Successful Embolization of a Direct Carotid Cavernous Fistula under Gadolinium-Based Angiography.

Endovascular neurointervention is typically performed with iodinated contrast medium (ICM) under fluoroscopy. However, some patients may be contraindicated to such procedures based on their sensitivity to ICM. In this report, we describe a case of successful coil embolization of a direct carotid cavernous fistula using angiography with gadolinium-based contrast agents in a patient with severe allergic reaction to ICM. The clinical decision-making for this patient was further complicated by comorbidities of renal impairment, drug allergies, and previously severe gastrointestinal bleeding.

Land surface conductance linked to precipitation: Co-evolution of vegetation and climate in Earth system models.

Vegetation and precipitation are known to fundamentally influence each other. However, this interdependence is not fully represented in climate models because the characteristics of land surface (canopy) conductance to water vapor and CO2 are determined independently of precipitation. Working within a coupled atmosphere and land modelling framework (CAM6/CLM5; coupled Community Atmosphere Model v6/Community Land Model v5), we have developed a new theoretical approach to characterizing land surface conductance by explicitly linking its dynamic properties to local precipitation, a robust proxy for moisture available to vegetation. This will enable regional surface conductance characteristics to shift fluidly with climate change in simulations, consistent with general principles of co-evolution of vegetation and climate. Testing within the CAM6/CLM5 framework shows that climate simulations incorporating the new theory outperform current default configurations across several error metrics for core output variables when measured against observational data. In climate simulations for the end of this century the new, adaptive stomatal conductance scheme provides a revised prognosis for average and extreme temperatures over several large regions, with increased primary productivity through central and east Asia, and higher rainfall through North Africa and the Middle East. The new projections also reveal more frequent heatwaves than originally estimated for the south-eastern US and sub-Saharan Africa but less frequent heatwaves across east Europe and northeast Asia. These developments have implications for evaluating food security and risks from extreme temperatures in areas that are vulnerable to climate change.

Emergent constraints on carbon budgets as a function of global warming.

Earth System Models (ESMs) continue to diagnose a wide range of carbon budgets for each level of global warming. Here, we present emergent constraints on the carbon budget as a function of global warming, which combine the available ESM historical simulations and future projections for a range of scenarios, with observational estimates of global warming and anthropogenic CO2 emissions to the present day. We estimate mean and likely ranges for cumulative carbon budgets for the Paris targets of 1.5 °C and 2 °C of global warming of 812 [691, 933] PgC and 1048 [881, 1216] PgC, which are more than 10% larger than the ensemble mean values from the CMIP6 models. The linearity between cumulative emissions and global warming is found to be maintained at least until 4 °C, and is consistent with an effective Transient Climate Response to Emissions (eTCRE) of 2.1 [1.8, 2.6] °C/1000PgC, from a global warming of 1.2 °C onwards.

Compound Activity Prediction with Dose-Dependent Transcriptomic Profiles and Deep Learning.

Predicting compound activity in assays is a long-standing challenge in drug discovery. Computational models based on compound-induced gene expression signatures from a single profiling assay have shown promise toward predicting compound activity in other, seemingly unrelated, assays. Applications of such models include predicting mechanisms-of-action (MoA) for phenotypic hits, identifying off-target activities, and identifying polypharmacologies. Here, we introduce transcriptomics-to-activity transformer (TAT) models that leverage gene expression profiles observed over compound treatment at multiple concentrations to predict the compound activity in other biochemical or cellular assays. We built TAT models based on gene expression data from a RASL-seq assay to predict the activity of 2692 compounds in 262 dose-response assays. We obtained useful models for 51% of the assays, as determined through a realistic held-out set. Prospectively, we experimentally validated the activity predictions of a TAT model in a malaria inhibition assay. With a 63% hit rate, TAT successfully identified several submicromolar malaria inhibitors. Our results thus demonstrate the potential of transcriptomic responses over compound concentration and the TAT modeling framework as a cost-efficient way to identify the bioactivities of promising compounds across many assays.

