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Background To manage tick infestations and reduce tick-borne pathogen transmission risk to dogs, compliant administration of a fast-acting ectoparasiticide is necessary. Isoxazoline-containing ectoparasiticide products provide systemic whole-body coverage; however, differences in tick kill have been observed between products and these differences may be more pronounced when controlling common dose-limiting tick species such as Amblyomma americanum . Methods Dogs were ranked by tick carrying capacity, randomly allocated to one of three treatment groups, and administered Bravecto® Chews (minimum 25 mg/kg fluralaner), Simparica TRIO® (minimum 1.2 mg/kg sarolaner, 24 µg/kg moxidectin, 5 mg/kg pyrantel), or no treatment. Dogs were infested with approximately 50 unfed adult (25 female, 25 male) A. americanum on days −2, 21, 28, and 35. Live tick counts were performed at 8, 12, 24, 48, and 72 h post-treatment (day 0) and post-infestation on days 21, 28, and 35. At each tick count timepoint, product efficacy was determined by comparing geometric mean live tick counts for each product-treated group to the untreated group and a linear mixed model was used for between-group comparisons. Results Compared with untreated dogs, significant control of existing A. americanum infestations began by 8 h post-treatment (81.6%) and reached 98.0% control by 12-h for Bravecto®-treated dogs. In comparison, significant control for Simparica TRIO®-treated dogs began by 24 h post-treatment (97.7%). When reinfested on day 21, A. americanum infestations were controlled more quickly for Bravecto® compared with Simparica TRIO®-treated dogs at 12 h (efficacy 95.3% versus 25.5%, P <  0.001) and 24 h (efficacy 99.7% versus 70.9%, P  < 0.001) post-infestation. Similarly, when reinfested on day 28, faster A. americanum control occurred for Bravecto® compared with Simparica TRIO®-treated dogs at 12 h (efficacy 87.9% versus 18.3%, P  < 0.001) and at 24 h (99.2% versus 59.3%, P  < 0.001) post-infestation. Finally, when reinfested on day 35, time to ≥ 90% efficacy was achieved by 48 h for Bravecto®-treated dogs compared with 72 h post-infestation for Simparica TRIO®-treated dogs. Both products performed within label indications and no treatment-related adverse reactions occurred during the study. Conclusions Amblyomma americanum infestations are controlled more quickly immediately upon treatment and at 21, 28, and 35 days post-treatment for Bravecto® compared with Simparica TRIO®-treated dogs. Graphical Abstract

Abstract Background Canine acaricides with rapid onset and sustained activity can reduce pathogen transmission risk and enhance pet owner experience. This randomized, complete block design, investigator-masked study compared the speed of kill of Amblyomma americanum provided by three monthly-use isoxazoline-containing products. Methods Eight randomized beagles per group were treated (day 0), per label, with sarolaner (combined with moxidectin and pyrantel, Simparica Trio™), afoxolaner (NexGard™), or lotilaner (Credelio™), or remained untreated. Infestations with 50 adult A. americanum were conducted on days − 7, − 2, 21, and 28, and tick counts were performed on day − 5 (for blocking), and at 4, 8, 12, 24, 48, and 72 h following treatment and subsequent infestations. Efficacy calculations were based on geometric mean live tick counts. A linear mixed model was used for between-group comparisons. Results On day 0, only lotilaner significantly reduced an A. americanum infestation by 12 h (43.3%; P  = 0.002). Efficacy of lotilaner and afoxolaner at 24 h post-treatment was 95.3% and 97.6%, respectively, both significantly different from sarolaner (74%) ( P  = 0.002, P  < 0.001, respectively). On day 21, at 12 h postinfestation, lotilaner efficacy (59.6%) was significantly different from sarolaner (0.0%) ( P  < 0.001) and afoxolaner (6.3%) ( P  < 0.001). At 24 h, lotilaner efficacy (97.4%) was significantly different ( P  < 0.001) from sarolaner and afoxolaner (13.6% and 14.9%, respectively). On day 28, at 12 h postinfestation, lotilaner efficacy (47.8%) was significantly different from sarolaner (17.1%) ( P  = 0.020) and afoxolaner (9.0%) ( P  = 0.006). At 24 h, lotilaner efficacy (92.3%) was significantly different from sarolaner 4.9% ( P  < 0.001) and afoxolaner (0.0%) ( P  < 0.001). Speed of kill for sarolaner and afoxolaner, but not lotilaner, significantly declined over the study period. Following reinfestation on day 28, neither sarolaner nor afoxolaner reached 90% efficacy by 48 h. By 72 h, sarolaner efficacy was 97.4% and afoxolaner efficacy was 86.3%. Only lotilaner achieved ≥ 90% efficacy by 24 h post-treatment and 24 h postinfestation on days 21 and 28. Time to ≥ 90% efficacy following new infestations consistently occurred 24–48 h earlier for lotilaner compared with sarolaner or afoxolaner. Conclusions Credelio (lotilaner) has a more rapid onset of acaricidal activity against A. americanum than Simparica Trio (sarolaner-moxidectin-pyrantel) and NexGard (afoxolaner). Only lotilaner’s speed of tick kill is sustained throughout the dosing period. Graphical Abstract

