus, we conducted a family based case–control study of IBS cases and their relatives with the aims to (i) determine the frequency of childhood trauma among IBS cases and controls as well as their relatives, and (ii) assess childhood trauma among IBS cases with affected relatives (familial IBS). Methods Outpatients with IBS, matched controls, and their first-degree relatives completed a self-report version of Bremner' Early Trauma Inventory. Percent of cases and controls with a family history were compared and odds ratios were computed using chi-squared test; recurrence risks to relatives were computed using logistic regression and generalized estimating equations. Key Results Data were collected from 409 cases, 415 controls, 825 case relatives, and 921 control relatives. IBS cases had a median age of 50 and 83% were women. Of IBS cases, 74% had experienced any general trauma compared to 59% among controls, yielding an odds ratio of 1.56 (95% CI: 1.13–2.15, p

ObjectiveTo determine whether basing the decision to initiate immediate vs delayed disease-modifying therapy (DMT) on extent of recovery after initial relapse affects long-term disability accumulation in a multiple sclerosis (MS) evidence-based setting.MethodsWe analyzed the double-blind, placebo-controlled interferon beta-1a 30 mc once a week in clinically isolated syndrome and 10-year-follow-up extension trial. Good recovery after presenting relapse was defined as (1) full early recovery within 28 days of symptom onset (Expanded Disability Status Scale [EDSS] score of 0 at enrollment maintained ≥6 months) and (2) delayed good recovery (EDSS score > 0 at enrollment and improvement from peak deficit to 6th-month or 1-year visit ≥ median). Time from recovery assignment to future disability (EDSS score ≥ 2.5 or ≥4.0) was studied on a relapse-recovery-stratified age axis and immediate vs 3-year delayed treatment initiation with Kaplan-Meier statistics and hazard ratios (HRs).ResultsOne hundred seventy-five/328 patients had good recovery (94 immediate and 81 delayed treatment); 153 did not have good recovery (77 immediate and 76 delayed treatment). HRs for EDSS score ≥2.5 outcome were: delayed treatment without good recovery as reference (HR = 1.0), delayed treatment with good recovery (HR6th-month: 0.67, p = 0.207; HR1st-year: 0.40, p = 0.027), immediate treatment without good recovery (HR6th-month: 0.56, p = 0.061; HR1st-year: 0.40, p = 0.011), and immediate treatment with good recovery (HR6th-month: 0.43, p = 0.014; HR1st-year: 0.48, p = 0.034). Placebo patients were switched to long-term treatment after 3 years, and insufficient EDSS score ≥4.0 outcome events were available to study.ConclusionsIn patients with MS presenting without good recovery after the initial relapse, immediate DMT initiation favorably influences the likelihood of more ambulatory-benign disease akin to patients with good recovery after the initial relapse.Classification of evidenceThis study provides Class III evidence that for patients with MS without good recovery after the initial relapse, immediate DMT initiation increases the likelihood of a benign disease course.

Senescent cells drive age-related tissue dysfunction through their potent secretome, termed the senescence associated secretory phenotype (SASP). Circulating concentrations of SASP factors may reflect biological age and serve as clinically useful biomarkers of surgical risk and ultimately, surrogate endpoints in clinical trials. However, they remain largely uncharacterized. We tested associations between circulating concentrations of SASP proteins and biological age, as determined by the accumulation of age-related health deficits, and/or postoperative outcomes in a sample of residents in Olmstead County, MN, age 60-90 years (n = 115) and cohorts of older adults undergoing surgery for severe aortic stenosis (prospective; n = 97) or ovarian cancer (case-control; n = 36). Circulating concentrations of SASP factors were associated with biological age and adverse postoperative outcomes, including risk of any adverse event or rehospitalization within the year following surgery (aortic stenosis group) or admission to an intensive care unit within 30 days of hospital discharge (ovarian cancer group). Gradient boosting machine modeling revealed a panel of SASP factors that predicted adverse outcomes across both surgical groups better than biological age or chronological age and sex. This suggests that the circulating SASP is a robust indicator of age-related health status and may help guide clinical decision making. Furthermore, circulating SASP factors may be harnessed as a readily quantifiable biomarkers in senescence-targeting interventional human studies.

Although distal forearm fractures (DFFs) are common during childhood and adolescence, it is unclear whether they reflect underlying skeletal deficits or are simply a consequence of the usual physical activities, and associated trauma, during growth. Therefore, we examined whether a recent DFF, resulting from mild or moderate trauma, is related to deficits in bone strength and cortical and trabecular bone macro- and microstructure compared with nonfracture controls. High-resolution peripheral quantitative computed tomography was used to assess micro-finite element-derived bone strength (ie, failure load) and to measure cortical and trabecular bone parameters at the distal radius and tibia in 115 boys and girls with a recent (

To assess recent trends in fracture incidence from all causes at all skeletal sites, we used the comprehensive (inpatient and outpatient) data resources of the Rochester Epidemiology Project to estimate rates for Olmsted County, MN, USA, residents in 2009 to 2011 compared with similar data from 1989 to 1991. During the 3-year study period, 2009 to 2011, 3549 residents ≥50 years of age experienced 5244 separate fractures. The age- and sex-adjusted (to the 2010 US white population) incidence of any fracture was 2704 per 100,000 person-years (95% confidence interval [CI] 2614 to 2793) and that for all fractures was 4017 per 100,000 (95% CI 3908 to 4127). Fracture incidence increased with age in both sexes, but age-adjusted rates were 49% greater among the women. Overall, comparably adjusted fracture incidence rates increased by 11% (from 3627 to 4017 per 100,000 person-years; p = 0.008) between 1989 to 1991 and 2009 to 2011. This was mainly attributable to a substantial increase in vertebral fractures (+47% for both sexes combined), which was partially offset by a decline in hip fractures (−25%) among the women. There was also a 26% reduction in distal forearm fractures among the women; an increase in distal forearm fractures among men aged 50 years and over was not statistically significant. The dramatic increase in vertebral fractures, seen in both sexes and especially after age 75 years, was attributable in part to incidentally diagnosed vertebral fractures. However, the fall in hip fracture incidence, observed in most age groups, continues the steady decline observed among women in this community since 1950. More generally, these data indicate that the dramatic increases in the incidence of fractures at many skeletal sites that were observed decades ago have now stabilized. © 2014 American Society for Bone and Mineral Research.

