Dose-dependent influence of didanosine on immune recovery in HIV-infected patients treated with tenofovir

BACKGROUND: Antiretroviral therapy (ART) containing tenofovir disoproxil fumarate (TDF) and didanosine (ddI) has been associated with poor immune recovery despite virologic success. This effect might be related to ddI toxicity since ddI exposure is substantially increased by TDF. OBJECTIVE: To analyze whether immune recovery during ART with TDF and ddI is ddI-dose dependent. DESIGN AND METHODS: A retrospective longitudinal analysis of immune recovery measured by the CD4 T-cell slope in 614 patients treated with ART containing TDF with or without ddI. Patients were stratified according to the tertiles of their weight-adjusted ddI dose: low dose (< 3.3 mg/kg), intermediate dose (3.3-4.1 mg/kg) and high dose (> 4.1 mg/kg). Cofactors modifying the degree of immune recovery after starting TDF-containing ART were identified by univariable and multivariable linear regression analyses. RESULTS: CD4 T-cell slopes were comparable between patients treated with TDF and a weight-adjusted ddI-dose of < 4.1 mg/kg per day (n = 143) versus TDF-without-ddI (n = 393). In the multivariable model the slopes differed by -13 CD4 T cells/mul per year [95% confidence interval (CI), -42 to 17; P = 0.40]. In contrast, patients treated with TDF and a higher ddI dose (> 4.1 mg/kg per day, n = 78) experienced a significantly impaired immune recovery (-47 CD4 T cells/microl per year; 95% CI, -82 to -12; P = 0.009). The virologic response was comparable between the different treatment groups. CONCLUSIONS: Immune recovery is impaired, when high doses of ddI (> 4.1 mg/kg) are given in combination with TDF. If the dose of ddI is adjusted to less than 4.1 mg/kg per day, immune recovery is similar to other TDF-containing ART regimen.

La Yeguada volcanic complex, western Panama : an assessment of the geologic hazards using new 40AR/39Ar Ages

La Yeguada volcanic complex is one of three Quaternary volcanic centers in Panama, and is located on the southern slope of the Cordillera Central mountain range in western Panama, province of Veraguas. To assess potential geologic hazards, this study focused on the main dome complex near the village of La Laguna and also examined a cinder cone 10 km to the northwest next to the village of Media Luna. Based on newly obtained 40Ar/39Ar ages, the most recent eruption occurred approximately 32 000 years ago at the Media Luna cinder cone, while the youngest dated eruption at the main dome complex occurred 0.357 ± 0.019 Ma, producing the Castillo dome unit. Cerro Picacho is a separate dome located 1.5 km east of the main complex with a date of 4.47 ± 0.23 Ma, and the El Satro Pyroclastic Flow unit surrounds the northern portion of the volcanic complex and has an age of 11.26 ± 0.17 Ma. No Holocene (10 000 years ago to present) activity is recorded at the La Yeguada volcanic complex and therefore, it is unlikely to produce another eruption. The emergence of a new cinder cone is a possibility, but the associated hazards tend to be low and localized, and this does not pose a significant threat to the small communities scattered throughout the area. The main geologic hazard at the La Yeguada volcanic complex is from landslides coming off the many steep slopes.

