Search

In up to 25% of patients with acquired TTP, anti-ADAMTS13 antibodies are not identified, the mechanism resulting from ADAMTS13 deficiency remains unidentified (uTTP). In this study, we provide further insights on clinical presentation and outcome of uTTP. In patients with baseline undetectable anti-ADAMTS13 antibodies, usual features of iTTP (young age, cerebral involvement, severe thrombocytopenia) with no other associated context than a history of systemic autoimmune disease or pregnancy, should prompt to consider the diagnosis of iTTP.

The Shaken Baby Syndrome (SBS) is the result of a severe form of physical abuse inflicted on children under the age of 2, mostly by parents or other caregivers, to quiet their inconsolable crying. The violent shaking of the child results in devastating consequences up to death or can lead to serious neurological sequelae and/or compromise of their neurodevelopment. The clinical diagnosis of SBS is not always easy and immediate, especially in cases where the picture presents with subtle signs and symptoms not directly attributable to abuse: it is therefore fundamental that the family pediatrician is aware of this nosological entity, suspects it in the presence of certain risk factors, always considers it in the differential diagnosis like any other pathology, and above all prevents it through sensitization and education of parents and other caregivers to adequately manage their child's crying. This article aims to emphasize the role of primary care pediatricians in knowing, recognizing, and preventing the shaken baby syndrome.

Abstract Pyoderma gangrenosum (PG) is a rare reactive noninfectious inflammatory dermatosis. More than 50% of PG patients have an associated systemic disease, which, in most cases, is an inflammatory bowel disease. PG affects more females than males and patients with active colitis. This case report describes a 12‐year‐old girl previously diagnosed with ulcerative colitis (UC) and on infliximab treatment. She came to our attention with a painful leg ulcer during admission for acute respiratory failure and fever. The lesion was classified as PG and a diagnosis of UC pulmonary involvement was made. Infliximab was substitute by ustekinumab and the girl is in remission after 1 year of treatment. To the best of our knowledge, this is the first case in the literature of a UC‐related paediatric PG treated with ustekinumab. Our data suggest that more studies are required as to the efficacy of ustekinumab in paediatric PG settings.

Background: Real-world evidence (RWE) can reinforce clinical trial evidence in health technology assessment (HTA). Objectives: Review HTA bodies’ (HTAbs) requirements for RWE, real uses, and acceptance across seven countries (Brazil, Canada, France, Germany, Italy, Spain, and the United Kingdom) and outline recommendations that may improve acceptance of RWE in efficacy/effectiveness assessments and appraisals processes. Methods: RWE requirements were summarized based on HTAbs’ guidelines. Acceptance by HTAbs was evaluated based on industry experience and case studies. Results: As of June 2022, RWE methodological guidelines were in place in three of the seven countries. HTAbs typically requested analyses based on local data sources, but the preferred study design and data sources differed. HTAbs had individual submission, assessment, and appraisal processes; some allowed early meetings for the protocol and/or results validation, though few involved external experts or medical societies to provide input to assessment and appraisal. The extent of submission, assessment, and appraisal requirements did not necessarily reflect the degree of acceptance. Conclusion: All the countries reviewed face common challenges regarding the use of RWE. Our proposals address the need to facilitate collaboration and communication with industry and regulatory agencies and the need for specific guidelines describing RWE design and criteria of acceptance throughout the assessment and appraisal processes.

(1) Background: Since new intraoral scanner (IOS) versions are introduced to the market and software continues to advance, there is an ongoing need to assess the accuracy of newer IOS models. (2) Methods: Four types of IOSs and one laboratory scanner (used as a reference) were used to scan an edentulous model with six parallel implants and their respective scan bodies, which were connected to each other. Using dedicated software, the distances between all scan bodies were calculated, generating a total of 540 measurements. Trueness (comparisons to the reference model) and precision (intragroup comparisons) were statistically compared with ANOVA and Tukey tests. (3) Results: When considering trueness values, statistically significant differences were observed between the tested scanner for all subgroups considered (p < 0.05). By contrast, no statistically significant differences were reported for precision values. (4) Conclusions: Within the limitations of the present in vitro study, it can be concluded that all tested IOSs were similar in terms of precision, while Trios and i700W yielded the worst trueness values. Nevertheless, increasing the measuring distance leads to a decrease in both trueness and precision.

