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The article presents case study of a 57-year-old man who was suspected with pyoderma gangrenosum (PG) of the right leg, diagnosed with central necrosis and ulceration. It mentions the laboratory tests which revealed anaemia and thrombocytopenia with myelocytosis along with diagnosis necrotizing fasciitis followed by surgical debridement. It also discusses the efficacy of Cyclosporine and anti-TNF alpha infliximab using systemic corticosteroid technique.

Les antipaludéens de synthèse (APS) sont largement utilisés dans le traitement des connectivites. L'exposition chronique aux APS peut engendrer une cardiomyopathie, diagnostic mal connu des cliniciens et possiblement sous-estimé. Nous avons réalisé une étude nationale, multicentrique et rétrospective via un appel à observations national par la SNFMI, le groupe myocardite et les pathologistes cardiaques. Les critères d'inclusion étaient la prise de chloroquine (CQ) ou d'hydroxychloroquine (HCQ), la survenue d'une atteinte cardiaque après le début du traitement par APS, et l'absence d'étiologie alternative retrouvée expliquant la cardiopathie, entre le 01/05/2000 et le 01/02/2024. Les critères d'exclusion étaient l'allongement du QT isolé et la prise du traitement moins de 6 mois. Les données ont été recueillies de manière rétrospective via un questionnaire standardisé anonymisé. Nous avons identifié les cas probables (amélioration de la cardiopathie après arrêt de l'APS sans autre explication), les cas histologiquement confirmés (histologie en faveur d'une toxicité des APS), et classé les autres patients comme cas possibles. Nous avons également interrogé la base nationale de pharmacovigilance pour les cas déclarés de toxicité cardiaque secondaire aux APS. Via l'appel à observations, nous avons identifié 18 patients, dont 3 ont été exclus (traitement cardiotoxique antérieur, n = 2, diagnostic de maladie de Fabry, n = 1). Les 15 patients inclus (80 % de femmes) avaient un âge médian de 59 ans au diagnostic de la cardiopathie (IQR 49,5–61,5). Il s'agissait de cas histologiquement confirmés (n = 5), probables (n = 5) et possibles (n = 5). Les patients recevaient de l'HCQ (n = 10), de la CQ (n = 1), ou les 2 successivement (n = 4), majoritairement pour un lupus systémique (53 %) ou cutané (26 %). La durée médiane d'exposition aux APS était de 16,5 ans (extrêmes 1 an–39 ans) avec une dose cumulée médiane de 1980 g (150 g–5616 g). L'atteinte cardiaque se manifestait par une décompensation cardiaque gauche (66 %), des troubles de conduction (46 %, dont 26 % de BAV3 et 20 % de blocs de branche gauche) et/ou de la repolarisation (40 %). L'échocardiographie retrouvait une cardiomyopathie dilatée (CMD) chez 6 patients (40 %), une cardiomyopathie hypertrophique (CMH) chez 5 patients (33 %), une dysfonction VG chez 2 patients (13 %) ; elle était normale chez 3 patients (20 %). Une IRM cardiaque, réalisée chez 10 patients, retrouvait une dysfonction ventriculaire gauche (n = 5), une hypertrophie ventriculaire gauche (n = 3) ou biventriculaire (n = 1). Une biopsie endomyocardique, réalisée chez 6 patients (40 %), objectivait une vacuolisation des myocytes (n = 5) ou était normale (n = 1) ; 3 biopsies, étudiées en microscopie électronique, visualisaient des figures myéliniques et de corps curvilinéaires sur 2 d'entre elles. Une autre toxicité des APS était retrouvée chez 4 patients (myopathie n = 2, rétinopathie n = 1 et neuropathie n = 1). Le suivi était en médiane de 2,5 ans (IQR 1–3,75) après le diagnostic de cardiopathie. L'APS était arrêté chez tous les patients en médiane 1 mois après le diagnostic de cardiopathie (IQR 0–1). Au cours du suivi, 8 patients (53 %) se sont améliorés sur le plan clinique et/ou échocardiographique, avec un délai médian de 5 mois. Parmi les 7 autres patients, 1 est décédé (mort subite), 2 ont eu une transplantation cardiaque (2 et 10 ans après le diagnostic de l'atteinte cardiaque), 3 ont bénéficié d'un pacemaker et 1 d'un défibrillateur implantable (avant transplantation), et aucune amélioration n'a été observée chez 1 patient. La base nationale de pharmacovigilance a permis d'identifier 56 patients entre le 01/11/1987 et le 01/12/2023. Nous avons exclu 32 patients (prise d'un autre traitement cardiotoxique, n = 4, prise d'APS moins de 6 mois, n = 3, autre cause à l'origine de l'atteinte cardiaque, n = 7, patients déjà inclus, n = 5, allongement du QT isolé, n = 1, et dossiers avec informations manquantes, n = 12). Les 24 cas restants ont été classés en cas confirmés (n = 1), cas probables (n = 8), et cas possibles (n = 15) Les cardiomyopathies liées aux APS semblent donc rares, mais leur diagnostic précoce par le spécialiste est important afin de permettre une récupération à l'arrêt. La présentation est hétérogène, principalement sous forme de cardiomyopathie hypertrophique ou dilatée avec des troubles de la conduction comme dans les cas rapportés dans la littérature [1,2]. L'élimination des diagnostics alternatifs comme une poussée de lupus ou une maladie de Fabry est parfois difficile. La réalisation d'une biopsie endomyocardique permet d'appuyer le diagnostic. Un des mécanismes impliqué dans leur survenue semble être une anomalie d'activité des enzymes lysosomales dans les cardiomyocytes [3]. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is an autoimmune disease, the pathophysiology and genetic basis of which are incompletely understood. Using a forward genetic screen in multiplex families with SLE, we identified an association between SLE and compound heterozygous deleterious variants in the non-receptor tyrosine kinases (NRTKs) ACK1 and BRK . Experimental blockade of ACK1 or BRK increased circulating autoantibodies in vivo in mice and exacerbated glomerular IgG deposits in an SLE mouse model. Mechanistically, NRTKs regulate activation, migration, and proliferation of immune cells. We found that the patients' ACK1 and BRK variants impair efferocytosis, the MERTK-mediated anti-inflammatory response to apoptotic cells, in human induced pluripotent stem cell (hiPSC)-derived macrophages, which may contribute to SLE pathogenesis. Overall, our data suggest that ACK1 and BRK deficiencies are associated with human SLE and impair efferocytosis in macrophages., Competing Interests: SG, TL, NJ, BB, MT, BC, TZ, CN, RB, HY, FR, RF, SD, DI, DD, NL, OE, AV, NS, LA, SN, MH, WM, JC, FG No competing interests declared, (© 2024, Guillet, Lazarov et al.)

