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By the late 1980s, widespread dramatic declines in amphibian populations were causing alarm. The culprit was identified as Batrachochytrium dendrobatidis (Bd), a chytrid fungus that infects the skin of various amphibian hosts, particularly anurans (frogs), and the first example of a chytridiomycete parasitising vertebrates. The disease, chytridiomycosis, has spread globally and is linked to the decline and extinction of many amphibian species. This review summarises the discovery of Bd, its emergence as a panzootic pathogen, and some current mitigation strategies to conserve amphibians.

Research, based on both observations and ocean models, has indicated that strong East Pacific El Niños are preceded by the development of unusually low sea levels at the western end of the North Equatorial Trough early in the year. This results in an increase in the strength of the North Equatorial Counter Current which, aided by low sea levels due to the annual Rossby wave, then transports West Pacific Warm Pool water to the central and eastern Pacific. Here, an ocean model is used to investigate the factors affecting sea level prior to the 1982–1983 East Pacific El Niño. The results indicate that during this period the reduction in sea level was caused by Ekman pumping, due to the local winds, acting over a period of many months. The north–south distances involved mean that such upwelling can be connected to the westerly wind phase of Madden–Julian Oscillations. Since the 1980s, the quality and quantity of global wind measurement has steadily improved. So, if the Ekman pumping hypothesis is correct, the better-quality wind data available prior to the 1997–1998 and 2015–2016 East Pacific El Niños should also show unusually large Ekman pumping in the same region, over a similar long period. This is tested and found to be correct. However, a study of the integrated Ekman pumping for the period 1976 to 2015 indicates that in some years similar events did not develop despite a comparable amount of pumping during the first part of the year. The results imply that significant Ekman pumping early in the year is a necessary but not sufficient requirement for the development of a strong East Pacific El Niño.

Emissions of ammonia (NH3), nitrous oxide (N2O) and methane (CH4) from livestock production may be measured for different reasons and in consequence reported in a wide range of units. For the purpose of compiling national inventories of emissions of those gases, emissions from buildings and stores usually need to be expressed per animal or as a proportion of nitrogen (N) (NH3 and N2O) or volatile solids (VS) (CH4) excreted or stored. Much of the published data on gaseous emissions from livestock production is not reported in units that can be readily used for inventory compilation. This paper provides guidance for researchers wishing to convert a wide range of emission units into emission factors (EFs) and opens up opportunities for increased use of published data. We developed our methodology using reported emissions from housing and storage systems compiled from studies for the DATAMAN database so that we could convert reported emissions into agreed EFs referred to as 'required EFs' (RqEFs). Required EFs were either derived using data reported in the associated publication or estimated, using default data (e.g. annual N excretion by a particular type of livestock). The approach greatly increased the number of RqEFs. For example, the number of RqEFs of N2O-N from livestock buildings as a proportion of excreted N increased from 16 to 326, while the number of N2O RqEFs from manure stores as a proportion of stored N increased from 126 to 353. For two subsets of NH3-N emissions from livestock buildings and from slurry stores there were very good correlations between emissions estimated using the methodology we developed and reported emissions (R2 = 0.97 and 0.97, respectively). We include a list of recommended information for inclusion in publications reporting emissions that will enable other workers to utilize this methodology.

Background. Fungal infections are a recognized complication of immunosuppression in solid organ transplant recipients. Phaeohyphomycoses are fungal infections caused by a diverse group of dematiaceous fungi. Methods. We share the learning points from 2 Australian cases of phaeohyphomycosis secondary to Phaeacreomonium species (spp). A literature review was performed using Medline, Embase, and Google Scholar to identify this condition among kidney transplant recipients. Results. With the 2 cases reported in this article, a total of 17 cases were identified in the literature. Phaeacremonium spp is ubiquitous in humid and temperate flora, including Australia. Minor trauma is likely the source of inoculation in most cases and diagnosis is often delayed. Presently, no guidelines for management exist given the rarity of this condition. Most known cases have been treated with surgical debulking combined with long-course antifungal therapy. Conclusion. This paper describes 2 Australian cases of phaeohyphomycosis in kidney transplant recipients. A high index of suspicion, especially in the immunosuppressed, is essential for timely diagnosis in kidney transplant recipients. There are several diagnostic and therapeutic challenges that remain with this condition.

Longitudinal evidence on the association between air pollution and blood pressure (BP) in adolescence is scarce. We explored this association in an ethnically diverse cohort of schoolchildren. Sex-stratified, linear random-effects modelling was used to examine how modelled residential exposure to annual average nitrogen dioxide (NO2), particulate matter (PM2.5, PM10) and ozone (O3), measures in μg/m3, associated with blood pressure. Estimates were based on 3,284 adolescents; 80% from ethnic minority groups, recruited from 51 schools, and followed up from 11–13 to 14–16 years old. Ethnic minorities were exposed to higher modelled annual average concentrations of pollution at residential postcode level than their White UK peers. A two-pollutant model (NO2 & PM2.5), adjusted for ethnicity, age, anthropometry, and pubertal status, highlighted associations with systolic, but not diastolic BP. A μg/m3 increase in NO2 was associated with a 0.30 mmHg (95% CI 0.18 to 0.40) decrease in systolic BP for girls and 0.19 mmHg (95% CI 0.07 to 0.31) decrease in systolic BP for boys. In contrast, a 1 μg/m3 increase in PM2.5 was associated with 1.34 mmHg (95% CI 0.85 to 1.82) increase in systolic BP for girls and 0.57 mmHg (95% CI 0.04 to 1.03) increase in systolic BP for boys. Associations did not vary by ethnicity, body size or socio-economic advantage. Associations were robust to adjustments for noise levels and lung function at 11–13 years. In summary, higher ambient levels of NO2 were associated with lower and PM2.5 with higher systolic BP across adolescence, with stronger associations for girls.

