Ethnoracial Disparities in Perinatal Outcomes Among Women Veterans.

Objective: Non-Hispanic Black women have increased rates of preterm birth and low infant birth weight. However, we do not know if these disparities replicate in women veterans, a population that may be at further risk for poor perinatal outcomes. This study sought to examine ethnoracial differences in preterm birth and low infant birth weight in veterans. Methods: A national sample of randomly chosen women veterans (i.e., oversampled for residency in high crime neighborhoods) reported information about all pregnancies they have had in their life, demographic characteristics, and history of childhood trauma exposures. The analytic sample was limited to individuals who identified as Hispanic/Latinx, Black, or White (n = 972). Mixed-effects regression models were used to examine ethnoracial differences in gestational age at delivery and infant birth weight, controlling for age at pregnancy, childhood trauma exposure, pregnancy during military service, income, and education. Results: Both Black and Hispanic/Latinx veterans were significantly more likely to have an infant born at lower gestational age (B = -1.04 and B = -1.11, respectively) and lower infant birth weight (B = -195.83 and B = -144.27, respectively) as compared with White veterans in covariate-adjusted models. Black (odds ratio = 3.24, confidence interval = 1.16, 9.09) veterans were more likely to meet the clinical definition of preterm birth as compared with White veterans. Conclusions: Results align with what is seen in the general population regarding ethnoracial disparities in gestational age at delivery and infant birth weight. Findings highlight the critical need for more research on mechanisms and prevention efforts for ethnoracial disparities in perinatal outcomes.

Posttraumatic cognitions about the self are associated with depression symptoms in veterans endorsing a history of assaultive military sexual trauma.

Depressive symptoms are a commonly observed yet understudied mental health sequalae of military sexual trauma (MST). Prior research supports the relationship between negative posttraumatic cognitions (NPCs) and the onset and course of trauma symptoms more broadly. We hypothesized that NPCs would be associated with depression symptoms in veterans endorsing a history of MST, specifically assaultive type MST. Our clinical sample included veterans presenting for treatment related to assaultive MST (N = 158; 70.9% female, 65.2% White, 27.8% Black). Participants completed self-report measures of posttraumatic stress disorder (PTSD), depression, and NPCs during intake at a Veteran's Affairs specialty trauma clinic. Linear regressions were used to analyze the association between NPCs and depression symptoms controlling for PTSD symptom severity. PTSD severity and NPCs about the self were significantly associated with depression symptoms, explaining 46% of the variance severity, F(4, 153) = 33.16, R² = .46, p < .001. These findings newly demonstrate a relationship between NPCs about the self and depression in veterans with a history of MST. Clinicians may benefit from incorporating cognitive interventions into preexisting depression treatments to directly address NPCs in this population. Future study is needed to determine how these results may extend to other forms of MST or trauma types. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Brief family involvement enhances veteran homework quality during trauma-focused psychotherapy.

OBJECTIVE: Homework has been shown to improve outcomes in cognitive-behavioral therapy, though less is known about the importance of homework during trauma-focused psychotherapy. Similarly, prior research suggests family context plays a key role in posttraumatic stress disorder (PTSD)-related distress and treatment engagement. One potential way that families can facilitate better treatment outcomes is by promoting homework engagement. This study examined the impact of a brief family intervention (BFI) for PTSD toward this aim. We hypothesized that veterans with PTSD whose family members (FMs) received the BFI would have better homework completion and quality than those who did not receive the BFI. METHOD: This mixed-methods analysis examined 24 veteran-family dyads enrolled in a randomized clinical trial examining the BFI. All veterans were currently engaged in trauma-focused psychotherapy. Each veteran's clinician rated their homework quality and completion after each therapy session. A subset of dyads also completed semistructured interviews posttreatment. A rapid qualitative analysis approach was used to examine themes in shifting family behavior post-BFI. RESULTS: Quantitative analyses yielded partial support for our hypotheses: those in the BFI condition had significantly higher clinician-rated homework quality. While participants in the BFI condition had a higher homework completion rate, this difference did not reach statistical significance. Qualitative analyses suggested that the BFI prompted meaningful discussions about PTSD and increased FMs' use of supportive (rather than accommodative) behavior when responding to PTSD-related distress. CONCLUSIONS: Involving FMs in PTSD treatment appears to shift the family context in a manner that improves homework quality in veterans. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Long-Term Effectiveness of Benralizumab in Eosinophilic Granulomatosis With Polyangiitis.

