Search

Abstract Objectives To analyse the presentation, management and long‐term outcomes of renal transplant patients who formed kidney stones in their allograft. The secondary aim was to identify risk factors for stone formation in this cohort. Materials and Methods Patient information from an institutional renal transplant database was used to identify individuals who both did and did not form kidney stones following renal transplantation. Computerized tomography (CT) imaging was used to make the diagnosis of kidney stones and measure stone size. Age‐ and gender‐matched controls never forming a stone in their allograft were used for comparative analysis to identify risk factors for stone formation in transplant patients. Results A total of 8835 transplant patients were included in the study, of which 128 (1.4%) formed a kidney stone in their allograft after surgery. The mean time to kidney stone identification was 6.2 years, and the mean number of stones formed was 1.7, with a mean maximum size dimension on a CT scan of 5.7 mm per stone. A total of 26 patients were subjected to stone‐removing procedures, the most common being ureteroscopy (42.3%). The primary intervention failed in eight patients requiring a secondary intervention, and percutaneous nephrolithotomy (PCNL) had the lowest success rate (60%). A total of 164 controls were identified. In comparison to controls, stone formers had lower serum calcium (p = 0.008), lower estimated glomerular filtration rates (p = 0.019), higher lymphocyte counts (p = 0.021) and greater rate of urinary tract infection (p = 0.003). Graft failure rates were the same (p = 0.524), but time to graft failure was significantly longer in stone patients compared with controls (p = 0.008). Conclusions The rate of stone formation is low in transplant patients. Success rates for stone treatment vary based on the surgery selected, with PCNL being the worst. Graft survival rates were equivocal, but survival time was better in stone patients. Our analysis calls for further investigation of this important topic.

The width of the Inter-Tropical Convergence Zone (ITCZ) affects tropical rainfall, Earth's albedo, large-scale circulation, and climate sensitivity. To better understand the ITCZ width and its effects on global climate, we present a protocol to force changes in ITCZ width in climate models. Starting from an aquaplanet configuration with a slab ocean, adding surface heat fluxes in the deep tropics forces the ITCZ to narrow, and subtracting them causes it to widen. The protocol successfully generates changes in ITCZ width in all four climate models used in this study. ITCZ width in each model responds linearly to forcing magnitude and sign. Comparing across the four climate models, a response to varying ITCZ width that is remarkably consistent among models is the ITCZ strength, which is greater the narrower the ITCZ. On the other hand, the effect of varying ITCZ width on climate sensitivity is divergent among our four models, varying even in sign. Results from this pilot study highlight the connections between surface fluxes, ITCZ width, and the wider climate. A comprehensive model intercomparison project (MIP) has the potential to advance understanding of both the physical processes shaping ITCZ width and its influence on remote atmospheric circulations and global climate.

Abstract Background A trial performed among unvaccinated, high-risk outpatients with COVID-19 during the delta period showed remdesivir reduced hospitalization. We used our real-world data platform to determine the effectiveness of remdesivir on reducing 28-day hospitalization among outpatients with mild-moderate COVID-19 during an Omicron period including BQ.1/BQ.1.1/XBB.1.5. Methods We did a propensity-matched, retrospective cohort study of non-hospitalized adults with SARS-CoV-2 infection between April 7, 2022, and February 7, 2023. Electronic healthcare record data from a large health system in Colorado were linked to statewide vaccination and mortality data. We included patients with a positive SARS-CoV-2 test or outpatient remdesivir administration. Exclusion criteria were other SARS-CoV-2 treatments or positive SARS-CoV-2 test more than seven days before remdesivir. The primary outcome was all-cause hospitalization up to day 28. Secondary outcomes included 28-day COVID-related hospitalization and 28-day all-cause mortality. Results Among 29,270 patients with SARS-CoV-2 infection, 1,252 remdesivir-treated patients were matched to 2,499 untreated patients. Remdesivir was associated with lower 28-day all-cause hospitalization (1.3% vs. 3.3%, adjusted hazard ratio (aHR) 0.39 [95% CI 0.23–0.67], p

Can a combination of the extracellular vesicle (EV) research community’s latest consensus guidance (MISEV2023) along with synthetic biology’s engineering approaches and responsible innovation framework help to accelerate future EV-based industrial and medical applications?

Abstract Although patients benefit from immune checkpoint inhibition (ICI) therapy in a broad variety of tumors, resistance may arise from immune suppressive tumor microenvironments (TME), which is particularly true of hepatocellular carcinoma (HCC). Since oncolytic viruses (OV) can generate a highly immune-infiltrated, inflammatory TME, OVs could potentially restore ICI responsiveness via recruitment, priming, and activation of anti-tumor T cells. Here we find that on the contrary, an oncolytic vesicular stomatitis virus, expressing interferon-ß (VSV-IFNß), antagonizes the effect of anti-PD-L1 therapy in a partially anti-PD-L1-responsive model of HCC. Cytometry by Time of Flight shows that VSV-IFNß expands dominant anti-viral effector CD8 T cells with concomitant relative disappearance of anti-tumor T cell populations, which are the target of anti-PD-L1. However, by expressing a range of HCC tumor antigens within VSV, combination OV and anti-PD-L1 therapeutic benefit could be restored. Our data provide a cautionary message for the use of highly immunogenic viruses as tumor-specific immune-therapeutics by showing that dominant anti-viral T cell responses can inhibit sub-dominant anti-tumor T cell responses. However, through encoding tumor antigens within the virus, oncolytic virotherapy can generate anti-tumor T cell populations upon which immune checkpoint blockade can effectively work.

