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Purpose: In the past, XLA was described as associated with several inflammatory conditions, but with adequate immune globulin treatment, these are presumed to have diminished. The actual prevalence is not known.

Peritoneal metastasis (PM) from appendiceal cancer or colorectal cancer (CRC) has significant morbidity and limited survival. Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) is a minimally invasive approach to treat PM. We aim to conduct a dose-escalation trial of mitomycin C (MMC)-PIPAC combined with systemic chemotherapy (FOLFIRI) in patients with PM from appendiceal cancer or CRC.

Cantor sets are constructed from iteratively removing sections of intervals. This process yields a cumulative distribution function (CDF), constructed from the invariant Borel probability measure associated with their iterated function systems. Under appropriate assumptions, we identify sampling schemes of such CDFs, meaning that the underlying Cantor set can be reconstructed from sufficiently many samples of its CDF. To this end, we prove that two Cantor sets have almost-nowhere intersection with respect to their corresponding invariant measures.

Abstract Background Reactive oxygen species (ROS) are known mediators of cellular damage in multiple diseases including diabetic complications. Despite its importance, no comprehensive database is currently available for the genes associated with ROS. Methods We present ROS- and diabetes-related targets (genes/proteins) collected from the biomedical literature through a text mining technology. A web-based literature mining tool, SciMiner, was applied to 1,154 biomedical papers indexed with diabetes and ROS by PubMed to identify relevant targets. Over-represented targets in the ROS-diabetes literature were obtained through comparisons against randomly selected literature. The expression levels of nine genes, selected from the top ranked ROS-diabetes set, were measured in the dorsal root ganglia (DRG) of diabetic and non-diabetic DBA/2J mice in order to evaluate the biological relevance of literature-derived targets in the pathogenesis of diabetic neuropathy. Results SciMiner identified 1,026 ROS- and diabetes-related targets from the 1,154 biomedical papers (http://jdrf.neurology.med.umich.edu/ROSDiabetes/). Fifty-three targets were significantly over-represented in the ROS-diabetes literature compared to randomly selected literature. These over-represented targets included well-known members of the oxidative stress response including catalase, the NADPH oxidase family, and the superoxide dismutase family of proteins. Eight of the nine selected genes exhibited significant differential expression between diabetic and non-diabetic mice. For six genes, the direction of expression change in diabetes paralleled enhanced oxidative stress in the DRG. Conclusions Literature mining compiled ROS-diabetes related targets from the biomedical literature and led us to evaluate the biological relevance of selected targets in the pathogenesis of diabetic neuropathy.

Abstract Background A reduction in the number of podocytes and podocyte density has been documented in the kidneys of patients with diabetes mellitus. Additional studies have shown that podocyte injury and loss occurs in both diabetic animals and humans. However, most studies in animals have examined relatively long-term changes in podocyte number and density and have not examined effects early after initiation of diabetes. We hypothesized that streptozotocin diabetes in rats and mice would result in an early reduction in podocyte density and that this reduction would be prevented by antioxidants. Methods The number of podocytes per glomerular section and the podocyte density in glomeruli from rats and mice with streptozotocin (STZ)-diabetes mellitus was determined at several time points based on detection of the glomerular podocyte specific antigens, WT-1 and GLEPP1. The effect of insulin administration or treatment with the antioxidant, α-lipoic acid, on podocyte number was assessed. Results Experimental diabetes resulted in a rapid decline in apparent podocyte number and podocyte density. A significant reduction in podocytes/glomerular cross-section was found in STZ diabetes in rats at 2 weeks (14%), 6 weeks (18%) and 8 weeks (34%) following STZ injection. Similar declines in apparent podocyte number were found in STZ diabetes in C57BL/6 mice at 2 weeks, but not at 3 days after injection. Treatment with α-lipoic acid substantially prevented podocyte loss in diabetic rats but treatment with insulin had only a modest effect. Conclusion STZ diabetes results in reduction in apparent podocyte number and in podocyte density within 2 weeks after onset of hyperglycemia. Prevention of these effects with antioxidant therapy suggests that this early reduction in podocyte density is due in part to increased levels of reactive oxygen species as well as hyperglycemia.

