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Hidradenitis suppurativa (HS) is a chronic inflammatory disorder characterized by painful nodules, sinus tracts, and scars occurring predominantly in intertriginous regions. The prevalence of HS is currently 0.053-4%, with a predominance in African-American women and has been linked to low socioeconomic status. The majority of the reported literature is  retrospective, population based, epidemiologic studies. In this regard, there is a need to establish a repository of biospecimens, which represent appropriate gender and racial demographics amongst HS patients. These efforts will diminish knowledge gaps in understanding the disease pathophysiology. Hence, we sought to outline a step-by-step protocol detailing how we established our HS biobank to facilitate the formation of other HS tissue banks. Equipping researchers with carefully detailed processes for collection of HS specimens would accelerate the accumulation of well-organized human biological material. Over time, the scientific community will have access to a broad range of HS tissue biospecimens, ultimately leading to more rigorous basic and translational research. Moreover, an improved understanding of the pathophysiology is necessary for the discovery of novel therapies for this debilitating disease. We aim to provide high impact translational research methodology for cutaneous biology research and foster multidisciplinary collaboration and advancement of our understanding of cutaneous diseases.

Eighty-three patients with ACL reconstructions using the quadriceps patellar tendon graft were evaluated in a 10 year (mean, 5.5 years) follow-up study. A five-part analysis, consisting of physical examination, questionnaire, Genucom analysis, operative note review, and radiographs, was performed. Seventy-six percent were categorized as satisfactory. Ninety-two percent were content with their results, while only 4% were unsatisfied. Ninety-three percent of the patients had no significant pain and 95% had no giving way postreconstruction. Ninety-two percent had no more than a mild functional deficit. Eighty-seven percent and 90% of the patients had no significant Lachman or pivot shift by examination, respectively. Our results showed no increase in failure over time (1 to 10 years), although those operated on during the initial 5 years showed more radiographic degenerative changes. Plotting our results in classification systems of other authors yielded success rates as good as or better than those using our own criteria. An objective means by which to quantify laxity did not reliably correlate with the quantifying of laxity made by physical examination. Only the lack of a formal rehabilitation program greater than 4 months postoperatively and repaired tears of the medial or lateral collateral ligaments proved to be significant risk factors for poor recovery. [ABSTRACT FROM AUTHOR]

Eighty-three patients, from a 10 year follow-up study, who underwent ACL reconstruction with a quadriceps patellar tendon graft were reviewed. A questionnaire qualifying their sports performance in 20 possible sports compared their preinjury status to postinjury and postreconstructive surgery. Successful and unsuccessful patients, as determined by our previous investigation, were likewise compared. Sports performance, regardless of the sport or level of competition, decreased substantially postinjury and then rose significantly to near but not equal to patient preinjury status. The most strenuous sports dipped to the lowest performance level after injury and returned with a correspondingly more modest gain after the reconstruction. Not surprisingly, successful patients had a more impressive return in performance than unsuccessful patients, mirroring their clinical grading. Of those deemed unsatisfactory (N = 20), graft failures were no worse off in performance rating than those that were classified as unsatisfactory because of persistent symptoms. [ABSTRACT FROM AUTHOR]

The evolution of mandibular reconstruction following composite resection is advanced by improved alloplastic prosthesis and reliable microvascular free tissue transfers. A 42-case, 6-year experience is presented using both methods at the University of California, San Francisco. The advantages and complications of both are discussed. The authors conclude that the success rate for lateral defect restoration is equivalent with either technique, and that the anterior defects are more reliably reconstructed with free tissue transfer. The advantage of microvascular flaps in the anterior defect must be gauged against the physical status of the patient, disease extent, and likelihood of dental rehabilitation by interosseous fixation. [ABSTRACT FROM AUTHOR]

Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Mariana Kaplan received support from NIAMS.

