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Abstract Background Infliximab is currently recommended as a third-line treatment for refractory sarcoidosis. Data in function of clinical phenotype are currently lacking. We evaluated patients’ characteristics and responses to infliximab according to their GenPhenReSa cluster. Methods We evaluated clinical and biological characteristics of patients diagnosed with sarcoidosis who received infliximab between September 2008 and April 2019 at our centre. Results Fifty-five patients (median disease duration, 87 months) received infliximab: 48 (87%) as a second- or third-line treatment, and 7 (13%) as a first-line treatment. After a median duration of 12 months, 24 (45%) and 14 (25%) patients achieved complete and partial responses, respectively, together with a significant decrease in the number of affected organs and tapering of steroid doses. All patients with neurosarcoidosis (OR 17), 90% in group 2 (ocular-cardiac-cutaneous-CNS, OR 7.4), and approximately two-thirds of those in groups 1 (abdominal organs), 4 (pulmonary-lympho-nodal), and 5 (extrapulmonary), achieved a response, whereas patients in group 3 (musculoskeletal-cutaneous) had a treatment-failure OR of 9. Infliximab could be stopped after complete remission was achieved in 7 patients: 4 relapsed after a median of 6 months. Overall, 36% of patients experienced serious adverse events, mainly infections, which led to treatment cessation in 29% of patients and caused two deaths. Conclusions Other than patients with musculoskeletal-cutaneous involvement (group 3), infliximab led to a good response for patients with CNS (group 2) and liver (group 1) organ-predominant sarcoidosis. However, it led to serious infections and merely suspended sarcoidosis, so further research on factors predictive of relapse is needed.

Objectives Discontinuation or continuation of maintenance immunosuppressive therapy (MIST) after a severe lupus nephritis (LN) requires measuring the risk of relapse but reliable clinical and biological markers are lacking. The WIN-IgE study assesses the value of serum anti-dsDNA IgE autoantibodies as a biomarker for the prediction of relapse in severe LN.Methods WIN-IgE is an ancillary study of the WIN-Lupus study (NCT01284725), a prospective controlled clinical trial which evaluated the discontinuation of MIST after 2–3 years in class III or IV±V LN with active lesions. WIN-IgE included all patients with available serum collected at randomisation for continuation or discontinuation of MIST. In these sera, anti-dsDNA antibodies, IgE and IgG, were quantified by ELISA and compared between patients who experienced LN relapse and those who did not during the 24 months of follow-up.Results 52 patients were included, 25 in the MIST continuation group and 27 in the MIST discontinuation group, 12 experienced a biopsy-proven relapse of LN. Initial anti-dsDNA IgE antibodies levels were higher in patients with subsequent LN relapse. Anti-dsDNA IgG was not associated with relapse. Survival without LN relapse was lower in patients with anti-dsDNA IgE levels above vs below a threshold of 1.9 arbitrary units (p=0.019), particularly in the subgroup of patients randomised to discontinue MIST (p=0.002). In all patients, anti-dsDNA IgE above 1.9 arbitrary units had a positive predictive value of 0.8 for severe LN relapse.Conclusions These results suggest blood anti-dsDNA IgE as a non-invasive predictive marker of LN relapse.

Abstract Background Feature selection is a critical step for translating advances afforded by systems-scale molecular profiling into actionable clinical insights. While data-driven methods are commonly utilized for selecting candidate genes, knowledge-driven methods must contend with the challenge of efficiently sifting through extensive volumes of biomedical information. This work aimed to assess the utility of large language models (LLMs) for knowledge-driven gene prioritization and selection. Methods In this proof of concept, we focused on 11 blood transcriptional modules associated with an Erythroid cells signature. We evaluated four leading LLMs across multiple tasks. Next, we established a workflow leveraging LLMs. The steps consisted of: (1) Selecting one of the 11 modules; (2) Identifying functional convergences among constituent genes using the LLMs; (3) Scoring candidate genes across six criteria capturing the gene’s biological and clinical relevance; (4) Prioritizing candidate genes and summarizing justifications; (5) Fact-checking justifications and identifying supporting references; (6) Selecting a top candidate gene based on validated scoring justifications; and (7) Factoring in transcriptome profiling data to finalize the selection of the top candidate gene. Results Of the four LLMs evaluated, OpenAI's GPT-4 and Anthropic's Claude demonstrated the best performance and were chosen for the implementation of the candidate gene prioritization and selection workflow. This workflow was run in parallel for each of the 11 erythroid cell modules by participants in a data mining workshop. Module M9.2 served as an illustrative use case. The 30 candidate genes forming this module were assessed, and the top five scoring genes were identified as BCL2L1, ALAS2, SLC4A1, CA1, and FECH. Researchers carefully fact-checked the summarized scoring justifications, after which the LLMs were prompted to select a top candidate based on this information. GPT-4 initially chose BCL2L1, while Claude selected ALAS2. When transcriptional profiling data from three reference datasets were provided for additional context, GPT-4 revised its initial choice to ALAS2, whereas Claude reaffirmed its original selection for this module. Conclusions Taken together, our findings highlight the ability of LLMs to prioritize candidate genes with minimal human intervention. This suggests the potential of this technology to boost productivity, especially for tasks that require leveraging extensive biomedical knowledge.

