Insomnia and short sleep duration, but not chronotype, is associated with chronic widespread pain: Mendelian randomization study.

OBJECTIVES: Sleep disturbance has been associated with chronic widespread pain (CWP), but their causal relationship remains unclear. We aimed to examine the causal relationship and direction between CWP and sleep traits, namely insomnia, sleep duration and chronotype, using Mendelian Randomization. METHOD: We used genetic association data from ~0.5 million individuals and up to 1.8 million controls from the UK Biobank (UKB). All traits were defined predominantly by self-report. Short sleep duration was defined as average ≤6 hours per 24 hours. Chronotype refers to the inclination to sleep at certain times where some wake and go to bed early ('morning' person), and others wake and go to sleep later ('evening' person). To permit use of the largest available genetic association data, we used the Causal Analysis Using Summary Effect estimates (CAUSE) method, which allows for sample overlap. RESULTS: Insomnia (OR 1.009, 95% credible interval 1.005, 1.014; p = 0.018 that the causal model is a better fit than non-causal model) and short sleep duration (OR 1.060, 95%CrI 1.038, 1.083; p = 0.040) were causally associated with increased risk of CWP, with limited evidence for reverse causation. There was no evidence in support of long sleep duration or chronotype being associated with CWP. CONCLUSIONS: This study suggest that insomnia and short sleep duration (≤6 hours) are associated with an increased risk of CWP. Improving short sleep duration and insomnia, rather than chronotype, may be effective in reducing the risk of CWP, although these results should be replicated in epidemiological and interventional studies.

Investigation of the activity of a novel tropolone in osteosarcoma.

Osteosarcoma (OS) is a primary malignant bone tumor characterized by frequent metastasis, rapid disease progression, and a high rate of mortality. Treatment options for OS have remained largely unchanged for decades, consisting primarily of cytotoxic chemotherapy and surgery, thus necessitating the urgent need for novel therapies. Tropolones are naturally occurring seven-membered non-benzenoid aromatic compounds that possess antiproliferative effects in a wide array of cancer cell types. MO-OH-Nap is an α-substituted tropolone that has activity as an iron chelator. Here, we demonstrate that MO-OH-Nap activates all three arms of the unfolded protein response (UPR) pathway and induces apoptosis in a panel of human OS cell lines. Co-incubation with ferric chloride or ammonium ferrous sulfate completely prevents the induction of apoptotic and UPR markers in MO-OH-Nap-treated OS cells. MO-OH-Nap upregulates transferrin receptor 1 (TFR1) protein levels, as well as TFR1, divalent metal transporter 1 (DMT1), iron-regulatory proteins (IRP1, IRP2), ferroportin (FPN), and zinc transporter 14 (ZIP14) transcript levels, demonstrating the impact of MO-OH-Nap on iron-homeostasis pathways in OS cells. Furthermore, MO-OH-Nap treatment restricts the migration and invasion of OS cells in vitro. Lastly, metabolomic profiling of MO-OH-Nap-treated OS cells revealed distinct changes in purine and pyrimidine metabolism. Collectively, we demonstrate that MO-OH-Nap-induced cytotoxic effects in OS cells are dependent on the tropolone's ability to alter cellular iron availability and that this agent exploits key metabolic pathways. These studies support further evaluation of MO-OH-Nap as a novel treatment for OS.

BG2: Bayesian variable selection in generalized linear mixed models with nonlocal priors for non-Gaussian GWAS data.