Federal and state policy influence on woody biomass utilization

A considerable portion of public lands in the United States is at risk of uncharacteristically severe wildfires due to a history of fire suppression. Wildfires already have detrimental impacts on the landscape and on communities in the wildland-urban interface (WUI) due to unnatural and overstocked forests. Strategies to mitigate wildfire risk include mechanical thinning and prescribed burning in areas with high wildfire risk. The material removed is often of little or no economic value. Woody biomass utilization (WBU) could offset the costs of hazardous fuel treatments if removed material could be used for wood products, heat, or electricity production. However, barriers due to transportation costs, removal costs, and physical constraints (such as steep slopes) hinder woody biomass utilization. Various federal and state policies attempt to overcome these barriers. WBU has the potential to aid in wildfire mitigation and meet growing state mandates for renewable energy. This research utilizes interview data from individuals involved with on-the-ground woody biomass removal and utilization to determine how federal and state policies influence woody biomass utilization. Results suggest that there is not one over-arching policy that hinders or promotes woody biomass utilization, but rather woody biomass utilization is hindered by organizational constraints related to time, cost, and quality of land management agencies’ actions. However, the use of stewardship contracting (a hybrid timber sale and service contract) shows promise for increased WBU, especially in states with favorable tax policies and renewable energy mandates. Policy recommendations to promote WBU include renewal of stewardship contracting legislations and a re-evaluation of land cover types suited for WBU. Potential future policies to consider include the indirect role of carbon dioxide emission reduction activities to promote wood energy and future impacts of air quality regulations.

Wolf habitat selection at the territory level : seasonal and interannual variation and influence on reproductive success

Habitat selection has been one of the main research topics in ecology for decades. Nevertheless, many aspects of habitat selection still need to be explored. In particular, previous studies have overlooked the importance of temporal variation in habitat selection and the value of including data on reproductive success in order to describe the best quality habitat for a species. We used data collected from radiocollared wolves in Yellowstone National Park (USA), between 1996 and 2008, to describe wolf habitat selection. In particular, we aimed to identify i) seasonal differences in wolf habitat selection, ii) factors influencing interannual variation in habitat selection, and iii) the effect of habitat selection on wolf reproductive success. We used probability density functions to describe wolf habitat use and habitat coverages to represent the habitat available to wolves. We used regression analysis to connect habitat use with habitat characteristics and habitat selection with reproductive success. Our most relevant result was discovering strong interannual variability in wolf habitat selection. This variability was in part explained by pack identity and differences in litter size and leadership of a pack between two years (summer) and in pack size and precipitation (winter). We also detected some seasonal differences. Wolves selected open habitats, intermediate elevations, intermediate distances from roads, and avoided steep slopes in late winter. They selected areas close to roads and avoided steep slopes in summer. In early winter, wolves selected wetlands, herbaceous and shrub vegetation types, and areas at intermediate elevation and distance from roads. Surprisingly, the habitat characteristics selected by wolves were not useful in predicting reproductive success. We hypothesize that interannual variability in wolf habitat selection may be too strong to detect effects on reproductive success. Moreover, prey availability and competitor pressure may also have an influence on wolf reproductive success, which we did not assess. This project demonstrated how important temporal variation is in shaping patterns of habitat selection. We still believe in the value of running long-term studies, but the effect of temporal variation should always be taken into account.

Topographic and meteorological influences on spatial scaling of heavy convective rainfall in mountainous regions

Characterizing the spatial scaling and dynamics of convective precipitation in mountainous terrain and the development of downscaling methods to transfer precipitation fields from one scale to another is the overall motivation for this research. Substantial progress has been made on characterizing the space-time organization of Midwestern convective systems and tropical rainfall, which has led to the development of statistical/dynamical downscaling models. Space-time analysis and downscaling of orographic precipitation has received less attention due to the complexities of topographic influences. This study uses multiscale statistical analysis to investigate the spatial scaling of organized thunderstorms that produce heavy rainfall and flooding in mountainous regions. Focus is placed on the eastern and western slopes of the Appalachian region and the Front Range of the Rocky Mountains. Parameter estimates are analyzed over time and attention is given to linking changes in the multiscale parameters with meteorological forcings and orographic influences on the rainfall. Influences of geographic regions and predominant orographic controls on trends in multiscale properties of precipitation are investigated. Spatial resolutions from 1 km to 50 km are considered. This range of spatial scales is needed to bridge typical scale gaps between distributed hydrologic models and numerical weather prediction (NWP) forecasts and attempts to address the open research problem of scaling organized thunderstorms and convection in mountainous terrain down to 1-4 km scales.

