Using temperature sensitivity to estimate shiftable electricity demand.

The growth of intermittent renewable energy and climate change makes it increasingly difficult to manage electricity demand variability. Centralized storage can help but is costly. An alternative is to shift demand. Cooling and heating demands are substantial and can be economically shifted using thermal storage. To estimate what thermal storage, employed at a scale, might due to reshape electricity loads, we pair fine-scale weather data with hourly electricity use to estimate the share of temperature-sensitive demand across 31 regions that span the continental United States. We then show how much variability can be reduced by shifting temperature-sensitive loads, with and without improved transmission between regions. We find that approximately three-quarters of within-day, within-region demand variability can be eliminated by shifting just half of temperature-sensitive demand. The variability-reducing benefits of shifting temperature-sensitive demand complement those gained from the improved interregional transmission, and greatly mitigate the challenge of serving higher peaks under climate change.

Interannual monsoon wind variability as a key driver of East African small pelagic fisheries.

Small pelagic fisheries provide food security, livelihood support and economic stability for East African coastal communities-a region of least developed countries. Using remotely- sensed and field observations together with modelling, we address the biophysical drivers of this important resource. We show that annual variations of fisheries yield parallel those of chlorophyll-a (an index of phytoplankton biomass). While enhanced phytoplankton biomass during the Northeast monsoon is triggered by wind-driven upwelling, during the Southeast monsoon, it is driven by two current induced mechanisms: coastal "dynamic uplift" upwelling; and westward advection of nutrients. This biological response to the Southeast monsoon is greater than that to the Northeast monsoon. For years unaffected by strong El-Niño/La-Niña events, the Southeast monsoon wind strength over the south tropical Indian Ocean is the main driver of year-to-year variability. This has important implications for the predictability of fisheries yield, its response to climate change, policy and resource management.

Prospective Assessment of Linox Implantable Cardioverter Defibrillator Leads for Structural or Electrical Abnormalities.

INTRODUCTION: Insulation failure leading to conductor externalization (CE) of a Linox (Biotronik, Berlin, Germany) implantable cardioverter defibrillator (ICD) lead has recently been reported. The aim of this study was to assess prospectively all Linox family ICD leads implanted at our center for evidence of CE or an electrical abnormality. METHODS: All patients with a Linox family ICD lead implanted at our center, between November 2007 and March 2015, were identified and all living patients were invited to attend for fluoroscopic screening and electrical assessment of the lead. RESULTS: A total of 183 patients had a Linox family ICD lead implanted at our center. Of these, 5 patients (2.7%) had the lead extracted because of electrical failure and 2 of these leads had evidence of CE. Out of 158 living patients with a Linox family ICD lead, 111 patients attended for screening (mean age 63.1 years, 22.5% female). In this group of patients, no cases of CE or electrical abnormalities of the lead were identified. CONCLUSION: In this study evaluating 183 patients with a Linox family ICD lead implanted at a single center, 5 leads (2.7%) were explanted because of electrical failure and 2 of these leads had evidence of CE. Prospective fluoroscopic assessment of 111 Linox family ICD leads, with a mean dwell time of 31.5 months, revealed no further cases of CE.

From global to regional and back again: common climate stressors of marine ecosystems relevant for adaptation across five ocean warming hotspots.

Ocean warming 'hotspots' are regions characterized by above-average temperature increases over recent years, for which there are significant consequences for both living marine resources and the societies that depend on them. As such, they represent early warning systems for understanding the impacts of marine climate change, and test-beds for developing adaptation options for coping with those impacts. Here, we examine five hotspots off the coasts of eastern Australia, South Africa, Madagascar, India and Brazil. These particular hotspots have underpinned a large international partnership that is working towards improving community adaptation by characterizing, assessing and projecting the likely future of coastal-marine food resources through the provision and sharing of knowledge. To inform this effort, we employ a high-resolution global ocean model forced by Representative Concentration Pathway 8.5 and simulated to year 2099. In addition to the sea surface temperature, we analyse projected stratification, nutrient supply, primary production, anthropogenic CO2 -driven ocean acidification, deoxygenation and ocean circulation. Our simulation finds that the temperature-defined hotspots studied here will continue to experience warming but, with the exception of eastern Australia, may not remain the fastest warming ocean areas over the next century as the strongest warming is projected to occur in the subpolar and polar areas of the Northern Hemisphere. Additionally, we find that recent rapid change in SST is not necessarily an indicator that these areas are also hotspots of the other climatic stressors examined. However, a consistent facet of the hotspots studied here is that they are all strongly influenced by ocean circulation, which has already shown changes in the recent past and is projected to undergo further strong change into the future. In addition to the fast warming, change in local ocean circulation represents a distinct feature of present and future climate change impacting marine ecosystems in these areas.

