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COPA syndrome is a recently described autosomal dominant disorder with key immune dysregulation caused by defects within the COPA gene. These mutations lead to endoplasmic reticulum stress and autoimmune response with upregulation of Th17 cytokines. The clinical phenotype of COPA syndrome primarily comprised pulmonary disease, arthritis, and renal disease secondary to immune dysregulation, with onset of symptoms commonly in the first decade of life. Herein, we describe a family with an attenuated Behçet-like phenotype of COPA syndrome, further expanding the phenotypic understanding of this syndrome.

Benzotriazoles (BZTs) and benzothiazoles (BTs) are high-production-volume chemicals utilized in many different commercial products and industrial processes, such as metal corrosion inhibitors, vulcanization accelerators, plastic-associated UV stabilizers, and pharmaceutical precursors. This study assessed age, gender, and temporal trends of BZTs and BTs in deidentified surplus pathology urine samples, pooled and stratified by age, gender, and sample collection year from a general Australian population (168 pools representing 16,800 individuals). Tolyltriazole (TTri), 5,6-dimethyl-1H-benzotriazole (DMBZT), 1,3-benzothiazole (BTH), 2-hydroxybenzothiazole (2-OH-BTH), and 2-aminobenzothiazole (2-amino-BTH) were detected in >50% of the pools. TTri was frequently detected in pooled samples representing ≤45-year-olds (both genders). Concentrations of DMBZT, BTH (females), 2-OH-BTH, and 2-amino-BTH (females) increased with age significantly, with adults (>15 years old) showing higher levels than children (≤15 years old). Gender differences in DMBZT concentrations (females > males) were observed across all sampling years and only in some for TTri (males > females: >45 years old), BTH (females > males), and 2-amino-BTH (males > females). A temporal increase in BTH, 2-OH-BTH, and 2-amino-BTH levels within the studied period (2012-2023) has been observed. Our findings suggest ongoing exposure of the Australian general population to BZTs and BTs, highlighting age, gender, and temporal trends of these compounds as measured via their urinary concentrations.