Background: Autoimmune cytopenias (AICs) regularly occur in profoundly IgG-deficient patients with common variable immunodeficiency (CVID). The isotypes, antigenic targets, and origin(s) of their disease-causing autoantibodies are unclear., Objective: We sought to determine reactivity, clonality, and provenance of AIC-associated IgM autoantibodies in patients with CVID., Methods: We used glycan arrays, patient erythrocytes, and platelets to determine targets of CVID IgM autoantibodies. Glycan-binding profiles were used to identify autoreactive clones across B-cell subsets, specifically circulating marginal zone (MZ) B cells, for sorting and IGH sequencing. The locations, transcriptomes, and responses of tonsillar MZ B cells to different T H - cell subsets were determined by confocal microscopy, RNA-sequencing, and cocultures, respectively., Results: Autoreactive IgM coated erythrocytes and platelets from many CVID patients with AICs (CVID+AIC). On glycan arrays, CVID+AIC plasma IgM narrowly recognized erythrocytic i antigens and platelet i-related antigens and failed to bind hundreds of pathogen- and tumor-associated carbohydrates. Polyclonal i antigen-recognizing B-cell receptors were highly enriched among CVID+AIC circulating MZ B cells. Within tonsillar tissues, MZ B cells secreted copious IgM when activated by the combination of IL-10 and IL-21 or when cultured with IL-10/IL-21-secreting FOXP3 - CD25 hi T follicular helper (Tfh) cells. In lymph nodes from immunocompetent controls, MZ B cells, plentiful FOXP3 + regulatory T cells, and rare FOXP3 - CD25 + cells that represented likely CD25 hi Tfh cells all localized outside of germinal centers. In CVID+AIC lymph nodes, cellular positions were similar but CD25 hi Tfh cells greatly outnumbered regulatory cells., Conclusions: Our findings indicate that glycan-reactive IgM autoantibodies produced outside of germinal centers may contribute to the autoimmune pathogenesis of CVID., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Competing Interests: Disclosures The authors have no conflicts of interest to report.

Background: Prior studies have reported that renal insufficiency occurs in a small percentage of patients with predominantly antibody deficiency (PAD) and in about 2% of patients with common variable immunodeficiency., Objective: The goal of our study was to understand and evaluate the prevalence and type of renal complications in patients with PAD in the United States Immunodeficiency Network (USIDNET) cohort. We hypothesized that there is an association between certain renal complications and severity of immunophenotype in patients with PAD., Methods: We performed a query of patients with PAD from the USIDNET cohort with renal complications. Patients with documented renal disease such as chronic kidney disease (CKD), nephrolithiasis, nephritis, and renal failure syndrome were included. We compared immunophenotype, flow cytometry findings, and immunoglobulin levels of patients with PAD accompanied by renal complications with those of the total USIDNET cohort of patients with PAD., Results: We determined that 140 of 2071 patients with PAD (6.8%) had renal complications. Of these 140 patients, 50 (35.7%) had CKD, 46 (32.9%) had nephrolithiasis, 18 (12.9 %) had nephritis, and 50 (35.7%) had other renal complications. Compared with the total USIDNET cohort of patients with PAD, patients with CKD had lower absolute lymphocyte counts, CD3 + T-cell counts, CD4 + T-cell counts, CD19 + B-cell counts, CD20 + B-cell counts, and CD27 + IgD - B-cell counts (P < .05 for all). Patients with nephritis had lower absolute lymphocyte counts, CD19 + B-cell counts, CD27 + B-cell counts, and IgE levels (P < .05 for all) than patients with PAD without renal disease., Conclusions: We determined that 6.8% of the USIDNET cohort of patients with PAD had a documented renal complication. Compared with the overall cohort of patients with PAD, those patients with nephritis and CKD had a more severe immunophenotype., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Glomerulonephritis remains a major cause of morbidity and mortality in systemic lupus erythematosus (SLE). We have reported that expression of HER2/ErbB2, a member of the EGFR family, is increased in kidneys of patients and mice with lupus nephritis. We therefore asked if EGFR-family inhibition could ameliorate murine lupus nephritis. We used lapatinib, an EGFR-ErbB2 dual kinase inhibitor in female lupus-prone NZBxW/F1 mice, in which lupus onset was accelerated by injecting an IFN-α-expressing adenovirus. Mice received lapatinib (75 mg/Kg) or vehicle from the beginning of the acceleration or after the mice developed severe proteinuria (>300 mg/dL). Autoantibodies, kidney disease and markers of fibrosis and wound healing were analyzed. Exposure to IFNα induced ErbB2 expression in the kidney of lupus prone mice. Lapatinib, administered before but not after renal disease onset, lowered autoantibody titers and lessened immune complex deposition in the kidney. However, lapatinib increased proteinuria, kidney fibrosis and mouse mortality. Lapatinib also inhibited an in vitro wound healing assay testing renal cells. Our results suggest that EGFR-ErbB2 dual kinase inhibitor lapatinib decreases autoimmunity but worsens renal disease in IFNα-accelerated lupus, by increasing fibrosis and inhibiting wound healing. Type I Interferons are highlighted as important regulators of HER2/ErbB2 expression in the kidney. Further studies are required to parse the beneficial aspects of EGFR inhibition on autoimmunity from its negative effects on wound healing in lupus nephritis., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Competing Interests: Disclosures The authors declare no conflicts of interest.