Insulation Failure of the Linox Defibrillator Lead: A Case Report and Retrospective Review of a Single Center Experience.

Implantable cardioverter defibrillator (ICD) lead insulation failure and conductor externalization have been increasingly reported. The 7.8F silicon-insulated Linox SD and Linox S ICD leads (Biotronik, Berlin, Germany) were released in 2006 and 2007, respectively, with an estimated 85,000 implantations worldwide. A 39-year-old female suffered an out-of-hospital ventricular fibrillation (VF) arrest with successful resuscitation. An ICD was implanted utilizing a single coil active fixation Linox(Smart) S lead (Biotronik, Berlin, Germany). A device-triggered alert approximately 3 years after implantation confirmed nonphysiological high rate sensing leading to VF detection. A chest X-ray showed an abnormality of the ICD lead and fluoroscopic screening confirmed conductor externalization proximal to the defibrillator coil. In view of the combined electrical and fluoroscopic abnormalities, urgent lead extraction and replacement were performed. A review of Linox (Biotronik) and Vigila (Sorin Group, Milan, Italy) lead implantations within our center (n = 98) identified 3 additional patients presenting with premature lead failure, 2 associated with nonphysiological sensed events and one associated with a significant decrease in lead impedance. All leads were subsequently removed and replaced. This case provides a striking example of insulation failure affecting the Linox ICD lead and, we believe, is the first to demonstrate conductor externalization manifesting both electrical and fluoroscopic abnormalities.

Fluoroscopic and electrical assessment of implantable cardioverter defibrillator leads: a prospective observational study.

BACKGROUND: Insulation defects resulting in conductor externalization (CE) have been reported in the Riata family of implantable cardioverter defibrillator (ICD) leads (St. Jude Medical, Sylmar, CA, USA). The aim of this study was to identify, prospectively, the rate of CE and outcomes following this, within a group of patients with a Riata ICD lead. METHODS: Patients with a Riata ICD lead attended for fluoroscopic screening and electrical assessment of the lead at yearly intervals between 2010 and 2012. RESULTS: One hundred and forty patients had no or borderline evidence of CE on initial assessment in 2010. These patients were prospectively followed for 3 years (304.6 patient-years). During this time, 11 patients developed definite CE, equating to an event rate of 3.6 (95% confidence intervals: 1.8-6.5) per 100 patient-years of follow-up. Of those patients developing definite CE, one patient had the ICD lead explanted (for reasons unrelated to CE) and no patients died. CE was not associated with any electrical abnormalities of the ICD lead. CONCLUSIONS: CE was observed at a rate of 3.6 per 100 patient-years of follow-up, in 140 individuals with a Riata ICD lead and no definite evidence of CE at baseline.

Greater sensitivity to drought accompanies maize yield increase in the U.S. Midwest.

A key question for climate change adaptation is whether existing cropping systems can become less sensitive to climate variations. We use a field-level data set on maize and soybean yields in the central United States for 1995 through 2012 to examine changes in drought sensitivity. Although yields have increased in absolute value under all levels of stress for both crops, the sensitivity of maize yields to drought stress associated with high vapor pressure deficits has increased. The greater sensitivity has occurred despite cultivar improvements and increased carbon dioxide and reflects the agronomic trend toward higher sowing densities. The results suggest that agronomic changes tend to translate improved drought tolerance of plants to higher average yields but not to decreasing drought sensitivity of yields at the field scale.

Multi-targeted therapy of cancer by niclosamide: A new application for an old drug.

The rapid development of new anticancer drugs that are safe and effective is a common goal shared by basic scientists, clinicians and patients. The current review discusses one such agent, namely niclosamide, which has been used in the clinic for the treatment of intestinal parasite infections. Recent studies repeatedly identified niclosamide as a potential anticancer agent by various high-throughput screening campaigns. Niclosamide not only inhibits the Wnt/ß-catenin, mTORC1, STAT3, NF-κB and Notch signaling pathways, but also targets mitochondria in cancer cells to induce cell cycle arrest, growth inhibition and apoptosis. A number of studies have established the anticancer activities of niclosamide in both in vitro and in vivo models. Moreover, the inhibitory effects of niclosamide on cancer stem cells provide further evidence for its consideration as a promising drug for cancer therapy. This article reviews various aspects of niclosamide as they relate to its efficacy against cancer and associated molecular mechanisms.

