Variation in herbivore space use: comparing two savanna ecosystems with different anthrax outbreak patterns in southern Africa.

BACKGROUND: The distribution of resources can affect animal range sizes, which in turn may alter infectious disease dynamics in heterogenous environments. The risk of pathogen exposure or the spatial extent of outbreaks may vary with host range size. This study examined the range sizes of herbivorous anthrax host species in two ecosystems and relationships between spatial movement behavior and patterns of disease outbreaks for a multi-host environmentally transmitted pathogen. METHODS: We examined range sizes for seven host species and the spatial extent of anthrax outbreaks in Etosha National Park, Namibia and Kruger National Park, South Africa, where the main host species and outbreak sizes differ. We evaluated host range sizes using the local convex hull method at different temporal scales, within-individual temporal range overlap, and relationships between ranging behavior and species contributions to anthrax cases in each park. We estimated the spatial extent of annual anthrax mortalities and evaluated whether the extent was correlated with case numbers of a given host species. RESULTS: Range size differences among species were not linearly related to anthrax case numbers. In Kruger the main host species had small range sizes and high range overlap, which may heighten exposure when outbreaks occur within their ranges. However, different patterns were observed in Etosha, where the main host species had large range sizes and relatively little overlap. The spatial extent of anthrax mortalities was similar between parks but less variable in Etosha than Kruger. In Kruger outbreaks varied from small local clusters to large areas and the spatial extent correlated with case numbers and species affected. Secondary host species contributed relatively few cases to outbreaks; however, for these species with large range sizes, case numbers positively correlated with outbreak extent. CONCLUSIONS: Our results provide new information on the spatiotemporal structuring of ranging movements of anthrax host species in two ecosystems. The results linking anthrax dynamics to host space use are correlative, yet suggest that, though partial and proximate, host range size and overlap may be contributing factors in outbreak characteristics for environmentally transmitted pathogens.

Elephant rewilding affects landscape openness and fauna habitat across a 92-year period.

Trophic rewilding aims to promote biodiverse self-sustaining ecosystems through the restoration of ecologically important taxa and the trophic interactions and cascades they propagate. How rewilding effects manifest across broad temporal scales will determine ecosystem states; however, our understanding of post-rewilding dynamics across longer time periods is limited. Here we show that the restoration of a megaherbivore, the African savannah elephant (Loxodonta africana), promotes landscape openness (i.e., various measures of vegetation composition/complexity) and modifies fauna habitat and that these effects continue to manifest up to 92 years after reintroduction. We conducted a space-for-time floristic survey and assessment of 17 habitat attributes (e.g., floristic diversity and cover, ground wood, tree hollows) across five comparable nature reserves in South African savannah, where elephants were reintroduced between 1927 and 2003, finding that elephant reintroduction time was positively correlated with landscape openness and some habitat attributes (e.g., large-sized tree hollows) but negatively associated with others (e.g., large-sized coarse woody debris). We then indexed elephant site occurrence between 2006 and 2018 using telemetry data and found positive associations between site occurrence and woody plant densities. Taken alongside the longer-term space-for-time survey, this suggests that elephants are attracted to dense vegetation in the short term and that this behavior increases landscape openness in the long term. Our results suggest that trophic rewilding with elephants helps promote a semi-open ecosystem structure of high importance for African biodiversity. More generally, our results suggest that megafauna restoration represents a promising tool to curb Earth's recent ecological losses and highlights the importance of considering long-term ecological responses when designing and managing rewilding projects.

Method development to characterise elephant tail hairs by LA-ICP-MS to reflect changes in elemental chemistry.

