Aspergillus nodules: Natural history and the effect of antifungals.

BACKGROUND: Aspergillus nodules are classified as a subset of chronic pulmonary aspergillosis. The optimal management approach is not known as their natural evolution following biopsy, the rate of progression to chronic cavitary pulmonary aspergillosis (CCPA) and the effect of antifungal treatment have not been described. OBJECTIVES: To describe the clinical course of patients diagnosed with Aspergillus nodules and the effect of antifungal treatment. PATIENTS/METHODS: We present a series of 23 patients with histologically confirmed Aspergillus nodules and describe serial imaging, antifungal treatment and progression to other diagnoses. RESULTS: Thirteen patients were diagnosed after a CT-guided biopsy and 10 after surgical resection. Among those who had CT-guided biopsy, 8 did not receive antifungal treatment; the nodule was stable or smaller in all cases on subsequent CT scan after a mean of 15.5 months. However, one patient developed squamous cell carcinoma after 16 months and another developed CCPA after 7 months. Among the 5 patients who received antifungals for at least 4 weeks, the nodule was smaller in 1 and stable in 4. One patient developed CCPA 3 years after the biopsy. No patient who had a surgical resection subsequently had a CCPA diagnosis. CONCLUSION: Most Aspergillus nodules remained stable or improved following biopsy, irrespective of the effect of antifungals. However, CCPA can develop occasionally in patients with Aspergillus nodules and ongoing radiological follow-up may be warranted when the nodule is not resected.

Netrin-1 feedforward mechanism promotes pancreatic cancer liver metastasis via hepatic stellate cell activation, retinoid, and ELF3 signaling.

The biology of metastatic pancreatic ductal adenocarcinoma (PDAC) is distinct from that of the primary tumor due to changes in cell plasticity governed by a distinct transcriptome. Therapeutic strategies that target this distinct biology are needed. We detect an upregulation of the neuronal axon guidance molecule Netrin-1 in PDAC liver metastases that signals through its dependence receptor (DR), uncoordinated-5b (Unc5b), to facilitate metastasis in vitro and in vivo. The mechanism of Netrin-1 induction involves a feedforward loop whereby Netrin-1 on the surface of PDAC-secreted extracellular vesicles prepares the metastatic niche by inducing hepatic stellate cell activation and retinoic acid secretion that in turn upregulates Netrin-1 in disseminated tumor cells via RAR/RXR and Elf3 signaling. While this mechanism promotes PDAC liver metastasis, it also identifies a therapeutic vulnerability, as it can be targeted using anti-Netrin-1 therapy to inhibit metastasis using the Unc5b DR cell death mechanism.

Predictive factors for treatment response and mortality in chronic pulmonary aspergillosis.

OBJECTIVES: Chronic pulmonary aspergillosis (CPA) is associated with significant mortality, and suboptimal antifungal treatment response. We describe predictive factors for treatment response and survival. METHODS: We retrospectively analysed clinical, serological and radiological parameters at baseline and following antifungal treatment in patients with CPA and correlated with clinical and radiological response and survival. RESULTS: Fifty-nine patients were included with a mean age of 61 years. Thirty (51%) had a diagnosis of COPD. On clinical assessment at 6 months, 21 (36%) had clinically improved, 20 (34%) were clinically stable and 15 (25%) had deteriorated. Radiological improvement was observed in 30 (53%), stability in 11 (19%) and deterioration in 16 (28%). Only a lower C-reactive protein (CRP) at baseline was associated with a favourable clinical-radiological response. On univariate analysis, lower CRP, higher albumin, lower Aspergillus IgG and use of inhaled steroids were associated with lower mortality. An overall favourable response at 6 months was associated with lower mortality. CONCLUSION: Inflammatory markers and Aspergillus IgG were predictors of mortality in CPA. This suggests that mortality in CPA is driven mainly by the chronic fungal infection itself rather than the underlying disease, therefore early optimised treatment of CPA may lead to improved outcomes.

Comparison of diagnoses of early-onset sepsis associated with use of Sepsis Risk Calculator versus NICE CG149: a prospective, population-wide cohort study in London, UK, 2020-2021.