Objectives The association between immune-mediated thrombotic thrombocytopenic purpura (iTTP) and Sjögren disease (SjD) has been poorly investigated. This study presents the first retrospective cohort of iTTP-SjD aiming to identify risk factors for iTTP occurrence in SjD patients and examine their clinical course.Methods Patients with iTTP-SjD were identified within the French TTP Registry based on American College of Rheumatology/European League Against Rheumatism 2016 criteria. A comparative analysis was conducted with two control groups comprising primary SjD (pSjD) patients from the French ASSESS cohort and idiopathic iTTP patients from the French TTP Registry. Demographic, clinical and biological data were retrospectively collected.Results Thirty iTTP-SjD patients were included and compared with 65 pSjD and 45 idiopathic iTTP patients. The majority of iTTP-SjD patients (n=18) were diagnosed with SjD at the time of iTTP diagnosis. In comparison with the pSjD cohort, iTTP-SjD patients were diagnosed with SjD at a younger age (p=0.039) and showed a higher prevalence of anti-SjS-related antigen A antibody positivity and xerostomia (p=0.015, p=0.035, respectively). EULAR Sjogren’s Syndrome Disease Activity Index showed similar activity levels between the two groups. iTTP-SjD patients were treated with plasma exchange (n=28), corticosteroids, rituximab (n=19) and caplacizumab (n=3). In comparison with the idiopathic iTTP cohort, mortality rates (log-rank tests, p=0.228), biological and clinical iTTP relapses (multivariate analysis, p=0.181) were comparable and short-term outcomes (survival at day 30, relapse) were favourable.Conclusion iTTP can be a rare complication in patients with SjD. Further studies involving larger cohorts and long-term follow-up are warranted to confirm these findings and to explore the efficacy of immunomodulators and caplacizumab in iTTP-SjD patients.

The cornerstone treatment for immune-mediated thrombotic thrombocytopenic purpura (iTTP) in children is a combination of therapeutic plasma exchange (TPE), corticosteroids, and rituximab. Caplacizumab is an anti-von Willebrand factor (VWF) NANOBODY molecule approved as a frontline therapy of iTTP for adults and children aged ≥12 years. Using caplacizumab in children aged

IntroductionVascular anomalies (VAs) constitute a heterogeneous group of tumors and malformations capable of inducing significant clinical events in specific patients, such as the compression of vital organs, pain, functional impairment, or acquired coagulopathy. Molecular investigations into the underlying mechanisms of VAs have unveiled the frequent involvement of the PI3 K/AKT/mTOR pathway. Sirolimus, a specific mTOR inhibitor, has emerged as a potential therapeutic agent; however, its routine clinical application in complex VAs is currently restricted by a lack of extensive clinical experience.MethodsBetween 2015 and 2024, we administered sirolimus to 14 pediatric patients with various types of vascular anomalies in two Italian centers, subjecting them to clinical and instrumental follow-up to investigate its efficacy and the possible occurrence of adverse events.ResultsAn overall improvement in or stability of their vascular anomalies was reported by 86% of patients. We also assessed toxicity, noting a low prevalence of life-threatening adverse events: only one case of sepsis was reported in a patient with a severe clinical condition, and four cases of recurrent aphthosis (28%) were reported. The most common side effect was dyslipidemia, with 43% of patients developing hypercholesterolemia (21%) or hypertriglyceridemia (21%), although these patients generally did not reach severe levels.DiscussionIn line with data in the literature, according to our experience, medical therapy with sirolimus should be considered in pediatric patients affected by vascular anomalies.

