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Over the last several years, numerous outcrop localities have been revisited to add quantitative detail to submarine lobe facies models that previously focussed on facies relationships in a qualitative sense. This study utilises well‐exposed submarine lobe deposits of the Point Loma Formation in Cabrillo National Monument (San Diego, CA) to provide quantitative and statistical insights into the lateral variability of event‐bed (i.e. turbidite) architecture within and between lobe elements. Within a lobe element (defined as a surface‐bounded, genetically related package), event beds compensationally stack, thinning over subtle sea floor topography created by the previous event bed. Between lobe elements, larger‐scale compensation is observed, with clearly defined stratal surfaces and facies architecture distinguishing the four lobe elements. A lateral facies transition is observed for one lobe element, where sandstone beds pinch out and the element thickness halves over a distance of 100 m. However, architectural parameters of event beds (e.g. bed thickness, thinning rate, fining rate) are not appreciably different between these elements, suggesting that the observed stratal architecture does not readily translate into vertical bed thickness (i.e. stacking) patterns that could be easily recognised in common subsurface data types like borehole‐derived core. While the data derived from this outcrop study are valuable for improving the construction of realistic geological and reservoir models, caution is necessary when interpreting lobe element boundaries from borehole data. The lobe deposits measured in this study have event‐bed thicknesses and thinning rates most similar to semi‐confined proximal lobes, suggesting a more proximal position and more confined than previously interpreted. Based on the relationships between sandstone and mudstone thicknesses and thinning rates, bed and lobe‐element compensation and minimal evidence of erosion, the Point Loma Formation at Cabrillo National Monument is reinterpreted as a medial lobe environment with some degree of lateral and/or frontal confinement.

Aims To compare the safety and efficacy of insulin glargine 300 U/mL (Gla-300) versus first-generation standard-of-care basal insulin analogues (SOC-BI; insulin glargine 100 U/mL or insulin detemir) at 6 months. Methods In the 12-month, open-label, multicentre, randomized, pragmatic ACHIEVE Control trial, insulin-naive adults with type 2 diabetes (T2D) and glycated haemoglobin A1c (HbA1c) 64-97 mmol/mol (8.0%-11.0%) after ≥1 year of treatment with ≥2 diabetes medications were randomized to Gla-300 or SOC-BI. The composite primary endpoint, evaluated at 6 months, was the proportion of participants achieving individualized HbA1c targets per HEDIS criteria without documented symptomatic (blood glucose ≤3.9 mmol/L [≤70 mg/dL]) or severe hypoglycaemia at any time of the day at 6 months. Results Of 1651 and 1653 participants randomized to Gla-300 and SOC-BI, respectively, 31.3% and 27.9% achieved the composite primary endpoint at 6 months (odds ratio [OR] 1.19; 95% CI 1.01-1.39; P = 0.03 for superiority); 78.4% and 75.3% had no documented symptomatic or severe hypoglycaemia (OR 1.19; 95% CI 1.01-1.41). Changes from baseline to month 6 in HbA1c, fasting plasma glucose, weight, and BI analogue dose were similar between groups. Conclusions Among insulin-naive adults with poorly controlled T2D, Gla-300 was associated with a statistically significant higher proportion of participants achieving individualized HEDIS HbA1c targets without documented symptomatic or severe hypoglycaemia (versus SOC-BI) in a real-life population managed in a usual-care setting. The ACHIEVE Control study results add value to treatment decisions and options for patients, healthcare providers, payers, and decision makers. ClinicalTrials.gov identifier: NCT02451137 This article is protected by copyright. All rights reserved.

The transport of Ca2+ across membranes precedes the fusion and fission of various lipid bilayers. Yeast vacuoles under hyperosmotic stress become fragmented through fission events that requires the release of Ca2+ stores through the TRP channel Yvc1. This requires the phosphorylation of phosphatidylinositol-3-phosphate (PI3P) by the PI3P-5-kinase Fab1 to produce transient PI(3,5)P2 pools. Ca2+ is also released during vacuole fusion upon trans-SNARE complex assembly, however, its role remains unclear. The effect of PI(3,5)P2 on Ca2+ flux during fusion was independent of Yvc1. Here, we show that while low levels of PI(3,5)P2 were required for Ca2+ uptake into the vacuole, increased concentrations abolished Ca2+ efflux. This was as shown by the addition of exogenous dioctanoyl PI(3,5)P2 or increased endogenous production of by the hyperactive fab1T2250A mutant. In contrast, the lack of PI(3,5)P2 on vacuoles from the kinase dead fab1EEE mutant showed delayed and decreased Ca2+ uptake. The effects of PI(3,5)P2 were linked to the Ca2+ pump Pmc1, as its deletion rendered vacuoles resistant to the effects of excess PI(3,5)P2 . Experiments with Verapamil inhibited Ca2+ uptake when added at the start of the assay, while adding it after Ca2+ had been taken up resulted in the rapid expulsion of Ca2+ . Vacuoles lacking both Pmc1 and the H+ /Ca2+ exchanger Vcx1 lacked the ability to take up Ca2+ and instead expelled it upon the addition of ATP. Together these data suggest that a balance of efflux and uptake compete during the fusion pathway and that the levels of PI(3,5)P2 can modulate which path predominates.

Aims To compare 12‐month clinical effectiveness of insulin glargine 300 units/mL (Gla‐300) versus first‐generation basal insulin analogues (BIAs) (insulin glargine 100 units/mL [Gla‐100] or insulin detemir [IDet]) in patients with type 2 diabetes (T2D) who were at high risk of hypoglycaemia and switched from one BIA to a different one (Gla‐300 or Gla‐100/IDet) in a real‐world setting. Methods DELIVER High Risk was a retrospective observational cohort study of 2550 patients with T2D who switched BIA to Gla‐300 (Gla‐300 switchers) and were propensity score‐matched (1:1) to patients who switched to Gla‐100 or IDet (Gla‐100/IDet switchers). Outcomes were change in glycated haemoglobin A1c (HbA1c), attainment of HbA1c goals (, In patients with type 2 diabetes at high risk of hypoglycaemia, risk of inpatient/emergency department‐related hypoglycaemia was significantly lower during 12 months after switching to insulin glargine 300 units/mL, compared with switching to insulin glargine 100 units/mL or insulin detemir.

