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Cultural trauma theory provides a framework for studying the socio-cultural process which takes place between an event and its (socially accepted) representation. This article will apply the process-oriented approach of cultural trauma theory to studying biblical narratives of the Babylonian conquest of Jerusalem, focusing in particular on the destruction and pillage of the temple. The comparison of the various accounts of the Babylonian conquest of Jerusalem, and of their different versions transmitted in Hebrew and in Greek, reveals that the memory of this event was by no means unified and developed over a longer period of time. Discussing passages from 2 Kgs 24–25 and their parallels in the book of Jeremiah, this article will argue that the devastation of the temple of Jerusalem, which is often regarded as a major traumatizing event in the history of ancient Judah, became remembered as such only as the result of a longer process.

Background: Trials on implantable cardioverter-defibrillators (ICD) for patients after acute myocardial infarction (AMI) have highlighted the need for risk assessment of arrhythmic events (AE). The aim of this study was to evaluate risk predictors based on a novel approach of interpreting signal-averaged electrocardiogram (SAECG) and ejection fraction (EF). Methods: SAECG, interpreted with a new index, and EF were prospectively evaluated to predict AE in 144 patients with AMI. Results: During the mean follow-up period of 4.1 years, 19 AE occurred. The new SAECG index showed a sensitivity of 84%, a specificity of 62%, a positive predictive value (PPV) of 25%, and a negative predictive value (NPV) of 96%. A combination of a normal new SAECG index and an EF >35% resulted in a sensitivity of 100%, a specificity of 47%, a PPV of 22%, and a NPV of 100%; this corresponded to an AE incidence rate of 0%. When both tests were abnormal, the AE incidence rate was 21.3%. Conclusions: This is the first contemporary study reporting predictive values based on a combination of SAECG and EF. If confirmed in an appropriately designed and powered trial, this novel approach might be used to identify both patients at very low risk for AE not requiring further risk assessment and patients at high risk in whom ICD implantation can be considered without further risk assessment. [ABSTRACT FROM AUTHOR]

Introduction: Understanding the prevalence of multiple sclerosis (MS) provides information for healthcare planning and helps identify trends and patterns of disease occurrence. For Switzerland, the number of persons with MS (pwMS) was last estimated at approximately 15,000 in 2016. The study's objectives are to update estimates of MS prevalence and characterise the change in MS prevalence in Switzerland between 2016 and 2021, the last year with complete administrative data., Methods: The Swiss MS Registry (SMSR) is an ongoing, longitudinal study in Switzerland. It has previously established a methodology to assess the epidemiology of MS in Switzerland by integrating SMSR data with administrative data on reimbursement approvals for disease-modifying therapies (DMTs). Subsequently, the benchmark-multiplier method is applied to the combined data. Using the same methodology, we calculated overall and sex- and age-specific prevalence rates for 2021. Furthermore, we descriptively analysed changes since 2016 by comparing the prevalence figures and demographic and clinical characteristics of pwMS in both years., Results: We estimated the population of pwMS in Switzerland at 18,140 [95% simulation interval 17,550-18,750], corresponding to a period prevalence of 200.8-214.5/100,000 inhabitants. Peak prevalence was observed in the 50 to 55-year age group. Compared to 2016, the 2021 estimate corresponds to a 20% increase (n=3,000). Extrapolating from Swiss population growth, we estimated that one-fifth of the observed prevalence increase may be attributed to a rising population. The proportion of pwMS in the age range from 50 to 64 (32.5% vs. 35.9%) and above 65 (8.0% vs. 11.1%) years increased. Consequently, the median [interquartile range] age increased from 47 [37-55] to 49 [38-57] years. The median age at diagnosis (36 [28-45] years) and the female-to-male ratio (2.7:1) remained stable since 2016. The proportion of pwMS treated with DMTs increased from 62.1% to 69.0%, with the largest change observed in infusion therapies (15.7% vs. 23.3%)., Conclusion: The estimated MS prevalence in Switzerland has increased since the previous estimate in 2016, with a shift in peak prevalence towards older ages. Population growth explained around one-fifth of this increase, thus leaving room for contributions by additional factors, which require further investigation. The rising MS prevalence has several implications for healthcare, research and society., (The Author(s). Published by S. Karger AG, Basel.)

