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Densely labelled segmentation data for digital pathology images is costly to produce but is invaluable to training effective machine learning models. We make available 290 hand-annotated histopathology tissue sections of the 3 most common skin cancers; basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and intraepidermal carcinoma (IEC). These non-melanoma skin cancers constitute over 90% of all skin cancer diagnoses and hence this dataset gives an opportunity to the scientific community to benchmark analytic methodologies on a significant portion of the dermatopathology workflow. The data represents typical cases of the three cancer types (not requiring a differential diagnosis) across shave, punch and excision biopsy contexts. Each image is accompanied with a segmentation mask which characterizes the section into 12 tissue types, specifically: keratin, epidermis, papillary dermis, reticular dermis, hypodermis, inflammation, glands, hair follicles and background, as well as BCC, SCC and IEC. Included also are cancer margin measurements to work towards automated assessment of surgical margin clearance and tumour invasion. This leaves open many opportunities for researchers to utilize or extend the dataset, building upon recent work on image analysis problems in skin cancer (Thomas et al., 2021).

This article provides detailed information on manually tracked cap mesenchyme cells from timelapse imaging of multiple ex vivo embryonic mouse kidneys. Cells were imaged for up to 18 h at 15 or 20 min intervals, and multiple cell divisions were tracked. Positional data is supplemented with a range of information including the relative location of the closest ureteric tip and a correction for drift due to bulk movement and tip growth. A subset of tracks were annotated to indicate the presence of processes attached to the ureteric epithelium. The calculations used for drift correction are described, as are the main methods used in the analysis of this data for the purpose of describing cap cell motility. The outcomes of this analysis are discussed in “Cap mesenchyme cell swarming during kidney development is influenced by attraction, repulsion, and adhesion to the ureteric tip” (A.N. Combes, J.G. Lefevre, S. Wilson, N.A. Hamilton, M.H. Little, 2016) [1].

Female ticks deposit large egg clusters that range in size from hundreds to thousands. These egg clusters are restricted to a deposition site as they are stationary, usually under leaf litter and other debris. In some habitats, these sites can be exposed to periodic flooding. When the clusters of tick eggs are disturbed, they may float to the surface or remain underneath organic debris entirely submerged underwater. Here, we examined the viability of egg clusters from winter ticks, Dermacentor albipictus, and lone star ticks, Amblyomma americanum, when partially or fully submerged in water and in relation to the developmental stages of the eggs under lab conditions. In general, egg clusters that were older and partially submerged had a higher viability than fully submerged, younger eggs. Of the two species, A. americanum was more resistant to water exposure. These studies highlight that egg clusters for certain tick species can remain viable when exposed to water for at least two weeks. These results also suggest that distribution by flooding of egg clusters could occur for some species and water submersion will differentially impact tick egg survival based on the specific developmental stage of exposure and species., (© The Author(s) 2024. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

We investigated using a custom NGS panel of 149 genes the mutational landscape of 64 consecutive adult patients with tyrosine kinase fusion-negative hypereosinophilia (HE)/hypereosinophilic syndrome (HES) harboring features suggestive of myeloid neoplasm. At least one mutation was reported in 50/64 (78%) patients (compared to 8/44 (18%) patients with idiopathic HE/HES/HE US used as controls; p < .001). Thirty-five patients (54%) had at least one mutation involving the JAK-STAT pathway, including STAT5B (n = 18, among which the hotspot N642H, n = 13), JAK1 (indels in exon 13, n = 5; V658F/L, n = 2), and JAK2 (V617F, n = 6; indels in exon 13, n = 2). Other previously undescribed somatic mutations were also found in JAK2, JAK1, STAT5B, and STAT5A, including three patients who shared the same STAT5A V707fs mutation and features consistent with primary polycythemia. Nearly all JAK-STAT mutations were preceded by (or associated with) myelodysplasia-related gene mutations, especially in RNA-splicing genes or chromatin modifiers. In multivariate analysis, neurologic involvement (hazard ratio [HR] 4.95 [1.87-13.13]; p = .001), anemia (HR 5.50 [2.24-13.49]; p < .001), and the presence of a high-risk mutation (as per the molecular international prognosis scoring system: HR 6.87 [2.39-19.72]; p < .001) were independently associated with impaired overall survival. While corticosteroids were ineffective in all treated JAK-STAT-mutated patients, ruxolitinib showed positive hematological responses including in STAT5A-mutated patients. These findings emphasize the usefulness of NGS for the workup of tyrosine kinase fusion-negative HE/HES patients and support the use of JAK inhibitors in this setting. Updated classifications could consider patients with JAK-STAT mutations and eosinophilia as a new "gene mutated-entity" that could be differentiated from CEL, NOS, and idiopathic HES., (© 2024 Wiley Periodicals LLC.)