Abstract: Glioblastoma (GBM) is the most prevalent malignant tumor of the central nervous system. The prognosis of GBM is grim, with a median overall survival of 14.6 months and only 6.9% of patients surviving 5 years after the initial diagnosis. Despite poor outcomes, standard therapy of surgical resection, radiotherapy, chemotherapy, and tumor-treating fields has remained largely unchanged. The introduction of immune checkpoint inhibitors (ICI) has been a paradigm shift in oncology, with efficacy across a broad spectrum of cancer types. Nonetheless, investigations of ICIs in both newly diagnosed and recurrent GBM have thus far been disappointing. This lack of clinical benefit has been largely attributed to the highly immunosuppressive nature of GBM. However, immunotherapy still holds promise for the treatment of GBM, with combinatorial strategies offering hope for potentially overcoming these current limitations. In this review, we discuss the outcomes of clinical trials employing ICIs in patients with GBM. Afterward, we review ICI combination strategies and how these combinations may overcome the immunosuppressive microenvironment of GBM in the context of preclinical/clinical evidence and ongoing clinical trials.

Abstract Evidence‐based conservation has made some major steps forward in the last two decades. However, the ‘landscape’ in which evidence is generated, funded and disseminated still has some elements that will need to be further developed if the UK's conservation sector is to achieve its collective nature recovery goals. This paper articulates a shared vision of the conservation evidence landscape in 2035. It was developed by representatives of 27 organisations involved in conservation and nature recovery across the UK. Solution: the authors identified a range of issues that will need to be addressed to allow the evidence base to support and guide nature recovery efforts. These will require action in four key areas: (1) evidence creation, (2) access to evidence, (3) evidence culture, and (4) enabling evidence‐based conservation.

Abstract Body size is a fundamental biological trait shaping ecological interactions, evolutionary processes, and our understanding of the structure and dynamics of marine communities on a global scale. Accurately defining a species' body size, despite the ease of measurement, poses significant challenges due to varied methodologies, tool usage, and subjectivity among researchers, resulting in multiple, often discrepant size estimates. These discrepancies, stemming from diverse measurement approaches and inherent variability, could substantially impact the reliability and precision of ecological and evolutionary studies reliant on body size data across extensive species datasets. This study examines the variation in reported maximum body sizes across 69,570 individual measurements of maximum size, ranging from 45 m, for 27,271 species of marine metazoans. The research aims to investigate how reported maximum size variations within species relate to organism size, taxonomy, habitat, and the presence of skeletal structures. The investigation particularly focuses on understanding why discrepancies in maximum size estimates arise and their potential implications for broader ecological and evolutionary studies relying on body size data. Variation in reported maximum sizes is zero for 38% of species, and low for most species, although it exceeds two orders of magnitude for some species. The likelihood of zero variation in maximum size decreased with more measurements and increased in larger species, though this varied across phyla and habitats. Pelagic organisms consistently had low maximum size range values, while small species with unspecified habitats had the highest variation. Variations in maximum size within a species were notably smaller than interspecific variation at higher taxonomic levels. Significant variation in maximum size estimates exists within marine species, and partially explained by organism size, taxonomic group, and habitat. Variation in maximum size could be reduced by standardized measurement protocols and improved meta‐data. Despite the variation, egregious errors in published maximum size measurements are rare, and their impact on comparative macroecological and macroevolutionary research is likely minimal.

Abstract Tropical high cloud cover decreases with surface warming in most general circulation models. This reduction, according to the “stability‐iris” hypothesis, is thermodynamically controlled and linked to a decrease in the radiatively‐driven clear‐sky convergence, when the peak anvil clouds rise because of the rising isotherms. The influence of the large‐scale dynamical changes on the tropical high cloud fraction remains difficult to disentangle from the local thermodynamic influence, given that the mean meridional circulation remains inextricably tied to the local thermodynamic structure of the atmosphere. However, using idealized general circulation model simulations, we propose a novel method to segregate the dynamical impact from the thermodynamic impact on the tropical high cloud fraction. To this end, our investigation primarily focuses on the mechanisms underpinning changes in the high cloud cover in the deep tropics in response to extratropical surface warming, when the tropical sea surface temperatures remain invariant. Net convective detrainment of ice cloud condensates decreases at the peak detrainment region, without a rise in its altitude. We also find that the importance of depositional growth of ice cloud condensates in controlling the high cloud fraction response in the deep tropics varies with altitude.