Primary hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome caused by inborn errors of cytotoxicity. Patients with biallelic PRF1 null mutations (encoding perforin) usually develop excessive immune cell activation, hypercytokinemia, and life-threatening immunopathology in the first 6 months of life, often without an apparent infectious trigger. In contrast, perforin-deficient (PKO) mice only develop HLH after systemic infection with lymphocytic choriomeningitis virus (LCMV). We hypothesized that restricted microbe-immune cell interactions due to specific pathogen-free (SPF) housing might explain the need for this specific viral trigger in PKO mice. To investigate the influence of a "wild" microbiome in PKO mice, we fostered PKO newborns with Wildling microbiota ('PKO-Wildlings') and monitored them for signs of HLH. PKO-Wildlings survived long-term without spontaneous disease. Also, systemic infection with vaccinia virus did not reach the threshold of immune activation required to trigger HLH in PKO-Wildlings. Interestingly, after infection with LCMV, PKO-Wildlings developed an altered HLH pattern. This included lower IFN-γ serum levels along with improved IFN-γ-driven anemia, but more elevated levels of IL-17 and increased liver inflammation compared with PKO-SPF mice. Thus, wild microbiota alone is not sufficient to trigger HLH in PKO mice, but host-microbe interactions shape inflammatory cytokine patterns, thereby influencing manifestations of HLH immunopathology., (© 2024 The Author(s). European Journal of Immunology published by Wiley‐VCH GmbH.)

Remote longitudinal studies are on the rise and promise to increase reach and reduce participation barriers in chronic disease research. However, maintaining long-term retention in these studies remains challenging. Early identification of participants with different patterns of long-term retention offers the opportunity for tailored survey adaptations. Using data from the online arm of the Swiss Multiple Sclerosis Registry (SMSR), we assessed sociodemographic, health-related, and daily-life related baseline variables against measures of long-term retention in the follow-up surveys through multivariable logistic regressions and unsupervised clustering analyses. We further explored follow-up survey completion measures against survey requirements to inform future survey designs. Our analysis included data from 1,757 participants who completed a median of 4 (IQR 2-8) follow-up surveys after baseline with a maximum of 13 possible surveys. Survey start year, age, citizenship, MS type, symptom burden and independent driving were significant predictors of long-term retention at baseline. Three clusters of participants emerged, with no differences in long-term retention outcomes revealed across the clusters. Exploratory assessments of follow-up surveys suggest possible trends in increased survey complexity with lower rates of survey completion. Our findings offer insights into characteristics associated with long-term retention in remote longitudinal studies, yet they also highlight the possible influence of various unexplored factors on retention outcomes. Future studies should incorporate additional objective measures that reflect participants' individual contexts to understand their ability to remain engaged long-term and inform survey adaptations accordingly., Competing Interests: CPK has received honoraria for lectures as well as research support from Biogen, Novartis, Almirall, Teva, Merck, Sanofi Genzyme, Roche, Janssen, Eli Lilly, Celgene and the Swiss MS Society (SMSG). MS reports employment by Roche branch in Serbia, Roche d.o.o., from February 2019 to February 2020. CZ receives financial support for speaking, educational, research or travel grants from Abbvie, Almirall, Biogen Idec, Celgene, Sanofi, Merck, Novartis, Teva Pharma, Roche., (Copyright: © 2024 Daniore et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

CRAC channels enable calcium entry from the extracellular space in response to a variety of stimuli and are crucial for gene expression and granule exocytosis in lymphocytes. Here we find that Syntaxin11, a Q-SNARE, associated with FHLH4 disease in human patients, directly binds Orai1, the pore forming subunit of CRAC channels. Syntaxin11 depletion strongly inhibited SOCE, CRAC currents, IL-2 expression and cytotoxicity in cell lines and FHLH4 patient T lymphocytes. Constitutively active H134 Orai1 mutant completely reconstituted calcium entry in Syntaxin11 depleted cells and the defects of granule exocytosis as well as gene expression could be bypassed by ionomycin induced calcium influx in FHLH4 T lymphocytes. Our data reveal a Syntaxin11 induced pre-activation state of Orai which is necessary for its subsequent coupling and gating by the endoplasmic reticulum resident Stim protein. We propose that ion channel regulation by specific SNAREs is a primary and conserved function which may have preceded their role in vesicle fusion.