To examine the effect of low-magnitude whole body vibration on bone density and microstructure in women and men with chronic motor complete paraplegia.We studied nine subjects (four women and five men) with motor complete paraplegia of 2 years duration or more, age 20-50 years. Subjects were instructed to stand on a low-magnitude vibration plate within a standing frame for 20 minutes per day, 5 days a week, and for 6 months. Bone density at the proximal femur by dual-energy X-ray absorptiometry and bone microstructure at the distal tibia by high-resolution peripheral quantitative computed tomography were assessed at four timepoints over 12 months (baseline, at 3 months and 6 months while on intervention, and after 6 months off intervention).Standing on the low-magnitude vibration plate with a standing frame was well tolerated by participants. However, most subjects did not show an improvement in bone density or microstructure after 6 months of intervention, or any relevant changes 6 months following the discontinuation of the low-magnitude vibration.We were unable to identify an improvement in either bone density or microstructure following 6 months use of a low-magnitude vibration plate in women or men with chronic motor complete paraplegia. Longer duration of use may be necessary, or it is possible that this intervention is of limited benefit following chronic spinal cord injury.

Biochemical response to ursodeoxycholic acid among patients with primary biliary cirrhosis remains variable, and there is no agreement of an ideal model. Novel assessment of response coupled to histologic progression was recently defined by the Toronto criteria. We retrospectively assessed transplant-free survival and clinical outcomes associated with ursodeoxycholic acid response to evaluate the Toronto criteria using a large North American cohort of PBC patients. Three hundred and ninety-eight PBC patients from the Mayo Clinic PBC Genetic Epidemiology Registry were assessed for ursodeoxycholic acid treatment and biochemical response per the Toronto criteria. Responders were defined by reduction in alkaline phosphatase to less than or equal to 1.67 times the upper normal limit by 2 years of treatment, whereas non-responders had alkaline phosphatase values greater than 1.67 times the upper normal limit. Probability of survival was estimated using the Kaplan–Meier method. Three hundred and two (76 %) patients were responders and 96 (24 %) were non-responders. Significantly more non-responders developed adverse events related to chronic liver disease compared to responders (hazard ratio (HR) 2.77, P = 0.001). Biochemical responders and early-stage disease at treatment start was associated with improved overall transplant-free survival compared to non-responders (HR 1.9) and patients with late-stage disease (HR 2.7) after age and sex adjustment. The Toronto criteria are capable of identifying ursodeoxycholic acid-treated primary biliary cirrhosis patients at risk of poor transplant-free survival and adverse clinical outcomes. Our data reveal that despite advanced disease at diagnosis, biochemical response per the Toronto criteria associates with improved overall transplant-free survival.

We isolate and characterize osteoblasts from humans without in vitro culture. These techniques should be broadly applicable to studying the pathogenesis of osteoporosis and other bone disorders.There is currently no data regarding the expression of specific genes or pathways in human osteoblasts that have not been subjected to extensive in vitro culture. Thus, we developed methods to rapidly isolate progressively enriched osteoblast populations from humans and characterized these cells.Needle bone biopsies of the posterior iliac crest were subjected to sequential collagenase digests. The cells from the second digest were stained with an alkaline phosphatase (AP) antibody, and the AP+ cells were isolated using magnetic cell sorting.Relative to AP- cells, the AP+ cells contained virtually all of the mineralizing cells and were enriched for key osteoblast marker genes. The AP+ cells were further purified by depletion of cells expressing CD45, CD34, or CD31 (AP+/CD45/34/31- cells), which represented a highly enriched human osteoblast population devoid of hematopoietic/endothelial cells. These cells expressed osteoblast marker genes but very low to undetectable levels of SOST. We next used high-throughput RNA sequencing to compare the transcriptome of the AP+/CD45/34/31- cells to human fibroblasts and identified genes and pathways expressed only in human osteoblasts in vivo, but not in fibroblasts, including 448 genes unique to human osteoblasts.We provide a detailed characterization of highly enriched human osteoblast populations without in vitro culture. These techniques should be broadly applicable to studying the pathogenesis of osteoporosis and other bone disorders.

Objective.Older women and men with rheumatoid arthritis (RA) are at increased risk for fractures, but limited information is available on fracture risk in younger individuals with RA and whether such risk occurs early in the disease onset or only when older. We determined the risk for fractures in both young and older women and men following RA diagnosis.Methods.We studied a population-based inception cohort with RA from Olmsted County, Minnesota, USA. We identified 822 women and 349 men diagnosed with RA between 1955 and 2007 (308 women and 110 men diagnosed before age 50) and an equal number of paired non-RA subjects, matched by sex and birth year. Incident fractures were collected through review of complete (inpatient and outpatient) medical records available through the linkage system of the Rochester Epidemiology Project.Results.The hazard ratio (HR; 95% CI) for a non-pathologic fracture occurring from no more than moderate trauma was 1.63 (1.36–1.96) for women and 1.40 (1.02–1.93) for men with RA. Findings were consistent for women and men diagnosed with RA at age ≥ 50 years [HR, 1.43 (1.16–1.77) and 1.34 (0.92–1.94), respectively], or at age < 50 years [HR, 2.34 (1.61–3.42) and 1.74 (0.91–3.30), respectively]. However, young women, but not young men, with RA were at increased fracture risk even before age 50 years (HR, 1.95 [1.08–3.51] and 0.82 [0.28–2.45], respectively).Conclusion.Young men with RA are at increased risk for fractures only when older, whereas young women with RA have an elevated fracture risk even while still young.

