Genomic footprints of (pre) colonialism: Population declines in urban and forest túngara frogs coincident with historical human activity.

Urbanisation is rapidly altering ecosystems, leading to profound biodiversity loss. To mitigate these effects, we need a better understanding of how urbanisation impacts dispersal and reproduction. Two contrasting population demographic models have been proposed that predict that urbanisation either promotes (facilitation model) or constrains (fragmentation model) gene flow and genetic diversity. Which of these models prevails likely depends on the strength of selection on specific phenotypic traits that influence dispersal, survival, or reproduction. Here, we a priori examined the genomic impact of urbanisation on the Neotropical túngara frog (Engystomops pustulosus), a species known to adapt its reproductive traits to urban selective pressures. Using whole-genome resequencing for multiple urban and forest populations we examined genomic diversity, population connectivity and demographic history. Contrary to both the fragmentation and facilitation models, urban populations did not exhibit substantial changes in genomic diversity or differentiation compared with forest populations, and genomic variation was best explained by geographic distance rather than environmental factors. Adopting an a posteriori approach, we additionally found both urban and forest populations to have undergone population declines. The timing of these declines appears to coincide with extensive human activity around the Panama Canal during the last few centuries rather than recent urbanisation. Our study highlights the long-lasting legacy of past anthropogenic disturbances in the genome and the importance of considering the historical context in urban evolution studies as anthropogenic effects may be extensive and impact nonurban areas on both recent and older timescales.

Sexual selection and population divergence III: Interspecific and intraspecific variation in mating signals.

A major challenge for studying the role of sexual selection in divergence and speciation is understanding the relative influence of different sexually selected signals on those processes in both intra- and interspecific contexts. Different signals may be more or less susceptible to co-option for species identification depending on the balance of sexual and ecological selection acting upon them. To examine this, we tested three predictions to explain geographic variation in long- versus short-range sexual signals across a 3,500 + km transect of two related Australian field cricket species (Teleogryllus spp.): (a) selection for species recognition, (b) environmental adaptation and (c) stochastic divergence. We measured male calling song and male and female cuticular hydrocarbons (CHCs) in offspring derived from wild populations, reared under common garden conditions. Song clearly differentiated the species, and no hybrids were observed suggesting that hybridization is rare or absent. Spatial variation in song was not predicted by geography, genetics or climatic factors in either species. In contrast, CHC divergence was strongly associated with an environmental gradient supporting the idea that the climatic environment selects more directly upon these chemical signals. In light of recently advocated models of diversification via ecological selection on secondary sexual traits, the different environmental associations we found for song and CHCs suggest that the impact of ecological selection on population divergence, and how that influences speciation, might be different for acoustic versus chemical signals.

Behavioural mechanisms of sexual isolation involving multiple modalities and their inheritance.

Speciation research dissects the genetics and evolution of reproductive barriers between parental species. Hybrids are the "gatekeepers" of gene flow, so it is also important to understand the behavioural mechanisms and genetics of any potential isolation from their parental species. We tested the role of multiple behavioural barriers in reproductive isolation among closely related field crickets and their hybrids (Teleogryllus oceanicus and Teleogryllus commodus). These species hybridize in the laboratory, but the behaviour of hybrids is unusual and there is little evidence for gene flow in the wild. We found that heterospecific pairs exhibited reduced rates of courtship behaviour due to discrimination by both sexes, and that this behavioural isolation was symmetrical. However, hybrids were not sexually selected against and exhibited high rates of courtship behaviour even though hybrid females are sterile. Using reciprocal hybrid crosses, we characterized patterns of interspecific divergence and inheritance in key sexual traits that might underlie the mating patterns we found: calling song, courtship song and cuticular hydrocarbons (CHCs). Song traits exhibited both sex linkage and transgressive segregation, whereas CHCs exhibited only the latter. Calculations of the strength of isolation exerted by these sexual traits suggest that close-range signals are as important as long-distance signals in contributing to interspecific sexual isolation. The surprisingly weak mating barriers observed between hybrids and parental species highlight the need to examine reproductive isolating mechanisms and their genetic bases across different potential stages of introgressive hybridization.

Hemodynamic Instability Secondary to Vasopressin Withdrawal in Septic Shock.

