Elucidating individual differences in chronic pain and whole person health with allostatic load biomarkers.

Chronic pain is a stressor that affects whole person functioning. Persistent and prolonged activation of the body's stress systems without adequate recovery can result in measurable physiological and neurobiological dysregulation recognized as allostatic load. We and others have shown chronic pain is associated with measures of allostatic load including clinical biomarker composites, telomere length, and brain structures. Less is known regarding how different measures of allostatic load align. The purpose of the study was to evaluate relationships among two measures of allostatic load: a clinical composite and pain-related brain structures, pain, function, and socioenvironmental measures. Participants were non-Hispanic black and non-Hispanic white community-dwelling adults between 45 and 85 years old with knee pain. Data were from a brain MRI, questionnaires specific to pain, physical and psychosocial function, and a blood draw. Individuals with all measures for the clinical composite were included in the analysis (n = 175). Indicating higher allostatic load, higher levels of the clinical composite were associated with thinner insula cortices with trends for thinner inferior temporal lobes and dorsolateral prefrontal cortices (DLPFC). Higher allostatic load as measured by the clinical composite was associated with greater knee osteoarthritis pathology, pain disability, and lower physical function. Lower allostatic load as indicated by thicker insula cortices was associated with higher income and education, and greater physical functioning. Thicker insula and DLPFC were associated with a lower chronic pain stage. Multiple linear regression models with pain and socioenvironmental measures as the predictors were significant for the clinical composite, insular, and inferior temporal lobes. We replicate our previously reported bilateral temporal lobe group difference pattern and show that individuals with high chronic pain stage and greater socioenvironmental risk have a higher allostatic load as measured by the clinical composite compared to those individuals with high chronic pain stage and greater socioenvironmental buffers. Although brain structure differences are shown in individuals with chronic pain, brain MRIs are not yet clinically applicable. Our findings suggest that a clinical composite measure of allostatic load may help identify individuals with chronic pain who have biological vulnerabilities which increase the risk for poor health outcomes.

Clinical vitamin D levels are associated with insular volume and inferior temporal gyrus white matter surface area in community-dwelling individuals with knee pain.

Context: Vitamin D is an essential, fat soluble micronutrient long-known for its effects on calcium homeostasis and bone health. With advances in technology, it is being discovered that Vitamin D exerts its effects beyond the musculoskeletal system. Vitamin D has since been noted in nervous system health and functioning, and is becoming a target of interest in brain health, aging, and chronic pain outcomes. Objectives: We and others have previously shown that deficient Vitamin D status is associated with greater pain severity across a variety of conditions, however the reason as to why this relationship exists is still being understood. Here, we sought to examine associations between Vitamin D status and brain structure in those with chronic knee pain. Methods: Structural MRI imaging techniques and whole brain analyses were employed and serum Vitamin D were collected on 140 participants with chronic pain. Covariates included age, sex, race and site, as these data were collected at two separate institutions. ANOVAs using the clinical cut points for Vitamin D status (deficient, insufficient, and optimal) as well as continuous regression-based Vitamin D effects were employed to observe differences in brain volume. P-value was set to 0.017 after correction for multiple comparisons. Results: We discovered that individuals in our sample (age = 50+; 63.6% female; 52.1% Non-Hispanic Black) who were either clinically deficient (<20 ng/mL) or insufficient (20-30 ng/mL) in serum Vitamin D had significant differences in the gray matter of the left circular insular cortex, left inferior temporal gyrus, right middle temporal gyrus, as well as decreased white matter surface area in the right inferior temporal gyrus compared to those considered to have optimal levels (>30 ng/mL) of serum Vitamin D. Conclusion: Evidence from these data suggests that Vitamin D, or lack thereof, may be associated with pain outcomes by mediating changes in regions of the brain known to process and interpret pain. More research understanding this phenomenon as well as the effects of Vitamin D supplementation is warranted.

Single-Cell RNA Sequencing of Urinary Cells Reveals Distinct Cellular Diversity in COVID-19-Associated AKI.