Eruptive history of Maderas volcano using new 40Ar/39Ar ages and geochemical analyses

Maderas volcano is a small, andesitic stratovolcano located on the island of Ometepe, in Lake Nicaragua, Nicaragua with no record of historic activity. Twenty-one samples were collected from lava flows from Maderas in 2010. Selected samples were analyzed for whole-rock geochemical data using ICP-AES and/or were dated using the 40Ar/39Ar method. The results of these analyses were combined with previously collected data from Maderas as well as field observations to determine the eruptive history of the volcano and create a geologic map. The results of the geochemical analyses indicate that Maderas is a typical Central American andesitic volcano similar to other volcanoes in Nicaragua and Costa Rica and to its nearest neighbor, Concepción volcano. It is different from Concepción in one important way – higher incompatible elements. Determined age dates range from 176.8 ± 6.1 ka to 70.5 ± 6.1 ka. Based on these ages and the geomorphology of the volcano which is characterized by a bisecting graben, it is proposed that Maderas experienced two clear generations of development with three separate phases of volcanism: initial build-up of the older cone, pre-graben lava flows, and post-graben lava flows. The ages also indicate that Maderas is markedly older than Concepción which is historically active. Results were also analyzed regarding geologic hazards. The 40Ar/39Ar ages indicate that Maderas has likely been inactive for tens of thousands of years and the risk of future volcanic eruptions is low. However, earthquake, lahar and landslide hazards exist for the communities around the volcano. The steep slopes of the eroded older cone are the most likely source of landslide and lahar hazards.

Cut slope design for the access to an underground copper mine

Slope stability analysis is a major area of research in geotechnical engineering. That being said, very little is written in the geotechnical engineering literature on the design of box-cuts. The goal of this thesis will be to investigate the proper design of a boxcuts, and to design a box-cut for access to an underground copper mine. Issues that need to be considered in the box-cut design include, long term dewatering design, slope stability analysis, and erosion control. The soils at the project site were extremely low permeability, as a result a system of ejectors was designed both to improve the stability of the slopes and prevent flooding. Based on the results of limit equilibrium analysis and finite element analysis, a slope design of two horizontal on one vertical was selection, with a rock fill buttress providing reinforcement. Finally, Michigan DOT standards for seeding were used to provide erosion control

PROBABILISTIC MODELING OF RAINFALL INDUCED LANDSLIDE HAZARD ASSESSMENT IN SAN JUAN LA LAGUNA, SOLOLÁ, GUATEMALA

The municipality of San Juan La Laguna, Guatemala is home to approximately 5,200 people and located on the western side of the Lake Atitlán caldera. Steep slopes surround all but the eastern side of San Juan. The Lake Atitlán watershed is susceptible to many natural hazards, but most predictable are the landslides that can occur annually with each rainy season, especially during high-intensity events. Hurricane Stan hit Guatemala in October 2005; the resulting flooding and landslides devastated the Atitlán region. Locations of landslide and non-landslide points were obtained from field observations and orthophotos taken following Hurricane Stan. This study used data from multiple attributes, at every landslide and non-landslide point, and applied different multivariate analyses to optimize a model for landslides prediction during high-intensity precipitation events like Hurricane Stan. The attributes considered in this study are: geology, geomorphology, distance to faults and streams, land use, slope, aspect, curvature, plan curvature, profile curvature and topographic wetness index. The attributes were pre-evaluated for their ability to predict landslides using four different attribute evaluators, all available in the open source data mining software Weka: filtered subset, information gain, gain ratio and chi-squared. Three multivariate algorithms (decision tree J48, logistic regression and BayesNet) were optimized for landslide prediction using different attributes. The following statistical parameters were used to evaluate model accuracy: precision, recall, F measure and area under the receiver operating characteristic (ROC) curve. The algorithm BayesNet yielded the most accurate model and was used to build a probability map of landslide initiation points. The probability map developed in this study was also compared to the results of a bivariate landslide susceptibility analysis conducted for the watershed, encompassing Lake Atitlán and San Juan. Landslides from Tropical Storm Agatha 2010 were used to independently validate this study’s multivariate model and the bivariate model. The ultimate aim of this study is to share the methodology and results with municipal contacts from the author's time as a U.S. Peace Corps volunteer, to facilitate more effective future landslide hazard planning and mitigation.

