Long-term outcomes of pelvic exenterations for gynecological malignancies: a single-center retrospective cohort study.

BACKGROUND: Recently, with the advancement of medical technology, the postoperative morbidity of pelvic exenteration (PE) has gradually decreased, and it has become a curative treatment option for some patients with recurrent gynecological malignancies. However, more evidence is still needed to support its efficacy. This study aimed to explore the safety and long-term survival outcome of PE and the feasibility of umbilical single-port laparoscopic PE for gynecologic malignancies in a single medical center in China. PATIENTS AND METHODS: PE for gynecological cancers except for ovarian cancer conducted by a single surgical team in Sun Yat-sen University Cancer Center between July 2014 and December 2019 were included and the data were retrospectively analyzed. RESULTS: Forty-one cases were included and median age at diagnosis was 53 years. Cervical cancer accounted for 87.8% of all cases, and most of them received prior treatment (95.1%). Sixteen procedures were performed in 2016 and before, and 25 after 2016. Three anterior PE were performed by umbilical single-site laparoscopy. The median operation time was 460 min, and the median estimated blood loss was 600 ml. There was no perioperative death. The years of the operations was significantly associated with the length of the operation time (P = 0.0018). The overall morbidity was 52.4%, while the severe complications rate was 19.0%. The most common complication was pelvic and abdominal infection. The years of surgery was also significantly associated with the occurrence of severe complication (P = 0.040). The median follow-up time was 55.8 months. The median disease-free survival (DFS) was 17.9 months, and the median overall survival (OS) was 25.3 months. The 5-year DFS was 28.5%, and the 5-year OS was 30.8%. CONCLUSION: PE is safe for patient who is selected by a multi-disciplinary treatment, and can be a curative treatment for some patients. PE demands a high level of experience from the surgical team. Umbilical single-port laparoscopy was a technically feasible approach for APE, meriting further investigation.

Trends in glucagon-like peptide 1 receptor agonist use, 2014 to 2022.

BACKGROUND: Recent Food and Drug Administration approvals of glucagon-like peptide 1 (GLP-1) receptor agonists linked to substantial weight loss have generated interest in demand projections. However, a longitudinal analysis in a large, diverse, current, real-world database has not been published. OBJECTIVES: The study objective was to determine user frequency of GLP-1 receptor agonist products overall and by type 2 diabetes (T2D), cardiovascular disease (CVD), and overweight or obese status. Secondary objective was monthly growth rate estimation by product since first appearance in University of California Health. METHODS: This retrospective cohort study included patients who were dispensed a GLP-1 receptor agonist from 2014 to 2022 in the University of California Health Data Warehouse. Exponential growth rates were estimated using a log-linear regression model. RESULTS: Between 2014 and 2018, only Trulicity and Victoza exceeded 5000 annual users. Ozempic users increased from 569 in 2019 to 7667 in 2020. Use accelerated with more than 13,310 users in 2021 to surpass Trulicity. Ozempic count was 22,891 in 2022. Wegovy rose from 989 in 2021 to 2992 in 2022. Mounjaro increased to 1508 users in 2022. Although generally similar trends were observed for T2D, CVD, and overweight or obese subgroups, the ascent of Ozempic as most frequently used was more apparent in the overweight or obese group. The monthly growth rates were 83.9% for Ozempic, 119.2% for Wegovy, 84.8% for Rybelsus, 53.3% for Saxenda, 12.9% for Adlyxin, 78.8% for Trulicity, and 254.3% for Mounjaro. CONCLUSION: This first cohort study of weight loss-associated GLP-1 receptor agonists in a large, diverse, state-wide health system demonstrated a rapid increased use that represents a clear and likely durable transition in utilization for this category. Informed decision making and longitudinal studies are needed to ensure evidence-concordant prescribing and supply stability.

Zinc-Carnosine Metallodrug Network as Dual Metabolism Inhibitor Overcoming Metabolic Reprogramming for Efficient Cancer Therapy.