This paper evaluated analytical methods used to generate time-series data from elephant tail hairs, which can be used to reflect changing exposure to environmental geochemistry. Elephant tail hairs were analysed by three methods sequentially, each providing data to inform subsequent analysis. Scanning Electron Microscopy (SEM) and X-ray Microanalysis visually showed the structure of the hair, specific structures such as tubules, and the mineral crusting around the edge of the hair, informing targeting of subsequent analysis by Laser Ablation-Inductively Coupled Plasma Mass Spectrometry (LA-ICP-MS). LA-ICP-MS generated time-series data which informed sectioning of the tail hairs for subsequent quantitative analysis for potentially toxic elements and micronutrients using Inductively Coupled Plasma Mass Spectrometry (ICP-MS) of dissolved tail hairs. This novel approach to characterise the tail hair enabled time-series analysis to reflect changes in environmental exposure which may result from seasonal or geochemical spatial variation and could inform elephant movement patterns. The seasonal change between wet and dry seasons was reflected down the length of the hair. Correlations were seen between LA-ICP-MS data and ICP-MS data in several elements including Mg, P, Ca, Fe, Na, Mn and U. This study provided time-series data for the analysis of elephant tail hairs by evaluating analytical challenges to obtaining quantitative data, such as improving protocols to ensure removal of extraneous material, determining where to section the tail hairs to best reflect environmental changes/exposure and ensuring representative analyses. A protocol was established to determine mineral status across a 12-18 month time period utilizing single elephant tail hairs.

Developing welfare parameters for African elephants (Loxodonta africana) in fenced reserves in South Africa.

South Africa has many fenced reserves harbouring small to medium sized populations of African elephant (Loxodonta africana), most of which have been translocated. Elephants on fenced reserves may be exposed to various management interventions and practices (translocation, hunting, darting, high tourism impact, contraception programs, disruption due to infrastructure maintenance, etc.). These factors may impact the welfare of elephants. Poor elephant welfare may have serious consequences such as increased inter- and intra-species aggression that could result in fatalities. This is the first study to attempt to define behavioural and physiological welfare parameters for free-ranging elephants on small to medium sized reserves. The eight study sites incorporated reserves with different social structure combinations, elephant life-histories, reserve sizes, habitat, management, and tourism intensity. Data collection consisted of behavioural observations (10-minute videos) as well as faecal samples. By incorporating both behavioural and physiological (faecal glucocorticoid metabolite (fGCM) concentration) parameters, we aimed to investigate whether the two parameters showed similar trends. Five behavioural categories were identified (Arousal, Assessing, Ambivalent, Ambivalent/ Body care, and Frustrated behaviour), with various detailed behaviours demonstrated by the elephants that may indicate the influence of anthropogenic disturbance and possibly impact on animal welfare. The study showed significant differences between the selected detailed behaviours, behavioural categories and fGCM concentrations of elephants across the eight reserves. History seemed to be a decisive factor, as reserves with predominantly ex-captive elephants showed higher frequencies of certain behaviours as well as higher fGCM concentrations. Age, sex, reserve size and season were also found to contribute to our defined welfare indices and fGCM concentrations. This indicates that behavioural parameters, indicative of certain behavioural states, are valuable indicators of welfare, as supported by the physiological response of the elephants. The results also highlight the importance of taking multiple specified behaviours from a category into consideration when evaluating the welfare of elephants, to account for individual variation.

Social and Seasonal Factors Contribute to Shifts in Male African Elephant (Loxodonta africana) Foraging and Activity Patterns in Kruger National Park, South Africa.

African savannah elephants (Loxodonta africana) are well-known as ecosystem engineers with the ability to modify vegetation structure. The present study aimed to examine how male elephant foraging behaviour is affected across (a) season (wet versus dry); (b) time of day (before or after noon); (c) presence or absence of other elephants; and (d) reproductive state (musth versus no musth). Six radio-collared adult elephant bulls were observed twice per week from June 2007-June 2008 in Kruger National Park (KNP), South Africa. Using generalized linear mixed effect modeling, results indicate that elephant bulls graze more during the wet season and browse more during the dry season. To potentially offset the costs associated with thermoregulation during the heat of the day, KNP elephants spent more time foraging during the morning, and more time resting during the afternoon. Male elephants also foraged significantly less when they were associated with females compared to when they were alone or with other males. This is likely due to male-female associations formed mainly for reproductive purposes, thus impeding on male foraging behaviours. In contrast, the condition of musth, defined by the presence of related physical signs, had no significant effect on foraging behaviour.