IFN-signaling gene (ISG) expression scores are potential markers of inflammation with significance from cancer to genetic syndromes. In Aicardi Goutières Syndrome (AGS), a disorder of abnormal DNA and RNA metabolism, this score has potential as a diagnostic biomarker, although the approach to ISG calculation has not been standardized or validated. To optimize ISG calculation and validate ISG as a diagnostic biomarker, mRNA levels of 36 type I IFN response genes were quantified from 997 samples (including 334 AGS), and samples were randomized into training and test data sets. An independent validation cohort (n = 122) was also collected. ISGs were calculated using all potential combinations up to 6 genes. A 4-gene approach (IFI44L, IFI27, USP18, IFI6) was the best-performing model (AUC of 0.8872 [training data set], 0.9245 [test data set]). The majority of top-performing gene combinations included IFI44L. Performance of IFI44L alone was 0.8762 (training data set) and 0.9580 (test data set) by AUC. The top approaches were able to discriminate individuals with genetic interferonopathy from control samples. This study validates the context of use for the ISG score as a diagnostic biomarker and underscores the importance of IFI44L in diagnosis of genetic interferonopathies.

Distinguishing RALD from JMML can be difficult. This review discusses the clinical features, genetic aetiology and the treatments that are common and distinct between the two diagnoses., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

Background: The CDC and ACIP recommend COVID-19 vaccination for patients with inborn errors of immunity (IEI). Not much is known about vaccine safety in IEI, and whether vaccination attenuates infection severity in IEI., Objective: To estimate COVID-19 vaccination safety and examine effect on outcomes in patients with IEI., Methods: We built a secure registry database in conjunction with the US Immunodeficiency Network to examine vaccination frequency and indicators of safety and effectiveness in IEI patients. The registry opened on January 1, 2022, and closed on August 19, 2022., Results: Physicians entered data on 1245 patients from 24 countries. The most common diagnoses were antibody deficiencies (63.7%). At least one COVID-19 vaccine was administered to 806 patients (64.7%), and 216 patients received vaccination prior to the development of COVID-19. The most common vaccines administered were mRNA-based (84.0%). Seventeen patients were reported to seek outpatient clinic or emergency room care for a vaccine-related complication, and one patient was hospitalized for symptomatic anemia. Eight hundred twenty-three patients (66.1%) experienced COVID-19 infection. Of these, 156 patients required hospitalization (19.0%), 47 required ICU care (5.7%), and 28 died (3.4%). Rates of hospitalization (9.3% versus 24.4%, p < 0.001), ICU admission (2.8% versus 7.6%, p = 0.013), and death (2.3% versus 4.3%, p = 0.202) in patients who had COVID-19 were lower in patients who received vaccination prior to infection. In adjusted logistic regression analysis, not having at least one COVID-19 vaccine significantly increased the odds of hospitalization and ICU admission., Conclusion: Vaccination for COVID-19 in the IEI population appears safe and attenuates COVID-19 severity., (© 2024. The Author(s).)