The targeting of tumor metabolism as a novel strategy for cancer therapy has attracted tremendous attention. Herein, we develop a dual metabolism inhibitor, Zn-carnosine metallodrug network nanoparticles (Zn-Car MNs), which exhibits good Cu-depletion and Cu-responsive drug release, causing potent inhibition of both OXPHOS and glycolysis. Notably, Zn-Car MNs can decrease the activity of cytochrome c oxidase and the content of NAD+, so as to reduce ATP production in cancer cells. Thereby, energy deprivation, together with the depolarized mitochondrial membrane potential and increased oxidative stress, results in apoptosis of cancer cells. In result, Zn-Car MNs exerted more efficient metabolism-targeted therapy than the classic copper chelator, tetrathiomolybdate (TM), in both breast cancer (sensitive to copper depletion) and colon cancer (less sensitive to copper depletion) models. The efficacy and therapy of Zn-Car MNs suggest the possibility to overcome the drug resistance caused by metabolic reprogramming in tumors and has potential clinical relevance.

Debiased lasso for generalized linear models with a diverging number of covariates.

Modeling and drawing inference on the joint associations between single-nucleotide polymorphisms and a disease has sparked interest in genome-wide associations studies. In the motivating Boston Lung Cancer Survival Cohort (BLCSC) data, the presence of a large number of single nucleotide polymorphisms of interest, though smaller than the sample size, challenges inference on their joint associations with the disease outcome. In similar settings, we find that neither the debiased lasso approach (van de Geer et al., 2014), which assumes sparsity on the inverse information matrix, nor the standard maximum likelihood method can yield confidence intervals with satisfactory coverage probabilities for generalized linear models. Under this "large n, diverging p" scenario, we propose an alternative debiased lasso approach by directly inverting the Hessian matrix without imposing the matrix sparsity assumption, which further reduces bias compared to the original debiased lasso and ensures valid confidence intervals with nominal coverage probabilities. We establish the asymptotic distributions of any linear combinations of the parameter estimates, which lays the theoretical ground for drawing inference. Simulations show that the proposed refined debiased estimating method performs well in removing bias and yields honest confidence interval coverage. We use the proposed method to analyze the aforementioned BLCSC data, a large-scale hospital-based epidemiology cohort study investigating the joint effects of genetic variants on lung cancer risks.

Ratiometric Semiconducting Polymer Nanoparticle for Reliable Photoacoustic Imaging of Pneumonia-Induced Vulnerable Atherosclerotic Plaque in Vivo.

Acute pneumonia can greatly increase the vulnerable risk of atherosclerotic plaque and contribute to the mortality of cardiovascular disease. To accurately assess the rupture risk caused by acute pneumonia, we developed a novel kind of ratiometric semiconducting polymer nanoparticle (RSPN) for photoacoustic imaging of vulnerable plaque in apolipoprotein E-deficient mice complicated with pneumonia. Specifically, RSPN can react with O2•- and exhibit the enhanced photoacoustic signals at about 690 nm, while 800 nm is regarded as an internal photoacoustic reference. As a result, RSPN can provide reliable determination of O2•- within aortic atherosclerosis by analyzing the ratios of photoacoustic signals, which can successfully reflect the oxidative stress level in vulnerable plaque. Therefore, RSPN enable to specifically distinguish plaque-bearing mice and plaque-bearing mice complicated with pneumonia from healthy mice, which provides a promising tool to predict the vulnerability of plaque for reducing the mortality of atherosclerotic-induced cardiovascular disease.

Examination of Medication Use Patterns by Age Group, Comorbidity, and Month in COVID-19 Positive Patients in a Large Statewide Health System During the Pandemic in 2020.