Toolkit for Best Practice Use of Electronic Health Record Data in Quality Improvement.

This project piloted an educational intervention focused on use and management of EHR data by Doctor of Nursing Practice students in quality improvement initiatives. Recommendations from academic and clinical nursing promote the integration of EHR data findings into practice. Nursing's general lack of understanding about how to use and manage data is a barrier to using EHR data to guide quality improvement initiatives. Doctor of Nursing Practice students at a hospital-affiliated university participated in a pre-test, training, and post-test through an online learning management system. Training content and assessments focused on data and planning for its use in quality improvement initiatives. Sixteen students experienced a median of 17.6% increase in scores after completing the post-test. There was a statistically significant increase in scores between the pre-test and post-test (P = .0006). These results suggest educational content included in the Doctor of Nursing Practice Quality Improvement Toolkit increases knowledge about use and management of EHR data. Future considerations include use for educating a variety of students and healthcare staff.

Human footprint and protected areas shape elephant range across Africa.

Over the last two millennia, and at an accelerating pace, the African elephant (Loxodonta spp. Lin.) has been threatened by human activities across its range.1-7 We investigate the correlates of elephant home range sizes across diverse biomes. Annual and 16-day elliptical time density home ranges8 were calculated by using GPS tracking data collected from 229 African savannah and forest elephants (L. africana and L. cyclotis, respectively) between 1998 and 2013 at 19 sites representing bushveld, savannah, Sahel, and forest biomes. Our analysis considered the relationship between home range area and sex, species, vegetation productivity, tree cover, surface temperature, rainfall, water, slope, aggregate human influence, and protected area use. Irrespective of these environmental conditions, long-term annual ranges were overwhelmingly affected by human influence and protected area use. Only over shorter, 16-day periods did environmental factors, particularly water availability and vegetation productivity, become important in explaining space use. Our work highlights the degree to which the human footprint and existing protected areas now constrain the distribution of the world's largest terrestrial mammal.9,10 A habitat suitability model, created by evaluating every square kilometer of Africa, predicts that 18,169,219 km2 would be suitable as elephant habitat-62% of the continent. The current elephant distribution covers just 17% of this potential range of which 57.4% falls outside protected areas. To stem the continued extirpation and to secure the elephants' future, effective and expanded protected areas and improved capacity for coexistence across unprotected range are essential.

Acoustic cues to individuality in wild male adult African savannah elephants (Loxodonta africana).

The ability to recognize conspecifics plays a pivotal role in animal communication systems. It is especially important for establishing and maintaining associations among individuals of social, long-lived species, such as elephants. While research on female elephant sociality and communication is prevalent, until recently male elephants have been considered far less social than females. This resulted in a dearth of information about their communication and recognition abilities. With new knowledge about the intricacies of the male elephant social structure come questions regarding the communication basis that allows for social bonds to be established and maintained. By analyzing the acoustic parameters of social rumbles recorded over 1.5 years from wild, mature, male African savanna elephants (Loxodonta africana) we expand current knowledge about the information encoded within these vocalizations and their potential to facilitate individual recognition. We showed that social rumbles are individually distinct and stable over time and therefore provide an acoustic basis for individual recognition. Furthermore, our results revealed that different frequency parameters contribute to individual differences of these vocalizations.

Spatial geochemistry influences the home range of elephants.