A theory of demographic optimality in forests.

Carbon uptake by the land is a key determinant of future climate change. Unfortunately, Dynamic Global Vegetation Models have many unknown internal parameters which leads to significant uncertainty in projections of the future land carbon sink. By contrast, observed forest inventories in both Amazonia and the USA show strikingly common tree-size distributions, pointing to a simpler modelling paradigm. The curvature of these size-distributions is related to the ratio of mortality to growth in Demographic Equilibrium Theory (DET). We extend DET to include recruitment limited by competitive exclusion from existing trees. From this, we find simultaneous maxima of tree density and biomass in terms of respectively the ratio of mortality to growth and the proportion of primary productivity allocated to reproduction, an idea we call Demographic Optimality (DO). Combining DO with the ratio of mortality to growth common to the US and Amazon forests, results in the prediction that about an eighth of productivity should be allocated to reproduction, which is broadly consistent with observations. Another prediction of the model is that seed mortality should decrease with increasing seed size, such that the advantage of having many small seeds is nullified by the higher seed mortality. Demographic Optimality is therefore consistent with the common shape of tree-size distributions seen in very different forests, and an allocation to reproduction that is independent of seed size.

Modelling the impact of forest management and CO2-fertilisation on growth and demography in a Sitka spruce plantation.

Afforestation and reforestation to meet 'Net Zero' emissions targets are considered a necessary policy by many countries. Their potential benefits are usually assessed through forest carbon and growth models. The implementation of vegetation demography gives scope to represent forest management and other size-dependent processes within land surface models (LSMs). In this paper, we evaluate the impact of including management within an LSM that represents demography, using both in-situ and reanalysis climate drivers at a mature, upland Sitka spruce plantation in Northumberland, UK. We compare historical simulations with fixed and variable CO2 concentrations, and with and without tree thinning implemented. Simulations are evaluated against the observed vegetation structure and carbon fluxes. Including thinning and the impact of increasing CO2 concentration ('CO2 fertilisation') gave more realistic estimates of stand-structure and physical characteristics. Historical CO2 fertilisation had a noticeable effect on the Gross Primary Productivity seasonal-diurnal cycle and contributed to approximately 7% higher stand biomass by 2018. The net effect of both processes resulted in a decrease of tree density and biomass, but an increase in tree height and leaf area index.

A rare case of mobile diplopodia mistaken for polydactyly.

We present a rare case of a mobile diplopodia in an infant with disorganization syndrome. This was initially mistaken for polydactyly due to the more typical association between these conditions. The resulting corrective surgery was more extensive and complicated than anticipated, with the removal of a partial foot duplication and reconstruction of residual hindfoot structures, rather than the planned digit amputation. We highlight the association of diplopodia with disorganization syndrome, discuss differentiating diplopodia from polydactyly and describe the surgical management of an unusual case.

UK general practice: Continuing to fail in the care of people with epilepsy?

PURPOSE: To review the standard of clinical care of people with epilepsy (PWE) attending UK general practice after epilepsy was removed from the Quality and Outcomes Framework (QOF) in 2014. METHOD: The case notes of 324 people were reviewed against standards based on National Institute for Health and Care Excellence (NICE), Drug Safety Unit (DSU), and Medicines and Healthcare products Regulatory Agency (MHRA) guidelines. RESULTS: Annual face-to-face review fell significantly (p = 0.021) after the removal of epilepsy from QOF in 2014. Clinical Commissioning Group (CCG) downloaded review rates fell significantly from 95% in 2010 to only 14% in 2016. One hundred and twenty seven (39%) people had seen their GP, and108 (33%) had not seen any doctor, in the past year. One hundred and seventy three (53%) were under specialist care. Forty nine percent not under specialist care had poor control. Two hundred and fifty four (78%) people were on ASM (Anti-Seizure Medication) associated with poor bone health, of these 41 (16%) were prescribed vitamin D. Fourteen women of childbearing age were taking sodium valproate, of whom only 5 (36%) had written confirmation of being counseled of the associated risks. Fifty six (17%) people were non-complaint with prescription collection, of which 66% had documented poor control. There was a discrepancy between actual face-to-face review rates and the review rates the CCG collected. CONCLUSION: This study reveals poor annual review rates for PWE in UK primary care, which have fallen further since the removal of epilepsy from QOF. Unmet needs persist for people with poorly controlled epilepsy not under specialist care, bone health, and the care of women of child bearing age. This study, along with previous work, brings into question the concept of shared care for PWE. Clinical Commissioning Groups should consider investing in the training and employment of GPwSIe (GP with Special Interest in epilepsy) and ENS (Epilepsy Nurse Specialists) to work in the community. The Government should examine re-introducing epilepsy back into QOF with measurable clinical targets and adequate remuneration.