Performance criteria play a key role in the calibration and evaluation of hydrological models and have been extensively developed and studied, but some of the most used criteria still have unknown pitfalls. This study set out to examine counterbalancing errors, which are inherent to the Kling–Gupta efficiency (KGE) and its variants. A total of nine performance criteria – including the KGE and its variants, as well as the Nash–Sutcliffe efficiency (NSE) and the modified index of agreement (d1) – were analysed using synthetic time series and a real case study. Results showed that, when assessing a simulation, the score of the KGE and some of its variants can be increased by concurrent overestimation and underestimation of discharge. These counterbalancing errors may favour bias and variability parameters, therefore preserving an overall high score of the performance criteria. As bias and variability parameters generally account for two-thirds of the weight in the equation of performance criteria such as the KGE, this can lead to an overall higher criterion score without being associated with an increase in model relevance. We recommend using (i) performance criteria that are not or less prone to counterbalancing errors (d1, modified KGE, non-parametric KGE, diagnostic efficiency) and/or (ii) scaling factors in the equation to reduce the influence of relative parameters.

Hydrological models are widely used to characterize, understand and manage hydrosystems. Lumped parameter models are of particular interest in karst environments given the complexity and heterogeneity of these systems. There is a multitude of lumped parameter modelling approaches, which can make it difficult for a manager or researcher to choose. We therefore conducted a comparison of two lumped parameter modelling approaches: artificial neural networks (ANNs) and reservoir models. We investigate five karst systems in the Mediterranean and Alpine regions with different characteristics in terms of climatic conditions, hydrogeological properties and data availability. We compare the results of ANN and reservoir modelling approaches using several performance criteria over different hydrological periods. The results show that both ANNs and reservoir models can accurately simulate karst spring discharge but also that they have different advantages and drawbacks: (i) ANN models are very flexible regarding the format and amount of input data, (ii) reservoir models can provide good results even with a few years of relevant discharge in the calibration period and (iii) ANN models seem robust for reproducing high-flow conditions, while reservoir models are superior in reproducing low-flow conditions. However, both modelling approaches struggle to reproduce extreme events (droughts, floods), which is a known problem in hydrological modelling. For research purposes, ANN models have been shown to be useful for identifying recharge areas and delineating catchments, based on insights into the input data. Reservoir models are adapted to understand the hydrological functioning of a system by studying model structure and parameters.

Introduction Aseptic abscess (AA) syndrome is a rare disease whose pathophysiology is unknown. It is often associated with inflammatory bowel disease and characterised by sterile inflammation with collections of neutrophils affecting several organs, especially the spleen. Microbiota are known to influence local and systemic immune responses, and both gut and oral microbiota perturbations have been reported in diseases associated with AA syndrome. However, interactions between these factors have never been studied in AA syndrome. The purpose of this translational case-control study (ABSCESSBIOT) is to investigate gut and/or oral microbiota in patients with AA syndrome compared with healthy controls. Moreover, microbiota associated metabolites quantification and Treg/Th17 balance characterisation will give a mechanistic insight on how microbiota may be involved in the pathophysiology of AA syndrome.Methods and analysis This French multicentre case-control study including 30 French centres (University hospital or regional hospital) aims to prospectively enrol 30 patients with AA syndrome with 30 matched controls and to analyse microbiota profiling (in stools and saliva), microbial metabolites quantification in stools and circulating CD4+ T cell populations.Ethics and dissemination This study protocol was reviewed and approved by an independent French regional review board (n° 2017-A03499-44, Comité de Protection des Personnes Ile de France 1) on 10 October 2022, and declared to the competent French authority (Agence Nationale de Sécurité du Médicament et des produits de santé, France). Oral and written informed consent will be obtained from each included patient and the control participant. Study results will be reported to the scientific community at conferences and in peer-reviewed scientific journals.Trial registration number Clinical Trials web-based platform (NCT05537909).