Understanding the cell-type composition and spatial organization of brain regions is crucial for interpreting brain computation and function. In the thalamus, the anterior thalamic nuclei (ATN) are involved in a wide variety of functions, yet the cell-type composition of the ATN remains unmapped at a single-cell and spatial resolution. Combining single-cell RNA sequencing, spatial transcriptomics, and multiplexed fluorescent in situ hybridization, we identify three discrete excitatory cell-type clusters that correspond to the known nuclei of the ATN and uncover marker genes, molecular pathways, and putative functions of these cell types. We further illustrate graded spatial variation along the dorsomedial-ventrolateral axis for all individual nuclei of the ATN and additionally demonstrate that the anteroventral nucleus exhibits spatially covarying protein products and long-range inputs. Collectively, our study reveals discrete and continuous cell-type organizational principles of the ATN, which will help to guide and interpret experiments on ATN computation and function., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Infectious susceptibility is a component of many inborn errors of immunity. Nevertheless, antibiotic use is often used as a surrogate in history taking for infectious susceptibility, thereby disadvantaging patients who present with viral infections as their phenotype. Further complicating clinical evaluations are unusual manifestations of viral infections which may be less familiar that the typical respiratory viral infections. This review covers several unusual viral phenotypes arising in patients with inborn errors of immunity and other settings of immune compromise. In some cases, chronic infections lead to oncogenesis or tumor-like growths and the conditions and mechanisms of viral-induced oncogenesis will be described. This review covers enterovirus, rubella, measles, papillomavirus, and parvovirus B19. It does not cover EBV and hemophagocytic lymphohistiocytosis nor lymphomagenesis related to EBV. EBV susceptibility has been recently reviewed. Our goal is to increase awareness of the unusual manifestations of viral infections in patients with IEI and to describe treatment modalities utilized in this setting. Coincidentally, each of the discussed viral infections can have a cutaneous component and figures will serve as a reminder of the physical features of these viruses. Given the high morbidity and mortality, early recognition can only improve outcomes., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Acute kidney injury (AKI) occurs frequently after infant cardiac surgery and is associated with poor outcomes, including mortality and prolonged length of stay. AKI mechanisms are poorly understood, limiting therapeutic targets. Emerging data implicates dysregulated immune activation in post-cardiac surgery AKI development. We sought to identify immune-mediated AKI biomarkers after infant cardiopulmonary bypass (CPB)-assisted cardiac surgery., Methods: A single-center prospective study of 126 infants less than 1 year old undergoing CPB-assisted surgery enrolled between 10/2017 and 6/2019. Urine samples were collected before CPB and at 6, 24, 48, and 72 h after surgery. Immune-mediated biomarkers were measured using commercial ELISA and Luminex™ multiplex kits. Based on subject age, neonatal KDIGO (< 1 month) or KDIGO criteria defined AKI. The Kruskal-Wallis rank test determined the relationship between urinary biomarker measurements and AKI., Results: A total of 35 infants (27%) developed AKI. AKI subjects were younger, underwent more complex surgery, and had longer CPB time. Subjects with AKI vs. those without AKI had higher median urinary chemokine 10 (C-X-C motif) ligand levels at 24, 48, and 72 h, respectively: 14.3 pg/ml vs. 5.3 pg/ml, 3.4 pg/ml vs. 0.8 pg/ml, and 1.15 pg/ml vs. 0.22 pg/ml (p < 0.05) post-CPB. At 6 h post-CPB, median vascular cell adhesion protein 1 (VCAM) levels (pg/mL) were higher among AKI subjects (491 pg/ml vs. 0 pg/ml, p = 0.04)., Conclusions: Urinary CXCL10 and VCAM are promising pro-inflammatory biomarkers for early AKI detection and may indicate eventual AKI therapeutic targets. A higher resolution version of the Graphical abstract is available as Supplementary information., (© 2023. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Kagami-Ogata syndrome is a rare imprinting disorder and its phenotypic overlap with multiple different etiologies hampers diagnosis. Genetic etiologies include paternal uniparental isodisomy (upd(14)pat), maternal allele deletions of differentially methylated regions (DMR) in 14q32.2 or pure primary epimutations. We report a patient with Kagami-Ogata syndrome and an atypical diagnostic odyssey with several negative standard-of-care genetic tests followed by epigenetic testing using methylation microarray and a targeted analysis of whole-genome sequencing to reveal a 203 bp deletion involving the MEG3 transcript and MEG3:TSS-DMR. Long-read sequencing enabled the simultaneous detection of the deletion, phasing, and biallelic hypermethylation of the MEG3:TSS-DMR region in a single assay. This case highlights the challenges in the sequential genetic testing paradigm, the utility of long-read sequencing as a single comprehensive diagnostic assay, and the smallest reported deletion causing Kagami-Ogata syndrome allowing important insights into the mechanism of imprinting effects at this locus., (© 2024. The Author(s).)