Introduction: Eosinophils have widespread procoagulant effects. In daily practice, eosinophil-related cardiovascular toxicity consists of endomyocardial damage, eosinophilic vasculitis and arterial or venous thrombosis. Here we aim to report on the clinical features and treatment outcomes of patients with unexplained ophthalmic vascular manifestations and eosinophilia., Methods: We conducted a retrospective, multicenter, observational study and a literature review of patients with eosinophilia (≥0.5 x10 9 /L) and concomitant ophthalmic vascular manifestations independent of the underlying eosinophilic disease but with no alternative cause for ophthalmic manifestations., Results: Fifty-seven patients were included (20 from the observational study and 37 from the literature review). Ophthalmic vascular features were the initial manifestation of eosinophil-related disease in 34 (59%) patients and consisted of 29 central retinal artery occlusions, six branch retinal artery occlusions, five central retinal vein occlusions, two branch retinal vein occlusions, seven retinal vasculitides, two retinal vasospasms, 12 Purtscher's retinopathies, 13 anterior ischemic optic neuropathies and two posterior ischemic optic neuropathies. The median [IQR] absolute eosinophil count at onset of ophthalmic vascular manifestations was 3.5 [1.7-7.8] x10 9 /L. Underlying eosinophil-related diseases included eosinophilic granulomatosis with polyangiitis (n=32), clonal hypereosinophilic syndrome (HES) (n=1), idiopathic HES (n=13), lymphocytic HES (n=2), adverse drug reactions (n=3), parasitosis (n=2), polyarteritis nodosa (n=1), IgG4-related disease (n=1), eosinophilic fasciitis (n=1) and primary sclerosing cholangitis (n=1). Other extra-ophthalmologic arterial or venous thromboses related to eosinophilia were reported in four (7%) and nine (16%) patients, respectively. Visual prognosis was poor: only eight (10%) patients achieved full recovery of ophthalmologic symptoms. After a median follow-up of 10.5 [1-18] months, one patient (3%) had a recurrence of an ophthalmic vascular manifestation, and three patients (10%) had a recurrence of other vascular symptoms (deep vein thrombosis in two and pulmonary embolism in one patient). At the time of recurrence, absolute eosinophil counts were above 0.5 x10 9 /L in all cases (n=4)., Discussion: This study broadens the spectrum of vascular manifestations associated with hypereosinophilia by adding ophthalmic vascular manifestations. In patients with ophthalmological vascular manifestations and hypereosinophilia, aggressive treatment of the underlying pathology (and normalization of blood count) should be implemented., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer AVM declared a shared parent affiliation with the author LL to the handling editor at the time of review., (Copyright © 2024 Chapuis, Bousquet, Viallard, Terrier, Amoura, Batani, Brézin, Cacoub, Caminati, Chazal, Comarmond, Durieu, Ebbo, Grall, Ledoult, Losappio, Mattioli, Mékinian, Padoan, Regola, Schroeder, Seluk, Trefond, Wechsler, Lefevre, Kahn, Sève and Groh.)

Anti-nuclear antibodies are the hallmark of autoimmune diseases such as systemic lupus erythematosus (SLE) and scleroderma. However, the molecular mechanisms of B cell tolerance breakdown in these pathological contexts are poorly known. The study of rare familial forms of autoimmune diseases could therefore help to better describe common biological mechanisms leading to B cell tolerance breakdown. By Whole-Exome Sequencing, we identified a new heterozygous mutation (p.R594C) in ERN1 gene, encoding IRE1α (Inositol-Requiring Enzyme 1α), in a multiplex family with several members presenting autoantibody-mediated autoimmunity. Using human cell lines and a knock-in (KI) transgenic mouse model, we showed that this mutation led to a profound defect of IRE1α ribonuclease activity on X-Box Binding Protein 1 (XBP1) splicing. The KI mice developed a broad panel of autoantibodies, however in a subclinical manner. These results suggest that a decrease of spliced form of XBP1 (XBP1s) production could contribute to B cell tolerance breakdown and give new insights into the function of IRE1α which are important to consider for the development of IRE1α targeting strategies., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Activated phosphoinositide-3-kinase δ syndrome (APDS) is an inborn error of immunity (IEI) with infection susceptibility and immune dysregulation, clinically overlapping with other conditions. Management depends on disease evolution, but predictors of severe disease are lacking., Objectives: This study sought to report the extended spectrum of disease manifestations in APDS1 versus APDS2; compare these to CTLA4 deficiency, NFKB1 deficiency, and STAT3 gain-of-function (GOF) disease; and identify predictors of severity in APDS., Methods: Data was collected from the ESID (European Society for Immunodeficiencies)-APDS registry and was compared with published cohorts of the other IEIs., Results: The analysis of 170 patients with APDS outlines high penetrance and early onset of APDS compared to the other IEIs. The large clinical heterogeneity even in individuals with the same PIK3CD variant E1021K illustrates how poorly the genotype predicts the disease phenotype and course. The high clinical overlap between APDS and the other investigated IEIs suggests relevant pathophysiological convergence of the affected pathways. Preferentially affected organ systems indicate specific pathophysiology: bronchiectasis is typical of APDS1; interstitial lung disease and enteropathy are more common in STAT3 GOF and CTLA4 deficiency. Endocrinopathies are most frequent in STAT3 GOF, but growth impairment is also common, particularly in APDS2. Early clinical presentation is a risk factor for severe disease in APDS., Conclusions: APDS illustrates how a single genetic variant can result in a diverse autoimmune-lymphoproliferative phenotype. Overlap with other IEIs is substantial. Some specific features distinguish APDS1 from APDS2. Early onset is a risk factor for severe disease course calling for specific treatment studies in younger patients., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

IPOPI held its first Global Multi-Stakeholders' Summit on 23-24 June 2022 in Cascais, Portugal. This IPOPI initiative was designed to set the stage for a stimulating forward-thinking meeting and brainstorming discussion among stakeholders on the future priorities of the PID community. All participants were actively engaged in the entire Summit, bringing provocative questions to ensure a high level of discussion and engagement, and partnered in identifying the outlooks, unmet needs, hurdles and opportunities of PIDs for 2030. The topics that were covered include diagnosis (e.g., newborn screening [NBS], genomic sequencing- including ethical aspects on the application of genomics on NBS, the role of more accurate and timely diagnostics in impacting personalized management), treatment (e.g., the therapeutic evolution of immunoglobulins in a global environment, new therapies such as targeted therapies, new approaches in curative therapies), the interactions of Primary ID with Secondary ID, Autoinflammatory Diseases and other diseases as the field experiences an incessant evolution, and also the avenues for research in the field of humanities and human sciences such as Patient-Reported Outcome Measures (PROMs), Patient-Reported Experience Measures (PREMs), and Health-Related Quality Of Life (HRQoL). During this meeting, all participants contributed to the drafting of recommendations based on our common understanding of the future opportunities, challenges, and scenarios. As a collection of materials, perspectives and summaries, they are succinct and impactful and may help determine some of the next key steps for the PID community., Competing Interests: Author MH is employed by Marketing Research Bureau, Inc and author CB is employed by Health-Ecore B.V. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. This study received funding from CSL Behring and Grifols. The funder had the following involvement with the study: Company representatives contributed to the stakeholder discussions and reviewed the manuscript., (Copyright © 2023 Tadros, Prévot, Meyts, Sánchez-Ramón, Erwa, Fischer, Lefevre, Hotchko, Jaworski, Leavis, Boersma, Drabwell, van Hagen, Van Coillie, Pergent, Burns and Mahlaoui.)