The accumulation of copper in organisms can lead to altered functions of various pathways and become cytotoxic through the generation of reactive oxygen species. In yeast, cytotoxic metals such as Hg+ , Cd2+ and Cu2+ are transported into the lumen of the vacuole through various pumps. Copper ions are initially transported into the cell by the copper transporter Ctr1 at the plasma membrane and sequestered by chaperones and other factors to prevent cellular damage by free cations. Excess copper ions can subsequently be transported into the vacuole lumen by an unknown mechanism. Transport across membranes requires the reduction of Cu2+ to Cu+ . Labile copper ions can interact with membranes to alter fluidity, lateral phase separation and fusion. Here we found that CuCl2 potently inhibited vacuole fusion by blocking SNARE pairing. This was accompanied by the inhibition of V-ATPase H+ pumping. Deletion of the vacuolar reductase Fre6 had no effect on the inhibition of fusion by copper. This suggests that Cu2+ is responsible for the inhibition of vacuole fusion and V-ATPase function. This notion is supported by the differential effects of chelators. The Cu2+ -specific chelator triethylenetetramine rescued fusion, whereas the Cu+ -specific chelator bathocuproine disulfonate had no effect on the inhibited fusion.

BACKGROUND AND AIMS Problem gambling is a significant public health issue world-wide. There is substantial investment in publicly funded intervention services, but limited evaluation of effectiveness. This study investigated three brief telephone interventions to determine whether they were more effective than standard helpline treatment in helping people to reduce gambling. DESIGN Randomized clinical trial. SETTING National gambling helpline in New Zealand. PARTICIPANTS A total of 462 adults with problem gambling. INTERVENTIONS AND COMPARATOR: (1) Single motivational interview (MI), (2) single motivational interview plus cognitive-behavioural self-help workbook (MI + W) and (3) single motivational interview plus workbook plus four booster follow-up telephone interviews (MI + W + B). Comparator was helpline standard care [treatment as usual (TAU)]. Blinded follow-up was at 3, 6 and 12 months. MEASUREMENTS Primary outcomes were days gambled, dollars lost per day and treatment goal success. FINDINGS There were no differences across treatment arms, although participants showed large reductions in gambling during the 12-month follow-up period [mean reduction of 5.5 days, confidence interval (CI) = 4.8, 6.2; NZ$38 lost ($32, $44; 80.6%), improved (77.2%, 84.0%)]. Subgroup analysis revealed improved days gambled and dollars lost for MI + W + B over MI or MI + W for a goal of reduction of gambling (versus quitting) and improvement in dollars lost by ethnicity, gambling severity and psychological distress (all P

The landscape of fear theory proposes that prey should utilize habitat over space and time such that demographic risk is minimized. White-tailed deer Odocoileus virginianus respond to temporally and spatially predictable threats posed by humans consistent with the landscape of fear theory. However, few studies examining the response of deer to hunting have accounted for the localized nature of risk. To determine if white-tailed deer are able to recognize and respond to risks posed by hunters relative to specific hunting locations, we equipped 38 female white-tailed deer with GPS collars August–December 2013–2015. Deer were generally found to increase use of feeders, food plots, and vulnerability zones during crepuscular and nocturnal periods as the hunting season progressed. However, deer use of areas around hunting stands decreased during the middle of the day and increased at night in the days immediately following a stand being hunted. We detected no change in use of areas around hunting stands during crepuscular hours in days following when a stand was hunted. Our results suggest that female white-tailed deer are able to recognize and respond to localized risks and do so with a gradient of responses based on localized risk history. However, response was only apparent when analysis accounted for the localized nature of risk, suggesting previous studies may have underestimated the ability of deer to respond to such threats.

Female white‐tailed deer (Odocoileus virginianus) are thought to choose between two behavioral strategies to maximize the quality of potential mates: sit and wait, characterized by concentrating activity within a restricted area, and excursive behavior, characterized by increased activity and excursions outside the home range. As movement patterns may influence conception, our goal was to examine the patterns of female white‐tailed deer movements to evaluate which breeding strategy was employed. We equipped 36 female white‐tailed deer with GPS collars from August 2013 to December 2015. We found that movement rate and probability of activity were greatest near the peak of the breeding season, and we observed increases in both metrics during the 40 days prior to estimated conception. Peak size of home range and core area occurred in the days surrounding conception. We found that 11 deer performed an excursion, ranging from 43 days before until 36 days after conception, with the peak probability of being outside of an individual home range occurring 1 day prior to conception. Our results suggest that female white‐tailed deer may attempt to maximize the quality of their mates by advertising availability for breeding through excursive behaviors just prior to entering estrus.