Autism Spectrum Disorder (ASD) is a developmental condition characterized by social and communication differences. Recent research suggests ASD affects 1-in-44 children in the United States. ASD is diagnosed more commonly in males, though it is unclear whether this diagnostic disparity is a result of a biological predisposition or limitations in diagnostic tools, or both. One hypothesis centers on the ‘female protective effect,’ which is the theory that females are biologically more resistant to the autism phenotype than males. In this examination, phenotypic data were acquired and combined from four leading research institutions and subjected to multivariate linear discriminant analysis. A linear discriminant model was trained on the training set and then deployed on the test set to predict group membership. Multivariate analyses of variance were performed to confirm the significance of the overall analysis, and individual analyses of variance were performed to confirm the significance of each of the resulting linear discriminant axes. Two discriminant dimensions were identified between the groups: a dimension separating groups by the diagnosis of ASD (LD1: 87% of variance explained); and a dimension reflective of a diagnosis-by-sex interaction (LD2: 11% of variance explained). The strongest discriminant coefficients for the first discriminant axis divided the sample in domains with known differences between ASD and comparison groups, such as social difficulties and restricted repetitive behavior. The discriminant coefficients for the second discriminant axis reveal a more nuanced disparity between boys with ASD and girls with ASD, including executive functioning and high-order behavioral domains as the dominant discriminators. These results indicate that phenotypic differences between males and females with and without ASD are identifiable using parent report measures, which could be utilized to provide additional specificity to the diagnosis of ASD in female patients, potentially leading to more targeted clinical strategies and therapeutic interventions. The study helps to isolate a phenotypic basis for future empirical work on the female protective effect using neuroimaging, EEG, and genomic methodologies.

We add to a growing literature suggesting that demographic grade gaps should be attributed to biases embedded in the courses themselves. Changes in the structure of two different introductory physics classes were made while leaving the topics covered and the level of coverage unchanged. First, a class where conceptual issues were studied before doing any complicated calculations had zero final exam grade gap between students from underrepresented racial or ethnic groups and their peers. Next, four classes that offered students a retake exam each week between the regular bi-weekly exams during the term had zero gender gap in course grades. Our analysis indicates that demographic grade gaps can be attributed to the course structure (a course deficit model) rather than to student preparation (a student deficit model).

On the basis of a 1957 geographic Coccidioides seropositivity survey, 3 counties in southwestern Utah, USA, were considered coccidioidomycosis-endemic, but there has been a paucity of information on the disease burden in Utah since. We report findings from a recent clinical and epidemiologic study of coccidioidomycosis in Utah. To describe clinical characteristics, we identified all coccidioidomycosis cases in an integrated health system in the state during 2006–2015. For epidemiologic analysis, we used cases reported to the Utah Department of Health during 2009–2015. Mean state incidence was 1.83 cases/100,000 population/year. Washington County, in southwestern Utah, had the highest incidence, 17.2 cases/100,000 population/year. In a generalized linear model with time as a fixed effect, mean annual temperature, population, and new construction were associated with regional variations in incidence. Using these variables in a spatiotemporal model, we estimated the adjusted regional variation by county to predict areas where Coccidioides infections might increase.

Abstract Environmental and ecosystem models can help to guide management of changing natural systems by projecting alternative future states under a common set of scenarios. Combining contrasting models into multi-model ensembles (MMEs) can improve the skill and reliability of projections, but associated uncertainty complicates communication of outputs, affecting both the effectiveness of management decisions and, sometimes, public trust in scientific evidence itself. Effective data visualisation can play a key role in accurately communicating such complex outcomes, but we lack an evidence base to enable us to design them to be visually appealing whilst also effectively communicating accurate information. To address this, we conducted a survey to identify the most effective methods for visually communicating the outputs of an ensemble of global climate models. We measured the accuracy, confidence, and ease with which the survey participants were able to interpret 10 visualisations depicting the same set of model outputs in different ways, as well as their preferences. Dot and box plots outperformed all other visualisations, heat maps and radar plots were comparatively ineffective, while our infographic scored highly for visual appeal but lacked information necessary for accurate interpretation. We provide a set of guidelines for visually communicating the outputs of MMEs across a wide range of research areas, aimed at maximising the impact of the visualisations, whilst minimizing the potential for misinterpretations, increasing the societal impact of the models and ensuring they are well-placed to support management in the future.

The association of liver biochemistry with clinical outcomes of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection is currently unclear, and the utility of longitudinally measured liver biochemistry as prognostic markers for mortality is unknown. We aimed to determine whether abnormal liver biochemistry, assessed at baseline and at repeat measures over time, was associated with death in hospitalized patients with COVID‐19 compared to those without COVID‐19, in a United Kingdom population. We extracted routinely collected clinical data from a large teaching hospital in the United Kingdom, matching 585 hospitalized patients who were SARS‐CoV‐2 real‐time reverse transcription‐polymerase chain reaction (RT‐PCR) positive to 1,165 hospitalized patients who were RT‐PCR negative for age, sex, ethnicity, and preexisting comorbidities. A total of 26.8% (157/585) of patients with COVID‐19 died compared to 11.9% (139/1,165) in the group without COVID‐19 (P