SYNTAXIN-11 (STX11) is a SNARE protein that mediates the fusion of cytotoxic granules with the plasma membrane at the immunological synapses of CD8 T or NK cells. Autosomal recessive inheritance of deleterious STX11 variants impairs cytotoxic granule exocytosis, causing familial hemophagocytic lymphohistiocytosis type 4 (FHL-4). In several FHL-4 patients, we also observed hypogammaglobulinemia, elevated frequencies of naive B cells, and increased double-negative DN2:DN1 B cell ratios, indicating a hitherto unrecognized role of STX11 in humoral immunity. Detailed analysis of Stx11-deficient mice revealed impaired CD4 T cell help for B cells, associated with disrupted germinal center formation, reduced isotype class switching, and low antibody avidity. Mechanistically, Stx11-/- CD4 T cells exhibit impaired membrane fusion leading to reduced CD107a and CD40L surface mobilization and diminished IL-2 and IL-10 secretion. Our findings highlight a critical role of STX11 in SNARE-mediated membrane trafficking and vesicle exocytosis in CD4 T cells, important for successful CD4 T cell-B cell interactions. Deficiency in STX11 impairs CD4 T cell-dependent B cell differentiation and humoral responses., (© 2024 Kögl et al.)

Background: While potential risk factors for multiple sclerosis (MS) have been extensively researched, it remains unclear how persons with MS theorize about their MS. Such theories may affect mental health and treatment adherence. Using natural language processing techniques, we investigated large-scale text data about theories that persons with MS have about the causes of their disease. We examined the topics into which their theories could be grouped and the prevalence of each theory topic., Methods: A total of 486 participants of the Swiss MS Registry longitudinal citizen science project provided text data on their theories about the etiology of MS. We used the transformer-based BERTopic Python library for topic modeling to identify underlying topics. We then conducted an in-depth characterization of the topics and assessed their prevalence., Results: The topic modeling analysis identifies 19 distinct topics that participants theorize as causal for their MS. The topics most frequently cited are Mental Distress (31.5%), Stress (Exhaustion, Work) (29.8%), Heredity/Familial Aggregation (27.4%), and Diet, Obesity (16.0%). The 19 theory topics can be grouped into four high-level categories: physical health (mentioned by 56.2% of all participants), mental health (mentioned by 53.7%), risk factors established in the scientific literature (genetics, Epstein-Barr virus, smoking, vitamin D deficiency/low sunlight exposure; mentioned by 47.7%), and fate/coincidence (mentioned by 3.1%). Our study highlights the importance of mental health issues for theories participants have about the causes of their MS., Conclusions: Our findings emphasize the importance of communication between healthcare professionals and persons with MS about the pathogenesis of MS, the scientific evidence base and mental health., (© 2024. The Author(s).)

The diagnosis of cardiac sarcoidosis, particularly in its isolated cardiac form, represents a major challenge due to non-specific symptoms and the limited sensitivity and specificity of basic cardiac investigations. MRI and metabolic PET-CT are important elements in the diagnostic process. Corticosteroids remain the cornerstone for the treatment of the inflammatory phase, in association with biological agents and steroid-sparing therapies. The goal is to limit the progression of fibrosis, which is a source of malignant arrhythmias and heart failure. The indication for implantation of a cardiac defibrillator must be carefully evaluated to reduce the risk of sudden death. Multidisciplinary collaboration is essential for optimal care., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