Stress urinary incontinence (SUI), a prevalent condition, is represented by an involuntary leakage of urine that results, at least in part, from weakened or damaged pelvic floor muscles and is triggered by physical stress. Current treatment options are limited with no oral therapies available. The pelvic floor is rich in androgen receptor and molecules with anabolic activity including selective androgen receptor modulators (SARMs) may serve as therapeutic options for individuals with SUI. In this study, two SARMs (GTx-024 and GTx-027) were evaluated in a post-menopausal animal model in order to determine their effect on pelvic floor muscles. Female C57BL/6 mice were ovariectomized and their pelvic muscles allowed to regress. The animals were then treated with vehicle or doses of GTx-024 or GTx-027. Animal total body weight, lean body mass, and pelvic floor muscle weights were measured along with the expression of genes associated with muscle catabolism. Treatment with the SARMs resulted in a restoration of the pelvic muscles to the sham-operated weight. Coordinately, the induction of genes associated with muscle catabolism was inhibited. Although a trend was observed towards an increase in total lean body mass in the SARM-treated groups, no significant differences were detected. Treatment of an ovariectomized mouse model with SARMs resulted in an increase in pelvic floor muscles, which may translate to an improvement of symptoms associated with SUI and serves as the basis for evaluating their clinical use. J. Cell. Biochem. 118: 640-646, 2017. © 2016 Wiley Periodicals, Inc.

Spinal cord injury (SCI) triggers an "accelerated aging" process that may include development of hypogonadism, even among younger men with SCI; however, few studies have investigated the prevalence or etiology of hypogonadism in men with SCI. Young men with SCI also are at increased risk for developing metabolic dysfunction after injury, which may be exacerbated by concomitant testosterone (T) deficiency, thus identifying the prevalence and risk factors for T deficiency in men with SCI is important for their long-term health.To investigate the prevalence, risk factors, and etiology of T deficiency (hypogonadism) in otherwise-healthy men with chronic, motor complete SCI.Secondary cross-sectional analysis.Rehabilitation research centers in Washington, DC, and Miami, Florida.Men (n = 58) aged 18-45 years with chronic (≥1 year), motor complete SCI without comorbidities or use of testosterone therapy.Plasma concentrations of hormones were measured with standardized assays. Body composition was assessed with dual-energy x-ray absorptiometry scan.Serum total T and calculated free T.T deficiency was more common in men after SCI than in a matched cohort of similarly-aged men without SCI (25%, SCI versus 6.7%, non-SCI, P.001). The risk of hypogonadism appeared to be increased in men with more extensive injury and with higher percent body fat. The majority of men with SCI with low T had low serum LH levels, suggesting that central suppression of the hypothalamic-pituitary-gonadal axis may be the most common etiology of hypogonadism after SCI.Hypogonadism is more common in young men with SCI than in similarly aged men without SCI, suggesting that SCI should be identified as a risk factor for T deficiency and that routine screening for hypogonadism should be performed in the SCI population.II.

Most satiety-inducing obesity therapeutics, despite modest efficacy, have safety concerns that underscore the need for effective peripherally acting drugs. An attractive therapeutic approach for obesity is to optimize/maximize energy expenditure by increasing energy-utilizing thermogenic brown adipose tissue. We used in vivo and in vitro models to determine the role of estrogen receptor β (ER-β) and its ligands on adipose biology. RNA sequencing and metabolomics were used to determine the mechanism of action of ER-β and its ligands. Estrogen receptor β (ER-β) and its selective ligand reprogrammed preadipocytes and precursor stem cells into brown adipose tissue and increased mitochondrial respiration. An ER-β-selective ligand increased markers of tricarboxylic acid–dependent and –independent energy biogenesis and oxygen consumption in mice without a concomitant increase in physical activity or food consumption, all culminating in significantly reduced weight gain and adiposity. The antiobesity effects of ER-β ligand were not observed in ER-β-knockout mice. Serum metabolite profiles of adult lean and juvenile mice were comparable, while that of adult obese mice was distinct, indicating a possible impact of obesity on age-dependent metabolism. This phenotype was partially reversed by ER-β-selective ligand. These data highlight a new role for ER-β in adipose biology and its potential to be a safer alternative peripheral therapeutic target for obesity.—Ponnusamy, S., Tran, Q. T., Harvey, I., Smallwood, H. S., Thiyagarajan, T., Banerjee, S., Johnson, D. L., Dalton, J. T., Sullivan, R. D., Miller, D. D., Bridges, D., Narayanan, R. Pharmacologic activation of estrogen receptor β increases mitochondrial function, energy expenditure, and brown adipose tissue.

PURPOSE Common labs such as a daily complete blood count or a daily basic metabolic panel represent possible waste and have been targeted by professional societies and the Choosing Wisely campaign for critical evaluation. We undertook a multifaceted quality-improvement (QI) intervention in a large community hospitalist group to decrease unnecessary common labs. METHODS The QI intervention was composed of academic detailing, audit and feedback, and transparent reporting of the frequency with which common labs were ordered as daily within the hospitalist group. We performed a pre-post analysis, comparing a cohort of patients during the 10-month baseline period before the QI intervention and the 7-month intervention period. Demographic and clinical data were collected from the electronic medical record. The primary endpoint was number of common labs ordered per patient-day as estimated by a clustered multivariable linear regression model clustering by ordering hospitalist. Secondary endpoints included length of stay, hospital mortality, 30-day readmission, blood transfusion, amount of blood transfused, and laboratory cost per patient. RESULTS The baseline (n = 7824) and intervention (n = 5759) cohorts were similar in their demographics, though the distribution of primary discharge diagnosis-related groups differed. At baseline, a mean of 2.06 (standard deviation 1.40) common labs were ordered per patient-day. Adjusting for age, sex, and principle discharge diagnosis, the number of common labs ordered per patient-day decreased by 0.22 (10.7%) during the intervention period compared to baseline (95% confidence interval [CI], 0.34 to 0.11; P