To manage tick infestations and reduce tick-borne pathogen transmission risk to dogs, compliant administration of a fast-acting ectoparasiticide is necessary. Isoxazoline-containing ectoparasiticide products provide systemic whole-body coverage; however, differences in tick kill have been observed between products and these differences may be more pronounced when controlling common dose-limiting tick species such as Amblyomma americanum. Dogs were ranked by tick carrying capacity, randomly allocated to one of three treatment groups, and administered Bravecto® Chews (minimum 25 mg/kg fluralaner), Simparica TRIO® (minimum 1.2 mg/kg sarolaner, 24 µg/kg moxidectin, 5 mg/kg pyrantel), or no treatment. Dogs were infested with approximately 50 unfed adult (25 female, 25 male) A. americanum on days -2, 21, 28, and 35. Live tick counts were performed at 8, 12, 24, 48, and 72 h post-treatment (day 0) and post-infestation on days 21, 28, and 35. At each tick count timepoint, product efficacy was determined by comparing geometric mean live tick counts for each product-treated group to the untreated group and a linear mixed model was used for between-group comparisons. Compared with untreated dogs, significant control of existing A. americanum infestations began by 8 h post-treatment (81.6%) and reached 98.0% control by 12-h for Bravecto®-treated dogs. In comparison, significant control for Simparica TRIO®-treated dogs began by 24 h post-treatment (97.7%). When reinfested on day 21, A. americanum infestations were controlled more quickly for Bravecto® compared with Simparica TRIO®-treated dogs at 12 h (efficacy 95.3% versus 25.5%, P < 0.001) and 24 h (efficacy 99.7% versus 70.9%, P < 0.001) post-infestation. Similarly, when reinfested on day 28, faster A. americanum control occurred for Bravecto® compared with Simparica TRIO®-treated dogs at 12 h (efficacy 87.9% versus 18.3%, P < 0.001) and at 24 h (99.2% versus 59.3%, P < 0.001) post-infestation. Finally, when reinfested on day 35, time to [greater than or equal to] 90% efficacy was achieved by 48 h for Bravecto®-treated dogs compared with 72 h post-infestation for Simparica TRIO®-treated dogs. Both products performed within label indications and no treatment-related adverse reactions occurred during the study. Amblyomma americanum infestations are controlled more quickly immediately upon treatment and at 21, 28, and 35 days post-treatment for Bravecto® compared with Simparica TRIO®-treated dogs.

Abstract Canine acaricides with rapid onset and sustained activity can reduce pathogen transmission risk and enhance pet owner experience. This randomized, complete block design, investigator-masked study compared the speed of kill of Amblyomma americanum provided by three monthly-use isoxazoline-containing products. Eight randomized beagles per group were treated (day 0), per label, with sarolaner (combined with moxidectin and pyrantel, Simparica Trio[TM]), afoxolaner (NexGard[TM]), or lotilaner (Credelio[TM]), or remained untreated. Infestations with 50 adult A. americanum were conducted on days - 7, - 2, 21, and 28, and tick counts were performed on day - 5 (for blocking), and at 4, 8, 12, 24, 48, and 72 h following treatment and subsequent infestations. Efficacy calculations were based on geometric mean live tick counts. A linear mixed model was used for between-group comparisons. On day 0, only lotilaner significantly reduced an A. americanum infestation by 12 h (43.3%; P = 0.002). Efficacy of lotilaner and afoxolaner at 24 h post-treatment was 95.3% and 97.6%, respectively, both significantly different from sarolaner (74%) (P = 0.002, P < 0.001, respectively). On day 21, at 12 h postinfestation, lotilaner efficacy (59.6%) was significantly different from sarolaner (0.0%) (P < 0.001) and afoxolaner (6.3%) (P < 0.001). At 24 h, lotilaner efficacy (97.4%) was significantly different (P < 0.001) from sarolaner and afoxolaner (13.6% and 14.9%, respectively). On day 28, at 12 h postinfestation, lotilaner efficacy (47.8%) was significantly different from sarolaner (17.1%) (P = 0.020) and afoxolaner (9.0%) (P = 0.006). At 24 h, lotilaner efficacy (92.3%) was significantly different from sarolaner 4.9% (P < 0.001) and afoxolaner (0.0%) (P < 0.001). Speed of kill for sarolaner and afoxolaner, but not lotilaner, significantly declined over the study period. Following reinfestation on day 28, neither sarolaner nor afoxolaner reached 90% efficacy by 48 h. By 72 h, sarolaner efficacy was 97.4% and afoxolaner efficacy was 86.3%. Only lotilaner achieved [greater than or equal to] 90% efficacy by 24 h post-treatment and 24 h postinfestation on days 21 and 28. Time to [greater than or equal to] 90% efficacy following new infestations consistently occurred 24-48 h earlier for lotilaner compared with sarolaner or afoxolaner. Credelio (lotilaner) has a more rapid onset of acaricidal activity against A. americanum than Simparica Trio (sarolaner-moxidectin-pyrantel) and NexGard (afoxolaner). Only lotilaner's speed of tick kill is sustained throughout the dosing period.