Summary: Background: Circadian rhythm impacts broad biological processes, including response to cancer treatment. Evidence conflicts on whether treatment time affects risk of radiotherapy side-effects, likely because of differing time analyses and target tissues. We previously showed interactive effects of time and genotypes of circadian genes on late toxicity after breast radiotherapy and aimed to validate those results in a multi-centre cohort. Methods: Clinical and genotype data from 1690 REQUITE breast cancer patients were used with erythema (acute; n=340) and breast atrophy (two years post-radiotherapy; n=514) as primary endpoints. Local datetimes per fraction were converted into solar times as predictors. Genetic chronotype markers were included in logistic regressions to identify primary endpoint predictors. Findings: Significant predictors for erythema included BMI, radiation dose and PER3 genotype (OR 1.27(95%CI 1.03-1.56); P < 0.03). Effect of treatment time effect on acute toxicity was inconclusive, with no interaction between time and genotype. For late toxicity (breast atrophy), predictors included BMI, radiation dose, surgery type, treatment time and SNPs in CLOCK (OR 0.62 (95%CI 0.4-0.9); P < 0.01), PER3 (OR 0.65 (95%CI 0.44-0.97); P < 0.04) and RASD1 (OR 0.56 (95%CI 0.35-0.89); P < 0.02). There was a statistically significant interaction between time and genotypes of circadian rhythm genes (CLOCK OR 1.13 (95%CI 1.03-1.23), P < 0.01; PER3 OR 1.1 (95%CI 1.01-1.2), P < 0.04; RASD1 OR 1.15 (95%CI 1.04-1.28), P < 0.008), with peak time for toxicity determined by genotype. Interpretation: Late atrophy can be mitigated by selecting optimal treatment time according to circadian genotypes (e.g. treat PER3 rs2087947C/C genotypes in mornings; T/T in afternoons). We predict triple-homozygous patients (14%) reduce chance of atrophy from 70% to 33% by treating in mornings as opposed to mid-afternoon. Future clinical trials could stratify patients treated at optimal times compared to those scheduled normally. Funding: EU-FP7.

Despite decades of research and numerous clinical trials, the prognosis of patients diagnosed with glioblastoma (GBM) remains dire with median observed survival at 8 months. There is a critical need for novel treatments for GBM, which is the most common malignant primary brain tumor. Major advances in cancer therapeutics such as immune checkpoint inhibitors and chimeric antigen receptor (CAR) T-cell therapy have not yet led to improved outcomes for GBM. Conventional therapy of surgery followed by chemoradiation with or without tumor treating fields remains the standard of care. One of the many approaches to GBM therapy currently being explored is viral therapies. These typically work by selectively lysing target neoplastic cells, called oncolysis, or by the targeted delivery of a therapeutic transgene via a viral vector. In this review, we discuss the underlying mechanisms of action and describe both recent and current human clinical trials using these viruses with an emphasis on promising viral therapeutics that may ultimately break the field’s current stagnant paradigm.

The author assesses the effectiveness of Thomas Schreiner's exegesis of Revelation 20 in his recent technical Revelation commentary (Baker Academic, 2023). Schreiner boldly takes up the new creation millennialism interpretative solution, following J. Webb Mealy's monographs After the Thousand Years and New Creation Millennialism , but he resists perhaps the most significant potential consequence of that model, namely, that John's picture of the final fate of the stubbornly unrepentant is to be imagined as annihilation in a temporary pool (Gr. λίμνη) of fire, and not, as commonly understood, as everlasting torment in a permanent lake of fire. The author argues that Schreiner's resisting of this element leads to an exposition that misses crucial ties between Rev. 19–20 and the Isaiah Apocalypse (Isa. 24:1–27:5) and to a disjointed and at points internally inconsistent story of the end of the unrepentant. [ABSTRACT FROM AUTHOR]

Ice-nucleating particles (INPs) influence the formation of ice crystals in clouds and many types of precipitation. This study reports unique properties of INPs collected from 42 precipitation samples in the Texas Panhandle region from June 2018 to July 2019. We used a cold stage instrument called the West Texas Cryogenic Refrigerator Applied to Freezing Test system to estimate INP concentrations per unit volume of air (nINP) through immersion freezing in our precipitation samples with our detection capability of > 0.006 INP L−1. A disdrometer was used for two purposes: (1) to characterize the ground-level precipitation type and (2) to measure the precipitation intensity as well as size of precipitating particles at the ground level during each precipitation event. While no clear seasonal variations of nINP values were apparent, the analysis of yearlong ground-level precipitation observation as well as INPs in the precipitation samples showed some INP variations, e.g., the highest and lowest nINP values at −25 ∘C both in the summer for hail-involved severe thunderstorm samples (3.0 to 1130 INP L−1), followed by the second lowest at the same temperature from one of our snow samples collected during the winter (3.2 INP L−1). Furthermore, we conducted bacteria community analyses using a subset of our precipitation samples to examine the presence of known biological INPs. In parallel, we also performed metagenomics characterization of the bacterial microbiome in suspended ambient dust samples collected at commercial open-lot livestock facilities (cattle feedyards hereafter) in the Texas Panhandle (i.e., the northernmost counties of Texas, also known as “West Texas”) to ascertain whether local cattle feedyards can act as a source of bioaerosol particles and/or INPs found in the precipitation samples. Some key bacterial phyla present in cattle feedyard samples appeared in precipitation samples. However, no known ice nucleation active species were detected in our samples. Overall, our results showed that cumulative nINP in our precipitation samples below −20 ∘C could be high in the samples collected while observing > 10 mm h−1 precipitation with notably large hydrometeor sizes and an implication of cattle feedyard bacteria inclusion.