Allergic bronchopulmonary aspergillosis (ABPA) is a rare disease characterized by a complex allergic inflammatory reaction of airways against Aspergillus affecting patients with chronic respiratory diseases (asthma, cystic fibrosis). Exacerbation is often the way to diagnose ABPA and marks its evolution by its recurrent character leading to cortico-requirement or long-term antifungal treatment. Early diagnosis allows treatment of ABPA at an initial stage, preventing recurrence of exacerbations and long-term complications, mainly represented by bronchiectasis. This review of the literature aims to present the current state of the art in terms of diagnosis and treatment of ABPA from a multidisciplinary perspective. As there is no clinical, biological nor radiological specific sign, diagnostic criteria are regularly revised. They are mainly based on the elevation of total and specific IgE against Aspergillus fumigatus and the presence of suggestive CT abnormalities such as mucoid impaction and consolidations. ABPA management includes eviction of mold and pharmacological therapy. Exacerbations are treated in first line with a moderate dose of oral corticosteroids. Azole antifungal agents represent an alternative for the treatment of exacerbations and are the preferential strategy to reduce the future risk of exacerbations and for corticosteroids sparing. Asthma biologics may be of interest; however, their place remains to be determined. Avoiding complications of ABPA while limiting the side effects of systemic drugs remains a major challenge of ABPA management. Several drugs, including new antifungals and asthma biologics, are currently being tested and may be useful in the future., Competing Interests: Declaration of Competing Interest Amytis Roboubi declares no conflict of interest. Camille Audousset declares a grant from the Richard and Edith Strauss Foundation and funding from the ZAMBON laboratory. Emilie Frealle declares research grant from Gilead, travel grants for conference attendance by Gilead, consulting fees by Chiesi. Anne-Laure Brun declares no conflict of interest. François Laurent declares no conflict of interest. Joana Vitte declares speaker and consultancy fees from AstraZeneca, HpVac, Meda Pharma (Mylan), Novartis, Sanofi, ThermoFisher Scientific. Geoffrey Mortuaire declares research grants from AstraZeneca, laboratoires de la mer, Sanofi-Genzyme and personal fees for speaker and consultancy from AstraZeneca, ALK-Abello, Novartis, Sanofi-Genzyme, Zambon, Amplifon, Audika, Medtronic. Guillaume Lefevre grants research from AstraZeneca and GlaxoSmithKlein, consulting from AstraZeneca, GlaxoSmithKlein and Sanofi-Genzyme and congress support from and GlaxoSmithKlein. Jacques Cadranel declares no conflict of interest. Cécile Chenivesse declares research grants from Santelys and Novartis, personal fees from ALK-Abello, AstraZeneca, Sanofi-Regeneron and GlaxoSmithKlein and congress support from , Boehringer Ingelheim, and Novartis., (Copyright © 2023 SFMM. Published by Elsevier Masson SAS. All rights reserved.)

Alternatives are urgently needed in patients with CD3 - CD4 + lymphocytic-variant hypereosinophilic syndrome (L-HES) requiring high-level steroids or who are unresponsive and/or intolerant to conventional alternative therapies. We report five L-HES patients (44-66 years) with cutaneous involvement (n = 5) and persistent eosinophilia (n = 3) despite conventional therapies, who successfully received JAK inhibitors (tofacitinib n = 1, ruxolitinib n = 4). JAKi led to complete clinical remission in the first 3 months in all (with prednisone withdrawal in four). Absolute eosinophil counts normalized in cases receiving ruxolitinib, while reduction was partial under tofacitinib. After switch from tofacitinib to ruxolitinib, complete clinical response persisted despite prednisone withdrawal. The clone size remained stable in all patients. After 3-13 months of follow-up, no adverse event was reported. Prospective clinical trials are warranted to examine the use of JAKi in L-HES., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Neutralizing antibodies (NAbs) against SARS-CoV-2 have been shown to correlate with protection against infection. Simple tools such as lateral flow assays (LFA) that can accurately measure NAbs may be useful for monitoring anti-SARS-CoV-2 immunity in the future., Objectives: We assessed the performance of the ichroma™ COVID-19 nAb test, a rapid semiquantitative LFA, for the prediction of serum neutralizing activity against SARS-CoV-2 variants., Study Design: Serum samples were collected from COVID-19 recovered patients and vaccinated individuals. The result of the ichroma assay was provided as inhibition rate, and was compared to anti-SARS-CoV-2 IgG levels, and NAbs against Alpha, Delta and Omicron variants., Results: A total of 90 sera from recovered unvaccinated patients and 209 sera from the vaccine cohort were included in this study. In post-infection samples, the ichroma inhbition rate was found to be correlated with IgG levels (ρ = 0.83), and with anti-Alpha NAbs levels (ρ = 0.78). In the vaccine cohort, a good correlation was also observed between the ichroma inhibition rate and IgG levels (ρ = 0.84), as well as NAbs against Alpha (ρ = 0.62), Delta (ρ = 0.88) and Omicron (ρ = 0.74). An ichroma inhbition rate of 77.2%, 90.8% and 99.6% accurately predicted neutralization against Alpha, Delta and Omicron variants respectively., Conclusions: The ichroma™ COVID-19 nAb assay, with appropriate variant cut-offs, can be useful for the monitoring of anti-SARS-CoV-2 immunization and may provide a rapid prediction of protection, especially in individuals with significant levels of NAbs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