RATIONALE: Vasopressors such as norepinephrine are first line for support of mean arterial pressure (MAP) in the management of septic shock. Their use, however, is commonly associated with many adverse events. These detriments frequently trigger the use of alternative, noncatecholamine therapies, including vasopressin. Vasopressin deficiency is a known physiologic consequence of septic shock, and while guidelines recommend vasopressin in addition to norepinephrine, no consensus exists on the duration of deficiency or ideal time of cessation. Studies have suggested that vasopressin discontinuation prior to other vasopressors may lead to hypotension; however, data are limited. This study evaluates the optimal sequence for the discontinuation of vasopressin therapy in septic shock. METHODS: This was a 1-year retrospective study of 152 patients admitted to the medical intensive care unit (ICU) with septic shock who received concurrent norepinephrine and vasopressin for vasoactive support. Patients were excluded if death occurred on vasopressors, within 24 hours after discontinuation of vasopressors, or within 48 hours of ICU admission. The primary outcome of hemodynamic instability included incidence of hypotension after vasopressor discontinuation (2 consecutive MAPs < 60 mm Hg), fluid bolus administration, greater than 0.05 µg/kg/min increase in norepinephrine requirements, or addition of an alternative vasopressor. Secondary outcomes included time to hypotension, total vasopressor duration, arrhythmias, mortality, and length of stay. RESULTS: Ninety-one patients met exclusion criteria, resulting in 61 patients for evaluation. Vasopressin was the first vasoactive therapy to be discontinued in 19 patients and last in 42 patients. Baseline characteristics and the use of potentially confounding treatments known to effect MAP were similar between groups. Discontinuation of vasopressin first was associated with a significant increase in hemodynamic instability (74% vs 16.7%, P < .01), with a shorter time to hemodynamic instability (5 vs 15 hours, P < .01). Secondary outcomes were similar. CONCLUSION: Vasopressin discontinuation prior to cessation of norepinephrine infusion was associated with an increased risk of hemodynamic instability.

Saving sevoflurane: Automated gas control can reduce consumption of anesthetic vapor by one-third in pediatric anesthesia.

BACKGROUND: Many modern anesthetic machines offer automated control of anesthetic vapor. The user simply sets a desired end-tidal concentration and the machine will manipulate the vaporizer and gas flow rates to obtain and maintain the preset target. Greater efficiency, and more accurate delivery of anesthetic vapor have been documented across multiple machines within the adult setting however, there is little evidence for their use in children. AIMS: The aim of this study was to compare the consumption of sevoflurane using the Maquet Flow-i anesthesia machine (Maquet, Solna, Sweden) in automatic gas control mode vs manual mode in pediatric anesthesia. The primary outcome measure is rate of sevoflurane use. METHOD: Data logs were collected from our three Maquet Flow-i anesthesia machines over a 4-week period. We compared the rate of sevoflurane use when in manual mode vs cases where the automatic gas control mode was used. We also examined each automatic gas control case to determine whether percentage of anesthesia time in this mode correlated significantly with average rate of sevoflurane consumption. RESULTS: Sevoflurane was the primary anesthetic used in 220 cases, comprising over 230 hours of anesthesia time. Of these, 36 cases were identified as automatic gas control cases and 184 as manual cases. Consumption of sevoflurane liquid in mL/min was significantly lower in automatic gas control cases (median 0.46, IQR 0.32-0.72 mL/min for automatic gas control; median 0.82, IQR 0.62-1.17 mL/min for manual; P < 0.001 by Wilcoxon Rank Sum test). For a case of median duration (49 minutes), average rate of sevoflurane liquid consumption was 0.54 mL/min for automatic gas control cases vs 0.81 mL/min for manual cases, a reduction of 33% (bootstrapped 95% CI 0.21-0.61 mL/min, P < 0.001). CONCLUSION: Maquet's Flow-i automatic gas control mode reduced use of sevoflurane an average of one-third in a pediatric anesthesia setting.

Insidious Harm of Medication Diluents as a Contributor to Cumulative Volume and Hyperchloremia: A Prospective, Open-Label, Sequential Period Pilot Study.