An open prospective, multicenter study enrolled 48 selected patients with chronic immune thrombocytopenia who achieved complete response for 1 year on thrombopoietin receptor agonists, half of the patients maintained a sustained response off treatment 4 years after treatment discontinuation. NCT03119974., (Copyright © 2024 American Society of Hematology.)

Debris-flow activity in the Alps is anticipated to undergo pronounced changes in response to a warming climate. Yet, a fundamental challenge in comprehensively assessing changes in process activity is the systematic lack of long-term observational debris-flow records. Here, we reconstruct the longest, continuous time series (1626-2020) of debris flows at Multetta, a supply-limited torrential system in the Eastern Swiss Alps. Relying on growth-ring records of trees that were damaged by debris flows, we do not detect significant changes in the frequency or magnitude over time. This seeming absence of a direct climatic influence on debris-flow initiation aligns with the regular distribution of repose time patterns, indicating a dependence of local process activity on sediment discharge and recharge. This stark difference in process behavior between our supply-limited site and transport-limited catchments has implications for assessing torrential hazard and risk mitigation in a context of global warming., (© 2024. The Author(s).)

In this Letter, we use a model fluid mechanics experiment to elucidate the impact of curvature heterogeneities on two-dimensional fields deriving from harmonic potential functions. This result is directly relevant to explain the smooth stationary structures in physical systems as diverse as curved liquid crystal and magnetic films, heat and Ohmic transport in wrinkled two-dimensional materials, and flows in confined channels. Combining microfluidic experiments and theory, we explain how curvature heterogeneities shape confined viscous flows. We show that isotropic bumps induce local distortions to Darcy's flows, whereas anisotropic curvature heterogeneities disturb them algebraically over system-spanning scales. Thanks to an electrostatic analogy, we gain insight into this singular geometric perturbation, and quantitatively explain it using both conformal mapping and numerical simulations. Altogether, our findings establish the robustness of our experimental observations and their broad relevance to all Laplacian problems beyond the specifics of our fluid mechanics experiment.

