Publications by authors named "Elizabeth Duncan"

146 Publications

Exposure-related, global alterations in innate and adaptive immunity; a consideration for re-use of non-human primates in research.

PeerJ 2021 8;9:e10955. Epub 2021 Mar 8.

Malaria Department, Naval Medical Research Center, Silver Spring, MD, United States of America.

Background: Non-human primates (NHPs) play an important role in biomedical research, where they are often being re-used in multiple research studies over the course of their life-time. Researchers employ various study-specific screening criteria to reduce potential variables associated with subsequent re-use of NHPs. However, criteria set for NHP re-assignments largely neglect the impact of previous exposures on overall biology. Since the immune system is a key determinant of overall biological outcome, an altered biological state could be predicted by monitoring global changes in the immune profile. We postulate that every different exposure or a condition can generate a unique global immune profile in NHPs.

Methods: Changes in the global immune profile were evaluated in three different groups of rhesus macaques previously enrolled in dengue or malaria vaccine studies over six months after their last exposure. Naïve animals served as the baseline. Fresh blood samples were stained with various immune cell surface markers and analyzed by multi-color flow-cytometry to study immune cell dynamics in the peripheral blood. Serum cytokine profile in the pre-exposed animals were analyzed by mesoscale assay using a customized U-PLEX NHP biomarker panel of 12 cytokines/chemokines.

Results: Pre-exposed macaques showed altered dynamics in circulating cytokines and certain innate and adaptive immune cell subsets such as monocytes, HLA-DR+NKT cells, B cells and T cells. Some of these changes were transient, while some lasted for more than six months. Each group seemed to develop a global immune profile unique to their particular exposure.

Conclusion: Our data strongly suggest that re-used NHPs should be evaluated for long-term, overall immunological changes and randomly assigned to new studies to avoid study bias.
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http://dx.doi.org/10.7717/peerj.10955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7950202PMC
March 2021

Extending the post-thaw viability of cryoprecipitate.

Transfusion 2021 May 17;61(5):1578-1585. Epub 2021 Mar 17.

SA Pathology - Flinders Medical Centre and Royal Adelaide Hospital, South Australia, Australia.

Background: Cryoprecipitate has a short post-thaw expiry time of 6 h. The aim of this study was to assess the stability and function of cryoprecipitate components (FVIII, fibrinogen, vWF, and FXIII) and cryoprecipitate sterility up to 120 h post-thawing when stored at two temperatures (2-6°C and room temperature [20-24°C]).

Methods And Materials: Twenty batches (110 individual units) of time-expired, thawed cryoprecipitate were collected. Units were sampled at the 6-h expiration mark and then stored at 2-6°C or room temperature (RT). They were resampled every 24 h for 120 h. One unit from each batch was sent for sterility testing at 120 h. Samples had FVIII (one stage and chromogenic), fibrinogen, FXIII, vWFag, and vWF:RCo assays performed in batches. Rotational thromboelastometry (ROTEM) was also performed.

Results: FVIII levels declined significantly at 120 h post-thawing at both RT and 2-6°C, but still met international standards for FVIII content. Fibrinogen, vWF antigen, and FXIII levels reduced minimally over 120 h and always met international standard requirements when stored at either temperature. ROTEM analysis demonstrated that fibrinogen function was not compromised at 120 h post-thawing under both storage conditions. vWF:RCo levels declined significantly over 120 h at both storage temperatures. No bacterial contamination was detected in 20 units of cryoprecipitate following storage for 120 h post-thawing.

Conclusion: These results demonstrate that extension of the storage time of thawed cryoprecipitate to 120 h, stored at either 2-6°C or RT, is feasible while still maintaining required FVIII, fibrinogen, and vWFag levels. Storage at 2-6°C has the advantage of reduced risk of potential bacterial contamination.
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http://dx.doi.org/10.1111/trf.16366DOI Listing
May 2021

A multicenter laboratory assessment of a new automated chemiluminescent assay for ADAMTS13 activity.

J Thromb Haemost 2021 02 21;19(2):417-428. Epub 2020 Nov 21.

Department of Haematology, Institute of Clinical Pathology and Medical Research (ICPMR), NSW Health Pathology, Westmead Hospital, Westmead, NSW, Australia.

Background: Thrombotic thrombocytopenic purpura (TTP) is a rare but potentially fatal disorder caused by ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) deficiency. Prompt identification/exclusion of TTP can thus be facilitated by rapid ADAMTS13 testing. The most commonly utilized (enzyme-linked immunosorbent assay [ELISA]-based) assay takes several hours to perform and so does not generally permit rapid testing.

Objectives: To evaluate the utility of a new automated test for ADAMTS13 activity, the HemosIL AcuStar ADAMTS13 Activity assay, based on chemiluminescence and able to be performed on an ACL AcuStar instrument within 33 minutes.

Patients/methods: This multicenter (n = 8) assessment included testing of more than 700 test samples, with similar numbers of prospective (n = 348) and retrospective (n = 385) samples. The main comparator was the Technozym ADAMTS13 Activity ELISA. We also assessed comparative performance for detection of ADAMTS13 inhibitors using a Bethesda assay.

Results: Overall, the chemiluminescent assay yielded similar results to the comparator ELISA, albeit with slight negative bias. ADAMTS13 inhibitor detection was also comparable, albeit with slight positive bias with the AcuStar assay. Assay precision was similar with both assays, and we also verified assay normal reference ranges.

Conclusions: The HemosIL AcuStar ADAMTS13 Activity assay provided results rapidly, which were largely comparable with the Technozym ADAMTS13 Activity ELISA assay, albeit lower on average. Conversely, inhibitor levels tended to be identified at a higher level on average. Thus, the HemosIL AcuStar ADAMTS13 Activity assay provides a fast and accurate means to quantitate plasma levels of ADAMTS13 for TTP/ADAMTS13 identification/exclusion, and potentially also for other applications.
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http://dx.doi.org/10.1111/jth.15157DOI Listing
February 2021

Laboratory Maintenance and Propagation of Freshwater Planarians.

