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The pediatric International IgA Nephropathy (IgAN) Prediction Tool comprises two models with and without ethnicity and is the first method to predict the risk of a 30% decline in estimated glomerular filtration rate (eGFR) or kidney failure in children at the time of biopsy using clinical risk factors and Oxford MEST histology scores. However, it is unknown if the Prediction Tool can be applied after a period of observation post-biopsy. Using an international multi-ethnic cohort of 947 children with IgAN, 38% of whom were followed into adulthood, the Prediction Tool was updated for use one year after biopsy. Compared to the original pediatric Prediction Tool, the updated post-biopsy Prediction Tool had a better model fit with higher R2D(51%/50% vs 20%), significant increase in 4-year C-statistics (0.83 vs 0.73/0.69, ΔC 0.09 [95% confidence interval 0.07-0.10] and ΔC 0.14 [0.12-0.15]) and better 4-year calibration with lower integrated calibration indices (0.74/0.54 vs 2.45/1.01). Results were similar after internal validation and when the models were applied two years after biopsy. Trajectories of eGFR after a baseline one year post-biopsy were non-linear and those at higher predicted risk started with a lower eGFR and experienced a more rapid decline over time. In children, eGFR had a variable rate of increase until 15-18 years old and then decreased linearly with a more rapid decline in higher risk groups that was similar to young adults of comparable risk. Thus, the original pediatric Prediction Tool should be used in children at the time of biopsy, and the updated pediatric Prediction Tool should be used to re-evaluate risk one or two years after biopsy.

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AbstractIn the present work, two large eddy simulations (LESs) of single isothermal jets discharging into large enclosure facilities are proposed. The geometries and tested flow conditions correspond to scaled experiments of the upper plenum of high-temperature gas-cooled reactors. More specifically, two reference experiments were conducted at Texas A&M University and Michigan University. The objective of the present work is to validate these simulations with their corresponding reference experiments. The proposed LES models are performed with NekRS, a spectral element code with graphics processing unit capabilities developed at Argonne National Laboratory. These simulations were performed on the Summit supercomputer at Oak Ridge National Laboratory. For validation purposes, first- and second-order statistics from the computational fluid dynamics (CFD) calculation are compared with measurements obtained from the experiments. The models proved to be accurate, as these results are in good agreement. Additionally, flow visualization is provided showing that these models are able to retrieve similar effects to what are described in the literature for this type of flow configuration. Finally, the proposed models are part of a broader effort under the current Integrated Research Project of Nuclear Energy Advanced Modeling and Simulation 1.1, whose main objective is to deliver fast-running models to accurately predict complex physical phenomena, including for instance, turbulent mixing and thermal stratification. In this regard, the CFD models proposed here will be used to generate a high-fidelity data set to be applied in conjunction with data-driven methods to improve turbulence modeling closures.

AbstractTraditional one-dimensional system thermal-hydraulic analysis has been widely applied in the nuclear industry for licensing purposes because of its numerical efficiency. However, such tools have inherently limited opportunities for modeling multiscale multidimensional flows in large reactor enclosures. Recent interest in three-dimensional coarse grid (CG) simulations has shown their potential in improving the predictive capability of system-level analysis. At the same time, CGs do not allow one to accurately resolve and capture turbulent mixing and stratification, whereas implemented in CG solvers relatively simple turbulence models exhibit large model form uncertainties. Therefore, there is a strong interest in further advances in CG modeling techniques. In this work, two high-to-low data-driven (DD) methodologies (and their combination) are explored to reduce grid and model-induced errors using a case study based on the Texas A&M upper plenum of a high-temperature gas-cooled reactor facility. The first approach relies on the use of a DD turbulence closure [eddy viscosity predicted by a neural network (NN)]. A novel training framework is suggested to consider the influence of grid cell size on closure. The second methodology uses a NN to predict velocity errors to improve low-fidelity results. Both methodologies and their combination have shown the potential to improve CG simulation results by using data with higher fidelity.

Laboratory diagnosis of immune-mediated thrombotic thrombocytopenic purpura (iTTP) remains challenging when ADAMTS-13 activity ranges between 10% and 20%. To prevent misdiagnosis, open ADAMTS-13 conformation gained clinical attention as a novel biomarker, especially to diagnose acute iTTP in patients with diagnostic undecisive ADAMTS-13 activity. Plasma ADAMTS-13 conformation analysis corrects for ADAMTS-13 antigen, with both parameters being characterized in enzyme-linked immunosorbent assay (ELISA)-based reference assays requiring expert technicians.