BACKGROUND: Genome-wide association studies (GWASes) aim to identify single nucleotide polymorphisms (SNPs) associated with a given phenotype. A common approach for the analysis of GWAS is single marker analysis (SMA) based on linear mixed models (LMMs). However, LMM-based SMA usually yields a large number of false discoveries and cannot be directly applied to non-Gaussian phenotypes such as count data. RESULTS: We present a novel Bayesian method to find SNPs associated with non-Gaussian phenotypes. To that end, we use generalized linear mixed models (GLMMs) and, thus, call our method Bayesian GLMMs for GWAS (BG2). To deal with the high dimensionality of GWAS analysis, we propose novel nonlocal priors specifically tailored for GLMMs. In addition, we develop related fast approximate Bayesian computations. BG2 uses a two-step procedure: first, BG2 screens for candidate SNPs; second, BG2 performs model selection that considers all screened candidate SNPs as possible regressors. A simulation study shows favorable performance of BG2 when compared to GLMM-based SMA. We illustrate the usefulness and flexibility of BG2 with three case studies on cocaine dependence (binary data), alcohol consumption (count data), and number of root-like structures in a model plant (count data).

BGWAS: Bayesian variable selection in linear mixed models with nonlocal priors for genome-wide association studies.

BACKGROUND: Genome-wide association studies (GWAS) seek to identify single nucleotide polymorphisms (SNPs) that cause observed phenotypes. However, with highly correlated SNPs, correlated observations, and the number of SNPs being two orders of magnitude larger than the number of observations, GWAS procedures often suffer from high false positive rates. RESULTS: We propose BGWAS, a novel Bayesian variable selection method based on nonlocal priors for linear mixed models specifically tailored for genome-wide association studies. Our proposed method BGWAS uses a novel nonlocal prior for linear mixed models (LMMs). BGWAS has two steps: screening and model selection. The screening step scans through all the SNPs fitting one LMM for each SNP and then uses Bayesian false discovery control to select a set of candidate SNPs. After that, a model selection step searches through the space of LMMs that may have any number of SNPs from the candidate set. A simulation study shows that, when compared to popular GWAS procedures, BGWAS greatly reduces false positives while maintaining the same ability to detect true positive SNPs. We show the utility and flexibility of BGWAS with two case studies: a case study on salt stress in plants, and a case study on alcohol use disorder. CONCLUSIONS: BGWAS maintains and in some cases increases the recall of true SNPs while drastically lowering the number of false positives compared to popular SMA procedures.

Cytologic atypia of benign inflammatory versus neoplastic cutaneous squamous lesions.

BACKGROUND: Cytologic atypia encompasses several features of abnormal cellular morphology. We sought to quantify these features in benign and premalignant/malignant squamous cell lesions to better characterize criteria for malignancy. METHODS: We conducted a rater-blinded observational study in which histopathology slides were evaluated under light microscopy, and the presence and relative quantity of 24 distinct cytological features were recorded, along with respective diagnoses. Each slide was evaluated, and the ratings were recorded and analyzed. RESULTS: The most helpful findings, whose presence in high numbers indicates an increased likelihood that the tissue sample is premalignant/malignant, were: (1) pleomorphic parakeratosis; (2) pleomorphic nuclei in the epithelium; (3) irregular nuclei; (4) thick refractile nuclear envelope; (5) presence of nuclear hyperchromasia (dark gray); (6) peripheral nucleoli; and (7) nucleolar stems. Higher values of round or oval nuclear shape and vesicular nuclei increase the likelihood that the tissue sample is benign. CONCLUSIONS: Certain nuclear features have a higher association with premalignancy/malignancy and may guide histologic evaluation of a given lesion. These findings can be used in combination with architectural features and clinical history to add to a complete diagnostic picture.

Evaluation of geranylgeranyl diphosphate synthase inhibition as a novel strategy for the treatment of osteosarcoma and Ewing sarcoma.