Are there risk factors in alpine skiing? A controlled multicentre survey of 1278 skiers

OBJECTIVE: To analyse risk factors in alpine skiing. DESIGN: A controlled multicentre survey of injured and non-injured alpine skiers. SETTING: One tertiary and two secondary trauma centres in Bern, Switzerland. PATIENTS AND METHODS: All injured skiers admitted from November 2007 to April 2008 were analysed using a completed questionnaire incorporating 15 parameters. The same questionnaire was distributed to non-injured controls. Multiple logistic regression was performed. Patterns of combined risk factors were calculated by inference trees. A total of 782 patients and 496 controls were interviewed. RESULTS: Parameters that were significant for the patients were: high readiness for risk (p = 0.0365, OR 1.84, 95% CI 1.04 to 3.27); low readiness for speed (p = 0.0008, OR 0.29, 95% CI 0.14 to 0.60); no aggressive behaviour on slopes (p<0.0001, OR 0.19, 95% CI 0.09 to 0.37); new skiing equipment (p = 0.0228, OR 59, 95% CI 0.37 to 0.93); warm-up performed (p = 0.0015, OR 1.79, 95% CI 1.25 to 2.57); old snow compared with fresh snow (p = 0.0155, OR 0.31, 95% CI 0.12 to 0.80); old snow compared with artificial snow (p = 0.0037, OR 0.21, 95% CI 0.07 to 0.60); powder snow compared with slushy snow (p = 0.0035, OR 0.25, 95% CI 0.10 to 0.63); drug consumption (p = 0.0044, OR 5.92, 95% CI 1.74 to 20.11); and alcohol abstinence (p<0.0001, OR 0.14, 95% CI 0.05 to 0.34). Three groups at risk were detected: (1) warm-up 3-12 min, visual analogue scale (VAS)(speed) >4 and bad weather/visibility; (2) VAS(speed) 4-7, icy slopes and not wearing a helmet; (3) warm-up >12 min and new skiing equipment. CONCLUSIONS: Low speed, high readiness for risk, new skiing equipment, old and powder snow, and drug consumption are significant risk factors when skiing. Future work should aim to identify more precisely specific groups at risk and develop recommendations--for example, a snow weather index at valley stations.

Long-term gas exchange characteristics as marker of deterioration in patients with cystic fibrosis

Background and Aim In patients with cystic fibrosis (CF) the architecture of the developing lungs and the ventilation of lung units are progressively affected, influencing intrapulmonary gas mixing and gas exchange. We examined the long-term course of blood gas measurements in relation to characteristics of lung function and the influence of different CFTR genotype upon this process. Methods Serial annual measurements of PaO2 and PaCO2 assessed in relation to lung function, providing functional residual capacity (FRCpleth), lung clearance index (LCI), trapped gas (VTG), airway resistance (sReff), and forced expiratory indices (FEV1, FEF50), were collected in 178 children (88 males; 90 females) with CF, over an age range of 5 to 18 years. Linear mixed model analysis and binary logistic regression analysis were used to define predominant lung function parameters influencing oxygenation and carbon dioxide elimination. Results PaO2 decreased linearly from age 5 to 18 years, and was mainly associated with FRCpleth, (p < 0.0001), FEV1 (p < 0.001), FEF50 (p < 0.002), and LCI (p < 0.002), indicating that oxygenation was associated with the degree of pulmonary hyperinflation, ventilation inhomogeneities and impeded airway function. PaCO2 showed a transitory phase of low PaCO2 values, mainly during the age range of 5 to 12 years. Both PaO2 and PaCO2 presented with different progression slopes within specific CFTR genotypes. Conclusion In the long-term evaluation of gas exchange characteristics, an association with different lung function patterns was found and was closely related to specific genotypes. Early examination of blood gases may reveal hypocarbia, presumably reflecting compensatory mechanisms to improve oxygenation.