Background Sandy beaches are dynamic environments housing a large diversity of organisms and providing important environmental services. Meiofaunal metazoan are small organisms that play a key role in the sediment. Their diversity, distribution and composition are driven by sedimentary and oceanographic parameters. Understanding the diversity patterns of marine meiofauna is critical in a changing world. Methods In this study, we investigate if there is seasonal difference in meiofaunal assemblage composition and diversity along 1 year and if the marine seascapes dynamics (water masses with particular biogeochemical features, characterized by temperature, salinity, absolute dynamic topography, chromophoric dissolved organic material, chlorophyll-a, and normalized fluorescent line height), rainfall, and sediment parameters (total organic matter, carbonate, carbohydrate, protein, lipids, protein-to-carbohydrate, carbohydrate-to-lipids, and biopolymeric carbon) affect significatively meiofaunal diversity at a tropical sandy beach. We tested two hypotheses here: (i) meiofaunal diversity is higher during warmer months and its composition changes significatively among seasons along a year at a tropical sandy beach, and (ii) meiofaunal diversity metrics are significantly explained by marine seascapes characteristics and sediment parameters. We used metabarcoding (V9 hypervariable region from 18S gene) from sediment samples to assess the meiofaunal assemblage composition and diversity (phylogenetic diversity and Shannon’s diversity) over a period of 1 year. Results Meiofauna was dominated by Crustacea (46% of sequence reads), Annelida (28% of sequence reads) and Nematoda (12% of sequence reads) in periods of the year with high temperatures (>25 °C), high salinity (>31.5 ppt), and calm waters. Our data support our initial hypotheses revealing a higher meiofaunal diversity (phylogenetic and Shannon’s Diversity) and different composition during warmer periods of the year. Meiofaunal diversity was driven by a set of multiple variables, including biological variables (biopolymeric carbon) and organic matter quality (protein content, lipid content, and carbohydrate-to-lipid ratio).

IntroductionAngioimmunoblastic T-cell lymphoma (AITL) is a peripheral T-cell lymphoma characterized by a T follicular helper cell phenotype expressing PD-1 (programmed cell death-1). AITL exhibits a poor response to conventional chemotherapy, with a median 5-year overall survival of 44% and a progression-free survival of 32%. Relapse is common, resulting in a median overall survival of 6 months. Recurrent mutations are detected in genes regulating DNA methylation, including TET2, DNMT3A, and IDH2 variants, along with the prevalent RHOA G17V mutation. In this context, patients treated with the hypomethylating agent 5-azacytidine achieved overall response and complete response rates of 75% and 41%, respectively. We hypothesized that targeted therapies combining anti-PD-1 checkpoint blockers with hypomethylating agents could be efficient in AITL patients and less toxic than standard chemotherapy.MethodsHere, we report the efficacy of a regimen combining 5-azacytidine and nivolumab in nine relapsed or refractory AITL patients.ResultsThis regimen was well-tolerated, especially in elderly patients. The overall response rate was 78%, including four partial responses (44%) and three complete responses (33%). Allogeneic hematopoietic stem cell transplantation was performed in two patients who reached complete response.DiscussionThese preliminary favorable results may serve as a basis for further investigation in prospective studies.

Da oltre quarant’anni si utilizzano gli ultrasuoni per rilevare una placca carotidea e per seguire nel tempo la sua evoluzione. I protocolli terapeutici hanno ridotto enormemente il suo impatto sulla salute delle persone ma la scelta fra terapia medica e chirurgica si fonda su una valutazione clinica e strumentale che è solo apparentemente semplice. Nei referti di un esame ultrasonografico riportiamo il più delle volte delle percentuali di stenosi, a volte puntuali, a volte in termini di range oppure ci esprimiamo con aggettivi che descrivono la gravità della stenosi ma spesso ci facciamo confondere dai numeri e dalle differenti modalità di calcolo del range di stenosi ed è indubbio che, a volte, le conclusioni risultano ambigue ed estremamente dipendenti dall’interpretazione dell’operatore. Il problema è che l’angiografia digitale, gold standard diagnostico per la stenosi carotidea, adotta delle metriche non del tutto riproducibili con gli ultrasuoni. Con questo documento vogliamo condividere la ricerca di un linguaggio comune, a partire dal referto dei nostri esami. Noi refertiamo così… voi?

BackgroundThe COVID-19 pandemic related to SARS-CoV-2 virus was responsible for global pandemic. The severe form of the disease was linked to excessive activation of immune pathways together with a systemic cytokine storm response and thrombotic venous or arterial complications. Factors predicting severe outcomes including venous and/or pulmonary thrombosis (VT) and death were identified, but the prognostic role of their combination was not addressed extensively.ObjectivesWe investigated the role of prognostic factors from the coagulation or inflammatory pathways to better understand the outcome of the disease.MethodsFor this, we prospectively studied 167 SARS-CoV-2-positive patients from admission in intensive care units (ICU) or emergency departments from four academic hospitals over a 14-month period. Besides standard biology, we assessed serum concentrations of inflammatory markers, coagulation factors and peripheral blood cells immunophenotyping.ResultsThirty-nine patients (23.3%) developed VT and 30 patients (18%) died. By univariate analysis, C-reactive protein (CRP) level > 150 mg/L, interleukin-6 (IL-6) ≥ 20 pg/mL, D-dimers > 1,500 μg/L, ADAMTS13 activity ≤ 50%, VonConclusionA combination of coagulation and inflammatory markers can refine the prognostication of severe outcome in COVID-19, and could be useful for the initial evaluation of other types of viral infection.