OBJECTIVE: We sought to compare the incidence of early-onset sepsis (EOS) in infants ≥34 weeks' gestation identified >24 hours after birth, in hospitals using the Kaiser Permanente Sepsis Risk Calculator (SRC) with hospitals using the National Institute for Health and Care Excellence (NICE) guidance. DESIGN AND SETTING: Prospective observational population-wide cohort study involving all 26 hospitals with neonatal units colocated with maternity services across London (10 using SRC, 16 using NICE). PARTICIPANTS: All live births ≥34 weeks' gestation between September 2020 and August 2021. OUTCOME MEASURES: EOS was defined as isolation of a bacterial pathogen in the blood or cerebrospinal fluid (CSF) culture from birth to 7 days of age. We evaluated the incidence of EOS identified by culture obtained >24 hours to 7 days after birth. We also evaluated the rate empiric antibiotics were commenced >24 hours to 7 days after birth, for a duration of ≥5 days, with negative blood or CSF cultures. RESULTS: Of 99 683 live births, 42 952 (43%) were born in SRC hospitals and 56 731 (57%) in NICE hospitals. The overall incidence of EOS (<72 hours) was 0.64/1000 live births. The incidence of EOS identified >24 hours was 2.3/100 000 (n=1) for SRC vs 7.1/100 000 (n=4) for NICE (OR 0.5, 95% CI (0.1 to 2.7)). This corresponded to (1/20) 5% (SRC) vs (4/45) 8.9% (NICE) of EOS cases (χ=0.3, p=0.59). Empiric antibiotics were commenced >24 hours to 7 days after birth in 4.4/1000 (n=187) for SRC vs 2.9/1000 (n=158) for NICE (OR 1.5, 95% CI (1.2 to 1.9)). 3111 (7%) infants received antibiotics in the first 24 hours in SRC hospitals vs 8428 (15%) in NICE hospitals. CONCLUSION: There was no significant difference in the incidence of EOS identified >24 hours after birth between SRC and NICE hospitals. SRC use was associated with 50% fewer infants receiving antibiotics in the first 24 hours of life.

Adaptive Multioutput Gradient RBF Tracker for Nonlinear and Nonstationary Regression.

Multioutput regression of nonlinear and nonstationary data is largely understudied in both machine learning and control communities. This article develops an adaptive multioutput gradient radial basis function (MGRBF) tracker for online modeling of multioutput nonlinear and nonstationary processes. Specifically, a compact MGRBF network is first constructed with a new two-step training procedure to produce excellent predictive capacity. To improve its tracking ability in fast time-varying scenarios, an adaptive MGRBF (AMGRBF) tracker is proposed, which updates the MGRBF network structure online by replacing the worst performing node with a new node that automatically encodes the newly emerging system state and acts as a perfect local multioutput predictor for the current system state. Extensive experimental results confirm that the proposed AMGRBF tracker significantly outperforms existing state-of-the-art online multioutput regression methods as well as deep-learning-based models, in terms of adaptive modeling accuracy and online computational complexity.

On the role of exploitation and exploration strategies in the maintenance of cognitive biases: Beyond the pursuit of instrumental rewards.

Why can initial biases persist in repeated choice tasks? Previous research has shown that frequent rewards can lure the decision maker into premature exploitation of a supposedly best option, which can result in the persistence of initial biases. Here, we demonstrate that even in the absence of rewards, initial biases can be perpetuated through a positive testing strategy. After eliciting a biased preference for one of two equally rewarding options, participants (N = 203) could sample freely from both options without the lure of any financial rewards. When participants were told to rule out alternatives in this phase, they explored the supposedly worse option and thereby managed to overcome their initial bias. When told to optimize their strategy, however, they exhibited a positive testing strategy resulting in the continued exploitation of the supposedly better option, a bias they maintained in an incentivized choice phase and later judgments. Across all participants, individual tendencies to exploit one option in earlier phases predicted biased behavior in subsequent phases. The findings highlight that not only the pursuit of instrumental rewards can lead to exploitation and the maintenance of initial biases. We discuss potential consequences for interventions.

Deep Cascade Gradient RBF Networks With Output-Relevant Feature Extraction and Adaptation for Nonlinear and Nonstationary Processes.