Curr Protoc Microbiol 2020 12;59(1):e120

Department of Biology, University of Kentucky, Lexington, Kentucky.

Freshwater planarians are a powerful model organism for the study of animal regeneration, stem cell maintenance and differentiation, and the development and functions of several highly conserved complex tissues. At the same time, planarians are easy to maintain, inexpensive to propagate, and reasonably macroscopic (1 mm to 1 cm in length), making them excellent organisms to use in both complex academic research and hands-on teaching laboratories. Here, we provide a detailed description of how to maintain and propagate these incredibly versatile animals in any basic laboratory setting. © 2020 Wiley Periodicals LLC. Basic Protocol 1: Salt solution preparation Basic Protocol 2: Cleaning planarian housing Basic Protocol 3: Food preparation Basic Protocol 4: Feeding planarians Basic Protocol 5: Expansion and amplification of colony.
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http://dx.doi.org/10.1002/cpmc.120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941200PMC
December 2020

A multicentre assessment of contemporary laboratory assays for heparin induced thrombocytopenia.

Pathology 2021 Feb 5;53(2):247-256. Epub 2020 Oct 5.

NSW Health Pathology, NSW, Australia; Prince of Wales Hospital, Randwick, NSW, Australia.

Heparin induced thrombocytopenia (HIT) is a rare but potentially fatal complication of heparin therapy. In some patients, HIT causes platelet activation and thrombosis (sometimes abbreviated HITT), which leads to adverse clinical sequalae ('pathological HIT'). The likelihood of HIT is initially assessed clinically, typically using a scoring system, of which the 4T score is that most utilised. Subsequent laboratory testing to confirm or exclude HIT facilitates exclusion or diagnosis and management. The current investigation comprises a multicentre (n=9) assessment of contemporary laboratory testing for HIT, as performed over the past 1-3 years in each site and comprising testing of over 1200 samples. The primary laboratory test used by study participants (n=8) comprised a chemiluminescence procedure (HIT-IgG) performed on an AcuStar instrument. Additional immunological testing performed by study sites included lateral flow (STiC, Stago), enzyme linked immunosorbent assay (ELISA), Asserachrom (HPIA IgG), PaGIA (BioRad), plus functional assays, primarily serotonin release assay (SRA) or platelet aggregation methods. The chemiluminescence procedure yielded a highly sensitive screening method for identifying functional HIT, given high area under the curve (AUC, generally ≥0.9) in a receiver operator characteristic (ROC) analysis against SRA as gold standard. ELISA testing resulted in lower ROC AUC scores (<0.8) and higher levels of false positives. Although there is clear association with the likelihood of HIT, the 4T score had less utility than literature suggests, and was comparable to a previous study reported by some of the authors.
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http://dx.doi.org/10.1016/j.pathol.2020.07.012DOI Listing
February 2021

An open label study of the safety and efficacy of a single dose of weekly chloroquine and azithromycin administered for malaria prophylaxis in healthy adults challenged with 7G8 chloroquine-resistant Plasmodium falciparum in a controlled human malaria infection model.

Malar J 2020 Sep 16;19(1):336. Epub 2020 Sep 16.

Walter Reed Army Institute of Research, 503 Robert Grant Ave, Silver Spring, MD, 20910, USA.

Background: Malaria remains the top infectious disease threat facing the U.S. military in many forward operating environments. Compliance with malaria chemoprophylaxis remains a critical component in preventing malaria in the deployed Service Member. Studies of previous military operations show that compliance is consistently higher with weekly versus daily dosing regimens. Current FDA approved weekly chemoprophylaxis options have contraindications that can limit prescribing. The combination of chloroquine (CQ) with azithromycin (AZ) has previously been shown to be an efficacious treatment option for malaria, has pharmacokinetics compatible with weekly dosing, and has shown synergy when combined in vitro.

Methods: In this open label study, 18 healthy volunteers, aged 18-50 years (inclusive), were randomly assigned to receive either 300 mg CQ or 300 mg CQ and 2 gm azithromycin (CQAZ) of directly observed therapy, weekly for 3 weeks prior to undergoing mosquito bite challenge with chloroquine-resistant Plasmodium falciparum. Volunteers that remained asymptomatic and had no evidence of parasitaemia continued to receive weekly post-exposure chemoprophylaxis for 3 weeks following malaria challenge. The primary endpoint was the number of volunteers that remained asymptomatic and had no evidence of parasitaemia 28 days after the malaria challenge.

Results: All 6 (100%) volunteers randomized to the CQ control group became symptomatic with parasitaemia during the 28-day post-challenge period. Only 1/12 (8.3%) of volunteers in the CQAZ group developed symptoms and parasitaemia during the 28-day post-challenge period. However, after chemoprophylaxis was discontinued an additional 6 volunteers developed parasitaemia between days 28-41 after challenge, with 4 of 6 experiencing symptoms. 80% of subjects in the CQAZ group experienced treatment related gastrointestinal adverse events (including 13% that experienced severe nausea) compared to 38% in the CQ group. A comparison of the pharmacokinetics in the CQAZ group demonstrated higher azithromycin Cmax (p = 0.03) and AUC (p = 0.044) levels in those volunteers who never became parasitaemic compared to those who did.

Conclusion: Given the high rate of side effects and poor efficacy when administered for 3 weeks before and after challenge, the combination of weekly chloroquine and azithromycin is a suboptimal regimen combination for weekly malaria chemoprophylaxis. Trial registration ClinicalTrials.gov NCT03278808.
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http://dx.doi.org/10.1186/s12936-020-03409-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7493140PMC
September 2020

Social competition stimulates cognitive performance in a sex-specific manner.

Proc Biol Sci 2020 09 16;287(1935):20201424. Epub 2020 Sep 16.

School of Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK.

