Association between baseline cardiovascular risk and incidence rates of major adverse cardiovascular events and malignancies in patients with psoriatic arthritis and psoriasis receiving tofacitinib.

Background: Tofacitinib is a Janus kinase inhibitor for the treatment of psoriatic arthritis (PsA) and has been investigated for psoriasis (PsO). Objectives: This post hoc analysis examined baseline cardiovascular (CV) disease risk and its association with the occurrence of major adverse cardiovascular events (MACE) and malignancies in tofacitinib-treated patients with PsA and PsO. Design: Included three phase III/long-term extension (LTE) PsA trials and seven phase II/phase III/LTE PsO trials of patients receiving ⩾ 1 dose of tofacitinib. Methods: Incidence rates (IRs: patients with events/100 patient-years) for MACE and malignancies (excluding non-melanoma skin cancer) were determined in subgroups according to history of atherosclerotic CV disease (ASCVD), baseline 10-year risk of ASCVD (in patients without history of ASCVD), and baseline metabolic syndrome (MetS). Results: For patients with PsA (N = 783) and PsO (N = 3663), respectively, tofacitinib exposure was 2038 and 8950 patient-years (median duration: 3.0 and 2.4 years), and 40.9% and 32.7% had MetS. Excluding missing CV risk profile data, 51/773 (6.6%) and 144/3629 (4.0%) patients had history of ASCVD, and in patients without history of ASCVD, around 20.0% had intermediate/high baseline 10-year ASCVD risk. For PsA and PsO, IRs of MACE were greatest in those with history of ASCVD or high baseline 10-year ASCVD risk. For PsA, five of six patients with MACE had baseline MetS. Malignancy IRs in patients with PsA were greatest in those with intermediate/high baseline 10-year ASCVD risk. Of these, eight of nine patients with malignancies had baseline MetS. In the PsO cohort, IR of malignancies was notably greater with high versus low/borderline/intermediate baseline 10-year ASCVD risk. Conclusion: In tofacitinib-treated patients with PsA/PsO, increased ASCVD risk and baseline MetS were associated with higher IRs for MACE and malignancies. Our results support assessing CV risk in patients with PsA/PsO and suggest enhanced cancer monitoring in those with increased ASCVD risk. Registration ClinicalTrialsgov: NCT01877668/NCT01882439/NCT01976364/NCT00678210/NCT01710046/NCT01241591/NCT01186744/NCT01276639/NCT01309737/NCT01163253. Plain Language Summary: People who have psoriatic arthritis or psoriasis may have more heart-related problems and cancer if they have a higher risk of cardiovascular disease: A study in people with psoriatic arthritis or psoriasis receiving tofacitinib Why was this study done? • People with psoriatic arthritis (PsA) and psoriasis (PsO) are more likely than the general population to have a disease affecting the heart and blood vessels [cardiovascular (CV) disease].• People who are more likely to have CV disease may also be more likely to have certain types of cancer.• Tofacitinib is a medicine to treat people with PsA and has been tested in people with PsO.• We wanted to know if the risk of CV disease affects the number of heart-related problems (including heart attack, stroke, or death) and cancer in people with PsA and PsO. What did the researchers do? • We used results from 10 clinical trials.• In these trials, people with PsA and PsO were taking tofacitinib 5 or 10 mg twice a day.• After the trials had ended, we measured people's risk of CV disease using a risk calculator. This risk calculator showed if they had a low, borderline, intermediate, or high risk of CV disease over the next 10 years. We also checked if they had had CV disease before treatment.• We checked if people had a group of conditions linked to CV disease: diabetes, high blood pressure, and obesity.• We counted the cases of heart-related problems and cancer in people once they started taking tofacitinib. What did the researchers find? In people with PsA and PsO taking tofacitinib:• There were more cases of heart-related problems and cancer in people who had intermediate or high risk of CV disease.• There were more cases of heart-related problems in people who had had CV disease before.• More people with diabetes, high blood pressure, and obesity had heart-related problems and cancer than people without those conditions. What do the findings mean? • It is important to measure risk and assess history of CV disease in people with PsA and PsO, including those taking tofacitinib.• We should test for cancer in people with high risk of CV disease.

Broad-scale eDNA sampling for describing aquatic species distributions in running waters: Pacific lamprey Entosphenus tridentatus in the upper Snake River, USA.