Distal forearm fractures are among the most common fractures during childhood, but it remains unclear whether they predict an increased fracture risk later in life. We studied a population-based cohort of 1776 children ≤18 years of age, from Olmsted County, MN, USA, who had a distal forearm fracture in 1935–1992. Incident fractures occurring at age ≥35 years were identified through review of complete medical records using the linkage system of the Rochester Epidemiology Project. Observed nonpathologic fractures resulting from no more than moderate trauma (fragility fractures) were compared with expected numbers estimated from fracture site–specific incidence rates, based on age, sex, and calendar year, for Olmsted County (standardized incidence ratios [SIR]). In 1086 boys (mean ± SD age; 11 ± 4 years) and 690 girls (10 ± 4 years) followed for 27,292 person-years after the age of 35 years, subsequent fragility fractures were observed in 144 (13%) men and 74 (11%) women. There was an increased risk for future fragility fractures in boys who had a distal forearm fracture (SIR, 1.9; 95% CI, 1.6–2.3) but not girls (SIR, 1.0; 95% CI, 0.8–1.2). Fragility fractures at both major osteoporotic (hip, spine, wrist, and shoulder) sites (SIR, 2.6; 95% CI, 2.1–3.3) and remaining sites (SIR, 1.7; 95% CI, 1.3–2.0) were increased in men, irrespective of age at distal forearm fracture as boys. A distal forearm fracture in boys, but not girls, is associated with an increased risk for fragility fractures as older adults. It is necessary to determine whether the increased fractures observed in men is due to persistent deficits of bone strength, continued high fracture risk activity, or both. Until then, men should be asked about a childhood distal forearm fracture and, if so, warrant further screening and counseling on measures to optimize bone health and prevent fractures.

Primary biliary cirrhosis is a cholestatic liver disease characterized by immune-mediated destruction of bile ducts. Its pathogenesis is largely unknown, although complex interactions between environment and genetic predisposition are proposed.Identify disease risk factors using a detailed patient questionnaire and compare study findings to 3 published reports.Questionnaire data were prospectively collected from 522 cases and 616 controls of the Mayo Clinic Primary Biliary Cirrhosis Genetic Epidemiology Registry. Case and control responses were compared using logistic regression, adjusting for recruitment age, sex, and education level.Cases reported ever regularly smoking cigarettes more frequently than controls (P0.001). History of urinary tract infection was similar between groups; however, cases reported multiple urinary tract infections more commonly than controls (P0.001). Frequency of other autoimmune disease was higher in cases than controls (P0.001). As well, prevalence of primary biliary cirrhosis among first-degree relatives was higher in case families than control families (P0.001).Our study confirms prior reported risk factors associated with disease risk. Given the potential importance of gene and environment interactions, further examination of environmental risk factors considering genetic background may provide new insight into primary biliary cirrhosis pathogenesis.

Aging is associated with worsening bone structure and increasing risk of hip fracture. However, the commonly used clinical tool, dual-energy x-ray absorptiometry, does not provide information on changes with age or disease separately in trabecular versus cortical bone or in bone geometry. Here we used 3D quantitative computed tomography (QCT) to analyze age-related changes in femoral volumetric bone mineral density (vBMD) and structure in a well characterized, population-based cohort of Rochester, Minnesota women.MIAF-Femur (MIAF: medical image analysis framework) was used for the analysis of CT datasets from 358 women age 20 to 97 years. Integral, "apparent" cortical (rather than true cortical vBMD, due to volume averaging effects) and trabecular vBMD, volume, and bone mineral content (BMC) as well as cortical thickness of the femur head, neck, trochanter, inter-trochanteric, and proximal shaft volumes of interest (VOIs) were measured. In addition, changes in vBMD in the superior, inferior, posterior and anterior quadrants of the femur neck were assessed.Cross-sectional percent decreases in vBMD across life were 2- to 5-fold higher in trabecular versus cortical bone at all sites in the femur, although absolute changes in the trabecular and cortical bone were fairly similar. In addition, the slopes of the relationships of trabecular vBMD with age were generally similar in pre- and postmenopausal women, whereas apparent cortical vBMD in the femur neck, trochanter, inter-trochanteric region, and proximal shaft remained relatively stable in premenopausal women but decreased significantly with age following the menopause. Bone volume increased at all sites, more so in pre- compared to postmenopausal women. Age-related BMC changes were not significant in premenopausal women, but BMC losses were highly significant in postmenopausal women. Detailed analyses of femur neck cortical bone showed that percent apparent vBMD decreases in the superior quadrants were 2- to 3-fold greater than in the inferior quadrants; changes in absolute values were most different (~2-fold) between the superior-posterior and inferior-posterior quadrants.These data demonstrate that patterns of changes with age within the femur differ in the trabecular versus cortical bone. In the cortical compartment which, due to limitations in spatial resolution, contains some subcortical bone and should be regarded as an "apparent" cortical VOI, the superior quadrants in the femur neck undergo the greatest decreases. These findings may have important implications for understanding the structural basis for increased hip fracture risk with aging.