Rab GTPases are critical regulators of protein trafficking in the cell. To ensure proper cellular localization and function, Rab proteins must undergo a posttranslational modification, termed geranylgeranylation. In the isoprenoid biosynthesis pathway, the enzyme geranylgeranyl diphosphate synthase (GGDPS) generates the 20-carbon isoprenoid donor (geranylgeranyl pyrophosphate [GGPP]), which is utilized in the prenylation of Rab proteins. We have pursued the development of GGDPS inhibitors (GGSI) as a novel means to target Rab activity in cancer cells. Osteosarcoma (OS) and Ewing sarcoma (ES) are aggressive childhood bone cancers with stagnant survival statistics and limited treatment options. Here we show that GGSI treatment induces markers of the unfolded protein response (UPR) and triggers apoptotic cell death in a variety of OS and ES cell lines. Confirmation that these effects were secondary to cellular depletion of GGPP and disruption of Rab geranylgeranylation was confirmed via experiments using exogenous GGPP or specific geranylgeranyl transferase inhibitors. Furthermore, GGSI treatment disrupts cellular migration and invasion in vitro. Metabolomic profiles of OS and ES cell lines identify distinct changes in purine metabolism in GGSI-treated cells. Lastly, we demonstrate that GGSI treatment slows tumor growth in a mouse model of ES. Collectively, these studies support further development of GGSIs as a novel treatment for OS and ES.

BICOSS: Bayesian iterative conditional stochastic search for GWAS.

BACKGROUND: Single marker analysis (SMA) with linear mixed models for genome wide association studies has uncovered the contribution of genetic variants to many observed phenotypes. However, SMA has weak false discovery control. In addition, when a few variants have large effect sizes, SMA has low statistical power to detect small and medium effect sizes, leading to low recall of true causal single nucleotide polymorphisms (SNPs). RESULTS: We present the Bayesian Iterative Conditional Stochastic Search (BICOSS) method that controls false discovery rate and increases recall of variants with small and medium effect sizes. BICOSS iterates between a screening step and a Bayesian model selection step. A simulation study shows that, when compared to SMA, BICOSS dramatically reduces false discovery rate and allows for smaller effect sizes to be discovered. Finally, two real world applications show the utility and flexibility of BICOSS. CONCLUSIONS: When compared to widely used SMA, BICOSS provides higher recall of true SNPs while dramatically reducing false discovery rate.

Testing the role of aerobic exercise in the treatment of posttraumatic stress disorder (PTSD) symptoms in U.S. active duty military personnel: a pilot study.

The purpose of this pilot study was to determine if the efficacy of imaginal exposure for symptoms of posttraumatic stress disorder (PTSD) could be improved by adding aerobic exercise. We hypothesized that aerobic exercise would enhance the efficacy of exposure therapy. Active duty service members with clinically significant symptoms of posttraumatic stress (PTSD Checklist-Stressor-Specific Version, [PCL-S], ≥25) were randomized into one of four conditions: exercise only; imaginal exposure only; imaginal exposure plus exercise; no exercise/no exposure therapy (control). Participants (N = 72) were primarily male, Army, noncommissioned officers ranging in age from 22 to 52. PTSD symptom severity decreased over time (p < .0001); however, there were no significant differences between the experimental conditions. The prediction that imaginal exposure augmented with aerobic exercise would be superior to either imaginal exposure alone or aerobic exercise alone was not supported, suggesting that engaging in exercise and imaginal exposure simultaneously may not be any better than engaging in either activity alone. A better understanding of individually administered and combined exercise and exposure therapy interventions for PTSD is warranted.

Long-term strength and functional status in inclusion body myositis and identification of trajectory subgroups.

INTRODUCTION: Objective information on longitudinal disease progression in inclusion body myositis (IBM) is lacking. METHODS: Longitudinal dynamometry and functional status data were collated from a cohort of IBM patients. Annual change was calculated by means of linear modeling. Trajectories of change in grip, knee extension, IBM Functional Rating Scale (IBM-FRS) and Neuromuscular Symptom Score (NSS) were identified by means of latent growth mixture modeling. RESULTS: Data were collated from 75 IBM patients (348 person-years follow-up). Annual strength loss was greatest for pinch (-10%) and knee extension (-4%). Functional deterioration was greatest for males. Three distinct trajectory groups were identified. Rapid deterioration trajectory for grip strength was associated with younger diagnosis age. Rapid deterioration for knee extension strength was associated with older age of diagnosis. DISCUSSION: This study has quantified strength change in IBM and identified distinct trajectory groups, which will aid prognostication and stratification for inclusion into future clinical trials.