BACKGROUND: Eosinophilic granulomatosis with polyangiitis (EGPA) is a multisystemic disease characterized by eosinophilic tissue inflammation. Benralizumab, an anti-IL-5 receptor (anti-IL-5R) monoclonal antibody, induces rapid depletion of eosinophils; its longer-term effect in EGPA is unknown. OBJECTIVE: To assess the real-world effectiveness and clinical remission rates of anti-IL-5R therapy in EGPA. METHODS: We performed a retrospective cohort analysis of patients with EGPA, who commenced treatment with benralizumab. Clinical remission, assessed at 1 year and 2 years after the initiation of benralizumab, was defined as an absence of active vasculitis (Birmingham Vasculitis Activity Score of 0) and an oral corticosteroid (OCS) dose of ≤4 mg/d of prednisolone. "Super-responders" were defined as patients in remission and free of any significant relapses (asthma or extrapulmonary) over the preceding 12 months. The corticosteroid-sparing capacity of benralizumab, patient-reported outcome measures, and characteristics associated with clinical remission and super-responder status were also analyzed. RESULTS: A total of 70 patients completed at least 1 year of treatment with benralizumab, of whom 53 completed 2 years. Of 70 patients, 47 (67.1%) met the definition for clinical remission at 1 year, with a similar proportion in remission at 2 years. Excluding asthma-related relapses, 61 of 70 (87.1%) patients were relapse free at 1 year, and of the 53 who completed 2 years, 45 (84.9%) were relapse free. A total of 67.9% of patients no longer needed any OCS for disease control. No significant difference was seen between antineutrophilic cytoplasmic antibody (ANCA)-positive and ANCA-negative subgroups. CONCLUSIONS: In this real-world setting of patients with EGPA, treatment with benralizumab was well tolerated and resulted in corticosteroid-free clinical remission for the majority of patients.

Differential Associations Between Posttraumatic Cognitions, Posttraumatic Stress Disorder Symptoms, and Race Among Black and White Veterans Seeking Treatment for Assaultive Military Sexual Trauma.

Past research supports the role of negative posttraumatic cognitions (NPCs) in the development and maintenance of posttraumatic stress disorder (PTSD). The relationship between NPCs and PTSD may be uniquely impacted by racial status and experiences of military sexual trauma (MST), both of which may have a unique impact on one's understanding of self, others, and the world. We explored racial differences in the association between NPCs and PTSD symptom clusters in a sample of veterans endorsing MST (N = 139; 74.8% White, 25.2% Black). A path model was created and analyzed both with the full sample and separately by racial group. In the full sample, NPCs about the self and world were significantly associated with intrusion, negative alterations in cognitions and mood (NACM), and arousal, but not avoidance. Self-blame was not a significant predictor of negative alterations in cognition in mood. This model was consistent in the White veteran model, whereas only negative cognitions about the self were associated with NACM in the Black veteran path model. NPCs about the self and world appear important to non-avoidance PTSD symptomatology related to MST and thus should be targeted in treatment. For Black veterans endorsing distress related to NACM symptoms, negative beliefs about the self should be specifically considered for intervention.

The role of cardiovascular magnetic resonance in the evaluation of acute myocarditis and inflammatory cardiomyopathies in clinical practice - a comprehensive review.