Objective: Systemic lupus erythematosus (SLE) increases cardiovascular disease (CVD) risk, and this is not explained by traditional risk factors. Characterization of blood immunologic signatures that associate with subclinical CVD and predict its progression has been challenging and may help identify subgroups at risk., Methods: Patients with SLE (n = 77) and healthy controls (HCs) (n = 27) underwent assessments of arterial stiffness, vascular wall inflammation, and coronary atherosclerosis burden with cardio-ankle vascular index (CAVI); fluorodeoxyglucose-positron emission tomography/computed tomography (CT) (target-to-background ratio [TBR]); and coronary CT angiography. Whole blood bulk RNA sequencing was performed in a subset of study participants (HC n = 10, SLE n = 20). In a partially overlapping subset (HC n = 24, SLE n = 64), serum inflammatory protein biomarkers were quantified with an Olink platform., Results: CAVI, TBR, and noncalcified coronary plaque burden (NCB) were increased in patients with SLE compared to HCs. When comparing patients with SLE with high CAVI scores to those with low CAVI scores or to HCs, there was a down-regulation of genes in pathways involved in the cell cycle and differentially regulated pathways related to metabolism. Distinct serum proteins associated with increased CAVI (CCL23, colony-stimulating factor 1, latency-activating peptide transforming growth factor β1, interleukin 33 [IL-33], CD8A, and IL-12B), NCB (monocyte chemotactic protein 4 and FMS-like tyrosine kinase 3 ligand [Flt3L]), and TBR (CD5, IL-1α, AXIN1, cystatin D [CST5], and tumor necrosis factor receptor superfamily 9; P < 0.05)., Conclusion: Blood gene expression patterns and serum proteins that associate with worse vascular phenotypes suggest dysregulated immune and metabolic pathways linked to premature CVD. Cytokines and chemokines identified in associations with arterial stiffness, inflammation, and NCB in SLE may allow for characterization of new CVD biomarkers in lupus., (Published 2024. This article is a U.S. Government work and is in the public domain in the USA. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

The evolution of hematophagy involves a series of adaptations that allow blood-feeding insects to access and consume blood efficiently while managing and circumventing the host's hemostatic and immune responses. Mosquito, and other insects, utilize salivary proteins to regulate these responses at the bite site during and after blood feeding. We investigated the function of Anopheles gambiae salivary apyrase (AgApyrase) in regulating hemostasis in the mosquito blood meal and in Plasmodium transmission. Our results demonstrate that salivary apyrase, a known inhibitor of platelet aggregation, interacts with and activates tissue plasminogen activator, facilitating the conversion of plasminogen to plasmin, a human protease that degrades fibrin and facilitates Plasmodium transmission. We show that mosquitoes ingest a substantial amount of apyrase during blood feeding, which reduces coagulation in the blood meal by enhancing fibrin degradation and inhibiting platelet aggregation. AgApyrase significantly enhanced Plasmodium infection in the mosquito midgut, whereas AgApyrase immunization inhibited Plasmodium mosquito infection and sporozoite transmission. This study highlights a pivotal role for mosquito salivary apyrase for regulation of hemostasis in the mosquito blood meal and for Plasmodium transmission to mosquitoes and to the mammalian host, underscoring the potential for strategies to prevent malaria transmission., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Hidradenitis suppurativa (HS) is an inflammatory chronic skin disorder of unknown etiology characterized by inflamed abscess-like nodules and boils resulting in sinus tract formation, tissue scarring, and massive infiltration of neutrophils. Multiple lines of evidence have highlighted the potential association between alterations in the Notch pathway and HS pathogenesis, but the mechanisms remain incompletely characterized., Objective: We aimed to elucidate the role of neutrophil extracellular traps in Notch-γ-secretase signaling., Methods: Twenty-six HS lesional tissues, primary HS macrophages, and skin fibroblasts were interrogated by quantitative PCR, Western blot, and ELISA analyses. γ-Secretase and TNF-α converting enzyme activities were measured in HS skin lesions, macrophages, and skin fibroblasts. Immunofluorescence and RNAscope analyses were performed in HS and control skin., Results: A prominent presence of Notch ligands, Delta-like ligand 4 (DLL4), and Jagged (JAG) 2 were detected at the protein and mRNA levels in HS skin lesion compared to control. Levels of DLL4, JAG1, citrullinated histone H3 DNA, and γ-secretase activity correlated with HS disease severity. Additionally, significantly elevated levels of Notch ligands and γ-secretase activity were found in dissected sinus tracts compared to the rest of HS tissue. Immunofluorescence microscopy of HS skin lesions revealed activation of Notch-1 signaling in macrophages and skin fibroblasts. Neutrophil extracellular traps (NETs) purified from HS patients displayed elevated levels of DLL4. HS NETs activated the Notch pathway in macrophages and dermal fibroblasts isolated from HS patients. HS skin fibroblasts displayed elevated levels of CD90 and DPP4 in association with increased migratory capacity and Notch activation. Inhibition of Notch decreased migratory capacity and profibrotic markers in HS fibroblasts., Conclusion: These data support a pathogenic connection between NETs, Notch-γ-secretase activation, and the release of profibrotic molecules that promote dysregulation of macrophages and skin fibroblasts in HS. Unveiling the relevance of these molecular events not only expands our understanding of HS but also opens new venues for the development of targeted therapies to address the fibrotic complications of advanced stages of HS., Competing Interests: Disclosure statement Supported by the Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases/National Institutes of Health (ZIA AR041199 to M.J.K.), Danby Hidradenitis Suppurativa Foundation grant (C.C.-R.), and the Skin of Color Society CDA (C.C.-R.). Disclosure of potential conflict of interest: A. S. Byrd has been a consultant for Senté and Sonoma Biotherapeutics. G. A. Okoye serves on the advisory boards for Pfizer, Unilever, Janssen, UCB, Novartis, Sanofi-Genzyme, Lilly, AbbVie, Vaseline Healing Program, Dermatology Foundation, and the HS Foundation. The rest of the authors declare that they have no relevant conflicts of interest., (Published by Elsevier Inc.)

