Plasma exchange for the management of digoxin toxicity in an individual with an acute kidney injury: A case report.

Digoxin toxicity can be life-threatening. Digoxin-specific antibody (DSA) fragments are used in severe digoxin toxicity, binding to serum-free digoxin and enabling increased renal excretion. In severe renal impairment, clearance of these complexes is prolonged, leading to rebound toxicity. Digoxin and DSA complexes are not dialysable. We present a case of a gentleman with severe digoxin toxicity and acute kidney injury (AKI). Despite receiving DSA doses, his digoxin levels rebounded and symptoms persisted. Based on published case reports, plasma exchange (PEX) after further dosing was arranged. PEX facilitated the removal of digoxin-DSA complexes, bypassing renal excretion. During PEX, clinical signs improved and were sustained. He did not require further dialysis or PEX, renal function recovered and he was discharged. This case highlights challenges in the management of severe digoxin toxicity in patients with a concurrent AKI. The use of PEX enabled digoxin-DSA complex removal and should be considered in these circumstances.

Cyber-WISE: A Cyber-Physical Deep Wireless Indoor Positioning System and Digital Twin Approach.

In recent decades, there have been significant research efforts focusing on wireless indoor localization systems, with fingerprinting techniques based on received signal strength leading the way. The majority of the suggested approaches require challenging and laborious Wi-Fi site surveys to construct a radio map, which is then utilized to match radio signatures with particular locations. In this paper, a novel next-generation cyber-physical wireless indoor positioning system is presented that addresses the challenges of fingerprinting techniques associated with data collection. The proposed approach not only facilitates an interactive digital representation that fosters informed decision-making through a digital twin interface but also ensures adaptability to new scenarios, scalability, and suitability for large environments and evolving conditions during the process of constructing the radio map. Additionally, it reduces the labor cost and laborious data collection process while helping to increase the efficiency of fingerprint-based positioning methods through accurate ground-truth data collection. This is also convenient for working in remote environments to improve human safety in locations where human access is limited or hazardous and to address issues related to radio map obsolescence. The feasibility of the cyber-physical system design is successfully verified and evaluated with real-world experiments in which a ground robot is utilized to obtain a radio map autonomously in real-time in a challenging environment through an informed decision process. With the proposed setup, the results demonstrate the success of RSSI-based indoor positioning using deep learning models, including MLP, LSTM Model 1, and LSTM Model 2, achieving an average localization error of ≤2.16 m in individual areas. Specifically, LSTM Model 2 achieves an average localization error as low as 1.55 m and 1.97 m with 83.33% and 81.05% of the errors within 2 m for individual and combined areas, respectively. These outcomes demonstrate that the proposed cyber-physical wireless indoor positioning approach, which is based on the application of dynamic Wi-Fi RSS surveying through human feedback using autonomous mobile robots, effectively leverages the precision of deep learning models, resulting in localization performance comparable to the literature. Furthermore, they highlight its potential for suitability for deployment in real-world scenarios and practical applicability.

Characterisation of the immune repertoire of a humanised transgenic mouse through immunophenotyping and high-throughput sequencing.

Immunoglobulin loci-transgenic animals are widely used in antibody discovery and increasingly in vaccine response modelling. In this study, we phenotypically characterised B-cell populations from the Intelliselect Transgenic mouse (Kymouse) demonstrating full B-cell development competence. Comparison of the naïve B-cell receptor (BCR) repertoires of Kymice BCRs, naïve human, and murine BCR repertoires revealed key differences in germline gene usage and junctional diversification. These differences result in Kymice having CDRH3 length and diversity intermediate between mice and humans. To compare the structural space explored by CDRH3s in each species' repertoire, we used computational structure prediction to show that Kymouse naïve BCR repertoires are more human-like than mouse-like in their predicted distribution of CDRH3 shape. Our combined sequence and structural analysis indicates that the naïve Kymouse BCR repertoire is diverse with key similarities to human repertoires, while immunophenotyping confirms that selected naïve B cells are able to go through complete development.

A computational method for immune repertoire mining that identifies novel binders from different clonotypes, demonstrated by identifying anti-pertussis toxoid antibodies.