Serum micronutrient analysis can provide insight into diet and clinical assessment, despite the complicated interplay between micronutrients and species idiosyncrasies. Approach serum nutrient analytes with skepticism, before jumping to alter diets or offering supplementation. Utilize across species but know that some exotics have exceptions to typical ranges, such as calcium in rabbits or iron in reptiles. Make sure you trust that referenced ranges reflect normal and healthy for that species. Micronutrients are integral to every bodily process, so measurement of serum analytes can tell a story that aids in the clinical picture, when one can recognize what stands out., Competing Interests: Disclosure The authors declare that they have no relevant or material financial interests that relate to the research described in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Bronchiectasis is a major respiratory complication in patients with common variable immunodeficiency (CVID) and is associated with recurrent pulmonary infections. However, it is unclear whether other infections or non-infectious respiratory conditions are related to its development., Objective: To identify respiratory comorbidities associated with bronchiectasis in patients with CVID., Methods: A total of 1470 CVID patients enrolled in the USIDNET registry were included in a cross-sectional analysis. The primary outcome of our study was to determine the clinical characteristics and other respiratory conditions associated with respiratory comorbidities and physician-reported bronchiectasis., Results: One hundred ninety-seven CVID patients were noted to have bronchiectasis (13.4%). Affected patients were significantly older than patients without bronchiectasis (median age 54 years vs. 49 years, p = 0.0004). These patients also had lower serum IgA (13 mg/dL IQR 60 mg/dL vs. 28.4 mg/dL IQR 66 mg/dL, p = 0.000). Notably, chronic rhinosinusitis (OR = 1.69 95%CI 1.05-2.75), sinusitis (OR = 2.06 95%CI 1.38-3.09), pneumonia (OR = 2.70 95%CI 1.88-3.88), COPD (OR = 2.66 95%CI 1.51-4.67), and interstitial lung disease (OR = 2.34 95%CI 1.41-3.91) were independently associated with the development of bronchiectasis in this population., Conclusion: These data suggest that lower and upper respiratory infections, chronic lower airway disease, and interstitial lung diseases are independently associated with bronchiectasis in CVID patients. Further study into predisposing conditions related to the development of bronchiectasis in CVID patients may allow prediction and early intervention strategies to prevent the development of this complication., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: There are currently more than 480 primary immune deficiency (PID) diseases and about 7000 rare diseases that together afflict around 1 in every 17 humans. Computational aids based on data mining and machine learning might facilitate the diagnostic task by extracting rules from large datasets and making predictions when faced with new problem cases. In a proof-of-concept data mining study, we aimed to predict PID diagnoses using a supervised machine learning algorithm based on classification tree boosting., Methods: Through a data query at the USIDNET registry we obtained a database of 2396 patients with common diagnoses of PID, including their clinical and laboratory features. We kept 286 features and all 12 diagnoses to include in the model. We used the XGBoost package with parallel tree boosting for the supervised classification model, and SHAP for variable importance interpretation, on Python v3.7. The patient database was split into training and testing subsets, and after boosting through gradient descent, the predictive model provides measures of diagnostic prediction accuracy and individual feature importance. After a baseline performance test, we used the Class Weighting Hyperparameter, or scale&#95;pos&#95;weight to correct for imbalanced classification., Results: The twelve PID diagnoses were CVID (1098 patients), DiGeorge syndrome, Chronic granulomatous disease, Congenital agammaglobulinemia, PID not otherwise classified, Specific antibody deficiency, Complement deficiency, Hyper-IgM, Leukocyte adhesion deficiency, ectodermal dysplasia with immune deficiency, Severe combined immune deficiency, and Wiskott-Aldrich syndrome. For CVID, the model found an accuracy on the train sample of 0.80, with an area under the ROC curve (AUC) of 0.80, and a Gini coefficient of 0.60. In the test subset, accuracy was 0.76, AUC 0.75, and Gini 0.51. The positive feature value to predict CVID was highest for upper respiratory infections, asthma, autoimmunity and hypogammaglobulinemia. Features with the highest negative predictive value were high IgE, growth delay, abscess, lymphopenia, and congenital heart disease. For the rest of the diagnoses, accuracy stayed between 0.75 and 0.99, AUC 0.46-0.87, Gini 0.07-0.75, and LogLoss 0.09-8.55., Discussion: Clinicians should remember to consider the negative predictive features together with the positives. We are calling this a proof-of-concept study to continue with our explorations. A good performance is encouraging, and feature importance might aid feature selection for future endeavors. In the meantime, we can learn from the rules derived by the model and build a user-friendly decision tree to generate differential diagnoses., Competing Interests: Declaration of Competing Interest All authors declare no competing interests to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Modifications to UV irradiance for indoor housed herpetofauna can affect behavior and physiology. Low ultraviolet B (UVB) irradiance can result in vitamin D3 deficiency resulting in calcium metabolism disorders including metabolic bone disease and immune suppression. High UVB can result in skin and eye issues, which can be severe enough to cause shock and death. Using tools available for the assessment of UV light, including Ferguson zones and the UV working tool designed by the British and Irish Association of Zoos and Aquaria, we redesigned lighting in our indoor komodo dragon (Varanus komodoensis) habitat to better suit the UV requirements of this species, while studying changes in behavior and physiology. We measured serum vitamin 25-hydroxy D3 values in one male and one female komodo dragon before and after they were housed in indoor and outdoor habitats. We also measured behavior changes in our male komodo as he moved from an outdoor habitat, to an indoor habitat with changing UV irradiance. Our female komodo showed a 98% increase in vitamin D3 values after being moved outdoors, and laid her first clutch of eggs. Our male dragon's vitamin D3 remained consistent 200 days after moving inside. He did show increased activity when higher UV irradiance was available. Importantly, we found the UV lamps we used stopped producing desired UV irradiance within 3.5 months of regular use. We suggest all animal care facilities develop UV monitoring programs to research output and longevity of UVB lamps used in indoor herpetofauna habitats., (© 2023 Wiley Periodicals LLC.)

Rubella is a highly contagious viral infection that usually causes a mild disease in children and adults. However, infection during pregnancy can result in a fetal or newborn death or congenital rubella syndrome (CRS), a constellation of permanent birth defects including cataracts, heart defects, and sensorineural deafness. The live-attenuated rubella vaccine has been highly effective, with the Americas declared free of endemic rubella transmission in 2015. However, rubella remains a significant problem worldwide and the leading cause of vaccine-preventable birth defects globally. Thus, elimination of rubella and CRS is a goal of the World Health Organization. No specific therapeutics are approved for the rubella virus. Therefore, we set out to identify whether existing small molecules may be repurposed for use against rubella virus infection. Thus, we performed a high-throughput screen for small molecules active against rubella virus in human respiratory cells and identified two nucleoside analogs, NM107 and AT-527, with potent antiviral activity. Furthermore, we found that combining these nucleoside analogs with inhibitors of host nucleoside biosynthesis had synergistic antiviral activity. These studies open the door to new potential approaches to treat rubella infections., (© The Author(s) 2023. Published by Oxford University Press on behalf of National Academy of Sciences.)