Purpose of Review: Dysregulation in neutrophil extracellular trap (NET) formation and degradation has been reported in several inflammatory rheumatic diseases. This review summarizes the recent advances in the understanding the role of NETs in the context of inflammatory rheumatic diseases., Recent Findings: NET formation is enhanced in peripheral blood of patients with large vessel vasculitis and polymyalgia rheumatica. NETs are detected in affected organs in autoimmune conditions, and they might play pathological roles in tissues. Several understudied medications and supplements suppress NET formation and ameliorate animal models of inflammatory rheumatic diseases. NETs and anti-NET antibodies have potential utility as disease biomarkers., Summary: Growing evidence has suggested the contribution of NET dysregulation to the pathogenesis of several inflammatory rheumatic diseases. Further research is warranted in regard to clinical impact of modulating aberrant NET formation and clearance in inflammatory rheumatic diseases., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The Krebs cycle enzyme aconitate decarboxylase 1 (ACOD1) mediates itaconate synthesis in monocytes and macrophages. Previously, we reported that administration of 4-octyl itaconate to lupus-prone mice abrogated immune dysregulation and clinical features. In this study, we explore the role of the endogenous ACOD1/itaconate pathway in the development of TLR7-induced lupus (imiquimod [IMQ] model). We found that, in vitro, ACOD1 was induced in mouse bone marrow-derived macrophages and human monocyte-derived macrophages following TLR7 stimulation. This induction was partially dependent on type I IFN receptor signaling and on specific intracellular pathways. In the IMQ-induced mouse model of lupus, ACOD1 knockout (Acod1-/-) displayed disruptions of the splenic architecture, increased serum levels of anti-dsDNA and proinflammatory cytokines, and enhanced kidney immune complex deposition and proteinuria, when compared with the IMQ-treated wild-type mice. Consistent with these results, Acod1-/- bone marrow-derived macrophages treated in vitro with IMQ showed higher proinflammatory features. Furthermore, itaconate serum levels in systemic lupus erythematosus patients were decreased compared with healthy individuals, in association with disease activity and specific perturbed cardiometabolic parameters. These findings suggest that the ACOD1/itaconate pathway plays important immunomodulatory and vasculoprotective roles in systemic lupus erythematosus, supporting the potential therapeutic role of itaconate analogs in autoimmune diseases.