The incidence and prevalence of cardiovascular diseases in gout: a systematic review and meta-analysis.

The aims of this systematic review and meta-analysis were to describe prevalence of cardiovascular disease in gout, compare these results with non-gout controls and consider whether there were differences according to geography. PubMed, Scopus and Web of Science were systematically searched for studies reporting prevalence of any cardiovascular disease in a gout population. Studies with non-representative sampling, where a cohort had been used in another study, small sample size (< 100) and where gout could not be distinguished from other rheumatic conditions were excluded, as were reviews, editorials and comments. Where possible meta-analysis was performed using random-effect models. Twenty-six studies comprising 949,773 gout patients were included in the review. Pooled prevalence estimates were calculated for five cardiovascular diseases: myocardial infarction (2.8%; 95% confidence interval (CI)s 1.6, 5.0), heart failure (8.7%; 95% CI 2.9, 23.8), venous thromboembolism (2.1%; 95% CI 1.2, 3.4), cerebrovascular accident (4.3%; 95% CI 1.8, 9.7) and hypertension (63.9%; 95% CI 24.5, 90.6). Sixteen studies reported comparisons with non-gout controls, illustrating an increased risk in the gout group across all cardiovascular diseases. There were no identifiable reliable patterns when analysing the results by country. Cardiovascular diseases are more prevalent in patients with gout and should prompt vigilance from clinicians to the need to assess and stratify cardiovascular risk. Future research is needed to investigate the link between gout, hyperuricaemia and increased cardiovascular risk and also to establish a more thorough picture of prevalence for less common cardiovascular diseases.

Overshooting tipping point thresholds in a changing climate.

Palaeorecords suggest that the climate system has tipping points, where small changes in forcing cause substantial and irreversible alteration to Earth system components called tipping elements. As atmospheric greenhouse gas concentrations continue to rise as a result of fossil fuel burning, human activity could also trigger tipping, and the impacts would be difficult to adapt to. Previous studies report low global warming thresholds above pre-industrial conditions for key tipping elements such as ice-sheet melt. If so, high contemporary rates of warming imply that exceeding these thresholds is almost inevitable, which is widely assumed to mean that we are now committed to suffering these tipping events. Here we show that this assumption may be flawed, especially for slow-onset tipping elements (such as the collapse of the Atlantic Meridional Overturning Circulation) in our rapidly changing climate. Recently developed theory indicates that a threshold may be temporarily exceeded without prompting a change of system state, if the overshoot time is short compared to the effective timescale of the tipping element. To demonstrate this, we consider transparently simple models of tipping elements with prescribed thresholds, driven by global warming trajectories that peak before returning to stabilize at a global warming level of 1.5 degrees Celsius above the pre-industrial level. These results highlight the importance of accounting for timescales when assessing risks associated with overshooting tipping point thresholds.

Absence of genotoxicity of purified Aloe vera whole leaf dry juice as assessed by an in vitro mouse lymphoma tk assay and an in vivo comet assay in male F344 rats.