•Three distinct entities of pregnancy-onset TTP are singled out: iTTP, uTTP, and cTTP, with fetal outcome closely linked to gestational age.•In the context of pregnancy, most iTTP and uTTP are shown to have an open ADAMTS13 conformation at acute phase.

Western Europe boasts advanced health care systems, robust kidney care guidelines, and a well-established health care workforce. Despite this, significant disparities in kidney replacement therapy incidence, prevalence, and transplant access exist. This paper presents the third International Society of Nephrology Global Kidney Health Atlas’s findings on kidney care availability, accessibility, affordability, and quality in 22 Western European countries, representing 99% of the region’s population. The known chronic kidney disease (CKD) prevalence across Western Europe averages 10.6%, slightly above the global median. Cardiovascular diseases account for a substantial portion of CKD-related deaths. Kidney failure incidence varies. Government health expenditure differs; however, most countries offer government-funded acute kidney injury, dialysis, and kidney transplantation care. Hemodialysis and peritoneal dialysis are universally available, with variations in the number of dialysis centers. Kidney transplantation is available in all countries (except for 3 microstates), with variable transplant center prevalence. Conservative kidney management (CKM) is increasingly accessible. The region’s kidney care workforce is substantial, exceeding global averages; however, workforce shortages are reported. Barriers to optimal kidney care include limited workforce capacity, lack of surveillance mechanisms, and suboptimal integration into national noncommunicable disease (NCD) strategies. Policy recognition of CKD as a health priority varies across countries. Although Western Europe exhibits strong kidney care infrastructure, opportunities for improvement exist, particularly in CKD prevention, surveillance, awareness, and policy implementation. Efforts to improve CKD care should include automated detection, educational support, and enhanced workflows. Based on these findings, health care professionals, stakeholders, and policymakers are called to act to enhance kidney care across the region.

Small-cell neuroendocrine carcinoma (SCNEC) of the cervix is a rare disease characterized by a high incidence of mixed tumors with other types of cancer. The mechanism underlying this mixed phenotype is not well understood. This study established a panel of organoid lines from patients with SCNEC of the cervix and ultimately focused on one line, which retained a mixed tumor phenotype, both in vitroand in vivo. Histologically, both organoids and xenograft tumors showed distinct differentiation into either SCNEC or adenocarcinoma in some regions and ambiguous differentiation in others. Tracking single cells indicated the existence of cells with bipotential differentiation toward SCNEC and adenocarcinomas. Single-cell transcriptional analysis identified three distinct clusters: SCNEC-like, adenocarcinoma-like, and a cluster lacking specific differentiation markers. The expression of neuroendocrine markers was enriched in the SCNEC-like cluster but not exclusively. Human papillomavirus 18 E6 was enriched in the SCNEC-like cluster, which showed higher proliferation and lower levels of the p53 pathway. After treatment with anticancer drugs, the expression of adenocarcinoma markers increased, whereas that of SCNEC decreased. Using a reporter system for keratin 19 expression, changes in the differentiation of each cell were shown to be associated with the shift in differentiation induced by drug treatment. These data suggest that mixed SCNEC/cervical tumors have a clonal origin and are characterized by an ambiguous and flexible differentiation state.

ADAMTS-13 adopts an open conformation in patients with immune-mediated thrombotic thrombocytopenic purpura (iTTP) in acute phase while being closed in healthy donors. We reported that a substantial number of patients with iTTP in remission with restored ADAMTS-13 activity (>50%) still had an open ADAMTS-13 conformation, although a closed conformation is expected given the extent of remission.