Objectives: Inflammatory cytokines that signal through the Janus kinases-signal transducer and activator of transcription (JAK-STAT) pathway, especially interferons (IFNs), are implicated in Sjögren's disease (SjD). Although inhibition of JAKs is effective in other autoimmune diseases, a systematic investigation of IFN-JAK-STAT signalling and the effect of JAK inhibitor (JAKi) therapy in SjD-affected human tissues has not been fully investigated., Methods: Human minor salivary glands (MSGs) and peripheral blood mononuclear cells (PBMCs) were investigated using bulk or single-cell (sc) RNA sequencing (RNAseq), immunofluorescence (IF) microscopy and flow cytometry. Ex vivo culture assays on PBMCs and primary salivary gland epithelial cell (pSGEC) lines were performed to model changes in target tissues before and after JAKi., Results: RNAseq and IF showed activated JAK-STAT pathway in SjD MSGs. Elevated IFN-stimulated gene (ISGs) expression associated with clinical variables (eg, focus scores, anti-SSA positivity). scRNAseq of MSGs exhibited cell type-specific upregulation of JAK-STAT and ISGs; PBMCs showed similar trends, including markedly upregulated ISGs in monocytes. Ex vivo studies showed elevated basal pSTAT levels in SjD MSGs and PBMCs that were corrected with JAKi. SjD-derived pSGECs exhibited higher basal ISG expressions and exaggerated responses to IFN-β, which were normalised by JAKi without cytotoxicity., Conclusions: SjD patients' tissues exhibit increased expression of ISGs and activation of the JAK-STAT pathway in a cell type-dependent manner. JAKi normalises this aberrant signalling at the tissue level and in PBMCs, suggesting a putative viable therapy for SjD, targeting both glandular and extraglandular symptoms. Predicated on these data, a phase Ib/IIa randomised controlled trial to treat SjD with tofacitinib was initiated., Competing Interests: Competing interests: BMW has Cooperative Research Award and Development Agreements (CRADA) from Pfizer and Mitobridge (a subsidiary of Astellas Pharma). NIAMS has CRADAs with AstraZeneca and Bristol Myers Squibb. These CRADA did not financially support the experimental results presented herein., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

We describe a previously-unappreciated role for Bruton's tyrosine kinase (BTK) in fungal immune surveillance against aspergillosis, an unforeseen complication of BTK inhibitors (BTKi) used for treating B-cell lymphoid malignancies. We studied BTK-dependent fungal responses in neutrophils from diverse populations, including healthy donors, BTKi-treated patients, and X-linked agammaglobulinemia patients. Upon fungal exposure, BTK was activated in human neutrophils in a TLR2-, Dectin-1-, and FcγR-dependent manner, triggering the oxidative burst. BTK inhibition selectively impeded neutrophil-mediated damage to Aspergillus hyphae, primary granule release, and the fungus-induced oxidative burst by abrogating NADPH oxidase subunit p40phox and GTPase RAC2 activation. Moreover, neutrophil-specific Btk deletion in mice enhanced aspergillosis susceptibility by impairing neutrophil function, not recruitment or lifespan. Conversely, GM-CSF partially mitigated these deficits by enhancing p47phox activation. Our findings underline the crucial role of BTK signaling in neutrophils for antifungal immunity and provide a rationale for GM-CSF use to offset these deficits in susceptible patients.