Wavelet-denoising of electroencephalogram and the absolute slope method: a new tool to improve electroencephalographic localization and lateralization

OBJECTIVE: In ictal scalp electroencephalogram (EEG) the presence of artefacts and the wide ranging patterns of discharges are hurdles to good diagnostic accuracy. Quantitative EEG aids the lateralization and/or localization process of epileptiform activity. METHODS: Twelve patients achieving Engel Class I/IIa outcome following temporal lobe surgery (1 year) were selected with approximately 1-3 ictal EEGs analyzed/patient. The EEG signals were denoised with discrete wavelet transform (DWT), followed by computing the normalized absolute slopes and spatial interpolation of scalp topography associated to detection of local maxima. For localization, the region with the highest normalized absolute slopes at the time when epileptiform activities were registered (>2.5 times standard deviation) was designated as the region of onset. For lateralization, the cerebral hemisphere registering the first appearance of normalized absolute slopes >2.5 times the standard deviation was designated as the side of onset. As comparison, all the EEG episodes were reviewed by two neurologists blinded to clinical information to determine the localization and lateralization of seizure onset by visual analysis. RESULTS: 16/25 seizures (64%) were correctly localized by the visual method and 21/25 seizures (84%) by the quantitative EEG method. 12/25 seizures (48%) were correctly lateralized by the visual method and 23/25 seizures (92%) by the quantitative EEG method. The McNemar test showed p=0.15 for localization and p=0.0026 for lateralization when comparing the two methods. CONCLUSIONS: The quantitative EEG method yielded significantly more seizure episodes that were correctly lateralized and there was a trend towards more correctly localized seizures. SIGNIFICANCE: Coupling DWT with the absolute slope method helps clinicians achieve a better EEG diagnostic accuracy.

Dual-energy X-ray absorptiometry for measuring total bone mineral content in the rat: study of accuracy and precision

Sequential studies of osteopenic bone disease in small animals require the availability of non-invasive, accurate and precise methods to assess bone mineral content (BMC) and bone mineral density (BMD). Dual-energy X-ray absorptiometry (DXA), which is currently used in humans for this purpose, can also be applied to small animals by means of adapted software. Precision and accuracy of DXA was evaluated in 10 rats weighing 50-265 g. The rats were anesthetized with a mixture of ketamine-xylazine administrated intraperitoneally. Each rat was scanned six times consecutively in the antero-posterior incidence after repositioning using the rat whole-body software for determination of whole-body BMC and BMD (Hologic QDR 1000, software version 5.52). Scan duration was 10-20 min depending on rat size. After the last measurement, rats were sacrificed and soft tissues were removed by dermestid beetles. Skeletons were then scanned in vitro (ultra high resolution software, version 4.47). Bones were subsequently ashed and dissolved in hydrochloric acid and total body calcium directly assayed by atomic absorption spectrophotometry (TBCa[chem]). Total body calcium was also calculated from the DXA whole-body in vivo measurement (TBCa[DXA]) and from the ultra high resolution measurement (TBCa[UH]) under the assumption that calcium accounts for 40.5% of the BMC expressed as hydroxyapatite. Precision error for whole-body BMC and BMD (mean +/- S.D.) was 1.3% and 1.5%, respectively. Simple regression analysis between TBCa[DXA] or TBCa[UH] and TBCa[chem] revealed tight correlations (n = 0.991 and 0.996, respectively), with slopes and intercepts which were significantly different from 1 and 0, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Development of an array of ion-selective microelectrodes aimed for the monitoring of extracellular ionic activities