Per- and polyfluoroalkyl substances (PFAS) are a class of ubiquitously detected chemicals, some of which are highly persistent and bioaccumulative in humans. Within the general population, dietary ingestion is considered a primary pathway for PFAS exposure, and seafood consumption specifically has been associated with higher serum PFAS concentrations. Proximity of residence to the ocean may influence dietary habits, particularly seafood consumption, and exposure to geographically specific PFAS sources such as sea spray aerosols (SSA). The objective of this study was to evaluate potential spatial trends in serum PFAS concentrations between Australian coastal and island populations compared to those with inland residency. Human sera were obtained from deidentified surplus pathology samples and pooled with respect to geographical location, sex (male or female), and age group (males: ≥15-<45 years, ≥45 years; females: ≥15-<45 years, ≥45-<60 years, ≥60 years) stratification criteria. Serum samples were then analysed for PFAS using High Performance Liquid Chromatography-Mass Spectrometry (HP LC-MS). A total of 13 of the 45 targeted PFAS were quantifiable in at least one pooled sample, including the detection of perfluorooctane sulfonate (PFOS) replacement compounds 5:3 fluorotelomer carboxylic acid (5:3 FTCA) and potassium 9-chlorohexadecafluoro-3-oxanonane-1-sulfonate (9Cl-F53B). Significant spatial trends were observed in males aged ≥45 years, with serum concentrations of PFOS, perfluorobutanoic acid (PFBA), perfluorodecanoic acid (PFDA) and perfluoroheptane sulfonic acid (PFHpS) demonstrated to be 32-77% higher in pooled samples from island locations compared with inland. A similar trend was observed for PFHpS in coastal locations. Whilst deidentification of samples limited inferences about exposure pathways associated with the observed trends, this study indicated the feasibility of utilising pooled samples for assessing spatial variations in serum PFAS concentrations between geographically distinct subpopulations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Abstract: We investigated efficacy and safety of mavorixafor, an oral CXCR4 antagonist, in participants with warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome, a rare immunodeficiency caused by CXCR4 gain-of-function variants. This randomized (1:1), double-blind, placebo-controlled, phase 3 trial enrolled participants aged ≥12 years with WHIM syndrome and absolute neutrophil count (ANC) ≤0.4 × 103/μL. Participants received once-daily mavorixafor or placebo for 52 weeks. The primary end point was time (hours) above ANC threshold ≥0.5 × 103/μL (TATANC; over 24 hours). Secondary end points included TAT absolute lymphocyte count ≥1.0 × 103/μL (TATALC; over 24 hours); absolute changes in white blood cell (WBC), ANC, and absolute lymphocyte count (ALC) from baseline; annualized infection rate; infection duration; and total infection score (combined infection number/severity). In 31 participants (mavorixafor, n = 14; placebo, n = 17), mavorixafor least squares (LS) mean TATANC was 15.0 hours and 2.8 hours for placebo (P < .001). Mavorixafor LS mean TATALC was 15.8 hours and 4.6 hours for placebo (P < .001). Annualized infection rates were 60% lower with mavorixafor vs placebo (LS mean 1.7 vs 4.2; nominal P = .007), and total infection scores were 40% lower (7.4 [95% confidence interval [CI], 1.6-13.2] vs 12.3 [95% CI, 7.2-17.3]). Treatment with mavorixafor reduced infection frequency, severity, duration, and antibiotic use. No discontinuations occurred due to treatment-emergent adverse events (TEAEs); no related serious TEAEs were observed. Overall, mavorixafor treatment demonstrated significant increases in LS mean TATANC and TATALC, reduced infection frequency, severity/duration, and was well tolerated. The trial was registered at www.clinicaltrials.gov as #NCT03995108., (© 2024 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Objectives: The objective of this study is to map the range and variety of direct-to-consumer (DTC) tests advertised online in Australia and analyse their potential clinical utility and implications for medical overuse., Design: Systematic online search of DTC test products in Google and Google Shopping. DTC test advertisements data were collected and analysed to develop a typology of potential clinical utility of the tests at population level, assessing their potential benefits and harms using available evidence, informed by concepts of medical overuse., Results: We identified 484 DTC tests (103 unique products), ranging from $A12.99 to $A1947 in cost (mean $A197.83; median $A148.50). Using our typology, we assigned the tests into one of four categories: tests with potential clinical utility (10.7%); tests with limited clinical utility (30.6%); non-evidence-based commercial 'health checks' (41.9%); and tests whose methods and/or target conditions are not recognised by the general medical community (16.7%). Of the products identified, 56% did not state that they offered pretest or post-test consultation, and 51% did not report analytical performance of the test or laboratory accreditation., Conclusions: This first-in-Australia study shows most DTC tests sold online have low potential clinical utility, with healthy consumers constituting the main target market. Harms may be caused by overdiagnosis, high rates of false positives and treatment decisions led by non-evidence-based tests, as well as financial costs of unnecessary and inappropriate testing. Regulatory mechanisms should demand a higher standard of evidence of clinical utility and efficacy for DTC tests. Better transparency and reporting of health outcomes, and the development of decision-support resources for consumers are needed., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Human biomonitoring programs of per- and polyfluoroalkyl substances (PFAS) have been conducted around the world to assess human exposure and health risk. Inquiry into population PFAS levels in a socioeconomically and geographically unique region such as the Pacific Island Papua New Guinea, may provide new insights into PFAS exposure pathways and sources. This study presented the first indication of PFAS exposure in the