Background: AKI is a common sequela of infection with SARS-CoV-2 and contributes to the severity and mortality from COVID-19. Here, we tested the hypothesis that kidney alterations induced by COVID-19-associated AKI could be detected in cells collected from urine. Methods: We performed single-cell RNA sequencing (scRNAseq) on cells recovered from the urine of eight hospitalized patients with COVID-19 with (n=5) or without AKI (n=3) as well as four patients with non-COVID-19 AKI (n=4) to assess differences in cellular composition and gene expression during AKI. Results: Analysis of 30,076 cells revealed a diverse array of cell types, most of which were kidney, urothelial, and immune cells. Pathway analysis of tubular cells from patients with AKI showed enrichment of transcripts associated with damage-related pathways compared with those without AKI. ACE2 and TMPRSS2 expression was highest in urothelial cells among cell types recovered. Notably, in one patient, we detected SARS-CoV-2 viral RNA in urothelial cells. These same cells were enriched for transcripts associated with antiviral and anti-inflammatory pathways. Conclusions: We successfully performed scRNAseq on urinary sediment from hospitalized patients with COVID-19 to noninvasively study cellular alterations associated with AKI and established a dataset that includes both injured and uninjured kidney cells. Additionally, we provide preliminary evidence of direct infection of urinary bladder cells by SARS-CoV-2. The urinary sediment contains a wealth of information and is a useful resource for studying the pathophysiology and cellular alterations that occur in kidney diseases.

Nicotinamide Adenine Dinucleotide Biosynthetic Impairment and Urinary Metabolomic Alterations Observed in Hospitalized Adults With COVID-19-Related Acute Kidney Injury.

INTRODUCTION: Acute kidney injury (AKI) is common in COVID-19 and associated with increased morbidity and mortality. We investigated alterations in the urine metabolome to test the hypothesis that impaired nicotinamide adenine dinucleotide (NAD+) biosynthesis and other deficiencies in energy metabolism in the kidney, previously characterized in ischemic, toxic, and inflammatory etiologies of AKI, will be present in COVID-19-associated AKI. METHODS: This is a case-control study among the following 2 independent populations of adults hospitalized with COVID-19: a critically ill population in Boston, Massachusetts, and a general population in Birmingham, Alabama. The cases had AKI stages 2 or 3 by Kidney Disease Improving Global Outcomes (KDIGO) criteria; the controls had no AKI. Metabolites were measured by liquid chromatography-mass spectrometry. RESULTS: A total of 14 cases and 14 controls were included from Boston and 8 cases and 10 controls from Birmingham. Increased urinary quinolinate-to-tryptophan ratio (Q/T), found with impaired NAD+ biosynthesis, was present in the cases at each location and pooled across locations (median [interquartile range]: 1.34 [0.59-2.96] in cases, 0.31 [0.13-1.63] in controls, P = 0.0013). Altered energy metabolism and purine metabolism contributed to a distinct urinary metabolomic signature that differentiated patients with and without AKI (supervised random forest class error: 2 of 28 in Boston, 0 of 18 in Birmingham). CONCLUSION: Urinary metabolites spanning multiple biochemical pathways differentiate AKI versus non-AKI in patients hospitalized with COVID-19 and suggest a conserved impairment in NAD+ biosynthesis, which may present a novel therapeutic target to mitigate COVID-19-associated AKI.

Fine-mapping, trans-ancestral and genomic analyses identify causal variants, cells, genes and drug targets for type 1 diabetes.

We report the largest and most diverse genetic study of type 1 diabetes (T1D) to date (61,427 participants), yielding 78 genome-wide-significant (P < 5 × 10-8) regions, including 36 that are new. We define credible sets of T1D-associated variants and show that they are enriched in immune-cell accessible chromatin, particularly CD4+ effector T cells. Using chromatin-accessibility profiling of CD4+ T cells from 115 individuals, we map chromatin-accessibility quantitative trait loci and identify five regions where T1D risk variants co-localize with chromatin-accessibility quantitative trait loci. We highlight rs72928038 in BACH2 as a candidate causal T1D variant leading to decreased enhancer accessibility and BACH2 expression in T cells. Finally, we prioritize potential drug targets by integrating genetic evidence, functional genomic maps and immune protein-protein interactions, identifying 12 genes implicated in T1D that have been targeted in clinical trials for autoimmune diseases. These findings provide an expanded genomic landscape for T1D.

Elevated HIV Infection of CD4 T Cells in MRKAd5 Vaccine Recipients Due to CD8 T Cells Targeting Adapted Epitopes.