The unique geochemistry surrounding the Palabora Mining Company (PMC) land may act as a micronutrient hotspot, attracting elephants to the area. The PMC produces refined copper and extracts phosphates and other minerals. Understanding the spatial influence of geochemistry on the home range size of African elephants is important for elephant population management and conservation. The home ranges of collared elephants surrounding the PMC were significantly smaller (P = 0.001) than conspecifics in surrounding reserves, suggesting that their resource needs were met within these smaller areas. Environmental samples (soil, water and plants) were analysed from the mine area and along six transects radiating from the mine centre. Tail hair and faecal samples from elephants at the PMC, and conspecifics within the surrounding area were analysed. All samples were analysed for minerals essential to health and potentially toxic elements (PTEs; As, Ca, Cd, Cu, Fe, K, Mg, Mn, Na, P, Pb, Se, U, V and Zn). Results show that the geochemistry at the PMC is different compared to surrounding areas, with significant elevations seen in all analysed minerals and PTEs in soil closer to the mine, thereby drawing the elephants to the area. Additionally significant elevations were seen in elements analysed in water and vegetation samples. Elephant tail hair from elephants at the mine was significantly greater in Cd, whilst Mg, P, Cu, As, Cd, Pb and U concentrations were significantly greater in elephant faecal samples at the mine compared to the non-mine samples. When micronutrient hotspots overlap with human activity (such as mining), this can lead to poor human-elephant coexistence and thus conflict. When managing elephant populations, the influence of mineral provision on elephant movement must be considered. Such detailed resource information can inform conservation efforts for coordinated programmes (UN SDGs 15 and 17) and underpin sustainable economic activity (UN SDG 8, 11 and 12).

Conservation Genetic Assessment of Savannah Elephants (Loxodonta africana) in the Greater Kruger Biosphere, South Africa.

Savannah elephant populations have been severely reduced and fragmented throughout its remaining range. In general, however, there is limited information regarding their genetic status, which is essential knowledge for conservation. We investigated patterns of genetic variation in savannah elephants from the Greater Kruger Biosphere, with a focus on those in previously unstudied nature reserves adjacent to Kruger National Park, using dung samples from 294 individuals and 18 microsatellites. The results of genetic structure analyses using several different methods of ordination and Bayesian clustering strongly suggest that elephants throughout the Greater Kruger National Park (GKNP) constitute a single population. No evidence of a recent genetic bottleneck was detected using three moment-based approaches and two coalescent likelihood methods. The apparent absence of a recent genetic bottleneck associated with the known early 1900s demographic bottleneck may result from a combination of rapid post-bottleneck population growth, immigration and long generation time. Point estimates of contemporary effective population size (Ne) for the GKNP were ~ 500-700, that is, at the low end of the range of Ne values that have been proposed for maintaining evolutionary potential and the current ratio of Ne to census population size (Nc) may be quite low (<0.1). This study illustrates the difficulties in assessing the impacts on Ne in populations that have suffered demographic crashes but have recovered rapidly and received gene flow, particularly in species with long generation times in which genetic time lags are longer. This work provides a starting point and baseline information for genetic monitoring of the GKNP elephants.

Mining morphometrics and age from past survey photographs.

BACKGROUND: Researchers often document wildlife surveys using images. These images contain data that can be used to understand alterative research objectives, even years after they were originally captured. We have developed a method to measure age and morphology (body size measurements and tusk size) from survey image databases and future surveys, without the availability of a known subject distance or a scale in each image. African savanna elephants (Loxodonta africana) serve as an ideal model species to develop a non-invasive, image-based morphometric methodology: as handling these animals is particularly invasive and expensive, involving anaesthesia and because of their IUCN 'vulnerable' status. We compare in situ measurements, taken during collaring events, to tusk-to-body-size ratios, measured from the images. RESULTS: We provide evidence that relative morphological measurements, musth timing, and age of male African savanna elephants can accurately be obtained from a survey image database of over 30,000 images, taken over an 18-year period. Of the 11 tusk to body size ratios calculated, we recommend the use of two in particular for future measurement in African elephants to determine size and age: 1) tusk length to tusk diameter and 2) tusk length to body height. CONCLUSIONS: We present a practical, non-invasive measure to estimate morphometrics, including both age and tusk size from photographs, which has conservation applications to the protection of elephants and is relevant to a range of other taxa.

African bush elephants respond to a honeybee alarm pheromone blend.

We here report the responses of African bush elephants (Loxodonta africana) to a crude approximation of the honeybee alarm pheromone blend. We show that the elephants had an avoidance response to the semiochemical blend. The use of honeybee alarm pheromones to manage elephant movements in a non-invasive manner, using natural cues to which elephants may have an evolved response, holds potential for development of new options for an integrated system for elephant movement management and protection.