Social interactions are thought to be a critical driver in the evolution of cognitive ability. Cooperative interactions, such as pair bonding, rather than competitive interactions have been largely implicated in the evolution of increased cognition. This is despite competition traditionally being a very strong driver of trait evolution. Males of many species track changes in their social environment and alter their reproductive strategies in response to anticipated levels of competition. We predict this to be cognitively challenging. Using a model, we are able to distinguish between the effects of a competitive environment versus generic social contact by exposing flies to same-sex same-species competition versus different species partners, shown to present non-competitive contacts. Males increase olfactory learning/memory and visual memory after exposure to conspecific males only, a pattern echoed by increased expression of synaptic genes and an increased need for sleep. For females, largely not affected by mating competition, the opposite pattern was seen. The results indicate that specific social contacts dependent on sex, not simply generic social stimulation, may be an important evolutionary driver for cognitive ability in fruit flies.
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http://dx.doi.org/10.1098/rspb.2020.1424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542822PMC
September 2020

High-Quality Assemblies for Three Invasive Social Wasps from the Genus.

G3 (Bethesda) 2020 10 5;10(10):3479-3488. Epub 2020 Oct 5.

Genomics Aotearoa and Department of Biochemistry, University of Otago, Dunedin 9054, Aotearoa, New Zealand

Social wasps of the genus have spread to nearly all landmasses worldwide and have become significant pests in their introduced ranges, affecting economies and biodiversity. Comprehensive genome assemblies and annotations for these species are required to develop the next generation of control strategies and monitor existing chemical control. We sequenced and annotated the genomes of the common wasp (), German wasp (), and the western yellowjacket (). Our chromosome-level assemblies each contain 176-179 Mb of total sequence assembled into 25 scaffolds, with 10-200 unanchored scaffolds, and 16,566-18,948 genes. We annotated gene sets relevant to the applied management of invasive wasp populations, including genes associated with spermatogenesis and development, pesticide resistance, olfactory receptors, immunity and venom. These genomes provide evidence for active DNA methylation in Vespidae and tandem duplications of venom genes. Our genomic resources will contribute to the development of next-generation control strategies, and monitoring potential resistance to chemical control.
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http://dx.doi.org/10.1534/g3.120.401579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7534447PMC
October 2020

Optimized flow cytometric protocol for the detection of functional subsets of low frequency antigen-specific CD4 and CD8 T cells.

MethodsX 2020 22;7:101005. Epub 2020 Jul 22.

Malaria Biologics Branch, Walter Reed Army Institute of Research, Silver Spring, MD 20910, United States.

Detection of low-frequency cells using flow cytometry is challenging, as the sensitivity of the analysis is dependent on the signal-to-noise ratio, and a cell frequency of 1 in 10,000 cells is accepted as the lower limit of detection for standard flow cytometry. A solution to this problem is to pre-enrich rare cell populations using magnetic-bead conjugated antibodies targeting lineage or activation markers. For measuring vaccine or pathogen induced immune responses, this method drastically increases the signal-to-noise ratio by enriching only activated (i.e., antigen-specific) cells and excluding all other peripheral blood leukocytes from the subsequent analysis. To date, magnetic enrichment of antigen-specific cells has only been described for CD4 T cells processed for surface staining. The current study significantly expands the methodology to allow detection of antigen-specific CD8 T cells and analysis of cells that had been processed for intracellular staining.•The protocol described here allows magnetic enrichment of PBMCs after fixation and intracellular staining steps without increasing the non-specific background.•The protocol is adapted to automated enrichment-mode on flow cytometers.•The procedure boosts the sensitivity of the flow cytometry analysis by significantly increasing the sample size of functional antigen-specific cells without skewing the composition of the functional cells pool.
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http://dx.doi.org/10.1016/j.mex.2020.101005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396823PMC
July 2020

The diversity and distribution of D1 proteins in cyanobacteria.

Photosynth Res 2020 Aug 18;145(2):111-128. Epub 2020 Jun 18.

Department of Botany, University of Otago, Dunedin, New Zealand.

The psbA gene family in cyanobacteria encodes different forms of the D1 protein that is part of the Photosystem II reaction centre. We have identified a phylogenetically distinct D1 group that is intermediate between previously identified G3-D1 and G4-D1 proteins (Cardona et al. Mol Biol Evol 32:1310-1328, 2015). This new group contained two subgroups: D1, which was frequently in the genomes of heterocystous cyanobacteria and D1 that was part of the far-red light photoacclimation gene cluster of cyanobacteria. In addition, we have identified subgroups within G3, the micro-aerobically expressed D1 protein. There are amino acid changes associated with each of the subgroups that might affect the function of Photosystem II. We show a phylogenetically broad range of cyanobacteria have these D1 types, as well as the genes encoding the G2 protein and chlorophyll f synthase. We suggest identification of additional D1 isoforms and the presence of multiple D1 isoforms in phylogenetically diverse cyanobacteria supports the role of these proteins in conferring a selective advantage under specific conditions.
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http://dx.doi.org/10.1007/s11120-020-00762-7DOI Listing
August 2020

Sawfly Genomes Reveal Evolutionary Acquisitions That Fostered the Mega-Radiation of Parasitoid and Eusocial Hymenoptera.

Genome Biol Evol 2020 07;12(7):1099-1188

Human Genome Sequencing Center, Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, Texas.

The tremendous diversity of Hymenoptera is commonly attributed to the evolution of parasitoidism in the last common ancestor of parasitoid sawflies (Orussidae) and wasp-waisted Hymenoptera (Apocrita). However, Apocrita and Orussidae differ dramatically in their species richness, indicating that the diversification of Apocrita was promoted by additional traits. These traits have remained elusive due to a paucity of sawfly genome sequences, in particular those of parasitoid sawflies. Here, we present comparative analyses of draft genomes of the primarily phytophagous sawfly Athalia rosae and the parasitoid sawfly Orussus abietinus. Our analyses revealed that the ancestral hymenopteran genome exhibited traits that were previously considered unique to eusocial Apocrita (e.g., low transposable element content and activity) and a wider gene repertoire than previously thought (e.g., genes for CO2 detection). Moreover, we discovered that Apocrita evolved a significantly larger array of odorant receptors than sawflies, which could be relevant to the remarkable diversification of Apocrita by enabling efficient detection and reliable identification of hosts.
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http://dx.doi.org/10.1093/gbe/evaa106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455281PMC
July 2020

Efficacy and safety of two doses of budesonide/formoterol fumarate metered dose inhaler in COPD.