Abstract In patients with chronic kidney disease (CKD), there is an unmet need for novel biomarkers that reliably track kidney injury, demonstrate treatment-response, and predict outcomes. Here, we investigate the potential of retinal optical coherence tomography (OCT) to achieve these ends in a series of prospective studies of patients with pre-dialysis CKD (including those with a kidney transplant), patients with kidney failure undergoing kidney transplantation, living kidney donors, and healthy volunteers. Compared to health, we observe similar retinal thinning and reduced macular volume in patients with CKD and in those with a kidney transplant. However, the choroidal thinning observed in CKD is not seen in patients with a kidney transplant whose choroids resemble those of healthy volunteers. In CKD, the degree of choroidal thinning relates to falling eGFR and extent of kidney scarring. Following kidney transplantation, choroidal thickness increases rapidly (~10%) and is maintained over 1-year, whereas gradual choroidal thinning is seen during the 12 months following kidney donation. In patients with CKD, retinal and choroidal thickness independently associate with eGFR decline over 2 years. These observations highlight the potential for retinal OCT to act as a non-invasive monitoring and prognostic biomarker of kidney injury.

Abstract Cell Penetrating Peptides (CPPs) are promising anticancer and antimicrobial drugs. We recently reported that a peptide derived from the human mitochondrial/ER membrane-anchored NEET protein, Nutrient Autophagy Factor 1 (NAF-1; NAF-144-67), selectively permeates and kills human metastatic epithelial breast cancer cells (MDA-MB-231), but not control epithelial cells. As cancer cells alter their phenotype during growth and metastasis, we tested whether NAF-144–67 would also be efficient in killing other human epithelial breast cancer cells that may have a different phenotype. Here we report that NAF-144–67 is efficient in killing BT-549, Hs 578T, MDA-MB-436, and MDA-MB-453 breast cancer cells, but that MDA-MB-157 cells are resistant to it. Upon closer examination, we found that MDA-MB-157 cells display a high content of intracellular vesicles and cellular protrusions, compared to MDA-MB-231 cells, that could protect them from NAF-144–67. Inhibiting the formation of intracellular vesicles and dynamics of cellular protrusions of MDA-MB-157 cells, using a protein translation inhibitor (the antibiotic Cycloheximide), rendered these cells highly susceptible to NAF-144–67, suggesting that under certain conditions, the killing effect of CPPs could be augmented when they are applied in combination with an antibiotic or chemotherapy agent. These findings could prove important for the treatment of metastatic cancers with CPPs and/or treatment combinations that include CPPs.

In multiple models of oncolytic virotherapy, it is common to see an early anti-tumor response followed by recurrence. We have previously shown that frontline treatment with oncolytic VSV-IFN-β induces APOBEC proteins, promoting the selection of specific mutations that allow tumor escape. Of these mutations in B16 melanoma escape (ESC) cells, a C-T point mutation in the cold shock domain-containing E1 (CSDE1) gene was present at the highest frequency, which could be used to ambush ESC cells by vaccination with the mutant CSDE1 expressed within the virus. Here, we show that the evolution of viral ESC tumor cells harboring the escape-promoting CSDE1C-T mutation can also be exploited by a virological ambush. By sequential delivery of two oncolytic VSVs in vivo, tumors which would otherwise escape VSV-IFN-β oncolytic virotherapy could be cured. This also facilitated the priming of anti-tumor T cell responses, which could be further exploited using immune checkpoint blockade with the CD200 activation receptor ligand (CD200AR-L) peptide. Our findings here are significant in that they offer the possibility to develop oncolytic viruses as highly specific, escape-targeting viro-immunotherapeutic agents to be used in conjunction with recurrence of tumors following multiple different types of frontline cancer therapies.

Aims: We compared the risks of re-revision and mortality between two-stage and single-stage revision surgeries among patients with infected primary hip arthroplasty. Methods: Patients with a periprosthetic joint infection (PJI) of their primary arthroplasty revised with single-stage or two-stage procedure in England and Wales between 2003 and 2014 were identified from the National Joint Registry. We used Poisson regression with restricted cubic splines to compute hazard ratios (HRs) at different postoperative periods. The total number of revisions and re-revisions undergone by patients was compared between the two strategies. Results: In total, 535 primary hip arthroplasties were revised with single-stage procedure (1,525 person-years) and 1,605 with two-stage procedure (5,885 person-years). All-cause re-revision was higher following single-stage revision, especially in the first three months (HR at 3 months = 1.98 (95% confidence interval (CI) 1.14 to 3.43), p = 0.009). The risks were comparable thereafter. Re-revision for PJI was higher in the first three postoperative months for single-stage revision and waned with time (HR at 3 months = 1.81 (95% CI 1.22 to 2.68), p = 0.003; HR at 6 months = 1.25 (95% CI 0.71 to 2.21), p = 0.441; HR at 12 months = 0.94 (95% CI 0.54 to 1.63), p = 0.819). Patients initially managed with a single-stage revision received fewer revision operations (mean 1.3 (SD 0.7) vs 2.2 (SD 0.6), p < 0.001). Mortality rates were comparable between these two procedures (29/10,000 person-years vs 33/10,000). Conclusion: The risk of unplanned re-revision was lower following two-stage revision, but only in the early postoperative period. The lower overall number of revision procedures associated with a single-stage revision strategy and the equivalent mortality rates to two-stage revision are reassuring. With appropriate counselling, single-stage revision is a viable option for the treatment of hip PJI. Cite this article: Bone Joint Res 2023;12(5):321–330.