Due to their shared genetic history, antibodies from the same clonotype often bind to the same epitope. This knowledge is used in immune repertoire mining, where known binders are used to search bulk sequencing repertoires to identify new binders. However, current computational methods cannot identify epitope convergence between antibodies from different clonotypes, limiting the sequence diversity of antigen-specific antibodies that can be identified. We describe how the antibody binding site, the paratope, can be used to cluster antibodies with common antigen reactivity from different clonotypes. Our method, paratyping, uses the predicted paratope to identify these novel cross clonotype matches. We experimentally validated our predictions on a pertussis toxoid dataset. Our results show that even the simplest abstraction of the antibody binding site, using only the length of the loops involved and predicted binding residues, is sufficient to group antigen-specific antibodies and provide additional information to conventional clonotype analysis. Abbreviations: BCR: B-cell receptor; CDR: complementarity-determining region; PTx: pertussis toxoid.

Localisation of Unmanned Underwater Vehicles (UUVs) in Complex and Confined Environments: A Review.

The inspection of aquatic environments is a challenging activity, which is made more difficult if the environment is complex or confined, such as those that are found in nuclear storage facilities and accident sites, marinas and boatyards, liquid storage tanks, or flooded tunnels and sewers. Human inspections of these environments are often dangerous or infeasible, so remote inspection using unmanned underwater vehicles (UUVs) is used. Due to access restrictions and environmental limitations, such as low illumination levels, turbidity, and a lack of salient features, traditional localisation systems that have been developed for use in large bodies of water cannot be used. This means that UUV capabilities are severely restricted to manually controlled low-quality visual inspections, generating non-geospatially located data. The localisation of UUVs in these environments would enable the autonomous behaviour and the development of accurate maps. This article presents a review of the state-of-the-art in localisation technologies for these environments and identifies areas of future research to overcome the challenges posed.

Increased winter drownings in ice-covered regions with warmer winters.

Winter activities on ice are culturally important for many countries, yet they constitute a high safety risk depending upon the stability of the ice. Because consistently cold periods are required to form stable and thick ice, warmer winters could degrade ice conditions and increase the likelihood of falling through the ice. This study provides the first large-scale assessment of winter drowning from 10 Northern Hemisphere countries. We documented over 4000 winter drowning events. Winter drownings increased exponentially in regions with warmer winters when air temperatures neared 0°C. The largest number of drownings occurred when winter air temperatures were between -5°C and 0°C, when ice is less stable, and also in regions where indigenous traditions and livelihood require extended time on ice. Rates of drowning were greatest late in the winter season when ice stability declines. Children and adults up to the age of 39 were at the highest risk of winter drownings. Beyond temperature, differences in cultures, regulations, and human behaviours can be important additional risk factors. Our findings indicate the potential for increased human mortality with warmer winter air temperatures. Incorporating drowning prevention plans would improve adaptation strategies to a changing climate.

Detection of Simulated Fukushima Daichii Fuel Debris Using a Remotely Operated Vehicle at the Naraha Test Facility.

The use of robotics in harsh environments, such as nuclear decommissioning, has increased in recent years. Environments such as the Fukushima Daiichi accident site from 2011 and the Sellafield legacy ponds highlight the need for robotic systems capable of deployment in hazardous environments unsafe for human workers. To characterise these environments, it is important to develop robust and accurate localization systems that can be combined with mapping techniques to create 3D reconstructions of the unknown environment. This paper describes the development and experimental verification of a localization system for an underwater robot, which enabled the collection of sonar data to create 3D images of submerged simulated fuel debris. The system was demonstrated at the Naraha test facility, Fukushima prefecture, Japan. Using a camera with a bird's-eye view of the simulated primary containment vessel, the 3D position and attitude of the robot was obtained using coloured LED markers (active markers) on the robot, landmarks on the test-rig (passive markers), and a depth sensor on the robot. The successful reconstruction of a 3D image has been created through use of a robot operating system (ROS) node in real-time.

Nosocomial transmission of influenza: A retrospective cross-sectional study using next generation sequencing at a hospital in England (2012-2014).