Fluoroscopic and electrical assessment of a series of defibrillation leads: prevalence of externalized conductors.

INTRODUCTION: Insulation defects with externalized conductors have been reported in the St. Jude Riata(®) family of defibrillation leads (St. Jude Medical, Sylmar, CA, USA). The objective of the Northern Ireland Riata(®) lead screening program was to identify insulation defects and externalized conductors by systematic fluoroscopic and electrical assessment in a prospectively defined cohort of patients. We sought to estimate the prevalence, identify risk factors, and determine the natural history of this abnormality. METHODS: All patients with a Riata(®) lead under follow-up at the Royal Victoria Hospital were invited for fluoroscopic imaging and implantable cardioverter-defibrillator lead parameter checks. Fluoroscopic images were read independently by two cardiologists and the presence of externalized conductors was classified as positive, negative, or borderline. RESULTS: One hundred and sixty-five of 212 patients with a Riata lead were evaluated by fluoroscopy and lead parameter measurements. The mean duration after implantation was 3.98+/-1.43 years. After screening 25 (15%) patients were classified as positive, 137 (83%) negative, and three (1.8%) borderline. Time since implantation (P = 0.001), presence of a single coil lead (P = 0.042), and patient age (P = 0.034) were significantly associated with externalized conductors. The observed rate of externalized conductors was 26.9% for 8-French and 4.7% for 7-French leads. No leads that were identified prospectively with externalized conductors had electrical abnormalities. Seven of 25 (28%) patients had a defective lead extracted by the end of this screening period. CONCLUSION: A significant proportion (15%) of patients with a Riata lead had an insulation breach 4 years after implantation. High-resolution fluoroscopic imaging in at least two orthogonal views is required to identify this abnormality.

Development and validation of a comparative genomic fingerprinting method for high-resolution genotyping of Campylobacter jejuni.

Campylobacter spp. are a leading cause of bacterial gastroenteritis worldwide. The need for molecular subtyping methods with enhanced discrimination in the context of surveillance- and outbreak-based epidemiologic investigations of Campylobacter spp. is critical to our understanding of sources and routes of transmission and the development of mitigation strategies to reduce the incidence of campylobacteriosis. We describe the development and validation of a rapid and high-resolution comparative genomic fingerprinting (CGF) method for C. jejuni. A total of 412 isolates from agricultural, environmental, retail, and human clinical sources obtained from the Canadian national integrated enteric pathogen surveillance program (C-EnterNet) were analyzed using a 40-gene assay (CGF40) and multilocus sequence typing (MLST). The significantly higher Simpson's index of diversity (ID) obtained with CGF40 (ID = 0.994) suggests that it has a higher discriminatory power than MLST at both the level of clonal complex (ID = 0.873) and sequence type (ID = 0.935). High Wallace coefficients obtained when CGF40 was used as the primary typing method suggest that CGF and MLST are highly concordant, and we show that isolates with identical MLST profiles are comprised of isolates with distinct but highly similar CGF profiles. The high concordance with MLST coupled with the ability to discriminate between closely related isolates suggests that CFG40 is useful in differentiating highly prevalent sequence types, such as ST21 and ST45. CGF40 is a high-resolution comparative genomics-based method for C. jejuni subtyping with high discriminatory power that is also rapid, low cost, and easily deployable for routine epidemiologic surveillance and outbreak investigations.

Niclosamide suppresses cancer cell growth by inducing Wnt co-receptor LRP6 degradation and inhibiting the Wnt/ß-catenin pathway.