Abstract Hemodialysis (HD) patients are at risk for severe COVID-19 and cannot comply with social distancing. SARS-COV2 seroprevalence in French patients and caregivers after the first wave of COVID-19 is unknown. SeroCOVIDial is a prospective study conducted between June and December 2020. SARS-COV2 seroprevalence was evaluated by a rapid serological test (BIOSYNEX) in HD patients and caregivers, and the presence or not of anti-SARS-COV2 neutralizing or non-neutralizing antibodies in patients was also determined by ELISA and seroneutralization. In June 2020, 451 HD patients and 238 caregivers were included. Overall SARS-COV2 seroprevalence was 8.4% (patients) and 6.7% (caregivers), and was 87.1% (patients) and 90.0% (caregivers) in participants with a previously documented SARS-COV2 infection. Overall seroprevalence reached 13.8% (patients) and 12.6% (caregivers) following the second epidemic wave. During the follow-up, 38 (8.4%) patients died (9 of COVID-19). Among the 44 (10.6%) patients who became infected, only two were seropositive at M0. The levels of anti-SARS-COV2 antibodies decreased over time in patients and caregivers. The BIOSYNEX test showed 82.9% sensitivity and 97.7% specificity. Prevalence of anti-SARS-COV2 antibodies was low in HD patients and caregivers after the first epidemic wave but rose after the second wave. A rapid serological test showed good performances and could be useful for future monitoring of anti-SARS-COV2 antibodies.

Despite many existing approaches, modeling karst water resources remains challenging as conventional approaches usually heavily rely on distinct system knowledge. Artificial neural networks (ANNs), however, require only little prior knowledge to automatically establish an input–output relationship. For ANN modeling in karst, the temporal and spatial data availability is often an important constraint, as usually no or few climate stations are located within or near karst spring catchments. Hence, spatial coverage is often not satisfactory and can result in substantial uncertainties about the true conditions in the catchment, leading to lower model performance. To overcome these problems, we apply convolutional neural networks (CNNs) to simulate karst spring discharge and to directly learn from spatially distributed climate input data (combined 2D–1D CNNs). We investigate three karst spring catchments in the Alpine and Mediterranean region with different meteorological–hydrological characteristics and hydrodynamic system properties. We compare the proposed approach both to existing modeling studies in these regions and to our own 1D CNN models that are conventionally trained with climate station input data. Our results show that all the models are excellently suited to modeling karst spring discharge (NSE: 0.73–0.87, KGE: 0.63–0.86) and can compete with the simulation results of existing approaches in the respective areas. The 2D models show a better fit than the 1D models in two of three cases and automatically learn to focus on the relevant areas of the input domain. By performing a spatial input sensitivity analysis, we can further show their usefulness in localizing the position of karst catchments.

