Deep-sea hiatus record reveals orbital pacing by 2.4 Myr eccentricity grand cycles.

Astronomical forcing of Earth's climate is embedded in the rhythms of stratigraphic records, most famously as short-period (104-105 year) Milankovitch cycles. Astronomical grand cycles with periods of millions of years also modulate climate variability but have been detected in relatively few proxy records. Here, we apply spectral analysis to a dataset of Cenozoic deep-sea hiatuses to reveal a ~2.4 Myr eccentricity signal, disrupted by episodes of major tectonic forcing. We propose that maxima in the hiatus cycles correspond to orbitally-forced intensification of deep-water circulation and erosive bottom current activity, linked to eccentricity maxima and peaks in insolation and seasonality. A prominent episode of cyclicity disturbance coincides with the Paleocene-Eocene Thermal Maximum (PETM) at ~56 Myr ago, and correlates with a chaotic orbital transition in the Solar System evident in several astronomical solutions. This hints at a potential intriguing coupling between the PETM and Solar System chaos.

Basilar artery occlusion: drip-and-ship versus direct-to-center for mechanical thrombectomy within the Neurovascular Network of Southwest Bavaria (NEVAS).

BACKGROUND: Recent clinical trials revealed a substantial clinical benefit for mechanical thrombectomy (MT) in patients with basilar artery occlusion (BAO). While urban areas are sufficiently covered with comprehensive stroke centers and MT expertise, rural areas lack such resources. Structured telemedical stroke networks offer rural hospitals instant consultation by stroke experts, enabling swift administration of intravenous thrombolysis (IVT) on-site and transportation for MT. For BAO patients, data on performance and clinical outcomes in telemedical stroke networks are lacking. METHODS: We retrospectively analyzed data from patients with acute BAO eligible for MT: those treated directly in our comprehensive stroke center (direct-to-center/DC) and those treated in rural hospitals that were telemedically consulted by the Neurovascular Network of Southwest Bavaria (NEVAS) and transferred to our center for MT (drip-and-ship, DS). Key time intervals, stroke management performance and functional outcome after 90 days were compared. RESULTS: Baseline characteristics, including premorbid status and stroke severity, were comparable. Time from symptom onset to IVT was identical in both groups (118 min). There was a delay of 180 min until recanalization in DS patients, mainly due to patient transport for MT. Procedural treatment time intervals, success of recanalization and complications were comparable. Clinical outcome at 3 months follow-up of DS patients was not inferior to DC patients. CONCLUSION: We show for the first time that patients with BAO in rural areas benefit from a structured telemedicine network such as NEVAS, regarding both on-site processing and drip-and-ship for MT. Clinical outcomes are comparable among DS and DC patients.

[IgG4-related disease: A proteiform pathology with frequent chest manifestations]. / Maladie associée aux IgG4 : une maladie protéiforme aux manifestations thoraciques fréquentes.

INTRODUCTION: While IgG4-related disease (IgG4-RD) was initially described in the early 2000s, its polymorphic clinical manifestations were previously reported under different names ; they have in common the presence of IgG4+ oligoclonal plasma cells and fibrosis. STATE OF THE ART: Ruling out certain differential diagnoses, the diagnosis of IgG4-RD is based on a bundle of clinical, biological and histological features. Chest involvement is variable and can affect the mediastinum, bronchi, parenchyma, pleura and/or, more rarely, bones and (pericardium, aorta, coronary…) vascular structures. The most frequent radiological manifestations are peribronchovascular thickening, mediastinal lymphadenopathy, and nodular or interstitial patterns. Pleural involvement and posterior mediastinal fibrosis are less frequent, while thoracic paravertebral tissue thickening is highly specific. Systemic corticosteroids are the cornerstone of treatment. In case of relapse or as frontline therapy in case of risk factors for relapse and/or poor tolerance of corticosteroids), a steroid-sparing agent (most often rituximab) is added, and biannual maintenance infusions are associated with a lower risk of relapse. PERSPECTIVES: An international consensus has recently led to the development of classification criteria that should standardize the diagnostic approach and homogenize the enrolment of patients in epidemiological as well as therapeutic studies. Other treatments are also under evaluation, including biologics targeting T2 inflammation, CD-19 (inebilizumab, obexelimab), SLAMF7 (elotuzumab) surface proteins, Bruton's tyrosine kinase, and the JAK/STAT pathway. CONCLUSIONS: Substantial progress has been made over recent years in understanding IgG4-RD pathophysiology, and personalized patient care seems to be an achievable medium-term goal.