The main challenge for industrial predictive models is how to effectively deal with big data from high-dimensional processes with nonstationary characteristics. Although deep networks, such as the stacked autoencoder (SAE), can learn useful features from massive data with multilevel architecture, it is difficult to adapt them online to track fast time-varying process dynamics. To integrate feature learning and online adaptation, this article proposes a deep cascade gradient radial basis function (GRBF) network for online modeling and prediction of nonlinear and nonstationary processes. The proposed deep learning method consists of three modules. First, a preliminary prediction result is generated by a GRBF weak predictor, which is further combined with raw input data for feature extraction. By incorporating the prior weak prediction information, deep output-relevant features are extracted using a SAE. Online prediction is finally produced upon the extracted features with a GRBF predictor, whose weights and structure are updated online to capture fast time-varying process characteristics. Three real-world industrial case studies demonstrate that the proposed deep cascade GRBF network outperforms existing state-of-the-art online modeling approaches as well as deep networks, in terms of both online prediction accuracy and computational complexity.

Tumor microbiome links cellular programs and immunity in pancreatic cancer.

Microorganisms are detected in multiple cancer types, including in putatively sterile organs, but the contexts in which they influence oncogenesis or anti-tumor responses in humans remain unclear. We recently developed single-cell analysis of host-microbiome interactions (SAHMI), a computational pipeline to recover and denoise microbial signals from single-cell sequencing of host tissues. Here we use SAHMI to interrogate tumor-microbiome interactions in two human pancreatic cancer cohorts. We identify somatic-cell-associated bacteria in a subset of tumors and their near absence in nonmalignant tissues. These bacteria predominantly pair with tumor cells, and their presence is associated with cell-type-specific gene expression and pathway activities, including cell motility and immune signaling. Modeling results indicate that tumor-infiltrating lymphocytes closely resemble T cells from infected tissue. Finally, using multiple independent datasets, a signature of cell-associated bacteria predicts clinical prognosis. Tumor-microbiome crosstalk may modulate tumorigenesis in pancreatic cancer with implications for clinical management.

Multiple health-related behaviours among Fly-In Fly-Out workers in the mining industry in Australia: A cross-sectional survey during the COVID-19 pandemic.

BACKGROUND: Fly-In-Fly-Out (FIFO) workers travel to work at isolated locations, and rotate continuous workdays with leave periods at home, and such work practice is common in the offshore oil and gas and onshore mining industry worldwide. The COVID-19 pandemic and accompanying public health actions appear to have had a negative impact on several health-related behaviours among the general population. However, little is known about the impact of the COVID-19 pandemic on the health behaviours of FIFO workers, who have shown higher pre-pandemic rates of risky behaviours than the general population in Australia. This study examined the health-related behaviours of FIFO workers in the mining industry during the COVID-19 pandemic. METHODS: A descriptive cross-sectional study was conducted. FIFO workers from an Australian mining company who underwent COVID-19 screening between May and November 2020 completed an online survey about their regular health-related behaviours. The independent sample t-test and Pearson's chi-square test where appropriate were conducted to examine the differences between males and females for the behavioural outcomes. RESULTS: A total of 768 FIFO workers (633 males and 135 females) participated in the study. Prevalence of smoking was high (32%). Males smoked more cigarettes per day than females (15.2±7.0 vs 13.1±7.1, p = .174). Most participants (74.7%) drank alcohol on more than two days per week. Compared to females, more males (20.2% vs 8.0%) consumed alcohol at short-term harmful levels (p = .010). About a third (34.4%) of the workers (33.5% of males and 38.5% of females, p = .264) engaged in inadequate moderate-vigorous exercises/physical activity. About a third (33.1%) of workers (33.7% of males and 30.4% of females; p = .699) had multiple risk behaviours. CONCLUSIONS: Prevalence of multiple risk behaviours was high. Interventions aimed at the prevention of risky health-related behaviours should target the different behavioural patterns and may require emphasis on gender-informed techniques particularly when addressing alcohol consumption.

Real-time 3D analysis during electron tomography using tomviz.

The demand for high-throughput electron tomography is rapidly increasing in biological and material sciences. However, this 3D imaging technique is computationally bottlenecked by alignment and reconstruction which runs from hours to days. We demonstrate real-time tomography with dynamic 3D tomographic visualization to enable rapid interpretation of specimen structure immediately as data is collected on an electron microscope. Using geometrically complex chiral nanoparticles, we show volumetric interpretation can begin in less than 10 minutes and a high-quality tomogram is available within 30 minutes. Real-time tomography is integrated into tomviz, an open-source and cross-platform 3D data analysis tool that contains intuitive graphical user interfaces (GUI), to enable any scientist to characterize biological and material structure in 3D.

