Nontuberculous Mycobacterium infections, particularly Mycobacterium abscessus, are increasingly common among patients with cystic fibrosis and chronic bronchiectatic lung diseases. Treatment is ...challenging due to intrinsic antibiotic resistance. Bacteriophage therapy represents a potentially novel approach. Relatively few active lytic phages are available and there is great variation in phage susceptibilities among M. abscessus isolates, requiring personalized phage identification.
Mycobacterium isolates from 200 culture-positive patients with symptomatic disease were screened for phage susceptibilities. One or more lytic phages were identified for 55 isolates. Phages were administered intravenously, by aerosolization, or both to 20 patients on a compassionate use basis and patients were monitored for adverse reactions, clinical and microbiologic responses, the emergence of phage resistance, and phage neutralization in serum, sputum, or bronchoalveolar lavage fluid.
No adverse reactions attributed to therapy were seen in any patient regardless of the pathogen, phages administered, or the route of delivery. Favorable clinical or microbiological responses were observed in 11 patients. Neutralizing antibodies were identified in serum after initiation of phage delivery intravenously in 8 patients, potentially contributing to lack of treatment response in 4 cases, but were not consistently associated with unfavorable responses in others. Eleven patients were treated with only a single phage, and no phage resistance was observed in any of these.
Phage treatment of Mycobacterium infections is challenging due to the limited repertoire of therapeutically useful phages, but favorable clinical outcomes in patients lacking any other treatment options support continued development of adjunctive phage therapy for some mycobacterial infections.
Abstract
The Human Phenotype Ontology (HPO)—a standardized vocabulary of phenotypic abnormalities associated with 7000+ diseases—is used by thousands of researchers, clinicians, informaticians and ...electronic health record systems around the world. Its detailed descriptions of clinical abnormalities and computable disease definitions have made HPO the de facto standard for deep phenotyping in the field of rare disease. The HPO’s interoperability with other ontologies has enabled it to be used to improve diagnostic accuracy by incorporating model organism data. It also plays a key role in the popular Exomiser tool, which identifies potential disease-causing variants from whole-exome or whole-genome sequencing data. Since the HPO was first introduced in 2008, its users have become both more numerous and more diverse. To meet these emerging needs, the project has added new content, language translations, mappings and computational tooling, as well as integrations with external community data. The HPO continues to collaborate with clinical adopters to improve specific areas of the ontology and extend standardized disease descriptions. The newly redesigned HPO website (www.human-phenotype-ontology.org) simplifies browsing terms and exploring clinical features, diseases, and human genes.
In 2011, a European Respiratory Society Task Force embarked on a process to determine the position and clinical relevance of the cough hypersensitivity syndrome, a disorder characterised by ...troublesome coughing often triggered by low levels of thermal, mechanical or chemical exposure, in the management of patients with chronic cough. A 21-component questionnaire was developed by an iterative process supported by a literature review. 44 key opinion leaders in respiratory medicine were selected and interviewed as to their opinions. There was a high degree of unanimity in the responses obtained, with all opinion leaders supporting the concept of cough hypersensitivity as a clinically useful paradigm. The classic stratification of cough into asthmatic, rhinitic and reflux-related phenotypes was supported. Significant disparity of opinion was seen in the response to two questions concerning the therapy of chronic cough. First, the role of acid suppression in reflux cough was questioned. Secondly, the opinion leaders were split as to whether a trial of oral steroids was indicated to establish a diagnosis of eosinophilic cough. The cough hypersensitivity syndrome was clearly endorsed by the opinion leaders as a valid and useful concept. They considered that support of patients with chronic cough was inadequate and the Task Force recommends that further work is urgently required in this neglected area.