The linear ubiquitin assembly complex (LUBAC) consists of HOIP, HOIL-1 and SHARPIN and is essential for proper immune responses. Individuals with HOIP and HOIL-1 deficiencies present with severe immunodeficiency, autoinflammation and glycogen storage disease. In mice, the loss of Sharpin leads to severe dermatitis due to excessive keratinocyte cell death. Here, we report two individuals with SHARPIN deficiency who manifest autoinflammatory symptoms but unexpectedly no dermatological problems. Fibroblasts and B cells from these individuals showed attenuated canonical NF-κB responses and a propensity for cell death mediated by TNF superfamily members. Both SHARPIN-deficient and HOIP-deficient individuals showed a substantial reduction of secondary lymphoid germinal center B cell development. Treatment of one SHARPIN-deficient individual with anti-TNF therapies led to complete clinical and transcriptomic resolution of autoinflammation. These findings underscore the critical function of the LUBAC as a gatekeeper for cell death-mediated immune dysregulation in humans., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Vascular disease is a major cause of morbidity and mortality in patients with systemic autoimmune diseases, particularly systemic lupus erythematosus (SLE). Although comorbid cardiovascular risk factors are frequently present in patients with SLE, they do not explain the high burden of premature vascular disease. Profound innate and adaptive immune dysregulation seems to be the primary driver of accelerated vascular damage in SLE. In particular, evidence suggests that dysregulation of type 1 interferon (IFN-I) and aberrant neutrophils have key roles in the pathogenesis of vascular damage. IFN-I promotes endothelial dysfunction directly via effects on endothelial cells and indirectly via priming of immune cells that contribute to vascular damage. SLE neutrophils are vasculopathic in part because of their increased ability to form immunostimulatory neutrophil extracellular traps. Despite improvements in clinical care, cardiovascular disease remains the leading cause of mortality among patients with SLE, and treatments that improve vascular outcomes are urgently needed. Improved understanding of the mechanisms of vascular injury in inflammatory conditions such as SLE could also have implications for common cardiovascular diseases, such as atherosclerosis and hypertension, and may ultimately lead to personalized therapeutic approaches to the prevention and treatment of this potentially fatal complication., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Purpose of Review: In this review, we summarize the current evidence that suggests that neutrophils play a key role in facilitating damage to local bone structures., Recent Findings: Neutrophil infiltration is a hallmark of inflammatory bone diseases such as rheumatoid arthritis (RA) and periodontitis disease (PD). Both of these human diseases are marked by an imbalance in bone homeostasis, favoring the degradation of local bone which ultimately leads to erosions. Osteoclasts, a multinucleated resident bone cell, are responsible for facilitating the turnover of bone and the bone damage observed in these diseases. The involvement of neutrophils and neutrophil extracellular trap formation have recently been implicated in exacerbating osteoclast function through direct and indirect mechanisms. We highlight a recent finding that NET proteins such as histones and elastase can generate non-canonical, inflammatory osteoclasts, and this process is mediated by post-translational modifications such as citrullination and carbamylation, both of which act as autoantigens in RA. It appears that NETs, autoantibodies, modified proteins, cytokines, and osteoclasts all ultimately contribute to local and permanent bone damage in RA and PD. However, more studies are needed to fully understand the role of neutrophils in inflammatory bone diseases., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Neutrophils are myeloid-lineage cells that form a crucial part of the innate immune system. The past decade has revealed additional key roles that neutrophils play in the pathogenesis of cancer, autoimmune diseases, and various acute and chronic inflammatory conditions by contributing to the initiation and perpetuation of immune dysregulation through multiple mechanisms, including the formation of neutrophil extracellular traps (NETs), which are structures crucial in antimicrobial defense. Limitations in techniques to quantify NET formation in an unbiased, reproducible, and efficient way have restricted our ability to further understand the role of neutrophils in health and diseases. We describe an automated, real-time, high-throughput method to quantify neutrophils undergoing NET formation using a live cell imaging platform coupled with a membrane permeability-dependent dual-dye approach using two different DNA dyes to image intracellular and extracellular DNA. This methodology is able to help assess neutrophil physiology and test molecules that can target NET formation.