Sulfur and oxygen isotope constraints on sulfate sources and neutral rock drainage-related processes at a South African colliery.

Understanding the fundamental controls that govern the generation of mine drainage is essential for waste management strategies. Combining the isotopic composition of water (H and O) and dissolved sulfate (S and O) with hydrogeochemical measurements of surface and groundwater, microbial analysis, composition of sediments and precipitates, and geochemical modeling results in this study we discussed the processes that control mine water chemistry and identified the potential source(s) and possible mechanisms governing sulfate formation and transformation around a South African colliery. Compared to various South African water standards, water samples collected from the surroundings of a coal waste disposal facility had elevated Fe2+ (0.9 to 56.9 mg L-1), Ca (33.0 to 527.0 mg L-1), Mg (6.2 to 457.0 mg L-1), Mn (0.1 to 8.6 mg L-1) and SO4 (19.7 to 3440.8 mg L-1) and circumneutral pH. The pH conditions are mainly controlled by the release of H+ from pyrite oxidation and the subsequent dissolution of carbonates and aluminosilicate minerals. The phases predicted to precipitate by equilibrium calculation were green rusts, ferrihydrite, gypsum, ±epsomite. Low concentrations of deleterious metals in solution are due to their low abundance in the local host rocks, and their attenuation through adsorption onto secondary Fe precipitates and co-precipitation at the elevated pH values. The δ34S values of sulfate are enriched (-6.5 ‰ to +5.6 ‰) compared to that of pyrite sampled from the mine (mean -22.5 ‰) and overlap with that of the organic sulfur of coal from the region (-2.5 to +4.9 ‰). The presence of both sulfur reducing and oxidizing bacteria were detected in the collected sediment samples. Combined, the data are consistent with the dissolved sulfate in the sampled waters from the colliery being derived primarily from pyrite probably with the subordinate contribution of organic sulfur, followed by its partial removal through precipitation and microbially-induced reduction.

Mitigation of SARS-CoV-2 transmission at a large public university.

In Fall 2020, universities saw extensive transmission of SARS-CoV-2 among their populations, threatening health of the university and surrounding communities, and viability of in-person instruction. Here we report a case study at the University of Illinois at Urbana-Champaign, where a multimodal "SHIELD: Target, Test, and Tell" program, with other non-pharmaceutical interventions, was employed to keep classrooms and laboratories open. The program included epidemiological modeling and surveillance, fast/frequent testing using a novel low-cost and scalable saliva-based RT-qPCR assay for SARS-CoV-2 that bypasses RNA extraction, called covidSHIELD, and digital tools for communication and compliance. In Fall 2020, we performed >1,000,000 covidSHIELD tests, positivity rates remained low, we had zero COVID-19-related hospitalizations or deaths amongst our university community, and mortality in the surrounding Champaign County was reduced more than 4-fold relative to expected. This case study shows that fast/frequent testing and other interventions mitigated transmission of SARS-CoV-2 at a large public university.

Hidden mechanical weaknesses within lava domes provided by buried high-porosity hydrothermal alteration zones.

Catastrophic lava dome collapse is considered an unpredictable volcanic hazard because the physical properties, stress conditions, and internal structure of lava domes are not well understood and can change rapidly through time. To explain the locations of dome instabilities at Merapi volcano, Indonesia, we combined geochemical and mineralogical analyses, rock physical property measurements, drone-based photogrammetry, and geoinformatics. We show that a horseshoe-shaped alteration zone that formed in 2014 was subsequently buried by renewed lava extrusion in 2018. Drone data, as well as geomechanical, mineralogical, and oxygen isotope data suggest that this zone is characterized by high-porosity hydrothermally altered materials that are mechanically weak. We additionally show that the new lava dome is currently collapsing along this now-hidden weak alteration zone, highlighting that a detailed understanding of dome architecture, made possible using the monitoring techniques employed here, is essential for assessing hazards associated with dome and edifice failure at volcanoes worldwide.

They Told Me "This Isn't a Hotel": Young People's Experiences and Perceptions of Care When Presenting to the Emergency Department with Suicide-Related Behaviour.