Disorders of water balance, an excess or deficit of total body water relative to body electrolyte content, are common and ascertained by plasma hypo- or hypernatremia, respectively. We performed a two-stage genome-wide association study meta-analysis on plasma sodium concentration in 45,889 individuals of European descent (stage 1 discovery) and 17,637 additional individuals of European descent (stage 2 replication), and a transethnic meta-analysis of replicated single-nucleotide polymorphisms in 79,506 individuals (63,526 individuals of European descent, 8765 individuals of Asian Indian descent, and 7215 individuals of African descent). In stage 1, we identified eight loci associated with plasma sodium concentration at P-6. Of these, rs9980 at NFAT5 replicated in stage 2 meta-analysis (P=3.1 3 x 10-5), with combined stages 1 and 2 genomewide significance of P=5.6 x 10-10. Transethnic meta-analysis further supported the association at rs9980 (P=5.9 x 10-12). Additionally, rs16846053 at SLC4A10 showed nominally, but not genome-wide, significant association in combined stages 1 and 2 meta-analysis (P=6.7 x 10-8). NFAT5 encodes a ubiquitously expressed transcription factor that coordinates the intracellular response to hypertonic stress but was not previously implicated in the regulation of systemic water balance. SLC4A10 encodes a sodium bicarbonate transporter with a brain-restricted expression pattern, and variant rs16846053 affects a putative intronic NFAT5 DNA binding motif. The lead variants for NFAT5 and SLC4A10 are cis expression quantitative trait loci in tissues of the central nervous systemand relevant to transcriptional regulation. Thus, genetic variation in NFAT5 and SLC4A10 expression and function in the central nervous system may affect the regulation of systemic water balance.

Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by interstitial remodelling, leading to compromised lung function. Cellular senescence markers are detectable within IPF lung tissue and senescent cell deletion rejuvenates pulmonary health in aged mice. Whether and how senescent cells regulate IPF or if their removal may be an efficacious intervention strategy is unknown. Here we demonstrate elevated abundance of senescence biomarkers in IPF lung, with p16 expression increasing with disease severity. We show that the secretome of senescent fibroblasts, which are selectively killed by a senolytic cocktail, dasatinib plus quercetin (DQ), is fibrogenic. Leveraging the bleomycin-injury IPF model, we demonstrate that early-intervention suicide-gene-mediated senescent cell ablation improves pulmonary function and physical health, although lung fibrosis is visibly unaltered. DQ treatment replicates benefits of transgenic clearance. Thus, our findings establish that fibrotic lung disease is mediated, in part, by senescent cells, which can be targeted to improve health and function., Removal of senescent cells rejuvenates lungs of aged mice. Here the authors show that elimination of senescent cells using either genetic or pharmacological means improves lung function and physical health in a mouse model of idiopathic pulmonary fibrosis (IPF), suggesting potential therapy for treatment of human IPF.

Objective To evaluate whether bisphosphonates modulate vascular calcification by a modification in endothelial progenitor cells (EPCs) coexpressing osteoblastic surface markers and genes. Patients and Methods We performed a double-blind, randomized study of 20 healthy, early postmenopausal women (from February 1, 2008, through July 31, 2008) treated with placebo or risedronate sodium (35 mg/wk) for 4 months. Peripheral blood was collected at baseline and 4 months to determine serum inflammatory markers, osteoprotegerin, and receptor activator of nuclear factor–κB ligand levels and bone turnover markers. Peripheral blood mononuclear cells were stained for EPC surface markers (CD34, CD133, and vascular endothelial growth factor receptor/kinase insert domain receptor) and osteoblast markers (osteocalcin, alkaline phosphatase, and Stro-1). Results Risedronate treatment resulted in a significant down-regulation of gene sets for osteoblast differentiation and proliferation in EPCs with a trend of decreasing EPCs coexpressing osteocalcin. Conclusion Our findings indicate that bisphosphonate treatment down-regulates the expression of osteogenic genes in EPCs and suggest a possible mechanism by which bisphosphonates may inhibit vascular calcification.

Migraine is a complex trait in which multiple genetic loci, as well as environmental factors, likely contribute to its clinical manifestation. Many genetic associations reported in previous studies either have not been replicated to date or showed only marginal statistical significance, possibly due to the genetic heterogeneity of the common forms of migraine. One major phenotypic and possibly genetically identifiable migraine subgroup consists of women whose attacks are influenced by fluctuation in gonadal hormones. We hypothesized that for these women, the association between migraine attacks and the menstrual cycle might be attributable to an increased prevalence of genetic polymorphisms in the hypothalamic-pituitary-gonadal axis. We selected 21 such polymerphisms previously reported to be associated with the common forms of migraine and genotyped 1740 individuals (1132 migraineurs) to determine whether any of these selected polymorphisms occurred more frequently in females with hormonally modulated migraine. We were able to confirm the association of migraine with 3 genetic polymorphisms seen in previous studies (rs4680 [COMT], rs2283265 [DRD2], and rs7131056 [DRD2]). Interestingly, we found 2 additional genetic polymorphisms (rs2070762 [TH] and rs6356 [TH]) to be associated with migraine when defining the phenotype as hormonally modulated migraine.

Growth and differentiation factor 11 (GDF11) is a transforming growth factor β superfamily member with a controversial role in aging processes. We have developed a highly specific LC-MS/MS assay to quantify GDF11, resolved from its homologue, myostatin (MSTN), based on unique amino acid sequence features. Here, we demonstrate that MSTN, but not GDF11, declines in healthy men throughout aging. Neither GDF11 nor MSTN levels differ as a function of age in healthy women. In an independent cohort of older adults with severe aortic stenosis, we show that individuals with higher GDF11 were more likely to be frail and have diabetes or prior cardiac conditions. Following valve replacement surgery, higher GDF11 at surgical baseline was associated with rehospitalization and multiple adverse events. Cumulatively, our results show that GDF11 levels do not decline throughout aging but are associated with comorbidity, frailty, and greater operative risk in older adults with cardiovascular disease.