BACKGROUND: The extent of transmission of influenza in hospital settings is poorly understood. Next generation sequencing may improve this by providing information on the genetic relatedness of viral strains. OBJECTIVES: We aimed to apply next generation sequencing to describe transmission in hospital and compare with methods based on routinely-collected data. METHODS: All influenza samples taken through routine care from patients at University College London Hospitals NHS Foundation Trust (September 2012 to March 2014) were included. We conducted Illumina sequencing and identified genetic clusters. We compared nosocomial transmission estimates defined using classical methods (based on time from admission to sample) and genetic clustering. We identified pairs of cases with space-time links and assessed genetic relatedness. RESULTS: We sequenced influenza sampled from 214 patients. There were 180 unique genetic strains, 16 (8.8%) of which seeded a new transmission chain. Nosocomial transmission was indicated for 32 (15.0%) cases using the classical definition and 34 (15.8%) based on genetic clustering. Of the 50 patients in a genetic cluster, 11 (22.0%) had known space-time links with other cases in the same cluster. Genetic distances between pairs of cases with space-time links were lower than for pairs without spatial links (P < .001). CONCLUSIONS: Genetic data confirmed that nosocomial transmission contributes significantly to the hospital burden of influenza and elucidated transmission chains. Prospective next generation sequencing could support outbreak investigations and monitor the impact of infection and control measures.

Fire-mediated habitat change regulates woodland bird species and functional group occurrence.

In an era characterized by recurrent large wildfires in many parts of the globe, there is a critical need to understand how animal species respond to fires, the rates at which populations can recover, and the functional changes fires may cause. Using quantified changes in habitat parameters over a ~400-yr post-fire chronosequence in an obligate-seeding Australian eucalypt woodland, we build and test predictions of how birds, as individual species and aggregated into functional groups according to their use of specific habitat resources, respond to time since fire. Individual bird species exhibited four generalized response types to time since fire: incline, decline, delayed, and bell. All significant relationships between bird functional group richness or abundance and time since fire were consistent with predictions based on known time-since-fire-associated changes in habitat features putatively important for these bird groups. Consequently, we argue that the bird community is responding to post-fire successional changes in habitat as per the habitat accommodation model, rather than to time since fire per se, and that our functional framework will be of value in predicting bird responses to future disturbances in this and other obligate-seeder forest and woodland ecosystems. Most bird species and functional groups that were affected by time since fire were associated with long-unburned woodlands. In the context of recent large, stand-replacement wildfires that have affected a substantial proportion of obligate-seeder eucalypt woodlands, and the multi-century timescales over which post-fire succession occurs, it would appear preferable from a bird conservation perspective if fires initiating loss of currently long-unburned woodlands were minimized. Once long-unburned woodlands are transformed by fire into recently burned woodlands, there is limited scope for alternative management interventions to accelerate the rate of habitat development after fire, or supplement the resources formerly provided to birds by long-unburned woodlands, with the limited exception of augmenting hollow availability for key hollow-nesting species.

Modeling variability in the fire response of an endangered bird to improve fire-management.

Conservation managers regularly burn vegetation to regenerate habitat for fire-dependent species. When determining the time since fire at which to burn, managers model change in a species' occurrence over time, post-fire (fire-response curve) and identify the time since fire associated with decline in occurrence. However, where species exhibit variability in their fire response across space, using a single fire-response curve to determine the timing of burns may lead to burning habitat at an inappropriate time since fire. We tested if elevation, local topography, soil properties, vegetation type or evapotranspiration affect the fire response of the endangered Mallee Emu-wren Stipiturus mallee and its hummock-grass habitat Triodia scariosa in southeastern Australia (n = 217). Previous work on the Mallee Emu-wren found a unimodal fire response with decline in occurrence at ~30-50 yr since fire and a time window of occurrence of ~30 yr. We found that time since fire and elevation interact to affect the Mallee Emu-wren fire response. At high elevations (55-98 m), Mallee Emu-wrens declined in occurrence at ~50 yr since fire, with a time window of occurrence of 20-40 yr. However, at low elevations (28-55 m), Mallee Emu-wrens showed no decline in occurrence with increasing time since fire with a time window of occurrence of up to 107 yr. Extent cover of Tall T. scariosa showed similar patterns to the Mallee Emu-wren, indicating that vegetation structure is a likely driver of variability in the Mallee Emu-wren fire response. We speculate that the effect of low elevation is mediated by increased soil nutrient and water availability for key plants. We used our findings to map the appropriate time since fire at which to burn to regenerate habitat for the Mallee Emu-wren across the study region. We recommend no burning for regeneration across one-third of potential habitat, because the Mallee Emu-wren showed no decline in occurrence in these areas. We recommend managers model variability in species' fire responses across space to improve the timing of burns for regeneration.

Cassowary casques act as thermal windows.