Abstract Background Hypocomplementemic urticarial vasculitis (HUV) is a rare systemic vasculitis. We aimed to describe the kidney involvement of HUV in a multicenter national cohort with an extended follow-up. Methods All patients with HUV (international Schwartz criteria) with a biopsy-proven kidney involvement, identified through a survey of the French Vasculitis Study Group (FVSG), were included. A systematic literature review on kidney involvement of HUV was performed. Results Twelve patients were included, among whom 8 had positive anti-C1q antibodies. All presented with proteinuria, from mild to nephrotic, and 8 displayed acute kidney injury (AKI), requiring temporary haemodialysis in 2. Kidney biopsy showed membrano-proliferative glomerulonephritis (MPGN) in 8 patients, pauci-immune crescentic GN or necrotizing vasculitis in 3 patients (with a mild to severe interstitial inflammation), and an isolated interstitial nephritis in 1 patient. C1q deposits were observed in the glomeruli (n = 6), tubules (n = 4) or renal arterioles (n = 3) of 8 patients. All patients received corticosteroids, and 9 were also treated with immunosuppressants or apheresis. After a mean follow-up of 8.9 years, 6 patients had a preserved renal function, but 2 patients had developed stage 3–4 chronic kidney disease (CKD) and 4 patients had reached end-stage kidney disease (ESKD), among whom 1 had received a kidney transplant. Conclusion Renal involvement of HUV can be responsible for severe AKI, CKD and ESRD. It is not always associated with circulating anti-C1q antibodies. Kidney biopsy shows mostly MPGN or crescentic GN, with frequent C1q deposits in the glomeruli, tubules or arterioles.

Abstract Background Few data is available on the risk/benefit balance of native kidney biopsy (KB) in very elderly patients. Methods Multicenter retrospective cohort study in the Aix-Marseille area: the results of KB and medical charts of all patients over 85 years biopsied between January 2010 and December 2018 were reviewed. Results 104 patients were included. Median age was 87 years. Indications for KB were: acute kidney injury (AKI) in 69.2% of patients, nephrotic syndrome (NS) with AKI in 13.5%, NS without AKI in 12.5%, and proteinuria in 4.8%. Median serum creatinine was 262 μmol/L, 21% of patients required dialysis at the time of KB. Significant bleeding occurred in 7 (6.7%) patients, requiring blood cell transfusion in 4 (3.8%), and radiological embolization in 1 (1%). The most frequent pathological diagnoses were: non-diabetic glomerular diseases (29.8%, including pauci-immune crescentic glomerulonephritis in 9.6%), hypertensive nephropathy (27.9%), acute interstitial nephritis (16.3%), renal involvement of hematological malignancy (8.7%), and acute tubular necrosis (6.7%). After KB, 51 (49%) patients received a specific treatment: corticosteroids (41.3%), cyclophosphamide (6.7%), rituximab (6.7%), bortezomib (3.8%), other chemotherapies (3.8%). Median overall survival was 31 months. Conclusions KB can reveal a diagnosis with therapeutic impact even in very elderly patients. Severe bleeding was not frequent in this cohort, but KB may have not been performed in more vulnerable patients.

Abstract Background Gemcitabine is a broadly prescribed chemotherapy, the use of which can be limited by renal adverse events, including thrombotic microangiopathy (TMA). Methods This study evaluated the efficacy of eculizumab, a monoclonal antibody targeting the terminal complement pathway, in patients with gemcitabine-induced TMA (G-TMA). We conducted an observational, retrospective, multicenter study in 5 French centres, between 2011 and 2016. Results Twelve patients with a G-TMA treated by eculizumab were included. The main characteristics were acute renal failure (100%), including stage 3 acute kidney injury (AKI, 58%) and renal replacement therapy (17%), hypertension (92%) and diffuse oedema (83%). Eculizumab was started after a median of 15 days (range 4–44) following TMA diagnosis. A median of 4 injections of eculizumab was performed (range 2–22). Complete hematological remission was achieved in 10 patients (83%) and blood transfusion significantly decreased after only one injection of eculizumab (median of 3 packed red blood cells (range 0–10) before treatment vs 0 (range 0–1) after one injection, P

The blood transcriptome of human subjects can be profiled on an almost routine basis in translational research settings. Here the authors show that a fixed and well-characterized repertoire of transcriptional modules can be employed as a reusable framework for the analysis, visualization and interpretation of such data

The objective of this study was to evaluate the relevance of using excess air (EA) for the characterization of drain/matrix exchange in karst systems using a rainfall discharge model coupled with the simulation of EA measured at the outlet of the studied system. The conceptual model assumes a linear relationship between the formation of EA and the increase of hydrostatic pressure in the capacitive part of the aquifer. The simulated EA at the spring consists of the mixing of water circulating in the different compartments of the aquifer, with their own EA signature. The analysis is performed taking as an example the Durzon karst system (Larzac, France). The modeling is applied using daily rainfall discharge time series and 18 EA measurements at the main outlet of the karst system within 3 hydrological cycles. The main modeling results show that EA variations measured at the karst spring can be explained by recharge processes and exchange between conduit and matrix. EA measurements at the spring thus contain valuable information about the flow dynamics within the aquifer. Furthermore, results show that the use of EA measurements, despite their sparse temporal resolution, allows for reducing uncertainties in the estimation of some parameters of the reservoir model used for the simulation of karst spring discharge.