The paper in the first place introduces the figure of Guido Sutermeister and his fundamental work. The second part offers a concise summary of the data relating to decorated coarse ware gathered from a preliminary survey of the collections of the Guido Sutermeister museum in Legnano and from a consideration of what has already been written upon the subject to date.

Abstract Although clinical applications represent the next challenge in single-cell genomics and digital pathology, we still lack computational methods to analyze single-cell or pathomics data to find sample-level trajectories or clusters associated with diseases. This remains challenging as single-cell/pathomics data are multi-scale, i.e., a sample is represented by clusters of cells/structures, and samples cannot be easily compared with each other. Here we propose PatIent Level analysis with Optimal Transport (PILOT). PILOT uses optimal transport to compute the Wasserstein distance between two individual single-cell samples. This allows us to perform unsupervised analysis at the sample level and uncover trajectories or cellular clusters associated with disease progression. We evaluate PILOT and competing approaches in single-cell genomics or pathomics studies involving various human diseases with up to 600 samples/patients and millions of cells or tissue structures. Our results demonstrate that PILOT detects disease-associated samples from large and complex single-cell or pathomics data. Moreover, PILOT provides a statistical approach to find changes in cell populations, gene expression, and tissue structures related to the trajectories or clusters supporting interpretation of predictions.

The highly variable rate of decline in kidney function in patients with immunoglobulin A nephropathy (IgAN) provides a major clinical challenge. Predicting which patients will progress to kidney failure, and how quickly, is difficult. Multiple novel therapies are likely to be approved in the short-term, but clinicians lack the tools to identify patients most likely to benefit from specific treatments at the right time. Noninvasive and validated markers for selecting at-risk patients and longitudinal monitoring are urgently needed.This review summarizes what is known about demographic, clinical, and histopathologic prognostic markers in the clinician’s toolkit, including the International IgAN Prediction Tool. We also briefly review what is known on these topics in children and adolescents with IgAN. Although helpful, currently used markers leave clinicians heavily reliant on histologic features from the diagnostic kidney biopsy and standard clinical data to guide treatment choice, and very few noninvasive markers reflect treatment efficacy over time. Novel prognostic and predictive markers are under clinical investigation, with considerable progress being made in markers of complement activation. Other areas of research are the interplay between gut microbiota and galactose-deficient IgA1 expression; microRNAs; imaging; artificial intelligence; and markers of fibrosis.Given the rate of therapeutic advancement, the remaining gaps in biomarker research need to be addressed. We finish by describing our route to clinical utility of predictive and prognostic markers in IgAN. This route will provide us with the chance to improve IgAN prognosis by using robust, clinically practical markers to inform patient care.

The ICESat-2 and SWOT satellite earth observation missions have provided highly accurate water surface slope (WSS) observations in global rivers for the first time. While water surface slope is expected to remain constant in time for approximately uniform flow conditions, we observe time varying water surface slope in many river reaches around the globe in the ICESat-2 record. Here, we investigate the causes of time variability of WSSs using simplified river hydraulic models based on the theory of steady, gradually varied flow. We identify bed slope or cross section shape changes, river confluences, flood waves, and backwater effects from lakes, reservoirs, or the ocean as the main non-uniform hydraulic situations in natural rivers that cause time changes of WSSs. We illustrate these phenomena at selected river sites around the world, using ICESat-2 data and river discharge estimates. The analysis shows that WSS observations from space can provide new insights into river hydraulics and can enable the estimation of river discharge from combined observations of water surface elevation and WSSs at sites with complex hydraulic characteristics.