IgA nephropathy is the most common primary glomerulonephritis worldwide, and an important cause of kidney failure, as 20–40% of patients progress to renal replacement therapy 20–30 years after diagnosis. Its clinical presentation ranges from isolated microscopic hematuria to nephrotic syndrome, and even to a rapidly progressive course. Ethnicity and epigenetics play a key role in its clinical aggressiveness. Selection of patients at risk needing immunosuppressive treatment is a challenge for the nephrologist. Some active and chronic kidney lesions detected on kidney biopsy have been demonstrated to have prognostic value according to the Oxford Classification of IgA nephropathy, later validated by numerous studies. However, KDIGO 2021 guidelines still consider persistent proteinuria > 1 g/24 h to be the most relevant risk factor for the progression of IgA nephropathy and the only one requiring immunosuppressive treatment. KDIGO guidelines have proposed a therapeutic algorithm, but many patients present peculiar characteristics that are not addressed by the current guidelines, pointing to the need for alternative approaches. In these cases, a tailored approach to each patient should be followed in which clinical, histological, laboratory, social and ethical aspects must be considered. In this manuscript we present three cases of IgA nephropathy from different countries, highlighting many of the aspects encountered in clinical practice that illustrate an individualized approach to the treatment of these patients.

Background: Although thrombotic thrombocytopenic purpura frequently affects women of childbearing age, there is no clear recommendation for the management of subsequent pregnancies in women with established thrombotic thrombocytopenic purpura. Methods: This single-center, retrospective, observational study included all women with hereditary thrombotic thrombocytopenic purpura or immune thrombotic thrombocytopenic purpura who had had at least one subsequent pregnancy after thrombotic thrombocytopenic purpura diagnosis between 2003 and 2022. The strategy comprised weekly surveillance of platelet count during pregnancy (and quarterly monitoring of ADAMTS13 activity) for women with immune thrombotic thrombocytopenic purpura, without any routine prophylactic treatment. In case of thrombocytopenia < 150,000/mm3(with or without hemolysis relapse), women with hereditary thrombotic thrombocytopenic purpura systematically received plasma infusions twice weekly until platelet count normalized. Results: A total of 13 patients were included (7 with hereditary thrombotic thrombocytopenic purpura and 6 with immune thrombotic thrombocytopenic purpura, with 20 planned pregnancies (11 and 9, respectively). All pregnancies resulted in live births, and all mothers survived. There was a marked improvement in pregnancy terms in the hereditary thrombotic thrombocytopenic purpura group compared to index pregnancies (37 [35;39] versus 31 [24;38] weeks, p= 0.037) and birth weights (3265 [3029;3410] versus 2160 [1240;2705] grams, p= 0.016), with need for plasma support mostly starting during the third trimester (5/7 patients, 7/11 pregnancies). A single hereditary thrombotic thrombocytopenic purpura relapse occurred, with rapid resolution after plasma support intensification. There were no relapses in the immune thrombotic thrombocytopenic purpura group, with ADAMTS13 activity systematically above 40% during all monitored pregnancies. Conclusion: These real-life data support the feasibility of a preemptive approach to pregnancy monitoring in women with known thrombotic thrombocytopenic purpura who undergo active surveillance within a multidisciplinary network. Graphical abstract:

PIK3CA pathogenic variants are responsible for a group of overgrowth syndromes, collectively known as PIK3CA-Related Overgrowth Spectrum (PROS). These gain-of-function variants arise postzygotically, and, according to time of onset, kind of embryonal tissue affected and regional body extension, give rise to heterogeneous phenotypes. PROS rarity and heterogeneity hamper the correct estimation of its epidemiology. Our work represents the first attempt to define the prevalence of PROS according to the established diagnostic criteria and molecular analysis and based on solid demographic data. We assessed the prevalence in Piedmont Region (Italy), including in the study all participants diagnosed with PROS born there from 1998 to 2021. The search identified 37 cases of PROS born across the 25-year period, providing a prevalence of 1:22,313 live births. Molecular analysis was positive in 81.0% of participants. Taking into account the cases with a detected variant in PIK3CA (n= 30), prevalence of molecularly positive PROS was 1:27,519.

Brentuximab vedotin in combination with doxorubicin, vinblastine, and dacarbazine (AVD) is approved in the upfront setting for advanced stage classical Hodgkin lymphoma (cHL). People living with HIV have been excluded from these studies. We aimed to understand the activity and safety of brentuximab vedotin–AVD in people living with HIV diagnosed with Hodgkin lymphoma, while focusing on HIV disease parameters and antiretroviral therapy (ART) interactions.

The benefits and risks of systemic corticosteroids in the treatment of IgA nephropathy are still controversial. Part A results of the Efficacy and Safety of Nefecon in PatientsWith Primary IgA Nephropathy (NefIgArd) trial provide significant effects on decrease in proteinuria and protection from estimated glomerular filtration rate decline after 9 months of treatment with budesonide (Nefecon). Targeting the initiating pathogenetic event in the gut-associated lymphoid tissue would offer a disease-modifying approach to IgA nephropathy. Results, adverse events, and possible multiple effects of this treatment are critically discussed.