Papua New Guinea population. De-identified serum samples were pooled from surplus pathology serum samples collected between 2019 and 2020. A total of 11 PFAS were detected in the serum pools including 10 perfluoroalkyl acids (PFAA) and 9Cl-F53B (a perfluorooctane sulfonic acid - PFOS alternative). The observed PFAA profile was somewhat similar to that observed for general population data of other countries such as Australia, Malaysia, and Canada suggesting similar exposure sources and/or pathways. However, PFAS concentrations were consistently lower than concentrations in the serum measured in pools obtained from Australia. The detection of 9Cl-F53B in all pools was a new finding which might be related to exposure from locally industrial sources., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome (WS) is a combined immunodeficiency caused by gain-of-function mutations in the C-X-C chemokine receptor type 4 (CXCR4) gene. We characterize a unique international cohort of 66 patients, including 57 (86%) cases previously unreported, with variable clinical phenotypes. Of 17 distinct CXCR4 genetic variants within our cohort, 11 were novel pathogenic variants affecting 15 individuals (23%). All variants affect the same CXCR4 region and impair CXCR4 internalization resulting in hyperactive signaling. The median age of diagnosis in our cohort (5.5 years) indicates WHIM syndrome can commonly present in childhood, although some patients are not diagnosed until adulthood. The prevalence and mean age of recognition and/or onset of clinical manifestations within our cohort were infections 88%/1.6 years, neutropenia 98%/3.8 years, lymphopenia 88%/5.0 years, and warts 40%/12.1 years. However, we report greater prevalence and variety of autoimmune complications of WHIM syndrome (21.2%) than reported previously. Patients with versus without family history of WHIM syndrome were diagnosed earlier (22%, average age 1.3 years versus 78%, average age 5 years, respectively). Patients with a family history of WHIM syndrome also received earlier treatment, experienced less hospitalization, and had less end-organ damage. This observation reinforces previous reports that early treatment for WHIM syndrome improves outcomes. Only one patient died; death was attributed to complications of hematopoietic stem cell transplantation. The variable expressivity of WHIM syndrome in pediatric patients delays their diagnosis and therapy. Early-onset bacterial infections with severe neutropenia and/or lymphopenia should prompt genetic testing for WHIM syndrome, even in the absence of warts., (© 2022. The Author(s).)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a serious threat to human health. Current methods such as reverse transcription polymerase chain reaction (qRT-PCR) are complex, expensive, and time-consuming. Rapid, and simple screening methods for the detection of SARS-CoV-2 are critically required to fight the current pandemic. In this work we present a proof of concept for, a simple optical sensing method for the screening of SARS-CoV-2 through its spike protein subunit S1. The method utilizes a target-specific extractor chip to bind the protein from the biological specimens. The disulfide bonds of the protein are then reduced into a biothiol with sulfhydryl (SH) groups that react with a blue-colored benzothiazole azo dye-Hg complex (BAN-Hg) and causes the spontaneous change of its blue color to pink which is observable by the naked eye. A linear relationship between the intensity of the pink color and the logarithm of reduced S1 protein concentration was found within the working range 130 ng.mL -1 -1.3 pg mL -1 . The lowest limit of detection (LOD) of the assay was 130 fg mL -1 . A paper based optical sensor was fabricated by loading the BAN-Hg sensor onto filter paper and used to screen the S1 protein in spiked saliva and patients' nasopharyngeal swabs. The results obtained by the paper sensor corroborated with those obtained by qRT-PCR. The new paper-based sensing method can be extended to the screening of many viruses (e.g. the human immunodeficiency virus, the human polyomavirus, the human papilloma virus, the adeno associated viruses, the enteroviruses) through the cysteine residues of their capsid proteins. The new method has strong potential for screening viruses at pathology labs and in remote areas that lacks advanced scientific infrastructure. Further clinical studies are warranted to validate the new sensing method., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Purpose: The purpose of this phase 3 study was to evaluate the efficacy, pharmacokinetics (PK), and safety of Immune Globulin Subcutaneous (Human), 20% Caprylate/Chromatography Purified (IGSC 20%) in patients with primary immunodeficiency (PI)., Methods: Immunoglobulin treatment-experienced subjects with PI received 52 weeks of IGSC 20% given weekly at the same dose as the subject's previous IgG regimen (DAF 1:1); the minimum dose was 100 mg/kg/week. The primary endpoint was serious bacterial infections (SBIs [null vs alternative hypothesis: SBI rate per person per year ≥ 1 vs < 1]). IgG subclasses and specific pathogen antibody levels were also measured., Results: Sixty-one subjects (19 children [≤ 12 years], 10 adolescents [> 12-16 years], and 32 adults) were enrolled. The rate of SBIs per person per year was 0.017. The 1-sided 99% upper confidence limit was 0.036 (< 1), and the null hypothesis was rejected. The rate of hospitalization due to infection per person per year was 0.017 (2-sided 95% confidence interval: 0.008-0.033) overall. The mean trough total IgG concentrations were comparable to the previous IgG replacement regimen. The average of the individual mean trough ratios (IGSC 20%:previous regimen) was 1.078 (range: 0.83-1.54). The average steady-state mean trough IgG concentrations were 947.64 and 891.37 mg/dL, respectively. Seven subjects had serious treatment-emergent adverse events (TEAEs); none was drug-related. The rate of all TEAEs, including local infusion site reactions, during 3045 IGSC 20% infusions was 0.135. Most TEAEs were mild or moderate., Conclusions: IGSC 20% demonstrated efficacy and good safety and tolerability in subjects with PI., (© 2021. The Author(s).)