Adjusting for age, sex, and precipitating cause, the relative risk of death was increased following fractures at most skeletal sites.This study aims to determine long-term survival following fractures due to any cause at each skeletal site.In a historical cohort study, 2,901 Olmsted County, MN, USA, residents ≥35 years old who experienced any fracture in 1989-1991 were followed passively for up to 22 years for death from any cause. Standardized mortality ratios (SMRs) compared observed to expected deaths.During 38,818 person-years of follow-up, 1,420 deaths were observed when 1,191 were expected (SMR, 1.2; 95 % CI, 1.1-1.3). The overall SMR was greatest soon after fracture, especially among the men, but remained elevated for over a decade thereafter. Adjusting for age and sex, relative death rates were greater for pathological fractures and less for severe trauma fractures compared to the fractures due to no more than moderate trauma. In the latter group, long-term mortality was increased following fractures at many skeletal sites. After further adjustment for precipitating cause, overall SMRs were elevated not only following fractures at the traditional major osteoporotic sites (i.e., distal forearm, proximal humerus, thoracic/lumbar vertebrae, and proximal femur) combined (SMR, 1.2; 95 % CI, 1.1-1.3) but also following all other fracture types combined (SMR 1.2; 95 % CI, 1.1-1.4), excluding the hand and foot fractures not associated with any increased mortality.The persistence of increased mortality long after the occurrence of a fracture has generally been attributed to underlying comorbidity, but this needs to be defined in much greater detail if specific opportunities are to be identified for reducing the excess deaths observed.

Context: Studies in rodents have demonstrated that sympathetic activity reduces bone formation and bone mass; these effects are mediated by the noncollagenous matrix protein, osteopontin. Objective: The objective of the study was to relate sympathetic activity (measured using microneurography at the peroneal nerve) to bone microstructure (assessed by high resolution peripheral quantitative computed tomography), bone turnover, and plasma osteopontin levels. Design, Setting, and Patients: Twenty-three women aged 20–72 yr (10 premenopausal and 13 postmenopausal) were studied in the Clinical Research Unit. Results: Sympathetic activity (bursts per 100 heart beats) was 2.4-fold higher in postmenopausal as compared with premenopausal women (P < 0.001). In the two groups combined and after age adjustment, sympathetic activity was inversely correlated with trabecular bone volume fraction (r = −0.55, P < 0.01) and thickness (r = −0.59, P < 0.01) and positively correlated with trabecular separation (r = 0.45, P < 0...

Smaller studies have evaluated SLC6A4 5-HTTLPR and GNβ3 825C>T polymorphisms in IBS, and interactions between 5-HTT LPR with life events have been reported in the psychiatric literature, but gene–environment studies in IBS are lacking. The purpose of this study was to assess the association of two polymorphisms with IBS and age of onset, and whether there are gene–environment interactions with IBS. Outpatients with IBS and controls completed a validated questionnaire and provided blood for DNA. Comparisons of genotype/allele frequencies between cases and controls were performed with logistic regression. Linear regression was used to evaluate the association between the variants and age of onset. Environmental variables tested included abuse, parental alcohol abuse, parental psychiatric disorders, and gastrointestinal infections. Genotyping was performed in 385 cases and 262 controls with median age of 50 years (range, 18.0–70.0) and 498 (77 %) females. The IBS subtype distribution among cases was: 102 (26 %) D-IBS, 40 (10 %) C-IBS, 125 (32 %) M-IBS, 118 (31 %) other. No association was observed between IBS or age of onset and both variants. Significant interactions were observed between GI infection and the GNβ3 825T allele. For those reporting gastrointestinal infection, the OR for IBS was 3.9 (95 % CI 1.2–12.7) whereas the OR was 0.86 (95 % CI 0.65–1.13) for those without prior infection. There was a significant interaction between the GNβ3 polymorphism and infection in the development of IBS, suggesting that its etiology is the result of a combination of specific genetic and environmental risk factors.

A positive association has been reported between greater bone density and higher breast cancer risk, suggesting that these women could be at reduced risk of fracture. To estimate fracture risk among unselected community women with breast cancer and to systematically assess associations with various risk factors including breast cancer treatments, we conducted a population-based historical cohort study of 608 Olmsted County, MN, USA, women with invasive breast cancer first diagnosed in 1990 to 1999 (mean age 61.6 ± 14.8 years), who were followed for 5776 person-years. Altogether, 568 fractures were observed in 270 women (98 per 1000 person-years). Overall fracture risk was elevated 1.8-fold, but the absolute increase in risk was only 9%, and 56% of the women did not experience a fracture during follow-up. Excluding pathologic fractures (15%) and those found incidentally (24%), to allow for ascertainment bias, the standardized incidence ratio was 1.2 (95% confidence interval [CI] 0.99 to 1.3) for total fracture risk and 0.9 (95% CI 0.7 to 1.2) for osteoporotic fracture risk alone. Various breast cancer treatments were associated with an increased risk of fracture, but those associations were strongest for pathologic fractures, which were relatively more common among the women who were premenopausal when their breast cancer was diagnosed. Moreover, underlying clinical characteristics prompting different treatments may have been partially responsible for the associated fracture outcomes (indication bias). These data thus demonstrate that breast cancer patients in general are not at greatly increased risk of fracture but neither are they protected from fractures despite any determinants that breast cancer and high bone density may have in common.