Efficacy and safety of twice-daily glycopyrrolate in patients with stable, symptomatic COPD with moderate-to-severe airflow limitation: the GEM1 study.

BACKGROUND: The purpose of this study was to confirm the efficacy and safety of twice-daily glycopyrrolate 15.6 µg, a long-acting muscarinic antagonist, in patients with stable, symptomatic, chronic obstructive pulmonary disease (COPD) with moderate-to-severe airflow limitation. METHODS: The GEM1 study was a 12-week, multicenter, double-blind, parallel-group, placebo-controlled study that randomized patients with stable, symptomatic COPD with moderate-to-severe airflow limitation to twice-daily glycopyrrolate 15.6 µg or placebo (1:1) via the Neohaler(®) device. The primary objective was to demonstrate superiority of glycopyrrolate versus placebo in terms of forced expiratory volume in 1 second area under the curve between 0 and 12 hours post morning dose at week 12. Other outcomes included additional spirometric end points, transition dyspnea index, St George's Respiratory Questionnaire, COPD Assessment Test, rescue medication use, and symptoms reported by patients via electronic diary. Safety was also assessed during the study. RESULTS: Of the 441 patients randomized (glycopyrrolate, n=222; placebo, n=219), 96% of patients completed the planned treatment phase. Glycopyrrolate demonstrated statistically significant (P<0.001) improvements in lung function versus placebo. Glycopyrrolate showed statistically significant improvement in the transition dyspnea index focal score, St George's Respiratory Questionnaire total score, COPD Assessment Test score, rescue medication use, and daily total symptom score versus placebo at week 12. Safety was comparable between the treatment groups. CONCLUSION: Significant improvement in lung function, dyspnea, COPD symptoms, health status, and rescue medication use suggests that glycopyrrolate is a safe and effective treatment option as maintenance bronchodilator in patients with stable, symptomatic COPD with moderate-to-severe airflow limitation.

Efficacy and Safety of Twice-Daily Glycopyrrolate Versus Placebo in Patients With COPD: The GEM2 Study.

Long-acting bronchodilators including muscarinic antagonists are central to the management of patients with COPD. The Glycopyrrolate Effect on syMptoms and lung function (GEM2) study assessed the efficacy and safety of twice-daily glycopyrrolate 15.6 µg in patients with moderate-to-severe airflow limitation. This 12-week multicenter, double-blind study randomized (1:1) patients to glycopyrrolate 15.6 µg twice daily (b.i.d.) or placebo both delivered via the NeohalerTM device. The primary objective was superiority of glycopyrrolate compared with placebo for forced expiratory volume in 1 second (FEV1) standardized area under curve (AUC) between 0 and 12 hours post dosing (FEV1 AUC0-12h)at week 12. Other outcomes included additional spirometry parameters, health status using St George's Respiratory Questionnaire (SGRQ), dyspnea via Transition Dyspnea Index (TDI), rescue medication use and COPD symptoms reported by patients via the electronic diary. Safety was also assessed. Of the 432 patients randomized (glycopyrrolate, n=216; placebo, n=216), 96% completed the planned treatment phase. The study met its primary objective (superiority of glycopyrrolate compared with placebo for FEV1 AUC0-12h).Compared with placebo, glycopyrrolate showed significant improvements in lung function parameters (p<0.001). Health status (SGRQ total score and COPD assessment test), rescue medication use and daily total COPD symptom scores were significantly improved with glycopyrrolate versus placebo over 12 weeks. Improvements in dyspnea were observed with glycopyrrolate and placebo although the treatment difference was not statistically significant. Overall, differences in the incidences of adverse events and serious adverse events between the groups were not considered clinically meaningful. No deaths were reported. Twice-daily glycopyrrolate 15.6 µg showed statistically significant and clinically meaningful improvements compared with placebo in lung function, COPD symptoms, health status, and rescue medication usage in COPD patients with moderate-to-severe airflow limitation. CLINICAL TRIAL REGISTRATION: NCT01715298.