IgA nephropathy (IgAN) is a progressive form of kidney disease defined by glomerular deposition of IgA. Here we performed a genome-wide association study of 10,146 kidney-biopsy-diagnosed IgAN cases and 28,751 controls across 17 international cohorts. We defined 30 genome-wide significant risk loci explaining 11% of disease risk. A total of 16 loci were new, including TNFSF4/TNFSF18, REL, CD28, PF4V1, LY86, LYN, ANXA3, TNFSF8/TNFSF15, REEP3, ZMIZ1, OVOL1/RELA, ETS1, IGH, IRF8, TNFRSF13Band FCAR. The risk loci were enriched in gene orthologs causing abnormal IgA levels when genetically manipulated in mice. We also observed a positive genetic correlation between IgAN and serum IgA levels. High polygenic score for IgAN was associated with earlier onset of kidney failure. In a comprehensive functional annotation analysis of candidate causal genes, we observed convergence of biological candidates on a common set of inflammatory signaling pathways and cytokine ligand–receptor pairs, prioritizing potential new drug targets.

Caplacizumab demonstrated efficacy and safety in patients with immune‐mediated thrombotic thrombocytopenic purpura (iTTP) in the phase 3 HERCULES trial. However, data on long‐term outcomes following caplacizumab treatment are limited. The post‐HERCULES trial (NCT02878603) evaluated long‐term outcomes of patients with iTTP treated with caplacizumab in HERCULES and safety and efficacy of repeated caplacizumab use. Over 3 years of follow‐up, patients could receive open‐label caplacizumab with therapeutic plasma exchange (TPE) and immunosuppressive therapy (IST) in case of recurrence. Adverse events (AEs) were assessed during the overall study period (intention‐to‐observe [ITO] population) and during recurrences (recurrence population). TTP‐related events (TTP‐related death, recurrence, major thromboembolic events) were assessed in the efficacy ITO population (patients without recurrence during HERCULES or before post‐HERCULES). Among 104 enrolled patients, incidences of AEs and serious AEs were similar between patients who had received caplacizumab + TPE + IST during HERCULES (n= 75) and those treated with placebo + TPE + IST (placebo; n= 29). TTP‐related events occurred in 8% of patients (4/49) randomized to caplacizumab during HERCULES versus 38% (11/29) randomized to placebo. Nineteen patients had ≥1 recurrence; 13 of these were treated with caplacizumab. The first recurrence episode was resolved or resolving for all patients treated with caplacizumab, including nine patients with repeat caplacizumab use. All second recurrences (6/6) were resolved. Safety profile of caplacizumab for treatment of recurrence was consistent with HERCULES; most bleeding events were nonserious. No major cases of organ dysfunction were observed. Long‐term follow‐up supports the safety and efficacy of caplacizumab for iTTP and its repeated use for recurrences.

Caplacizumab demonstrated efficacy and safety in patients with immune‐mediated thrombotic thrombocytopenic purpura (iTTP) in the phase 3 HERCULES trial. However, data on long‐term outcomes following caplacizumab treatment are limited.

We have developed an artificial neural network prediction model for end-stage kidney disease (ESKD) in patients with primary immunoglobulin A nephropathy (IgAN) using a retrospective cohort of 948 patients with IgAN. Our tool is based on a two-step procedure of a classifier model that predicts ESKD, and a regression model that predicts development of ESKD over time. The classifier model showed a performance value of 0.82 (area under the receiver operating characteristic curve) in patients with a follow-up of five years, which improved to 0.89 at the ten-year follow-up. Both models had a higher recall rate, which indicated the practicality of the tool. The regression model showed a mean absolute error of 1.78 years and a root mean square error of 2.15 years. Testing in an independent cohort of 167patients with IgAN found successful results for 91% of the patients. Comparison of our system with other mathematical models showed the highest discriminant Harrell C index at five- and ten-years follow-up (81% and 86%, respectively), paralleling the lowest Akaike information criterion values (355.01 and 269.56, respectively). Moreover, our system was the best calibrated model indicating that the predicted and observed outcome probabilities did not significantly differ. Finally, the dynamic discrimination indexes of our artificial neural network, expressed as the weighted average of time-dependent areas under the curve calculated at one and two years, were 0.80 and 0.79, respectively. Similar results were observed over a 25-year follow-up period. Thus, our tool identified individuals who were at a high risk of developing ESKD due to IgAN and predicted the time-to-event endpoint. Accurate prediction is an important step toward introduction of a therapeutic strategy for improving clinical outcomes.