The Wnt/ß-catenin signaling pathway is important for tumor initiation and progression. The low density lipoprotein receptor-related protein-6 (LRP6) is an essential Wnt co-receptor for Wnt/ß-catenin signaling and represents a promising anticancer target. Recently, the antihelminthic drug, niclosamide was found to inhibit Wnt/ß-catenin signaling, although the mechanism was not well defined. We found that niclosamide was able to suppress LRP6 expression and phosphorylation, block Wnt3A-induced ß-catenin accumulation, and inhibit Wnt/ß-catenin signaling in HEK293 cells. Furthermore, the inhibitory effects of niclosamide on LRP6 expression/phosphorylation and Wnt/ß-catenin signaling were conformed in human prostate PC-3 and DU145 and breast MDA-MB-231 and T-47D cancer cells. Moreover, we showed that the mechanism by which niclosamide suppressed LRP6 resulted from increased degradation as evident by a shorter half-life. Finally, we demonstrated that niclosamide was able to induce cancer cell apoptosis, and displayed excellent anticancer activity with IC(50) values less than 1 µM for prostate PC-3 and DU145 and breast MDA-MB-231 and T-47D cancer cells. The IC(50) values are comparable to those shown to suppress the activities of Wnt/ß-catenin signaling in prostate and breast cancer cells. Our data indicate that niclosamide is a unique small molecule Wnt/ß-catenin signaling inhibitor targeting the Wnt co-receptor LRP6 on the cell surface, and that niclosamide has a potential to be developed a novel chemopreventive or therapeutic agent for human prostate and breast cancer.

Nonlinear temperature effects indicate severe damages to U.S. crop yields under climate change.

The United States produces 41% of the world's corn and 38% of the world's soybeans. These crops comprise two of the four largest sources of caloric energy produced and are thus critical for world food supply. We pair a panel of county-level yields for these two crops, plus cotton (a warmer-weather crop), with a new fine-scale weather dataset that incorporates the whole distribution of temperatures within each day and across all days in the growing season. We find that yields increase with temperature up to 29 degrees C for corn, 30 degrees C for soybeans, and 32 degrees C for cotton but that temperatures above these thresholds are very harmful. The slope of the decline above the optimum is significantly steeper than the incline below it. The same nonlinear and asymmetric relationship is found when we isolate either time-series or cross-sectional variations in temperatures and yields. This suggests limited historical adaptation of seed varieties or management practices to warmer temperatures because the cross-section includes farmers' adaptations to warmer climates and the time-series does not. Holding current growing regions fixed, area-weighted average yields are predicted to decrease by 30-46% before the end of the century under the slowest (B1) warming scenario and decrease by 63-82% under the most rapid warming scenario (A1FI) under the Hadley III model.

Assessment of the environmental toxicity and carcinogenicity of tungsten-based shot.

The toxicity of elemental tungsten released from discharged shot was assessed against previous studies that established a 1% toxic threshold for soil organisms. Extremely heavy theoretical shot loadings of 69,000shot/ha were used to generate estimated environmental concentrations (EEC) for two brands of tungsten-based shot containing 51% and 95% tungsten. The corresponding tungsten EEC values were 6.5-13.5mg W/kg soil, far below the 1% toxic threshold. The same shot loading in water produced tungsten EEC values of 2.1-4.4mg W/L, levels that are not toxic under experimental conditions. Pure tungsten has not been shown to exhibit carcinogenic properties when ingested or embedded in animal tissues, but nickel, with which it is often alloyed, has known carcinogenicity. Given the large number of waterfowl that carry shot embedded in their body, it is advisable to screen lead shot substitutes for their carcinogenic potential through intra-muscular implantation.

Discovery and biological evaluation of benzo[a]carbazole-based small molecule agonists of the thrombopoietin (Tpo) receptor.

A novel series of benzo[a]carbazole-based small molecule agonists of the thrombopoietin (Tpo) receptor is reported. Starting from a 3.4 microM high throughput screen hit, members of this series have been identified which are full agonists with functional potency <50 nM and oral bioavailability in mice.

A pilot study of a low-tilt biphasic waveform for transvenous cardioversion of atrial fibrillation: improved efficacy compared with conventional capacitor-based waveforms in patients.