A plethora of leukocyte modulations have been reported in critically ill patients. Critical illnesses such as acute respiratory distress syndrome and cardiogenic shock, which potentially require extracorporeal membrane oxygenation (ECMO) support, are associated with changes in leukocyte numbers, phenotype, and functions. The changes observed in these illnesses could be compounded by exposure of blood to the non-endothelialized surfaces and non-physiological conditions of ECMO. This can result in further leukocyte activation, increased platelet-leukocyte interplay, pro-inflammatory and pro-coagulant state, alongside features of immunosuppression. However, the effects of ECMO on leukocytes, in particular their phenotypic and functional signatures, remain largely overlooked, including whether these changes have attributable mortality and morbidity. The aim of our narrative review is to highlight the importance of studying leukocyte signatures to better understand the development of complications associated with ECMO. Increased knowledge and appreciation of their probable role in ECMO-related adverse events may assist in guiding the design and establishment of targeted preventative actions., 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 © 2021 Ki, Millar, Langguth, Passmore, McDonald, Shekar, Shankar-Hari, Cho, Suen and Fraser.)

Use of extracorporeal membrane oxygenation (ECMO) is expanding, however, it is still associated with significant morbidity and mortality. Activation of inflammatory and innate immune responses and hemostatic alterations contribute to complications. Hyperoxia may play a role in exacerbating these responses. Nine ex vivo ECMO circuits were tested using fresh healthy human whole blood, with two oxygen levels: 21% inspired fraction of oxygen (FiO 2 ; mild hyperoxia; n = 5) and 100% FiO 2 (severe hyperoxia; n = 4). Serial blood samples were taken for analysis of platelet aggregometry, leukocyte activation, inflammatory, and oxidative stress markers. ECMO resulted in reduced adenosine diphosphate- (P < .05) and thrombin receptor activating peptide-induced (P < .05) platelet aggregation, as well as increasing levels of the neutrophil activation marker, neutrophil elastase (P = .013). Additionally, levels of the inflammatory chemokine interleukin-8 were elevated (P < .05) and the activity of superoxide dismutase, a marker of oxidative stress, was increased (P = .002). Hyperoxia did not augment these responses, with no significant differences detected between mild and severe hyperoxia. Our ex vivo model of ECMO revealed that the circuit itself triggers a pro-inflammatory and oxidative stress response, however, exposure to supra-physiologic oxygen does not amplify that response. Extended-duration studies and inclusion of an endothelial component could be beneficial in characterizing longer term changes., (© 2020 International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)

Background and Aims: Patients with inflammatory bowel disease (IBD) often have subjective symptoms for months or years prior to their diagnosis. Blood tests taken prior to diagnosis may provide objective evidence of duration of pre-diagnosis disease. We aim to describe the pre-diagnosis laboratory pattern of patients with IBD., Methods: A total of 838 patients diagnosed with IBD between 01/01/1996 and 01/03/2014, with pre-diagnosis laboratory testing available, contributed data for analysis. C-reactive protein, erythrocyte sedimentation rate, hemoglobin level, mean cell volume (MCV) platelet count, white blood cell count, neutrophil count, albumin level, ferritin level, serum iron level, alanine transaminase level, and fecal calprotectin were examined in the 24 months leading up to diagnosis and compared to baseline data taken between 24 and 36 months prior to diagnosis., Results: For patients with Crohn's disease, a significant drop in serum albumin and MCV levels and a significant rise in platelet count were observed between 115 and 385 days prior to diagnosis (p < 0.01, two-tailed t test). For patients with ulcerative colitis, a significant change in albumin level, MCV, hemoglobin level, platelet count, and serum iron level was observed at diagnosis (p < 0.01, two-tailed t test) but was not detectable before., Conclusions: These data provide objective evidence of duration of delay between disease onset and diagnosis in a cohort of patients with IBD. Expediting diagnostic testing in patients presenting with symptoms consistent with IBD, who also have abnormal laboratory results, may reduce diagnostic delay, speed access to therapy, and improve clinical outcomes.

The autoimmune/autoinflammatory syndrome induced by adjuvants (ASIA) was first described in 2011. The aluminium containing adjuvants of vaccines were stated to be one of the main causes of the condition. Other disorders associated with ASIA include siliconosis, Gulf war syndrome, sick building syndrome and the macrophagic myositis syndrome. We have recently reviewed ASIA as defined by its authors. We have shown that the definition of ASIA is imprecise and includes all patients with an autoimmune disorder as well as potentially the entire population. Application of the Bradford Hill criteria for causality does not support ASIA as an outcome of exposure to aluminium containing adjuvants in vaccines. The advocates of ASIA highlight animal models as evidence for the existence of the disorder. However, as this review will demonstrate, animal models purporting to support the existence of ASIA have methodological, analytical and ethical flaws which, in our view, refute the existence of the condition. Three publications by the advocates of ASIA were recently retracted from peer-reviewed journals. We call for an immediate moratorium on animal experiments of ASIA until an independent inquiry has been conducted to determine the existence of a clinically relevant syndrome, identifiable as ASIA in humans., (Copyright © 2018. Published by Elsevier B.V.)