The International IgA Nephropathy (IgAN) Prediction Tool is the preferred method in the 2021 KDIGO guidelines to predict, at the time of kidney biopsy, the risk of a 50% drop in estimated glomerular filtration rate or kidney failure. However, it is not known if the Prediction Tool can be accurately applied after a period of observation post-biopsy. Using an international multi-ethnic derivation cohort of 2,507 adults with IgAN, we updated the Prediction Tool for use one year after biopsy, and externally validated this in a cohort of 722 adults. The original Prediction Tool applied at one-year without modification had a coefficient of variation (R2) of 55% and 54% and four-year concordance (C statistic) of 0.82 but poor calibration with under-prediction of risk (integrated calibration index (ICI) 1.54 and 2.11, with and without race, respectively). Our updated Prediction Tool had a better model fit with higher R2(61% and 60%), significant increase in four-year C-statistic (0.87 and 0.86) and better four-year calibration with lower ICI (0.75 and 0.35). On external validation, the updated Prediction Tool had similar R2(60% and 58%) and four-year C-statistics (both 0.85) compared to the derivation analysis, with excellent four-year calibration (ICI 0.62 and 0.56). This updated Prediction Tool had similar prediction performance when used two years after biopsy. Thus, the original Prediction Tool should be used only at the time of biopsy whereas our updated Prediction Tool can be used for risk stratification one or two years post-biopsy.

Patients with high-risk lymphoma have a poor prognosis when treated with standard chemoimmunotherapy. This retrospective study included 23 high-risk lymphoma patients with a median age at diagnosis of 59 (range, 35–68) years. They received 2 cycles of R-COPADM and 2 cycles of CYVE, completed by ASCT for fit patients. With a median follow-up of 46 (range, 3–78) months, three (13%) patients in the cohort died. Nearly half of the patients had an ECOG performance status of 2 or 3. Most patients in the cohort (91%, n= 21) had Ann Arbor stage III-IV disease, and 88% (n= 20) had an IPI of 3 to 5. LDH levels were elevated in 83% (n= 19) of patients. Overall, 30% of patients were identified as having double-expressor lymphoma and 22% as having DHL, while two patients (9%) had THL. The origin of the lymphoma was GC B-cell-like in 15 patients (65%) and ABC-like in 8 patients (35%). Cumulative incidence of relapse at 46 months was 14% (95% CI, 5–37), while overall survival was 87% (95% CI, 64–95) and progression-free survival was 83% (95% CI, 60–93). These results showed the efficacy and an acceptable safety profile of the R-COPADM/CYVE/ASCT regimen in high-risk lymphoma, including patients with DHL.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare disease in adults and exceptional in childhood. Caplacizumab has proven its effectiveness in the treatment of iTTP in adulthood in association with standard of care. Unfortunately, this treatment is restricted to adults. We report our experience in three children who were treated successfully with caplacizumab.

Introduction: Candida auris(C. auris) is an emerging nosocomial pathogen, and a sharp rise in cases of colonization and infection has been registered in intensive care units (ICUs) during the ongoing coronavirus disease 2019 (COVID-19) pandemic. The unfavorable resistance profile of C. aurisand the potential high mortality of C. aurisinfections represent an important challenge for physicians. Methods: We conducted a single-center retrospective study including all patients admitted to ICUs with isolation of C. aurisin any non-sterile body site between February 20, 2020, and May 31, 2021. The primary aim of the study was to assess the cumulative incidence of C. auriscandidemia in colonized patients. The secondary aim was to identify predictors of C. auriscandidemia in the study population. Results: During the study period, 157 patients admitted to ICUs in our hospital became colonized with C. auris; 59% of them were affected by COVID-19. Overall, 27 patients (17%) developed C. auriscandidemia. The cumulative risk of developing C. auriscandidemia was > 25% at 60 days after first detection of C. auriscolonization. Seven patients with C. auriscandidemia (26%) also developed a late recurrent episode. All C. aurisblood isolates during the first occurring episode were resistant to fluconazole and susceptible to echinocandins, while 15 (56%) were resistant to amphotericin B. During late recurrent episodes, emergent resistance to caspofungin and amphotericin B occurred in one case each. In the final multivariable model, only multisite colonization retained an independent association with the development of C. auriscandidemia. Conclusion: Candida auriscandidemia may occur in up to one fourth of colonized critically ill patients, and multisite colonization is an independent risk factor for the development of candidemia. Implementing adequate infection control measures remains crucial to prevent colonization with C. aurisand indirectly the subsequent development of infection.