The known interactions between the somatotropic and hypothalamic‐pituitary‐gonadal (HPG) axes have not been well delineated in older individuals. Aging‐associated decline in insulin like growth factor‐1 (IGF‐1) levels has been proposed to play a role in reproductive senescence in animals. However, the effects of GH on LH secretion are unknown in older individuals. Our objective was to determine whether GH modulates LH secretion or levels of sex steroids (SS) in healthy older (ages 65–88 years) men (n = 24) and women (n = 24) with low‐normal plasma IGF‐1 levels. In a double‐masked, placebo‐controlled (n = 24), randomized study, we evaluated the effects of GH (n = 24, 20 μg/kg sc 3×/week) for 26 weeks on nocturnal LH secretory dynamics [(8 pm to 8 am, Q20) min sampling and analyzed by multiparameter deconvolution algorithm]. Indices of LH secretion [frequency, mass per burst, pulsatile production rate, and approximate entropy (ApEn)] and fasting serum IGF‐1, SHBG, and SS (TT, fT, or E2) were measured. At baseline, all indices of LH secretion (frequency, mass per burst, pulsatile production rate) were inversely (P

Objective To estimate the incidence and rate of outpatient antibiotic and antiviral medication use among children receiving methotrexate and/or an injectable tumor necrosis factor α (iTNFα) inhibitor (etanercept and/or adalimumab) and to compare these rates with those of a control population. Methods Data were obtained from a pharmacy benefit manager (PBM) database. Children were included if they had ≥1 prescription claim for an iTNFα inhibitor or methotrexate prescribed by a pediatric or adult rheumatologist between 2008 and 2010 and if they were age

To (1) quantify mucosal cooling (ie, heat loss) spatially in the nasal passages of nasal airway obstruction (NAO) patients before and after surgery using computational fluid dynamics (CFD) and (2) correlate mucosal cooling with patient-reported symptoms, as measured by the Nasal Obstruction Symptom Evaluation (NOSE) and a visual analog scale (VAS) for sensation of nasal airflow.Prospective.Academic tertiary medical center.Computed tomography (CT) scans and NOSE and VAS surveys were obtained from 10 patients before and after surgery to relieve NAO. Three-dimensional models of each patient's nasal anatomy were used to run steady-state CFD simulations of airflow and heat transfer during inspiration. Heat loss across the nasal vestibule and the entire nasal cavity, as well as the surface area of mucosa exposed to heat fluxes50 W/m(2), were compared pre- and postoperatively.After surgery, heat loss increased significantly on the preoperative most obstructed side (P.0002). A larger surface area of nasal mucosa was exposed to heat fluxes50 W/m(2) after surgery. The best correlation between patient-reported and CFD measures of nasal patency was obtained for NOSE against surface area in which heat fluxes were50 W/m(2) (Pearson r = -0.76).A significant postoperative increase in mucosal cooling correlates well with patients' perception of better nasal patency after NAO surgery. Computational fluid dynamics-derived heat fluxes may prove to be a valuable predictor of success in NAO surgery.

Objective To systematically appraise published comparative effectiveness evidence (clinical and economic) of epidural steroid injections (ESI) for lumbar spinal stenosis and to estimate Medicare reimbursement amounts for ESI procedures. Type Systematic review. Literature Survey PubMed, Embase, and CINAHL were searched through August 2012 for key words that pertain to low back pain, spinal stenosis or sciatica, and epidural steroid injection. We used institutional and Medicare reimbursement amounts for our cost estimation. Articles published in English that assessed ESIs for adults with lumbar spinal stenosis versus a comparison intervention were included. Our search identified 146 unique articles, and 138 were excluded due to noncomparative study design, not having a study population with lumbar spinal stenosis, not having an appropriate outcome, or not being in English. We fully summarized 6 randomized controlled trials and 2 large observational studies. Methodology Randomized controlled trial articles were reviewed, and the study population, sample size, treatment groups, ESI dosage, ESI approaches, concomitant interventions, outcomes, and follow-up time were reported. Descriptive resource use estimates for ESIs were calculated with use of data from our institution during 2010 and Medicare-based reimbursement amounts. Synthesis ESIs or anesthetic injections alone resulted in better short-term improvement in walking distance compared with control injections. However, there were no longer-term differences. No differences between ESIs versus anesthetic in self-reported improvement in pain were reported. Transforaminal approaches had better improvement in pain scores (≤4 months) compared with interlaminar injections. Two observational studies indicated increased rates of lumbar ESI in Medicare beneficiaries. Our sample included 279 patients who received at least 1 ESI during 2010, with an estimated mean total outpatient reimbursement for one ESI procedure "event" to be $637, based on 2010 Medicare reimbursement amounts ($505 technical and $132 professional payments). Conclusion This systematic review of ESI for treating lumbar spinal stenosis found a limited amount of data that suggest that ESI is effective in some patients for improving select short-term outcomes, but results differed depending on study design, outcome measures used, and comparison groups evaluated. Overall, there are relatively few comparative clinical or economic studies for ESI procedures for lumbar spinal stenosis in adults, which indicated a need for additional evidence.

Diabet. Med. 29, e67–e74 (2012) Abstract Aims Post-hoc evaluation of relationships between first-year change in glycaemic control (HbA1c) and change in patient-reported outcomes among ACCORD health-related quality of life (HRQoL) substudy participants. Methods Data from 2053 glycaemia-trial subjects were analysed. We assessed physical and mental health status (36-Item Short Form Health Survey, Version-2), symptom count and severity (Diabetes Symptoms Distress Checklist) and treatment satisfaction (Diabetes Treatment Satisfaction Questionnaire). Linear mixed models were used to test relationships between 1-year changes in HbA1c and patient reported outcomes sequentially adjusting for correlates (baseline characteristics, baseline patient reported outcomes, treatment assignment, frequency of clinical contact and post-randomization weight change plus new complications). Results Poorer baseline control of HbA1c and cardiovascular disease risk factors predicted greater one-year improvements in treatment satisfaction. Similarly, poorer baseline patient reported outcome scores all individually predicted greater 1-year improvement in that same outcome. Accounting for baseline and post-randomization characteristics and treatment arm, 1-year change in HbA1c was unrelated to changes in overall physical or mental health; however, every one percentage-point (10.9 mmol/mol) reduction in HbA1c was associated with lower symptom count (β = 0.599; P = 0.012), lower symptom distress (β = 0.051; P = 0.001), and higher treatment satisfaction (β = −2.514; P