The effect of mycophenolate mofetil on podocytes in nephrotoxic serum nephritis.

Mycophenolate mofetil (MMF) is applied in proteinuric kidney diseases, but the exact mechanism of its effect on podocytes is still unknown. Our previous in vitro experiments suggested that MMF can ameliorate podocyte damage via restoration of the Ca2+-actin cytoskeleton axis. The goal of this study was to characterize podocyte biology during MMF treatment in nephrotoxic serum (NTS) nephritis (NTN). NTN was induced in three-week old wild-type mice. On day 3, half of the mice were treated with MMF (100 mg/kgBW/d p.o.) for one week. On day 10, we performed proteomic analysis of glomeruli as well as super-resolution imaging of the slit diaphragm. For multiphoton imaging of Ca2+ concentration ([Ca2+]i), the experimental design was repeated in mice expressing podocyte-specific Ca2+ sensor. MMF ameliorated the proteinuria and crescent formation induced by NTS. We identified significant changes in the abundance of proteins involved in Ca2+ signaling and actin cytoskeleton regulation, which was further confirmed by direct [Ca2+]i imaging in podocytes showing decreased Ca2+ levels after MMF treatment. This was associated with a tendency to restoration of podocyte foot process structure. Here, we provide evidence that MPA has a substantial direct effect on podocytes. MMF contributes to improvement of [Ca2+]i and amelioration of the disorganized actin cytoskeleton in podocytes. These data extend the knowledge of direct effects of immunosuppressants on podocytes that may contribute to a more effective treatment of proteinuric glomerulopathies with the least possible side effects.

Earth's interior dynamics drive marine fossil diversity cycles of tens of millions of years.

The fossil record reveals that biotic diversity has fluctuated quasi-cyclically through geological time. However, the causal mechanisms of biotic diversity cycles remain unexplained. Here, we highlight a common, correlatable 36 ± 1 Myr (million years) cycle in the diversity of marine genera as well as in tectonic, sea-level, and macrostratigraphic data over the past 250 Myr of Earth history. The prominence of the 36 ± 1 Myr cycle in tectonic data favors a common-cause mechanism, wherein geological forcing mechanisms drive patterns in both biological diversity and the preserved rock record. In particular, our results suggest that a 36 ± 1 Myr tectono-eustatically driven sea-level cycle may originate from the interaction between the convecting mantle and subducting slabs, thereby pacing mantle-lithospheric deep-water recycling. The 36 ± 1 Myr tectono-eustatic driver of biodiversity is likely related to cyclic continental inundations, with expanding and contracting ecological niches on shelves and in epeiric seas.

Kimberlite eruptions driven by slab flux and subduction angle.

Kimberlites are sourced from thermochemical upwellings which can transport diamonds to the surface of the crust. The majority of kimberlites preserved at the Earth's surface erupted between 250 and 50 million years ago, and have been attributed to changes in plate velocity or mantle plumes. However, these mechanisms fail to explain the presence of strong subduction signatures observed in some Cretaceous kimberlites. This raises the question whether there is a subduction process that unifies our understanding of the timing of kimberlite eruptions. We develop a novel formulation for calculating subduction angle based on trench migration, convergence rate, slab thickness and density to connect the influx of slab material into the mantle with the timing of kimberlite eruptions. We find that subduction angles combined with peaks in slab flux predict pulses of kimberlite eruptions. High rates of subducting slab material trigger mantle return flow that stimulates fertile reservoirs in the mantle. These convective instabilities transport slab-influenced melt to the surface at a distance inbound from the trench corresponding to the subduction angle. Our deep-time slab dip formulation has numerous potential applications including modelling the deep carbon and water cycles, and an improved understanding of subduction-related mineral deposits.