One of the most fundamental yet challenging tasks for aquatic ecologists is to precisely delineate the range of species, particularly those that are broadly distributed, require specialized sampling methods, and may be simultaneously declining and increasing in different portions of their range. An exemplar is the Pacific lamprey Entosphenus tridentatus, a jawless anadromous fish of conservation concern that is actively managed in many coastal basins in western North America. To efficiently determine its distribution across the accessible 56,168 km of the upper Snake River basin in the north-western United States, we first delimited potential habitat by using predictions from a species distribution model based on conventionally collected historical data and from the distribution of a potential surrogate, Chinook salmon Oncorhynchus tshawytscha, which yielded a potential habitat network of 10,615 km. Within this area, we conducted a two-stage environmental DNA survey involving 394 new samples and 187 archived samples collected by professional biologists and citizen scientists using a single, standardized method from 2015 to 2021. We estimated that Pacific lamprey occupied 1875 km of lotic habitat in this basin, of which 1444 km may have been influenced by recent translocation efforts. Pacific lamprey DNA was consistently present throughout most river main stems, although detections became weaker or less frequent in the largest and warmest downstream channels and near their headwater extent. Pacific lamprey were detected in nearly all stocked tributaries, but there was no evidence of indigenous populations in such habitats. There was evidence of post-stocking movement because detections were 1.8-36.0 km upstream from release sites. By crafting a model-driven spatial sampling template and executing an eDNA-based sampling campaign led by professionals and volunteers, supplemented by previously collected samples, we established a benchmark for understanding the current range of Pacific lamprey across a large portion of its range in the interior Columbia River basin. This approach could be tailored to refine range estimates for other wide-ranging aquatic species of conservation concern.

Effect of tofacitinib on dactylitis and patient-reported outcomes in patients with active psoriatic arthritis: post-hoc analysis of phase III studies.

BACKGROUND: Tofacitinib is an oral Janus kinase inhibitor for the treatment of psoriatic arthritis (PsA). This post-hoc analysis of two phase III studies in patients with PsA treated with tofacitinib assessed dactylitis by location, and the impact on patient-reported outcomes (PROs). METHODS: Patients received tofacitinib 5 or 10 mg twice daily (BID), or placebo. Endpoints included change from baseline in Dactylitis Severity Score (DSS), proportions of patients with dactylitis, Psoriatic Arthritis Disease Activity Score (PASDAS), and PROs (Health Assessment Questionnaire-Disability Index [HAQ-DI]; Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-F]; Short Form-36 Health Survey [SF-36] Physical Component Summary [PCS], Mental Component Summary [MCS], and physical functioning [PF]; arthritis pain; and Work Limitations Questionnaire [WLQ]). Descriptive statistics were generated by visit and treatment. Change from baseline in PROs were evaluated by multivariate linear regression. RESULTS: The analysis included 373/337 patients with baseline DSS > 0/DSS = 0. Regardless of location, DSS improvements in patients with DSS > 0 were greater from month 1 with tofacitinib (10 mg BID) versus placebo. For patients with DSS > 0/DSS = 0, both doses of tofacitinib led to mean dactylitis presence ≤ 15%/< 2% for all digits at month 6, and PASDAS (by dactylitis location) was lower versus placebo at month 3. Dactylitis location was not significantly associated with change from baseline in PROs. CONCLUSION: Tofacitinib resulted in sustained improvements in dactylitis irrespective of location, with minimal emergence of new dactylitis. Trial registration NCT01877668; NCT01882439.

Do metapopulations and management matter for relict headwater bull trout populations in a warming climate?