Study Objective To determine the impact of primary prophylactic colony-stimulating factor (CSF) use on febrile neutropenia in a large patient population receiving contemporary chemotherapy regimens to treat breast cancer, colorectal cancer, or non–small cell lung cancer (NSCLC). Design Retrospective claims analysis. Data Sources The Surveillance, Epidemiology, and End Results (SEER)-Puget Sound cancer registry and insurance claims records. Patients A total of 2728 patients aged 25 years or older who received a diagnosis of breast cancer (998 patients), colorectal cancer (688 patients), or NSCLC (1042 patients) between January 1, 2002, and December 31, 2005, and received chemotherapy. Measurements and Main Results Initial chemotherapy regimen, CSF use (filgrastim or pegfilgrastim), and febrile neutropenia events were evaluated after the first chemotherapy administration. Subsequently, febrile neutropenia rates in patients receiving primary prophylactic CSF were compared with febrile neutropenia rates in patients receiving CSF in settings other than primary prophylaxis or not at all. The impact of primary prophylactic CSF could not be assessed for patients with colorectal cancer or NSCLC because only 1 and 18 febrile neutropenia events, respectively, occurred in those receiving primary prophylactic CSF. Of the 998 patients with breast cancer, 72 (7.2%) experienced febrile neutropenia, 28 of whom received primary prophylactic CSF. In the patients with breast cancer, we observed that primary prophylactic CSF use was associated with reduced febrile neutropenia rates; however, the analysis may have been confounded by unmeasured factors associated with febrile neutropenia. Conclusion The impact of primary prophylactic CSFs on febrile neutropenia rates could not be demonstrated. Given the substantive cost of CSFs to pharmacy budgets, there are numerous opportunities for pharmacists to optimize CSF use. Research studies are needed to evaluate if guideline-directed prescribing of primary prophylactic CSFs can improve clinical outcomes.

(Headache 2011;51:1058-1077) Objective.— To evaluate and compare healthcare resource use and related costs in chronic migraine and episodic migraine in the USA and Canada. Background.— Migraine is a common neurological disorder that produces substantial disability for sufferers around the world. Several studies have quantified overall costs associated with migraine in general, with recent estimates ranging from $581 to $7089 per year. Although prior studies have characterized the clinical and humanistic burden of chronic migraine relative to episodic migraine, to the best of our knowledge only 1 previous study has compared chronic migraine and episodic migraine healthcare costs. The purpose of this study was to quantify and compare the direct medical costs of chronic migraine and episodic migraine using medical resource use data collected as part of the International Burden of Migraine Study. Methods.— Cross-sectional data were collected from respondents in 10 countries via a Web-based survey. Respondents were classified as chronic migraine (≥15 headache days/month) or episodic migraine (

The R-MAT graph generator introduced by Chakrabarti et al (Int Conf Data Mining, 2004) offers a simple, fast method for generating very large directed graphs. These properties have made it a popular choice as a method of generating graphs for objects of study in a variety of disciplines, from social network analysis to high performance computing. We analyze the graphs generated by R-MAT and model the generator in terms of occupancy problems to prove results about the degree distributions of these graphs. We prove that the limiting degree distributions can be expressed as a mixture of normal distributions with means and variances that can be easily calculated from the R-MAT parameters. Additionally, this article offers an efficient computational technique for computing the exact degree distribution and concise expressions for a number of properties of R-MAT graphs. ©2011 Wiley Periodicals, Inc.*. NETWORKS, 2011 The United States Government retains and the publisher, by accepting the article for publication, acknowledges that the United States Government retains a non-exclusive, paid-up, irrevocable, world-wide license to publish or reproduce the published form of this manuscript, or allow others to do so, for United States Government purposes.

Hypertensive disorders of pregnancy (HDP), including pre‐existing hypertension, gestational hypertension, and preeclampsia, further complicate already high‐risk pregnancies in women with diabetes mellitus (DM). Women with both pre‐existing and gestational diabetes are at increased risk for HDP, leading to higher maternal and fetal morbidity. Further, particularly in diabetic women and women with a history of gestational diabetes, HDP significantly increases the risk for future cardiovascular events. For clinicians, women with hypertension and diabetes during pregnancy pose a management challenge. Specifically, preconception management should stress strict control of glycemia, blood pressure, and prevention of diabetic complications, specifically nephropathy, which specifically increases the risk for preeclampsia. During gestation, clinicians must be aware of potential maternal and fetal complications associated with various anti‐hypertensive therapies, including known fetotoxicity of ACE inhibitors and ARBs when given in the 2nd or 3rd trimester, and the risks and benefits of expectant management versus delivery in cases of severe gestational hypertension or preeclampsia. Indeed, diabetic women must be followed closely prior to conception and throughout gestation to minimize the risk of HDP and its associated complications. J Clin Hypertens (Greenwich). 2011;13:275–284. © 2011 Wiley Periodicals, Inc.