Abstract Molecular biology achieves control over complex reaction networks by means of molecular systems that translate a chemical input (such as ligand binding) into an orthogonal chemical output (such as acylation or phosphorylation). We present an artificial molecular translation device that converts a chemical input – the presence of chloride ions – into an unrelated chemical output: modulation of the reactivity of an imidazole moiety, both as a Brønsted base and as a nucleophile. The modulation of reactivity operates through the allosteric remote control of imidazole tautomer states. The reversible coordination of chloride to a urea binding site triggers a cascade of conformational changes in a chain of ethylene-bridged hydrogen-bonded ureas, switching the chain’s global polarity, that in turn modulates the tautomeric equilibrium of a distal imidazole, and hence its reactivity. Switching reactivities of active sites by dynamically controlling their tautomer states is an untapped strategy for building functional molecular devices with allosteric enzyme-like properties.

Realistic and modifiable infection models are required to study the pathogenesis of amphibian chytridiomycosis. Understanding the mechanism by which Batrachochytrium dendrobatidis (Bd) can infect and kill diverse amphibians is key to mitigating this pathogen and preventing further loss of biodiversity. In vitro studies of Bd typically rely on a tryptone based growth media, whereas the recent development of a kidney cell-line infection model has provided a more realistic alternative, without the need for live animals. Here we use expression of a fluorescent reporter to enhance the in vitro cell-line based growth assay, and show that transformed Bd cells are able to invade and grow in an amphibian kidney epithelial cell line (A6) as well as in a new system using a lung fibroblast cell line (DWJ). Both Bd and host cells were modified to express reporter fluorescent proteins, enabling immediate and continuous observation of the infection process without the need for destructive sampling for fixation and staining. Plasmid DNA conferring hygromycin resistance and TdTomato (RFP) expression was delivered to Bd zoospores via electroporation, and continuous antibiotic selection after recovery produced stable fluorescent Bd transformants. Host cells (A6 and DWJ) were transfected before each assay using lipofection to deliver plasmid DNA conferring green fluorescent protein (GFP) and containing an empty shRNA expression cassette. Bd RFP expression allowed easy localisation of fungal cells and identification of endobiotic growth was assisted by host GFP expression, by allowing visualization of the space in the host cell occupied by the invading fungal body. In addition to enabling enhanced live imaging, these methods will facilitate future genetic modification and characterisation of specific genes and their effect on Bd virulence.

The neuronal differences contributing to the etiology of autism spectrum disorder (ASD) are still not well defined. Previous studies have suggested that myelin and axons are disrupted during development in ASD. By combining structural and diffusion MRI techniques, myelin and axons can be assessed using extracellular water, aggregate g-ratio, and a new approach to calculating axonal conduction velocity termed aggregate conduction velocity, which is related to the capacity of the axon to carry information. In this study, several innovative cellular microstructural methods, as measured from magnetic resonance imaging (MRI), are combined to characterize differences between ASD and typically developing adolescent participants in a large cohort. We first examine the relationship between each metric, including microstructural measurements of axonal and intracellular diffusion and the T1w/T2w ratio. We then demonstrate the sensitivity of these metrics by characterizing differences between ASD and neurotypical participants, finding widespread increases in extracellular water in the cortex and decreases in aggregate g-ratio and aggregate conduction velocity throughout the cortex, subcortex, and white matter skeleton. We finally provide evidence that these microstructural differences are associated with higher scores on the Social Communication Questionnaire (SCQ) a commonly used diagnostic tool to assess ASD. This study is the first to reveal that ASD involves MRI-measurable in vivo differences of myelin and axonal development with implications for neuronal and behavioral function. We also introduce a novel formulation for calculating aggregate conduction velocity, that is highly sensitive to these changes. We conclude that ASD may be characterized by otherwise intact structural connectivity but that functional connectivity may be attenuated by network properties affecting neural transmission speed. This effect may explain the putative reliance on local connectivity in contrast to more distal connectivity observed in ASD.

Abstract We investigate positive subtropical low cloud feedback mechanisms in climate models which have performed the CMIP6/CFMIP‐3 AMIP and AMIP uniform +4K experiments while saving CFMIP‐3 process diagnostics on model levels. Our analysis focuses on the trade cumulus/stratocumulus transition region between California and Hawaii, where positive low cloud feedbacks are present in the JJA season. We introduce a methodology to test various positive cloud feedback mechanisms proposed in the literature as the main causes of the low cloud responses in the models. Causal hypotheses are tested by comparing their predictions with the models' responses of clouds, cloud controlling factors, boundary layer depth and temperature/humidity tendencies to climate warming. Changes in boundary layer depth, relative humidity in the cloud layer, convective moistening rate and large‐scale humidity advection at the top of the boundary layer are shown to be crucial for identifying the main causes of the low cloud reductions in the models. For the cases examined, our approach narrows down the seven mechanisms considered to between one and three remaining candidates for each model. No single mechanism considered can explain the feedback in all of the models at the locations examined, but the surface latent heat flux/convective entrainment mechanism remains a candidate for BCC‐CSM2‐MR, IPSL‐CM6A‐LR, and MRI‐ESM2.0, while the surface upwelling longwave mechanism remains for CESM2, HadGEM3‐GC3.1‐LL, and MIROC6.