Introduction of laparoscopic nephrectomy for autosomal dominant polycystic kidney disease as the standard procedure.

PURPOSE: Autosomal dominant polycystic kidney disease (ADPKD) is a common hereditary disorder and accounts for 5-10% of all cases of kidney failure. 50% of ADPKD patients reach kidney failure by the age of 58 years requiring dialysis or transplantation. Nephrectomy is performed in up to 20% of patients due to compressive symptoms, renal-related complications or in preparation for kidney transplantation. However, due to the large kidney size in ADPKD, nephrectomy can come with a considerable burden. Here we evaluate our institution's experience of laparoscopic nephrectomy (LN) as an alternative to open nephrectomy (ON) for ADPKD patients. MATERIALS AND METHODS: We report the results of the first 12 consecutive LN for ADPKD from August 2020 to August 2021 in our institution. These results were compared with the 12 most recent performed ON for ADPKD at the same institution (09/2017 to 07/2020). Intra- and postoperative parameters were collected and analyzed. Health related quality of life (HRQoL) was assessed using the SF36 questionnaire. RESULTS: Age, sex, and median preoperative kidney volumes were not significantly different between the two analyzed groups. Intraoperative estimated blood loss was significantly less in the laparoscopic group (33 ml (0-200 ml)) in comparison to the open group (186 ml (0-800 ml)) and postoperative need for blood transfusion was significantly reduced in the laparoscopic group (p = 0.0462). Operative time was significantly longer if LN was performed (158 min (85-227 min)) compared to the open procedure (107 min (56-174 min)) (p = 0.0079). In both groups one postoperative complication Clavien Dindo ≥ 3 occurred with the need of revision surgery. SF36 HRQol questionnaire revealed excellent postoperative quality of life after LN. CONCLUSION: LN in ADPKD patients is a safe and effective operative procedure independent of kidney size with excellent postoperative outcomes and benefits of minimally invasive surgery. Compared with the open procedure patients profit from significantly less need for transfusion with comparable postoperative complication rates. However significant longer operation times need to be taken in account.

[Four types of old patients in the emergency department : A geriatric medicine qualitative and economic viewpoint]. / Vier Typen von alten Patienten in der Notaufnahme : Eine altersmedizinische, qualitative und ökonomische Betrachtung.

BACKGROUND: Lack of clinical management of old patients in the emergency department. QUESTION: How can we manage old patients in the emergency department more effectively, medically and economically? METHODS: Evaluation of current selection and screening methods and recommendations for old patients in the emergency department. Acute inpatient treatment needs, presence of dysfunction in at least two core areas and assessment of advance care needs are examined. RESULT: The identification of old patients in the emergency department as geriatric patients alone shows no control potential. Combining the three test criteria of acute inpatient need for treatment, the presence of dysfunction in at least two core areas and the assessment of advance care needs generates four old patient types that have interesting control potential: the medical traumatology patient, the acute geriatric patient, the rehabilitative geriatric patient, and the ambulatory patient. DISCUSSION: in addition to identifying geriatric patients, screening should map acute inpatient treatment needs, assessment of dysfunction, and analysis of advance care needs to define clinically steerable old patients.

fMRI BOLD and MEG theta power reflect complementary aspects of activity during lexicosemantic decision in adolescents with ASD.