Abstract Background There is excess amenable mortality risk and evidence of healthcare quality deficits for persons with serious mental illness (SMI). We sought to identify sociodemographic and clinical characteristics associated with variations in two 2015 Healthcare Effectiveness Data and Information Set (HEDIS) measures, antipsychotic medication adherence and preventive diabetes screening, among Medicaid enrollees with serious mental illness (SMI). Methods We retrospectively analyzed claims data from September 2014 to December 2015 from enrollees in a Medicaid specialty health plan in Florida. All plan enrollees had SMI; analyses included continuously enrolled adults with antipsychotic medication prescriptions and schizophrenia or bipolar disorder. Associations were identified using mixed effects logistic regression models. Results Data for 5502 enrollees were analyzed. Substance use disorders, depression, and having both schizophrenia and bipolar disorder diagnoses were associated with both HEDIS measures but the direction of the associations differed; each was significantly associated with antipsychotic medication non-adherence (a marker of suboptimal care quality) but an increased likelihood of diabetes screening (a marker of quality care). Compared to whites, blacks and Hispanics had a significantly greater risk of medication non-adherence. Increasing age was significantly associated with increasing medication adherence, but the association between age and diabetes screening varied by sex. Other characteristics significantly associated with quality variations according to one or both measures were education (associated with antipsychotic medication adherence), urbanization (relative to urban locales, residing in suburban areas was associated with both adherence and diabetes screening), obesity (associated with both adherence and diabetes screening), language (non-English speakers had a greater likelihood of diabetes screening), and anxiety, asthma, and hypertension (each positively associated with diabetes screening). Conclusions The characteristics associated with variations in the quality of care provided to Medicaid enrollees with SMI as gauged by two HEDIS measures often differed, and at times associations were directionally opposite. The variations in the quality of healthcare received by persons with SMI that were identified in this study can guide quality improvement and delivery system reform efforts; however, given the sociodemographic and clinical characteristics’ differing associations with different measures of care quality, multidimensional approaches are warranted.

Corns are a common foot problem accounting for nearly half of all problems seen within podiatry and chiropody clinics. Hard corns are concentrated areas of hyperkeratosis within the stratum corneum, typically found on the weight-bearing (plantar) surfaces of the feet. For many patients, they are a source of pain and have been shown to negatively affect a patient’s activity and quality of life. Most of the currently available treatments are short-lived in their effectiveness, with corns frequently being recurrent, requiring repeated visits to remove the painful lesions. The use of handheld microwave devices indicated for surface applications has demonstrated effectiveness in clearing recalcitrant plantar warts and significantly reducing the pain associated with them. The authors report 2 cases of patients with persistent and painful plantar corns who underwent microwave treatment of their plantar corns with a successful, lasting reduction in pain levels after the intervention. Further work is required to fully assess the potential of this treatment modality in the management of painful plantar corns.

Abstract Background Airway bacterial dysbiosis is a feature of chronic obstructive pulmonary disease (COPD). However, there is limited comparative data of the lung microbiome between healthy smokers, non-smokers and COPD. Methods We compared the 16S rRNA gene-based sputum microbiome generated from pair-ended Illumina sequencing of 124 healthy subjects (28 smokers and 96 non-smokers with normal lung function), with single stable samples from 218 COPD subjects collected from three UK clinical centres as part of the COPDMAP consortium. Results In healthy subjects Firmicutes, Bacteroidetes and Actinobacteria were the major phyla constituting 88% of the total reads, and Streptococcus, Veillonella, Prevotella, Actinomyces and Rothia were the dominant genera. Haemophilus formed only 3% of the healthy microbiome. In contrast, Proteobacteria was the most dominant phylum accounting for 50% of the microbiome in COPD subjects, with Haemophilus and Moraxella at genus level contributing 25 and 3% respectively. There were no differences in the microbiome profile within healthy and COPD subgroups when stratified based on smoking history. Principal coordinate analysis on operational taxonomic units showed two distinct clusters, representative of healthy and COPD subjects (PERMANOVA, p = 0·001). Conclusion The healthy and COPD sputum microbiomes are distinct and independent of smoking history. Our results underline the important role for Gammaproteobacteria in COPD.

Abstract Predicting how species will respond to increased environmental temperatures is key to understanding the ecological consequences of global change. The physiological tolerances of a species define its thermal limits, while its thermal affinity is a summary of the environmental temperatures at the localities at which it actually occurs. Experimentally derived thermal limits are known to be related to observed latitudinal ranges in marine species, but accurate range maps from which to derive latitudinal ranges are lacking for many marine species. An alternative approach is to combine widely available data on global occurrences with gridded global temperature datasets to derive measures of species‐level “thermal affinity”—that is, measures of the central tendency, variation, and upper and lower bounds of the environmental temperatures at the locations at which a species has been recorded to occur. Here, we test the extent to which such occupancy‐derived measures of thermal affinity are related to the known thermal limits of marine species using data on 533 marine species from 24 taxonomic classes and with experimentally derived critical upper temperatures spanning 2–44.5°C. We show that thermal affinity estimates are consistently and positively related to the physiological tolerances of marine species, despite gaps and biases in the source data. Our method allows thermal affinity measures to be rapidly and repeatably estimated for many thousands more marine species, substantially expanding the potential to assess vulnerability of marine communities to warming seas.

Descriptions of the ocean's role in the El Niño usually focus on equatorial Kelvin waves and the ability of such waves to change the mean thermocline depth and the sea surface temperature (SST) in the central and eastern Pacific. In contrast, starting from a study of the transport of water with temperatures greater than 28 ∘C, sufficient to trigger deep atmospheric convection, Webb (2018) found that, during the strong El Niños of 1983–1984 and 1997–1998, advection by the North Equatorial Counter Current (NECC) had a much greater impact on sea surface temperatures than processes occurring near the Equator. Webb's analysis, which supports the scheme proposed by Wyrtki (1973, 1974), made use of archived data from a high-resolution ocean model. Previously the model had been checked in a preliminary comparison against SST observations in the equatorial Pacific, but, given the contentious nature of the new analysis, the model's behaviour in key areas needs to be checked further against observations. In this paper this is done for the 1987–1988 El Niño, making use of satellite observations of SST and sea level. SST is used to check the movement of warm water near the Equator and at the latitudes of the NECC. Sea level is used to check the model results at the Equator and at 6∘ N in the North Equatorial Trough. Sea level differences between these latitudes affect the transport of the NECC, the increased transport at the start of each strong El Niño being associated with a drop in sea level at 6∘ N in the western Pacific. Later rises in sea level at the Equator increase the transport of the NECC in mid-ocean. The variability of sea level at 6∘ N is also used to compare the strength of tropical instability waves in the model and in the observations. The model showed that in a normal year these act to dilute the temperature in the core of the NECC. However their strength declined during the development of the strong El Niños, allowing the NECC to carry warm water much further than normal across the Pacific. The results of this paper should not be taken as providing proof of the hypotheses of Wyrtki (1973, 1974) or Webb (2018) but instead as a failure of a targeted study, using satellite observations, to disprove the hypotheses.