The structures, strain fields, and defect distributions in solid materials underlie the mechanical and physical properties across numerous applications. Many modern microstructural microscopy tools characterize crystal grains, domains and defects required to map lattice distortions or deformation, but are limited to studies of the (near) surface. Generally speaking, such tools cannot probe the structural dynamics in a way that is representative of bulk behavior. Synchrotron X-ray diffraction based imaging has long mapped the deeply embedded structural elements, and with enhanced resolution, dark field X-ray microscopy (DFXM) can now map those features with the requisite nm-resolution. However, these techniques still suffer from the required integration times due to limitations from the source and optics. This work extends DFXM to X-ray free electron lasers, showing how the [Formula: see text] photons per pulse available at these sources offer structural characterization down to 100 fs resolution (orders of magnitude faster than current synchrotron images). We introduce the XFEL DFXM setup with simultaneous bright field microscopy to probe density changes within the same volume. This work presents a comprehensive guide to the multi-modal ultrafast high-resolution X-ray microscope that we constructed and tested at two XFELs, and shows initial data demonstrating two timing strategies to study associated reversible or irreversible lattice dynamics., (© 2023. Springer Nature Limited.)

The primary goal of paleoflood hydrology is to estimate the frequency and magnitude of past floods. Botanical evidence, and particularly scars on trees, has been used repeatedly as paleostage indicators to reconstruct peak discharges and flood height. Yet, these reconstructions depend on the presence of visible scars on tree stems which tend to be masked as trees grow older. Here, we estimated flood magnitude using an alternative approach based on growth disturbances in tree-ring series, tree positions and the minimal discharge necessary to submerge the root collar of a tree as estimated by hydraulic modeling. We tested the reliability of this newly developed approach by using the traditional scar-based reconstruction as a benchmark. To this end, we sampled 60 trees showing evidence of flood damage on their stems along a 787-m long segment of the Asco river (Corsica, France). Based on 440 growth disturbances dated in tree-ring series, we reconstructed 28 floods between 1759 and 2020 and 18 during the 20th century. Using the two-dimensional Iber hydraulic model and detailed topographic data of the study site obtained from UAV imagery, we estimated that peak discharges of the 28 reconstructed events ranged between 10 and 210 m 3 s -1 , with 200 m 3 s -1 being considered as the threshold for extreme floods. Not only do the scar-based and root collar submersion approaches yield similar results, findings are also clearly in line with the sparse information available from historical archives and short gauge station records on past floods. The unprecedented length and depth of the record presented here opens new avenues for climate change and flood impact research., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Markus Stoffel reports financial support was provided by Chinese Scholarship Council., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Sustained response off treatment (SROT) after thrombopoietin receptor agonist (TPO-RA) discontinuation has been reported in immune thrombocytopenia (ITP). This prospective multicenter interventional study enrolled adults with persistent or chronic primary ITP and complete response (CR) on TPO-RAs. The primary end point was the proportion of patients achieving SROT (platelet count >30 × 109/L and no bleeding) at week 24 (W24) with no other ITP-specific medications. Secondary end points included the proportion of sustained CR off-treatment (SCROT, platelet count >100 × 109/L and no bleeding) and SROT at W52, bleeding events, and pattern of response to a new course of TPO-RAs. We included 48 patients with a median age of 58.5 years; 30 of 48 had chronic ITP at TPO-RA initiation. In the intention-to-treat analysis, 27 of 48 achieved SROT, 15 of 48 achieved SCROT at W24; 25 of 48 achieved SROT, and 14 of 48 achieved SCROT at W52. No severe bleeding episode occurred in patients who relapsed. Among patients rechallenged with TPO-RA, 11 of 12 achieved CR. We found no significant clinical predictors of SROT at W24. Single-cell RNA sequencing revealed enrichment of a tumor necrosis factor α signaling via NF-κB signature in CD8+ T cells of patients with no sustained response after TPO-RA discontinuation, which was further confirmed by a significant overexpression of CD69 on CD8+ T cells at baseline in these patients as compared with those achieving SCROT/SROT. Our results strongly support a strategy based on progressive tapering and discontinuation of TPO-RAs for patients with chronic ITP who achieved a stable CR on treatment. This trial was registered at www.clinicaltrials.gov as #NCT03119974., (© 2023 by The American Society of Hematology.)