Neuroimaging studies of autism spectrum disorder (ASD) have been predominantly unimodal. While many fMRI studies have reported atypical activity patterns for diverse tasks, the MEG literature in ASD remains comparatively small. Our group recently reported atypically increased event-related theta power in individuals with ASD during lexicosemantic processing. The current multimodal study examined the relationship between fMRI BOLD signal and anatomically-constrained MEG (aMEG) theta power. Thirty-three adolescents with ASD and 23 typically developing (TD) peers took part in both fMRI and MEG scans, during which they distinguished between standard words (SW), animal words (AW), and pseudowords (PW). Regions-of-interest (ROIs) were derived based on task effects detected in BOLD signal and aMEG theta power. BOLD signal and theta power were extracted for each ROI and word condition. Compared to TD participants, increased theta power in the ASD group was found across several time windows and regions including left fusiform and inferior frontal, as well as right angular and anterior cingulate gyri, whereas BOLD signal was significantly increased in the ASD group only in right anterior cingulate gyrus. No significant correlations were observed between BOLD signal and theta power. Findings suggest that the common interpretation of increases in BOLD signal and theta power as 'activation' require careful differentiation, as these reflect largely distinct aspects of regional brain activity. Some group differences in dynamic neural processing detected with aMEG that are likely relevant for lexical processing may be obscured by the hemodynamic signal source and low temporal resolution of fMRI.

Culture of 3D bioprinted bone constructs requires an increased fluid dynamic stimulation.

In vitro flow-induced mechanical stimulation of developing bone tissue constructs has been shown to favor mineral deposition in scaffolds seeded with cells directly exposed to the fluid flow. However, the effect of fluid dynamic parameters, such as shear stress (SS), within 3D bioprinted constructs is still unclear. Thus, this study aimed at correlating the SS levels and the mineral deposition in 3D bioprinted constructs, evaluating the possible dampening effect of the hydrogel. Human mesenchymal stem cells (hMSCs) were embedded in 3D bioprinted porous structures made of alginate and gelatin. 3D bioprinted constructs were cultured in an osteogenic medium assessing the influence of different flow rates (0, 0.7 and 7 ml/min) on calcium and collagen deposition through histology, and bone volume (BV) through micro-computed tomography. Uniform distribution of calcium and collagen was observed in all groups. Nevertheless, BV significantly increased in perfused groups as compared to static control, ranging from 0.35±0.28 mm3, 11.90±8.74 mm3 and 25.81±5.02 mm3 at week 3 to 2.28±0.78 mm3, 22.55±2.45 mm3 and 46.05±5.95 mm3 at week 6 in static, 0.7 and 7 ml/min groups, respectively. SS values on construct fibers in the range 10-100 mPa in 7 ml/min samples were twice as high as those in 0.7 ml/min samples showing the same trend of BV. The obtained results suggest that it is necessary to enhance the flow-induced mechanical stimulation of cell-embedding hydrogels to increase the amount of mineral deposited by hMSCs, compared to what is generally reported for the development of in vitro bone constructs. STATEMENT OF SIGNIFICANCE: In this study, we evaluated for the first time how the hydrogel structure dampens the effect of flow-induced mechanical stimulation during the culture of 3D bioprinted bone tissue constructs. By combining computational and experimental techniques we demonstrated that those shear stress thresholds generally considered for culturing cells seeded on scaffold surface, are no longer applicable when cells are embedded in 3D bioprinted constructs. Significantly, more bone volume was formed in constructs exposed to shear stress values generally considered as detrimental than in constructs exposed shear stress values generally considered as beneficial after 3 weeks and 6 weeks of dynamic culture using a perfusion bioreactor.

Perspectives on in silico bone mechanobiology: computational modelling of multicellular systems.