Seasonally dry tropical forests (SDTF) are located in regions with alternating wet and dry seasons, with dry seasons that last several months or more. By the end of the 21st century, climate models ...predict substantial changes in rainfall regimes across these regions, but little is known about how individuals, species, and communities in SDTF will cope with the hotter, drier conditions predicted by climate models. In this review, we explore different rainfall scenarios that may result in ecological drought in SDTF through the lens of two alternative hypotheses: 1) these forests will be sensitive to drought because they are already limited by water and close to climatic thresholds, or 2) they will be resistant/resilient to intra- and inter-annual changes in rainfall because they are adapted to predictable, seasonal drought. In our review of literature that spans microbial to ecosystem processes, a majority of the available studies suggests that increasing frequency and intensity of droughts in SDTF will likely alter species distributions and ecosystem processes. Though we conclude that SDTF will be sensitive to altered rainfall regimes, many gaps in the literature remain. Future research should focus on geographically comparative studies and well-replicated drought experiments that can provide empirical evidence to improve simulation models used to forecast SDTF responses to future climate change at coarser spatial and temporal scales.
Background Sensory nerves innervating the airways play an important role in regulating various cardiopulmonary functions, maintaining homeostasis under healthy conditions and contributing to ...pathophysiology in disease states. Hypo-osmotic solutions elicit sensory reflexes, including cough, and are a potent stimulus for airway narrowing in asthmatic patients, but the mechanisms involved are not known. Transient receptor potential cation channel, subfamily V, member 4 (TRPV4) is widely expressed in the respiratory tract, but its role as a peripheral nociceptor has not been explored. Objective We hypothesized that TRPV4 is expressed on airway afferents and is a key osmosensor initiating reflex events in the lung. Methods We used guinea pig primary cells, tissue bioassay, in vivo electrophysiology, and a guinea pig conscious cough model to investigate a role for TRPV4 in mediating sensory nerve activation in vagal afferents and the possible downstream signaling mechanisms. Human vagus nerve was used to confirm key observations in animal tissues. Results Here we show TRPV4-induced activation of guinea pig airway–specific primary nodose ganglion cells. TRPV4 ligands and hypo-osmotic solutions caused depolarization of murine, guinea pig, and human vagus and firing of Aδ-fibers (not C-fibers), which was inhibited by TRPV4 and P2X3 receptor antagonists. Both antagonists blocked TRPV4-induced cough. Conclusion This study identifies the TRPV4-ATP-P2X3 interaction as a key osmosensing pathway involved in airway sensory nerve reflexes. The absence of TRPV4-ATP–mediated effects on C-fibers indicates a distinct neurobiology for this ion channel and implicates TRPV4 as a novel therapeutic target for neuronal hyperresponsiveness in the airways and symptoms, such as cough.
Intermittent breeding, in which an adult skips a breeding opportunity, can represent a non-adaptive constraint or an adaptive response to the tradeoff between current and future reproduction. In ...group-living animals, the social group may also affect the frequency of reproduction, but this possibility has received little attention. Here we use an 11-year data set to investigate intermittent breeding in the greater ani (Crotophaga major), a tropical bird that nests in stable breeding groups containing several unrelated co-breeding females. Population-wide, an average of 62% of females laid eggs in a given year (range 35–84%), and the average female failed to lay eggs once every 3.2 years. We found little support for the hypothesis that intermittent breeding reflects a tradeoff between current and future reproduction: breeding in year t did not affect a female’s likelihood of breeding in year t + 1, and clutch size in year t did not affect clutch size in year t + 1. Increases in clutch size were associated with decreases in egg mass for eggs laid at the end of that clutch, but this did not affect subsequent nesting attempts. However, reproductive skipping was associated with changes in group membership. Females whose groups changed in composition after year t were significantly less likely to breed in year t + 1 than females whose groups remained stable. These results indicate that breeding group stability influences the frequency of reproduction, suggesting that transitions between groups may be costly to females and their mates.
Preclinical studies of viral vector–based HIV-1 vaccine candidates have previously shown partial protection against neutralization-resistant virus challenges in rhesus monkeys. In this study, we ...evaluated the protective efficacy of adenovirus serotype 26 (Ad26) vector priming followed by purified envelope (Env) glycoprotein boosting. Rhesus monkeys primed with Ad26 vectors expressing SIVsmE543 Env, Gag, and Pol and boosted with AS01B-adjuvanted SIVmac32H Env gp140 demonstrated complete protection in 50% of vaccinated animals against a series of repeated, heterologous, intrarectal SIVmac251 challenges that infected all controls. Protective efficacy correlated with the functionality of Env-specific antibody responses. Comparable protection was also observed with a similar Ad/Env vaccine against repeated, heterologous, intrarectal SHIV-SF162P3 challenges. These data demonstrate robust protection by Ad/Env vaccines against acquisition of neutralization-resistant virus challenges in rhesus monkeys.