Background: Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory disorder characterized by a life-threatening cytokine storm and immunopathology. Familial HLH type 3 (FHL3) accounts for approximately 30% of all inborn HLH cases worldwide. It is caused by mutations in the UNC13D gene that result in impaired degranulation of cytotoxic vesicles and hence compromised T-cell- and natural killer-cell-mediated killing. Current treatment protocols, including allogeneic hematopoietic stem cell (HSC) transplantation, still show high mortality., Objective: We sought to develop and evaluate a curative genome editing strategy in the preclinical FHL3 Jinx mouse model. Jinx mice harbor a cryptic splice donor site in Unc13d intron 26 and develop clinical symptoms of human FHL3 upon infection with lymphocytic choriomeningitis virus (LCMV)., Methods: We employed clustered regularly interspaced short palindromic repeats (CRISPR)-Cas technology to delete the disease-causing mutation in HSCs and transplanted Unc13d-edited stem cells into busulfan-conditioned Jinx recipient mice. Safety studies included extensive genotyping and chromosomal aberrations analysis by single targeted linker-mediated PCR sequencing (CAST-Seq)-based off-target analyses. Cure from HLH predisposition was assessed by LCMV infection., Results: Hematopoietic cells isolated from transplanted mice revealed efficient gene editing (>95%), polyclonality of the T-cell receptor repertoire, and neither signs of off-target effects nor leukemogenesis. Unc13d transcription levels of edited and wild-type cells were comparable. While LCMV challenge resulted in acute HLH in Jinx mice transplanted with mock-edited HSCs, Jinx mice grafted with Unc13d-edited cells showed rapid virus clearance and protection from HLH., Conclusions: Our study demonstrates that transplantation of CRISPR-Cas edited HSCs supports the development of a functional polyclonal T-cell response in the absence of genotoxicity-associated clonal outgrowth., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

A pregnant woman presented with an asthma attack with a poor clinical evolution, requiring intubation. Medications traditionally used for the treatment of asthma in non-pregnant patients (short-acting beta-2 agonists, short-acting muscarinic antagonists, systemic corticosteroids) are considered safe during pregnancy, except for epinephrine. A systematic obstetrical evaluation is a key component in the evaluation and management of an asthmatic crisis during pregnancy. The use of peak-flow spirometers and arterial blood gas can help to recognize the degree of severity of an acute asthma attack.

Introduction: Inborn errors of immunity (IEI) are characterized by a dysfunction of the immune system leading to increased susceptibility to infections, impaired immune regulation and cancer. We present a unique consanguineous family with a history of Hodgkin lymphoma, impaired EBV control and a late onset hemophagocytic lymphohistiocytosis (HLH)., Methods and Results: Overall, family members presented with variable impairment of NK cell and cytotoxic T cell degranulation and cytotoxicity. Exome sequencing identified homozygous variants in RAB27A , FBP1 ( Fructose-1,6-bisphosphatase 1 ) and ACAD9 ( Acyl-CoA dehydrogenase family member 9 ). Variants in RAB27A lead to Griscelli syndrome type 2, hypopigmentation and HLH predisposition., Discussion: Lymphoma is frequently seen in patients with hypomorphic mutations of genes predisposing to HLH. We hypothesize that the variants in FBP1 and ACAD9 might aggravate the clinical and immune phenotype, influence serial killing and lytic granule polarization by CD8 T cells. Understanding of the interplay between the multiple variants identified by whole exome sequencing (WES) is essential for correct interpretation of the immune phenotype and important for critical treatment decisions., Competing Interests: KS is an employee of AstraZeneca and has stock ownership and/or stock options or interests in the company. 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., (Copyright © 2023 Brauer, Maruta, Lisci, Strege, Oschlies, Nakamura, Böhm, Lehmberg, Brandhoff, Ehl, Parvaneh, Klapper, Fukuda, Griffiths, Hennies, Niehues and Ammann.)

Interferon-γ (IFNγ) is an important mediator of cellular immune responses, but high systemic levels of this cytokine are associated with immunopathology. IFNγ binds to its receptor (IFNγR) and to extracellular matrix (ECM) via four positively charged C-terminal amino acids (KRKR), the ECM-binding domain (EBD). Across evolution, IFNγ is not well conserved, but the EBD is highly conserved, suggesting a critical function. Here, we show that IFNγ lacking the EBD (IFNγ ΔKRKR ) does not bind to ECM but still binds to the IFNγR and retains bioactivity. Overexpression of IFNγ ΔKRKR in tumors reduced local ECM binding, increased systemic levels and induced sickness behavior, weight loss and toxicity. To analyze the function of the EBD during infection, we generated IFNγ ΔKRKR mice lacking the EBD by using CRISPR-Cas9. Infection with lymphocytic choriomeningitis virus resulted in higher systemic IFNγ ΔKRKR levels, enhanced sickness behavior, weight loss and fatal toxicity. We conclude that local retention of IFNγ is a pivotal mechanism to protect the organism from systemic toxicity during prolonged immune stimulation., (© 2023. The Author(s).)