ERJ Open Res 2020 Apr 27;6(2). Epub 2020 Apr 27.

AstraZeneca, Durham, NC, USA.

Inhaled corticosteroid/long-acting β-agonist combination therapy is a recommended treatment option for patients with chronic obstructive pulmonary disease (COPD) and increased exacerbation risk, particularly those with elevated blood eosinophil levels. SOPHOS (NCT02727660) evaluated the efficacy and safety of two doses of budesonide/formoterol fumarate dihydrate metered dose inhaler (BFF MDI) formoterol fumarate dihydrate (FF) MDI, each delivered using co-suspension delivery technology, in patients with moderate-to-very severe COPD and a history of exacerbations. In this phase 3, randomised, double-blind, parallel-group, 12-52-week, variable length study, patients received twice-daily BFF MDI 320/10 µg or 160/10 µg, or FF MDI 10 µg. The primary endpoint was change from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV) at week 12. Secondary and other endpoints included assessments of moderate/severe COPD exacerbations and safety. The primary analysis (modified intent-to-treat) population included 1843 patients (BFF MDI 320/10 µg, n=619; BFF MDI 160/10 µg, n=617; and FF MDI, n=607). BFF MDI 320/10 µg and 160/10 µg improved morning pre-dose trough FEV at week 12 FF MDI (least squares mean differences 34 mL [p=0.0081] and 32 mL [p=0.0134], respectively), increased time to first exacerbation (hazard ratios 0.827 [p=0.0441] and 0.803 [p=0.0198], respectively) and reduced exacerbation rate (rate ratios 0.67 [p=0.0001] and 0.71 [p=0.0010], respectively). Lung function and exacerbation benefits were driven by patients with blood eosinophil counts ≥150 cells·mm. The incidence of adverse events was similar, and pneumonia rates were low (≤2.4%) across treatments. SOPHOS demonstrated the efficacy and tolerability of BFF MDI 320/10 µg and 160/10 µg in patients with moderate-to-very severe COPD at increased risk of exacerbations.
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http://dx.doi.org/10.1183/23120541.00187-2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184113PMC
April 2020

Genome Architecture Facilitates Phenotypic Plasticity in the Honeybee (Apis mellifera).

Mol Biol Evol 2020 07;37(7):1964-1978

Genomics Aotearoa and Biochemistry Department, University of Otago, Dunedin, New Zealand.

Phenotypic plasticity, the ability of an organism to alter its phenotype in response to an environmental cue, facilitates rapid adaptation to changing environments. Plastic changes in morphology and behavior are underpinned by widespread gene expression changes. However, it is unknown if, or how, genomes are structured to ensure these robust responses. Here, we use repression of honeybee worker ovaries as a model of plasticity. We show that the honeybee genome is structured with respect to plasticity; genes that respond to an environmental trigger are colocated in the honeybee genome in a series of gene clusters, many of which have been assembled in the last 80 My during the evolution of the Apidae. These clusters are marked by histone modifications that prefigure the gene expression changes that occur as the ovary activates, suggesting that these genomic regions are poised to respond plastically. That the linear sequence of the honeybee genome is organized to coordinate widespread gene expression changes in response to environmental influences and that the chromatin organization in these regions is prefigured to respond to these influences is perhaps unexpected and has implications for other examples of plasticity in physiology, evolution, and human disease.
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http://dx.doi.org/10.1093/molbev/msaa057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7306700PMC
July 2020

Mating status and the evolution of eusociality: Oogenesis is independent of mating status in the solitary bee Osmia bicornis.

J Insect Physiol 2020 Feb - Mar;121:104003. Epub 2019 Dec 26.

Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, United Kingdom. Electronic address:

The fundamental trait underlying eusociality is the reproductive division of labour. In honeybees (Apis mellifera), queens lay eggs while workers forage, defend and care for brood. The division of labour is maintained by pheromones including queen mandibular pheromone (QMP) produced by the queen. QMP constrains reproduction in adult honeybee workers, but in the absence of their queen workers can activate their ovaries and, although they cannot mate, they lay haploid male eggs. The reproductive ground plan hypothesis suggests that reproductive constraint may have evolved by co-opting mechanisms of reproductive control in solitary ancestors. In many insects mating is required to activate or accelerate oogenesis. Here, we use the solitary bee Osmia bicornis (Megachilidae) to test whether reproductive constraint evolved from ancestral control of reproduction by mating status. We present a structural study of the O. bicornis ovary, and compare key stages of oogenesis with honeybee workers. Importantly, we show that mating does not affect any aspect of the reproductive physiology of O. bicornis. We therefore conclude that mechanisms governing reproductive constraint in honeybees were unlikely to have been co-opted from mechanisms pertaining to mating status.
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http://dx.doi.org/10.1016/j.jinsphys.2019.104003DOI Listing
December 2020

Ancestral hymenopteran queen pheromones do not share the broad phylogenetic repressive effects of honeybee queen mandibular pheromone.

J Insect Physiol 2019 Nov - Dec;119:103968. Epub 2019 Oct 25.