Previous studies using dual-energy X-ray absorptiometry (DXA) have demonstrated that age is a major predictor of bone fragility and fracture risk independent of areal bone mineral density (aBMD). Although this aBMD-independent effect of age has been attributed to poor bone "quality," the structural basis for this remains unclear. Because high-resolution peripheral quantitative computed tomography (HRpQCT) can assess bone microarchitecture, we matched younger and older subjects for aBMD at the ultradistal radius and assessed for possible differences in trabecular or cortical microstructure by HRpQCT. From an age-stratified, random sample of community adults, 44 women aged

Percent mammographic breast density (PMD) is a strong heritable risk factor for breast cancer. However, the pathways through which this risk is mediated are still unclear. To explore whether PMD and breast cancer have a shared genetic basis, we identified genetic variants most strongly associated with PMD in a published meta-analysis of five genome-wide association studies (GWAS) and used these to construct risk scores for 3,628 breast cancer cases and 5,190 controls from the UK2 GWAS of breast cancer. The signed per-allele effect estimates of single-nucleotide polymorphisms (SNP) were multiplied with the respective allele counts in the individual and summed over all SNPs to derive the risk score for an individual. These scores were included as the exposure variable in a logistic regression model with breast cancer case–control status as the outcome. This analysis was repeated using 10 different cutoff points for the most significant density SNPs (1%–10% representing 5,222–50,899 SNPs). Permutation analysis was also conducted across all 10 cutoff points. The association between risk score and breast cancer was significant for all cutoff points from 3% to 10% of top density SNPs, being most significant for the 6% (2-sided P = 0.002) to 10% (P = 0.001) cutoff points (overall permutation P = 0.003). Women in the top 10% of the risk score distribution had a 31% increased risk of breast cancer [OR = 1.31; 95% confidence interval (CI), 1.08–1.59] compared with women in the bottom 10%. Together, our results show that PMD and breast cancer have a shared genetic basis that is mediated through a large number of common variants. Cancer Res; 72(6); 1478–84. ©2012 AACR.

In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P = 5.6 × 10(-9)) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2 and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall P-values of 4.5 × 10(-4)-2.2 × 10(-7). Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance, would have been implicated by eGFR candidate gene approaches. LRP2, encoding the megalin receptor, was identified through connection with the previously known eGFR gene DAB2 and extends understanding of the megalin system in kidney function. These findings highlight integration of existing genome-wide association data with independent biological knowledge to uncover novel candidate eGFR associations, including candidates lacking known connections to kidney-specific pathways. The strategy may also be applicable to other clinical phenotypes, although more testing will be needed to assess its potential for discovery in general.

There remains little consensus on the link between vitamin levels and muscle mass or strength. We therefore investigated the association of serum 25-hydroxyvitamin D (25(OH)D), 1,25-dihydroxyvitamin D (1,25(OH)(2) D), and parathyroid hormone (PTH) levels with skeletal muscle mass and strength. We studied 311 men (mean age, 56 years; range, 23-91 years) and 356 women (mean age, 57 years; range, 21-97 years) representing an age-stratified, random sample of community adults. Multivariate linear regression models were used to examine the association of skeletal muscle mass (by total body dual-energy X-ray absorptiometry) and strength (handgrip force and isometric knee extension moment) with each of 25(OH)D, 1,25(OH)(2) D, and PTH quartiles, adjusted for age, physical activity, fat mass, and season. We found no consistent association between 25(OH)D or PTH and any of our measurements of muscle mass or strength, in either men or women. However, in subjects younger than 65 years, there was a statistically significant association between low 1,25(OH)(2) D levels and low skeletal mass in both men and women and low isometric knee extension moment in women, after adjustment for potential confounders. Modestly low 25(OH)D or high PTH levels may not contribute significantly to sarcopenia or muscle weakness in community adults. The link between low 25(OH)D and increased fall risk reported by others may be due to factors that affect neuromuscular function rather than muscle strength. The association between low 1,25(OH)(2) D and low skeletal mass and low knee extension moment, particularly in younger people, needs further exploration.

Using combined dual-energy X-ray absorptiometry (DXA) and quantitative computed tomography, we demonstrate that men matched with women for femoral neck (FN) areal bone mineral density (aBMD) have lower volumetric BMD (vBMD), higher bone cross-sectional area, and relatively similar values for finite element (FE)-derived bone strength. aBMD by DXA is widely used to identify patients at risk for osteoporotic fractures. aBMD is influenced by bone size (i.e., matched for vBMD, larger bones have higher aBMD), and increasing evidence indicates that absolute aBMD predicts a similar risk of fracture in men and women. Thus, we sought to define the relationships between FN aBMD (assessed by DXA) and vBMD, bone size, and FE-derived femoral strength obtained from quantitative computed tomography scans in men versus women. We studied men and women aged 40 to 90 years and not on osteoporosis medications. In 114 men and 114 women matched for FN aBMD, FN total cross-sectional area was 38% higher (P

The incidence of non-hip femur fractures increased between 1984 and 2007, with an increase in the rates for women after 1996.Recent reports have suggested that non-hip femur fractures may be decreasing over time, similar to proximal femur fractures.Incidence rates for non-hip femur fractures among Olmsted County, Minnesota, residents were assessed before and after 1995 when the oral bisphosphonate, alendronate, was approved in the USA.From 1984 to 2007, 727 non-hip femur fractures were observed in 690 Olmsted County residents (51% female [median age, 71.6 years] and 49% male [21.4 years]). Altogether, 20% of the fractures were subtrochanteric, 51% were diaphyseal, and 29% involved the distal femur. Causes included severe trauma in 51%, minimal to moderate trauma in 34%, and pathologic causes in 15%. The overall age- and sex-adjusted annual incidence of first non-hip femur fracture was 26.7 per 100,000 (25.0 per 100,000 for women and 26.6 per 100,000 for men). Incidence rates increased with age and were greater in women than men. Between 1984-1995 and 1996-2007, age-adjusted rates increased significantly for women (20.4 vs. 28.7 per 100,000; p = 0.002) but not for men (22.4 vs. 29.5 per 100,000; p = 0.202).The incidence of first non-hip femur fractures rose between 1984 and 2007, with an increase in the rates for women after 1995.