Background: Understanding medication use patterns for patients with COVID-19 will provide needed insight into the evolution of COVID-19 treatment over the course of the SARS-CoV-2 pandemic and aid clinical management considerations. Objectives: To systematically determine most frequently used medications among COVID-19 patients overall and by hospitalization status. Secondary objective was use measurement of medications considered potential therapeutic options. Methods: Retrospective cohort study was performed using data from the University of California COVID Research Data Set (UC CORDS) patients between March 10, 2020, and December 31, 2020. Main outcomes were percentages of patients prescribed medications, overall, by age group, and by comorbidity based on hospitalization status for COVID-19 patients. Use percentage by month of COVID-19 diagnosis was measured. Cumulative count of potential therapeutic options was measured over time. Results: Dataset included 22 896 unique patients with COVID-19 (mean [SD] age, 42.4 [20.4] years; 12 154 [53%] women). Most frequently used medications in patients overall were acetaminophen (21.2%), albuterol (14.9%), ondansetron (13.9%), and enoxaparin (10.8%). Dexamethasone use increased from fewer than 50 total hospitalized patients through April who had received the medication, to more than 500 patients by mid-August. Cumulative count of enoxaparin users was the largest throughout the study period. Conclusion and Relevance: In this retrospective cohort study, across age and comorbidity groups, predominant utilization was for supportive care therapy. Dexamethasone and remdesivir experienced large increases in use. Conversely, hydroxychloroquine and azithromycin use markedly dropped. Medication utilization rapidly shifted toward more evidence-concordant treatment of patients with COVID-19 as rigorous study findings emerged.

Ternary Alloy PtWMn as a Mn Nanoreservoir for High-Field MRI Monitoring and Highly Selective Ferroptosis Therapy.

Ferroptosis exhibits potential to damage drug-resistant cancer cells. However, it is still restricted with the "off-target" toxicity from the undesirable leakage of metal ions from ferroptosis agents, and the lack of reliable imaging for monitoring the ferroptosis process in living systems. Herein, we develop a novel ternary alloy PtWMn nanocube as a Mn reservoir, and further design a microenvironment-triggered nanoplatform that can accurately release Mn ions within the tumor to increase reactive oxygen species (ROS) generation, produce O2 and consume excess glutathione for synergistically enhancing nonferrous ferroptosis. Moreover, this nanoplatform exerts a responsive signal in high-field magnetic resonance imaging (MRI), which enables the real-time report of Mn release and the monitoring of ferroptosis initiation through the signal changes of T1 -/T2 -MRI. Thus, our nanoplatform provides a novel strategy to store, deliver and precisely release Mn ions for MRI-guided high-specificity ferroptosis therapy.

A Structured Brain-wide and Genome-wide Association Study Using ADNI PET Images.

A multi-stage variable selection method is introduced for detecting association signals in structured brain-wide and genome-wide association studies (brain-GWAS). Compared to conventional single-voxel-to-single-SNP approaches, our approach is more efficient and powerful in selecting the important signals by integrating anatomic and gene grouping structures in the brain and the genome, respectively. It avoids large number of multiple comparisons while effectively controls the false discoveries. Validity of the proposed approach is demonstrated by both theoretical investigation and numerical simulations. We apply the proposed method to a brain-GWAS using ADNI PET imaging and genomic data. We confirm previously reported association signals and also find several novel SNPs and genes that either are associated with brain glucose metabolism or have their association significantly modified by Alzheimer's disease status.

Circular RNA VMA21 ameliorates sepsis-associated acute kidney injury by regulating miR-9-3p/SMG1/inflammation axis and oxidative stress.

Accumulating evidence suggests that circular RNAs have the abilities to regulate gene expression during the progression of sepsis-associated acute kidney injury. Circular RNA VMA21 (circVMA21), a recent identified circular RNA, could reduce apoptosis to alleviate intervertebral disc degeneration in rats and protect WI-38 cells from lipopolysaccharide-induced injury. However, the role of circVMA21 in sepsis-associated acute kidney injury (sepsis-associated AKI) is unknown. In this study, we first demonstrated that circVMA21 alleviated sepsis-associated AKI by reducing apoptosis and inflammation in rats and HK-2 cells. Additionally, to explore the molecule mechanism underlying the amelioration, after the bioinformatics analysis, we confirmed that miR-9-3p directly bound to circVMA21 by luciferase and RNA immunoprecipitation assay, and the effector protein of miR-9-3p was SMG1. Furthermore, the oxidative stress caused by sepsis-associated AKI was down-regulated by circVMA21. In conclusion, circVMA21 plays an important role in the regulating sepsis-associated AKI via adjusting miR-9-39/SMG1/inflammation axis and oxidative stress.