School of Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK. Electronic address:

Queen pheromones effect the reproductive division of labour, a defining feature of eusociality. Reproductive division of labour ensures that one, or a small number of, females are responsible for the majority of reproduction within a colony. Much work on the evolution and function of these pheromones has focussed on Queen Mandibular Pheromone (QMP) which is produced by the Western or European honeybee (Apis mellifera). QMP has phylogenetically broad effects, repressing reproduction in a variety of arthropods, including those distantly related to the honeybee such as the fruit fly Drosophila melanogaster. QMP is highly derived and has little chemical similarity to the majority of hymenopteran queen pheromones which are derived from cuticular hydrocarbons. This raises the question of whether the phylogenetically widespread repression of reproduction by QMP also occurs with more basal saturated hydrocarbon-based queen-pheromones. Using D. melanogaster we show that saturated hydrocarbons are incapable of repressing reproduction, unlike QMP. We also show no interaction between the four saturated hydrocarbons tested or between the saturated hydrocarbons and QMP, implying that there is no conservation in the mechanism of detection or action between these compounds. We propose that the phylogenetically broad reproductive repression seen in response to QMP is not a feature of all queen pheromones, but unique to QMP itself, which has implications for our understanding of how queen pheromones act and evolve.
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http://dx.doi.org/10.1016/j.jinsphys.2019.103968DOI Listing
March 2020

Combining immunoprofiling with machine learning to assess the effects of adjuvant formulation on human vaccine-induced immunity.

Hum Vaccin Immunother 2020 7;16(2):400-411. Epub 2019 Oct 7.

Malaria Vaccine Branch, U.S. Military Malaria Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, USA.

Adjuvants produce complex, but often subtle, effects on vaccine-induced immune responses that, nonetheless, play a critical role in vaccine efficacy. In-depth profiling of vaccine-induced cytokine, cellular, and antibody responses ("immunoprofiling") combined with machine-learning holds the promise of identifying adjuvant-specific immune response characteristics that can guide rational adjuvant selection. Here, we profiled human immune responses induced by vaccines adjuvanted with two similar, clinically relevant adjuvants, AS01B and AS02A, and identified key distinguishing characteristics, or immune signatures, they imprint on vaccine-induced immunity. Samples for this side-by-side comparison were from malaria-naïve individuals who had received a recombinant malaria subunit vaccine (AMA-1) that targets the pre-erythrocytic stage of the parasite. Both adjuvant formulations contain the same immunostimulatory components, QS21 and MPL, thus this study reveals the subtle impact that adjuvant formulation has on immunogenicity. Adjuvant-mediated immune signatures were established through a two-step approach: First, we generated a broad immunoprofile (serological, functional and cellular characterization of vaccine-induced responses). Second, we integrated the immunoprofiling data and identify what combination of immune features was most clearly able to distinguish vaccine-induced responses by adjuvant using machine learning. The computational analysis revealed statistically significant differences in cellular and antibody responses between cohorts and identified a combination of immune features that was able to distinguish subjects by adjuvant with 71% accuracy. Moreover, the in-depth characterization demonstrated an unexpected induction of CD8 T cells by the recombinant subunit vaccine, which is rare and highly relevant for future vaccine design.
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http://dx.doi.org/10.1080/21645515.2019.1654807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062453PMC
October 2019

Planarians recruit piRNAs for mRNA turnover in adult stem cells.

Genes Dev 2019 11 19;33(21-22):1575-1590. Epub 2019 Sep 19.

Gene regulation by Non-coding RNA, Elite Network of Bavaria and University of Bayreuth, 95447 Bayreuth, Germany.

PIWI proteins utilize small RNAs called piRNAs to silence transposable elements, thereby protecting germline integrity. In planarian flatworms, PIWI proteins are essential for regeneration, which requires adult stem cells termed neoblasts. Here, we characterize planarian piRNAs and examine the roles of PIWI proteins in neoblast biology. We find that the planarian PIWI proteins SMEDWI-2 and SMEDWI-3 cooperate to degrade active transposons via the ping-pong cycle. Unexpectedly, we discover that SMEDWI-3 plays an additional role in planarian mRNA surveillance. While SMEDWI-3 degrades numerous neoblast mRNAs in a homotypic ping-pong cycle, it is also guided to another subset of neoblast mRNAs by antisense piRNAs and binds these without degrading them. Mechanistically, the distinct activities of SMEDWI-3 are primarily dictated by the degree of complementarity between target mRNAs and antisense piRNAs. Thus, PIWI proteins enable planarians to repurpose piRNAs for potentially critical roles in neoblast mRNA turnover.
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http://dx.doi.org/10.1101/gad.322776.118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6824462PMC
November 2019

Regulation of Genomic Output and (Pluri)potency in Regeneration.

Annu Rev Genet 2019 12 10;53:327-346. Epub 2019 Sep 10.

Howard Hughes Medical Institute, Stowers Institute for Medical Research, Kansas City, Missouri 64110, USA; email:

Regeneration is a remarkable phenomenon that has been the subject of awe and bafflement for hundreds of years. Although regeneration competence is found in highly divergent organisms throughout the animal kingdom, recent advances in tools used for molecular and genomic characterization have uncovered common genes, molecular mechanisms, and genomic features in regenerating animals. In this review we focus on what is known about how genome regulation modulates cellular potency during regeneration. We discuss this regulation in the context of complex tissue regeneration in animals, from to humans, with reference to ex vivo-cultured cell models of pluripotency when appropriate. We emphasize the importance of a detailed molecular understanding of both the mechanisms that regulate genomic output and the functional assays that assess the biological relevance of such molecular characterizations.
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http://dx.doi.org/10.1146/annurev-genet-112618-043733DOI Listing
December 2019

Correction to: From genes to environment in shaping of an embryo: understanding embryonic-extraembryonic interactions at the BSDB autumn meeting in Oxford.

Dev Genes Evol 2019 Nov;229(5-6):207

School of Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK.

The authors of the article Ajduk & Duncan 2019 sincerely apologize for specifying the incorrect institutional affiliation for Professor Ali Brivanlou and also the incorrect spelling of Professor Brivanlou's surname in the text of the article.
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http://dx.doi.org/10.1007/s00427-019-00638-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6887852PMC
November 2019

Including health impacts in environmental impact assessments for three Australian coal-mining projects: a documentary analysis.