Efficacy and safety of coadministration of once-daily indacaterol and glycopyrronium versus indacaterol alone in COPD patients: the GLOW6 study.

BACKGROUND: Addition of a second bronchodilator from a different pharmacological class may benefit patients with moderate-to-severe chronic obstructive pulmonary disease (COPD) whose symptoms are insufficiently controlled by bronchodilator monotherapy. GLOW6 evaluated the efficacy and safety of once-daily coadministration of the long-acting ß2-agonist indacaterol (IND) and the long-acting muscarinic antagonist glycopyrronium (GLY) versus IND alone in patients with moderate-to-severe COPD. MATERIALS AND METHODS: In this randomized, double-blind, parallel group, placebo-controlled, 12-week study, patients were randomized 1:1 to IND 150 µg and GLY 50 µg daily (IND + GLY) or IND 150 µg daily and placebo (IND + PBO) (all delivered via separate Breezhaler® devices). The primary objective was to demonstrate the superiority of IND + GLY versus IND + PBO for trough forced expiratory volume in 1 second (FEV1) at week 12. Other end points included trough FEV1 at day 1, FEV1 area under the curve from 30 minutes to 4 hours (AUC30min-4h), peak FEV1, inspiratory capacity and trough forced vital capacity (FVC) at day 1 and week 12, and transition dyspnea index (TDI) focal score, COPD symptoms, and rescue medication use over 12 weeks. RESULTS: A total of 449 patients were randomized (IND + GLY, 226; IND + PBO, 223); 94% completed the study. On day 1 and at week 12, IND + GLY significantly improved trough FEV1 versus IND + PBO, with treatment differences of 74 mL (95% CI 46-101 mL) and 64 mL (95% CI 28-99 mL), respectively (both P<0.001). IND + GLY significantly improved postdose peak FEV1, FEV1 AUC30min-4h, and trough FVC at day 1 and week 12 versus IND + PBO (all P<0.01). TDI focal score and COPD symptoms (percentage of days able to perform usual daily activities and change from baseline in mean daytime respiratory score) were significantly improved with IND + GLY versus IND + PBO (P<0.05). The incidence of adverse events was similar for the two treatment groups. CONCLUSION: In patients with moderate-to-severe COPD, once-daily coadministration of IND and GLY provides significant and sustained improvement in bronchodilation versus IND alone from day 1, with significant improvements in patient-centered outcomes.

Effect of QVA149 on lung volumes and exercise tolerance in COPD patients: the BRIGHT study.

INTRODUCTION: QVA149 is a novel, inhaled, once-daily dual bronchodilator containing a fixed-dose combination of the long-acting ß2-agonist indacaterol and the long-acting muscarinic antagonist glycopyrronium (NVA237), for the treatment of chronic obstructive pulmonary disease (COPD). This study evaluated the effects of QVA149 on exercise tolerance, hyperinflation, lung function and lung volumes versus placebo and tiotropium. METHODS: Patients with moderate-to-severe COPD were randomized to QVA149 110/50 µg, placebo or tiotropium 18 µg once daily in a blinded, 3-period crossover study for 3 weeks. The primary endpoint was exercise endurance time at Day 21 for QVA149 versus placebo. RESULTS: Eighty-five patients were randomized; 86% completed the study. QVA149 significantly improved exercise endurance time at Day 21 compared with placebo (least squares mean treatment difference 60 s [p = 0.006]). No significant improvements in exercise endurance time at Day 21 between QVA149 and tiotropium were found. Dynamic inspiratory capacity (IC) at exercise isotime, trough forced expiratory volume in 1 s, residual volume and functional residual capacity showed significant improvements with QVA149 from Day 1 of treatment that were maintained throughout the study. The safety profiles were similar across groups. CONCLUSIONS: In patients with moderate-to-severe COPD, once-daily QVA149 significantly improved exercise endurance time compared with placebo which was associated with sustained reductions of lung hyperinflation as indicated by significant improvement in IC at rest and during exercise. TRIAL REGISTRATION: ClinicalTrials.gov NCT01294787. TAKE HOME MESSAGE: Dual bronchodilation with QVA149 decreases lung hyperinflation and improves exercise tolerance and lung function in patients with moderate-to-severe COPD.