Synchronous hepatocellular carcinoma and gallbladder adenocarcinoma with neuroendocrine differentiation: a case report and literature review.

BACKGROUND: Double primary cancers have a low incidence rate, and synchronous hepatocellular carcinoma and gallbladder adenocarcinoma are rarely reported. Here, we report such a case- the 12th case of synchronous double primary cancers featuring HCC and GC, but the first case of neuroendocrine differentiation in the gallbladder. CASE PRESENTATION: A 77-year-old female was admitted to the hospital complaining of weakness and inappetence for six months. Contrast-enhanced computed tomography (CT) of the abdomen indicated an 11 cm space-occupying lesion in the right lobe of the liver. Later, magnetic resonance imaging showed a high possibility of a massive hepatoma, and multiple gallstones were also seen. After transhepatic arterial chemoembolization, a repeat abdominal CT showed obvious local nodular thickening in the gallbladder wall. Finally, resection of the right lobe of the liver and cholecystectomy were performed. During an approximately 2-year follow-up, the patient recovered uneventfully without recurrence or metastasis. CONCLUSION: The disease in this case is rare and lacked typical radiological features. More precise and advanced diagnostic techniques are needed to obtain a clear diagnosis and refine treatment strategies. The management strategy should always be curative, even in the presence of multiple malignancies.

Optimizing Electronic Release of Imaging Results through an Online Patient Portal.

Purpose To determine an optimal embargo period preceding release of radiologic test results to an online patient portal. Materials and Methods This prospective discrete choice conjoint survey with modified orthogonal design was administered to patients by trained interviewers at four outpatient sites and two institutions from December 2016 to February 2018. Three preferences for receiving imaging results associated with a possible or known cancer diagnosis were evaluated: delay in receipt of results (1, 3, or 14 days), method of receipt (online portal, physician's office, or phone), and condition of receipt (before, at the same time as, or after health care provider). Preferences (hereafter, referred to as utilities) were derived from parameter estimates (ß) of multinomial regression stratified according to study participant and choice set. Results Among 464 screened participants, the response and completion rates were 90.5% (420 of 464) and 99.5% (418 of 420), respectively. Participants preferred faster receipt of results (P < .001) from their physician (P < .001) over the telephone (P < .001). Each day of delay decreased preference by 13 percentage points. Participants preferred immediate receipt of results through an online portal (utility, -.57) if made to wait more than 6 days to get results in the office and more than 11 days to get results by telephone. Compared with receiving results in their physician's office on day 7 (utility, -.60), participants preferred immediate release through the online portal without physician involvement if followed by a telephone call within 6 days (utility, -0.49) or an office visit within 2 days (utility, -.53). Older participants preferred physician-directed communication (P < .001). Conclusion The optimal embargo period preceding release of results through an online portal depends on the timing of traditional telephone- and office-based styles of communication. © RSNA, 2018 Online supplemental material is available for this article. See also the editorial by Arenson et al in this issue.

Retention of Alzheimer Disease Research Participants.

INTRODUCTION: Participant retention is important to maintaining statistical power, minimizing bias, and preventing scientific error in Alzheimer disease and related dementias research. METHODS: We surveyed representative investigators from NIH-funded Alzheimer's Disease Research Centers (ADRC), querying their use of retention tactics across 12 strategies. We compared survey results to data from the National Alzheimer's Coordinating Center for each center. We used a generalized estimating equation with independent working covariance model and empirical standard errors to assess relationships between survey results and rates of retention, controlling for participant characteristics. RESULTS: Twenty-five (83%) responding ADRCs employed an average 42 (SD=7) retention tactics. In a multivariable model that accounted for participant characteristics, the number of retention tactics used by a center was associated with participant retention (odds ratio=1.68, 95% confidence interval: 1.42, 1.98; P<0.001 for the middle compared with the lowest tertile survey scores; odds ratio=1.59, 95% confidence interval: 1.30, 1.94; P<0.001 for the highest compared with the lowest tertile survey scores) at the first follow-up visit. Participant characteristics such as normal cognition diagnosis, older age, higher education, and Caucasian race were also associated with higher retention. CONCLUSIONS: Retention in clinical research is more likely to be achieved by employing a variety of tactics.