The molecular mechanisms that drive irreversible acute liver failure remain poorly characterized. Here, the authors show that the recently discovered platelet receptor CLEC-2 (C-type lectin-like receptor) perpetuates and worsens liver damage during acute liver injury by blocking restorative neutrophil driven inflammation.

Abstract Two α‐aminoisobutyric acid (Aib) foldamers bearing Zn(II)‐chelating N‐termini have been synthesized and compared with a reported Aib foldamer that has a bis(quinolinyl)/mono(pyridyl) cap (BQPA group). Replacement of the quinolinyl arms of the BQPA‐capped foldamer with pyridyl gave a BPPA‐capped foldamer, then further replacement of the linking pyridyl with a 1,2,3‐triazole gave a BPTA‐capped foldamer. Their ability to relay chiral information from carboxylate bound to Zn(II) at the N‐terminus to a glycinamide‐based NMR reporter of conformational preference at the C‐terminus was measured. The importance of the quinolinyl arms became readily apparent, as the foldamers with pyridyl arms were unable to report on the presence of chiral carboxylate in acetonitrile. Low solubility, X‐ray crystallography and 1H NMR spectroscopy suggested that interfoldamer interactions inhibited carboxylate binding. However changing solvent to methanol revealed that the end‐to‐end relay of chiral information could be observed for the Zn(II) complex of the BPTA‐capped foldamer at low temperature.

Objectives The Intermountain Risk Score (IMRS), composed using published sex-specific weightings of parameters in the complete blood count (CBC) and basic metabolic profile (BMP), is a validated predictor of mortality. We hypothesised that IMRS calculated from prepandemic CBC and BMP predicts COVID-19 outcomes and that IMRS using laboratory results tested at COVID-19 diagnosis is also predictive.Design Prospective observational cohort study.Setting Primary, secondary, urgent and emergent care, and drive-through testing locations across Utah and in sections of adjacent US states. Viral RNA testing for SARS-CoV-2 was conducted from 3 March to 2 November 2020.Participants Patients aged ≥18 years were evaluated if they had CBC and BMP measured in 2019 and tested positive for COVID-19 in 2020.Primary and secondary outcome measures The primary outcome was a composite of hospitalisation or mortality, with secondary outcomes being hospitalisation and mortality separately.Results Among 3883 patients, 8.2% were hospitalised and 1.6% died. Subjects with low, mild, moderate and high-risk IMRS had the composite endpoint in 3.5% (52/1502), 8.6% (108/1256), 15.5% (152/979) and 28.1% (41/146) of patients, respectively. Compared with low-risk, subjects in mild-risk, moderate-risk and high-risk groups had HR=2.33 (95% CI 1.67 to 3.24), HR=4.01 (95% CI 2.93 to 5.50) and HR=8.34 (95% CI 5.54 to 12.57), respectively. Subjects aged

Glioblastoma (GBM) is the most common malignant primary brain tumor and confers a dismal prognosis. With only two FDA-approved therapeutics showing modest survival gains since 2005, there is a great need for the development of other disease-targeted therapies. Due, in part, to the profound immunosuppressive microenvironment seen in GBMs, there has been a broad interest in immunotherapy. In both GBMs and other cancers, therapeutic vaccines have generally yielded limited efficacy, despite their theoretical basis. However, recent results from the DCVax-L trial provide some promise for vaccine therapy in GBMs. There is also the potential that future combination therapies with vaccines and adjuvant immunomodulating agents may greatly enhance antitumor immune responses. Clinicians must remain open to novel therapeutic strategies, such as vaccinations, and carefully await the results of ongoing and future trials. In this review of GBM management, the promise and challenges of immunotherapy with a focus on therapeutic vaccinations are discussed. Additionally, adjuvant therapies, logistical considerations, and future directions are discussed.

A progressive decline in soil fertility in taro (Colocasia esculenta L., Schott) production systems has contributed to reduced crop productivity and farm profitability, and is recognized to be a threat to soil nutrient and food security in Samoa. Evidence based on three years of field experimentation showed that appropriate nutrient budgeting is required to reduce soil nutrient deficits and mitigate soil organic carbon loss. Balanced crop nutrition coupled with appropriate crop husbandry can significantly improve productivity and narrow yield gaps. A framework to guide nutrient recommendations for taro production systems is presented and discussed. This framework proposes that recommendations for N be derived from the yield-to-N response function (from which the most economic rate of N can be estimated) and that for other nutrients, namely P, K, Ca, and Mg, recommendations be based on replacement. The replacement strategy requires the development of soil nutrient indexes, which can be used to define the long-term nutrient management policy at the field scale. This long-term policy is informed by soil analyses, and it will determine whether existing soil nutrient levels are to be maintained or increased depending on the focus (productivity, profitability, environmental protection). If soil nutrients were already at an agronomically satisfactory level, their application may be omitted in some years to help reduce crop production costs, improve use efficiency, and ensure environmentally safe levels in soil are not exceeded.