Bone mechanobiology is the study of the physical, biological and mechanical processes that continuously affect the multiscale multicellular system of the bone from the organ to the molecular scale. Current knowledge derives from experimental studies, which are often limited to gathering qualitative data in a cross-sectional manner, up to a restricted number of time points. Moreover, the simultaneous collection of information about 3D bone microarchitecture, cell activity as well as protein distribution and level is still a challenge. In silico models can expand qualitative information with hypothetical quantitative systems, which allow quantification, testing and comparison to existing quantifiable experimental data. An overview of multiscale, multiphysics, agent-based and hybrid techniques and their applications to bone mechanobiology is provided in the present review. The study analysed how mechanical signals, cells and proteins can be modelled in silico to represent bone remodelling and adaptation. Hybrid modelling of bone mechanobiology could combine the methods used in multiscale, multiphysics and agent-based models into a single model, leading to a unified and comprehensive understanding of bone mechanobiology. Numerical simulations of in vivo multicellular systems aided in hypothesis testing of such in silico models. Recently, in silico trials have been used to illustrate the mechanobiology of cells and signalling pathways in clinical biopsies and animal bones, including the effects of drugs on single cells and signalling pathways up to the organ level. This improved understanding may lead to the identification of novel therapies for degenerative diseases such as osteoporosis.

Evaluation of kurtosis-corrected sound exposure level as a metric for predicting onset of hearing threshold shifts in harbor porpoises (Phocoena phocoena).

Application of a kurtosis correction to frequency-weighted sound exposure level (SEL) improved predictions of risk of hearing damage in humans and terrestrial mammals for sound exposures with different degrees of impulsiveness. To assess whether kurtosis corrections may lead to improved predictions for marine mammals, corrections were applied to temporary threshold shift (TTS) growth measurements for harbor porpoises (Phocoena phocoena) exposed to different sounds. Kurtosis-corrected frequency-weighted SEL predicted accurately the growth of low levels of TTS (TTS1-4 < 10 dB) for intermittent sounds with short (1-13 s) silence intervals but was not consistent with frequency-weighted SEL data for continuous sound exposures.

Post-extinction recovery of the Phanerozoic oceans and biodiversity hotspots.

The fossil record of marine invertebrates has long fuelled the debate as to whether or not there are limits to global diversity in the sea1-5. Ecological theory states that, as diversity grows and ecological niches are filled, the strengthening of biological interactions imposes limits on diversity6,7. However, the extent to which biological interactions have constrained the growth of diversity over evolutionary time remains an open question1-5,8-11. Here we present a regional diversification model that reproduces the main Phanerozoic eon trends in the global diversity of marine invertebrates after imposing mass extinctions. We find that the dynamics of global diversity are best described by a diversification model that operates widely within the exponential growth regime of a logistic function. A spatially resolved analysis of the ratio of diversity to carrying capacity reveals that less than 2% of the global flooded continental area throughout the Phanerozoic exhibits diversity levels approaching ecological saturation. We attribute the overall increase in global diversity during the Late Mesozoic and Cenozoic eras to the development of diversity hotspots under prolonged conditions of Earth system stability and maximum continental fragmentation. We call this the 'diversity hotspots hypothesis', which we propose as a non-mutually exclusive alternative to the hypothesis that the Mesozoic marine revolution led this macroevolutionary trend12,13.

Knowledge and attitudes towards epilepsy: A survey of people with epilepsy.

PROBLEM: Many studies focus on knowledge and attitudes of unaffected people towards epilepsy and people with epilepsy (PWE). The perspective of PWE themselves is much less explored. METHODS: We invited PWE in Germany to answer a questionnaire on their knowledge and attitudes towards epilepsy and PWE. RESULTS: The questionnaire was completed by 230 PWE (median age: 40 years; min./max.: 19/83; 66 % female). Of PWE, 22 % thought that PWE are more helpful, and 10 % thought that PWE are friendlier than other people. Nevertheless, reservations about relationships and friendships with other PWE existed: of the participants, only 74 % would definitely go on a date with another PWE, and 90 % would definitely include another PWE they liked into their circle of friends. Swimming was judged as more dangerous for PWE than for healthy people by 71 % of PWE. Of PWE, 86 % correctly assumed it was not useful to hold a person having a seizure to the ground. Putting a solid object in the mouth was considered not useful by 85 % of PWE. Of PWE, 20 % would definitely administer an available emergency medication if another PWE had a seizure. For 67 % of PWE, certain preconditions should have to be fulfilled such as an available document with instructions. Of PWE, 11 % stated they would not administer an available emergency medication if another PWE had a seizure. CONCLUSION: Although positive attitudes of PWE towards other PWE exist, we also found some reservations calling for psychosocial support. Most PWE had sufficient knowledge about risks of certain activities and about measures to be taken during a seizure. Nevertheless, a small group of PWE showed knowledge gaps. Thus, educational support still seems essential.