Palaeontologists have long sought to explain the diversification of individual clades to whole biotas at global scales. Advances in our understanding of the spatial distribution of the fossil record through geological time, however, has demonstrated that global trends in biodiversity were a mosaic of regionally heterogeneous diversification processes. Drivers of diversification must presumably have also displayed regional variation to produce the spatial disparities observed in past taxonomic richness. Here, we analyse the fossil record of ammonoids, pelagic shelled cephalopods, through the Late Cretaceous, characterised by some palaeontologists as an interval of biotic decline prior to their total extinction at the Cretaceous-Paleogene boundary. We regionally subdivide this record to eliminate the impacts of spatial sampling biases and infer regional origination and extinction rates corrected for temporal sampling biases using Bayesian methods. We then model these rates using biotic and abiotic drivers commonly inferred to influence diversification. Ammonoid diversification dynamics and responses to this common set of diversity drivers were regionally heterogeneous, do not support ecological decline, and demonstrate that their global diversification signal is influenced by spatial disparities in sampling effort. These results call into question the feasibility of seeking drivers of diversity at global scales in the fossil record. Global trends in biodiversity are subject to regionally heterogeneous diversification processes. Here, the authors examine Late Cretaceous ammonoids, modelling the impact of sampling bias and potential biotic and abiotic drivers on our understanding of their biodiversity trends towards the Cretaceous-Paleogene boundary.

Robust diagnostic tools and surveillance are crucial for malaria control and elimination efforts. Malaria caused by neglected Plasmodium parasites is often underestimated due to the lack of rapid diagnostic tools that can accurately detect these species. While nucleic-acid amplification technologies stand out as the most sensitive methods for detecting and confirming Plasmodium species, their implementation in resource-constrained settings poses significant challenges. Here, we present a Pan Plasmodium recombinase polymerase amplification lateral flow (RPA–LF) assay, capable of detecting all six human infecting Plasmodium species in low resource settings. The Pan Plasmodium RPA-LF assay successfully detected low density clinical infections with a preliminary limit of detection between 10–100 fg/µl for P. falciparum. When combined with crude nucleic acid extraction, the assay can serve as a point-of-need tool for molecular xenomonitoring. This utility was demonstrated by screening laboratory-reared Anopheles stephensi mosquitoes fed with Plasmodium -infected blood, as well as field samples of An. funestus s.l. and An. gambiae s.l. collected from central Africa. Overall, our proof-of-concept Pan Plasmodium diagnostic tool has the potential to be applied for clinical and xenomonitoring field surveillance, and after further evaluation, could become an essential tool to assist malaria control and elimination.

T cell responses are initiated by antigen and promoted by a range of costimulatory signals. Understanding how T cells integrate alternative signal combinations and make decisions affecting immune response strength or tolerance poses a considerable theoretical challenge. Here, we report that T cell receptor (TCR) and costimulatory signals imprint an early, cell-intrinsic, division fate, whereby cells effectively count through generations before returning automatically to a quiescent state. This autonomous program can be extended by cytokines. Signals from the TCR, costimulatory receptors, and cytokines add together using a linear division calculus, allowing the strength of a T cell response to be predicted from the sum of the underlying signal components. These data resolve a long-standing costimulation paradox and provide a quantitative paradigm for therapeutically manipulating immune response strength.