In patients with hypereosinophilic syndrome (HES), mepolizumab reduces the incidence of HES-related clinical signs and symptoms (flares). However, reports characterizing flare manifestations are limited. The double-blind, parallel-group 200622 trial (NCT02836496) enrolled patients ≥12 years old with HES for ≥6 months, ≥2 flares in the previous year, and screening blood eosinophil count ≥1000 cells/μL. Patients maintained ≥4 weeks stable HES therapy, before randomization (1:1) to 4-weekly subcutaneous mepolizumab (300 mg) or placebo, plus baseline HES therapy, for 32 weeks. This post hoc analysis investigated flare manifestations and duration by re-examining the Core Assessments form and narrative recorded for each flare during the study. Flare symptoms were retrospectively categorized into constitutional, dermatological, respiratory, nasal, gastrointestinal, neurologic and other. The most frequently reported flare symptoms were constitutional (94% of flares), dermatological (82% of flares) and respiratory (72% of flares); flares reported in patients receiving mepolizumab compared with placebo were generally similar in terms of the frequency of symptoms reported. Mepolizumab was associated with a shorter median (range) duration of flares (10.0 [4, 126] days) versus placebo (26.0 [1, 154] days). In patients with HES, flares were associated with symptoms linked to multiple organ systems highlighting the challenges faced for treating flares., Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT02836496, identifier NCT02836496., Competing Interests: This study was funded by GSK (GSK ID: 200622; NCT02836496). The study sponsor had a role in study design, data collection, data analysis and interpretation, and in the writing of the study report. The sponsor did not place any restrictions on access to data or statements made in the manuscript report. Authors had full access to all study data and had final responsibility to submit the manuscript for publication. FP received advisory and speaker fees from Novartis, Bristol Myers Squibb, ARIAD Pharmaceuticals, GSK, AMGEN, Janssen, AbbVie, and Jazz Pharmaceutical, and research grants from Novartis and ARIAD Pharmaceuticals. GL received advisory fees from Shire, Takeda, AstraZeneca, and Sanofi Genzyme and has received research grants and travel/ accommodation expenses from AstraZeneca, Shire, Octapharma, and GSK. JB is an employee of GSK and own stocks/shares. NK, SWY and JS are former employees of GSK and own stocks/shares., (Copyright © 2022 Pane, Lefevre, Kwon, Bentley, Yancey and Steinfeld.)

Introduction: The Fourth Universal Definition of Myocardial Infarction Global Taskforce recommends the use of high sensitive troponin (hs-Tn) assays in the diagnosis of acute myocardial infarction. We evaluated the analytical performance of the Atellica IM High-sensitivity Troponin I Assay (hs-TnI) (Siemens Healthcare Diagnostics Inc., Tarrytown, USA) and compared its performance to other hs-TnI assays (Siemens Advia Centaur, Dimension Vista, Dimension EXL, and Abbott Architect (Wiesbaden, Germany)) at one or more sites across Europe., Materials and Methods: Precision, detection limit, linearity, method comparison, and interference studies were performed according to Clinical and Laboratory Standards Institute protocols. Values in 40 healthy individuals were compared to the manufacturer's cut-offs. Sample turnaround time (TAT) was examined., Results: Imprecision repeatability CVs were 1.1-4.7% and within-lab imprecision were 1.8-7.6% (10.0-25,000 ng/L). The limit of blank (LoB), detection (LoD), and quantitation (LoQ) aligned with the manufacturer's values of 0.5 ng/L, 1.6 ng/L, and 2.5 ng/L, respectively. Passing-Bablok regression demonstrated good correlations between Atellica IM analyser with other systems; some minor deviations were observed. All results in healthy volunteers fell below the 99th percentile URL, and greater than 50% of each sex demonstrated values above the LoD. No interference was observed for biotin (≤ 1500 µg/L), but a slight bias at 5.0 g/L haemoglobin and 50 ng/L Tn was observed. TAT from was fast (mean time = 10.9 minutes) and reproducible (6%CV)., Conclusions: Real-world analytical and TAT performance of the hs-TnI assay on the Atellica IM analyser make this assay fit for routine use in clinical laboratories., Competing Interests: Potential conflict of interest ABS has received consulting or lecturing fees from Siemens Healthcare Diagnostics Inc., Beckman Coulter, Radiometer and research grants from Radiometer and Roche. KP or her employer (APHP) has received consulting or lecturing fees from France Fresenius, Kabi, Masimo, Octapharma, Werfen, Vifor, Abbott, Brahms, Diasorin, and benefited from research grants from MSD Avenir and Fujirebio. VC-C or her employer (APHP) has received fees from Siemens Healthcare Diagnostics Inc. The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication., (Croatian Society of Medical Biochemistry and Laboratory Medicine.)