Study Objective. To compare the efficacy of biologic disease-modifying antirheumatic drugs (DMARDs) versus placebo with or without methotrexate, in treating rheumatoid arthritis. Design. Comparative effectiveness analysis using an indirect treatment comparison (ITC) method in a Bayesian framework. Patients. Adults with rheumatoid arthritis who had been enrolled in randomized controlled trials (RCTs) and had never failed biologic DMARD therapy. Measurements and Main Results. Two random-effects logistic regression models, representing 6 and 12 months of treatment, were created using RCTs identified in a literature search. Twenty-three RCTs (11,589 patients) were included in the 6-month model and 10 RCTs (6051 patients) in the 12-month model. Nine biologic DMARDs in five therapeutic drug classes were included in the 6-month model, and six biologic DMARDs in three classes were included in the 12-month model. Our efficacy end point was the American College of Rheumatology 50% improvement criteria. In the 6-month model, all biologic DMARDs and methotrexate were significantly more efficacious than placebo and ranked in the following order: certolizumab (median log odds ratio [OR] 2.6), tocilizumab (1.7), rituximab (1.6), infliximab (1.6), etanercept (1.4), adalimumab (1.4), golimumab (1.4), abatacept (1.2), anakinra (1.0), and methotrexate (0.8). Of 45 pairwise comparisons, certolizumab was significantly more efficacious than methotrexate, but no other comparisons were significant. The rank order in the 12-month analysis was certolizumab (median log OR 2.0), rituximab (2.0), adalimumab (1.4), infliximab (1.4), etanercept (0.9), abatacept (0.6), and methotrexate (0.8). Of the 21 pairwise comparisons, none were significant. The results of the model using therapeutic class revealed that each class was more efficacious than placebo. In pairwise comparisons, each class was more efficacious than methotrexate, but none was more efficacious than another. Conclusion. Use of emerging ITC methods enabled us to compare the efficacy of biologic DMARDs for the treatment of rheumatoid arthritis in the absence of direct head-to-head comparison trials. Our methods enabled us to rank order these treatments. Further analyses by drug and by therapeutic class suggest that biologic DMARDs are similarly efficacious.

Objective Assess long-term cost-effectiveness of rivastigmine patch in Alzheimer's disease (AD) management in the UK, using cognitive and functional models based on clinical trial efficacy data. Methods Incremental costs and Quality Adjusted Life Years (QALYs) associated with rivastigmine patch and capsule treatment versus best supportive care (BSC) were calculated using two economic models, one based solely on Mini-Mental State Examination (MMSE) scores, and one also incorporating activities of daily living (ADL) scores. The clinical pathway was populated with data from a clinical trial of rivastigmine patch (9.5 mg/24 h) and capsules (12 mg/day) versus placebo. Costs were based on the UK health and social care costs and basic UK National Health Service (NHS) prices. Disease progression was modelled beyond the trial period over 5 years using published equations to predict natural decline in AD patients. Base case costing variables included drugs, clinical monitoring, and institutionalization. Results The MMSE model estimated incremental costs per QALY of £10 579 for rivastigmine patch and £15 154 for capsule versus BSC. The MMSE-ADL model estimated incremental costs per QALY of £9114 for rivastigmine patch and £13 758 for capsules. The main difference between the models was a greater number of institutionalized days avoided for rivastigmine versus BSC estimated by the MMSE-ADL model. Conclusions Both the MMSE and MMSE-ADL models suggest that rivastigmine patch and capsules are cost-effective treatments versus BSC. Incorporating ADL evidence makes a marginal but important difference to estimates in this case. Future economic evaluations of AD treatment should include measures of both cognition and functioning. Copyright © 2010 John Wiley & Sons, Ltd.

Context: The terms evidence-based medicine (EBM), health technology assessment (HTA), comparative effectiveness research (CER), and other related terms lack clarity and so could lead to miscommunication, confusion, and poor decision making. The objective of this article is to clarify their definitions and the relationships among key terms and concepts. Methods: This article used the relevant methods and policy literature as well as the websites of organizations engaged in evidence-based activities to develop a framework to explain the relationships among the terms EBM, HTA, and CER. Findings: This article proposes an organizing framework and presents a graphic demonstrating the differences and relationships among these terms and concepts. Conclusions: More specific terminology and concepts are necessary for an informed and clear public policy debate. They are even more important to inform decision making at all levels and to engender more accountability by the organizations and individuals responsible for these decisions.

Objective To report trends and characteristics of long-term opioid use for non-cancer pain. Methods CONSORT (CONsortium to Study Opioid Risks and Trends) includes adult enrollees of two health plans serving over 1 per cent of the US population. Using automated data, we constructed episodes of opioid use between 1997 and 2005. We estimated age–sex standardized rates of opioid use episodes beginning in each year (incident) and on-going in each year (prevalent), and the per cent change in rates annualized (PCA) over the 9-year period. Long-term episodes were defined as > 90 days with 120+ days supply or 10+ opioid prescriptions in a given year. Results Over the study period, incident long-term use increased from 8.5 to 12.1 per 1000 at Group Health (GH) (6.0% PCA), and 6.3 to 8.6 per 1000 at Kaiser Permanente of Northern California (KPNC) (5.5% PCA). Prevalent long-term use doubled from 23.9 to 46.8 per 1000 at GH (8.5% PCA), and 21.5 to 39.2 per 1000 at KPNC (8.1% PCA). Non-Schedule II opioids were the most commonly used opioid among patients engaged in long-term opioid therapy, particularly at KPNC. Long-term use of Schedule II opioids also increased substantially at both health plans. Among prevalent long-term users in 2005, 28.6% at GH and 30.2% at KPNC were also regular users of sedative hypnotics. Conclusion Long-term opioid therapy for non-cancer pain is increasingly prevalent, but the benefits and risks associated with such therapy are inadequately understood. Concurrent use of opioids and sedative-hypnotics was unexpectedly common and deserves further study. Copyright © 2009 John Wiley & Sons, Ltd.