According to PubMed statistics when writing this review, the year 2022 is expected to mark the first dip in the number of articles published in relation to the Covid-19 pandemic. This review, without any mention to Sars-CoV-2, highlight this transition and addresses many topics in internal medicine: gastroenterology, cardiology, endocrinology, respiratory medicine, infectious diseases and venous access. Each year, the chief residents of the internal medicine ward in Lausanne university hospital (CHUV) in Switzerland meet up to share their readings: here is a selection of ten articles that have caught our attention, summarized and commented for you, which should change our daily practice., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

Primary hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome caused by impaired lymphocyte cytotoxicity. First-line therapeutic regimens directed against activated immune cells or secreted cytokines show limited efficacy since they do not target the underlying immunological problem: defective lymphocyte cytotoxicity causing prolonged immune stimulation. A potential rescue strategy would be the adoptive transfer of ex vivo gene-corrected autologous T cells. However, transfusion of cytotoxicity-competent T cells under conditions of hyperinflammation may cause more harm than benefit. As a proof-of-concept for adoptive T cell therapy (ATCT) under hyperinflammatory conditions, we transferred syngeneic, cytotoxicity-competent T cells into mice with virally triggered active primary HLH. ATCT with functional syngeneic trigger-specific T cells cured Jinx mice from active HLH without life-threatening side effects and protected Perforin-deficient mice from lethal HLH progression by reconstituting cytotoxicity. Cured mice were protected long-term from HLH relapses. A threshold frequency of transferred T cells with functional differentiation was identified as a predictive biomarker for long-term survival. This study is the first proof-of-concept for ATCT in active HLH., (© 2022 The Authors. Published under the terms of the CC BY 4.0 license.)

During the COVID-19 pandemic people were increasingly obliged to wear facial masks and to reduce the number of people they met in person. In this study, we asked how these changes in social interactions are associated with young children's emotional development, specifically their emotion recognition via the labeling of emotions. Preschoolers labeled emotional facial expressions of adults (Adult Faces Task) and children (Child Faces Task) in fully visible faces. In addition, we assessed children's COVID-19-related experiences (i.e., time spent with people wearing masks, number of contacts without masks) and recorded children's gaze behavior during emotion labeling. We compared different samples of preschoolers (4.00-5.75 years): The data for the no-COVID-19-experience sample were taken from studies conducted before the pandemic (Adult Faces Task: N = 40; Child Faces Task: N = 30). The data for the with-COVID-19-experience sample ( N = 99) were collected during the COVID-19 pandemic in Switzerland between June and November 2021. The results did not indicate differences in children's labeling behavior between the two samples except for fearful adult faces. Children with COVID-19-experience more often labeled fearful faces correctly compared to children with no COVID-19 experience. Furthermore, we found no relations between children's labeling behavior, their individual COVID-19-related experiences, and their gaze behavior. These results suggest that, even though the children had experienced differences in the amount and variability of facial input due to the pandemic, they still received enough input from visible faces to be able to recognize and label different emotions., 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., (Copyright © 2022 Wermelinger, Moersdorf, Ammann and Daum.)