The impact of the coronavirus disease 2019 (COVID-19) pandemic has been immense, and it continues to have lasting repercussions. While the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus primarily infects the respiratory system, other organ systems are affected, including the liver. Scientific knowledge on the role of SARS-CoV-2 infection and liver injury has evolved rapidly, with recent data suggesting specific hepatotropism of SARS-CoV-2. Moreover, additional concerns have been raised in regard to long-term liver damage, related to emerging cases of post-COVID-19 cholangiopathy and chronic cholestasis. Great effort has also been focused on studying how specific subpopulations with chronic medical conditions might be disproportionately impacted by COVID-19. One such population includes individuals with chronic liver disease (CLD) and cirrhosis, with an expanding body of research indicating these patients being particularly susceptible to adverse outcomes. In this review, we provide an updated summary on the current pathogenesis and mechanism of liver injury in the setting of SARS-CoV-2 infection, the association between health outcomes and SARS-CoV-2 infection in patients with CLD, and the unique consequences of the COVID-19 pandemic on the routine care of patients with CLD.

Abstract Background Adverse childhood experiences (ACEs) can have severe negative impacts on childhood and adult health via worsened school engagement and educational outcomes. This study seeks to identify the relative importance of various ACEs in predicting school engagement. Methods We analyzed data from the National Survey of Children’s Health for school-aged children (ages 6-17) for 2018 and 2019. The primary outcome was school engagement, measured through three variables: repeating a grade, doing required homework, and caring about doing well in school. We conducted three logistic regression models with dominance analyses to identify the relative importance of ACE variables in predicting school engagement outcomes. Results In unadjusted and adjusted dominance analyses, parental incarceration was the most important ACE in predicting repeating a grade. Living in a household in which it was hard to cover basics like food or housing was the most important ACE in predicting doing required homework and caring about doing well in school. Discussion Our study points toward the large influence of out-of-school factors on school engagement. Parental incarceration and economic hardship, the most important predictors of engagement, are issues that can be addressed and mitigated through policy interventions. With limited funds available for education and public health interventions, it is crucial that these two ACEs be priority considerations when developing policy. A multi-faceted approach that reduces the incarcerated population, encourages economic well-being, and emphasizes early-childhood education has the potential to significantly improve school engagement in vulnerable populations and ultimately advance social equity.

Abstract Low cloud feedback in global warming projections by climate models is characterized by its positive sign, the mechanism of which is not well understood. Here we propose that the positive sign is primarily caused by the increase in upward longwave radiation from the sea surface. We devise numerical experiments that enable separation of the feedback into components coming from physically distinct causes. Results of these experiments with a climate model indicate that increases in upward longwave radiation from the sea surface cause warming and absolute drying in the boundary layer, leading to the positive low cloud feedback. The absolute drying results from decrease in surface evaporation, and also from decrease in inversion strength which enhances vertical mixing of drier free tropospheric air into the boundary layer. This mechanism is different from previously proposed understanding that positive low cloud feedback is caused by increases in surface evaporation or vertical moisture contrast.

Cancer immunotherapy aims to unleash the power of the immune system against tumors without the side effects of traditional chemotherapy. Immunotherapeutic methods vary widely, but all follow the same basic principle: overcome the barriers utilized by cancers to avoid immune destruction. These approaches often revolve around classical T cells, such as with CAR T cells and neoantigen vaccines; however, the utility of the innate-like iNKT cell in cancer immunotherapy has gained significant recognition. iNKT cells parallel classic T cell recognition of peptide antigens presented on MHC through their recognition of lipid antigens presented on the MHC I-like molecule CD1d. Altered metabolism and a lipogenic phenotype are essential properties of tumor cells, representing a unique feature that may be exploited by iNKT cells. In this review, we will cover properties of iNKT cells, CD1d, and lipid antigen presentation. Next, we will discuss the cancer lipidome and how it may be exploited by iNKT cells through a window of opportunity. Finally, we will review, in detail, novel lipid antigens for iNKT cells in cancer.

Leptomeningeal disease (LMD) remains a challenging condition with a dismal prognosis. In this case study, we report partial response of LMD in a patient with metastatic large cell neuroendocrine carcinoma following treatment with proton craniospinal irradiation (CSI), bevacizumab, and pembrolizumab. Two years after the initial diagnosis, he presented with LMD. He underwent proton CSI with bevacizumab followed by combination therapy with pembrolizumab and bevacizumab. He had a partial disease response with progression-free survival after LMD diagnosis of 4.6 months. He unfortunately developed pembrolizumab induced hypophysitis, after which he experienced rapid neurologic clinical progression. Overall, this novel combination led to a durable partial response which warrants prospective evaluation.