Evolution of Earth's tectonic carbon conveyor belt.

Concealed deep beneath the oceans is a carbon conveyor belt, propelled by plate tectonics. Our understanding of its modern functioning is underpinned by direct observations, but its variability through time has been poorly quantified. Here we reconstruct oceanic plate carbon reservoirs and track the fate of subducted carbon using thermodynamic modelling. In the Mesozoic era, 250 to 66 million years ago, plate tectonic processes had a pivotal role in driving climate change. Triassic-Jurassic period cooling correlates with a reduction in solid Earth outgassing, whereas Cretaceous period greenhouse conditions can be linked to a doubling in outgassing, driven by high-speed plate tectonics. The associated 'carbon subduction superflux' into the subcontinental mantle may have sparked North American diamond formation. In the Cenozoic era, continental collisions slowed seafloor spreading, reducing tectonically driven outgassing, while deep-sea carbonate sediments emerged as the Earth's largest carbon sink. Subduction and devolatilization of this reservoir beneath volcanic arcs led to a Cenozoic increase in carbon outgassing, surpassing mid-ocean ridges as the dominant source of carbon emissions 20 million years ago. An increase in solid Earth carbon emissions during Cenozoic cooling requires an increase in continental silicate weathering flux to draw down atmospheric carbon dioxide, challenging previous views and providing boundary conditions for future carbon cycle models.

Impact of AJCC 8th edition staging system and definitive treatment choice on the prognosis of complete responders with p16+ and p16- oropharyngeal squamous cell carcinomas.

OBJECTIVES: To identify predictors of overall survival (OS) in oropharyngeal squamous cell carcinoma (OPSCC) patients who achieved complete response (CR). METHODS: We performed a retrospective study of OPSCC patients who achieved CR from a single academic medical center. Associations between OS, AJCC 8th edition staging system, definitive treatment choice, smoking history, and p16 status were assessed. RESULTS: p16+ status was associated with favorable prognosis for CR (p < 0.001) but not non-CR (p = 0.67) patients. For early stage, p16+ OPSCC patients who achieved CR, surgery + adjuvant radiation (RT) treatment was more durable compared to concurrent chemoradiation (CRT), particularly in smokers. CONCLUSIONS: Curative intent treatment choice and smoking history has an impact on the long-term OS of the CR p16+ OPSCC cohort. Prospective studies to define the optimal multi-modality treatment option to manage p16+ OPSCC patients is needed.

Constraining the response of continental-scale groundwater flow to climate change.

Numerical models of groundwater flow play a critical role for water management scenarios under climate extremes. Large-scale models play a key role in determining long range flow pathways from continental interiors to the oceans, yet struggle to simulate the local flow patterns offered by small-scale models. We have developed a highly scalable numerical framework to model continental groundwater flow which capture the intricate flow pathways between deep aquifers and the near-surface. The coupled thermal-hydraulic basin structure is inferred from hydraulic head measurements, recharge estimates from geochemical proxies, and borehole temperature data using a Bayesian framework. We use it to model the deep groundwater flow beneath the Sydney-Gunnedah-Bowen Basin, part of Australia's largest aquifer system. Coastal aquifers have flow rates of up to 0.3 m/day, and a corresponding groundwater residence time of just 2,000 years. In contrast, our model predicts slow flow rates of 0.005 m/day for inland aquifers, resulting in a groundwater residence time of [Formula: see text] 400,000 years. Perturbing the model to account for a drop in borehole water levels since 2000, we find that lengthened inland flow pathways depart significantly from pre-2000 streamlines as groundwater is drawn further from recharge zones in a drying climate. Our results illustrate that progressively increasing water extraction from inland aquifers may permanently alter long-range flow pathways. Our open-source modelling approach can be extended to any basin and may help inform policies on the sustainable management of groundwater.