Proportional cross-ratio model.

Cross-ratio is an important local measure of the strength of dependence among correlated failure times. If a covariate is available, it may be of scientific interest to understand how the cross-ratio varies with the covariate as well as time components. Motivated by the Tremin study, where the dependence between age at a marker event reflecting early lengthening of menstrual cycles and age at menopause may be affected by age at menarche, we propose a proportional cross-ratio model through a baseline cross-ratio function and a multiplicative covariate effect. Assuming a parametric model for the baseline cross-ratio, we generalize the pseudo-partial likelihood approach of Hu et al. (Biometrika 98:341-354, 2011) to the joint estimation of the baseline cross-ratio and the covariate effect. We show that the proposed parameter estimator is consistent and asymptotically normal. The performance of the proposed technique in finite samples is examined using simulation studies. In addition, the proposed method is applied to the Tremin study for the dependence between age at a marker event and age at menopause adjusting for age at menarche. The method is also applied to the Australian twin data for the estimation of zygosity effect on cross-ratio for age at appendicitis between twin pairs.

Low grip strength predicts incident diabetes among mid-life women: the Michigan Study of Women's Health Across the Nation.

Background: skeletal muscle is the primary site of glucose uptake, yet the impact of age-related changes in muscle strength on diabetes risk is unknown. Methods: four hundred and twenty-four participants (60% Black, 40% White) from the Michigan site of the Study of Women's Health Across the Nation contributed annual grip strength measures and were followed from 1996 to 2012 to identify incident cases of diabetes. Diabetes was defined as self-reported physician-diagnosed diabetes, use of anti-diabetic medications or measured fasting glucose ≥126 mg/dl or haemoglobin A1c > 6.5%. Results: the 16-year diabetes incidence was 37%. The average baseline weight-normalised grip strength (NGS, kg per kg body weight) was 0.41 ± 0.12 and a mean of 0.29 ± 0.14 kg of absolute grip strength was lost per year. Each 0.1 higher NGS was associated with a 19% lower hazard of incident diabetes (P = 0.006) after adjustment for age, race/ethnicity, economic strain, smoking, menopause status, hormone use, physical activity and waist-hip ratio. In race/ethnic-stratified models, each 0.10 increase in NGS was associated with a 54% lower hazard of incident diabetes (P < 0.0001) among White women but the association among Black women was not statistically significant. In models without adjustment for waist-hip ratio or restricted to women <48 years of age at baseline, there was a statistically significant association between baseline NGS and incident diabetes among Black women. The rate of change in grip strength was not associated with diabetes incidence. Conclusion: the mid-life is an important risk period for diabetes onset. Improving muscle strength. during mid-life may contribute to preventing diabetes among women.

Breast care problems on call: training residents to manage effectively.

PURPOSE: Our aim was to assess and address the challenges radiology residents face when managing breast imaging emergencies on call and to determine if targeted educational interventions improved resident confidence and knowledge. METHODS: We created surveys to determine resident comfort level with and knowledge of appropriate management of breast imaging emergencies. We also created structured educational interventions to improve resident confidence and knowledge. The effectiveness of these interventions was assessed with pre- and post-intervention surveys given to the 43 residents at our institution. RESULTS: Thirty-six of the 43 residents at our institution completed both surveys. The results showed that 33 of 36 residents (91.7%) felt an increase in their comfort level after utilizing one or both of the interventions. There was also significant improvement in resident knowledge; the average resident score on the knowledge questions improved from 40 to 68% (p < 0.0001). CONCLUSION: Managing breast imaging emergencies on call can be challenging and stressful for residents. Educational interventions such as our targeted teaching tools can significantly improve resident confidence and knowledge. Presenting dedicated teaching materials directed at a previously identified knowledge deficit and source of stress significantly improved resident knowledge base and confidence in managing breast imaging emergencies on call.