OBJECTIVES: Although the potential dangers of hyperchloremia from resuscitation fluids continue to emerge, no study to date has considered the contribution of medication diluents to cumulative volume and hyperchloremia. This study compares saline versus dextrose 5% in water as the primary medication diluent and the occurrence of hyperchloremia in critically ill patients. DESIGN: Prospective, open-label, sequential period pilot study. SETTING: Medical ICU of a large academic medical center. PATIENTS: Adult patients admitted to the medical ICU were eligible for inclusion. Patients who were admitted for less than 48 hours, less than 18 years old, pregnant, incarcerated, or who had brain injury were excluded. INTERVENTIONS: Saline as the primary medication diluent for 2 months followed by dextrose 5% in water as the primary medication diluent for 2 months. MEASUREMENTS AND MAIN RESULTS: A total of 426 patients were included, 216 in the saline group and 210 in the dextrose 5% in water group. Medication diluents accounted for 63% of the total IV volume over the observation period. In the saline group, 17.9% developed hyperchloremia compared with 10.5% in the dextrose 5% in water group (p = 0.037), which was statistically significant in multivariable analysis (odds ratio, 0.50; 95% CI, 0.26-0.94; p = 0.031). In the saline group, 34.2% developed acute kidney injury versus 24.5% in the dextrose 5% in water group (p = 0.035); however, this was not statistically significant when adjusting for baseline covariates. No other significant differences in dysnatremias, insulin requirements, glucose control, ICU length of stay, or ICU mortality were observed. CONCLUSIONS: This study identified that medication diluents contribute substantially to the total IV volume received by critically ill patients. Saline as the primary medication diluent compared with dextrose 5% in water is associated with hyperchloremia, a possible risk factor for acute kidney injury.

Opposing patterns of intraspecific and interspecific differentiation in sex chromosomes and autosomes.

Linking intraspecific and interspecific divergence is an important challenge in speciation research. X chromosomes are expected to evolve faster than autosomes and disproportionately contribute to reproductive barriers, and comparing genetic variation on X and autosomal markers within and between species can elucidate evolutionary processes that shape genome variation. We performed RADseq on a 16 population transect of two closely related Australian cricket species, Teleogryllus commodus and T. oceanicus, covering allopatry and sympatry. This classic study system for sexual selection provides a rare exception to Haldane's rule, as hybrid females are sterile. We found no evidence of recent introgression, despite the fact that the species coexist in overlapping habitats in the wild and interbreed in the laboratory. Putative X-linked loci showed greater differentiation between species compared with autosomal loci. However, population differentiation within species was unexpectedly lower on X-linked markers than autosomal markers, and relative X-to-autosomal genetic diversity was inflated above neutral expectations. Populations of both species showed genomic signatures of recent population expansions, but these were not strong enough to account for the inflated X/A diversity. Instead, most of the excess polymorphism on the X could better be explained by sex-biased processes that increase the relative effective population size of the X, such as interspecific variation in the strength of sexual selection among males. Taken together, the opposing patterns of diversity and differentiation at X versus autosomal loci implicate a greater role for sex-linked genes in maintaining species boundaries in this system.

Sustained Arginase 1 Expression Modulates Pathological Tau Deposits in a Mouse Model of Tauopathy.

Tau accumulation remains one of the closest correlates of neuronal loss in Alzheimer's disease. In addition, tau associates with several other neurodegenerative diseases, collectively known as tauopathies, in which clinical phenotypes manifest as cognitive impairment, behavioral disturbances, and motor impairment. Polyamines act as bivalent regulators of cellular function and are involved in numerous biological processes. The regulation of the polyamines system can become dysfunctional during disease states. Arginase 1 (Arg1) and nitric oxide synthases compete for l-arginine to produce either polyamines or nitric oxide, respectively. Herein, we show that overexpression of Arg1 using adeno-associated virus (AAV) in the CNS of rTg4510 tau transgenic mice significantly reduced phospho-tau species and tangle pathology. Sustained Arg1 overexpression decreased several kinases capable of phosphorylating tau, decreased inflammation, and modulated changes in the mammalian target of rapamycin and related proteins, suggesting activation of autophagy. Arg1 overexpression also mitigated hippocampal atrophy in tau transgenic mice. Conversely, conditional deletion of Arg1 in myeloid cells resulted in increased tau accumulation relative to Arg1-sufficient mice after transduction with a recombinant AAV-tau construct. These data suggest that Arg1 and the polyamine pathway may offer novel therapeutic targets for tauopathies.