Hydrogen storage for energy applications is of significant interest to researchers seeking to enable a transition to lower-pollution energy systems. Two of the key drawbacks of using hydrogen for energy storage are the low gas-phase storage density and the high energy cost of the gas-phase compression. Metal hydride materials have the potential to increase hydrogen storage density and decrease the energy cost of compression by storing the hydrogen as a solid solution. In this article, the technical viability of core-shell V90Al10-Pd80Ag20 as a hydrogen storage material is discussed. LaNi5, LaNi5/acrylonitrile-butadiene-styrene copolymer mixtures, core-shell V-Pd, and core-shell V90Al10-Pd80Ag20 are directly compared in terms of reversible hydrogen-storage content by weight and volume. The kinetic information for each of the materials is also compared; however, this work highlights missing information that would enable computational dynamics modelling. Results of this technical evaluation show that V90Al10-Pd80Ag20 has the potential to increase gravimetric and volumetric hydrogen capacity by 1.4 times compared to LaNi5/acrylonitrile-butadiene-styrene copolymer mixtures. In addition, the literature shows that Pd80Ag20 and V90Al10 both have similarly good hydrogen permeabilities, thermal conductivities, and specific heats. In summary, this evaluation demonstrates that core-shell V90Al10-Pd80Ag20 could be an excellent, less-expensive hydrogen storage material with the advantages of improved storage capacity, handleability, and safety compared to current AB5-polymer mixtures.

Background Accurate methods of identifying patients with COVID-19 who are at high risk of poor outcomes has become especially important with the advent of limited-availability therapies such as monoclonal antibodies. Here we describe development and validation of a simple but accurate scoring tool to classify risk of hospitalization and mortality. Methods All consecutive patients testing positive for SARS-CoV-2 from March 25-October 1, 2020 within the Intermountain Healthcare system were included. The cohort was randomly divided into 70% derivation and 30% validation cohorts. A multivariable logistic regression model was fitted for 14-day hospitalization. The optimal model was then adapted to a simple, probabilistic score and applied to the validation cohort and evaluated for prediction of hospitalization and 28-day mortality. Results 22,816 patients were included; mean age was 40 years, 50.1% were female and 44% identified as non-white race or Hispanic/Latinx ethnicity. 6.2% required hospitalization and 0.4% died. Criteria in the simple model included: age (0.5 points per decade); high-risk comorbidities (2 points each): diabetes mellitus, severe immunocompromised status and obesity (body mass index≥30); non-white race/Hispanic or Latinx ethnicity (2 points), and 1 point each for: male sex, dyspnea, hypertension, coronary artery disease, cardiac arrythmia, congestive heart failure, chronic kidney disease, chronic pulmonary disease, chronic liver disease, cerebrovascular disease, and chronic neurologic disease. In the derivation cohort (n = 16,030) area under the receiver-operator characteristic curve (AUROC) was 0.82 (95% CI 0.81–0.84) for hospitalization and 0.91 (0.83–0.94) for 28-day mortality; in the validation cohort (n = 6,786) AUROC for hospitalization was 0.8 (CI 0.78–0.82) and for mortality 0.8 (CI 0.69–0.9). Conclusion A prediction score based on widely available patient attributes accurately risk stratifies patients with COVID-19 at the time of testing. Applications include patient selection for therapies targeted at preventing disease progression in non-hospitalized patients, including monoclonal antibodies. External validation in independent healthcare environments is needed.

Although the antimicrobial potential of nitric oxide (NO) is widely published, it is little used clinically. NO is a key signalling molecule modulating vascular, neuronal, inflammatory and immune responses. Endogenous antimicrobial activity is largely mediated by high local NO concentrations produced by cellular inducible nitric oxide synthase, and by derivative reactive nitrogen oxide species including peroxynitrite and S-nitrosothiols. NO may be taken as dietary substrate (inorganic nitrate, L-arginine), and therapeutically as gaseous NO, and transdermal, sublingual, oral, intranasal and intravenous nitrite or nitrate. Numerous preclinical studies have demonstrated that NO has generic static and cidal activities against viruses (including β-coronaviruses such as SARS-CoV-2), bacteria, protozoa and fungi/yeasts in vitro. Therapeutic effects have been seen in animal models in vivo, and phase II trials have demonstrated that NO donors can reduce microbial infection. Nevertheless, excess NO, as occurs in septic shock, is associated with increased morbidity and mortality. In view of the dose-dependent positive and negative effects of NO, safety and efficacy trials of NO and its donors are needed for assessing their role in the prevention and treatment of infections. Trials should test dietary inorganic nitrate for pre- or post-exposure prophylaxis and gaseous NO or oral, topical or intravenous nitrite and nitrate for treatment of mild-to-severe infections, including due to SARS-CoV-2 (COVID-19). This review summarises the evidence base from in vitro, in vivo and early phase clinical studies of NO activity in viral, bacterial, protozoal and fungal infections.

A randomly scattering analyzer located in the far field and with a fixed aperture, in front of a multielement detector, is introduced as a means to access enhanced sensing information associated with far-subwavelength spatial features. This sensing method allows improved spatial resolution with coherent fields scattered from a moving object, or some other relative change that causes a modified field incident on the detector aperture. Experimental optical speckle correlation data with a translated diffusing structure show the salient features, and understanding in relation to the experimental variables is supported by numerical simulations. The conclusion is that more heavily scattering analyzers provide better spatial resolution because the measurements are more sensitive to changes in the incident field. Such randomly scattering analyzers offer a dimension for sensitive coherent optical metrology related to various sensing and motion application domains requiring large offset distances.

Although the antimicrobial potential of nitric oxide (NO) is widely published, it is little used clinically. NO is a key signalling molecule modulating vascular, neuronal, inflammatory and immune responses. Endogenous antimicrobial activity is largely mediated by high local NO concentrations produced by cellular inducible nitric oxide synthase, and by derivative reactive nitrogen oxide species including peroxynitrite and S-nitrosothiols. NO may be taken as dietary substrate (inorganic nitrate, L-arginine), and therapeutically as gaseous NO, and transdermal, sublingual, oral, intranasal and intravenous nitrite or nitrate. Numerous preclinical studies have demonstrated that NO has generic static and cidal activities against viruses (including β-coronaviruses such as SARS-CoV-2), bacteria, protozoa and fungi/yeasts in vitro. Therapeutic effects have been seen in animal models in vivo, and phase II trials have demonstrated that NO donors can reduce microbial infection. Nevertheless, excess NO, as occurs in septic shock, is associated with increased morbidity and mortality. In view of the dose-dependent positive and negative effects of NO, safety and efficacy trials of NO and its donors are needed for assessing their role in the prevention and treatment of infections. Trials should test dietary inorganic nitrate for pre- or post-exposure prophylaxis and gaseous NO or oral, topical or intravenous nitrite and nitrate for treatment of mild-to-severe infections, including due to SARS-CoV-2 (COVID-19). This review summarises the evidence base from in vitro, in vivo and early phase clinical studies of NO activity in viral, bacterial, protozoal and fungal infections.