In Australia, the number of young people presenting to the emergency department with mental health concerns, in particular, suicidal behaviour (defined here as suicidal ideation, thoughts, intent and attempts) is increasing. Little is known about the experiences of Australian young people who present to hospital emergency departments with suicidal behaviour. In this qualitative study, we conducted a series of focus groups with 55 young people aged 16-25 years, with a view to developing a framework for youth suicide prevention for Western Australia. The data were analysed using a general inductive analysis approach. We explored the experiences and perceptions of the care and management of 35 young people presenting to Western Australian hospital emergency departments. Participants described a range of negative experiences relating to the emergency department environment, staff attitudes and their treatment by staff. We argue that adapting ED practices and approaches to young people presenting with suicidal thoughts and behaviours based on these findings will result in lower rates of repeated presentations and admissions to hospital and lower rates of suicide attempts and deaths by suicide.

Multi-Output Selective Ensemble Identification of Nonlinear and Nonstationary Industrial Processes.

A key characteristic of biological systems is the ability to update the memory by learning new knowledge and removing out-of-date knowledge so that intelligent decision can be made based on the relevant knowledge acquired in the memory. Inspired by this fundamental biological principle, this article proposes a multi-output selective ensemble regression (SER) for online identification of multi-output nonlinear time-varying industrial processes. Specifically, an adaptive local learning approach is developed to automatically identify and encode a newly emerging process state by fitting a local multi-output linear model based on the multi-output hypothesis testing. This growth strategy ensures a highly diverse and independent local model set. The online modeling is constructed as a multi-output SER predictor by optimizing the combining weights of the selected local multi-output models based on a probability metric. An effective pruning strategy is also developed to remove the unwanted out-of-date local multi-output linear models in order to achieve low online computational complexity without scarifying the prediction accuracy. A simulated two-output process and two real-world identification problems are used to demonstrate the effectiveness of the proposed multi-output SER over a range of benchmark schemes for real-time identification of multi-output nonlinear and nonstationary processes, in terms of both online identification accuracy and computational complexity.

Defective Interferon-Gamma Production Is Common in Chronic Pulmonary Aspergillosis.

BACKGROUND: Immune defects in chronic pulmonary aspergillosis (CPA) are poorly characterized. We compared peripheral blood cytokine profiles in patients with CPA versus healthy controls and explored the relationship with disease severity. METHODS: Interferon-gamma (IFNγ), interleukin (IL)-17, tumor necrosis factor-α, IL-6, IL-12, and IL-10 were measured after in vitro stimulation of whole blood with lipopolysaccharide (LPS), phytohemagglutinin, ß-glucan, zymosan (ZYM), IL-12 or IL-18, and combinations. Clinical parameters and mortality were correlated with cytokine production. RESULTS: Cytokine profiles were evaluated in 133 patients (57.1% male, mean age 61 years). In comparison to controls, patients with CPA had significantly reduced production of IFNγ in response to stimulation with ß-glucan + IL-12 (312 vs 988 pg/mL), LPS + IL-12 (252 vs 1033 pg/mL), ZYM + IL-12 (996 vs 2347 pg/mL), and IL-18 + IL-12 (7193 vs 12 330 pg/mL). Age >60 (hazard ratio [HR], 1.71; 95% confidence interval [CI], 1.00-2.91; P = .05) and chronic obstructive pulmonary disease (HR, 1.69; 95% CI, 1.03-2.78; P = .039) were associated with worse survival, whereas high IFNγ production in response to beta-glucan + IL-12 stimulation (HR, 0.48; 95% CI, .25-0.92; P = .026) was associated with reduced mortality. CONCLUSIONS: Patients with CPA show impaired IFNγ production in peripheral blood in response to stimuli. Defective IFNγ production ability correlates with worse outcomes. Immunotherapy with IFNγ could be beneficial for patients showing impaired IFNγ production in CPA.

Mental Well-Being during COVID-19: A Cross-Sectional Study of Fly-In Fly-Out Workers in the Mining Industry in Australia.