Fractalkine over expression suppresses α-synuclein-mediated neurodegeneration.

In Parkinson's disease, α-synuclein is known to activate microglia and this activation has been proposed as one of the mechanisms of neurodegeneration. There are several signals produced by neurons that have an anti-inflammatory action on microglia, including CX3CL1 (fractalkine). We have shown that a soluble form of CX3CL1 is required to reduce neuron loss in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice and that fractalkine agonism can reduce neuron loss in a 6-hydroxydopamine lesion model. Here, we show that fractalkine can reduce α-synuclein-mediated neurodegeneration in rats. Rats that received fractalkine showed abrogated loss of tyrosine hydroxylase and Neu-N staining. This was replicated in animals where we expressed fractalkine from astrocytes with the glial fibrillary acid protein (GFAP) promoter. Interestingly, we did not observe a reduction in MHCII expression suggesting that soluble fractalkine is likely altering the microglial state to a more neuroprotective one rather than reducing antigen presentation.

Major trauma patients and their outcomes - A retrospective observational study of critical care trauma admissions to a trauma unit with special services.

INTRODUCTION: International data describes a changing pattern to trauma over the last decade, with an increasingly comorbid population presenting challenges to trauma management and resources. In Ireland, resource provision and management of trauma is being transformed to deliver a trauma network, in line with international best practice. Our hospital plays a crucial role within this network and is designated a Trauma Unit with Specialist Services (TUSS) to distinguish it from standard trauma units. METHODS: This study aims to describe the characteristics of patients and injuries and assess trends in mortality rates. It is a retrospective observational study of adult ICU trauma admissions from August 2010 to July 2021. Primary outcome was all-cause mortality at 30-days, 90-days, and 1 year. Secondary outcomes included length of stay, disposition, and complications. Patients were categorised by age, injury severity score (ISS), and mechanism of injury. RESULTS: In all, 709 patients were identified for final analysis. Annual admissions doubled since 2010/11, with a trough of 41 admissions, increasing to peak at 95 admissions in 2017/18. Blunt trauma accounted for 97.6% of cases. Falls <2 m (45.4%) and RTAs (29.2%) were the main mechanisms of injury. Polytrauma comprised 41.9% of admissions. Traumatic brain injury accounted for 30.2% of cases; 18.8% of these patients were transferred to a neurosurgical centre. The majority of patients, 58.1%, were severely injured (ISS ≥ 16). Patients ≥ 65 years of age accounted for 45.7% of admissions, with falls <2 m their primary mechanism of injury. The primary outcome of all-cause mortality reduced with an absolute risk reduction (ARR) of 8.0% (95% CI: -8.37%, 24.36%), 12.9% (95% CI: -4.19%, 29.94%) and 8.2% (95% CI: -9.64%, 26.09%) for 30-day, 90-day and 1-year respectively. Regression analysis demonstrated a significant reduction in mortality for 30-days and 90-days post presentation to hospital (P-values of 0.018, 0.033 and 0.152 for 30-day, 90-day and 1-year respectively). CONCLUSION: The burden of major trauma in our hospital is considerable and increasing over time. Substantial changes in demographics, injury mechanism and mortality were seen, with outcomes improving over time. This is consistent with international data where trauma systems have been adopted.

T-piece gas flow palpation as a clinical indicator of endotracheal intubation in neonates.

We aimed to determine if providers could detect simulated spontaneous respirations of an intubated neonate by palpating gas flow changes at the positive end expiratory pressure valve of a T-piece resuscitation device in an in vitro setting. We also aimed to demonstrate whether the sensitivity of this methodology was related to the exhaled tidal volumes and/or the gas flow settings on the resuscitation device. A T-piece resuscitator (Neopuff®) circuit was connected to a neonatal silicon test lung. Expiratory tidal volumes of 5, 10 and 15 ml were provided via the test lung, with the Neopuff® set at gas flow rates of 5, 10 and 15 L/min. Physician volunteers were asked to identify whether they could detect expiratory gas from the test lung at the circuit T-piece with the volar surface of their wrist, at different tidal volumes and gas flows. Ten doctors detected 315 of 450 expirations; 95, 73 and 42 % of tidal volumes of 15, 10 and 5 ml, respectively, were detected with an overall positive predictive value of 98.7 %. Detection of exhalations was similar at different gas flow rates for each tidal volume. No exhalations were detected at zero gas flow. We concluded that T-piece gas flow palpation may be a useful and previously unreported clinical sign, which may help to reassure clinicians that they have successfully intubated the trachea. As with any clinical sign, it should not be considered in isolation but within the context of the clinical picture.