Abstract Cloud feedbacks are the leading cause of uncertainty in climate sensitivity. The complex coupling between clouds and the large‐scale circulation in the tropics contributes to this uncertainty. To address this problem, the coupling between clouds and circulation in the latest generation of climate models is compared to observations. Significant biases are identified in the models. The implications of these biases are assessed by combining observations of the present day with future changes predicted by models to calculate observationally constrained feedbacks. For the dynamic cloud feedback (i.e., due to changes in circulation), the observationally constrained values are consistently larger than the model‐only values. This is due to models failing to capture a nonlinear minimum in cloud brightness for weakly descending regimes. Consequently, while the models consistently predict that these regimes increase in frequency in association with a weakening tropical circulation, they underestimate the positive cloud feedback associated with this increase.

Introduction The Florida-California Cancer Research, Education, and Engagement (CaRE 2 ) Health Equity Center is a triad partnership committed to increasing institutional capacity for cancer disparity research, the diversity of the cancer workforce, and community empowerment. This article provides an overview of the structure, process innovations, and initial outcomes from the first 4 years of the CaRE 2 triad partnership. Methods CaRE 2 serves diverse populations in Florida and California using a “molecule to the community and back” model. We prioritize research on the complex intersection of biological, environmental, and social determinants health, working together with scientific and health disparities communities, sharing expertise across institutions, bidirectional training, and community outreach. Partnership progress and outcomes were assessed using mixed methods and four Program Steering Committee meetings. Results Research capacity was increased through development of a Living Repository of 81 cancer model systems from minority patients for novel cancer drug development. CaRE 2 funded 15 scientific projects resulting in 38 publications. Workforce diversity entailed supporting 94 cancer trainees (92 URM) and 34 ESIs (32 URM) who coauthored 313 CaRE 2 -related publications and received 48 grants. Community empowerment was promoted via outreaching to more than 3000 individuals, training 145 community cancer advocates (including 28 Community Scientist Advocates), and publishing 10 community reports. CaRE 2 members and trainees together have published 639 articles, received 61 grants, and 57 awards. Conclusion The CaRE 2 partnership has achieved its initial aims. Infrastructure for translational cancer research was expanded at one partner institution, and cancer disparities research was expanded at the two cancer centers.

Background: African Americans (AA), Caribbeans (CA), and Hispanic/Latinx Americans (HL) experience higher rates of poor health and disease as compared to their non-Hispanic White counterparts. Research participation by older, ethnically diverse adults is essential in the effort to reduce these health disparities; yet they have lower enrollment and retention in health research. Little is known concerning enablers and barriers for older adults of diverse ethnic backgrounds living in the United States to participate in health research. Objective: The aim of this study was to discover the generational perceptions of health issues and research by race and age of AA, CA, and HL. Methods: Recruitment was by multiple methods of community outreach. Induction of themes was by constant comparison and thematic analysis of 86 transcripts from focus groups of three ethnic minorities by age: N = 363 older (65 years or greater) and younger adults (25-64 years). Results: There were both similarities and differences by race and age concerning perceptions of health and health research. Younger adults expressed a concern for lack of communication of family health history by earlier generations. Older adults value their privacy concerning their health. A common theme was that participation in health research is everyone’s responsibility to help family, brown and black communities for the greater good. Conclusions: This study reinforced the differences in health and health research perceptions among ethnic minorities by generation, implying the need for involving the community’s feedback in the design of health studies. Further implications are the consideration of enablers and barriers toward health research participation as a potential method to reduce health disparities.

ABSTRACT Rapid diagnostic tests (RDTs) that detect antigen indicative of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection can help in making quick health care decisions and regularly monitoring groups at risk of infection. With many RDT products entering the market, it is important to rapidly evaluate their relative performance. Comparison of clinical evaluation study results is challenged by protocol design variations and study populations. Laboratory assays were developed to quantify nucleocapsid (N) and spike (S) SARS-CoV-2 antigens. Quantification of the two antigens in nasal eluates confirmed higher abundance of N than S antigen. The median concentration of N antigen was 10 times greater than S per genome equivalent. The N antigen assay was used in combination with quantitative reverse transcription (RT)-PCR to qualify a panel composed of recombinant antigens, inactivated virus, and clinical specimen pools. This benchmarking panel was applied to evaluate the analytical performance of the SD Biosensor Standard Q COVID-19 antigen (Ag) test, Abbott Panbio COVID-19 Ag rapid test, Abbott BinaxNOW COVID-19 Ag test, and the LumiraDx SARS-CoV-2 Ag test. The four tests displayed different sensitivities toward the different panel members, but all performed best with the clinical specimen pool. The concentration for a 90% probability of detection across the four tests ranged from 21 to 102 pg/mL of N antigen in the extracted sample. Benchmarking panels provide a quick way to verify the baseline performance of a diagnostic and enable direct comparisons between diagnostic tests. IMPORTANCE This study reports the results for severe acute respiratory syndrome coronavirus-2 (SARS-COV-2) nucleocapsid (N) and spike (S) antigen quantification assays and their performance against clinical reverse transcription (RT)-PCR results, thus describing an open-access quantification method for two important SARS-CoV-2 protein analytes. Characterized N antigen panels were used to evaluate the limits of detection of four different rapid tests for SARS-CoV-2 against multiple sources of nucleocapsid antigen, demonstrating proof-of-concept materials and methodology to evaluate SARS-CoV-2 rapid antigen detection tests. Quantification of N antigen was used to characterize the relationship between viral count and antigen concentration among clinical samples and panel members of both clinical sample and viral culture origin. This contributes to a deeper understanding of protein antigen and molecular analytes and presents analytical methods complementary to clinical evaluation for characterizing the performance of both laboratory-based and point-of-care rapid diagnostics for SARS-CoV-2.