Mountain headwater streams have emerged as important climate refuges for native cold-water species due to their slow climate velocities and extreme physical conditions that inhibit non-native invasions. Species persisting in refuges often do so as fragmented, relict populations from broader historical distributions that are subject to ongoing habitat reductions and increasing isolation as climate change progresses. Key for conservation planning is determining where remaining populations will persist and how habitat restoration strategies can improve biological resilience to enhance the long-term prospects for species of concern. Studying bull trout, a headwater species in the northwestern USA, we developed habitat occupancy models using a data set of population occurrence in 991 natal habitat patches with a suite of novel geospatial covariates derived from high-resolution hydroclimatic scenarios and other sources representing watershed and instream habitat conditions, patch geometry, disturbance, and biological interactions. The best model correctly predicted bull trout occupancy status in 82.6% of the patches and included effects for: patch size estimated as habitat volume, extent of within-patch reaches <9°C mean August temperature, distance to nearest occupied patch, road density, invasive brook trout prevalence, patch slope, and frequency of high winter flows. The model was used to assess 16 scenarios of bull trout occurrence within the study streams that represented a range of restoration strategies under three climatic conditions (baseline, moderate change, and extreme change). Results suggested that regional improvements in bull trout status were difficult to achieve in realistic restoration strategies due to the pervasive nature of climate change and the limited extent of restoration actions given their high costs. However, occurrence probabilities in a subset of patches were highly responsive to restoration actions, suggesting that targeted investments to improve the resilience of some populations may be contextually beneficial. A possible strategy, therefore, is focusing effort on responsive populations near more robust population strongholds, thereby contributing to local enclaves where dispersal among populations further enhances resilience. Equally important, strongholds constituted a small numerical percentage of patches (5%-21%), yet encompassed the large majority of occupied habitat by volume (72%-89%) and their protection could have significant conservation benefits for bull trout.

Cost-effective composite methods for large-scale solid-state calculations.

Following the development in recent years of progressively more accurate approximations to the exchange-correlation functional, the use of density functional theory (DFT) methods to examine increasingly large and complex systems has grown, in particular for solids and other condensed matter systems. However the cost of these calculations is high, often requiring the use of specialist HPC facilities. As such, for the purpose of large-scale high-throughput screening of material properties, a hierarchy of simplified DFT methods has been proposed that allows rapid electronic structure calculation of large systems, and we have recently extended this scheme to the solid state (sol-3c). Here, we analyze the applicability and scaling of the new sol-3c DFT methods to molecules and crystals composed of light-elements, such as small proteins and model DNA-helices. Furthermore, the calculation of the electronic structure of large to very large porous systems, such as metal-organic frameworks and inorganic nanoparticles, is discussed. The new composite methods have been implemented in the CRYSTAL17 code, which efficiently implements hybrid functionals and enables routine application of the new methods to large-scale calculations of such materials with excellent performance, even with small-scale computing resources.

Extending and assessing composite electronic structure methods to the solid state.

A hierarchy of simplified Hartree-Fock (HF), density functional theory (DFT) methods, and their combinations has been recently proposed for the fast electronic structure computation of large systems. The covered methods are a minimal basis set Hartree-Fock (HF-3c), a small basis set global hybrid functional (PBEh-3c), and its screened exchange variant (HSE-3c), all augmented with semiclassical correction potentials. Here, we extend their applicability to inorganic covalent and ionic solids as well as layered materials. The new methods have been dubbed HFsol-3c, PBEsol0-3c, and HSEsol-3c, respectively, to indicate their parent functional as well as the correction potentials. They have been implemented in the CRYSTAL code to enable routine application for molecular as well as solid materials. We validate the new methods on diverse sets of solid state benchmarks that cover more than 90 solids ranging from covalent, ionic, semi-ionic, layered, and molecular crystals. While we focus on structural and energetic properties, we also test bandgaps, vibrational frequencies, elastic constants, and dielectric and piezoelectric tensors. HSEsol-3c appears to be most promising with mean absolute error for cohesive energies and unit cell volumes of molecular crystals of 1.5 kcal/mol and 2.8%, respectively. Lattice parameters of inorganic solids deviate by 3% from the references, and vibrational frequencies of α-quartz have standard deviations of 10 cm-1. Overall, this shows an accuracy competitive to converged basis set dispersion corrected DFT with a substantial increase in computational efficiency.

Exploring Nutrition Labelling of Food and Beverages in Vending Machines in Canadian Recreational Sport Settings.