Background: Eosinophilic annular erythema (EAE) is a rare eosinophil-related skin disease which typically manifests with annular erythematous plaques and severe pruritus. Besides the diagnosis, the treatment of EAE is challenging since relevant published data are sparse., Methods: The aim of this study was to assess the underlying diseases, treatments and outcomes of patients with EAE. To this end, we conducted a retrospective multicenter study and a systematic review of the MEDLINE database., Results: We included 18 patients with EAE followed in 8 centers. The MEDLINE database search yielded 37 relevant publications reporting 55 cases of EAE with 106 treatment sequences. The most common and efficient treatments included topical or systemic corticosteroids, hydroxychloroquine and dapsone. In refractory patients, a combination of systemic corticosteroids with hydroxychloroquine was associated with 88% of complete clinical response., Discussion: To improve the management of EAE patients, we discuss the following treatment strategy: in topical steroid-resistant patients, hydroxychloroquine can be given as first-line systemic treatment. Dapsone, hydroxychloroquine or systemic corticosteroids are second-line options to consider. Last, monoclonal antibodies or JAK inhibitors targeting type 2 inflammation could represent promising last-resort options in refractory patients., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Background: Identifying which patients with acute myocardial infarction (AMI) during sepsis are at risk of poor outcome is a clinical challenge., Aim: To evaluate Global Registry of Acute Coronary Events (GRACE) and Thrombolysis In Myocardial Infarction (TIMI) risk scores to predict in-hospital mortality and severe ischaemic events in this setting., Methods: In this single-centre retrospective study conducted from 2012 to 2016, all consecutive adults hospitalized in the intensive care unit for sepsis who had a concomitant AMI (within 72hours of admission) were enrolled. AMI was defined by an elevated cardiac troponin I value associated with at least one sign (clinical, electrocardiographic or echocardiographic) suggestive of myocardial ischaemia. The primary outcome was in-hospital mortality from any cause. Secondary outcomes were in-hospital occurrence of severe ischaemic events (cardiac arrest with resuscitation, ischaemic stroke and myocardial reinfarction) and major bleeding events., Results: Among 856 patients hospitalized for sepsis, 120 (14.5%) had a concomitant AMI (37.5% women; median age 65 years; median Sequential Organ Failure Assessment [SOFA] score 8). Severe ischaemic events occurred in 15 patients (12.5%), and 39 (33%) died in hospital. Neither the GRACE score (median 192, interquartile range 154-223) nor the TIMI score (median 3, interquartile range 2-4) was associated with occurrence of severe ischaemic events. Only the GRACE score was associated with in-hospital mortality (odds ratio 1.01, 95% confidence interval 1.00-1.02 per 1 point increase). Multivariable analysis identified previous aspirin use and SOFA score as independent factors associated with in-hospital mortality., Conclusions: GRACE and TIMI scores did not predict in-hospital severe ischaemic events and mortality in patients with AMI during sepsis. Among individual components of both scores, previous aspirin use was associated with poor prognosis. However, because of lack of statistical power, we cannot formally rule out the usefulness of these scores in this setting., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Introduction: Lithium treatment can induce nephrogenic diabetes insipidus (NDI), but no consensus intervention is offered to date. We evaluated in these patients patterns of urine concentration and the correlates of 24-hour urine output., Methods: Prospective, single-center, observational study of 217 consecutive lithium-treated individuals, with 24-hour urine collection, desmopressin (1-deamino-arginine vasopressin [DDAVP]) concentrating test, fasting plasma vasopressin measurement (copeptin measurement in n = 119), and measured glomerular filtration rate (mGFR). Maximal urine osmolality (MaxUosm) was the highest level during the DDAVP test., Results: Of the individuals, 21% displayed polyuria (>3 l/d), but 55% displayed elevated fasting vasopressin level (>5 pg/ml). Uosm was significantly lower and urinary output and free water clearance were significantly higher in individuals treated for >10 years. MaxUosm was >600 mOsm/KgH 2 O in 128 patients (59%), among which vasopressin was increased in 51%, associated with higher lithium dose (950 [750-1200] vs. 800 [500-1000] mg/d, P  < 0.001). All patients with lithium daily dose ≥1400 mg/d had high vasopressin levels. In multivariable analysis, 24-hour urine output was associated with higher lithium daily dose (β 0.49 ± 0.17, P  = 0.005), female sex (β -359 ± 123, P  = 0.004), daily osmolar intake (β 2.21 ± 0.24, P  < 0.001), MaxUosm (β -2.89 ± 0.35, P  < 0.001), and plasma vasopressin level (β 10.17 ± 4.76, P  = 0.03)., Conclusion: Higher lithium daily dose was associated with higher vasopressin levels and higher urine output, independently of other factors. Daily osmolar intake was also associated with higher 24-hour urine output. These results suggest that controlled salt and protein intake and lithium dose might reduce polyuria in these patients., (© 2022 International Society of Nephrology. Published by Elsevier Inc.)

Background: Current standard-of-care treatments for hypereosinophilic syndrome (HES) include oral corticosteroids (OCS) and immunosuppressive/cytotoxic (IS/CT) therapies. The anti-IL-5 monoclonal antibody mepolizumab has also recently been approved for patients with this disease. The objective of this analysis was to assess the relationship between baseline therapy and flare reduction in patients with HES treated with mepolizumab, using data from the Phase III 200622 study (NCT02836496)., Methods: In the double-blind, parallel-group 200622 study, eligible patients were ≥12 years old and had HES for ≥6 months, ≥2 flares in the previous 12 months, blood eosinophils ≥1000 cells/μL at screening and ≥4 weeks' stable HES therapy. Patients were randomised (1:1) to receive mepolizumab 300 mg subcutaneously or placebo every 4 weeks for 32 weeks plus their existing HES therapy. This post hoc , descriptive analysis assessed the effect of baseline HES therapy [IS/CT (± OCS), OCS No IS/CT, and No IS/CT/OCS] on the proportion of patients with ≥1 flare during the study period, the annualised rate of flares, time to first flare, and the proportion of patients with ≥1 flare during Weeks 20─32, with mepolizumab versus placebo., Results: Mepolizumab treatment was associated with a decrease in the proportion of patients who experienced ≥1 flare during the study period in all baseline therapy groups versus placebo (32-96% reduction). Similarly, the probability of a flare was lower with mepolizumab (14.3-31.4%) than placebo (35.7-74.1%) in all baseline therapy groups, as was the annualised flare rate (0.22-0.68 vs 1.14-1.62). The proportion of patients who experienced ≥1 flare during Weeks 20-32 was reduced with mepolizumab versus placebo for all baseline therapy groups (55-85% reduction). For all endpoints, the greatest effect of mepolizumab treatment was seen in the IS/CT (± OCS) group., Conclusions: Patients with poorly controlled HES are likely to achieve clinical benefit with mepolizumab in terms of flare reduction, regardless of their baseline therapy., Clinical Trial Registration: (https://clinicaltrials.gov/ct2/show/NCT02836496)., Competing Interests: AR declares consultancy and advisory board attendance for Blueprint, Novartis, Incyte, Celgene, Abbvie and AOP, and participation as a trial investigator for Blueprint, Novartis, Incyte, Celgene, Abbvie, AOP and GSK. GL reports consulting or advisory fees from Takeda, AstraZeneca, Shire, and Sanofi Genzyme and research grant and travel and accommodation expenses from Octapharma, Takeda, and GSK, Shire. MCC has received consultancy fees from, Janssen and GSK, research grant from Kiniksa Pharmaceuticals, lecturing fees from Vifor and GSK and Roche, and Scientific meeting expenses from Roche and Kiniksa Pharmaceuticals and GSK. NK, EM, SWY and JS are all employees of GSK and own stock/shares in GSK. This study received funding from GlaxoSmithKline. The funder had the following involvement with the study: this post hoc analysis, the parent study (GSK ID: 200622, Clinical Trial.gov number NCT02836496) and the editorial support provided were funded by GlaxoSmithKline., (Copyright © 2022 Reiter, Lefevre, Cid, Kwon, Mavropolou, Yancey and Steinfeld.)