Effects of Brief Behavioral Treatment for Insomnia on Daily Associations between Self-Reported Sleep and Objective Cognitive Performance in Older Adults.

OBJECTIVE: Behavioral treatments for insomnia improve sleep in older adults, but research documenting their effects on cognitive performance is mixed. We explored whether a brief behavioral treatment for insomnia (BBTi) impacts daily associations between sleep parameters and next day cognition. METHODS: Sixty-two older adults (Mage = 69.45 years, SD = 7.71) with insomnia completed either 4 weeks of BBTi or self-monitoring control (SMC). At baseline, post-treatment, and 3 month follow-up, participants completed 14 days of diaries measuring sleep onset latency (SOL), wake after sleep onset (WASO), total sleep time (TST), and sleep efficiency (SE), as well as daily cognitive tests measuring processing speed (i.e., symbol digit modalities test, SDMT), and reasoning (i.e., letter series). At each time period, associations between sleep parameters and daily cognition, controlling for age, education, insomnia duration, use of sleep medications, and depression (i.e., Beck Depression Inventory-2nd Edition scores), were examined through multilevel modeling. RESULTS: At post-treatment, we observed an interactive fixed effect of treatment condition (i.e., BBTi/SMC) and TST on daily SDMT and letter series performance. For BBTi, longer TST was associated with better letter series performance, and did not predict SDMT performance. For SMC, longer TST was associated with worse SDMT, and was not associated with letter series performance. Greater WASO (regardless of group) was associated with better SDMT performance at post-treatment. Associations were not maintained at follow-up. CONCLUSIONS: Sleep duration may play an important role in BBTi-related improvements in daily higher order cognition. Maintenance of these associations may be facilitated by booster sessions following post-treatment. CLINICAL TRIAL IDENTIFIER: NCT02967185.

Validity of Actigraphy in Young Adults With Insomnia.

Objective/Background: Actigraphy is an inexpensive and objective wrist-worn activity sensor that has been validated for the measurement of sleep onset latency (SOL), number of awakenings (NWAK), wake after sleep onset (WASO), total sleep time (TST), and sleep efficiency (SE) in both middle-aged and older adults with insomnia. However, actigraphy has not been evaluated in young adults. In addition, most previous studies compared actigraphy to in-lab polysomnography (PSG), but none have compared actigraphy to more ecologically valid ambulatory polysomnography.Participants: 21 young adults (mean age = 19.90 ± 2.19 years; n = 13 women) determined to have chronic primary insomnia through structured clinical interviews.Methods: Sleep diaries, actigraphy, and ambulatory PSG data were obtained over a single night to obtain measures of SOL, NWAK, WASO, time spent in bed after final awakening in the morning (TWAK), TST, and SE.Results: Actigraphy was a valid estimate of SOL, WASO, TST, and SE, based on significant correlations (r = 0.45 to 0.87), nonsignificant mean differences between actigraphy and PSG, and inspection of actigraphy bias from Bland Altman plots (SOL α = 1.52, WASO α = 7.95, TST α = -8.60, SE α = -1.38).Conclusions: Actigraphy was a valid objective measure of SOL, WASO, TST, and SE in a young adult insomnia sample, as compared to ambulatory PSG. Actigraphy may be a valid alternative for assessing sleep in young adults with insomnia when more costly PSG measures are not feasible.

Universal blood-borne virus screening in patients with severe mental illness managed in an outpatient clozapine clinic: uptake and prevalence.