Purpose: To evaluate whether interpretive "health" labels placed in vending machines in recreation centres represented products' nutrient content when compared with provincial nutrition guidelines. Methods: A cross-sectional audit (November 2015 - April 2016) of 139 vending machines in recreation facilities found 525 foods and beverages in 17 machines labelled by vendors according to healthfulness. Product nutrient content was compared with provincial nutrition guideline criteria. Cross-tabulation and weighted Cohen's kappa evaluated agreement between vendor interpretive labels and guideline ranks. Descriptive statistics evaluated how mislabelled products deviated from recommended nutrient content. Mann-Whitney tests compared nutrient content of "healthy" and "unhealthy" labelled products. Results: Almost one-third of all products were mislabelled by vendors with 72% of those labelled healthier than their actual guideline rank. Energy, total fat, sugar, and sodium contents exceeded recommended levels in one-third to one-half of mislabelled products. Overall, products labelled healthy by vendors were significantly lower in energy, sodium, and fat compared with those labelled unhealthy; however, not for all food types (e.g., bars, fruit snacks, nuts). Conclusions: For certain product categories, vendor interpretive nutrition labels poorly represented products' nutrient content according to provincial nutrition guidelines. Dietitians may be a valuable resource to help implement nutrition guidelines to create credible interpretive product labelling systems.

Combined Pharmacologic Therapy in Postmenopausal Osteoporosis.

Antiresorptive agents for treating postmenopausal osteoporosis include selective estrogen receptor modulator (SERM), bisphosphonates and denoumab. Teriparatide is the only Food and Drug Administration-approved anabolic agent. Synergistic effects of combining teriparatide with an antiresorptive agent have been proposed and studied. This article reviews the trial designs and the outcomes of combination therapies. Results of the combination therapy for teriparatide and bisphosphonates were mixed; while small increases of bone density were observed in the combination therapy of teriparatide and estrogen/SERM and that of teriparatide and denosumab. Those clinical studies were limited by small sample sizes and lack of fracture outcomes.

Climate, Demography, and Zoogeography Predict Introgression Thresholds in Salmonid Hybrid Zones in Rocky Mountain Streams.

Among the many threats posed by invasions of nonnative species is introgressive hybridization, which can lead to the genomic extinction of native taxa. This phenomenon is regarded as common and perhaps inevitable among native cutthroat trout and introduced rainbow trout in western North America, despite that these taxa naturally co-occur in some locations. We conducted a synthetic analysis of 13,315 genotyped fish from 558 sites by building logistic regression models using data from geospatial stream databases and from 12 published studies of hybridization to assess whether environmental covariates could explain levels of introgression between westslope cutthroat trout and rainbow trout in the U.S. northern Rocky Mountains. A consensus model performed well (AUC, 0.78-0.86; classification success, 72-82%; 10-fold cross validation, 70-82%) and predicted that rainbow trout introgression was significantly associated with warmer water temperatures, larger streams, proximity to warmer habitats and to recent sources of rainbow trout propagules, presence within the historical range of rainbow trout, and locations further east. Assuming that water temperatures will continue to rise in response to climate change and that levels of introgression outside the historical range of rainbow trout will equilibrate with those inside that range, we applied six scenarios across a 55,234-km stream network that forecast 9.5-74.7% declines in the amount of habitat occupied by westslope cutthroat trout populations of conservation value, but not the wholesale loss of such populations. We conclude that introgression between these taxa is predictably related to environmental conditions, many of which can be manipulated to foster largely genetically intact populations of westslope cutthroat trout and help managers prioritize conservation activities.

Safety and pharmacodynamic dose response of short-term prednisone in healthy adult subjects: a dose ranging, randomized, placebo-controlled, crossover study.

BACKGROUND: Glucocorticoids (GCs), such as prednisone, are the standard of care for several inflammatory and immunologically mediated diseases, but their chronic systemic administration is severely limited by serious adverse effects that are both dose and time dependent. Short-term treatment (7-14 days) with oral prednisone is used for many acute inflammatory and allergic conditions. This study was conducted to characterize the safety and pharmacodynamic (PD) dose-response of a 7-day course of oral prednisone on biomarkers of GC receptor agonism. METHODS: In this randomized, single-blind, placebo-controlled, crossover study (A9001309), 37 healthy subjects received placebo or a prednisone dose from 2.5-60 mg daily over 7 days in each of three treatment periods. White blood cell counts and plasma samples for measuring cortisol, osteocalcin and procollagen type 1 N-propeptide (P1NP) were obtained at 2, 4, 8, and 12 h post-dose on Day 1, immediately prior to dosing on Days 1, 2, and 4, and at nominal dosing time on Days 0 and 8. Urine samples for urinary N-terminal cross-linked telopeptide of type 1 collagen (uNTX) were collected on Days 0, 1, 2, 4, and 8. Serum samples for adiponectin were obtained prior to dosing on days 0, 1, 4 and 8. RESULTS: Daily doses of prednisone up to 60 mg resulted in dose- and time-dependent decreases in plasma osteocalcin, plasma P1NP, serum cortisol, and absolute blood eosinophil counts. Absolute blood neutrophil counts increased, while blood lymphocyte counts rebounded to an increased level following an initial rapid decrease after dosing. An increase was observed for uNTX and adiponectin. The incidence of adverse effects with prednisone was not dose related, and nervous system disorders, mainly headache, were the most frequently reported adverse effects. CONCLUSIONS: This characterization provides important and relevant information on safety and PD responses of short-term prednisone dosing over the commonly-used clinical dose range, and also provides a reference for early clinical development of dissociated agents targeting a differentiated PD profile. TRIAL REGISTRATION NUMBER: NCT02767089 (retrospectively registered: 21 April 2016).