Introduction: Several disease-modifying therapies (DMTs), covering a broad spectrum of mechanisms of action, have been approved by regulatory agencies for the treatment of relapsing-remitting multiple sclerosis (RRMS). However, only little is known about the current real-world treatment situation in Switzerland. Based on data from a diverse population of 668 persons with RRMS from the Swiss Multiple Sclerosis Registry (SMSR), the present study aims to fill this gap with a descriptive, cross-sectional approach., Methods: Data originated from the SMSR baseline questionnaire and follow-up surveys. Data on current health status and life situation in the last 6 months were extracted from the survey distributed throughout 2020 and 2021, while data on disease-modifying therapy (DMT) histories were included from preceding surveys. Initially, data was stratified into three DMT groups according to the current DMT status (NO (No DMT), CONTINUED (DMT started more than 6 months ago), and NEW (DMT started less than 6 months ago)). In a subsequent analysis, the sample was stratified into groups corresponding to the five most frequently prescribed DMTs. Self-reported outcomes including therapy discontinuation or interruption, relapses and side-effects in the last 6 months were analyzed per group. Life and health situation parameters were also determined and analyzed., Results: The study population consisted of 445 (66.6%) individuals belonging to the CONTINUED, 84 (12.6%) to the NEW, and 139 (20.8%) to the NO group. Within the NO group, 24 (17.3%) reported relapses. Furthermore, self-reported relapses (28 (33.3%)), side-effects (39 (46.4%)), and treatment discontinuations or interruptions (30 (35.7%)) occurred more frequently in the NEW compared to the CONTINUED group (37 (8.3%), 125 (28.1%), 8 (1.8%), respectively). The three groups also differed with respect to age, time since diagnosis, number of symptoms, DMT history, and health-related quality of life. The five most frequently prescribed DMTs included fingolimod (33.4%), dimethyl fumarate (25.0%), ocrelizumab (23.6%), natalizumab (10.6%) and teriflunomide (7.5%). The frequency of self-reported relapses ranged from 9.7% to 13.6%. Notable differences were found in the number of self-reported side-effects, ranging from 9.1% with natalizumab to 56.7% with dimethyl fumarate., Discussion: This cross-sectional analysis suggested that the majority of individuals with RRMS in Switzerland continuously receive tolerable DMT. However, groups not receiving DMT or struggling with side-effects or continued disease worsening while on DMT still persist. It is conceivable that the number of self-reported symptoms indicates the need for more detailed clarification of the DMT characteristics and expectations of treatment outcomes. Injectable DMTs no longer play a major role in the treatment of RRMS in Switzerland and a trend toward an early use of potent drugs is emerging., (Copyright © 2022. Published by Elsevier B.V.)

Calcium (Ca 2+ ) elevation is an essential secondary messenger in many cellular processes, including disease progression and adaptation to external stimuli, e.g., gravitational load. Therefore, mapping and quantifying Ca 2+ signaling with a high spatiotemporal resolution is a key challenge. However, particularly on microgravity platforms, experiment time is limited, allowing only a small number of replicates. Furthermore, experiment hardware is exposed to changes in gravity levels, causing experimental artifacts unless appropriately controlled. We introduce a new experimental setup based on the fluorescent Ca 2+ reporter CaMPARI2, onboard LED arrays, and subsequent microscopic analysis on the ground. This setup allows for higher throughput and accuracy due to its retrograde nature. The excellent performance of CaMPARI2 was demonstrated with human chondrocytes during the 75th ESA parabolic flight campaign. CaMPARI2 revealed a strong Ca 2+ response triggered by histamine but was not affected by the alternating gravitational load of a parabolic flight.

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.

We describe the case of a 62-year-old woman who presented with insidious onset and slowly progressive neurological complaints. This case illustrates the diagnostic challenges clinicians face because the lack of specific symptomatology and numerous complementary exams. The broad differential diagnosis of this disease requires a diagnostic strategy to be developed. Clinical reasoning is based on clinical, biological and radiological information and highlights the importance of an interdisciplinary approach to patient care., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