Recurrence of Colonic Diverticulitis: Identifying Predictive CT Findings-Retrospective Cohort Study.

Purpose To identify computed tomographic (CT) findings that are predictive of recurrence of colonic diverticulitis. Materials and Methods Institutional review board approval was obtained for this HIPAA-compliant, retrospective cohort study. Six abdominal fellowship-trained radiologists reviewed the CT studies of 440 consecutive subjects diagnosed with acute colonic diverticulitis between January 2004 and May 2008 to determine the involved segments, maximum wall thickness in the inflamed segment, severity of diverticulosis, presence of complications (abscess, fistula, stricture, or perforation), and severity of the inflammation. Electronic medical records were reviewed for a 5-year period after the patients' first CT study to determine clinical outcomes. Predictors of diverticulitis recurrence were assessed with univariate and multiple Cox proportional hazard regression models. Results Colonic diverticulitis most commonly involved the rectosigmoid (70%, 309 of 440) and descending (30%, 133 of 440) colon segments. Complicated diverticulitis was present in 22% (98 of 440) of patients. On the basis of the results of univariate analysis, significant predictors of diverticulitis recurrence were determined to be maximum colonic wall thickness in the inflamed segment (hazard ratio [HR], 1.07 per every millimeter of increase in wall thickness; P < .001), presence of a complication (HR, 1.75; P = .002), and subjective severity of inflammation (HR, 1.36 for every increase in severity category; P value for linear trend = .003). The difference in maximum wall thickness in the inflamed segment (HR, 1.05 per millimeter; P = .016) and subjective inflammation severity (HR, 1.29 per category; P = .018)remained statistically significant in a Cox multiple regression model. Conclusion Maximum colonic wall thickness and subjective severity of acute diverticulitis allow prediction of recurrent diverticulitis and may be useful for stratifying patients according to the need for elective partial colectomy. © RSNA, 2017 Online supplemental material is available for this article.

Cadmium and Alzheimer's disease mortality in U.S. adults: Updated evidence with a urinary biomarker and extended follow-up time.

Cadmium has been linked to impaired cognitive function in adults and may cause behavioral, physiological and molecular abnormalities characteristic of Alzheimer's disease (AD) in animals. Evidence linking cadmium and AD in humans is limited, but supportive. In the most recent epidemiologic study, blood cadmium in U.S. adults was positively associated with elevated AD mortality 7-13 years later. The association between urinary cadmium - an arguably more appropriate biomarker for studying chronic diseases - and AD mortality has not yet been explored. Further study of cadmium and AD mortality in an independent population, with longer follow-up, and stratified by sex is also needed. We sought to answer these questions using the U.S. National Health and Nutrition Examination Survey (NHANES) (1999-2006 cycles) and NHANES III (interviews in 1988-1994) datasets, separately linked to AD mortality as of 2011. We used survey-weighted Cox regression models predicting age at AD death and adjusted for race/ethnicity, sex, smoking status, education and urinary creatinine. An interquartile range (IQR; IQR=0.51ng/mL) increase in urinary cadmium was associated with 58% higher rate of AD mortality (hazard ratio (HR)=1.58, 95% CI: 1.20, 2.09. p-value=0.0009, mean follow-up: 7.5 years) in NHANES 1999-2006 participants. In contrast, in NHANES III participants, an IQR (IQR=0.78ng/mL) increase in urinary cadmium was not associated with AD mortality (HR=0.85, 95% CI: 0.63, 1.17, p-value=0.31, mean follow-up: 13 years). Also in the NHANES III sample however, when the maximum follow-up time was restricted to 12.7 years (i.e. the same as NHANES 1999-2006 participants) and urinary creatinine adjustments were not made, urinary cadmium was associated with elevated AD mortality (HR=1.11, 95% CI: 1.02, 1.20, p-value=0.0086). Our study partially supported an association between cadmium and AD mortality, but the sensitivity of results to follow-up time and creatinine adjustments necessitate cautious interpretation of the association. Further studies, particularly those on toxicological mechanisms, are required to fully understand the nature of the "cadmium-AD mortality" association.