OBJECTIVE: Patients with a severe mental illness have higher rates of infection with blood-borne viruses (BBVs) but are less likely to access testing and treatment. Enhanced testing of this population is therefore warranted. METHODS: In this single centre, prospective study, we sought to offer testing for BBVs to all patients who attended an appointment in the clozapine clinic (CC) over a six-month period. Those who consented were tested for HIV antigen/antibody, hepatitis C virus (HCV) antibody and hepatitis B virus surface antigen (HBsAg). RESULTS: During the study period, 192 patients attended an appointment, of which 164 were offered testing. Of those, 134 (81.7%) accepted and 30 declined. Among patients who agreed to be tested, results were returned for 96 (71.6%). There were no positive results for HBsAg or HIV. Seven patients (7.2%) were positive for HCV antibody. Of those, three were newly identified exposures of which two were found to be chronically infected and were referred for treatment. CONCLUSION: A routine offer of BBV testing for people with severe mental illness in the outpatient setting is feasible and may detect treatable infections.

Experimental and Computational Investigation of the Aerobic Oxidation of a Late Transition Metal-Hydride.

The rational development of homogeneous catalytic systems for selective aerobic oxidations of organics has been hampered by the limited available knowledge of how oxygen reacts with important organometallic intermediates. Recently, several mechanisms for oxygen insertion into late transition metal-hydride bonds have been described. Contributing to this nascent understanding of how oxygen reacts with metal-hydrides, a detailed mechanistic study of the reaction of oxygen with the IrIII hydride complex (dmPhebox)Ir(OAc)(H) (1) in the presence of acetic acid, which proceeds to form the IrIII complex (dmPhebox)Ir(OAc)2(OH2) (2), is described. The evidence supports a multifaceted mechanism wherein a small amount of an initially formed metal hydroperoxide proceeds to generate a metal-oxyl species that then initiates a radical chain reaction to rapidly convert the remaining IrIII-H. Insight into the initiation step was gained through kinetic and mechanistic studies of the radical chain inhibition by BHT (butylated hydroxytoluene). Computational studies were employed to contribute to a further understanding of initiation and propagation in this system.

A unified mechanism for plant polyketide biosynthesis derived from in silico modeling.

The polyketide synthases found in a variety of plants and fungi provide a varied source of biologically active compounds of pharmacological and medicinal interest. Stilbene synthase and chalcone synthase catalyze the formation of a common tetraketide intermediate, but use different cyclization mechanisms to produce distinct and separate natural products. While key structural differences have been identified to explain this functional diversity, a fuller explication of the factors responsible for this mechanistic disparity is required. Based on the energetics of our models of the bound tetraketides, and our structural analysis of the active sites we propose that a key tautomeric conversion provides a mechanistic framework common to both cyclizations. A previously unidentified active water molecule facilitates cyclization in chalcone synthase through a Claisen mechanism. Such a "Claisen switch" is comparable to the previously characterized "aldol switch" mechanism proposed for the biosynthesis of resveratrol in stilbene synthase.

Edward Ballard and the Practice of Epidemiology in the 19th-Century United Kingdom.

This article recovers the history of Victorian epidemiology through the career of British physician Edward Ballard (1820-1897). Ballard's career provides a useful window into the practices of epidemiology in the 19th century because he held notable public health posts as medical officer of health for Islington and inspector at the Medical Department of the Local Government Board. By the time of his death, in 1897, he typified the transition toward professional epidemiology. In exploring some of the most important environmental and health-related problems in preventive medicine in the 19th century, Ballard was part of a group of influential epidemiologists who studied infectious disease. In particular, he was noted for his research into typhoid fever and industrial health. Yet Ballard's career has largely been forgotten. In this article, I explore Ballard's work as a window into the everyday practices of Victorian epidemiology and suggest that the process of professionalizing epidemiology in the 20th century was about forgetting epidemiology's Victorian past as much as it was about championing it.

Airborne lidar detection and mapping of invasive lake trout in Yellowstone Lake.

The use of airborne lidar to survey fisheries has not yet been extensively applied in freshwater environments. In this study, we investigated the applicability of this technology to identify invasive lake trout (Salvelinus namaycush) in Yellowstone Lake, Yellowstone National Park, USA. Results of experimental trials conducted in 2004 and in 2015-16 provided lidar data that identified groups of fish coherent with current knowledge and models of lake trout spawning sites, and one identified site was later confirmed to have lake trout.