Background: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a recently described life-threatening autoimmune disorder associated with a characteristic multi-stage neuropsychiatric syndrome. Although it is known that the majority of patients experience neuropsychological disturbance post-treatment, some aspects of the cognitive profile remain unclear., Methods: This study sought to investigate patterns of cognitive functioning in a sample of anti-NMDAR encephalitis patients. Seven (6F:1M; mean age, 26.4 years; range, 16-37 years) treated patients completed a comprehensive set of neurocognitive and social functioning measures. Performance was analyzed using normative data (where available), and comparison with matched controls (10F:4M; mean age, 25.8 years; range, 16-38 years)., Results: Individual cognitive profiles ranged from within normal limits to extensive dysfunction. Relative to controls, the patient group's performance was affected in the domains of verbal/ visual memory, working memory, attention, processing speed, executive functioning, and social cognition. The patient group also reported significantly higher levels of anxiety compared to controls., Conclusions: These results add to the accumulating evidence that neurocognitive deficits, consistent with the distribution and functions of the NMDAR system can persist during recovery from anti-NMDAR encephalitis. This is the first study to provide evidence of performance decrements on measures of social cognition, including some involving theory of mind. (JINS, 2016, 22, 828-838).

Objective: We examined a cohort of Australian patients with statin exposure who developed a necrotizing autoimmune myopathy (NAM) associated with a novel autoantibody against 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) and describe the clinical and therapeutic challenges of managing these patients and an optimal therapeutic strategy., Methods: Clinical, laboratory, EMG, and histopathologic results and response to immunomodulation are reported in 6 Australian patients with previous statin exposure and antibodies targeting HMGCR., Results: All patients presented with painless proximal weakness following statin therapy, which persisted after statin cessation. Serum creatine kinase (CK) levels ranged from 2,700 to 16,200 IU/L. EMG was consistent with a myopathic picture. Muscle biopsies revealed a pauci-immune necrotizing myopathy. Detailed graphical representation of the clinical course of these patients showed a close association with rising CK and an increase in clinical weakness signifying relapses, particularly upon weaning or ceasing steroids. All 6 patients were responsive to initial steroid therapy, with 5 relapsing upon attempts to wean steroids. Both CK and clinical strength improved with the reinstitution of immunotherapy, in particular steroids and IV immunoglobulin (IVIg). All patients required treatment with varying multiagent immunosuppressive regimens to achieve clinical remission, including prednisone (n = 6), IVIg (n = 5), plasmapheresis (n = 2), and additional therapy including methotrexate (n = 6), cyclophosphamide (n = 2), rituximab (n = 2), azathioprine (n = 1), and cyclosporine (n = 1)., Conclusions: Recognition of HMGCR antibody-associated NAM is important because these patients are responsive to immunosuppression, and early multiagent therapy and a slow and cautious approach to withdrawing steroids may improve outcomes.

Background: Pollens of the Panicoideae subfamily of grasses including Bahia (Paspalum notatum) are important allergen sources in subtropical regions of the world. An assay for specific IgE to the major molecular allergenic component, Pas n 1, of Bahia grass pollen (BaGP) would have immunodiagnostic utility for patients with pollen allergy in these regions., Methods: Biotinylated Pas n 1 purified from BaGP was coated onto streptavidin ImmunoCAPs. Subjects were assessed by clinical history of allergic rhinitis and skin prick test (SPT) to aeroallergens. Serum total, BaGP-specific and Pas n 1-specific IgE were measured., Results: Pas n 1 IgE concentrations were highly correlated with BaGP SPT (r = 0.795, p < 0.0001) and BaGP IgE (r = 0.915, p < 0.0001). At 0.23 kU/l Pas n 1 IgE, the diagnostic sensitivity (92.4%) and specificity (93.1%) for the detection of BaGP allergy was high (area under receiver operator curve 0.960, p < 0.0001). The median concentrations of Pas n 1 IgE in non-atopic subjects (0.01 kU/l, n = 67) and those with other allergies (0.02 kU/l, n = 59) showed no inter-group difference, whilst grass pollen-allergic patients with allergic rhinitis showed elevated Pas n 1 IgE (6.71 kU/l, n = 182, p < 0.0001). The inter-assay coefficient of variation for the BaGP-allergic serum pool was 6.92%., Conclusions: Pas n 1 IgE appears to account for most of the BaGP-specific IgE. This molecular component immunoassay for Pas n 1 IgE has potential utility to improve the sensitivity and accuracy of diagnosis of BaGP allergy for patients in subtropical regions., (© 2015 S. Karger AG, Basel.)