Introduction: Laparoscopic cholecystectomy (LC), one of the most common surgical procedures performed in the U.S., offers a window into the effects of the COVID-19 pandemic on routine surgical care. The purpose of our study was to analyze the effects of the COVID-19 pandemic at a Level-1 trauma center on the performance rate of non-elective LC over time., Methods: A retrospective chart review from July 2019 to December 2020 identified all non-elective LC cases performed at a level-1 trauma center. Patients were categorized into 4 temporal phases along the course of the pandemic based on statewide incidence data on COVID-19: pre-pandemic, peak 1, recovery, and peak 2. We compared the phases based on demographic information and outcomes., Results: In total, 176 patients were reviewed. The performance rate in cases/day varied as follows: pre-pandemic .61, 1st peak .34, recovery .44, and 2nd peak .53. The complication rate was highest in the 2nd peak (16%) ( P < .05). Compared to the pre-pandemic period, the intra-pandemic period had a higher incidence of complicated gallbladder disease ( P < .05). In the non-elderly subgroup, complicated gallbladder disease was significantly more prevalent in the intra-pandemic period compared to the pre-pandemic period (25% vs 10%, P < .05)., Conclusions: Our data suggests a learning curve throughout the course of the pandemic, reflecting a stepwise increase in the performance rate of LC. The higher incidence of complicated gallbladder disease in the intra-pandemic period may imply patient hesitancy to seek routine surgical care, especially among younger patients., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Neutrophil infiltration is a hallmark of periodontitis, a prevalent oral inflammatory condition in which Th17-driven mucosal inflammation leads to destruction of tooth-supporting bone. Herein, we document that neutrophil extracellular traps (NETs) are early triggers of pathogenic inflammation in periodontitis. In an established animal model, we demonstrate that neutrophils infiltrate the gingival oral mucosa at early time points after disease induction and expel NETs to trigger mucosal inflammation and bone destruction in vivo. Investigating mechanisms by which NETs drive inflammatory bone loss, we find that extracellular histones, a major component of NETs, trigger upregulation of IL-17/Th17 responses, and bone destruction. Importantly, human findings corroborate our experimental work. We document significantly increased levels of NET complexes and extracellular histones bearing classic NET-associated posttranslational modifications, in blood and local lesions of severe periodontitis patients, in the absence of confounding disease. Our findings suggest a feed-forward loop in which NETs trigger IL-17 immunity to promote immunopathology in a prevalent human inflammatory disease., (© 2023 Moutsopoulos et al.)

Childhood-onset systemic lupus erythematosus (cSLE) patients are unique, with hallmarks of Mendelian disorders (early-onset and severe disease) and thus are an ideal population for genetic investigation of SLE. In this study, we use the transmission disequilibrium test (TDT), a family-based genetic association analysis that employs robust methodology, to analyze whole genome sequencing data. We aim to identify novel genetic associations in an ancestrally diverse, international cSLE cohort. Forty-two cSLE patients and 84 unaffected parents from 3 countries underwent whole genome sequencing. First, we performed TDT with single nucleotide variant (SNV)-based (common variants) using PLINK 1.9, and gene-based (rare variants) analyses using Efficient and Parallelizable Association Container Toolbox (EPACTS) and rare variant TDT (rvTDT), which applies multiple gene-based burden tests adapted for TDT, including the burden of rare variants test. Applying the GWAS standard threshold (5.0 × 10 -8 ) to common variants, our SNV-based analysis did not return any genome-wide significant SNVs. The rare variant gene-based TDT analysis identified many novel genes significantly enriched in cSLE patients, including HNRNPUL2, a DNA repair protein, and DNAH11, a ciliary movement protein, among others. Our approach identifies several novel SLE susceptibility genes in an ancestrally diverse childhood-onset lupus cohort., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Introduction: Elevated lactate levels are associated with increased mortality in both trauma and non-trauma patients. The relation between base deficit (BD) and mortality is less clear. Traumatologists debate the utility of elevated lactate (EL) versus BD in predicting mortality. We hypothesized that EL (2mmol/L to 5mmol/L) and BD (≤-2mmol/L) in combination could predict mortality in blunt trauma patients.  Methods: This is a retrospective analysis of the trauma registry from 2012 to 2021 at a level 1 trauma center. Blunt trauma patients with admission lactate and BD values were included in the analysis. Exclusion criteria were age <18, penetrating trauma, unknown mortality, and unknown lactate or BD. Logistics regression of the total 5153 charts showed 93% of the patients presented with lactate levels <5mmol/L, therefore patients with lactate >5mmol/L were excluded as outliers. The primary outcome was mortality., Results: A total of 4794 patients (151 non-survivors) were included in the analysis. Non-survivors had higher rates of EL + BD (35.8% vs. 14.4%, p <0.001). When comparing survivors and non-survivors, EL + BD (OR 5.69), age >65 (5.17), injury severity score (ISS) >25 (8.87), Glasgow coma scale <8 (8.51), systolic blood pressure (SBP) <90 (4.2), and ICU admission (2.61) were significant predictors of mortality. Other than GCS <8 and ISS >25, EL + BD had the highest odds of predicting mortality., Conclusion: Elevated lactate + BD on admission in combination represents a 5.6-fold increase in mortality in blunt trauma patients and can be used to predict a patient's outcome on admission. This combination variable provides an additional early data point to identify patients at elevated risk of mortality at the moment of admission., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Ward et al.)