A comprehensive overview of the effects of urbanisation on sexual selection and sexual traits.

Urbanisation can affect mating opportunities and thereby alter inter- and intra-sexual selection pressures on sexual traits. Biotic and abiotic urban conditions can influence an individual's success in pre- and post-copulatory mating, for example through impacts on mate attraction and mate preference, fertilisation success, resource competition or rival interactions. Divergent sexual selection pressures can lead to differences in behavioural, physiological, morphological or life-history traits between urban and non-urban populations, ultimately driving adaptation and speciation. Most studies on urban sexual selection and mating interactions report differences between urban and non-urban populations or correlations between sexual traits and factors associated with increased urbanisation, such as pollution, food availability and risk of predation and parasitism. Here we review the literature on sexual selection and sexual traits in relation to urbanisation or urban-associated conditions. We provide an extensive list of abiotic and biotic factors that can influence processes involved in mating interactions, such as signal production and transmission, mate choice and mating opportunities. We discuss all relevant data through the lens of two, non-mutually exclusive theories on sexual selection, namely indicator and sensory models. Where possible, we indicate whether these models provide the same or different predictions regarding urban-adapted sexual signals and describe different experimental designs that can be useful for the different models as well as to investigate the drivers of sexual selection. We argue that we lack a good understanding of: (i) the factors driving urban sexual selection; (ii) whether reported changes in traits result in adaptive benefits; and (iii) whether these changes reflect a short-term ecological, or long-term evolutionary response. We highlight that urbanisation provides a unique opportunity to study the process and outcomes of sexual selection, but that this requires a highly integrative approach combining experimental and observational work.

A Case of "Cryptammonia": Disseminated Cryptococcal Infection Generating Profound Hyperammonemia in a Liver Transplant Recipient.

Mycoplasma and Ureaplasma infections have been described as a cause of hyperammonemia syndrome leading to devastating neurological injury in the post-transplant period, most commonly in lung transplant recipients. The occurrence of significant hyperammonemia caused by other urease-producing organisms remains unclear. We describe a case of disseminated cryptococcosis presenting with profound hyperammonemia in a 55-year-old orthotopic liver transplant recipient. Through a process of elimination, other potential causes for hyperammonemia were excluded revealing a probable association between hyperammonemia and disseminated cryptococcosis.

Using a learning health system to understand the mismatch between medicines supply and actual medicines use among adults with cystic fibrosis.

BACKGROUND: Studies in separate cohorts suggest possible discrepancies between inhaled medicines supplied (median 50-60%) and medicines used (median 30-40%). We performed the first study that directly compares CF medicine supply against use to identify the cost of excess medicines supply. METHODS: This cross-sectional study included participants from 12 UK adult centres with ≥1 year of continuous adherence data from data-logging nebulisers. Medicine supply was measured as medication possession ratio (MPR) for a 1-year period from the first suitable supply date. Medicine use was measured as electronic data capture (EDC) adherence over the same period. The cost of excess medicines was calculated as whole excess box(es) supplied after accounting for the discrepancy between EDC adherence and MPR with 20% contingency. RESULTS: Among 275 participants, 133 (48.4%) were females and mean age was 30 years (95% CI 29-31 years). Median EDC adherence was 57% (IQR 23-86%), median MPR was 74% (IQR 46-96%) and the discrepancy between measures was median 14% (IQR 2-29%). Even with 20% contingency, mean potential cost of excess medicines was £1,124 (95% CI £855-1,394), ranging from £183 (95% CI £29-338) for EDC adherence ≥80% to £2,017 (95% CI £1,507-2,526) for EDC adherence <50%. CONCLUSIONS: This study provides a conservative estimate of excess inhaled medicines supply cost among adults with CF in the UK. The excess supply cost was highest among those with lowest EDC adherence, highlighting the importance of adherence support and supplying medicine according to actual use. MPR provides information about medicine supply but over-estimates actual medicine use.