Liquid biopsy (LB) is a non-invasive approach representing a promising tool for new precision medicine strategies for cancer treatment. However, a comprehensive analysis of its reliability for ...pancreatic cancer (PC) is lacking. To this aim, we performed the first meta-analysis on this topic. We calculated the pooled sensitivity, specificity, positive (LR+) and negative (LR-) likelihood ratio, and diagnostic odds ratio (DOR). A summary receiver operating characteristic curve (SROC) and area under curve (AUC) were used to evaluate the overall accuracy. We finally assessed the concordance rate of all mutations detected by multi-genes panels. Fourteen eligible studies involving 369 patients were included. The overall pooled sensitivity and specificity were 0.70 and 0.86, respectively. The LR+ was 3.85, the LR- was 0.34 and DOR was 15.84. The SROC curve with an AUC of 0.88 indicated a relatively high accuracy of LB for molecular characterization of PC. The concordance rate of all mutations detected by multi-genes panels was 31.9%. LB can serve as surrogate for tissue in the molecular profiling of PC, because of its relatively high sensitivity, specificity and accuracy. It represents a unique opportunity to be further explored towards its introduction in clinical practice and for developing new precision medicine approaches against PC.
Cooperative groups are ubiquitous in animals, as are the challenges of allocating labor to accomplish cooperative tasks, including territory defense, hunting, and brood care. Individual contributions ...can differ in two ways, both of which can influence fitness: group members can vary in overall helpfulness (workload) or they can specialize on different tasks (division of labor). In this review, we encourage additional, simultaneous study of both workload distribution and division of labor. Historically, workload distribution has been studied in the contexts of collective action and cooperative offspring care. Both areas of research aim to understand how shared benefits can emerge from individual contributions, but they remain poorly integrated. We argue that each of these literatures has strengths that could benefit the other, and we highlight potential areas of crosstalk. Next, we review the literature on division of labor in taxa other than the eusocial insects, discuss parallels and differences in division of labor between eusocial insects and other animals, and encourage more work on cooperative, noninsect taxa. Rigorous work on individual contributions to cooperative tasks will expand our understanding of the causes and consequences of individual variation and the evolutionary stability of social living.
Several hypotheses propose that parent birds might synchronize their visits to the nest, but field studies have historically overlooked the temporal pattern of parental care. Either synchrony or ...asynchrony could provide adaptive benefits; alternatively, any observed synchrony could simply be a byproduct of other coordinated behavior among caregivers. Few studies have quantified visit synchrony in cooperatively breeding birds with multiple caregivers. We tested whether visits to the nest are more or less synchronized than expected by chance in the communally nesting greater ani (
Crotophaga major
), a tropical bird that breeds in groups of four to eight adult caregivers. Across 27 breeding groups, anis did not consistently synchronize nest visits more than expected by chance; however, six groups (22%) did exhibit significant synchrony (up to 44% of visits). Nest visit synchrony was not associated with fledging success or brood size, as would be predicted by two common adaptive hypotheses, and instead might be a byproduct of synchronized foraging.
Significance statement
Various hypotheses may explain why birds either synchronize or evenly space their visits to the nest. Such coordination could increase fitness; however, its prevalence and consequences remain poorly understood, particularly in cooperative breeders. We tested whether nest visits were more or less synchronized than expected by chance in a communally nesting bird, the greater ani, which forms breeding groups of four to eight adults. While some breeding groups synchronized nest visits more than expected, most did not. Further, groups with more synchronized visits did not have increased fledging success, suggesting that the synchrony we observed might not provide a fitness benefit but rather could be a byproduct of adult social behavior away from the nest.
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