Background: Cytokine storm syndromes are life-threatening complications that can occur in children with rheumatic conditions (macrophage activation syndrome [MAS]), inherited cytotoxicity defects (ie, primary haemophagocytic lymphohistiocytosis [HLH]), or as a result of infection or malignancies (ie, secondary HLH). To adequately steer treatment, an early and clear discrimination of these entities is essential. We aimed to define and validate serum biomarker profiles that can differentiate between primary HLH, secondary HLH (predominantly infection-associated), and MAS associated with systemic juvenile idiopathic arthritis (systemic JIA-MAS)., Methods: In this multicentre, retrospective, cohort study, serum samples from patients (0-18 years) with a clinical diagnosis of primary HLH, secondary HLH, or systemic JIA-MAS were analysed by immunoassays for 55 cytokines and chemokines. Serum samples were collected from patients treated at seven clinical centres in Europe and North America. 15 serum biomarkers were validated using an independent commercial assay, and the diagnostic accuracy of the best performing biomarkers was tested in an independent validation cohort., Findings: Serum samples were collected between Dec 7, 2010, and Jan 26, 2018. In the discovery cohort of 43 patients (24 girls and 19 boys) multi-marker analyses revealed distinct serum biomarker profiles associated with primary or secondary HLH versus systemic JIA-MAS. Ten biomarkers were identified that were differentially elevated in either HLH or systemic JIA-MAS and distinguished between these clinical entities, six of which were tested in an independent validation cohort of 79 patients (34 girls and 45 boys). Serum concentrations of S100A12 and interleukin-18, as well as ratios of both S100A12 and IL-18 with chemokine (C-X-C motif) ligand (CXCL)9 and CXCL10 were identified as the most promising candidates for differential diagnostics., Interpretation: At initial presentation, when it is unclear whether a patient with excessive hyperferritinaemic inflammation has primary HLH, infection-associated secondary HLH, or MAS, high serum concentrations of S100A12 indicate an initial differential diagnosis of systemic JIA-MAS, thus helping to guide subsequent treatment decisions. We therefore suggest the inclusion of serum S100A12 and IL-18 in the diagnostic investigations for hyperferritinaemic syndromes; however, the definition and introduction of universially applicable cutoff values are still required., Funding: German Research Foundation, the Center for Interdisciplinary Clinical Research at University Hospital Muenster, the EU's Horizon 2020 research and innovation programme, and the Deutsche Kinderkrebsstiftung., Competing Interests: Declaration of interests CK served as a consultant for Novartis. AG served as a consultant for AB2Bio, SOBI, and Novartis, and received research support from Novimmune and AB2Bio. WdJ is an employee of Luminex Corp. SV served as a consultant for SOBI and Novartis and received non-restricted research support from SOBI. ACH received consulting fees from Novartis and SOBI. SE has received research funding from UCB outside the submitted work. SA, KL, and KB have served as consultants for SOBI. CW served as a consultant for SOBI, Novimmune, Novartis, and Roche, and has received unrestricted research grants from GSK, Roche, and Pfizer. FDB served as a consultant for AbbVie, SOBI, Novimmune, Novartis, Roche, and Sanofi, and has received unrestricted research grants from SOBI, Novartis, Novimmune, Sanofi, Roche, and Pfizer. CH has received honoraria (lecture fees) from Novartis. HW has received honoraria (lecture fees) from Novartis and Takeda, and travel support from Octapharma and CSL-Behring. DF received honoraria (speaker fees) from Chugai-Roche, Novartis, and SOBI, and research support from Novartis, Pfizer, and SOBI. DH received honoraria (lecture fees) from Novartis and SOBI. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Inherited defects in MyD88 and IRAK4, two regulators in Toll-like receptor (TLR) signaling, are clinically highly relevant, but still incompletely understood. MyD88- and IRAK4-deficient patients are exceedingly susceptible to a narrow spectrum of pathogens, with ∼50% lethality in the first years of life. To better understand the underlying molecular and cellular characteristics that determine disease progression, we aimed at modeling the cellular response to pathogens in vitro . To this end, we determined the immunophenotype of monocytes and macrophages derived from MyD88- and IRAK4-deficient patients. We recognized that macrophages derived from both patients were particularly poorly activated by streptococci, indicating that both signaling intermediates are essential for the immune response to facultative pathogens. To characterize this defect in more detail, we generated induced pluripotent stem cells (iPSCs) of fibroblasts derived from an MyD88-deficient patient. The underlying genetic defect was corrected using Sleeping Beauty transposon vectors encoding either the long (L) or the short (S) MYD88 isoform, respectively. Macrophages derived from these iPSC lines (iMacs) expressed typical macrophage markers, stably produced either MyD88 isoform, and showed robust phagocytic activity. Notably, iMacs expressing MyD88-L, but not MyD88-S, exhibited similar responses to external stimuli, including cytokine release patterns, as compared to genetically normal iMacs. Thus, the two MyD88 isoforms assume distinct functions in signaling. In conclusion, iPSC technology, in combination with efficient myeloid differentiation protocols, provides a valuable and inexhaustible source of macrophages, which can be used for disease modeling. Moreover, iPSC-derived macrophages may eventually aid in stabilizing MyD88-deficient patients during pyogenic infections., 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., (Copyright © 2020 Craig-Mueller, Hammad, Elling, Alzubi, Timm, Kolter, Knelangen, Bednarski, Gläser, Ammann, Ivics, Fischer, Speckmann, Schwarz, Lachmann, Ehl, Moritz, Henneke and Cathomen.)