Slow climate velocities of mountain streams portend their role as refugia for cold-water biodiversity.

The imminent demise of montane species is a recurrent theme in the climate change literature, particularly for aquatic species that are constrained to networks and elevational rather than latitudinal retreat as temperatures increase. Predictions of widespread species losses, however, have yet to be fulfilled despite decades of climate change, suggesting that trends are much weaker than anticipated and may be too subtle for detection given the widespread use of sparse water temperature datasets or imprecise surrogates like elevation and air temperature. Through application of large water-temperature databases evaluated for sensitivity to historical air-temperature variability and computationally interpolated to provide high-resolution thermal habitat information for a 222,000-km network, we estimate a less dire thermal plight for cold-water species within mountains of the northwestern United States. Stream warming rates and climate velocities were both relatively low for 1968-2011 (average warming rate = 0.101 °C/decade; median velocity = 1.07 km/decade) when air temperatures warmed at 0.21 °C/decade. Many cold-water vertebrate species occurred in a subset of the network characterized by low climate velocities, and three native species of conservation concern occurred in extremely cold, slow velocity environments (0.33-0.48 km/decade). Examination of aggressive warming scenarios indicated that although network climate velocities could increase, they remain low in headwaters because of strong local temperature gradients associated with topographic controls. Better information about changing hydrology and disturbance regimes is needed to complement these results, but rather than being climatic cul-de-sacs, many mountain streams appear poised to be redoubts for cold-water biodiversity this century.

The cold-water climate shield: delineating refugia for preserving salmonid fishes through the 21st century.

The distribution and future fate of ectothermic organisms in a warming world will be dictated by thermalscapes across landscapes. That is particularly true for stream fishes and cold-water species like trout, salmon, and char that are already constrained to high elevations and latitudes. The extreme climates in those environments also preclude invasions by most non-native species, so identifying especially cold habitats capable of absorbing future climate change while still supporting native populations would highlight important refugia. By coupling crowd-sourced biological datasets with high-resolution stream temperature scenarios, we delineate network refugia across >250 000 stream km in the Northern Rocky Mountains for two native salmonids-bull trout (BT) and cutthroat trout (CT). Under both moderate and extreme climate change scenarios, refugia with high probabilities of trout population occupancy (>0.9) were predicted to exist (33-68 BT refugia; 917-1425 CT refugia). Most refugia are on public lands (>90%) where few currently have protected status in National Parks or Wilderness Areas (<15%). Forecasts of refuge locations could enable protection of key watersheds and provide a foundation for climate smart planning of conservation networks. Using cold water as a 'climate shield' is generalizable to other species and geographic areas because it has a strong physiological basis, relies on nationally available geospatial data, and mines existing biological datasets. Importantly, the approach creates a framework to integrate data contributed by many individuals and resource agencies, and a process that strengthens the collaborative and social networks needed to preserve many cold-water fish populations through the 21st century.

French Validation of the Revised Algase Wandering Scale for Long-Term Care.

OBJECTIVES: The aim of this study was to create a French equivalent of the revised Algase wandering scale for long-term care (RAWS-LTC). METHODS: The RAWS-LTC French version (F-RAWS-LTC), Mini-Mental State Examination, and Neuropsychiatric Inventory were administered to a sample of 100 institutionalized patients from 12 specialized homes. RESULTS: The mean of the overall F-RAWS-LTC was 2.32 (standard deviation [SD]=0.74, range 1-4), and the mean of each subscale was 2.48 for persistent walking, 1.62 for eloping behavior, and 2.30 for spatial disorientation. The correlation between the overall F-RAWS-LTC and each subscale was between 0.73 (for Spatial Disorientation) and 0.87 (for Persistent Walking). The correlation between the degree of behavioral disturbances and the overall F-RAWS-LTC is 0.42, and the correlation with the cognitive impairment is 0.50. Differences between the wanderers and nonwanderers are significant for the overall F-RAWS-LTC and for all the subscales. DISCUSSION: Data demonstrate the statistical validity of the F-RAWS-LTC.