Background and Aim: To assess the clinical and economic outcomes of non-invasive testing strategies in the diagnosis of significant liver fibrosis (Metavir score ≥ 2) compared with liver biopsy. Methods: We developed a decision analytic model of non-invasive testing strategies in a hypothetical patient population with genotype 1 hepatitis C virus infection, with no contraindications to liver biopsy. The testing strategies included a testing algorithm using the Fibrosure test, a non-invasive measure of fibrosis, followed by liver biopsy for patients with indeterminate results, Fibrospect II, and Fibroscan. The primary outcomes were sensitivity, specificity, diagnostic accuracy (true positive + true negatives/total patients), and costs, evaluated from the health-care payer perspective. Results: The testing algorithm using Fibrosure was the most accurate non-invasive strategy with a sensitivity, specificity, and overall accuracy of 84%, 87%, and 86%, respectively. In comparison with liver biopsy alone, there was a cost savings of approximately $770/person with the Fibrosure testing algorithm, but a net decrease in accuracy of 14%. Fibrospect II and Fibroscan had poorer accuracy (decreases of 12% and 4%, respectively) and lower costs (−$138 and −$357, respectively) compared with the Fibrosure algorithm. In uncertainty analyses in which biopsy sampling error was considered, the Fibrosure algorithm remained consistently less accurate (5–14% decrease). Conclusions: The results of our study suggest that compared with liver biopsy, non-invasive testing algorithms can result in short-term cost savings, but the consequences of misdiagnosis in terms of health outcomes and treatment costs might outweigh the short-term gains in cost and convenience.

A post hoc analysis of data from a prospective cost-effectiveness analysis (CEA) conducted alongside a randomized controlled trial (National Emphysema Treatment Trial - NETT) was used to assess the impact of using different imputation methods for missing quality of life data on the estimation of the incremental cost-effectiveness ratio (ICER). The NETT compared lung-volume-reduction surgery plus medical therapy with medical therapy alone in patients with severe chronic obstructive pulmonary disease due to emphysema. One thousand sixty-six patients were followed for up to 3 years after randomization. The cost per quality-adjusted life-year gained was obtained, computing costs from a societal perspective and using the self-administered Quality of Well Being questionnaire to measure quality of life. Different methods of imputation resulted in substantial differences in ICERs as well as differences in estimates of the uncertainty in the point estimates as reflected in the CEA acceptability curves. Paradoxically, the use of a conservative single imputation method resulted in relatively less uncertainty (anticonservative) about the ICER. Owing to the effects of different imputation methods for missing quality of life data on the estimation of the ICER, we recommend use of a minimum of two imputation methods that always include multiple imputation.

The aim of this systematic review was to summarize and assess the quality of asthma intervention health economic studies from 2002 to 2007, compare the study findings with clinical management guidelines, and suggest avenues for future improvement of asthma health economic studies. Forty of the 177 studies met our inclusion criteria. We assessed the quality of studies using The Quality of Health Economic Studies validated instrument (total score range: 0-100). Six studies (15%) had quality category 2, 26 studies (65%) achieved quality category 3, and the remaining eight (20%) studies were scored as the highest quality level, category 4. Overall, the findings from this review are in line with the Global Initiative for Asthma clinical guidelines. Many asthma health economic studies lacked appropriate long term time horizons to match the chronic nature of the disease and suffered from using effectiveness measures that did not capture all disease related risks and benefits. We recommend that new asthma simulation models: be flexible to allow for long term time horizons, focus on using levels of asthma control in their structure, and estimate both long term asthma specific outcomes like well-controlled time as well as generic outcomes such as quality adjusted survival.

Background: Clinical tools for predicting poor outcomes in asthma patients are lacking. This study investigated the association of asthma control and subsequent severe asthma-related healthcare events in The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study. Methods: The extent of asthma control problems was determined from baseline values of the Asthma Therapy Assessment Questionnaire (ATAQ). Patients self-reported the presence of severe asthma-related events at 6- and 12-month follow up. Poisson regression models determined the adjusted association between baseline control and the likelihood of severe asthma-related events. Results: At baseline, 2942 patients (mean age, 49.6 years; female, 71.9%) had an ATAQ score (no control problems, 17.0%; 1 control problem, 20.0%; 2 control problems, 30.8%; 3 or 4 control problems, 32.2%) and at least one severe asthma-related event. After adjustment, subjects with three or four control problems were at greater risk for unscheduled office visits [relative risk (RR) = 2.8; 95% confidence interval (CI): 2.4–3.2], course of oral steroids (RR = 2.9; 95% CI: 2.5–3.3), emergency room visits (RR = 4.1; 95% CI: 2.7–6.2) or hospitalization (RR = 13.6; 95% CI: 7.4–24.9), vs no control problems. Progressively poorer levels of asthma control are associated with increasing risk of severe asthma-related events. Conclusions: This study provides evidence of an association between poor asthma control and future severe asthma-related healthcare events. A validated questionnaire may help clinicians identify patients requiring intervention to prevent future severe asthma-related events.

Background: Despite the publication of several management guidelines for exacerbations of chronic obstructive pulmonary disease (COPD), there is little information on standards of care in clinical practice. The aim of this audit was to examine the assessment, management and outcome of COPD admissions to a secondary and tertiary referring New Zealand hospital during two different seasons. Compliance to current recommendations was examined and compared with the available international published work. Methods: All COPD-related admissions to Waikato Hospital during the months of May and October 2004 were reviewed. Ninety-four cases (from 84 patients) were audited. Results: General characteristics, clinical features and lung function tests were similar to that of other cohorts. Twenty-three per cent of the admissions were Maori and the mean age of Maori admissions were significantly less than that of the non-Maori admissions (57 and 72 years, respectively; P = 0.0001). The geometric mean length of stay was 3.4 days, which is significantly less than most other reported hospital lengths of stays related to exacerbations of COPD. Fifty-five per cent of the cohort was admitted more than once to the hospital for COPD in the 12 months before the index admission. Thirteen per cent of all admissions received assisted ventilation. Overall 30-day mortality was 8% and the 12-month mortality was 31%. Decreased body mass index was a risk factor for death as was an increased CURB-65 (confusion, urea, respiratory rate, blood pressure age) score – a simple bedside assessment score, which has previously been used to predict mortality in patients with community-acquired pneumonia. Conclusion: This audit documented the general characteristics, assessment, management and outcome of the COPD admissions to a secondary New Zealand hospital. Further investigations into factors contributing to shorter length of stay and predictors of mortality are needed.