The solid phase of a commercial calcium phosphate (Graftys® HBS) was combined with ovine or human blood stabilized either with sodium citrate or sodium heparin. The presence of blood delayed the setting reaction of the cement by ca. 7–15 h, depending on the nature of the blood and blood stabilizer. This phenomenon was found to be directly related to the particle size of the HBS solid phase, since prolonged grinding of the latter resulted in a shortened setting time (10–30 min). Even though ca. 10 h were necessary for the HBS blood composite to harden, its cohesion right after injection was improved when compared to the HBS reference as well as its injectability. A fibrin-based material was gradually formed in the HBS blood composite to end-up, after ca. 100 h, with a dense 3D organic network present in the intergranular space, thus affecting the microstructure of the composite. Indeed, SEM analyses of polished cross-sections showed areas of low mineral density (over 10–20 µm) spread in the whole volume of the HBS blood composite. Most importantly, when the two cement formulations were injected in the tibial subchondral cancellous bone in a bone marrow lesion ovine model, quantitative SEM analyses showed a highly significant difference between the HBS reference versus its analogue combined with blood. After a 4-month implantation, histological analyses clearly showed that the HBS blood composite underwent high resorption (remaining cement: ca. 13.1 ± 7.3%) and new bone formation (newly formed bone: 41.8 ± 14.7%). This was in sharp contrast with the case of the HBS reference for which a low resorption rate was observed (remaining cement: 79.0 ± 6.9%; newly formed bone: 8.6 ± 4.8%). This study suggested that the particular microstructure, induced by the use of blood as the HBS liquid phase, favored quicker colonization of the implant and acceleration of its replacement by newly formed bone. For this reason, the HBS blood composite might be worth considering as a potentially suitable material for subchondroplasty.

Abstract Background Hydroxychloroquine (HCQ) levels can be measured in both serum and whole blood. No cut-off point for non-adherence has been established in serum nor have these methods ever been compared. The aims of this study were to compare these two approaches and determine if serum HCQ cut-off points can be established to identify non-adherent patients. Methods HCQ levels were measured in serum and whole blood from 573 patients with systemic lupus erythematosus (SLE). The risk factors for active SLE (SLEDAI score > 4) were identified by multiple logistic regression. Serum HCQ levels were measured in 68 additional patients known to be non-adherent, i.e. with whole-blood HCQ

Abstract Background The seroprevalence of human Parvovirus B19 (PVB19) is 70–85% in adults worldwide. PVB19 is the etiologic agent of the fifth disease, is a cause of aplastic anemia, and can be associated with kidney injury. We aimed to describe the cases of 4 patients with kidney injury related to PVB19 primary infection, and to evaluate the seroprevalence of PVB19 and the incidence of PVB19 primary infection in patients undergoing a native kidney biopsy. Methods Cases of PVB19 infection with kidney injury were reviewed from the archives of the department of Nephrology. A systematic screening of anti-PVB19 IgG and IgM antibodies and viral DNA was performed in sera from 100 consecutive patients with a kidney biopsy in 2017–2018. Results The 4 patients with PVB19 infection-associated kidney disease displayed: one lupus-like glomerulonephritis (GN) without lupus auto-antibodies, one minimal change disease with tubular necrosis, one secondary hemolytic and uremic syndrome and one membrano-proliferative GN. In the 100 patients biopsied, 67 had elevated anti-PVB19 IgG, among whom 8 had elevated IgM, without circulating viral DNA, without any particular renal pathological pattern. One additional patient showed a seroconversion at the time of kidney biopsy, which revealed a class V lupus nephritis. Conclusion PVB19 primary infection can be associated with different kidney diseases. The seroprevalence of PVB19 among patients with a kidney biopsy is similar to the overall population, and primary infection is rarely documented (1%) after systematic screening. Whether PV19 is nephrotoxic, or triggers renal endothelial injury and immune activation, remains to be elucidated.