Inflammatory cardiomyopathy (I-CMP) is defined as myocarditis in association with cardiac dysfunction and/or ventricular remodelling. It is characterized by inflammatory cell infiltration into the myocardium and has heterogeneous infectious and non-infectious aetiologies. A complex interplay of genetic, autoimmune, and environmental factors contributes to the substantial risk of deteriorating cardiac function, acute heart failure, and arrhythmia as well as chronic dilated cardiomyopathy and its sequelae. Multi-parametric cardiovascular magnetic resonance (CMR) imaging is sensitive to many tissue changes that occur during myocardial inflammation, regardless of its aetiology. In this review, we summarize the various aetiologies of I-CMP and illustrate how CMR contributes to non-invasive diagnosis.

Interferon inducible X-linked gene CXorf21 may contribute to sexual dimorphism in Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease, characterised by increased expression of type I interferon (IFN)-regulated genes and a striking sex imbalance towards females. Through combined genetic, in silico, in vitro, and ex vivo approaches, we define CXorf21, a gene of hitherto unknown function, which escapes X-chromosome inactivation, as a candidate underlying the Xp21.2 SLE association. We demonstrate that CXorf21 is an IFN-response gene and that the sexual dimorphism in expression is magnified by immunological challenge. Fine-mapping reveals a single haplotype as a potential causal cis-eQTL for CXorf21. We propose that expression is amplified through modification of promoter and 3'-UTR chromatin interactions. Finally, we show that the CXORF21 protein colocalises with TLR7, a pathway implicated in SLE pathogenesis. Our study reveals modulation in gene expression affected by the combination of two hallmarks of SLE: CXorf21 expression increases in a both an IFN-inducible and sex-specific manner.

Unraveling multiple MHC gene associations with systemic lupus erythematosus: model choice indicates a role for HLA alleles and non-HLA genes in Europeans.

We have performed a meta-analysis of the major-histocompatibility-complex (MHC) region in systemic lupus erythematosus (SLE) to determine the association with both SNPs and classical human-leukocyte-antigen (HLA) alleles. More specifically, we combined results from six studies and well-known out-of-study control data sets, providing us with 3,701 independent SLE cases and 12,110 independent controls of European ancestry. This study used genotypes for 7,199 SNPs within the MHC region and for classical HLA alleles (typed and imputed). Our results from conditional analysis and model choice with the use of the Bayesian information criterion show that the best model for SLE association includes both classical loci (HLA-DRB1(∗)03:01, HLA-DRB1(∗)08:01, and HLA-DQA1(∗)01:02) and two SNPs, rs8192591 (in class III and upstream of NOTCH4) and rs2246618 (MICB in class I). Our approach was to perform a stepwise search from multiple baseline models deduced from a priori evidence on HLA-DRB1 lupus-associated alleles, a stepwise regression on SNPs alone, and a stepwise regression on HLA alleles. With this approach, we were able to identify a model that was an overwhelmingly better fit to the data than one identified by simple stepwise regression either on SNPs alone (Bayes factor [BF] > 50) or on classical HLA alleles alone (BF > 1,000).

Genetically determined partial complement C4 deficiency states are not independent risk factors for SLE in UK and Spanish populations.

Systemic lupus erythematosus (SLE) is a chronic, multisystem autoimmune disease. Complete deficiency of complement component C4 confers strong genetic risk for SLE. Partial C4 deficiency states have also shown association with SLE, but despite much effort over the last 30 years, it has not been established whether this association is primarily causal or secondary to long-range linkage disequilibrium. The complement C4 locus, located in the major histocompatibility complex (MHC) class III region, exhibits copy-number variation (CNV) and C4 itself exists as two paralogs, C4A and C4B. In order to determine whether partial C4 deficiency is an independent genetic risk factor for SLE, we investigated C4 CNV in the context of HLA-DRB1 and MHC region SNP polymorphism in the largest and most comprehensive complement C4 study to date. Specifically, we genotyped 2,207 subjects of northern and southern European ancestry (1,028 SLE cases and 1,179 controls) for total C4, C4A, and C4B gene copy numbers, and the loss-of-function C4 exon 29 CT indel. We used multiple logistic regression to determine the independence of C4 CNV from known SNP and HLA-DRB1 associations. We clearly demonstrate that genetically determined partial C4 deficiency states are not independent risk factors for SLE in UK and Spanish populations. These results are further corroborated by the lack of association shown by the C4A exon 29 CT insertion in either cohort. Thus, although complete homozygous deficiency of complement C4 is one of the strongest genetic risk factors for SLE, partial C4 deficiency states do not independently predispose to the disease.