Griscelli syndrome type 2 (GS-2) is an inborn error of immunity characterized by partial albinism and episodes of hemophagocytic lymphohistiocytosis (HLH). It is caused by RAB27A mutations that encode RAB27A, a member of the Rab GTPase family. RAB27A is expressed in many tissues and regulates vesicular transport and organelle dynamics. Occasionally, GS-2 patients with RAB27A mutation display normal pigmentation. The study of such variants provides the opportunity to map distinct binding sites for tissue-specific effectors on RAB27A. Here we present a new case of GS-2 without albinism (GS-2 sine albinism) caused by a novel missense mutation (Val143Ala) in the RAB27A and characterize its functional cellular consequences. Using pertinent animal cell lines, the Val143Ala mutation impairs both the RAB27A-SLP2-A interaction and RAB27A-MUNC13-4 interaction, but it does not affect the RAB27A-melanophilin (MLPH)/SLAC2-A interaction that is crucial for skin and hair pigmentation. We conclude that disruption of the RAB27A-MUNC13-4 interaction in cytotoxic lymphocytes leads to the HLH predisposition of the GS-2 patient with the Val143Ala mutation. Finally, we include a review of GS-2 sine albinism cases reported in the literature, summarizing their genetic and clinical characteristics., Competing Interests: SA worked as a scientific advisor for Sobi. The IRB of Children’s Medical Center affiliated to TUMS approved this study (IR.TUMS.CHMC.REC.1399.080). 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. The reviewer HK declared a past co-authorship with one of the authors SE to the handling editor. The reviewer AF declared a past co-authorship with one of the authors SE to the handling editor., (Copyright © 2020 Ohishi, Ammann, Ziaee, Strege, Groß, Amos, Shahrooei, Ashournia, Razaghian, Griffiths, Ehl, Fukuda and Parvaneh.)

NK1.1 + cells found in salivary glands (SG) represent a unique cell population of innate lymphoid cells (ILC) with characteristics of both conventional NK cells and ILC1. Here, we demonstrate that these NK1.1 +  cells limit the accumulation and differentiation of virus-specific tissue-resident memory CD8 + T cells (T RM  cells) in SG of mice infected with lymphocytic choriomeningitis virus (LCMV). The negative regulation of LCMV-specific CD8 + T RM  cells by NK1.1 +  cells in SG is independent of NKG2D, NKp46, TRAIL, and perforin. Moreover, analysis of NKp46 iCre+ Eomes fl/fl mice revealed that Eomes-dependent conventional NK cells are dispensable for negative regulation. Since the SG are prone to autoimmune reactions, regulation of T RM  cells by tissue-resident ILC may be particularly important to prevent immunopathology in this organ., (© 2020 Wiley-VCH GmbH.)

Objectives: Distal radius fractures are among the most common fractures. Ultrasound is gaining importance in the treatment of and as a tool to diagnose distal radius fractures, guide regional anaesthesia and support reductions. Our aim was to demonstrate safety, feasibility and outcome in patients with a distal radius fractures undergoing ultrasound-guided regional anaesthesia (UGRA) with ultrasound-guided reduction (UGR), as compared with procedural sedation for the reduction., Methods: This retrospective cohort study was carried out in the emergency department of the University Hospital Basel (Switzerland) between February 2014 and October 2017. Adults with an isolated forearm fracture were eligible. The intervention group was treated with UGRA of the brachial plexus and subsequent ultrasound-assisted fracture reduction. Patients in the control group received usual care, which is blind fracture reduction with extension and immobilisation under procedural sedation., Results: 71 patients were enrolled in the intervention group and 142 were to the control group. There was one (1.4%) complication (pneumothorax) in the UGR group. Twenty-five patients (35%) in the intervention group and 67 patients (47%) in the control group underwent surgery. The association between surgery and study group was not significant (p = 0.08). The patient’s age was negatively associated with surgery (p <0.001). The association between surgery and study group was significant in patients ≥60 years (p = 0.035)., Conclusion: The combination of ultrasound-guided regional anaesthesia and ultrasound-guided reduction of distal radius fractures is feasible. Safety was shown by 70 out of 71 cases of UGRA being without complication. Effectiveness regarding the necessity of subsequent operation was comparable to usual care; in patients over 60 it may be lower with UGR.