This survey study aimed to assess the willingness of culturally diverse older adults to participate in COVID-19 research. The majority of the 276 participants were women (81%, n = 223) and Black/African American (62%, n = 172) or White Hispanic (20%, n = 56). A key finding from the survey was less than 1 of 10 respondents would be likely to participate in COVID-19 related research if given the opportunity. There were no differences observed by gender, race or ethnicity. Implications of these findings are considered. These study findings indicate continued effort and better messaging strategies are required to increase awareness that COVID-19 related research needs to include culturally diverse older adults to ensure vaccines and treatments are efficacious in different populations.

Abstract Extracellular vesicles (EVs) are lipid‐membrane nanoparticles that are shed or secreted by many different cell types. The EV research community has rapidly expanded in recent years and is leading efforts to deepen our understanding of EV biological functions in human physiology and pathology. These insights are also providing a foundation on which future EV‐based diagnostics and therapeutics are poised to positively impact human health. However, current limitations in our understanding of EV heterogeneity, cargo loading mechanisms and the nascent development of EV metrology are all areas that have been identified as important scientific challenges. The field of synthetic biology is also contending with the challenge of understanding biological complexity as it seeks to combine multidisciplinary scientific knowledge with engineering principles, to build useful and robust biotechnologies in a responsible manner. Within this context, cell‐free systems have emerged as a powerful suite of in vitro biotechnologies that can be employed to interrogate fundamental biological mechanisms, including the study of aspects of EV biogenesis, or to act as a platform technology for medical biosensors and therapeutic biomanufacturing. Cell‐free gene expression (CFE) systems also enable in vitro protein production, including membrane proteins, and could conceivably be exploited to rationally engineer, or manufacture, EVs loaded with bespoke molecular cargoes for use in foundational or translational EV research. Our pilot data herein, also demonstrates the feasibility of cell‐free EV engineering. In this perspective, we discuss the opportunities and challenges for accelerating EV research and healthcare applications with cell‐free synthetic biology.

Abstract Recently, imputation techniques have been adapted to predict activity values among sparse bioactivity matrices, showing improvements in predictive performance over traditional QSAR models. These models are able to use experimental activity values for auxiliary assays when predicting the activity of a test compound on a specific assay. In this study, we tested three different multi-task imputation techniques on three classification-based toxicity datasets: two of small scale (12 assays each) and one large scale with 417 assays. Moreover, we analyzed in detail the improvements shown by the imputation models. We found that test compounds that were dissimilar to training compounds, as well as test compounds with a large number of experimental values for other assays, showed the largest improvements. We also investigated the impact of sparsity on the improvements seen as well as the relatedness of the assays being considered. Our results show that even a small amount of additional information can provide imputation methods with a strong boost in predictive performance over traditional single task and multi-task predictive models.

Most of the dynamical mass loss from star clusters is thought to be caused by the time variability of the tidal field (“tidal shocks”). Systematic studies of tidal shocks have been hampered by the fact that each tidal history is unique, implying both a reproducibility and a generalization problem. Here we address these issues by investigating how star cluster evolution depends on the statistical properties of its tidal history. We run a large suite of direct N -body simulations of clusters with tidal histories generated from power spectra of a given slope and with different normalizations, which determine the timescales and amplitudes of the shocks, respectively. At fixed normalization (i.e., the same median tidal field strength), the dissolution timescale is nearly independent of the power spectrum slope. However, the dispersion in dissolution timescales, obtained by repeating simulations for different realizations of statistically identical tidal histories, increases with the power spectrum slope. This result means that clusters experiencing high-frequency shocks have more similar mass-loss histories than clusters experiencing low-frequency shocks. The density–mass relationship of the simulated clusters follows a power law with slope between 1.08 and 1.45, except for the lowest normalizations (for which clusters effectively evolve in a static tidal field). Our findings suggest that star cluster evolution can be described statistically from a time-series analysis of its tidal history, which is an important simplification for describing the evolution of the star cluster population during galaxy formation and evolution.

Increasing reports suggest the occurrence of co-infection between Ranaviruses such as Frog Virus 3 (FV3) and the chytrid fungus Batrachochytrium dendrobatidis (Bd) in various amphibian species. However, the potential direct interaction of these two pathogens has not been examined to date. In this study, we investigated whether FV3 can interact with Bd in vitro using qPCR, conventional microscopy, and immunofluorescent microscopy. Our results reveal the unexpected ability of FV3 to bind, promote aggregation, productively infect, and significantly increase Bd growth in vitro. To extend these results in vivo, we assessed the impact of FV3 on Xenopus tropicalis frogs previously infected with Bd. Consistent with in vitro results, FV3 exposure to previously Bd-infected X. tropicalis significantly increased Bd loads and decreased the host’s survival.