Antimicrobial resistance (AMR) is an urgent and growing global health concern, and a clear understanding of existing capacities to address AMR, particularly in low-income and middle-income countries (LMICs), is needed to inform national priorities, investment targets and development activities. Across LMICs, there are limited data regarding existing mechanisms to address AMR, including national AMR policies, current infection prevention and antimicrobial prescribing practices, antimicrobial use in animals, and microbiological testing capacity for AMR. Despite the development of numerous individual tools designed to inform policy formulation and implementation or surveillance interventions to address AMR, there is an unmet need for easy-to-use instruments that together provide a detailed overview of AMR policy, practice and capacity. This paper describes the development of a framework comprising five assessment tools which provide a detailed assessment of country capacity to address AMR within both the human and animal health sectors. The framework is flexible to meet the needs of implementers, as tools can be used separately to assess the capacity of individual institutions or as a whole to align priority-setting and capacity-building with AMR National Action Plans (NAPs) or national policies. Development of the tools was conducted by a multidisciplinary team across three phases: (1) review of existing tools; (2) adaptation of existing tools; and (3) piloting, refinement and finalisation. The framework may be best used by projects which aim to build capacity and foster cross-sectoral collaborations towards the surveillance of AMR, and by LMICs wishing to conduct their own assessments to better understand capacity and capabilities to inform future investments or the implementation of NAPs for AMR.

Abstract With increasing coverage, density, and accuracy of the global inland water altimetry record, remote sensing observations of water surface elevation (WSE) and water surface slope (WSS) are becoming available for the world's rivers. In steady, uniform flows, WSS is invariable, while there is a unique one‐to‐one relationship between WSE and discharge, the rating curve. While the assumptions of steady uniform flow are appropriate for many rivers, they are violated upstream of river confluences. We present a simple analytical hydraulic model of river confluences using the theory of steady, gradually varied flow. We apply the model to four river confluences in the Mississippi‐Missouri river system. We determine the spatial extent of the backwater‐affected zones and map WSE‐discharge and WSS‐discharge relationships. We show that coincident measurements of WSE and WSS from new satellite altimetry missions effectively constrain discharge estimates from space in the backwater‐affected zones upstream of river confluences.

BackgroundInfant leukemia is a rare form of acute leukemia diagnosed prior to the age of 1 and is characterized by an extremely poor prognosis due to its dismal response to current therapeutic approaches. It comprises about 4% of all childhood cases of acute lymphoblastic leukemia (ALL). Isolated initial cutaneous involvement in ALL is uncommon, and even more so in infant ALL.Case presentationHere, we present the case of a 2-month-old healthy-appearing infant, initially presenting with a single scalp nodule and subsequently diagnosed with an infant ALL. The leukemia was characterized by the most immature B-lineage immunophenotype [pro-B ALL/B-I, according to the European Group for the Immunological Characterization of Leukaemias (EGIL) classification] and chromosomal translocation t(9;11)(p22;q23), resulting in fusion gene KMTLA2::MLLT3, which is considered a negative prognostic factor. The patient underwent hematopoietic stem cell transplantation and is still in remission.ConclusionsThis case is peculiar because of the rare occurrence of isolated initial cutaneous involvement in ALL. Despite the healthy appearance of the patient, every suspicious symptom suggestive of malignancies should be further investigated to anticipate the diagnosis and start treatment early.

Background: Dupilumab has been shown to be a safe and effective drug for the treatment of atopic dermatitis (AD) in children from 6 months to 11 years in randomized clinical trials. Aim: The aim of this real-life study was to determine the effectiveness in disease control and safety of dupilumab at W52 in moderate-to-severe AD children aged 6-11 years. Methods: All data were collected from 36 Italian dermatological or paediatric referral centres. Dupilumab was administered at label dosage with an induction dose of 300 mg on day 1 (D1), followed by 300 mg on D15 and 300 mg every 4 weeks (Q4W). Treatment effect was determined as overall disease severity, using EASI, P-NRS, S-NRS and c-DLQI at baseline, W16, W24, and W52. Ninety-six AD children diagnosed with moderate-to-severe AD and treated with dupilumab were enrolled. Results: Ninety-one (94.8%) patients completed the 52-week treatment period and were included in the study. A significant improvement in EASI score, P-NRS, S-NRS and c-DLQI was observed from baseline to weeks 16, 24 and 52. Conclusions: Our real-life data seem to confirm dupilumab effectiveness and safety in paediatric patients. Moreover, our experience highlighted that patients achieving clinical improvement at W16 preserved this condition over time.