Foxp3 is regarded as the major transcription factor for T regulatory (T reg ) cells and expression of Foxp3 is used to identify and quantitate Treg cells in mouse models. However, several studies have demonstrated that human CD4 + T conventional (T conv ) cells activated in vitro by T cell receptor (TCR) stimulation can express Foxp3. This observation has raised doubt as to the suitability of Foxp3 as a T reg marker in man. Helios, a member of the Ikaros gene family, has been shown to be expressed by 80-90% of human Foxp3 + T reg cells and can potentially serve as a marker of human T reg . Here, we confirm that Foxp3 expression is readily upregulated by T conv upon TCR stimulation in vitro , while Helios expression is not altered. More importantly, we show that Foxp3 expression is not elevated by stimulation of hT conv in a humanized mouse model of graft versus host disease (GVHD) and in patients with a wide variety of acute and chronic inflammatory diseases including sickle cell disease, acute and chronic GVHD, systemic lupus erythematosus, as well as critical COVID-19. In all patients studied, an excellent correlation was observed between the percentage of CD4 + T cells expressing Foxp3 and the percentage expressing Helios. Taken together, these studies demonstrate that Foxp3 is not induced upon T conv cell activation in vivo and that Foxp3 expression alone can be used to quantitate T reg cells in humans. Nevertheless, the combined use of Foxp3 and Helios expression provides a more reliable approach for the characterization of T reg in humans., Competing Interests: MB is employed by the company Janssen Pharmaceuticals. AG is employed by the company Miltenyi Biotech. CO is employed by Axle Informatics. Studies unrelated to the present manuscript in the Shevach Laboratory (LM, MJ, ES, and MB) are supported by CRADAs from Janssen Pharmaceuticals and Boehringer Ingelheim Pharmaceuticals. 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 Morina, Jones, Oguz, Kaplan, Gangaplara, Fitzhugh, Kanakry, Shevach and Buszko.)

Systemic autoimmune diseases are characterized by the failure of the immune system to differentiate self from non-self. These conditions are associated with significant morbidity and mortality, and they can affect many organs and systems, having significant clinical heterogeneity. Recent discoveries have highlighted that neutrophils, and in particular the neutrophil extracellular traps that they can release upon activation, can have central roles in the initiation and perpetuation of systemic autoimmune disorders and orchestrate complex inflammatory responses that lead to organ damage. Dysregulation of neutrophil cell death can lead to the modification of autoantigens and their presentation to the adaptive immune system. Furthermore, subsets of neutrophils that seem to be more prevalent in patients with systemic autoimmune disorders can promote vascular damage and increased oxidative stress. With the emergence of new technologies allowing for improved assessments of neutrophils, the complexity of neutrophil biology and its dysregulation is now starting to be understood. In this Review, we provide an overview of the roles of neutrophils in systemic autoimmune and autoinflammatory diseases and address putative therapeutic targets that may be explored based on this new knowledge., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: As palliative medicine concepts emerge as essential surgical education, there has been a resulting spike in surgical palliative care research. Historic surgical dogma viewed mortality and comfort-focused care as a failure of the providers' endurance, knowledge base, or technical skill. Therefore, many providers avoided consultation to a palliative medicine service until it became evident a patient could not survive or was actively dying. As the need for surgical palliative care grows, the identification of deficits in surgical providers' understanding of the scope of palliative medicine is necessary to direct further training and development efforts., Method: A ten-question survey was emailed to all residents, physician assistants, nurse practitioners, and attending physicians in the general surgery and subspecialty surgical departments within the Einstein Healthcare Network., Results: 30 non-trainees (attending surgeons, nurse practitioners, and physician assistants) and 26 trainees (PGY-1 to PGY-5) completed the survey. Less than half of participants reported training in conversations regarding withdrawal of life-prolonging treatments in the setting of expected poor outcomes, 55% reported receiving training in pain management, and 64% reported receiving training in delivery of bad news. 54% report being involved in five or more end-of-life discussions in the last year with trainees reporting fewer end-of-life discussions than non-trainees; 67% of trainees reported zero to four discussions while 23% of non-trainees reported over twenty discussions ( P = .009)., Conclusions: Despite many participants training in intensive care settings, providers lack the training to carry out major discussions regarding life-limiting illness, goals of care, and end-of-life independently.