Effect of once-daily indacaterol in a predominantly Chinese population with chronic obstructive pulmonary disease: a 26-week Asia-Pacific study.

BACKGROUND AND OBJECTIVE: This study, in a predominantly Chinese population, investigated the efficacy and safety of a once-daily (o.d.) inhaled ultra-long-acting ß2 -agonist indacaterol for the treatment of moderate-to-severe chronic obstructive pulmonary disease (COPD). METHODS: This is a 26-week, double-blind study on randomized patients who received indacaterol 150 µg or 300 µg or placebo o.d. The primary variable was trough forced expiratory volume in 1 s (FEV1 , average of 23 h 10 min and 23 h 45 min post-dose values) at Week 12. Health status (St George's Respiratory Questionnaire, SGRQ), dyspnoea (transition dyspnoea index, TDI) and safety were evaluated over 26 weeks. RESULTS: Of the 563 patients randomized, 561 (89.8% Chinese) received treatment and 482 completed. At Week 12, trough FEV1 improved significantly for indacaterol 150 and 300 µg versus placebo (1.32, 1.29 vs 1.17; P < 0.001 for both comparisons), with differences exceeding the pre-specified minimal clinically important difference of 0.12 L. At Week 26, TDI score was superior to placebo for indacaterol 150 and 300 µg (0.82, 1.15; P < 0.01), as was the percentage of patients with a clinically relevant improvement (≥1 point) (74.1%, 78.6% vs 55.5%; P < 0.05). Both doses provided ≥4-point improvements from baseline in SGRQ score at Week 26 that were numerically greater than placebo (unadjusted means: -9.6, -8.8 vs -7.0), with a similar pattern in percentage of patients with clinically relevant improvements in SGRQ score (65.0%, 61.5% vs 60.6%). Incidences of adverse events were comparable across treatment groups. CONCLUSIONS: Indacaterol delivered effective bronchodilation with significant improvements in breathlessness and health status in this predominantly Chinese population.

A blinded evaluation of the efficacy and safety of glycopyrronium, a once-daily long-acting muscarinic antagonist, versus tiotropium, in patients with COPD: the GLOW5 study.

BACKGROUND: Two once-daily long-acting muscarinic antagonists (LAMAs) are currently available for the treatment of chronic obstructive pulmonary disease (COPD) - tiotropium and glycopyrronium. Previous studies have compared glycopyrronium with open-label tiotropium. In the GLOW5 study, we compare glycopyrronium with blinded tiotropium. METHODS: In this blinded, double-dummy, parallel group, 12-week study, patients with moderate-to-severe COPD were randomized 1:1 to glycopyrronium 50 µg once daily or tiotropium 18 µg once daily. The primary objective was to demonstrate the non-inferiority of glycopyrronium versus blinded tiotropium with respect to trough forced expiratory volume in 1 second (FEV1) following 12 weeks of treatment (non-inferiority margin: -50 mL). Secondary objectives were to evaluate glycopyrronium versus tiotropium for other spirometric outcomes, breathlessness (Transition Dyspnea Index; TDI), health status (St George's Respiratory Questionnaire; SGRQ), daily rescue medication use, COPD exacerbations and COPD symptoms over 12 weeks of treatment. RESULTS: 657 patients were randomized (glycopyrronium: 327; tiotropium: 330); 96% (630 patients) completed the study. Least squares mean trough FEV1 for both glycopyrronium and tiotropium was 1.405 L at Week 12, meeting the criterion for non-inferiority (mean treatment difference: 0 mL, 95% CI: -32, 31 mL). Glycopyrronium demonstrated rapid bronchodilation following first dose on Day 1, with significantly higher FEV1 at all time points from 0-4 h post-dose versus tiotropium (all p < 0.001). FEV1 area under the curve from 0-4 h (AUC0-4h) post-dose with glycopyrronium was significantly superior to tiotropium on Day 1 (p < 0.001) and was comparable to tiotropium at Week 12. Glycopyrronium demonstrated comparable improvements to tiotropium in TDI focal score, SGRQ total score, rescue medication use and the rate of COPD exacerbations (all p = not significant). Patients on glycopyrronium also had a significantly lower total COPD symptom score versus patients on tiotropium after 12 weeks (p = 0.035). Adverse events were reported by a similar percentage of patients receiving glycopyrronium (40.4%) and tiotropium (40.6%). CONCLUSION: In patients with moderate-to-severe COPD, 12-week blinded treatment with once-daily glycopyrronium 50 µg or tiotropium 18 µg, provided similar efficacy and safety, with glycopyrronium having a faster onset of action on Day 1 versus tiotropium.