Coronavirus disease 2019 (COVID-19) has devastated the world, and its mental health impact has been recognized in the general population. However, little is known about the mental health impact of COVID-19 on fly-in fly-out (FIFO) workers, who are flown to temporarily stay and work in remote areas, during this pandemic. This study examined the mental well-being of FIFO workers in the mining industry during COVID-19 restrictions in Western Australia. An online survey was conducted between May to November 2020 among (N = 842) FIFO workers who underwent COVID-19 screening at a large mining company in Western Australia. The mental well-being score among workers was higher than population norms. One-way ANOVA with Bonferroni post-hoc tests showed significant differences in mental well-being by age, being placed under travel quarantine, undertaking self-isolation, impact of social distance guidelines, and experience of COVID-19 related symptoms. Multiple linear regression analysis showed workers who were younger, placed under travel quarantine and experienced two or more COVID-19 related symptoms were more likely to have worse mental well-being. Acknowledging the negative emotions and distress experiences among the vulnerable groups could help in providing suitable support to help lessen these negative experiences in FIFO workers.

Genetic Drivers of Ileal Neuroendocrine Tumors.

The genetic causes of ileal neuroendocrine tumors (ileal NETs, or I-NETs) have been a mystery. For most types of tumors, key genes were revealed by large scale genomic sequencing that demonstrated recurrent mutations of specific oncogenes or tumor suppressors. In contrast, genomic sequencing of ileal NETs demonstrated a distinct lack of recurrently mutated genes, suggesting that the mechanisms that drive the formation of I-NETs may be quite different than the cell-intrinsic mutations that drive the formation of other tumor types. However, recent mouse studies have identified the IGF2 and RB1 pathways in the formation of ileal NETs, which is supported by the subsequent analysis of patient samples. Thus, ileal NETs no longer appear to be a cancer without genetic causes.

The Circadian Clock Gene, Bmal1, Regulates Intestinal Stem Cell Signaling and Represses Tumor Initiation.

BACKGROUND & AIMS: Circadian rhythms are daily physiological oscillations driven by the circadian clock: a 24-hour transcriptional timekeeper that regulates hormones, inflammation, and metabolism. Circadian rhythms are known to be important for health, but whether their loss contributes to colorectal cancer is not known. We tested the nonredundant clock gene Bmal1 in intestinal homeostasis and tumorigenesis, using the Apcmin model of colorectal cancer. METHODS: Bmal1 mutant, epithelium-conditional Bmal1 mutant, and photoperiod (day/night cycle) disrupted mice bearing the Apcmin allele were assessed for tumorigenesis. Tumors and normal nontransformed tissue were characterized. Intestinal organoids were assessed for circadian transcription rhythms by RNA sequencing, and in vivo and organoid assays were used to test Bmal1-dependent proliferation and self-renewal. RESULTS: Loss of Bmal1 or circadian photoperiod increases tumor initiation. In the intestinal epithelium the clock regulates transcripts involved in regeneration and intestinal stem cell signaling. Tumors have no self-autonomous clock function and only weak clock function in vivo. Apcmin clock-disrupted tumors show high Yes-associated protein 1 (Hippo signaling) activity but show low Wnt (Wingless and Int-1) activity. Intestinal organoid assays show that loss of Bmal1 increases self-renewal in a Yes-associated protein 1-dependent manner. CONCLUSIONS: Bmal1 regulates intestinal stem cell pathways, including Hippo signaling, and the loss of circadian rhythms potentiates tumor initiation. Transcript profiling: GEO accession number: GSE157357.

Sunda arc mantle source δ18O value revealed by intracrystal isotope analysis.

Magma plumbing systems underlying subduction zone volcanoes extend from the mantle through the overlying crust and facilitate protracted fractional crystallisation, assimilation, and mixing, which frequently obscures a clear view of mantle source compositions. In order to see through this crustal noise, we present intracrystal Secondary Ion Mass Spectrometry (SIMS) δ18O values in clinopyroxene from Merapi, Kelut, Batur, and Agung volcanoes in the Sunda arc, Indonesia, under which the thickness of the crust decreases from ca. 30 km at Merapi to ≤20 km at Agung. Here we show that mean clinopyroxene δ18O values decrease concomitantly with crustal thickness and that lavas from Agung possess mantle-like He-Sr-Nd-Pb isotope ratios and clinopyroxene mean equilibrium melt δ18O values of 5.7 ‰ (±0.2 1 SD) indistinguishable from the δ18O range for Mid Ocean Ridge Basalt (MORB). The oxygen isotope composition of the mantle underlying the East Sunda Arc is therefore largely unaffected by subduction-driven metasomatism and may thus represent a sediment-poor arc end-member.