Immune dysregulation is characteristic of the more severe stages of SARS-CoV-2 infection. Understanding the mechanisms by which the immune system contributes to COVID-19 severity may open new avenues to treatment. Here, we report that elevated IL-13 was associated with the need for mechanical ventilation in 2 independent patient cohorts. In addition, patients who acquired COVID-19 while prescribed Dupilumab, a mAb that blocks IL-13 and IL-4 signaling, had less severe disease. In SARS-CoV-2-infected mice, IL-13 neutralization reduced death and disease severity without affecting viral load, demonstrating an immunopathogenic role for this cytokine. Following anti-IL-13 treatment in infected mice, hyaluronan synthase 1 (Has1) was the most downregulated gene, and accumulation of the hyaluronan (HA) polysaccharide was decreased in the lung. In patients with COVID-19, HA was increased in the lungs and plasma. Blockade of the HA receptor, CD44, reduced mortality in infected mice, supporting the importance of HA as a pathogenic mediator. Finally, HA was directly induced in the lungs of mice by administration of IL-13, indicating a new role for IL-13 in lung disease. Understanding the role of IL-13 and HA has important implications for therapy of COVID-19 and, potentially, other pulmonary diseases. IL-13 levels were elevated in patients with severe COVID-19. In a mouse model of the disease, IL-13 neutralization reduced the disease and decreased lung HA deposition. Administration of IL-13-induced HA in the lung. Blockade of the HA receptor CD44 prevented mortality, highlighting a potentially novel mechanism for IL-13-mediated HA synthesis in pulmonary pathology.

1. Fundamental ecological research is both intrinsically interesting and provides the basic knowledge required to answer applied questions of importance to the management of the natural world. The 100th anniversary of the British Ecological Society in 2013 is an opportune moment to reflect on the current status of ecology as a science and look forward to high-light priorities for future work. 2. To do this, we identified 100 important questions of fundamental importance in pure ecology. We elicited questions from ecologists working across a wide range of systems and disciplines. The 754 questions submitted (listed in the online appendix) from 388 participants were narrowed down to the final 100 through a process of discussion, rewording and repeated rounds of voting. This was done during a two-day workshop and thereafter. 3. The questions reflect many of the important current conceptual and technical pre-occupations of ecology. For example, many questions concerned the dynamics of environmental change and complex ecosystem interactions, as well as the interaction between ecology and evolution. 4. The questions reveal a dynamic science with novel subfields emerging. For example, a group of questions was dedicated to disease and micro-organisms and another on human impacts and global change reflecting the emergence of new subdisciplines that would not have been foreseen a few decades ago. 5. The list also contained a number of questions that have perplexed ecologists for decades and are still seen as crucial to answer, such as the link between population dynamics and life-history evolution. 6. Synthesis. These 100 questions identified reflect the state of ecology today. Using them as an agenda for further research would lead to a substantial enhancement in understanding of the discipline, with practical relevance for the conservation of biodiversity and ecosystem function.

Predominantly antibody deficiencies (PADs) are the most common type of primary immunodeficiency in adults. PADs frequently pass undetected leading to delayed diagnosis, delayed treatment, and the potential for end-organ damage including bronchiectasis. In addition, PADs are frequently accompanied by comorbid autoimmune disease, and an increased risk of malignancy. To characterize the diagnostic and clinical features of adult PAD patients in Victoria, Australia. We identified adult patients receiving, or having previously received immunoglobulin replacement therapy for a PAD at four hospitals in metropolitan Melbourne, and retrospectively characterized their clinical and diagnostic features. 179 patients from The Royal Melbourne, Alfred and Austin Hospitals, and Monash Medical Centre were included in the study with a median age of 49.7 years (range: 16-87 years), of whom 98 (54.7%) were female. The majority of patients (116; 64.8%) met diagnostic criteria for common variable immunodeficiency (CVID), and 21 (11.7%) were diagnosed with X-linked agammaglobulinemia (XLA). Unclassified hypogammaglobulinemia (HGG) was described in 22 patients (12.3%), IgG subclass deficiency (IGSCD) in 12 (6.7%), and specific antibody deficiency (SpAD) in 4 individuals (2.2%). The remaining four patients had a diagnosis of Good syndrome (thymoma with immunodeficiency). There was no significant difference between the age at diagnosis of the disorders, with the exception of XLA, with a median age at diagnosis of less than 1 year. The median age of reported symptom onset was 20 years for those with a diagnosis of CVID, with a median age at diagnosis of 35 years. CVID patients experienced significantly more non-infectious complications, such as autoimmune cytopenias and lymphoproliferative disease, than the other antibody deficiency disorders. The presence of non-infectious complications was associated with significantly reduced survival in the cohort. Our data are largely consistent with the experience of other centers internationally, with clear areas for improvement, including reducing diagnostic delay for patients with PADs. It is likely that these challenges will be in part overcome by continued advances in implementation of genomic sequencing for diagnosis of PADs, and with that opportunities for targeted treatment of non-infectious complications.