Although the antimicrobial potential of nitric oxide (NO) is widely published, it is little used clinically. NO is a key signalling molecule modulating vascular, neuronal, inflammatory and immune responses. Endogenous antimicrobial activity is largely mediated by high local NO concentrations produced by cellular inducible nitric oxide synthase, and by derivative reactive nitrogen oxide species including peroxynitrite and S-nitrosothiols. NO may be taken as dietary substrate (inorganic nitrate, L-arginine), and therapeutically as gaseous NO, and transdermal, sublingual, oral, intranasal and intravenous nitrite or nitrate. Numerous preclinical studies have demonstrated that NO has generic static and cidal activities against viruses (including β-coronaviruses such as SARS-CoV-2), bacteria, protozoa and fungi/yeasts in vitro. Therapeutic effects have been seen in animal models in vivo, and phase II trials have demonstrated that NO donors can reduce microbial infection. Nevertheless, excess NO, as occurs in septic shock, is associated with increased morbidity and mortality. In view of the dose-dependent positive and negative effects of NO, safety and efficacy trials of NO and its donors are needed for assessing their role in the prevention and treatment of infections. Trials should test dietary inorganic nitrate for pre- or post-exposure prophylaxis and gaseous NO or oral, topical or intravenous nitrite and nitrate for treatment of mild-to-severe infections, including due to SARS-CoV-2 (COVID-19). This review summarises the evidence base from in vitro, in vivo and early phase clinical studies of NO activity in viral, bacterial, protozoal and fungal infections.

Abstract: CXC chemokine receptor 4 (CXCR4) is overexpressed by a broad range of hematological disorders, and its interaction with CXC chemokine ligand 12 (CXCL12) is of central importance in the retention and chemoprotection of neoplastic cells in the bone marrow and lymphoid organs. In this article, we describe the biological evaluation of a new CXCR4-targeting and -antagonizing molecule (BAT1) that we designed and show that, when incorporated into a liposomal drug delivery system, it can be used to deliver cancer therapeutics at high levels to chronic lymphocytic leukemia (CLL) cells. CXCR4 targeting and antagonism by BAT1 were demonstrated alone and following its incorporation into liposomes (BAT1-liposomes). Antagonism of BAT1 against the CXCR4/CXCL12 interaction was demonstrated through signaling inhibition and function blocking: BAT1 reduced ERK phosphorylation and cell migration to levels equivalent to those seen in the absence of CXCL12 stimulation (P < .001). Specific uptake of BAT1-liposomes and delivery of a therapeutic cargo to the cell nucleus was seen within 3 hours of incubation and induced significantly more CLL cell death after 24 hours than control liposomes (P = .004). The BAT1 drug-delivery system is modular, versatile, and highly clinically relevant, incorporating elements of proven clinical efficacy. The combined capabilities to block CXCL12-induced migration and intracellular signaling while simultaneously delivering therapeutic cargo mean that the BAT1-liposome drug-delivery system could be a timely and relevant treatment of a range of hematological disorders, particularly because the therapeutic cargo can be tailored to the disease being treated.

Background: Acetylcysteine (NAC) is effective at preventing liver injury after paracetamol overdose. The Scottish and Newcastle Anti-emetic Pre-treatment for Paracetamol Poisoning (SNAP) Study demonstrated that a 12 h NAC regimen was associated with fewer adverse drug reactions compared with the standard 21 h regimen. Here, we describe the clinical effectiveness of the SNAP NAC regimen. Methods: The SNAP regimen, consisting of intravenous NAC 100 mg/kg over 2 h then 200 mg/kg over 10 h, was introduced to treat all paracetamol overdose patients at the Royal Infirmary of Edinburgh, the Royal Victoria Infirmary, Newcastle and St Thomas' Hospital, London. Patient data were prospectively and systematically collected before and after the change in treatment (total patients N = 3340, 21 h N = 1488, SNAP N = 1852). Health record linkage was used to determine patient outcome after hospital discharge. Findings: There was no difference in liver injury or liver synthetic dysfunction between regimens. Hepatotoxicity (peak ALT > 1000 U/L) occurred in 64 (4.3%) and 67 (3.6%) patients, respectively, in the 21 h and SNAP groups (absolute difference −0.7%, 95% CI −2.1 to 0.6). Multivariable logistic regression did not identify treatment regimen as an outcome-associated factor. No patients were readmitted to hospital with, or died from, liver failure within 30 days of discharge. Anti-histamine treatment (for NAC anaphylactoid drug reactions) was prescribed for 163 (11.0%) patients with the 21 h regimen and 37 (2.0%) patients with the SNAP regimen (absolute difference 9.0% (95% CI 7.3 to 10.7)). Interpretation: In clinical use the SNAP regimen has similar efficacy as standard therapy for preventing liver injury and produces fewer adverse reactions. Keywords: Acute liver failure, Paracetamol, NAC, Clinical practice, Drug-induced liver injury

Little is known about the mental health impact of having a family member or friend infected with COVID-19. Thus, the purpose of this study was to conduct a comprehensive national assessment of the psychological impact of COVID-19 infection, hospitalization, or death among family members and friends. A multi-item valid and reliable questionnaire was deployed online to recruit adults in the U.S. A total of 2797 adult Americans without a history of COVID-19 infection participated in the study and reported that they had a family member or friend infected with (54%), hospitalized due to (48%), or die (36%) of COVID-19 infection. Symptoms of depression, anxiety, or both (i.e., psychological distress) were statistically significantly higher among those who had family members/friends infected, hospitalized, or die due to COVID-19. Also, this study found that the greater the number of family members/friends affected by COVID-19, or the more severe the COVID-19 infection outcome (i.e., hospitalization vs. death), the higher the odds of symptoms of depression, anxiety, or both. There is an urgent need to develop educational interventions and implement policy measures that address the growing mental health needs of this subgroup of the population that was not infected but indirectly affected by COVID-19 infections among social networks.