Background: The Renal Activity Index for Lupus (RAIL) consists of urine protein assessment of neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, monocyte chemotactic protein 1, adiponectin, hemopexin, and ceruloplasmin, which non-invasively identifies lupus nephritis (LN). We aimed to delineate RAIL scores with inactive versus active LN and changes over time with response to LN induction therapy., Methods: There were 128 pediatric patients with systemic lupus erythematosus (SLE) and age-matched healthy controls recruited in a prospective case control study, with kidney biopsy confirmation of LN. Laboratory and clinical information was recorded and urine collected at diagnosis and end of induction and during maintenance therapy. Response to therapy was assessed by repeat kidney biopsy or laboratory parameters. Urine was assayed for RAIL biomarkers and the RAIL score calculated., Results: Pediatric RAIL (pRAIL) scores from 128 children and young adults with SLE (with/without LN: 70/38) including 25 during LN induction therapy, differentiated clinically active LN from inactive LN or without LN, and controls (all p < 0.0017). pRAIL scores significantly decreased with complete LN remission by 1.07 ± 1.7 (p = 0.03)., Conclusions: The RAIL biomarkers differentiate LN patients based on activity of kidney disease, with decreases of ≥ 1 in pRAIL scores indicating complete response to induction therapy. Significantly lower RAIL scores in healthy controls and in SLE patients without known LN raise the possibility of subclinical kidney disease. A higher resolution version of the Graphical abstract is available as Supplementary information., (© 2023. The Author(s).)

Purpose: To understand the natural history and clinical outcomes for patients with X-linked agammaglobulinemia (XLA) in the United States utilizing the United States Immunodeficiency Network (USIDNET) patient registry., Methods: The USIDNET registry was queried for data from XLA patients collected from 1981 to 2019. Data fields included demographics, clinical features before and after diagnosis of XLA, family history, genetic mutation in Bruton's tyrosine kinase (BTK), laboratory findings, treatment modalities, and mortality., Results: Data compiled through the USIDNET registry on 240 patients were analyzed. Patient year of birth ranged from 1945 to 2017. Living status was available for 178 patients; 158/178 (88.8%) were alive. Race was reported for 204 patients as follows: White, 148 (72.5%); Black/African American, 23 (11.2%); Hispanic, 20 (9.8%); Asian or Pacific Islander, 6 (2.9%), and other or more than one race, 7 (3.4%). The median age at last entry, age at disease onset, age at diagnosis, and length of time with XLA diagnosis was 15 [range (r) = 1-52 years], 0.8 [r = birth-22.3 years], 2 [r = birth-29 years], and 10 [r = 1-56 years] years respectively. One hundred and forty-one patients (58.7%) were < 18 years of age. Two hundred and twenty-one (92%) patients were receiving IgG replacement (IgGR), 58 (24%) were on prophylactic antibiotics, and 19 (7.9%) were on immunomodulatory drugs. Eighty-six (35.9%) patients had undergone surgical procedures, two had undergone hematopoietic cell transplantation, and two required liver transplantation. The respiratory tract was the most affected organ system (51.2% of patients) followed by gastrointestinal (40%), neurological (35.4%), and musculoskeletal (28.3%). Infections were common both before and after diagnosis, despite IgGR therapy. Bacteremia/sepsis and meningitis were reported more frequently before XLA diagnosis while encephalitis was more commonly reported after diagnosis. Twenty patients had died (11.2%). The median age of death was 21 years (range = 3-56.7 years). Neurologic condition was the most common underlying co-morbidity for those XLA patients who died., Conclusions: Current therapies for XLA patients reduce early mortality, but patients continue to experience complications that impact organ function. With improved life expectancy, more efforts will be required to improve post-diagnosis organ dysfunction and quality of life. Neurologic manifestations are an important co-morbidity associated with mortality and not yet clearly fully understood., (© 2023. The Author(s).)