Aim: To evaluate the proportion of neonates referred for extracorporeal membrane oxygenation (ECMO) support in the modern era of advanced conventional treatments for respiratory failure who actually had congenital heart disease (CHD), and to assess the impact of this diagnostic route on patient condition and outcome. Methods: A retrospective case-note review of neonatal ECMO and cardiac admissions to a single, tertiary ECMO and cardiac intensive care unit (ICU) between March 1999 and February 2002. Results: 287 symptomatic neonates presented to the ICU with previously undiagnosed cardiac or respiratory disease. Eighty-two with presumed respiratory failure were referred for ECMO, and 205 with suspected CHD were referred for cardiac evaluation. Eight (10%) ECMO referrals, all with presumed persistent pulmonary hypertension of the newborn (PPHN), were found to have CHD (transposition: 3; total anomalous pulmonary venous connection: 3; left heart obstructive lesions: 2). Mortality in this group was 50%, compared with 11% for correctly identified CHD patients (odds ratio 8.2, 95% CI 1.92, 35.4, p

Aims The ATTEMPT study was designed to chart the natural history of smoking cessation and associated short-term health outcomes and effects on medical resource utilization among a cohort recruited across multiple countries. This paper describes the methods for recruitment and follow-up, the baseline population characteristics of the enrolled population and 1-year response rates. Design ATTEMPT is a multi-national prospective cohort study that used the internet for subject recruitment and online assessments every 3 months for 2.5 years. Setting Subjects were recruited via e-mail from existing internet panels [Canada (n = 208), France (n = 201), the United Kingdom (n = 200) and the United States (n = 1400]. Subjects Panel members who were aged 35–65 years, smoked at least five cigarettes per day and at initiation stated an intention to quit smoking within the next 3 months were eligible for this study. Measurements Measures included: attempts to quit, smoking status, smoking history, nicotine dependence and craving, methods used to quit smoking, reasons for quitting or failing to quit smoking, short-term health effects, health resource utilization, wellbeing, concern over weight gain, confidence in preventing weight gain, body weight and demographics. In addition, in-home assessments of weight were undertaken by field staff for a random sample of US participants. Findings Country-specific recruitment was completed within 17 days. The recruitment method produced a sample with characteristics broadly similar to those found in national surveys of smokers except for higher prevalence of obesity in the US and Canadian samples and higher educational level. At the end of 1 year the response rate was 52%, and there was little evidence of differential loss to follow-up by key subject characteristics. Weight reported in the survey was found to correlate highly with weight measured during in-home visits. Conclusion This paper demonstrates the feasibility of enrolling and following a diverse cohort of smokers for self-reported health and behaviour measures via the internet.

Objectives: To estimate the prevalence of obesity in elderly Americans in 2010 and to discuss the health and economic implications of these estimates. Design: Three methods of generating future point-prevalence estimates using data from consecutive cross-sectional studies. Setting: All regions of the United States. Participants: Estimates were based on five nationally representative surveys of the adult population of the United States, conducted from 1960 to 2000, and population estimates from the U.S. Census Bureau. Measurements: Changes in obesity (body mass index (BMI) ≥30 kg/m2) and normal weight (BMI

BACKGROUND: Donors are deferred for multiple reasons. Losses related to disease marker rates are well established. Donor and donation losses for other reasons, however, have not been extensively quantified. STUDY DESIGN AND METHODS: To quantify these losses, three data sets from the Blood Centers of the Pacific were combined, permitting detailed analysis of year 2000 allogeneic whole-blood donations. RESULTS: During 2000, 13.6 percent of 116,165 persons who presented for donation were deferred at presentation. Short-term deferral accounted for 68.5 percent (hematocrit was most common at 60%); long-term deferral accounted for 21 percent (travel to a malarial area and tattoo or other nonintravenous drug use needle exposure were most common at 59 and 29%, respectively); and multiple-year or permanent deferral accounted for 10.5 percent (UK travel [variant Creutzfeldt-Jakob disease] risk and emigration from a malarial area were most common at 38 and 11%, respectively). Disease-markerreactive donations represented 0.9 percent of donor outcomes. The prevalence of deferral and also miscollection (under- and overweight units) varied by age, sex, and firsttime versus repeat donor status. Overall, miscollection led to a loss of 3.8 percent of 100,141 collections, ranging from 1.9 percent in repeat male donors 40 to 54 years of age to 10.7 percent in first-time female donors 16 to 24 years of age. CONCLUSION: Loss of units from both first-time and repeat donors due to temporary deferral and loss of units from miscollection are more common events than losses due to disease marker testing. Some of these losses may be avoidable and could increase the blood supply without having to recruit new donors. he voluntary-donor blood supply is dependent on the willingness of individuals to donate. Additional safety initiatives have been implemented to reduce the risk of communicable diseases, particularly those that cannot be detected though standard blood marker testing, such as variant Creutzfeldt-Jakob disease. As the number of initiatives has grown, concerns have been raised about their impact on the quantity of blood in the nation’s supply, the size of the population of potential donors, and the implications of temporary donor deferral. Presenting for donation does not mean a donor is eligible to donate or that an eligible donor will provide blood that can be released for transfusion. Both donor eligibility assessment and blood unit testing contribute to the safety of the supply. Presenting donors are deferred for multiple reasons related to safety for the donor and potential threats to the safety of the supply. Regardless of the reason, these predonation deferrals lead to a diminished eligible donor pool, even though the demand for blood has not decreased. 1