Transancestral mapping of the MHC region in systemic lupus erythematosus identifies new independent and interacting loci at MSH5, HLA-DPB1 and HLA-G.

OBJECTIVES: Systemic lupus erythematosus (SLE) is a chronic multisystem genetically complex autoimmune disease characterised by the production of autoantibodies to nuclear and cellular antigens, tissue inflammation and organ damage. Genome-wide association studies have shown that variants within the major histocompatibility complex (MHC) region on chromosome 6 confer the greatest genetic risk for SLE in European and Chinese populations. However, the causal variants remain elusive due to tight linkage disequilibrium across disease-associated MHC haplotypes, the highly polymorphic nature of many MHC genes and the heterogeneity of the SLE phenotype. METHODS: A high-density case-control single nucleotide polymorphism (SNP) study of the MHC region was undertaken in SLE cohorts of Spanish and Filipino ancestry using a custom Illumina chip in order to fine-map association signals in these haplotypically diverse populations. In addition, comparative analyses were performed between these two datasets and a northern European UK SLE cohort. A total of 1433 cases and 1458 matched controls were examined. RESULTS: Using this transancestral SNP mapping approach, novel independent loci were identified within the MHC region in UK, Spanish and Filipino patients with SLE with some evidence of interaction. These loci include HLA-DPB1, HLA-G and MSH5 which are independent of each other and HLA-DRB1 alleles. Furthermore, the established SLE-associated HLA-DRB1*15 signal was refined to an interval encompassing HLA-DRB1 and HLA-DQA1. Increased frequencies of MHC region risk alleles and haplotypes were found in the Filipino population compared with Europeans, suggesting that the greater disease burden in non-European SLE may be due in part to this phenomenon. CONCLUSION: These data highlight the usefulness of mapping disease susceptibility loci using a transancestral approach, particularly in a region as complex as the MHC, and offer a springboard for further fine-mapping, resequencing and transcriptomic analysis.

Determination of the loss of function complement C4 exon 29 CT insertion using a novel paralog-specific assay in healthy UK and Spanish populations.

Genetic variants resulting in non-expression of complement C4A and C4B genes are common in healthy European populations and have shown association with a number of diseases, most notably the autoimmune disease, systemic lupus erythematosus. The most frequent cause of a C4 "null" allele, following that of C4 gene copy number variation (CNV), is a non-sense mutation arising from a 2 bp CT insertion into codon 1232 of exon 29. Previous attempts to accurately genotype this polymorphism have not been amenable to high-throughput typing, and have been confounded by failure to account for CNV at this locus, as well as by inability to distinguish between paralogs. We have developed a novel, high-throughput, paralog-specific assay to detect the presence and copy number of this polymorphism. We have genotyped healthy cohorts from the United Kingdom (UK) and Spain. Overall, 30/719 (4.17%) individuals from the UK cohort and 8/449 (1.78%) individuals from the Spanish cohort harboured the CT insertion in a C4A gene. A single Spanish individual possessed a C4B CT insertion. There is weak correlation between the C4 CT insertion and flanking MHC polymorphism. Therefore it is important to note that, as with C4 gene CNV, disease-association due to this variant will be missed by current SNP-based genome-wide association strategies.

Investigation of the HIN200 locus in UK SLE families identifies novel copy number variants.