Hydroxyanthracene derivatives (HAD) are naturally present in the latex layer of Aloe vera leaf, predominantly as aloins A, B and aloe-emodin. HAD are typically removed from commercial ingestible aloe products through activated charcoal filtration (decolorization). Current research aimed to evaluate genotoxic potential of a purified aloe whole leaf dry juice containing 0.3 ppm of total aloins and non-detectable aloe-emodin (LOD =0.01 ppm) in the L5178Y mouse lymphoma assay (MLA; OECD 490) and in vivo comet assay (OECD 489). No marked increases in mutant frequency at the tk locus were observed in the MLA at concentrations up to 5000 µg/mL for 3 h and 24 h (-S9), and up to a precipitating concentration of 3000 µg/mL for 3 h (+S9) compared to concurrent vehicle control. Relative total growth at the highest analyzable concentrations at 3 h (±S9) and 24 h (-S9) ranged from 64 to 133 %. In the comet assay, no statistically significant increases in DNA strand breaks were detected in the colon or kidney following oral gavage of 500, 1000 or 2000 mg/kg/day in male F344 rats for 2 days compared to concurrent vehicle control. Overall, these findings demonstrated the test article containing minimal HAD is not genotoxic under the described experimental conditions.

A pilot study assessing the similarity between core outcome sets and outcomes included in health technology assessments.

Objective: Core outcome sets (COS) are an agreed standardised collection of outcomes created with representation from all key stakeholders (such as patients, clinicians, researchers), which should be reported as a minimum for all trials in that corresponding clinical area. There has been little research investigating the use of core outcomes in Health technology assessments (HTAs) and none in non-oncology HTAs. This study aimed to assess the similarity between COS and HTA outcomes. Methods: Ten COS published between 2015 and 2019 were selected, with patient participation taken as a proxy measure for a high quality COS. The INAHTA database was used as a source to identify relevant HTAs, which were accessed through the hyperlinks provided. Outcomes selected for these assessments were categorised as either a specific, partial or no match compared to the COS. An additional cohort of non-oncology HTAs published between 2019 and 2021 were identified from the NICE website and compared against a relevant COS. Results: Six hundred and fifty-one HTAs were matched to the ten COS areas, of which 119 were reviewed. Of a possible 1318 core outcome matches, there were 562 (43%) matches, 413 (31%) specific and 149 (11%) partial. NICE HTA matches against corresponding COS ranged from 44% to 100%, with a total of 78% (73/94) matches, 57 (61%) specific and 16 (17%) partial. Conclusion: Further work is required to promote the awareness and implementation of COS within HTAs. Improved uptake across NICE HTAs is encouraging, demonstrating acceptance of COS by HTA producers.

A spatial emergent constraint on the sensitivity of soil carbon turnover to global warming.

Carbon cycle feedbacks represent large uncertainties in climate change projections, and the response of soil carbon to climate change contributes the greatest uncertainty to this. Future changes in soil carbon depend on changes in litter and root inputs from plants and especially on reductions in the turnover time of soil carbon (τs) with warming. An approximation to the latter term for the top one metre of soil (ΔCs,τ) can be diagnosed from projections made with the CMIP6 and CMIP5 Earth System Models (ESMs), and is found to span a large range even at 2 °C of global warming (-196 ± 117 PgC). Here, we present a constraint on ΔCs,τ, which makes use of current heterotrophic respiration and the spatial variability of τs inferred from observations. This spatial emergent constraint allows us to halve the uncertainty in ΔCs,τ at 2 °C to -232 ± 52 PgC.

Implementation of quantitative microbial risk assessment (QMRA) for public drinking water supplies: Systematic review.