The COVID-19 pandemic has significantly impacted many aspects of our social and professional life. To this end, Higher Education institutions reacted rather vastly to this unpreceded situation although many issues have been reported in the international literature since the emergence of the first global lockdown. As we are now transitioning back to the ‘normality’, universities and businesses consider the so-called ‘blended’ or ‘hybrid’ model as a means of facilitating the transition phase. In view of this decision, several studies can be identified wherein blended learning scenarios are proposed and described. The present work constitutes such an effort. Precisely, while adjusting the lens to the didactic of Robotics courses, we propose a blended learning model via which the laboratory activities are performed without the physical presence of the students in the physical context. The aforementioned objective is attained under the aid of the Virtual Reality technology coupled with the Digital Twin model. We hope that the ideas presented in this manuscript will motivate and inspire more researchers, instructional designers, and educators to consider the adoption of such alternative instructional techniques to mitigate the shortcomings that the remote education setting brings and further to improve the overall learning experience.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is caused by an autoantibody-mediated deficiency in ADAMTS13. In healthy individuals, ADAMTS13 has a folded conformation in which the central spacer (S) domain interacts with the C-terminal CUB domains. We recently showed that ADAMTS13 adopts an open conformation in iTTP and that patient immunoglobulin G antibodies (IgGs) can open ADAMTS13. Anti-ADAMTS13 autoantibodies in patients with iTTP are directed against the different ADAMTS13 domains, but almost all patients have autoantibodies binding to the cysteine/spacer (CS) domains. In this study, we investigated whether the autoantibodies against the CS and CUB domains can disrupt the S-CUB interaction of folded ADAMTS13, thereby opening ADAMTS13. To this end, we purified anti-CS and anti-CUB autoantibodies from 13 patients with acute iTTP by affinity chromatography. The successfully purified anti-CS (10/13 patients) and anti-CUB (4/13 patients) autoantibody fractions were tested further in our ADAMTS13 conformation enzyme-linked immunosorbent assay to study whether they could open ADAMTS13. Interestingly, all purified anti-CS fractions (10/10 patients) were able to open ADAMTS13. On the other hand, only half of the purified anti-CUB fractions (2/4 patients) opened ADAMTS13. Our finding highlights that anti-CS autoantibodies that open ADAMTS13 are a common feature of the autoimmune response in iTTP.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is caused by an autoantibody-mediated deficiency in ADAMTS13. In healthy individuals, ADAMTS13 has a folded conformation in which the central spacer (S) domain interacts with the C-terminal CUB domains. We recently showed that ADAMTS13 adopts an open conformation in iTTP and that patient immunoglobulin G antibodies (IgGs) can open ADAMTS13. Anti-ADAMTS13 autoantibodies in patients with iTTP are directed against the different ADAMTS13 domains, but almost all patients have autoantibodies binding to the cysteine/spacer (CS) domains. In this study, we investigated whether the autoantibodies against the CS and CUB domains can disrupt the S-CUB interaction of folded ADAMTS13, thereby opening ADAMTS13. To this end, we purified anti-CS and anti-CUB autoantibodies from 13 patients with acute iTTP by affinity chromatography. The successfully purified anti-CS (10/13 patients) and anti-CUB (4/13 patients) autoantibody fractions were tested further in our ADAMTS13 conformation enzyme-linked immunosorbent assay to study whether they could open ADAMTS13. Interestingly, all purified anti-CS fractions (10/10 patients) were able to open ADAMTS13. On the other hand, only half of the purified anti-CUB fractions (2/4 patients) opened ADAMTS13. Our finding highlights that anti-CS autoantibodies that open ADAMTS13 are a common feature of the autoimmune response in iTTP.