Many ideas have been put forward for the adaptive value of the cassowary casque; and yet, its purpose remains speculative. Homeothermic animals elevate body temperature through metabolic heat production. Heat gain must be offset by heat loss to maintain internal temperatures within a range for optimal performance. Living in a tropical climate, cassowaries, being large bodied, dark feathered birds, are under thermal pressure to offload heat. We tested the original hypothesis that the casque acts as a thermal window. With infrared thermographic analyses of living cassowaries over an expansive range of ambient temperatures, we provide evidence that the casque acts as a thermal radiator, offloading heat at high temperatures and restricting heat loss at low temperatures. Interestingly, at intermediate temperatures, the casque appears thermally heterogeneous, with the posterior of the casque heating up before the front half. These findings might have implications for the function of similar structures in avian and non-avian dinosaurs.

Analysis of unstable degradation impurities of a benzodiazepine and their quantification without isolation using multiple linear regression.

This manuscript presents a novel methodology for calculating the relative response factors (RRFs) of unstable degradation impurities of molibresib (1). The degradation impurities were observed by HPLC during stress testing and were accompanied by large mass balance deficits. However, the impurities could not be isolated for traditional RRF determination due to their instability. The RRFs of two degradation impurities were determined without isolation by multiple linear regression analysis of HPLC-UV data. The results permitted accurate quantification of the degradants. The benefits and drawbacks of the approach are discussed, including suggested validation acceptance criteria.

Animal movements in fire-prone landscapes.

Movement is a trait of fundamental importance in ecosystems subject to frequent disturbances, such as fire-prone ecosystems. Despite this, the role of movement in facilitating responses to fire has received little attention. Herein, we consider how animal movement interacts with fire history to shape species distributions. We consider how fire affects movement between habitat patches of differing fire histories that occur across a range of spatial and temporal scales, from daily foraging bouts to infrequent dispersal events, and annual migrations. We review animal movements in response to the immediate and abrupt impacts of fire, and the longer-term successional changes that fires set in train. We discuss how the novel threats of altered fire regimes, landscape fragmentation, and invasive species result in suboptimal movements that drive populations downwards. We then outline the types of data needed to study animal movements in relation to fire and novel threats, to hasten the integration of movement ecology and fire ecology. We conclude by outlining a research agenda for the integration of movement ecology and fire ecology by identifying key research questions that emerge from our synthesis of animal movements in fire-prone ecosystems.

Synchronized mechanical oscillations at the cell-matrix interface in the formation of tensile tissue.

The formation of uniaxial fibrous tissues with defined viscoelastic properties implies the existence of an orchestrated mechanical interaction between the cytoskeleton and the extracellular matrix. This study addresses the nature of this interaction. The hypothesis is that this mechanical interplay underpins the mechanical development of the tissue. In embryonic tendon tissue, an early event in the development of a mechanically robust tissue is the interaction of the pointed tips of extracellular collagen fibrils with the fibroblast plasma membrane to form stable interface structures (fibripositors). Here, we used a fibroblast-generated tissue that is structurally and mechanically matched to embryonic tendon to demonstrate homeostasis of cell-derived and external strain-derived tension over repeated cycles of strain and relaxation. A cell-derived oscillatory tension component is evident in this matrix construct. This oscillatory tension involves synchronization of individual cell forces across the construct and is induced in each strain cycle by transient relaxation and transient tensioning of the tissue. The cell-derived tension along with the oscillatory component is absent in the presence of blebbistatin, which disrupts actinomyosin force generation of the cell. The time period of this oscillation (60-90 s) is well-defined in each tissue sample and matches a primary viscoelastic relaxation time. We hypothesize that this mechanical oscillation of fibroblasts with plasma membrane anchored collagen fibrils is a key factor in mechanical sensing and feedback regulation in the formation of tensile tissues.

Genome-Wide Sequence Analysis of Kaposi Sarcoma-Associated Herpesvirus Shows Diversification Driven by Recombination.