Attaining transferable skills is increasingly important for undergraduates and, while such skill development may be embedded within the curriculum, it is often not well recognised by students. This mixed methods study explores the use of skills badges as icons displayed on curriculum materials in several disciplines at two universities. The badges are designed to draw students' attention to skill development opportunities; an approach that is easily scalable in any discipline. Results indicated that more than half of students found the badges helpful and their recognition of the development of some skills increased. Other benefits included understanding the wider purpose of learning tasks, increased motivation and satisfaction and identification of examples for use in the job application process. The badges prompted some staff to communicate with students about skills and to re-evaluate their teaching approach to maximise skill development opportunities. Communication between staff and students is key to ensuring students understand the purpose of the badges and how to use them.

Abstract Background Gd levels are higher in tissues of animals with compromised renal function, but studies to compare levels after exposure to different macrocyclic gadolinium-based contrast agents (GBCAs) are lacking. We compared Gd levels in tissues of subtotally nephrectomised (SN) rats after repeated exposure to macrocyclic GBCAs. Methods Sprague–Dawley SN male rats (19 per group) received 16 injections of gadoteridol, gadobutrol, or gadoterate meglumine at 0.6 mmol Gd/kg 4 times/weeks over 4 weeks. A control group of healthy male rats (n = 10) received gadoteridol at the same dosage. Plasma urea and creatinine levels were monitored. Blood, cerebrum, cerebellum, liver, femur, kidney(s), skin and peripheral nerves were harvested for Gd determination by inductively coupled plasma-mass spectrometry at 28 and 56 days after the end of treatment. Results Plasma urea and creatinine levels were roughly twofold higher in SN rats than in healthy rats at all timepoints. At day 28, Gd levels in the peripheral nerves of gadobutrol- or gadoterate-treated SN animals were 5.4 or 7.2 times higher than in gadoteridol-treated animals (p

Abstract Background Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare disease characterized by arteriolar and capillary microthrombosis precipitating organ failure. However, the contribution of endothelial dysfunction on impaired microvascular blood flow in iTTP patients has been poorly explored. This pilot observational study aimed to explore endothelial-mediated vasoreactivity in iTTP patients at admission and its changes after plasma exchange therapy (PE). Methods We conducted a prospective observational study in patients (> 18-year old) admitted in ICU for iTTP. Using laser Doppler flowmetry and acetylcholine (Ach) iontophoresis in the forearm, we recorded the skin microvascular blood flow and the endothelium-mediated vasoreactivity at admission and after PE. Demographics, biological, clinical courses, and outcomes were also collected. As a control group, we used a previously published cohort of young diabetic patients after correction of ketoacidosis. Results Eighteen confirmed iTTP patients and 34 controls were included in the study, mainly female (72%) aged 43 ± 16-year-old. At admission, 55% had neurological abnormalities, 50% cardiac issues and 27.8% an acute kidney injury. Median platelet count was 19 G/mL [10–37]. Baseline microvascular blood flow was decreased in iTTP patients when compared to controls (5.97 ± 4.5 vs. 10.1 ± 6.3 PU, P = 0.03), associated with markedly impaired endothelial-mediated skin microvascular reactivity (AUC: 9627 ± 8122 vs. 16,475 ± 11,738, P = 0.03). Microvascular reactivity improved after the first PE session (AUC: 9627 ± 8122 vs 16,558 ± 10,699, P = 0.007, respectively, baseline and post-PE1) and much more after the second session (26,431 ± 23,181, P = 0.04 post-PE1 vs post-PE2). Hemolysis biomarkers (LDH and bilirubin) negatively correlated with skin microvascular flow and vasoreactivity. Conclusion We highlighted a marked yet reversible skin endothelium-mediated microvascular hyporeactivity in iTTP patients that could participate in organ injury pathophysiology.