Protocol for a randomized controlled multicenter trial assessing the efficacy of leuprorelin for severe polycystic liver disease: the AGAINST-PLD study.

BACKGROUND: In patients with severe polycystic liver disease (PLD), there is a need for new treatments. Estrogens and possibly other female sex hormones stimulate growth in PLD. In some patients, liver volume decreases after menopause. Female sex hormones could therefore be a target for therapy. The AGAINST-PLD study will examine the efficacy of the GnRH agonist leuprorelin, which blocks the production of estrogen and other sex hormones, to reduce liver growth in PLD. METHODS: The AGAINST-PLD study is an investigator-driven, multicenter, randomized controlled trial. Institutional review board (IRB) approval was received at the University Medical Center of Groningen and will be collected in other sites before opening these sites. Thirty-six female, pre-menopausal patients, with a very large liver volume for age (upper 10% of the PLD population) and ongoing liver growth despite current treatment options will be randomized to direct start of leuprorelin or to 18 months standard of care and delayed start of leuprorelin. Leuprorelin is given as 3.75 mg subcutaneously (s.c.) monthly for the first 3 months followed by 3-monthly depots of 11.25 mg s.c. The trial duration is 36 months. MRI scans to measure liver volume will be performed at screening, 6 months, 18 months, 24 months and 36 months. In addition, blood will be drawn, DEXA-scans will be performed and questionnaires will be collected. This design enables comparison between patients on study treatment and standard of care (first 18 months) and within patients before and during treatment (whole trial). Main outcome is annualized liver growth rate compared between standard of care and study treatment. Secondary outcomes are PLD disease severity, change in liver growth within individuals and (serious) adverse events. The study is designed as a prospective open-label study with blinded endpoint assessment (PROBE). DISCUSSION: In this trial, we combined the expertise of hepatologist, nephrologists and gynecologists to study the effect of leuprorelin on liver growth in PLD. In this way, we hope to stop liver growth, reduce symptoms and reduce the need for liver transplantation in severe PLD. Trial registration Eudra CT number 2020-005949-16, registered at 15 Dec 2020. https://www.clinicaltrialsregister.eu/ctr-search/search?query=2020-005949-16 .

The evolution of basal mantle structure in response to supercontinent aggregation and dispersal.

Seismic studies have revealed two Large Low-Shear Velocity Provinces (LLSVPs) in the lowermost mantle. Whether these structures remain stable over time or evolve through supercontinent cycles is debated. Here we analyze a recently published mantle flow model constrained by a synthetic plate motion model extending back to one billion years ago, to investigate how the mantle evolves in response to changing plate configurations. Our model predicts that sinking slabs segment the basal thermochemical structure below an assembling supercontinent, and that this structure eventually becomes unified due to slab push from circum-supercontinental subduction. In contrast, the basal thermochemical structure below the superocean is generally coherent due to the persistence of a superocean in our imposed plate reconstruction. The two antipodal basal thermochemical structures exchange material several times when part of one of the structures is carved out and merged with the other one, similarly to "exotic" tectonic terranes. Plumes mostly rise from thick basal thermochemical structures and in some instances migrate from the edges towards the interior of basal thermochemical structures due to slab push. Our results suggest that the topography of basal structures and distribution of plumes change over time due to the changing subduction network over supercontinent cycles.