Anti-A Disintegrin and Metalloproteinase with a ThromboSpondin type 1 motif, member 13 (ADAMTS13) autoantibodies cause a severe ADAMTS13 deficiency in immune-mediated thrombotic thrombocytopenic purpura (iTTP). ADAMTS13 consists of a metalloprotease (M), a disintegrin-like (D) domain, 8 thrombospondin type 1 repeats (T1-T8), a cysteine-rich (C), a spacer (S), and 2 CUB domains (CUB1-2). We recently developed a high-throughput epitope mapping assay based on small, nonoverlapping ADAMTS13 fragments (M, DT, CS, T2-T5, T6-T8, CUB1-2). With this assay, we performed a comprehensive epitope mapping using 131 acute-phase samples and for the first time a large group of remission samples (n = 50). Next, samples were stratified according to their immunoprofiles, a field that is largely unexplored in iTTP. Three dominant immunoprofiles were found in acute-phase samples: profile 1: only anti-CS autoantibodies (26.7%); profile 2: both anti-CS and anti-CUB1-2 autoantibodies (12.2%); and profile 3: anti-DT, anti-CS, anti-T2-T5, anti-T6-T8, and anti-CUB1-2 autoantibodies (8.4%). Interestingly, profile 1 was the only dominant immunoprofile in remission samples (52.0%). Clinical data were available for a relatively small number of patients with acute iTTP (>68), and no correlation was found between immunoprofiles and disease severity. Nevertheless, profile 1 was linked with younger and anti-T2-T5 autoantibodies with older age and the absence of anti-CUB1-2 autoantibodies with cerebral involvement. In conclusion, identifying acute phase and remission immunoprofiles in iTTP revealed that anti-CS autoantibodies seem to persist or reappear during remission providing further support for the clinical development of a targeted anti-CS autoantibody therapy. A large cohort study with acute iTTP samples will validate possible links between immunoprofiles or anti-domain autoantibodies and clinical data.

Anti-A Disintegrin and Metalloproteinase with a ThromboSpondin type 1 motif, member 13 (ADAMTS13) autoantibodies cause a severe ADAMTS13 deficiency in immune-mediated thrombotic thrombocytopenic purpura (iTTP). ADAMTS13 consists of a metalloprotease (M), a disintegrin-like (D) domain, 8 thrombospondin type 1 repeats (T1-T8), a cysteine-rich (C), a spacer (S), and 2 CUB domains (CUB1-2). We recently developed a high-throughput epitope mapping assay based on small, nonoverlapping ADAMTS13 fragments (M, DT, CS, T2-T5, T6-T8, CUB1-2). With this assay, we performed a comprehensive epitope mapping using 131 acute-phase samples and for the first time a large group of remission samples (n = 50). Next, samples were stratified according to their immunoprofiles, a field that is largely unexplored in iTTP. Three dominant immunoprofiles were found in acute-phase samples: profile 1: only anti-CS autoantibodies (26.7%); profile 2: both anti-CS and anti-CUB1-2 autoantibodies (12.2%); and profile 3: anti-DT, anti-CS, anti-T2-T5, anti-T6-T8, and anti-CUB1-2 autoantibodies (8.4%). Interestingly, profile 1 was the only dominant immunoprofile in remission samples (52.0%). Clinical data were available for a relatively small number of patients with acute iTTP (>68), and no correlation was found between immunoprofiles and disease severity. Nevertheless, profile 1 was linked with younger and anti-T2-T5 autoantibodies with older age and the absence of anti-CUB1-2 autoantibodies with cerebral involvement. In conclusion, identifying acute phase and remission immunoprofiles in iTTP revealed that anti-CS autoantibodies seem to persist or reappear during remission providing further support for the clinical development of a targeted anti-CS autoantibody therapy. A large cohort study with acute iTTP samples will validate possible links between immunoprofiles or anti-domain autoantibodies and clinical data.