Simple subgroup approximations to optimal treatment regimes from randomized clinical trial data.

We consider the use of randomized clinical trial (RCT) data to identify simple treatment regimes based on some subset of the covariate space, A. The optimal subset, A, is selected by maximizing the expected outcome under a treat-if-in-A regime, and is restricted to be a simple, as it is desirable that treatment decisions be made with only a limited amount of patient information required. We consider a two-stage procedure. In stage 1, non-parametric regression is used to estimate treatment effects for each subject, and in stage 2 these treatment effect estimates are used to systematically evaluate many subgroups of a simple, prespecified form to identify A. The proposed methods were found to perform favorably compared with two existing methods in simulations, and were applied to prehypertension data from an RCT.

DNA methylation analysis of the temporal artery microenvironment in giant cell arteritis.

OBJECTIVE: To investigate the inflammatory response in giant cell arteritis (GCA) by characterising the DNA methylation pattern within the temporal artery microenvironment. METHODS: Twelve patients with non-equivocal histological evidence for GCA and 12 age-matched, sex-matched and ethnicity-matched controls with normal biopsies were studied. DNA was extracted from the affected portions of temporal artery tissue in patients with GCA and from histologically confirmed normal arteries in controls. Genome-wide DNA methylation status was evaluated using the Illumina Infinium HumanMethylation450 BeadChip Array. Differentially methylated loci between affected and unaffected arterial tissues were identified, and subsequent bioinformatic analysis performed. Immunohistochemistry was used to examine tissue expression patterns in temporal artery biopsies. RESULTS: We identified 1555 hypomethylated CG sites (853 genes) in affected temporal artery tissue from patients with GCA compared with normal controls. Gene ontology enrichment analysis of hypomethylated genes revealed significant representation in T cell activation and differentiation pathways, including both TH1 and TH17 signatures. Our DNA methylation data suggest a role for increased activity of the calcineurin/nuclear factor of activated T cells (NFAT) signalling pathway in GCA, confirmed by immunohistochemistry showing increased expression and nuclear localisation of NFAT1. NFAT signalling downstream targets such as interleukin (IL)-21/IL-21R and CD40L were overexpressed in GCA-affected arteries. Further, proinflammatory genes including TNF, LTA, LTB, CCR7, RUNX3, CD6, CD40LG, IL2, IL6, NLRP1, IL1B, IL18, IL21, IL23R and IFNG were hypomethylated in the cellular milieu of GCA arteries. CONCLUSIONS: We characterised the inflammatory response in GCA-affected arteries using 'epigenetic immunophenotyping' and identified molecules and pathways relevant to disease pathogenesis in GCA.

Multiple testing for neuroimaging via hidden Markov random field.

Traditional voxel-level multiple testing procedures in neuroimaging, mostly p-value based, often ignore the spatial correlations among neighboring voxels and thus suffer from substantial loss of power. We extend the local-significance-index based procedure originally developed for the hidden Markov chain models, which aims to minimize the false nondiscovery rate subject to a constraint on the false discovery rate, to three-dimensional neuroimaging data using a hidden Markov random field model. A generalized expectation-maximization algorithm for maximizing the penalized likelihood is proposed for estimating the model parameters. Extensive simulations show that the proposed approach is more powerful than conventional false discovery rate procedures. We apply the method to the comparison between mild cognitive impairment, a disease status with increased risk of developing Alzheimer's or another dementia, and normal controls in the FDG-PET imaging study of the Alzheimer's Disease Neuroimaging Initiative.