Many safe and effective severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) vaccinations dramatically reduce risks of coronavirus disease 2019 (COVID‐19) complications and deaths. We aimed to describe cases of SARS‐CoV‐2 infection among patients with chronic liver disease (CLD) and liver transplant (LT) recipients with at least one prior COVID‐19 vaccine dose. The SECURE‐Liver and COVID‐Hep international reporting registries were used to identify laboratory‐confirmed COVID‐19 in CLD and LT patients who received a COVID‐19 vaccination. Of the 342 cases of lab‐confirmed SARS‐CoV‐2 infections in the era after vaccine licensing, 40 patients (21 with CLD and 19 with LT) had at least one prior COVID‐19 vaccination, including 12 who were fully vaccinated (≥2 weeks after second dose). Of the 21 patients with CLD (90% with cirrhosis), 7 (33%) were hospitalized, 1 (5%) was admitted to the intensive care unit (ICU), and 0 died. In the LT cohort (n = 19), there were 6 hospitalizations (32%), including 3 (16%) resulting in mechanical ventilation and 2 (11%) resulting in death. All three cases of severe COVID‐19 occurred in patients who had a single vaccine dose within the last 1‐2 weeks. In contemporary patients with CLD, rates of symptomatic infection, hospitalization, ICU admission, invasive ventilation, and death were numerically higher in unvaccinated individuals. Conclusion: This case series demonstrates the potential for COVID‐19 infections among patients with CLD and LT recipients who had received the COVID‐19 vaccination. Vaccination against SARS‐CoV‐2 appears to result in favorable outcomes as attested by the absence of mechanical ventilation, ICU, or death among fully vaccinated patients.

Abstract Background Eye tracking (ET) is a powerful methodology for studying attentional processes through quantification of eye movements. The precision, usability, and cost-effectiveness of ET render it a promising platform for developing biomarkers for use in clinical trials for autism spectrum disorder (ASD). Methods The Autism Biomarkers Consortium for Clinical Trials conducted a multisite, observational study of 6–11-year-old children with ASD (n = 280) and typical development (TD, n = 119). The ET battery included: Activity Monitoring, Social Interactive, Static Social Scenes, Biological Motion Preference, and Pupillary Light Reflex tasks. A priori, gaze to faces in Activity Monitoring, Social Interactive, and Static Social Scenes tasks were aggregated into an Oculomotor Index of Gaze to Human Faces (OMI) as the primary outcome measure. This work reports on fundamental biomarker properties (data acquisition rates, construct validity, six-week stability, group discrimination, and clinical relationships) derived from these assays that serve as a base for subsequent development of clinical trial biomarker applications. Results All tasks exhibited excellent acquisition rates, met expectations for construct validity, had moderate or high six-week stabilities, and highlighted subsets of the ASD group with distinct biomarker performance. Within ASD, higher OMI was associated with increased memory for faces, decreased autism symptom severity, and higher verbal IQ and pragmatic communication skills. Limitations No specific interventions were administered in this study, limiting information about how ET biomarkers track or predict outcomes in response to treatment. This study did not consider co-occurrence of psychiatric conditions nor specificity in comparison with non-ASD special populations, therefore limiting our understanding of the applicability of outcomes to specific clinical contexts-of-use. Research-grade protocols and equipment were used; further studies are needed to explore deployment in less standardized contexts. Conclusions All ET tasks met expectations regarding biomarker properties, with strongest performance for tasks associated with attention to human faces and weakest performance associated with biological motion preference. Based on these data, the OMI has been accepted to the FDA’s Biomarker Qualification program, providing a path for advancing efforts to develop biomarkers for use in clinical trials.

Abstract Background Backgrounding (BKG), the stage between weaning and finishing, significantly impacts feedlot performance in beef cattle; however, the contributions of the rumen microbiome to this growth stage remain unexplored. A longitudinal study was designed to assess how BKG affects rumen bacterial communities and average daily gain (ADG) in beef cattle. At weaning, 38 calves were randomly assigned to three BKG systems for 55 days (d): a high roughage diet within a dry lot (DL, n = 13); annual cover crop within a strip plot (CC, n = 13); and perennial pasture vegetation within rotational paddocks (PP, n = 12), as before weaning. After BKG, all calves were placed in a feedlot for 142 d and finished with a high energy ration. Calves were weighed periodically from weaning to finishing to determine ADG. Rumen bacterial communities were profiled by collecting fluid samples via oral probe and sequencing the V4 region of the 16S rRNA bacterial gene, at weaning, during BKG and finishing. Results Rumen bacterial communities diverged drastically among calves once they were placed in each BKG system, including sharp decreases in alpha diversity for CC and DL calves only (P

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.

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.

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.

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.

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.

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.

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

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.

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.