OBJECTIVES:. Beta-lactam antibiotics exhibit high interindividual variability in drug concentrations in patients with critical illness which led to an interest in the use of therapeutic drug monitoring to improve effectiveness and safety. To implement therapeutic drug monitoring, it is necessary to define the beta-lactam therapeutic range—in essence, what drug concentration would prompt a clinician to make dose adjustments up or down. This objective of this narrative review was to summarize evidence for the “floor” (for effectiveness) and “ceiling” (for toxicity) for the beta-lactam therapeutic range to be used with individualized therapeutic drug monitoring. DATA SOURCES:. Research articles were sourced from PubMed using search term combinations of “pharmacokinetics,” “pharmacodynamics,” “toxicity,” “neurotoxicity,” “therapeutic drug monitoring,” “beta-lactam,” “cefepime,” “meropenem,” “piperacillin/tazobactam,” “ICU,” and “critical illness.” STUDY SELECTION:. Articles were selected if they included preclinical, translational, or clinical data on pharmacokinetic and pharmacodynamic thresholds for effectiveness and safety for beta-lactams in critical illness. DATA SYNTHESIS:. Experimental data indicate a beta-lactam concentration above the minimum inhibitory concentration of the organism for greater than or equal to 40–60% of the dosing interval is needed, but clinical data indicate that higher concentrations may be preferrable. In the first 48 hours of critical illness, a free beta-lactam concentration at or above the susceptibility breakpoint of the most likely pathogen for 100% of the dosing interval would be reasonable (typically based on Pseudomonas aeruginosa). After 48 hours, the lowest acceptable concentration could be tailored to 1–2× the observed minimum inhibitory concentration of the organism for 100% of the dosing interval (often a more susceptible organism). Neurotoxicity is the primary dose-dependent adverse effect of beta-lactams, but the evidence remains insufficient to link a specific drug concentration to greater risk. CONCLUSIONS:. As studies advance the understanding of beta-lactam exposure and response in critically ill patients, it is essential to clearly define the acceptable therapeutic range to guide regimen selection and adjustment.

Semaphorin 4D (Sema4D) is a glycoprotein that is expressed by several tumors and immune cells. It can function as a membrane bound protein or as a cleaved soluble protein (sSema4D). We sought to investigate the translational potential of plasma sSema4D as an immune marker in plasma of patients with head and neck squamous cell carcinoma (HNSCC). Paired peripheral blood and tumor tissue samples of 104 patients with HNSCC were collected at the same time point to allow for real time analysis. Scoring of the histological inflammatory subtype (HIS) was carried out using Sema4D immunohistochemistry on the tumor tissue. sSema4D was detected in plasma using direct ELISA assay. Defining elevated sSema4D as values above the 95th percentile in healthy controls, our data showed that sSema4D levels in plasma were elevated in 25.0% (95% CI, 16.7–34.9%) of the patients with HNSCC and showed significant association with HIS immune excluded (HIS-IE) (p = 0.007), Sema4D+ve tumor cells (TCs) (p = 0.018) and PD-L1+ve immune cells (ICs) (p = 0.038). A multi-variable logistic regression analysis showed that HIS was significantly (P = 0.004) associated with elevated sSema4D, an association not explained by available patient-level factors. Using the IO-360 nanoString platform, differential gene expression (DGE) analysis of 10 HNSCC tumor tissues showed that patients with high sSema4D in plasma (HsS4D) clustered as IFN-γ negative tumor immune signature and were mostly HIS-IE. The IC type in the HsS4D paired tumor tissue was predominantly myeloid, while the lymphoid compartment was higher in the low sSema4D (LsS4D). The Wnt signaling pathway was upregulated in the HsS4D group. Further analysis using the IO-360, 770 gene set, showed significant non-inflamed profile of the HsS4D tumors compared to the LsS4D. In conclusion, our data reveals an association between sSema4D and the histological inflammatory subtype.

In previous work we analyzed databases for 95 classes to show that the percent grade scale was correlated with a much higher student fail rate than the 4.0 grade scale. This paper builds on this work and investigates equity gaps occurring under both scales. By employing a “course deficit model” we attribute the responsibility for closing the gaps to those who are responsible for the policies that guide the course. When comparing course grades in classes graded using the percent scale with those in courses graded using the 4.0 scale, we find that students identifying as belonging to racial or ethnic minorities underrepresented in physics suffer a grade penalty under both grade scales but suffer an extra penalty under percent scale graded courses. We then use the fraction of A grades each student earns on individual exam items as a proxy for the instructor’s perception of each student’s understanding of the course material to control for student understanding and find that the extra grade penalty students from groups underrepresented in physics students suffer under percent scale grading is independent of the student’s understanding of physics. When we control for more student level variables to determine the source of the grade scale dependent penalty, we find that it is primarily the low F grades (partial credit scores) on exam problems that are the source of these inequities. We present an argument that switching from percent scale grading to a 4.0 grade scale (or similar grades scale) could reduce equity gaps by 20%–25% without making any other course changes or controlling for any incoming differences between students.