Dual bronchodilation with QVA149 versus single bronchodilator therapy: the SHINE study.

We investigated the efficacy and safety of dual bronchodilation with QVA149 versus its monocomponents indacaterol and glycopyrronium, tiotropium and placebo in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). This was a multicentre, randomised, double-blind, placebo- and active-controlled, 26-week trial. Patients (n = 2144) were randomised (2:2:2:2:1) to receive once-daily QVA149 (indacaterol 110 µg/glycopyrronium 50 µg), indacaterol 150 µg, glycopyrronium 50 µg, open-label tiotropium 18 µg or placebo. The primary end-point was trough forced expiratory volume in 1 s (FEV1) at week 26 for QVA149 versus its monocomponents. Secondary end-points included dyspnoea, health status, rescue medication use and safety. Trough FEV1 at week 26 was significantly improved (p<0.001) with QVA149 compared with indacaterol and glycopyrronium (least squares mean (LSM) differences 0.07 L and 0.09 L, respectively), tiotropium and placebo (LSM differences 0.08 L and 0.20 L, respectively); these beneficial effects were sustained throughout the 26-week study. QVA149 significantly improved dyspnoea and health status versus placebo (p<0.001 and p = 0.002, respectively) and tiotropium (p = 0.007 and p = 0.009, respectively) at week 26. All treatments were well tolerated. Dual bronchodilation with once-daily QVA149 demonstrated superior and clinically meaningful outcomes versus placebo and superiority versus treatment with a single bronchodilator, with a safety and tolerability profile similar to placebo, supporting the concept of fixed-dose long-acting muscarinic antagonist/long-acting ß2-agonist combinations for the treatment of COPD.

The spatial scaling of habitat selection by African elephants.

1. Understanding and accurately predicting the spatial patterns of habitat use by organisms is important for ecological research, biodiversity conservation and ecosystem management. However, this understanding is complicated by the effects of spatial scale, because the scale of analysis affects the quantification of species-environment relationships. 2. We therefore assessed the influence of environmental context (i.e. the characteristics of the landscape surrounding a site), varied over a large range of scales (i.e. ambit radii around focal sites), on the analysis and prediction of habitat selection by African elephants in Kruger National Park, South Africa. 3. We focused on the spatial scaling of the elephants' response to their main resources, forage and water, and found that the quantification of habitat selection strongly depended on the scales at which environmental context was considered. Moreover, the inclusion of environmental context at characteristic scales (i.e. those at which habitat selectivity was maximized) increased the predictive capacity of habitat suitability models. 4. The elephants responded to their environment in a scale-dependent and perhaps hierarchical manner, with forage characteristics driving habitat selection at coarse spatial scales, and surface water at fine spatial scales. 5. Furthermore, the elephants exhibited sexual habitat segregation, mainly in relation to vegetation characteristics. Male elephants preferred areas with high tree cover and low herbaceous biomass, whereas this pattern was reversed for female elephants. 6. We show that the spatial distribution of elephants can be better understood and predicted when scale-dependent species-environment relationships are explicitly considered. This demonstrates the importance of considering the influence of spatial scale on the analysis of spatial patterning in ecological phenomena.