Background: Kaposi sarcoma-associated herpesvirus (KSHV) establishes lifelong infection in the human host and has been associated with a variety of malignancies. KSHV displays striking geographic variation in prevalence, which is highest in sub-Saharan Africa. The current KSHV genome sequences available are all tumor cell line-derived or primary tumor-associated viruses, which have provided valuable insights into KSHV genetic diversity. Methods: Here, we sequenced 45 KSHV genomes from a Ugandan population cohort in which KSHV is endemic; these are the only genome sequences obtained from nondiseased individuals and of KSHV DNA isolated from saliva. Results: Population structure analysis, along with the 25 published genome sequences from other parts of the world, showed whole-genome variation, separating sequences and variation within the central genome contributing to clustering of genomes by geography. We reveal new evidence for the presence of intragenic recombination and multiple recombination events contributing to the divergence of genomes into at least 5 distinct types. Discussion: This study shows that large-scale genome-wide sequencing from clinical and epidemiological samples is necessary to capture the full extent of genetic diversity of KSHV, including recombination, and provides evidence to suggest a revision of KSHV genotype nomenclature.

Outpatient Treatment of Uncomplicated Urinary Tract Infections in the Emergency Department.

One of the most commonly treated infections in the emergency department (ED) is an uncomplicated urinary tract infection. Multiple classes of antibiotics are frequently used to treat this condition, but not all have equivalent efficacy, and many may confer risks to not only the patient but society as a whole if used on a large scale. These antibiotic selections should also be guided by local antimicrobial susceptibility patterns, and general multidisciplinary recommendations for therapy should be developed on a local scale to assist prescribing patterns. The proactive development of a routine approach to reviewing and addressing positive cultures following discharge from the ED should also be developed and implemented in order to ensure that optimal patient care is provided. The objective of this review is to assess the available literature to isolate which antibiotics and approaches to care are the most appropriate options for treating uncomplicated outpatient urinary tract infections in the ED.

Does foliage metal accumulation influence plant-insect interactions? A field study of two sympatric tree metallophytes.

Gossia (Myrtaceae) is a highly restricted tree genus most speciose in New Caledonia and eastern Australia. The latter group accumulates above-normal foliar manganese (Mn) concentrations, with some individuals exhibiting the rare Mn-hyperaccumulative trait. Whether foliar metals contribute to chemical defence has been addressed via numerous feeding experiments and very few field studies. This investigation exploited specifically different insect activities on the foliage of sympatric Gossia grayi (N.Snow & Guymer) and Gossia shepherdii (F.Muell.) N.Snow & Guymer, endemic to north-eastern Australia, to test for direct and indirect effects of foliar Mn enrichment on plant-insect interactions. Leaf organic and inorganic chemistries, specific weight, surface damage, gall infestation and occupancy were quantified. Discovery that both species are Mn hyperaccumulators augments the world listing by 5-7%. Highly elevated gall-Mn concentrations coupled with negligible gall parasitisation suggested chemical fortification and adaptation by the host insect - a Cecidomyiidae fly. Linear mixed modelling (LMM) showed differences in leaf Mn, phenolics, toughness and surface damage across tree species and leaf age. There was no direct relationship between leaf Mn and insect impact. However, LMM did resolve indirect effects, i.e. between insect impact and certain foliar elements, consistent with nutritional dynamics in a physiologically novel plant system where Mn is vastly overaccumulated.

Genome-wide evolutionary dynamics of influenza B viruses on a global scale.

The global-scale epidemiology and genome-wide evolutionary dynamics of influenza B remain poorly understood compared with influenza A viruses. We compiled a spatio-temporally comprehensive dataset of influenza B viruses, comprising over 2,500 genomes sampled worldwide between 1987 and 2015, including 382 newly-sequenced genomes that fill substantial gaps in previous molecular surveillance studies. Our contributed data increase the number of available influenza B virus genomes in Europe, Africa and Central Asia, improving the global context to study influenza B viruses. We reveal Yamagata-lineage diversity results from co-circulation of two antigenically-distinct groups that also segregate genetically across the entire genome, without evidence of intra-lineage reassortment. In contrast, Victoria-lineage diversity stems from geographic segregation of different genetic clades, with variability in the degree of geographic spread among clades. Differences between the lineages are reflected in their antigenic dynamics, as Yamagata-lineage viruses show alternating dominance between antigenic groups, while Victoria-lineage viruses show antigenic drift of a single lineage. Structural mapping of amino acid substitutions on trunk branches of influenza B gene phylogenies further supports these antigenic differences and highlights two potential mechanisms of adaptation for polymerase activity. Our study provides new insights into the epidemiological and molecular processes shaping influenza B virus evolution globally.

Correction to "Discovery of Fevipiprant (NVP-QAW039), a Potent and Selective DP2 Receptor Antagonist for Treatment of Asthma".

[This corrects the article DOI: 10.1021/acsmedchemlett.7b00157.].