BACKGROUND: The optimal waveform tilt for defibrillation is not known. Most modern defibrillators used for the cardioversion of atrial fibrillation (AF) employ high-tilt, capacitor-based biphasic waveforms. METHODS: We have developed a low-tilt biphasic waveform for defibrillation. This low-tilt waveform was compared with a conventional waveform of equivalent duration and voltage in patients with AF. Patients with persistent AF or AF induced during a routine electrophysiology study (EPS) were randomized to receive either the low-tilt waveform or a conventional waveform. Defibrillation electrodes were positioned in the right atrial appendage and distal coronary sinus. Phase 1 peak voltage was increased in a stepwise progression from 50 V to 300V. Shock success was defined as return of sinus rhythm for >/=30 seconds. RESULTS: The low-tilt waveform produced successful termination of persistent AF at a mean voltage of 223 V (8.2 J) versus 270 V (6.7 J) with the conventional waveform (P = 0.002 for voltage, P = ns for energy). In patients with induced AF the mean voltage for the low-tilt waveform was 91V (1.6 J) and for the conventional waveform was 158 V (2.0 J) (P = 0.005 for voltage, P = ns for energy). The waveform was much more successful at very low voltages (less than or equal to 100 V) compared with the conventional waveform (Novel: 82% vs Conventional 22%, P = 0.008). CONCLUSION: The low-tilt biphasic waveform was more successful for the internal cardioversion of both persistent and induced AF in patients (in terms of leading edge voltage).

Discovery of inhibitors of the channel-activating protease prostasin (CAP1/PRSS8) utilizing structure-based design.

Structure-based design was utilized to guide the early stage optimization of a substrate-like inhibitor to afford potent peptidomimetic inhibitors of the channel-activating protease prostasin. The first X-ray crystal structures of prostasin with small molecule inhibitors bound to the active site are also reported.

The vulvalgesiometer as a device to measure genital pressure-pain threshold.

The construction and application of the vulvalgesiometer are described. This manually-applied device allows for the quantifiable measurement of pressure-pain thresholds in the external female genital region. A set of five vulvalgesiometers exerting pressures from 3 to 950 g was used in two studies. The goal of the first study was to examine the ability of the vulvalgesiometers to discriminate between women with and without provoked vestibulodynia (PVD). In a matched sample of affected and non-affected women, women with PVD exhibited significantly lower vestibular pressure-pain thresholds as compared to control women. As well, approximately half the sample of women with PVD described the sensation elicited at pressure-pain threshold as similar to the pain experienced during sexual intercourse. The goal of the second study was to investigate the inter-rater reliability of the vulvalgesiometers. In this separate sample of women with and without PVD, each participant was tested for pressure-pain threshold by two different investigators at different times. Results demonstrated high levels of inter-rater reliability, indicating that the vulvalgesiometers can be consistently used by different investigators. Further, results indicated significant negative correlations between pressure-pain thresholds and pain intensity ratings recorded during the cotton-swab test, suggesting that the lower the threshold, the higher the pain ratings during vestibular palpation. The vulvalgesiometers can be utilized for several purposes, including treatment outcome studies and measuring the degree of PVD severity.

Activation patterns during selective pacing of the left ventricle can be characterized using noninvasive electrocardiographic imaging.

BACKGROUND: Noncontact endocardial mapping allows accurate beat-to-beat reconstruction of the reentrant pathway of ventricular tachycardia and improves outcomes after ablation. Several studies support electrocardiographic imaging (ECGI) as a means of noninvasively outlining epicardial activation despite constraints of internal geometry. However, few have explored its clinical application. This study aims to evaluate ECGI during selective left ventricular (LV) pacing, relative to an invasive approach. METHODS: Multisite pacing was performed within the left ventricles of 3 patients undergoing invasive procedures. Simultaneous recording of endocardial potentials using a noncontact multielectrode array and body surface potentials (BSP) using an 80-electrode torso vest was performed. A total of 16 recordings were made. The inverse solution was applied to BSP to reconstruct epicardial activation. Single-paced beats from real and virtual electrograms were used to construct 3-dimensional isochronal and isopotential maps. Endocardial and epicardial data were then superimposed onto a single geometry to allow quantitative comparison of activation foci. RESULTS: Good correlation was observed between endocardial activation patterns and those reconstructed from BSP using ECGI. This was repeatedly demonstrated in all LV regions except for the septum (3 recordings). Epicardial isochronal maps were able to locate early and late activation to mean distances of 13.8 +/- 4.7 and 12.5 +/- 3.7 mm from endocardial data. Isopotential maps localized pacing sites with comparable accuracy (14 +/- 5.3 mm). CONCLUSIONS: Body surface potentials and reconstructed epicardial activation patterns during LV pacing correlate well with endocardial data acquired invasively. The exception was during pacing of the septum. Although early results are encouraging, further quantitative data are required to fully validate and apply this noninvasive tool in the clinical arena.