Rapid development of interprofessional in situ simulation-based training in response to the COVID-19 outbreak in a tertiary-level hospital in Ireland: initial response and lessons for future disaster preparation.

Introduction: The first case of COVID-19 in Ireland was diagnosed on 29 February 2020. Within the same week, our Department of Anaesthesia and Critical Care at University Hospital Galway began to tackle the educational challenge by developing an  in situ interprofessional simulation programme to prepare staff for the impending outbreak. Principles and approaches used for simulation-based training: We describe principles applied to identify core educational and system engineering objectives to prepare healthcare workers (HCWs) for infection control, personal and psychological safety, technical and crisis resource management skills. We discuss application of educational theories, rationale for simulation modes and debriefing techniques. Development of the simulation programme: 3 anaesthesia (general, obstetric, paediatric) and 1 critical care silo were created. 13 simulated scenarios were developed for teaching as well as for testing workflows specific to the outbreak. To support HCWs and ensure safety, management guidelines, cognitive aids and checklists were developed using simulation. The cumulative number of HCWs trained in simulation was 750 over a 4-week period. Challenges and future directions: Due to the protracted nature of the pandemic, simulation educators should address questions related to sustainability, infection control while delivering simulation, establishment of hybrid programmes and support for psychological preparedness.

Evolution and Expression of the Immune System of a Facultatively Anadromous Salmonid.

Vertebrates have evolved a complex immune system required for the identification of and coordinated response to harmful pathogens. Migratory species spend periods of their life-cycle in more than one environment, and their immune system consequently faces a greater diversity of pathogens residing in different environments. In facultatively anadromous salmonids, individuals may spend parts of their life-cycle in freshwater and marine environments. For species such as the brown trout Salmo trutta, sexes differ in their life-histories with females more likely to migrate to sea while males are more likely to stay and complete their life-cycle in their natal river. Salmonids have also undergone a lineage-specific whole genome duplication event, which may provide novel immune innovations but our current understanding of the differences in salmonid immune expression between the sexes is limited. We characterized the brown trout immune gene repertoire, identifying a number of canonical immune genes in non-salmonid teleosts to be duplicated in S. trutta, with genes involved in innate and adaptive immunity. Through genome-wide transcriptional profiling ("RNA-seq") of male and female livers to investigate sex differences in gene expression amplitude and alternative splicing, we identified immune genes as being generally male-biased in expression. Our study provides important insights into the evolutionary consequences of whole genome duplication events on the salmonid immune gene repertoire and how the sexes differ in constitutive immune expression.

Alternative migratory tactics in brown trout (Salmo trutta) are underpinned by divergent regulation of metabolic but not neurological genes.

The occurrence of alternative morphs within populations is common, but the underlying molecular mechanisms remain poorly understood. Many animals, for example, exhibit facultative migration, where two or more alternative migratory tactics (AMTs) coexist within populations. In certain salmonid species, some individuals remain in natal rivers all their lives, while others (in particular, females) migrate to sea for a period of marine growth. Here, we performed transcriptional profiling ("RNA-seq") of the brain and liver of male and female brown trout to understand the genes and processes that differentiate between migratory and residency morphs (AMT-associated genes) and how they may differ in expression between the sexes. We found tissue-specific differences with a greater number of genes expressed differentially in the liver (n = 867 genes) compared with the brain (n = 10) between the morphs. Genes with increased expression in resident livers were enriched for Gene Ontology terms associated with metabolic processes, highlighting key molecular-genetic pathways underlying the energetic requirements associated with divergent migratory tactics. In contrast, smolt-biased genes were enriched for biological processes such as response to cytokines, suggestive of possible immune function differences between smolts and residents. Finally, we identified evidence of sex-biased gene expression for AMT-associated genes in the liver (n = 12) but not the brain. Collectively, our results provide insights into tissue-specific gene expression underlying the production of alternative life histories within and between the sexes, and point toward a key role for metabolic processes in the liver in mediating divergent physiological trajectories of migrants versus residents.