Objective: Autoantibodies to aquaporin-4 (AQP4) are specific and pathogenic for neuromyelitis optica (NMO). Therefore, we evaluated whether AQP4 single-nucleotide polymorphisms (SNPs) are associated with susceptibility to NMO or whether mutations that potentially alter AQP4 structure or expression are present in some patients. Methods: We genotyped 8 AQP4 SNPs chosen based on their minor allele frequency, location, and novelty in 177 NMO sporadic cases, 14 NMO familial cases, and 1,363 matched controls by TaqMan-based assay. We performed bidirectional sequencing of the promoter (1 kb), exons 0–4, and flanking splice consensus sequences, and the 5′ and 3′ untranslated regions of 177 sporadic and 14 familial NMO cases. Results: One of 8 SNPs (minor allele frequency = 0.01) was associated with NMO (NC 18.8; chrom pos. 22695167: T>A): odds ratio (95% confidence interval) = 13.1 (1.4–126.7); p = 0.026. In 3 patients with NMO (2 related), we detected 2 different missense allelic mutations at Arg19 (R19I and R19T). None of the 1,363 control subjects had Arg19 mutations (p = 0.001). Conclusions: Except for one uncommon SNP, no tested SNP was associated with NMO, nor were 3 SNP haplotypes, providing no support for the hypothesis that genetic variation in AQP4 accounts for overall susceptibility to NMO. Two different allelic Arg19 missense mutations are specific to NMO and segregated with the disease in one pedigree. Although the pathobiology underlying this is not yet established, their effects on the structure of the M1 isoform N terminus or the regulatory sequence of the M23 isoform by virtue of their location support a role of AQP4 orthogonal array formation on molecular susceptibility to NMO.

Recent studies in mice have demonstrated that osteocalcin (OCN) regulates testosterone (T) production in males but not in females. We hypothesized that this novel bone-testis axis may be most relevant during rapid skeletal growth to help maximize bone size. Thus we measured serum T, total and undercarboxylated (UC) OCN, and periosteal circumference at the radius in 56 boys (bone age 4 to 20 years). T was correlated with OCN (bone-age-adjusted r = 0.30, p = .024), with a similar trend for UC OCN. T began to increase in the boys at bone age 11 years, and OCN peaked at bone age 14 years. Thus we divided the boys into three groups: 4 to 10 years (n = 16), 11 to 14 years (n = 18), and 15 to 20 years (n = 22). In boys of bone age 11 to 14 years (but not the other two groups), OCN was correlated with T (r = 0.57, p = .013), with a similar trend for UC OCN; T, in turn, was correlated with periosteal circumference (r = 0.75, p

Fractures are increased among men with prostate cancer, especially those on androgen-deprivation therapy (ADT), but few data are available on men with localized prostate cancer. The purpose of this investigation was to estimate fracture risk among unselected community men with prostate cancer and systematically assess associations with ADT and other risk factors for fracture. In a population-based retrospective cohort study, 742 Olmsted County, MN, men with prostate cancer first diagnosed in 1990-1999 (mean age 68.2 ± 8.9 years) were followed for 6821 person-years. We estimated cumulative fracture incidence, assessed relative risk by standardized incidence ratios, and evaluated risk factors in time-to-fracture regression models. All together, 482 fractures were observed in 258 men (71 per 1000 person-years). Overall fracture risk was elevated 1.9-fold, with an absolute increase in risk of 9%. Relative to rates among community men generally, fracture risk was increased even among men not on ADT but was elevated a further 1.7-fold among ADT-treated compared with untreated men with prostate cancer. The increased risk following various forms of ADT was accounted for mainly by associations with pathologic fractures (14% of all fractures). Among men not on ADT (62% of the cohort), more traditional osteoporosis risk factors were implicated. In both groups, underlying clinical characteristics prompting different treatments (indication bias) may have been partially responsible for the associations seen with specific therapies. To the extent that advanced-stage disease and pathologic fractures account for the excess risk, the effectiveness of fracture prevention among men with prostate cancer may be limited.

Primary sclerosing cholangitis (PSC) is a chronic disease of the liver typified by lymphocytic portal tract inflammation and stricturing of the bile ducts because of concentric obliterative fibrosis. This results in progressive cholestasis leading to cirrhosis and end-stage liver disease (1, 2). The natural history of PSC is variable, although it is generally diagnosed in the fourth decade and the average time from diagnosis to death or liver transplantation, the only effective therapy, is 12–15 years (3). Inflammatory bowel disease (IBD), particularly ulcerative colitis (UC), is frequent in PSC, with some 75–85% of PSC patients having a diagnosis of IBD before or during the course of their disease (4, 5). The epidemiological picture of PSC remains incomplete, but it is certainly a rare disease, with an estimated prevalence in the USA of about one in 7100 individuals (6), consistent with studies from northern Europe (7–9). Despite its rarity, PSC accounts for a substantial percentage of orthotopic liver transplantation (OLT) in the USA (10). The mechanisms responsible for the development and variable progression of PSC are complex, the net result of the interaction between underlying genetics and environmental exposure (11). While genetic studies of many candidate loci have been performed in PSC, to date, the only convincing genetic associations reported are with extended human leucocyte antigen haplotypes in the major histocompatibility complex region of chromosome 6 [reviewed in (3, 12, 13)]. However, it should be noted that many previous studies were underpowered because of a small sample size, and a number of these loci deserve further study in PSC. Indeed, well-designed candidate gene studies utilizing modestly sized but highly characterized cohorts of PSC patients and controls will continue to be valuable despite the impending prospect of genome-wide studies from international collaborative groups. The matrix metalloproteinases (MMPs) are prime candidates for harbouring genetic variants potentially contributing to the development or the variable progression of PSC as they actively degrade the extracellular matrix, playing a major role in the modulation of portal-based fibrosis. Among these is MMP3, which is of particular interest to the study of PSC, as it has consistently been shown to be upregulated in inflamed colonic mucosa, contributing to tissue damage in IBD (14–17), is expressed in the liver by activated hepatic stellate cells and has likely antifibrotic activity because of its wide substrate specificity and ability to activate latent proforms of other MMPs (18, 19). Interestingly, MMP3 harbours a well-characterized insertion/deletion variant in its promoter characterized by the presence of either five or six adenine residues, commonly referred to as 5A/6A (rs3025058). The 5A allele has been shown to result in higher MMP3 expression because of disrupted binding of a nuclear factor kappa B dimmer, which acts as a transcriptional repressor (20–22), and shows signs of recent positive selection in northern European populations (23). Two previous studies have examined this polymorphism in PSC patients, the first of which reported an association of the MMP3 5A allele and the 5A/5A genotype with PSC and noted increased 5A/5A presence in PSC patients with documented portal hypertension (24). The second study was larger, and detected no such MMP3 association with PSC, but did identify an increased frequency of the 5A/5A genotype in PSC patients with UC compared with those without (25). Both of these studies focused only on the 5A/6A polymorphism of MMP3 and neither provided an analysis of the possible effect on progression to end-stage disease. Thus, the goal of our study was to more fully assess the potential effects of genetic variation in MMP3 on the development and progression of PSC.