Health Promot Int 2020 Jun;35(3):449-457

Level 2 The Hub, Charles Perkins Centre D17, The University of Sydney, NSW 2006, Australia.

Notwithstanding the historical benefits of coal in aiding human and economic development, the negative health and environmental impacts of coal extraction and processing are of increasing concern. Environmental impact assessments (EIAs) are a regulated policy mechanism that can be used to predict and consider the health impacts of mining projects to determine if consent is given. The ways in which health is considered within EIA is unclear. This research investigated 'How and to what extent are health, well-being and equity issues considered in Environmental Impact Assessments (EIAs) of major coal mining projects in New South Wales, Australia'. To this end we developed and applied a comprehensive coding framework designed to interrogate the publicly available environmental impact statements (EISs) of three mines in New South Wales (NSW), Australia, for their inclusion of health, well-being and equity issues. Analysis of the three EISs demonstrates that: the possible impacts of each mine on health and well-being were narrowly and inadequately considered; when health and well-being were considered there was a failure to assess the possible impacts specific to the particular mine and the communities potentially affected; the cumulative impacts on human health of multiple mines in the same geographical area were almost completely ignored; the discussions of intragenerational and intergenerational equity did not demonstrate a sound understanding of equity and, it is essential that governments' requirements for the EIA include detailed analysis of the health, well-being, equity and cumulative impacts specific to the proposed mine and relevant communities.
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http://dx.doi.org/10.1093/heapro/daz032DOI Listing
June 2020

Molecular evolutionary trends and feeding ecology diversification in the Hemiptera, anchored by the milkweed bug genome.

Genome Biol 2019 04 2;20(1):64. Epub 2019 Apr 2.

Department of Biological Sciences, University of Cincinnati, Cincinnati, OH, 45221, USA.

Background: The Hemiptera (aphids, cicadas, and true bugs) are a key insect order, with high diversity for feeding ecology and excellent experimental tractability for molecular genetics. Building upon recent sequencing of hemipteran pests such as phloem-feeding aphids and blood-feeding bed bugs, we present the genome sequence and comparative analyses centered on the milkweed bug Oncopeltus fasciatus, a seed feeder of the family Lygaeidae.

Results: The 926-Mb Oncopeltus genome is well represented by the current assembly and official gene set. We use our genomic and RNA-seq data not only to characterize the protein-coding gene repertoire and perform isoform-specific RNAi, but also to elucidate patterns of molecular evolution and physiology. We find ongoing, lineage-specific expansion and diversification of repressive C2H2 zinc finger proteins. The discovery of intron gain and turnover specific to the Hemiptera also prompted the evaluation of lineage and genome size as predictors of gene structure evolution. Furthermore, we identify enzymatic gains and losses that correlate with feeding biology, particularly for reductions associated with derived, fluid nutrition feeding.

Conclusions: With the milkweed bug, we now have a critical mass of sequenced species for a hemimetabolous insect order and close outgroup to the Holometabola, substantially improving the diversity of insect genomics. We thereby define commonalities among the Hemiptera and delve into how hemipteran genomes reflect distinct feeding ecologies. Given Oncopeltus's strength as an experimental model, these new sequence resources bolster the foundation for molecular research and highlight technical considerations for the analysis of medium-sized invertebrate genomes.
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http://dx.doi.org/10.1186/s13059-019-1660-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6444547PMC
April 2019

From genes to environment in shaping of an embryo: understanding embryonic-extraembryonic interactions at the BSDB autumn meeting in Oxford.

Dev Genes Evol 2019 05 23;229(2-3):83-87. Epub 2019 Feb 23.

School of Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK.

The British Society for Developmental Biology Autumn Meeting, held in Oxford in September 2018, was the third in a series of international workshops which have been focussed on development at the extraembryonic-embryonic interface. This workshop, entitled "Embryonic-Extraembryonic Interactions: from Genetics to Environment" built on the two previous workshops held in 2011 (Leuven, Belgium) and 2015 (Göttingen, Germany). This workshop brought together researchers utilising a diverse range of organisms (including both vertebrate and invertebrate species) and a range of experimental approaches to answer core questions in developmental biology. This meeting report highlights some of the major themes emerging from the workshop including an evolutionary perspective as well as recent advances that have been made through the adoption of emerging techniques and technologies.
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http://dx.doi.org/10.1007/s00427-019-00628-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6500506PMC
May 2019

Correlation Between Malaria-Specific Antibody Profiles and Responses to Artemisinin Combination Therapy for Treatment of Uncomplicated Malaria in Western Kenya.

J Infect Dis 2019 05;219(12):1969-1979

Department of Emerging and Infectious Diseases, United States Army Medical Research Directorate-Africa, Kenya Medical Research Institute/Walter Reed Project , Kisumu.

Background: The impact of preexisting immunity on the efficacy of artemisinin combination therapy must be examined to monitor resistance, and for implementation of new treatment strategies.

Methods: Serum samples obtained from a clinical trial in Western Kenya randomized to receive artemether-lumefantrine (AL) or artesunate-mefloquine (ASMQ) were screened for total immunoglobulin G against preerythrocytic and erythrocytic antigens. The association and correlation between different variables, and impact of preexisting immunity on parasite slope half-life (t½) was determined.

Results: There was no significant difference in t½, but the number of individuals with lag phase was significantly higher in the AL than in the ASMQ arm (29 vs 13, respectively; P < .01). Circumsporozoite protein-specific antibodies correlate positively with t½ (AL, P = .03; ASMQ, P = .09), but negatively with clearance rate in both study arms (AL, P = .16; ASMQ, P = .02). The t½ correlated negatively with age in ASMQ group. When stratified based on t½, the antibody titers against circumsporozoite protein and merozoite surface protein 1 were significantly higher in participants who cleared parasites rapidly in the AL group (P = .01 and P = .02, respectively).

Conclusion: Data presented here define immunoprofiles associated with distinct responses to 2 different antimalarial drugs, revealing impact of preexisting immunity on the efficacy of artemisinin combination therapy regimens in a malaria-holoendemic area.