Sports drink consumption and diet of children involved in organized sport.

BACKGROUND: Organized sport provides one option for children to be physically active. However, there is a paucity of information about the relationship between children's participation in organized sport and their diet, and specifically their sports drink consumption. Therefore, the relationship between sports participation in children and the consumption of sports drinks, sugar-sweetened beverages (SSBs) and other components of diet was examined. METHODS: A cross-sectional descriptive study was conducted using baseline data from the Action Schools! BC Dissemination study cohort (n = 1421; 9.90 (0.58) y; 736 girls, 685 boys). The differences between the dietary behaviours of children participating in organized sport (sport) versus those that did not participate (non-sport) was examined. A modified Physical Activity Questionnaire for Older Children (PAQ-C) was used to measure physical activity levels and participation in organized sport. A Food Frequency Questionnaire (FFQ) and 24-hour dietary recall were used to assess eating behaviour and macronutrient intake (including protein, fat, and carbohydrate as well as sugar, fibre and total calories). Fruit, vegetable and beverage quantities were hand-tallied from the dietary recall. Fruit, vegetable and beverage frequency was assessed using the FFQ. Analysis of covariance (ANCOVA) was used to analyse differences between groups and a chi-square test of association was use to determine if participation in sport was significantly associated with the proportion of children consuming sports drinks and SSBs, and with gender. RESULTS: Children involved in sport had a lower body mass index (BMI) and were more physically active than children in the non-sport group (p < 0.01). Only a small number (n = 20/1421) of children consumed sports drinks and no difference in consumption of sports drink between sport and non-sport participants (p > .05) was observed. However, children involved in organized sport consumed more total calories, fat, fibre, fruit, vegetables and non-flavoured milk (p < 0.01) than non-sport children. CONCLUSIONS: Children involved in organized sport were more physically active, consumed a healthier diet than non-participants and on average had lower BMI's despite consuming more calories. As consumption of sports drinks among this age group was low, this may be an ideal time to begin educating children and their parents about the appropriate consumption of sports drinks and the perils of consuming too many SSBs, specifically.

Maraviroc, a chemokine receptor-5 antagonist, fails to demonstrate efficacy in the treatment of patients with rheumatoid arthritis in a randomized, double-blind placebo-controlled trial.

INTRODUCTION: The purpose of this study was to determine whether maraviroc, a human CC chemokine receptor 5 (CCR5) antagonist, is safe and effective in the treatment of active rheumatoid arthritis (RA) in patients on background methotrexate (MTX). METHODS: This phase IIa study comprised two distinct components: an open-label safety study of the pharmacokinetics (PK) of MTX in the presence of maraviroc, and a randomized, double-blind, placebo-controlled, proof-of-concept (POC) component. In the PK component, patients were randomized 1:1 to receive maraviroc 150 or 300 mg twice daily (BID) for four weeks. In the POC component, patients were randomized 2:1 to receive maraviroc 300 mg BID or placebo for 12 weeks. Patients were not eligible for inclusion in both components. RESULTS: Sixteen patients were treated in the safety/PK component. Maraviroc was well tolerated and there was no evidence of drug-drug interaction with MTX. One hundred ten patients were treated in the POC component. The study was terminated after the planned interim futility analysis due to lack of efficacy, at which time 59 patients (38 maraviroc; 21 placebo) had completed their week 12 visit. There was no significant difference in the number of ACR20 responders between the maraviroc (23.7%) and placebo (23.8%) groups (treatment difference -0.13%; 90% CI -20.45, 17.70; P = 0.504). The most common all-causality treatment-emergent adverse events in the maraviroc group were constipation (7.8%), nausea (5.2%), and fatigue (3.9%). CONCLUSIONS: Maraviroc was generally well tolerated over 12 weeks; however, selective antagonism of CCR5 with maraviroc 300 mg BID failed to improve signs and symptoms in patients with active RA on background MTX. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00427934.