In this study, we present the development and the characterization of a generic platform for cell culture able to monitor extracellular ionic activities (K+, NH4+) for real-time monitoring of cell-based responses, such as necrosis, apoptosis, or differentiation. The platform for cell culture is equipped with an array of 16 silicon nitride micropipet-based ion-selective microelectrodes with a diameter of either 2 or 6 microm. This array is located at the bottom of a 200-microm-wide and 350-microm-deep microwell where the cells are cultured. The characterization of the ion-selective microelectrode arrays in different standard and physiological solutions is presented. Near-Nernstian slopes were obtained for potassium- (58.6 +/- 0.8 mV/pK, n = 15) and ammonium-selective microelectrodes (59.4 +/- 3.9 mV/pNH4, n = 13). The calibration curves were highly reproducible and showed an average drift of 4.4 +/- 2.3 mV/h (n = 10). Long-term behavior and response after immersion in physiological solutions are also presented. The lifetime of the sensors was found to be extremely long with a high recovery rate.

CD4 count slope and mortality in HIV-infected patients on antiretroviral therapy: multicohort analysis from South Africa

BACKGROUND In many resource-limited settings monitoring of combination antiretroviral therapy (cART) is based on the current CD4 count, with limited access to HIV RNA tests or laboratory diagnostics. We examined whether the CD4 count slope over 6 months could provide additional prognostic information. METHODS We analyzed data from a large multicohort study in South Africa, where HIV RNA is routinely monitored. Adult HIV-positive patients initiating cART between 2003 and 2010 were included. Mortality was analyzed in Cox models; CD4 count slope by HIV RNA level was assessed using linear mixed models. RESULTS About 44,829 patients (median age: 35 years, 58% female, median CD4 count at cART initiation: 116 cells/mm) were followed up for a median of 1.9 years, with 3706 deaths. Mean CD4 count slopes per week ranged from 1.4 [95% confidence interval (CI): 1.2 to 1.6] cells per cubic millimeter when HIV RNA was <400 copies per milliliter to -0.32 (95% CI: -0.47 to -0.18) cells per cubic millimeter with >100,000 copies per milliliter. The association of CD4 slope with mortality depended on current CD4 count: the adjusted hazard ratio (aHRs) comparing a >25% increase over 6 months with a >25% decrease was 0.68 (95% CI: 0.58 to 0.79) at <100 cells per cubic millimeter but 1.11 (95% CI: 0.78 to 1.58) at 201-350 cells per cubic millimeter. In contrast, the aHR for current CD4 count, comparing >350 with <100 cells per cubic millimeter, was 0.10 (95% CI: 0.05 to 0.20). CONCLUSIONS Absolute CD4 count remains a strong risk for mortality with a stable effect size over the first 4 years of cART. However, CD4 count slope and HIV RNA provide independently added to the model.

Is the development of infectious keratoconjunctivitis in Alpine ibex and Alpine chamois influenced by topographic features?

Infectious keratoconjunctivitis (IKC) caused by Mycoplasma conjunctivae is a widespread ocular affection of free-ranging Caprinae in the Alpine arc. Along with host and pathogen characteristics, it has been hypothesized that environmental factors such as UV light are involved in the onset and course of the disease. This study aimed at evaluating the role of topographic features as predisposing or aggravating factors for IKC in Alpine chamois (Rupicapra rupicapra rupicapra) and Alpine ibex (Capra ibex ibex). Geospatial analysis was performed to assess the effect of aspect (northness) and elevation on the severity of the disease as well as on the mycoplasmal load in the eyes of affected animals, using data from 723 ibex and chamois (583 healthy animals, 105 IKC-affected animals, and 35 asymptomatic carriers of M. conjunctivae), all sampled in the Swiss Alps between 2008 and 2010. An influence of northness was not found, except that ibex with moderate and severe signs of IKC seem to prefer more north-oriented slopes than individuals without corneal lesions, possibly hinting at a sunlight sensitivity consequent to the disease. In contrast, results suggest that elevation influences the disease course in both ibex and chamois, which could be due to altitude-associated environmental conditions such as UV radiation, cold, and dryness. The results of this study support the hypothesis that environmental factors may play a role in the pathogenesis of IKC.