Clinical Trials Registration: NCT01976780.
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http://dx.doi.org/10.1093/infdis/jiz027DOI Listing
May 2019

Identification of Immune Signatures of Novel Adjuvant Formulations Using Machine Learning.

Sci Rep 2018 11 30;8(1):17508. Epub 2018 Nov 30.

Malaria Vaccine Branch, US Military Malaria Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, USA.

Adjuvants have long been critical components of vaccines, but the exact mechanisms of their action and precisely how they alter or enhance vaccine-induced immune responses are often unclear. In this study, we used broad immunoprofiling of antibody, cellular, and cytokine responses, combined with data integration and machine learning to gain insight into the impact of different adjuvant formulations on vaccine-induced immune responses. A Self-Assembling Protein Nanoparticles (SAPN) presenting the malarial circumsporozoite protein (CSP) was used as a model vaccine, adjuvanted with three different liposomal formulations: liposome plus Alum (ALFA), liposome plus QS21 (ALFQ), and both (ALFQA). Using a computational approach to integrate the immunoprofiling data, we identified distinct vaccine-induced immune responses and developed a multivariate model that could predict the adjuvant condition from immune response data alone with 92% accuracy (p = 0.003). The data integration also revealed that commonly used readouts (i.e. serology, frequency of T cells producing IFN-γ, IL2, TNFα) missed important differences between adjuvants. In summary, broad immune-profiling in combination with machine learning methods enabled the reliable and clear definition of immune signatures for different adjuvant formulations, providing a means for quantitatively characterizing the complex roles that adjuvants can play in vaccine-induced immunity. The approach described here provides a powerful tool for identifying potential immune correlates of protection, a prerequisite for the rational pairing of vaccines candidates and adjuvants.
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http://dx.doi.org/10.1038/s41598-018-35452-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6269591PMC
November 2018

The genome of the water strider Gerris buenoi reveals expansions of gene repertoires associated with adaptations to life on the water.

BMC Genomics 2018 Nov 21;19(1):832. Epub 2018 Nov 21.

Department of Biological Sciences, McMicken College of Arts and Sciences, University of Cincinnati, 318 College Drive, Cincinnati, OH, 45221-0006, USA.

Background: Having conquered water surfaces worldwide, the semi-aquatic bugs occupy ponds, streams, lakes, mangroves, and even open oceans. The diversity of this group has inspired a range of scientific studies from ecology and evolution to developmental genetics and hydrodynamics of fluid locomotion. However, the lack of a representative water strider genome hinders our ability to more thoroughly investigate the molecular mechanisms underlying the processes of adaptation and diversification within this group.

Results: Here we report the sequencing and manual annotation of the Gerris buenoi (G. buenoi) genome; the first water strider genome to be sequenced thus far. The size of the G. buenoi genome is approximately 1,000 Mb, and this sequencing effort has recovered 20,949 predicted protein-coding genes. Manual annotation uncovered a number of local (tandem and proximal) gene duplications and expansions of gene families known for their importance in a variety of processes associated with morphological and physiological adaptations to a water surface lifestyle. These expansions may affect key processes associated with growth, vision, desiccation resistance, detoxification, olfaction and epigenetic regulation. Strikingly, the G. buenoi genome contains three insulin receptors, suggesting key changes in the rewiring and function of the insulin pathway. Other genomic changes affecting with opsin genes may be associated with wavelength sensitivity shifts in opsins, which is likely to be key in facilitating specific adaptations in vision for diverse water habitats.

Conclusions: Our findings suggest that local gene duplications might have played an important role during the evolution of water striders. Along with these findings, the sequencing of the G. buenoi genome now provides us the opportunity to pursue exciting research opportunities to further understand the genomic underpinnings of traits associated with the extreme body plan and life history of water striders.
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http://dx.doi.org/10.1186/s12864-018-5163-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6249893PMC
November 2018

A Raster-Based Subdividing Indicator to Map Urban Heat Vulnerability: A Case Study in Sydney, Australia.

Int J Environ Res Public Health 2018 11 9;15(11). Epub 2018 Nov 9.

School of Geosciences, The University of Sydney, Camperdown, NSW 2006, Australia.

Assessing and mapping urban heat vulnerability has developed significantly over the past decade. Many studies have mapped urban heat vulnerability with a census unit-based general indicator (CGI). However, this kind of indicator has many problems, such as inaccurate assessment results and lacking comparability among different studies. This paper seeks to address this research gap and proposes a raster-based subdividing indicator to map urban heat vulnerability. We created a raster-based subdividing indicator (RSI) to map urban heat vulnerability from 3 aspects: exposure, sensitivity and adaptive capacity. We applied and compared it with a raster-based general indicator (RGI) and a census unit-based general indicator (CGI) in Sydney, Australia. Spatial statistics and analysis were used to investigate the performance among those three indicators. The results indicate that: (1) compared with the RSI framework, 67.54% of very high heat vulnerability pixels were ignored in the RGI framework; and up to 83.63% of very high heat vulnerability pixels were ignored in the CGI framework; (2) Compared with the previous CGI framework, a RSI framework has many advantages. These include more accurate results, more flexible model structure, and higher comparability among different studies. This study recommends using a RSI framework to map urban heat vulnerability in the future.
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http://dx.doi.org/10.3390/ijerph15112516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6266879PMC
November 2018

Budesonide/formoterol MDI with co-suspension delivery technology in COPD: the TELOS study.

Eur Respir J 2018 09 16;52(3). Epub 2018 Sep 16.

Pearl - a member of the AstraZeneca Group, Durham, NC, USA.