Explosive volcanism is a key contributor to climate variability on interannual to centennial timescales 1 . Understanding the far-field societal impacts of eruption-forced climatic changes requires firm event chronologies and reliable estimates of both the burden and altitude (that is, tropospheric versus stratospheric) of volcanic sulfate aerosol 2,3 . However, despite progress in ice-core dating, uncertainties remain in these key factors 4 . This particularly hinders investigation of the role of large, temporally clustered eruptions during the High Medieval Period (HMP, 1100-1300 CE), which have been implicated in the transition from the warm Medieval Climate Anomaly to the Little Ice Age 5 . Here we shed new light on explosive volcanism during the HMP, drawing on analysis of contemporary reports of total lunar eclipses, from which we derive a time series of stratospheric turbidity. By combining this new record with aerosol model simulations and tree-ring-based climate proxies, we refine the estimated dates of five notable eruptions and associate each with stratospheric aerosol veils. Five further eruptions, including one responsible for high sulfur deposition over Greenland circa 1182 CE, affected only the troposphere and had muted climatic consequences. Our findings offer support for further investigation of the decadal-scale to centennial-scale climate response to volcanic eruptions., (© 2023. The Author(s).)

The risk of immune thrombocytopenia (ITP) worsening during pregnancy and neonatal ITP (NITP) have never been prospectively studied. We included 180 pregnant and 168 nonpregnant women with ITP in a prospective, multicenter, observational cohort study. A total of 131 pregnant women with ITP were matched to 131 nonpregnant women with ITP by history of splenectomy, ITP status (no response, response, complete response), and duration. Groups were followed for 15 months. The primary outcome was the first occurrence of ITP worsening defined by a composite end point including bleeding events and/or severe thrombocytopenia (<30 × 109/L) and/or ITP treatment modification. We also studied the recurrence of ITP worsening and the incidence of NITP and risk factors. The first occurrence of ITP worsening did not differ between pregnant and nonpregnant women with ITP (53.4 per 100 person-years [95% confidence interval {CI}, 40.8-69.9] vs 37.1 [95% CI, 27.5-50.0]; hazard ratio {HR}, 1.35 [95% CI, 0.89-2.03], P = .16). Pregnant women with ITP were more likely to have recurrence of severe thrombocytopenia and treatment modification (HR, 2.71 [95% CI, 1.41-5.23], P = .003; HR, 2.01 [95% CI, 1.14-3.57], P = .017, respectively). However, recurrence of severe bleeding events was not different between groups (P = .4). Nineteen (14%) neonates showed NITP <50 × 109/L. By multivariable analysis, NITP was associated with a previous offspring with NITP and maternal platelet count <50 × 109/L within 3 months before delivery (adjusted odds ratio, 5.55 [95% CI, 1.72-17.89], P = .004 and 4.07 [95% CI, 1.41-11.73], P = .009). To conclude, women with ITP do not increase their risk of severe bleeding during pregnancy. NITP is associated with NITP history and the severity of maternal ITP during pregnancy. These results will be useful for counseling women with ITP., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Autoimmune conditions in B-cell lymphomas are frequent. Steroids are standard of care, but many patients require other immunosuppressive agents. Ibrutinib is a Bruton Tyrosine Kinase inhibitor that is approved for B-cell indolent lymphoma treatment. We evaluated the use of ibrutinib in previously treated hematologic immune manifestations associated with B-cell lymphomas., Results: We conducted a retrospective multicentric observational study. Patients presenting with active, relapsed/refractory B-cell lymphoma associated hematological immune manifestation (autoimmune cytopenia, acquired immune-mediated bleeding disorders) were included. Twenty-five patients were identified. Median age at ibrutinib introduction was 69 years (range 44-84) and median number of previous treatment lines before ibrutinib was 2 (1-7). Twenty-two patients (88%) were on concomitant stable treatment at inclusion. Within a median exposure of 8 months (2-35), overall response rate to ibrutinib on immune manifestations was 76% (95% CI, 54.9-90.6); complete response rate 44%. Fourteen patients (63%) were able to be weaned from concomitant treatments. Fourteen patients (56%) presented treatment-related adverse events, mostly Grade 1 or 2., Conclusions: Ibrutinib in this setting provides good efficacy and safety profile. Clinical trials are needed to define subgroups of patients who will benefit from this strategy and establish its place in the therapeutic arsenal., (© 2022 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)