Effects of climate change and wildfire on stream temperatures and salmonid thermal habitat in a mountain river network.

Mountain streams provide important habitats for many species, but their faunas are especially vulnerable to climate change because of ectothermic physiologies and movements that are constrained to linear networks that are easily fragmented. Effectively conserving biodiversity in these systems requires accurate downscaling of climatic trends to local habitat conditions, but downscaling is difficult in complex terrains given diverse microclimates and mediation of stream heat budgets by local conditions. We compiled a stream temperature database (n = 780) for a 2500-km river network in central Idaho to assess possible trends in summer temperatures and thermal habitat for two native salmonid species from 1993 to 2006. New spatial statistical models that account for network topology were parameterized with these data and explained 93% and 86% of the variation in mean stream temperatures and maximas, respectively. During our study period, basin average mean stream temperatures increased by 0.38 degrees C (0.27 degrees C/decade), and maximas increased by 0.48 degrees C (0.34 degrees C/decade), primarily due to long-term (30-50 year) trends in air temperatures and stream flows. Radiation increases from wildfires accounted for 9% of basin-scale temperature increases, despite burning 14% of the basin. Within wildfire perimeters, however, stream temperature increases were 2-3 times greater than basin averages, and radiation gains accounted for 50% of warming. Thermal habitat for rainbow trout (Oncorhynchus mykiss) was minimally affected by temperature increases, except for small shifts towards higher elevations. Bull trout (Salvelinus confluentus), in contrast, were estimated to have lost 11-20% (8-16%/decade) of the headwater stream lengths that were cold enough for spawning and early juvenile rearing, with the largest losses occurring in the coldest habitats. Our results suggest that a warming climate has begun to affect thermal conditions in streams and that impacts to biota will be specific to both species and context. Where species are at risk, conservation actions should be guided based on considerations of restoration opportunity and future climatic effects. To refine predictions based on thermal effects, more work is needed to understand mechanisms associated with biological responses, climate effects on other habitat features, and habitat configurations that confer population resilience.

Hypoxia and adrenergic function: molecular mechanisms related to Egr-1 and Sp1 activation.

Hypoxia is shown to regulate the stress hormone epinephrine through its biosynthesis by phenylethanolamine N-methyltransferase (PNMT) via PNMT gene activation and transcription factors Egr-1 and Sp1 in adrenal medulla-derived PC12 cells. Moderate hypoxia (5% oxygen) markedly stimulates PNMT promoter-driven luciferase activity in the cells. Hypoxia increases Egr-1 and Sp1 mRNA and nuclear protein content and Egr-1 and Sp1 protein-DNA binding complex formation. Subsequent to transcription factor induction, endogenous PNMT mRNA and protein also increase. Egr-1 and Sp1 binding site inactivation or Egr-1 and Sp1 siRNA inhibit PNMT promoter stimulation by hypoxia. Hypoxia elevates protein kinase A (PKA), phospholipase C (PLC), phosphoinositide 3-kinase, protein kinase C, ERK1/2 mitogen-activated protein kinase and p38 mitogen-activated protein kinase expression while selective inhibitors of these signaling enzymes abrogate hypoxic induction of the PNMT promoter and the rise in Egr-1, Sp1 and PNMT mRNA and protein. PC12 cells lacking PKA or PLCgamma-1 show significant reduction in PNMT promoter activation by hypoxia. Signaling inhibitors do not affect these responses or reduce hypoxic induction of the PNMT promoter to a lesser extent. Findings suggest that Egr-1 and Sp1 through synergistic interaction are critical transcriptional activators for hypoxic stress-regulated adrenergic function controlled via cAMP/PKA and PLC signaling. Identification of Sp1 as a mediator of hypoxia-induced transcriptional activation of PNMT has not been previously been shown. The effects of hypoxia on PNMT and thereby epinephrine may have important ramifications for the stress hormone epinephrine, its ability to regulate behavioral and physiological processes associated with stress and stress-elicited illness.

Hypoxic stress-induced changes in adrenergic function: role of HIF1 alpha.