In the more than 15 years since its introduction, quantitative microbial risk assessment (QMRA) has become a widely used technique for assessing population health risk posed by waterborne pathogens. However, the variation in approaches taken for QMRA in relation to drinking water supply is not well understood. This systematic review identifies, categorises, and critically synthesises peer-reviewed and academic case studies of QMRA implementation for existing distributed public drinking water supplies. Thirty-nine English-language, peer-reviewed and academic studies published from 2003 to 2019 were identified. Key findings were synthesised in narrative form. The overall designs of the included studies varied widely, as did the assumptions used in risk calculation, especially in relation to pathogen dose. There was also substantial variation in the degree to which the use of location-specific data weighed with the use of assumptions when performing risk calculation. In general, the included studies' complexity did not appear to be associated with greater result certainty. Factors relating to pathogen dose were commonly influential on risk estimates whereas dose-response parameters tended to be of low relative influence. In two of the included studies, use of the 'susceptible fraction' factor was inconsistent with recognised guidance and potentially led to the underestimation of risk. While approaches and assumptions used in QMRA need not be standardised, improvement in the reporting of QMRA results and uncertainties would be beneficial. It is recommended that future authors consider the water supply QMRA reporting checklist developed for the current review. Consideration of the broad types of uncertainty relevant to QMRA is also recommended. Policy-makers should consider emergent discussion on acute microbial health-based targets when setting normative guidelines. The continued representation of QMRA case studies within peer-reviewed and academic literature would also enhance future implementation. Further research is needed on the optimisation of QMRA resourcing given the application context.

Stomatal optimization based on xylem hydraulics (SOX) improves land surface model simulation of vegetation responses to climate.

Land surface models (LSMs) typically use empirical functions to represent vegetation responses to soil drought. These functions largely neglect recent advances in plant ecophysiology that link xylem hydraulic functioning with stomatal responses to climate. We developed an analytical stomatal optimization model based on xylem hydraulics (SOX) to predict plant responses to drought. Coupling SOX to the Joint UK Land Environment Simulator (JULES) LSM, we conducted a global evaluation of SOX against leaf- and ecosystem-level observations. SOX simulates leaf stomatal conductance responses to climate for woody plants more accurately and parsimoniously than the existing JULES stomatal conductance model. An ecosystem-level evaluation at 70 eddy flux sites shows that SOX decreases the sensitivity of gross primary productivity (GPP) to soil moisture, which improves the model agreement with observations and increases the predicted annual GPP by 30% in relation to JULES. SOX decreases JULES root-mean-square error in GPP by up to 45% in evergreen tropical forests, and can simulate realistic patterns of canopy water potential and soil water dynamics at the studied sites. SOX provides a parsimonious way to incorporate recent advances in plant hydraulics and optimality theory into LSMs, and an alternative to empirical stress factors.

Emergent Constraints on Climate-Carbon Cycle Feedbacks.

PURPOSE OF REVIEW: Feedbacks between CO2-induced climate change and the carbon cycle are now routinely represented in the Earth System Models (ESMs) that are used to make projections of future climate change. The inconclusion of climate-carbon cycle feedbacks in climate projections is an important advance, but has added a significant new source of uncertainty. This review assesses the potential for emergent constraints to reduce the uncertainties associated with climate-carbon cycle feedbacks. RECENT FINDINGS: The emergent constraint technique involves using the full ensemble of models to find an across-ensemble relationship between an observable feature of the Earth System (such as a trend, interannual variation or change in seasonality) and an uncertain aspect of the future. Examples focussing on reducing uncertainties in future atmospheric CO2 concentration, carbon loss from tropical land under warming and CO2 fertilization of mid- and high-latitude photosynthesis are exemplars of these different types of emergent constraints. SUMMARY: The power of emergent constraints is that they use the enduring range in model projections to reduce uncertainty in the future of the real Earth System, but there are also risks that indiscriminate data-mining, and systematic model errors could yield misleading constraints. A hypothesis-driven theory-led approach can overcome these risks and also reveal the true promise of emergent constraints-not just as ways to reduce uncertainty in future climate change but also to catalyse advances in our understanding of the Earth System.

Long-lived particles at the energy frontier: the MATHUSLA physics case.