Introduction: Hypo- and hypercalcemia are common and some causes require urgent diagnosis and treatment. Measurement of ionized calcium is the reference test to diagnose calcium disorders but total calcium adjusted for protein or albumin concentration is more often used., Methods: Patients hospitalised in a general internal medicine department from September 2013 to December 2015 who had a total plasma calcium concentration and a serum albumin or protein concentration measured within 24h of a ionized calcium blood measurement were included. Total calcium was adjusted for protein or albumin concentration using widely used formulas and compared to ionized calcium as the gold standard., Results: Among 210 included patients, 46 (22%) had hypocalcemia, 124 (59%) normocalcemia and 40 (19%) hypercalcemia according to ionized calcium concentration. Total calcium had 50% sensitivity and 95% specificity to diagnose hypocalcemia and a 93% sensitivity and 89% specificity to diagnose hypercalcemia. Adjusting total calcium for protein or albumin concentrations did not increase and sometimes decreased diagnostic accuracy., Conclusion: Total calcium, with or without albumin/protein adjustment, is poorly sensitive to screen for hypocalcemia. Unadjusted total calcium is as sensitive as protein- or albumin-adjusted total calcium to screen for hypercalcemia. These data argue against the use of albumin- or protein-adjusted calcium. Ionized calcium measurement should be performed to confirm dyscalcemia in patients with abnormal total calcium concentration and to rule out hypocalcemia in patients with total calcium concentration in the lower range of normal values., (Copyright © 2021 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.)

We report on the influence of the liquid droplet composition on the Sn incorporation in GeSn nanowires (NWs) grown by the vapor-liquid-solid (VLS) mechanism with different catalysts. The variation of the NW growth rate and morphology with the growth temperature is investigated and 400 °C is identified as the best temperature to grow the longest untapered NWs with a growth rate of 520 nm min -1 . When GeSn NWs are grown with pure Au droplets, we observe a core-shell like structure with a low Sn concentration of less than 2% in the NW core regardless of the growth temperature. We then investigate the impact of adding different fractions of Ag, Al, Ga and Si to Au catalyst on the incorporation of Sn. A significant improvement of Sn incorporation up to 9% is obtained using 75:25 Au-Al catalyst, with a high degree of spatial homogeneity across the NW volume. Thermodynamic model based on the energy minimization at the solid-liquid interface is developed, showing a good correlation with the data. These results can be useful for obtaining technologically important GeSn material with a high Sn content and, more generally, for tuning the composition of VLS NWs in other material systems., (© 2022 IOP Publishing Ltd.)

[Figure: see text].

Eosinophils have widespread procoagulant effects. Eosinophilic cardiovascular toxicity mostly consists of endomyocardial damage or eosinophilic vasculitis, while reported cases of venous thrombosis (VT) are scarce. We aimed to report on the clinical features and treatment outcomes of patients with unexplained VT and eosinophilia, and to identify predictors of relapse. This retrospective, multicenter, observational study included patients aged over 15 years with VT, concomitant blood eosinophilia ≥ 1G/L and without any other moderate-to-strong contributing factors for VT. Fifty-four patients were included. VT was the initial manifestation of eosinophil-related disease in 29 (54%) patients and included pulmonary embolism (52%), deep venous thrombosis (37%), hepatic (11%) and portal vein (9%) thromboses. The median [IQR] absolute eosinophil count at VT onset was 3.3G/L [1.6-7.4]. Underlying eosinophil-related diseases included FIP1L1-PDGFRA-associated chronic myeloid neoplasm (n = 4), Eosinophilic Granulomatosis with Polyangiitis (n = 9), lymphocytic (n = 1) and idiopathic (n = 29) variants of hypereosinophilic syndrome. After a median [IQR] follow-up of 24 [10-62] months, 7 (13%) patients had a recurrence of VT. In multivariate analysis, persistent eosinophilia was the sole variable associated with a shorter time to VT relapse (HR 7.48; CI95% [1.94-29.47]; p = 0.015). Long-term normalization of eosinophil count could prevent the recurrence of VT in a subset of patients with unexplained VT and eosinophilia ≥ 1G/L.

Background: Despite maximum medical treatment and endoscopic sinus surgery (ESS), chronic rhinosinusitis with nasal polyps (CRSwNP) can require revision surgery. With a growing literature on the diversity of cytokine inflammation patterns in CRSwNP, an endotype-driven approach could lead to the identification of cytokine profiles that predict recurrence., Methods: A monocentric longitudinal study was carried out until June 2019 following CRSwNP patients who underwent surgery for the first time between December 2010 and January 2012. The biomarker profiles were established on blood and nasal secretions at the time of the first surgery (Interleukin (IL)-5, IgE, IgA, eosinophilic cationic protein (ECP) and eosinophilic- derived neurotoxin (EDN)). Profiles were compared between the patients still controlled by medical treatment and the patients requiring revision surgery during the course of the follow-up period., Results: Among the 48 patients initially enrolled in our study, 8 required revision surgery (16,7%). Clinical features (asthma, allergy, aspirin intolerance, active smoking) and levels of blood markers measured at the time of the first surgery were comparable between the 2 groups of patients. Levels of IL-5, IgE and ECP in nasal secretions were significantly increased in the group of patients needing revision surgery., Conclusions: Based on simple approach of nasal secretions sampling, we showed that a predominant T helper 2 proteins expression profile can be associated with recurrent CRSwNP after ESS. Initial immunoprofiling in CRSwNP disease may contribute to better predict the therapeutic response to optimal medical and surgical treatment, and help define the role of innovative targeted treatment, beside corticosteroids and ESS.

During the processes involved in pharmaceutical manufacturing, particulate matter may be introduced into a product from a variety of sources and at different points in the manufacturing process. Companies design quality at the beginning of the process to ensure against defects and strive to manufacture products that meet the pharmacopeial standard of being "practically/essentially free" of particles, which can be challenging, though necessary. As particulate matter recalls are predominantly associated with parenteral products, most companies employ a quality risk management program to identify critical parameters or conditions that could affect product quality or patient safety and incorporate systemic and procedural controls to mitigate or reduce the probability of their occurrence. Yet, determining where particulates are most likely to enter the process, what types of materials are most vulnerable, and how the size and number of particles might affect product quality can be very complex. Visual inspection and sampling of the manufactured drug product are designed to control the risk of particulate contamination; building prevention controls will ensure sustainability. This concept paper highlights the necessity of a more thorough understanding of the failure mechanisms that result in particle contamination across a range of products, such as elastomeric components and glass, and processes, such as the formulation and filling of injectables. The goal is to identify process steps within the end-to-end manufacturing process that are most critical to particle generation and entering of visible particles into the final drug product. LAY ABSTRACT: This concept paper highlights the necessity of a more thorough understanding of the failure mechanisms that result in particle contamination across a range of products, such as elastomeric components and glass, and processes, such as the formulation and filling of injectables. The goal is to identify process steps within the end-to-end manufacturing process that are most critical to particle generation and entering of visible particles into the final drug product., (© PDA, Inc. 2019.)