Advances in geodetic altimetry instruments are providing more accurate measurements, thus enabling satellite missions to produce useful data for narrow rivers and streams. Altimetry missions produce spatially dense land and water surface elevation (WSE) measurements in remote areas where in situ data are scarce that can be combined with hydraulic and/or hydrodynamic models to simulate WSE and estimate discharge. In this study, we combine ICESat-2 (Ice, Cloud and land Elevation Satellite) land and water surface elevation measurements with a low-parameterized hydraulic calibration to simulate WSE and discharge without the need for surveyed cross-sectional geometry and a rainfall–runoff model. ICESat-2 provides an opportunity to map river cross-sectional geometry very accurately, with an along-track resolution of 0.7 m, using the ATL03 product. These measurements are combined with the inland water product ATL13 to calibrate a steady-state hydraulic model to retrieve unobserved hydraulic parameters such as river depth or the roughness coefficient. The low-parameterized model, together with the assumption of steady-state hydraulics, enables the application of a global search algorithm for a spatially uniform parameter calibration at a manageable computational cost. The model performance is similar to that reported for highly parameterized models, with a root mean square error (RMSE) of around 0.41 m. With the calibrated model, we can calculate the WSE time series at any chainage point at any time for an available satellite pass within the river reach and estimate discharge from WSE. The discharge estimates are validated with in situ measurements at two available gauging stations. In addition, we use the calibrated parameters in a full hydrodynamic model simulation, resulting in a RMSE of 0.59 m for the entire observation period.

Long-term treatment of schizophrenia with clozapine (CLZ), an atypical antipsychotic drug, is associated with an increased incidence of metabolic disorders mediated by poorly understood mechanisms. We herein report that CLZ, while slowing down the morphological changes and lipid accumulation occurring during SW872 cell adipogenesis, also causes an early (day 3) inhibition of the expression/nuclear translocation of CAAT/enhancer-binding protein β and peroxisome proliferator-activated receptor γ. Under the same conditions, CLZ blunts NADPH oxidase-derived reactive oxygen species (ROS) by a dual mechanism involving enzyme inhibition and ROS scavenging. These effects were accompanied by hampered activation of the nuclear factor (erythroid-derived2)-like 2 (Nrf2)-dependent antioxidant responses compared to controls, and by an aggravated formation of mitochondrial superoxide. CLZ failed to exert ROS scavenging activities in the mitochondrial compartment but appeared to actively scavenge cytosolic H2O2 derived from mitochondrial superoxide. The early formation of mitochondrial ROS promoted by CLZ was also associated with signs of mitochondrial dysfunction. Some of the above findings were recapitulated using mouse embryonic fibroblasts.We conclude that the NADPH oxidase inhibitory and cytosolic ROS scavenging activities of CLZ slow down SW872 cell adipogenesis and suppress their Nrf2 activation, an event apparently connected with increased mitochondrial ROS formation, which is associated with insulin resistance and metabolic syndrome. Thus, the cellular events characterised herein may help to shed light on the more detailed molecular mechanisms explaining some of the adverse metabolic effects of CLZ.

Objective: The management of exacerbations and disease relapse is important for patients with immune-mediated thrombotic thrombocytopenic purpura (iTTP). Severe ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) deficiency during clinical remission is associated with risk of relapse and may guide prophylactic immune-modulatory therapy. We evaluated ADAMTS13 activity as a potential biomarker of exacerbation or relapse risk in the HERCULES and post-HERCULES studies. Methodology: This is a post hoc analysis of integrated data from the modified intent-to-treat (mITT) population of the Phase 3 HERCULES trial (NCT02553317) comparing caplacizumab and placebo (both plus standard-of-care treatment) in patients (pts) with iTTP and the 3-year follow-up post-HERCULES study (NCT02878603). ADAMTS13 activity was determined at baseline, weekly during treatment (post-TPE) and twice during follow-up. Recurrence risk was assessed according to ADAMTS13 activity, using TTP adverse event codes. Results: 49/144 (34%) pts in the HERCULES mITT had a recurrence during HERCULES or post-HERCULES. 140/144 pts had follow-up data after treatment end. Of these, 39 pts (28%) had a recurrence after treatment end; mean [SD] ADAMTS13 activity was 20.5% (28.7) in pts with recurrence vs 54.0% (34.9) in pts without; [P

Summary: Patient-derived tumor organoids are three-dimensionally cultured cancer cells that enable a suitable platform for studying heterogeneity and plasticity of cancer. We present a protocol for tracking the growth fate of single cells and isolating slow-growing cells in human colorectal cancer organoids. We describe steps for organoid preparation and culturing using the cancer-tissue-originating spheroid method, maintaining cell-cell contact throughout. We then detail a single-cell-derived spheroid-forming and growth assay, confirming single-cell plating, monitoring growth over time, and isolating slow-growing cells.For complete details on the use and execution of this protocol, please refer to Coppo et al.1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.