Forecasting flood and drought events requires accurate modeling tools. Hydraulic river models are based on estimates of riverbed geometry which are traditionally collected in situ. The novel Ice, Cloud and Land Elevation Satellite 2 [ICESat‐2] lidar altimetry mission with 6 simultaneous high‐resolution laser beams provides the opportunity to define river cross‐section geometries as well as observe water surface elevation [WSE] and water surface slope spatially resolved along the river chainage. This paper describes a method to utilize terrain altimetry and water surface slope estimates to define complete river geometries from ICESat‐2 data products, using the diffusive wave approximation to calculate depth in the submerged section not penetrated by the lidar. Exemplifying the method, cross‐sections are defined for a stretch of the Mekong River. Hydrodynamic model results of the stretch are compared with ICESat‐2 WSE estimates and in situ gauging station time series. Insights in river characteristics from satellite imagery and the ICESat‐2 slope estimates allow for fine‐tuning of the cross‐sections using spatially varying Manning numbers. The final model achieves a root mean square error against the ICESat‐2 WSE of 0.676 m and average Kling‐Gupta Efficiency against gauging station time series of 0.880. The method is limited by the diffusive wave approximation resulting in inaccurate cross‐section estimates in sections with supercritical flow or significant acceleration. Errors can be identified from ICESat‐2 WSE estimates and reduced with additional cross‐sections. Combined with hydrological models, the method will allow for cross‐section definition without in situ data. The depth and width of the river channel are important factors when seeking to predict floods. To predict water level in a river, computer models for flood forecasting must be informed with river channel geometry at cross‐sections along the river. Such cross‐sections are traditionally measured in the field which is expensive and time consuming. This paper describes a method to estimate river cross‐sectional shape from land and water height measurements from the satellite ICESat‐2. When the satellite path crosses the river, the precise laser instrument onboard outlines the surface to indicate the river channel shape, but it does not penetrate the water. We found that it was possible to estimate the shape of the submerged part of the cross‐section using the water surface slope obtained from the satellite's unique instrument. Evaluating the method on a stretch of the Mekong River, we were able to model water level along the river with accuracy sufficient for flood forecasting. In some sections, where the flow speed changes quickly, a hydraulic model with the defined cross‐sections does not reproduce observed water levels. Using satellite crossings from days with steadier flow reduces the error. The method allows for building hydraulic river models without cross‐section surveys. Land elevation and water surface slope estimates from the ICESat‐2 lidar altimetry mission are combined to define river cross‐sectionsRMSE of 0.676 m and KGE of 0.88 is achieved for a hydrodynamic model of a stretch of the Mekong River using the derived cross‐sectionsSections with significant flow acceleration lead to inaccurate cross‐sections, but errors are reduced with additional ICESat‐2 crossings Land elevation and water surface slope estimates from the ICESat‐2 lidar altimetry mission are combined to define river cross‐sections RMSE of 0.676 m and KGE of 0.88 is achieved for a hydrodynamic model of a stretch of the Mekong River using the derived cross‐sections Sections with significant flow acceleration lead to inaccurate cross‐sections, but errors are reduced with additional ICESat‐2 crossings

Evidence from the Oxford IgA nephropathy (IgAN) cohort supports the clinical value of subclassifying focal segmental glomerulosclerosis lesions (S1). Using the larger Validation in IgA (VALIGA) study cohort, we investigated the association between podocytopathic changes and higher proteinuria, kidney outcome and response to immunosuppressive therapy. All biopsies were evaluated for glomeruli with segmental capillary occlusion by matrix (“not otherwise specified”, NOS lesion), simple capsular adhesion without capillary occlusion (Adh), tip lesions, and podocyte hypertrophy (PH). S1 required a NOS lesion and/or Adh. A Chi-Squared Automatic Interaction Detection method was used to identify subgroups of FSGS lesions associated with distinctive proteinuria at biopsy and assessed survival from a combined event (kidney failure or 50% decline in estimated glomerular filtration rate). Finally, we evaluated within each subgroup if immunosuppression was associated with a favorable outcome using propensity analysis. In 1147 patients, S1 was found in 70% of biopsies. Subclassification found NOS lesions in 44%, Adh in 59%, PH in 13%, and tip lesions in 3%, with much overlap. Four subgroups were identified with progressively higher proteinuria: from lowest, S1 without NOS, S1 with NOS but without Adh/PH, to highest, S1 with NOS and Adh but without PH, and S1 with NOS and PH. These four subgroups showed progressively worse kidney survival. Immunosuppression was associated with a better outcome only in the two highest proteinuria subgroups. Propensity analysis in these two groups, adjusted for clinical and pathological findings, found a significant time-dependent hazard of combined outcome with corticosteroids. Podocyte hypertrophy and glomeruli with simple adhesions appeared to reflect active lesions associated with a response to corticosteroids, while other S1 lesions defined chronicity. Thus, our findings support subclassifying S1 lesions in IgAN.