Isolated right ventricular acute myocardial infarction is rare and its presentation can sometimes mimic an anterior ST-segment elevation myocardial infarction. We reported two cases of isolated right ventricular acute myocardial infarction presenting with a ST-elevation in anterior leads. The first case was admitted for an out-of-hospital cardiac arrest due to ventricular fibrillation. The patient died from neurologic consequences of the cardiac arrest, despite a successful prehospital thrombolysis, followed by a percutaneous angioplasty of the right coronary artery. The second case occurred after a complex percutaneous angioplasty of the right coronary artery, complicated by a total occlusion of a right marginal branch. These two cases illustrate the limits of the ECG for the diagnosis of isolated right ventricular acute infarction, and the difficulties of the differential diagnosis with anterior infarction, which may determine the treatment and the prognosis., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Purpose: Patients with primary immunodeficiency (PID) are at risk of serious complications. However, data on the incidence and causes of emergency hospital admissions are scarce. The primary objective of the present study was to describe emergency hospital admissions among patients with PID, with a view to identifying "at-risk" patient profiles., Methods: We performed a prospective observational 12-month multicenter study in France via the CEREDIH network of regional PID reference centers from November 2010 to October 2011. All patients with PIDs requiring emergency hospital admission were included., Results: A total of 200 admissions concerned 137 patients (73 adults and 64 children, 53% of whom had antibody deficiencies). Thirty admissions were reported for 16 hematopoietic stem cell transplantation recipients. When considering the 170 admissions of non-transplant patients, 149 (85%) were related to acute infections (respiratory tract infections and gastrointestinal tract infections in 72 (36%) and 34 (17%) of cases, respectively). Seventy-seven percent of the admissions occurred during winter or spring (December to May). The in-hospital mortality rate was 8.8% (12 patients); death was related to a severe infection in 11 cases (8%) and Epstein-Barr virus-induced lymphoma in 1 case. Patients with a central venous catheter (n = 19, 13.9%) were significantly more hospitalized for an infection (94.7%) than for a non-infectious reason (5.3%) (p = 0.04)., Conclusion: Our data showed that the annual incidence of emergency hospital admission among patients with PID is 3.4%. The leading cause of emergency hospital admission was an acute infection, and having a central venous catheter was associated with a significantly greater risk of admission for an infectious episode.

In the last two to three decades, many efforts have been made to evaluate the radiative properties of soot in flames. Due to the strong impact of soot on global warming and the aging process of soot particles in the atmosphere, it is necessary to gain a better understanding on how the radiative properties of soot are affected by coating with nonabsorbing organic aerosol compounds. In the present study, the aging process is experimentally mimicked in the laboratory by coating oleic acid onto freshly generated soot particles. The morphological restructuring of soot particles is determined by nonoptical techniques for mobility diameter and effective density and by angular light scattering for gyration radius and fractal dimension. Both approaches give results in good agreement. Moreover, spectrally resolved scattering measurements between 500 and 700 nm have been carried out. The experimental data are in satisfactory agreement with previously published numerical results and enable the validation of a Rayleigh-Debye-Gans theory for coated fractal aggregates (RDG-CFA) that could be integrated in climate models or for the interpretation of scattering based measurements.

Introduction: Estrogens and progesterone play critical roles in angiogenesis and vasodilation. Moreover, placental aromatase deficiency is detected in women with preeclampsia (PE) at delivery. We hypothesized that abnormal steroidogenesis occurs much earlier than typical PE diagnosis. Thus, we investigated whether the circulating steroid profile was already disturbed at 24-29 weeks of gestation in women with subsequent PE, and compared the profile with that of women with "placental" small gestational age (SGA) without PE., Methods: We selected nulliparous women (n = 90) from the MOMA trial, including women with PE (n = 25), SGA (n = 25), and controls (NP; n = 40), for plasma steroid profiling by gas chromatography/mass spectrometry and to measure placental growth factor and soluble fms-like tyrosine kinase-1. Placental aromatase expression was evaluated in a new set of women., Results: Compared with that of controls, the women with PE had a significantly lower estrone/androstenedione ratio, and exhibited a decreasing trend for estradiol and estrone levels. Lower estriol levels were observed in the SGA group compared to the NP group. Compared with that of controls, the women with PE and SGA had significantly higher levels of 20α-dihydroprogesterone (20α-DHP) and 20α-DHP/progesterone ratios. Pregnenolone sulfate levels were lower in the PE group than in the NP and SGA groups. Decreased expression of aromatase was observed in the PE group compared to the control group., Discussion: Preeclampsia appears to be characterized by specific steroidogenesis dysregulation long before PE diagnosis, highlighting potential new biomarkers of PE., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Immunoglobulin G (IgG) and IgG subclass assays are indicated in patients with suspected primary immunodeficiency (PID). Commercially available assays for IgG subclass determination are calibrated against various preparations, and so specific reference values are required for each of them. Using Optilite® reagents from The Binding Site Group Ltd., we sought to determine the pediatric IgG and IgG subclass reference intervals with respect to the ERM-DA470k certified reference material., Methods: Levels of IgG and IgG subclasses were analyzed in serum samples collected from a large cohort of PID-free children and adolescents. Reference intervals were calculated for previously published age groups (6-12 months, 12-18 months, 18 months-2 years, 2-3 years, 3-4 years, 4-6 years, 6-9 years, 9-12 years and 12-18 years), according to the Clinical and Laboratory Standards Institute's C28-A3c protocol., Results: A total of 456 serum samples were analyzed. The correlation between the total IgG and the sum of the IgG subclasses was good (r2=0.96). No statistically significant gender-specific differences were observed. Our results for the changes over time in IgG and IgG subclass levels are consistent with previous reports. The differences between our lower/upper reference limits and those in the literature are probably due to variations in calibration., Conclusions: Our present results provide a reliable basis for the diagnosis of PIDs in childhood and for the accreditation of laboratories using Optilite® immunoturbidimetric reagents for IgG subclass measurement. Laboratory scientists and clinicians should be aware of the need for manufacturer-specific IgG subclass reference intervals.