Sustaining epinephrine-elicited behavioral and physiological responses during stress requires replenishment of epinephrine stores. Egr-1 and Sp1 contribute by stimulating the gene encoding the epinephrine-synthesizing enzyme, phenylethanolamine N-methyltransferase (PNMT), as shown for immobilization stress in rats in adrenal medulla and for hypoxic stress in adrenal medulla-derived PC12 cells. Hypoxia (5% O(2)) also activates hypoxia inducible factor (HIF) 1alpha, increasing mRNA, nuclear protein and nuclear protein/hypoxia response element binding complex formation. Hypoxia and HIF1alpha over-expression also elevate PNMT promoter-driven luciferase activity in PC12 cells. Hypoxia may be limiting as HIF1alpha over-expression increases luciferase expression to no greater extent than oxygen reduction alone. HIF1alpha inducers CoCl(2) or deferoxamine elevate luciferase as well. PC12 cells harboring a HIF1alpha expression construct show markedly higher levels of Egr-1 and Sp1 mRNA and nuclear protein and PNMT mRNA and cytoplasmic protein. Inactivation of Egr-1 and Sp1 binding sites in the proximal -893 bp of PNMT promoter precludes HIF1alpha stimulation while a potential hypoxia response element (-282 bp) in the promoter shows weak HIF1alpha affinity at best. These findings are the first to suggest that hypoxia activates the proximal rat PNMT promoter primarily via HIF1alpha induction of Egr-1 and Sp1 rather than by co-activation by Egr-1, Sp1 and HIF1alpha. In addition, the rise in HIF1alpha protein leading to Egr-1 and Sp1 stimulation of PNMT appears to include HIF1alpha gene activation rather than simply prevention of HIF1alpha proteolytic degradation.

Applying team-based learning in primary care residency programs to increase patient alcohol screenings and brief interventions.

PURPOSE: Educational research demonstrates little evidence of long-term retention from traditional lectures in residency programs. Team-based learning (TBL), an alternative, active learning technique, incites competition and generates discussion. This report presents data evaluating the ability of TBL to reinforce and enhance concepts taught during initial training in a National Institutes of Health-funded alcohol screening and brief intervention (SBI) program conducted in eight residency programs from 2005 to 2007 under the auspices of Mercer University School of Medicine. METHOD: After initial training of three hours, the authors conducted three TBL booster sessions of one and a quarter hours, spaced four months apart at each site. They assessed feasibility through the amount of preparation time for faculty and staff, residents' evaluations of their training, self-reported use of SBI, residents' performance on individual quizzes compared with group quizzes, booster session evaluations, and levels of confidence in conducting SBI. RESULTS: After initial training and three TBL reinforcement sessions, 42 residents (63%) reported that they performed SBI and that their levels of confidence in performing interventions in their current and future practices was moderately high. Participants preferred TBL formats over lectures. Group performance was superior to individual performance on initial assessments. When invited to select a model for conducting SBI in current and future practices, all residents opted for procedures that included clinician involvement. Faculty found TBL to be efficient but labor-intensive for training large groups. CONCLUSIONS: TBL was well received by residents and helped maintain a newly learned clinical skill. Future research should compare TBL to other learning methods.

Plasma glycosylphosphatidylinositol-specific phospholipase D predicts the change in insulin sensitivity in response to a low-fat but not a low-carbohydrate diet in obese women.

Although circulating glycosylphosphatidylinositol-specific phospholipase D (GPI-PLD), a minor high-density lipoprotein-associated protein, is elevated in patients with insulin resistance or high triglycerides, no information is available on the effect of weight loss or changes in insulin sensitivity on circulating GPI-PLD levels. The objective of the study was to determine the effect of weight loss and changes in insulin sensitivity on plasma GPI-PLD levels. Forty-two nondiabetic obese women were included in the study, which involved a 3-month dietary intervention randomizing patients to a low-fat or a low-carbohydrate diet. The study's main outcome measures were plasma GPI-PLD levels and insulin sensitivity as estimated by the homeostasis model assessment. The very low carbohydrate diet group lost more weight after 3 months (-7.6 +/- 3.2 vs -4.2 +/- 3.5 kg, P < .01), although the decrease in insulin resistance was similar between groups. Weight loss with either diet did not alter plasma GPI-PLD levels. However, baseline GPI-PLD levels correlated with the change in insulin sensitivity in response to the low-fat diet, whereas baseline insulin sensitivity correlated with the change in insulin sensitivity in response to the low-carbohydrate diet. Plasma GPI-PLD may serve as a clinical tool to determine the effect of a low-fat diet on insulin sensitivity.