Background: Severe combined immunodeficiency (SCID) is fatal unless durable adaptive immunity is established, most commonly through allogeneic haematopoietic cell transplantation (HCT). The Primary Immune Deficiency Treatment Consortium (PIDTC) explored factors affecting the survival of individuals with SCID over almost four decades, focusing on the effects of population-based newborn screening for SCID that was initiated in 2008 and expanded during 2010-18., Methods: We analysed transplantation-related data from children with SCID treated at 34 PIDTC sites in the USA and Canada, using the calendar time intervals 1982-89, 1990-99, 2000-09, and 2010-18. Categorical variables were compared by χ 2 test and continuous outcomes by the Kruskal-Wallis test. Overall survival was estimated by the Kaplan-Meier method. A multivariable analysis using Cox proportional hazards regression models examined risk factors for HCT outcomes, including the variables of time interval of HCT, infection status and age at HCT, trigger for diagnosis, SCID type and genotype, race and ethnicity of the patient, non-HLA-matched sibling donor type, graft type, GVHD prophylaxis, and conditioning intensity., Findings: For 902 children with confirmed SCID, 5-year overall survival remained unchanged at 72%-73% for 28 years until 2010-18, when it increased to 87% (95% CI 82·1-90·6; n=268; p=0·0005). For children identified as having SCID by newborn screening since 2010, 5-year overall survival was 92·5% (95% CI 85·8-96·1), better than that of children identified by clinical illness or family history in the same interval (79·9% [69·5-87·0] and 85·4% [71·8-92·8], respectively [p=0·043]). Multivariable analysis demonstrated that the factors of active infection (hazard ratio [HR] 2·41, 95% CI 1·56-3·72; p<0·0001), age 3·5 months or older at HCT (2·12, 1·38-3·24; p=0·001), Black or African-American race (2·33, 1·56-3·46; p<0·0001), and certain SCID genotypes to be associated with lower overall survival during all time intervals. Moreover, after adjusting for several factors in this multivariable analysis, HCT after 2010 no longer conveyed a survival advantage over earlier time intervals studied (HR 0·73, 95% CI 0·43-1·26; p=0·097). This indicated that younger age and freedom from infections at HCT, both directly driven by newborn screening, were the main drivers for recent improvement in overall survival., Interpretation: Population-based newborn screening has facilitated the identification of infants with SCID early in life, in turn leading to prompt HCT while avoiding infections. Public health programmes worldwide can benefit from this definitive demonstration of the value of newborn screening for SCID., Funding: National Institute of Allergy and Infectious Diseases, Office of Rare Diseases Research, and National Center for Advancing Translational Sciences., Competing Interests: Declaration of interests MST is a member of the Scientific Advisory Board for Proteios Technology. JMP has received royalties from Up-To-Date, and her spouse is employed by and owns stock in Invitae (a DNA sequencing company). MJC has received royalties from Up-to-Date and is on the scientific board of Homology Medicines, a gene therapy company, and is a data and safety monitoring board (DSMB) member for Bluebird Bio, Chiesi USA, and Rocket Pharmaceuticals. LFS is a member of the adjudication committee for Orchard Therapeutics and has received consulting fees from Takeda, CSL Behring, ADMA Biologics, Grifols, and Horizon. JH is on an Investigator-initiated grant at CSL Behring; is a consultant for ADMA, Horizon, and CIRM; and a clinical trial primary investigator (industry sponsored research) for Regeneron. LMB has received clinical trial support through the Fred Hutchinson Cancer Research Center by Medac including supply of treosulfan), is a member of the DSMB for clinical trials with Rocket Pharmaceuticals and Jasper Therapeutics, and has served on an advisory board for Horizon Therapeutics USA. BDS has undertaken ad-hoc consultancies for Sobi and Orchard Therapeutics. ShC is a member on the advisory board for SOBI. JJB is a member of an advisory board for Sobi and Horizon Therapeutics. GDEC has received consultancy fees from Miltenyi Biotech. FDG has received consultancy fees from GLG and Guidepoint Global, and is on the advisory board for Omerus. EBS is on the speaker's bureau for Sobi. EHC is an advisory board member for Pfizer. SP has received funding for the conduct of sponsored trials Atara Biotherapeutics, AlloVir, and Jasper Therapeutics and is on the advisory board for ADMA and Neovii; and is the inventor of IP Licensed to Atara with all rights assigned to Memorial Sloan Kettering Cancer Center. KES has served as a consultant for Enzyvant and the Immune Deficiency Foundation. AP is on the advisory boards for Orchard (MLD GT), Horizon, and Enzyvant, serves on the DSMB for ExCellTheraMK, and is a consultant for Enzyvant (2020). TCQ has been on the speaker's bureau and advisory board for Alexion Pharmaceuticals. SS is on the advisory board and provides consultancy for Graphite, Takeda, Janssen, Bristol Myers Squibb, data and safety monitoring committee for the National Heart, Lung, and Blood Institute (NHLBI), and Aruvant Sciences. HD was an advisor on an Eli Lilly Canada Scientific Advisory Board in April 2020. JWL in the past 12 months has been a speaker and consultant for Sobi; has been a speaker and consultant, and has received research funding from Horizon Therapeutics; has been a speaker, consultant, and on an advisory board for Pharming; has been a speaker and consultant for CSL Behring; is on the advisory board for ADMA Biologics; and is the site primary investigator for Therapure and a GreenCross employee and shareholder at Bluebird Bio. MAP has served on the advisory boards of Novartis, Medexus, Equillium, and Mesoblast; has received clinical study support from Adaptive and Miltenyi Biotech; and has received financial support for educational lectures for Miltenyi Biotech and Novartis. DBK is an inventor for the UC Regents on a lentiviral vector for gene therapy of ADA-SCID and is a member of the DSMB for Revcovi PEG-ADA (Chiesi USA). EH has received consultancy fees from JASPERS, Takeda, CSL-Behring, Octapharma, and Leadiant Biosciences. CCD is a member of the DSMB for Revcovi PEG-ADA and is a consultant for Orchard Therapeutics. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Purpose: Duplication of chromosome 22q11.2 due to meiotic non-allelic homologous recombination results in a distinct syndrome, chromosome 22q11.2 duplication syndrome that has some overlapping phenotypic features with the corresponding 22q11.2 deletion syndrome. Literature on immunologic aspects of the duplication syndrome is limited. We conducted a retrospective study of 216 patients with this syndrome to better define the key features of the duplication syndrome., Methods: Single-center retrospective record review was performed. Data regarding demographics, clinical details, and immunological tests were compiled, extracted into a predetermined data collection form, and analyzed., Results: This cohort comprised 113 (52.3%) males and 103 (47.7%) females. The majority (54.6%) of mapped duplications were between low copy repeat regions A-D (LCR22A to -D). Though T cell subsets were relatively preserved, switched memory B cells, immunoglobulins, and specific antibodies were each found to be decreased in a subset of the cohort. One-fifth (17/79, 21.5%) of patients had at least 2 low immunoglobulin values, and panhypogammaglobulinemia was found in 11.7% (9/79) cases. Four children were on regular immunoglobulin replacement therapy. Asthma and eczema were the predominant atopic symptoms in our cohort., Conclusion: Significant immunodeficiencies were observed in our cohort, particularly in B cells and antibodies. Our study expands the current clinical understanding and emphasizes the need of immunological studies and multidisciplinary approaches for these patients., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: In 2014, germline signal transducer and activator of transcription (STAT) 3 gain-of-function (GOF) mutations were first described to cause a novel multisystem disease of early-onset lymphoproliferation and autoimmunity., Objective: This pivotal cohort study defines the scope, natural history, treatment, and overall survival of a large global cohort of patients with pathogenic STAT3 GOF variants., Methods: We identified 191 patients from 33 countries with 72 unique mutations. Inclusion criteria included symptoms of immune dysregulation and a biochemically confirmed germline heterozygous GOF variant in STAT3., Results: Overall survival was 88%, median age at onset of symptoms was 2.3 years, and median age at diagnosis was 12 years. Immune dysregulatory features were present in all patients: lymphoproliferation was the most common manifestation (73%); increased frequencies of double-negative (CD4-CD8-) T cells were found in 83% of patients tested. Autoimmune cytopenias were the second most common clinical manifestation (67%), followed by growth delay, enteropathy, skin disease, pulmonary disease, endocrinopathy, arthritis, autoimmune hepatitis, neurologic disease, vasculopathy, renal disease, and malignancy. Infections were reported in 72% of the cohort. A cellular and humoral immunodeficiency was observed in 37% and 51% of patients, respectively. Clinical symptoms dramatically improved in patients treated with JAK inhibitors, while a variety of other immunomodulatory treatment modalities were less efficacious. Thus far, 23 patients have undergone bone marrow transplantation, with a 62% survival rate., Conclusion: STAT3 GOF patients present with a wide array of immune-mediated disease including lymphoproliferation, autoimmune cytopenias, and multisystem autoimmunity. Patient care tends to be siloed, without a clear treatment strategy. Thus, early identification and prompt treatment implementation are lifesaving for STAT3 GOF syndrome., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

The laminae of the neocortex are fundamental processing layers of the mammalian brain. Notably, such laminae are believed to be relatively stereotyped across short spatial scales such that shared laminae between nearby brain regions exhibit similar constituent cells. Here, we consider a potential exception to this rule by studying the retrosplenial cortex (RSC), a brain region known for sharp cytoarchitectonic differences across its granular-dysgranular border. Using a variety of transcriptomics techniques, we identify, spatially map, and interpret the excitatory cell-type landscape of the mouse RSC. In doing so, we uncover that RSC gene expression and cell types change sharply at the granular-dysgranular border. Additionally, supposedly homologous laminae between the RSC and the neocortex are effectively wholly distinct in their cell-type composition. In collection, the RSC exhibits a variety of intrinsic cell-type specializations and embodies an organizational principle wherein cell-type identities can vary sharply within and between brain regions., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)