We undertook a candidate locus study of the HIN200 gene cluster on 1q21-23 in UK systemic lupus erythematosus (SLE) families. To date, despite mounting evidence demonstrating the importance of these proteins in autoimmune disease, cancer, apoptosis, inflammation, and cell cycle arrest, there has been a dearth of data with respect to the genetic characterisation of the HIN200 locus in SLE or any other disease. We typed 83 single nucleotide polymorphisms (SNPs) across 317 kb of the HIN200 cluster in 428 UK SLE families and sought replication from a European-American lupus cohort. We do not find strong evidence of SNP association in either cohort. Interestingly, we do observe a trend for association with certain HIN200 SNPs and serologic subphenotypes in UK SLE that parallels the association of lupus antibodies with the orthologous murine locus. Furthermore, we find the HIN200 locus to be unexpectedly complex in terms of genetic structural organisation. We have identified a number of copy number variants (CNVs) in this region in healthy French males, HapMap samples, and UK SLE families. In summary, candidate interferon signalling genes show evidence of common CNV in human SLE and healthy subjects. The impact of these CNVs in health and disease remains to be determined.

Assessment of complement C4 gene copy number using the paralog ratio test.

The complement C4 locus is in the class III region of the MHC, and exhibits copy number variation. Complement C4 null alleles have shown association with a number of diseases including systemic lupus erythematosus (SLE). However, most studies to date have used protein immunophenotyping and not direct interrogation of the genome to determine C4 null allele status. Moreover, a lack of accurate C4 gene copy number (GCN) estimation and tight linkage disequilibrium across the disease-associated MHC haplotypes has confounded attempts to establish whether or not these associations are causal. We have therefore developed a high throughput paralog ratio test (PRT) in association with two restriction enzyme digest variant ratio tests (REDVRs) to determine total C4 GCN, C4A GCN, and C4B GCN. In the densely genotyped CEU cohort we show that this method is accurate and reproducible when compared to gold standard Southern blot copy number estimation with a discrepancy rate of 9%. We find a broad range of C4 GCNs in the CEU and the 1958 British Birth Cohort populations under study. In addition, SNP-C4 CNV analyses show only moderate levels of correlation and therefore do not support the use of SNP genotypes as proxies for complement C4 GCN.

Mapping of multiple susceptibility variants within the MHC region for 7 immune-mediated diseases.

The human MHC represents the strongest susceptibility locus for autoimmune diseases. However, the identification of the true predisposing gene(s) has been handicapped by the strong linkage disequilibrium across the region. Furthermore, most studies to date have been limited to the examination of a subset of the HLA and non-HLA genes with a marker density and sample size insufficient for mapping all independent association signals. We genotyped a panel of 1,472 SNPs to capture the common genomic variation across the 3.44 megabase (Mb) classic MHC region in 10,576 DNA samples derived from patients with systemic lupus erythematosus, Crohn's disease, ulcerative colitis, rheumatoid arthritis, myasthenia gravis, selective IgA deficiency, multiple sclerosis, and appropriate control samples. We identified the primary association signals for each disease and performed conditional regression to identify independent secondary signals. The data demonstrate that MHC associations with autoimmune diseases result from complex, multilocus effects that span the entire region.

Familial clustering of non-nuclear autoantibodies and C3 and C4 complement components in systemic lupus erythematosus.