Crystalluria is an imbalance between promoters and inhibitors; the first are the engine of the crystals and the second are made of substances. The biological assays make it possible to demonstrate one or more lithogenic factors observed during the lithiasis. The objective of our work was to study the impact of acidification or alkalization of the urine of lithiasic patients during a cristallurie assessment. All urine in the morning must be stored at room temperature and examined within two-three hours following voiding. 80 lithiasic patients (40 for urinary calcium and 40 for urinary uric acid) were selected from the results of cristalluria: more than 20 calcium-dependent crystals or uric acid crystal/mm 3 . For calcium and uric acid, concentration differences, after acidification and alkalization are observed: r 2 =0.43 (p<0.01) and r 2 =0.36 (p<0.01) respectively. In conclusion, in this lithiasic population with the presence of cystals, this pre-analytical stage is essential for urinary calcium and uric acid, making it possible to establish a diagnosis of certainly for the patient.

Acute tubular damage is a major cause of renal failure, especially at the early phase of kidney transplant when ischemia-reperfusion injury and cyclosporin A toxicity may coexist. The mechanisms of the latter are largely unknown. Using an mRNA microarray on microdissected tubules from a rat model of cyclosporin A toxicity to describe the related epithelial-specific transcriptional signature in vivo, we found that cyclosporin A induces pathways dependent on the transcription factor ATF4 and identified nuclear protein transcriptional regulator 1 (Nupr1), a stress response gene induced by ATF4, as the gene most strongly upregulated. Upon cyclosporin A treatment, Nupr1-deficient mice exhibited worse renal tubular lesions than wild-type mice. In primary cultures treated with cyclosporin A, renal tubular cells isolated from Nupr1-deficient mice exhibited more apoptosis and ATP depletion than cells from wild-type mice. Furthermore, cyclosporin A decreased protein synthesis and abolished proliferation in wild-type tubular cells, but only reduced proliferation in Nupr1-deficient cells. Compared with controls, mouse models of ischemia-reperfusion injury, urinary obstruction, and hypertension exhibited upregulated expression of renal NUPR1, and cyclosporin A induced Nupr1 expression in cultured human tubular epithelial cells. Finally, immunohistochemical analysis revealed strong expression of NUPR1 in the nuclei of renal proximal tubules of injured human kidney allografts, but not in those of stable allografts. Taken together, these results suggest that epithelial expression of NUPR1 has a protective role in response to injury after renal transplant and, presumably, in other forms of acute tubular damage., (Copyright © 2017 by the American Society of Nephrology.)

Background: An accurate assessment of septic patients at risk for poor clinical outcomes is challenging for clinicians in the emergency department (ED)., Objectives: We aimed to evaluate the prognostic value of procalcitonin (PCT) in septic patients in the ED for predicting death., Results: In a retrospective study, 188 septic patients (median age 63 [IQR 51-80]) of two French university hospitals were included. Patients who deceased within 30 days (20 %, n = 37) presented higher PCT value at admission (median 34.0 µg/L [5.0-71.9]) in comparison with the survivals (median 6.4 µg/L [4.1-13.1], p = 0.0005). ROC curve analysis indicated a moderate AUC of 0.686 [95 % CI 0.613-0.752] and an optimal PCT threshold value at 32.5 [95 % CI 21.8-43.3] µg/L that was associated with a 51 % [34-67] sensitivity, a 96 % [90-98] specificity, a 73 % [52-88] positive predictive value, and a 89 % [83-93] negative predictive value for death. Only 26 patients (14 %) had PCT values above this threshold (19 in the deceased group vs 7 in survival group, p < 0.0001). By multivariate analysis, only three variables remained significantly predictive of the death: personal history of cardiovascular disease (OR 3.1 [1.0-9.4], p = 0.046), the presence of severe sepsis/septic shock in the ER (OR 4.4 [1.3-12.3], p = 0.013), and a PCT level >32.5 µg/L (OR 36.0 [10.0-128.4], p < 0.0001). Similar results were obtained when considering the combined outcome death and/or admission in ICU., Conclusion: Elevated value of PCT at admission has moderate accuracy to identify poor outcome in ED septic patients in daily practice.

Background: Recent 2015 ESC recommendations for the management of patients with suspected acute myocardial infarction (AMI) support that a single value of high-sensitivity cardiac troponin (HS-cTn) measured at presentation could rule out AMI if below the limit of blank (LoB) or detection (LoD)., Objectives: We aimed to evaluate whether an undetectable HS-cTnT at presentation safely rules out NSTEMI in unselected patients with chest pain., Patients and Methods: This is a post hoc analysis of two prospective cohorts with similar design that included patients suspected of AMI at three French university hospitals. Patients were followed-up during one month, before the adjudication of a final diagnosis., Results: 413 patients (mean age 58±17years) were analyzed; 45 (11%) had a final diagnosis of NSTEMI, and 26 (6%) had STEMI. The sensitivity of HS-cTnT value at 3ng/L (LoB) for NSTEMI was 97.8% [95% CI: 86.8-99.9], yielding a negative predictive value (NPV) of 99.3% [95% CI: 95.4-100.0]. Proportion of patients ruled out for NSTEMI was 32% when applying the LoB. The sensitivity of HS-cTnT value at 5ng/L (LoD) was 97.8% [95% CI: 86.8-99.9] yielding a NPV of 99.5% [95% CI: 96.5-100.0]. Proportion of patients ruled out for NSTEMI was 43% when applying the LoD. One patient (delay between onset of chest pain and presentation <3h) had NSTEMI and HS-cTnT