Objective: Neutrophil infiltration into the synovial joint is a hallmark of rheumatoid arthritis (RA), a disease characterised by progressive bone erosion. However, the mechanisms by which neutrophils participate in bone destruction remain unclear. Carbamylation is a posttranslational modification linked to increased bone erosion in RA and we previously showed that carbamylation is present in RA neutrophil extracellular traps (NETs). However, it remains unclear whether NETs and their carbamylated protein cargo directly promote bone destruction and alter osteoclast biology., Methods: NETs and carbamylated NETs (cNETs) were assessed for their capacity to induce osteoclast formation in CD14+ monocytes. Chemical inhibitors and neutralising antibodies were used to elucidate the pathway by which NETs induce osteoclastogenesis. HLA-DRB1*04:01 mice received intra-articular injection of cNETs for 4 weeks. Joints were isolated and assessed for osteoclast formation. Plasma and synovial fluid samples from patients with RA (n=32) were assessed for the presence of carbamylated histone, and correlations to disease specific outcomes were performed., Results: We found that NETs, when cNETs, instruct monocytes to undergo rapid osteoclast formation. NET-mediated osteoclastogenesis appears to depend on Toll-like receptor 4 signalling and NET-associated proteins including histones and neutrophil elastase. In vivo, we identified that the number of osteoclasts increased following immunisation with cNETs in HLA-DRB1*04:01 transgenic mice. Furthermore, carbamylated histones are increased in plasma and synovial fluid from patients with RA and correlate with active bone resorption and inflammatory markers., Conclusions: Our results suggest that NETs have a direct role in RA-associated bone erosion by promoting osteoclast formation., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Systemic autoimmune diseases are characteristically associated with aberrant autoreactive innate and adaptive immune responses that lead to tissue damage and increased morbidity and mortality. Autoimmunity has been linked to alterations in the metabolic functions of immune cells (immunometabolism) and, more specifically, to mitochondrial dysfunction. Much has been written about immunometabolism in autoimmunity in general, so this Essay focuses on recent research into the role of mitochondrial dysfunction in the dysregulation of innate and adaptive immunity that is characteristic of systemic autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Enhancing the understanding of mitochondrial dysregulation in autoimmunity will hopefully contribute to accelerating the development of immunomodulatory treatments for these challenging diseases., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Neutrophilic inflammation is a hallmark of many monogenic autoinflammatory diseases; pathomechanisms that regulate extravasation of damaging immune cells into surrounding tissues are poorly understood. Here we identified three unrelated boys with perinatal-onset of neutrophilic cutaneous small vessel vasculitis and systemic inflammation. Two patients developed liver fibrosis in their first year of life. Next-generation sequencing identified two de novo truncating variants in the Src-family tyrosine kinase, LYN, p.Y508*, p.Q507* and a de novo missense variant, p.Y508F, that result in constitutive activation of Lyn kinase. Functional studies revealed increased expression of ICAM-1 on induced patient-derived endothelial cells (iECs) and of β2-integrins on patient neutrophils that increase neutrophil adhesion and vascular transendothelial migration (TEM). Treatment with TNF inhibition improved systemic inflammation; and liver fibrosis resolved on treatment with the Src kinase inhibitor dasatinib. Our findings reveal a critical role for Lyn kinase in modulating inflammatory signals, regulating microvascular permeability and neutrophil recruitment, and in promoting hepatic fibrosis., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)