OBJECTIVE: To determine whether key features of systemic lupus erythematosus (SLE), namely, production of non-nuclear antibodies (anti-C1q and anticardiolipin antibodies [aCL]) and depletion of complement components C3 and C4, aggregate in families. In addition, we examined relationships between anti-C1q and C3 and C4 levels. METHODS: The study cohort comprised 1,037 predominantly white (82%) nuclear families in which at least 1 member had SLE. Associations of antibody measurements between probands and their unaffected siblings were examined using parametric and nonparametric analyses, along with associations between unaffected siblings and their parents. The heritability of anti-C1q, C3, and C4 was estimated, and interdependencies between these factors were examined in a regression model accounting for the family structure of the data set. RESULTS: We demonstrated associations between siblings for anti-C1q (odds ratio [OR] 3.74, 95% confidence interval [95% CI] 2.65, 5.28) and IgG and IgM aCL (OR 4.08, 95% CI 1.83, 5.13 and OR 2.06, 95% CI 1.46, 2.91, respectively) and, for anti-C1q, association between unaffected parents and their unaffected offspring (OR 4.34, 95% CI 2.16, 8.72). We also demonstrated significant heritability of anti-C1q, C3, and C4 (approximately 45%). Anti-C1q was negatively associated with C3 and C4 in SLE probands but not in their healthy relatives. CONCLUSION: Non-nuclear antibodies and C3 and C4 cluster within the families of SLE probands, suggesting that specific autoantibody formation is partly genetically determined, even if the total genetic effect in unaffected relatives is insufficient to cause disease. Anti-C1q antibodies accelerate C3 and C4 depletion in patients with SLE but have no effect in the absence of disease.

Defining the role of the MHC in autoimmunity: a review and pooled analysis.

The major histocompatibility complex (MHC) is one of the most extensively studied regions in the human genome because of the association of variants at this locus with autoimmune, infectious, and inflammatory diseases. However, identification of causal variants within the MHC for the majority of these diseases has remained difficult due to the great variability and extensive linkage disequilibrium (LD) that exists among alleles throughout this locus, coupled with inadequate study design whereby only a limited subset of about 20 from a total of approximately 250 genes have been studied in small cohorts of predominantly European origin. We have performed a review and pooled analysis of the past 30 years of research on the role of the MHC in six genetically complex disease traits - multiple sclerosis (MS), type 1 diabetes (T1D), systemic lupus erythematosus (SLE), ulcerative colitis (UC), Crohn's disease (CD), and rheumatoid arthritis (RA) - in order to consolidate and evaluate the current literature regarding MHC genetics in these common autoimmune and inflammatory diseases. We corroborate established MHC disease associations and identify predisposing variants that previously have not been appreciated. Furthermore, we find a number of interesting commonalities and differences across diseases that implicate both general and disease-specific pathogenetic mechanisms in autoimmunity.

Conversion of discoid lupus to antiphospholipid syndrome and SLE.

BACKGROUND: A 64-year-old man was admitted to hospital with increasing seizure frequency, lethargy and confusion. He had a history of discoid lupus erythematosus, complex partial seizures, cerebral thromboses associated with antiphospholipid syndrome (APS) and hypertension. After admission to hospital, he developed autoimmune hemolytic anemia, thrombocytopenia, severe hypertension, proteinuria and a fluctuating level of consciousness. INVESTIGATIONS: Physical examination, biochemical and hematological indices, urine dipstick, electrocardiography and chest radiography on admission, with subsequent electroencephalography, lumbar puncture, septic screen, autoimmune screen, CT of the head, MRI of the brain and renal biopsy. DIAGNOSIS: Conversion of discoid lupus erythematosus with APS to systemic lupus erythematosus with APS. MANAGEMENT: Pulsed intravenous methylprednisolone and a single infusion of intravenous cyclophosphamide, followed by oral prednisolone, were initially administered for presumed cerebral lupus. When renal biopsy revealed dual pathology, another dose of intravenous cyclophosphamide was administered with intravenous heparin therapy to treat systemic lupus erythematosus and APS, respectively. Intravenous immunoglobulin was used to treat thrombocytopenia, which was unresponsive to immunosuppression and anticoagulation. Gradual improvement occurred with maximal antihypertensive therapy and supportive treatment. The patient was discharged after 9 months of hospital treatment. His medication at this stage included warfarin, clopidogrel, prednisolone, carbamazepine, ramipril, atenolol, calcium and vitamin D supplements, and alendronate.