We examine the theoretical motivations for long-lived particle (LLP) signals at the LHC in a comprehensive survey of standard model (SM) extensions. LLPs are a common prediction of a wide range of theories that address unsolved fundamental mysteries such as naturalness, dark matter, baryogenesis and neutrino masses, and represent a natural and generic possibility for physics beyond the SM (BSM). In most cases the LLP lifetime can be treated as a free parameter from the [Formula: see text]m scale up to the Big Bang Nucleosynthesis limit of [Formula: see text] m. Neutral LLPs with lifetimes above [Formula: see text]100 m are particularly difficult to probe, as the sensitivity of the LHC main detectors is limited by challenging backgrounds, triggers, and small acceptances. MATHUSLA is a proposal for a minimally instrumented, large-volume surface detector near ATLAS or CMS. It would search for neutral LLPs produced in HL-LHC collisions by reconstructing displaced vertices (DVs) in a low-background environment, extending the sensitivity of the main detectors by orders of magnitude in the long-lifetime regime. We study the LLP physics opportunities afforded by a MATHUSLA-like detector at the HL-LHC, assuming backgrounds can be rejected as expected. We develop a model-independent approach to describe the sensitivity of MATHUSLA to BSM LLP signals, and compare it to DV and missing energy searches at ATLAS or CMS. We then explore the BSM motivations for LLPs in considerable detail, presenting a large number of new sensitivity studies. While our discussion is especially oriented towards the long-lifetime regime at MATHUSLA, this survey underlines the importance of a varied LLP search program at the LHC in general. By synthesizing these results into a general discussion of the top-down and bottom-up motivations for LLP searches, it is our aim to demonstrate the exceptional strength and breadth of the physics case for the construction of the MATHUSLA detector.

Mapping the Heterogeneity of Histone Modifications on Hepatitis B Virus DNA Using Liver Needle Biopsies Obtained from Chronically Infected Patients.

Covalently closed circular DNA (cccDNA) forms the basis for replication and persistence of hepatitis B virus (HBV) in the chronically infected liver. We have previously shown that viral transcription is subject to regulation by posttranslational modifications (PTMs) of histone proteins bound to cccDNA through analysis of de novo HBV-infected cell lines. We now report the successful adaptation of this chromatin immunoprecipitation sequencing (ChIPseq) approach for analysis of fine-needle patient liver biopsy specimens to investigate the role of histone PTMs in chronically HBV-infected patients. Using 18 specimens from patients in different stages of chronic HBV infection, our work shows that the profile of histone PTMs in chronic infection is more nuanced than previously observed in in vitro models of acute infection. In line with our previous findings, we find that the majority of HBV-derived sequences are associated with the activating histone PTM H3K4me3. However, we show a striking interpatient variability of its deposition in this patient cohort correlated with viral transcription and patient HBV early antigen (HBeAg) status. Unexpectedly, we detected deposition of the classical inhibitory histone PTM H3K9me3 on HBV-DNA in around half of the patient biopsy specimens, which could not be linked to reduced levels of viral transcripts. Our results show that current in vitro models are unable to fully recapitulate the complex epigenetic landscape of chronic HBV infection observed in vivo and demonstrate that fine-needle liver biopsy specimens can provide sufficient material to further investigate the interaction of viral and host proteins on HBV-DNA.IMPORTANCE Hepatitis B virus (HBV) is a major global health concern, chronically infecting millions of patients and contributing to a rising burden of liver disease. The viral genome forms the basis for chronic infection and has been shown to be subject to regulation by epigenetic mechanisms, such as posttranslational modification of histone proteins. Here, we confirm and expand on previous results by adapting a high-resolution technique for analysis of histone modifications for use with patient-derived fine-needle liver biopsy specimens. Our work highlights that the situation in vivo is more complex than predicted by current in vitro models, for example, by suggesting a novel, noncanonical role of the histone modification H3K9me3 in the HBV life cycle. Importantly, enabling the use of fine-needle liver biopsy specimens for such high-resolution analyses may facilitate further research into the epigenetic regulation of the HBV genome.