TELOS compared budesonide (BD)/formoterol fumarate dihydrate (FF) metered dose inhaler (BFF MDI), formulated using innovative co-suspension delivery technology that enables consistent aerosol performance, with its monocomponents and budesonide/formoterol fumarate dihydrate dry powder inhaler (DPI) in patients with moderate to very severe chronic obstructive pulmonary disease (COPD), without a requirement for an exacerbation history.In this phase III, double-blind, parallel-group, 24-week study (NCT02766608), patients were randomised to BFF MDI 320/10 µg (n=664), BFF MDI 160/10 µg (n=649), FF MDI 10 µg (n=648), BD MDI 320 µg (n=209) or open-label budesonide/formoterol DPI 400/12 µg (n=219). Primary end-points were change from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV) and FEV area under the curve from 0-4 h (AUC). Time to first and rate of moderate/severe exacerbations were assessed.BFF MDI 320/10 µg improved pre-dose trough FEV FF MDI (least squares mean (LSM) 39 mL; p=0.0018), and BFF MDI 320/10 µg and 160/10 µg improved FEV AUC BD MDI (LSM 173 mL and 157 mL, respectively; both p<0.0001) at week 24. BFF MDI 320/10 µg and 160/10 µg improved time to first and rate of moderate/severe exacerbations FF MDI. Treatments were well tolerated, with pneumonia incidence ranging from 0.5-1.4%.BFF MDI improved lung function monocomponents and exacerbations FF MDI in patients with moderate to very severe COPD.
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http://dx.doi.org/10.1183/13993003.01334-2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6383599PMC
September 2018

Evaluation of C-Methionine PET and Anatomic MRI Associations in Diffuse Intrinsic Pontine Glioma.

J Nucl Med 2019 03 2;60(3):312-319. Epub 2018 Aug 2.

Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis, Tennessee.

The role of metabolic imaging in the diagnosis, treatment, and response assessment of diffuse intrinsic pontine glioma (DIPG) is poorly defined. We investigated the uptake of C-methionine in pediatric patients with newly diagnosed DIPG and evaluated the associations of C-methionine PET metrics with conventional MRI indices and survival outcomes. Twenty-two patients with newly diagnosed DIPG were prospectively enrolled on an institutional review board-approved investigational study of C-methionine PET. All patients underwent baseline C-methionine PET/CT, and initial treatment-response scans after chemotherapy or radiation therapy were obtained for 17 patients. Typical and atypical DIPGs were assessed clinically and radiographically and defined by multidisciplinary consensus. Three-dimensional regions of interest, reviewed by consensus between a nuclear medicine physician and a radiation oncologist, were delineated after coregistration of PET and MR images. Associations of C-methionine uptake intensity and uniformity with survival, along with associations between C-methionine uptake and conventional MRI tumor indices over time, were evaluated. C-methionine PET voxel values within regions of interest were assessed as threshold values across proportions of the study population, and C-methionine uptake at baseline was assessed relative to MRI-defined tumor progression. C-methionine uptake above that of uninvolved brain tissue was observed in 18 of 22 baseline scans (82%) and 15 of 17 initial response scans (88%). C-methionine avidity within MRI-defined tumor was limited in extent, with 11 of 18 positive baseline C-methionine PET scans (61%) showing less than 25% C-methionine-avid tumor. The increase in total tumor volume with C-methionine PET was relatively limited (17.2%; interquartile range, 6.53%-38.90%), as was the extent of C-methionine uptake beyond the MRI-defined tumor (2.2%; interquartile range, 0.55%-10.88%). Although baseline C-methionine PET intensity and uniformity metrics did not correlate with survival outcomes, initial C-methionine avidity overlapped with recurrent tumor in 100% of cases. A clinical diagnosis of atypical DIPG was associated with borderline significantly prolonged progression-free survival (  =  0.07), yet C-methionine PET indices at diagnosis did not differ significantly between atypical and typical DIPGs. Most newly diagnosed DIPGs are successfully visualized by C-methionine PET. Baseline C-methionine uptake delineates regions at increased risk for recurrence, yet intensity and uniformity metrics did not correlate with treatment outcomes in children with DIPG in this study.
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http://dx.doi.org/10.2967/jnumed.118.212514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6424234PMC
March 2019

Efficacy, safety, and dose response of glycopyrronium administered by metered dose inhaler using co-suspension delivery technology in subjects with intermittent or mild-to-moderate persistent asthma: A randomized controlled trial.

Respir Med 2018 06 19;139:39-47. Epub 2018 Apr 19.

Pearl - a member of the AstraZeneca Group, Durham, NC, USA.

Objectives: This randomized, double-blind, placebo-controlled, cross-over, Phase II dose-ranging study investigated the efficacy and safety of GP MDI (glycopyrronium administered by metered dose inhaler formulated using co-suspension delivery technology) compared with an open-label active comparator, salmeterol dry powder inhaler (SAL DPI), in subjects with intermittent or mild-to-moderate persistent asthma.

Methods: Subjects were randomized to receive five of seven treatments (GP MDI 28.8, 14.4, 7.2, 3.6, and 1.9 μg, placebo MDI, and SAL DPI 50 μg), each for a 14-day period. The primary endpoint was peak change from baseline in forced expiratory volume in 1 s (FEV) on Day 15. Secondary endpoints included additional lung function parameters and symptoms (Asthma Control Questionnaire-5). Safety was monitored throughout.

Results: Of 248 subjects randomized, 211 completed the study. All doses of GP MDI resulted in significant improvements in the primary endpoint compared with placebo MDI in a dose-ordered fashion (range 85-155 mL, p < .0001), without appreciable differences between the two highest doses of GP MDI (28.8 and 14.4 μg) and SAL DPI 50 μg. Improvements in secondary lung function endpoints and symptoms were generally dose-ordered, with GP MDI 28.8 μg showing the greatest improvements. Similar results were observed when endpoints were analyzed based on subjects' background use of inhaled corticosteroids (yes/no). All GP MDI doses were well tolerated with no evidence of a dose-related effect on adverse events.

Conclusions: The results of this study suggest that GP MDI could offer an important treatment option for maintenance therapy of asthma, and warrants further investigation in Phase III clinical trials.
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http://dx.doi.org/10.1016/j.rmed.2018.04.013DOI Listing
June 2018