Objectives We tested the hypothesis that shock success differs with initial and recurrent episodes of ventricular fibrillation (VF). Methods From September 2008 to March 2010 out-of-hospital cardiac arrest patients with VF as the initial rhythm at 9 study sites were defibrillated by paramedics using a rectilinear biphasic waveform. Shock success was defined as termination of VF within 5s post-shock. We used generalized estimating equation (GEE) analysis to assess the association between shock type (initial versus refibrillation) and shock success. Results Ninety-four patients presented in VF. Mean age was 65.4 years, 78.7% were male, and 80.9% were bystander-witnessed. VF recurred in 75 (79.8%). There were 338 shocks delivered for initial ( n =90) or recurrent ( n =248) VF available for analysis. Initial shocks terminated VF in 79/90 (87.8%) and subsequent shocks in 209/248 (84.3%). GEE odds ratio (OR) for shock type was 1.37 (95% CI 0.68–2.74). After adjusting for potential confounders, the OR for shock type remained insignificant (1.33, 95% CI 0.60–2.53). We observed no significant difference in ROSC (54.7% versus 52.6%, absolute difference 2.1%, p =0.87) or neurologically intact survival to hospital discharge (21.9% versus 33.3%, absolute difference 11.4%, p =0.31) between those with and without VF recurrence. Conclusions Presenting VF was terminated with one shock in 87.8% of cases. We observed no significant difference in the frequency of shock success between initial versus recurrent VF. VF recurred in the majority of patients and did not adversely affect shock success, ROSC, or survival.

Bone strength at the ultradistal radius, quantified by micro-finite element modeling, can be predicted by variables obtained from high-resolution peripheral quantitative computed tomography scans. The specific formula for this bone strength surrogate (-555.2 + 8.1 × [trabecular vBMD] + 19.6 × [cortical area] + 4.2 × [total cross-sectional area]) should be validated and tested in fracture risk assessment.The purpose of this study was to identify key determinants of ultradistal radius (UDR) strength and evaluate their relationships with age, sex steroid levels, and measures of habitual skeletal loading.UDR failure load (~strength) was assessed by micro-finite element (μFE) modeling in 105 postmenopausal controls from an earlier forearm fracture case-control study. Predictors of bone strength obtained by high-resolution peripheral quantitative computed tomography (HRpQCT) in this group were then evaluated in a population-based cohort of 214 postmenopausal women. Sex steroids were measured by mass spectrometry.A surrogate variable (-555.2 + 8.1 × [trabecular vBMD] + 19.6 × [cortical area] + 4.2 × [total cross-sectional area]) predicted UDR strength modeled by μFE (R(2) = 0.81), and all parameters except total cross-sectional area declined with age. Evaluated cross-sectionally, the 21% fall in predicted bone strength between ages 40-49 years and 80+ years more resembled the change in trabecular volumetric bone mineral density (vBMD) (-15%) than that in cortical area (-41%). In multivariable analyses, measures of body composition and physical activity were stronger predictors of UDR trabecular vBMD, cortical area, total cross-sectional area, and predicted bone strength than were sex steroid levels, but bio-available estradiol and testosterone were correlated with body mass.Bone strength at the UDR, as quantified by μFE, can be predicted from variables obtained by HRpQCT. Predicted bone strength declines with age with changes in UDR trabecular vBMD and cortical area, related in turn to reduced skeletal loading and sex steroid levels. The predicted bone strength formula should be validated and tested in fracture risk assessment.

Objective: Our goal was to evaluate the influence of quality control (QC) decisions using two genotype calling algorithms, CRLMM and Birdseed, designed for the Affymetrix SNP Array 6.0. Methods: Various QC options were tried using the two algorithms and comparisons were made on subject and call rate and on association results using two data sets. Results: For Birdseed, we recommend using the contrast QC instead of QC call rate for sample QC. For CRLMM, we recommend using the signal-to-noise rate ≧4 for sample QC and a posterior probability of 90% for genotype accuracy. For both algorithms, we recommend calling the genotype separately for each plate, and dropping SNPs with a lower call rate (Conclusions: Using our suggested workflow both algorithms performed similarly; however, fewer samples were removed and CRLMM took half the time to run our 854 study samples (4.2 h) compared to Birdseed (8.4 h).