HIV frequently escapes CD8 T cell responses, leading to the accumulation of viral adaptations. We recently demonstrated that during chronic HIV infection, adapted epitopes can promote maturation of dendritic cells (DCs) through direct CD8 T cell interactions and lead to enhanced HIV trans-infection of CD4 T cells. Here, we sought to determine the role of such adaptations following HIV MRKAd5 vaccination. We observed that vaccine-induced adapted epitope-specific CD8 T cells promoted higher levels of DC maturation than nonadapted ones and that these matured DCs significantly enhanced HIV trans-infection. These matured DCs were associated with higher levels of interleukin 5 (IL-5) and IL-13 and a lower level of CXCL5, which have been shown to impact DC maturation, as well as a lower level of CXCL16. Finally, we observed that vaccine recipients with high HLA-I-associated adaptation became HIV infected more quickly. Our results offer another possible mechanism for enhanced infection among MRKAd5 vaccinees. IMPORTANCE Despite the well-established contribution of CD8 T cells in HIV control, prior CD8 T cell-based HIV vaccines have failed to demonstrate any efficacy in preventing viral infection. One such vaccine, known as the MRKAd5 vaccine, showed a potential increased risk of viral infection among vaccine recipients. However, the underlying mechanism(s) remains unclear. In this study, we observed that vaccine recipients with high adaptation to their HLA-I alleles were associated with an increased HIV infection risk in comparison to the others. Similar to what we observed in HIV infection in the prior study, adapted epitope-specific CD8 T cells obtained from vaccine recipients exhibit a greater capacity in facilitating viral infection by promoting dendritic cell maturation. Our findings provide a possible explanation for the enhanced viral acquisition risk among MRKAd5 vaccine recipients and highlight the importance of optimizing vaccine design with consideration of HLA-I-associated HIV adaptation.

A state-based approach to genomics for rare disease and population screening.

PURPOSE: The Alabama Genomic Health Initiative (AGHI) is a state-funded effort to provide genomic testing. AGHI engages two distinct cohorts across the state of Alabama. One cohort includes children and adults with undiagnosed rare disease; a second includes an unselected adult population. Here we describe findings from the first 176 rare disease and 5369 population cohort AGHI participants. METHODS: AGHI participants enroll in one of two arms of a research protocol that provides access to genomic testing results and biobank participation. Rare disease cohort participants receive genome sequencing to identify primary and secondary findings. Population cohort participants receive genotyping to identify pathogenic and likely pathogenic variants for actionable conditions. RESULTS: Within the rare disease cohort, genome sequencing identified likely pathogenic or pathogenic variation in 20% of affected individuals. Within the population cohort, 1.5% of individuals received a positive genotyping result. The rate of genotyping results corroborated by reported personal or family history varied by gene. CONCLUSIONS: AGHI demonstrates the ability to provide useful health information in two contexts: rare undiagnosed disease and population screening. This utility should motivate continued exploration of ways in which emerging genomic technologies might benefit broad populations.

Identifying rare, medically relevant variation via population-based genomic screening in Alabama: opportunities and pitfalls.

PURPOSE: To evaluate the effectiveness and specificity of population-based genomic screening in Alabama. METHODS: The Alabama Genomic Health Initiative (AGHI) has enrolled and evaluated 5369 participants for the presence of pathogenic/likely pathogenic (P/LP) variants using the Illumina Global Screening Array (GSA), with validation of all P/LP variants via Sanger sequencing in a CLIA-certified laboratory before return of results. RESULTS: Among 131 variants identified by the GSA that were evaluated by Sanger sequencing, 67 (51%) were false positives (FP). For 39 of the 67 FP variants, a benign/likely benign variant was present at or near the targeted P/LP variant. Variants detected within African American individuals were significantly enriched for FPs, likely due to a higher rate of nontargeted alternative alleles close to array-targeted P/LP variants. CONCLUSION: In AGHI, we have implemented an array-based process to screen for highly penetrant genetic variants in actionable disease genes. We demonstrate the need for clinical validation of array-identified variants in direct-to-consumer or population testing, especially for diverse populations.

Skewed allelic expression on X chromosome associated with aberrant expression of XIST on systemic lupus erythematosus lymphocytes.

A common feature of autoimmune diseases, including systemic lupus erythematosus (SLE), is an increased prevalence in women. However, the molecular basis for sex disparity in SLE remains poorly understood. To examine the role of X-linked transcription in SLE adaptive immune cells, we performed RNA-seq in T cell and B cell subsets from either healthy donors or patients with SLE. Analyses of allelic expression (AE) profiles identified a pattern of increased allelic imbalance across the entire X chromosome in SLE lymphocytes. X-linked genes exhibiting AE in SLE had an extensive overlap with genes known to escape X chromosome inactivation (XCI). XIST RNA was overexpressed in SLE patients. Differential XIST expression correlated with AE profiles more positively at X-linked genes than the genome-wide background. Analysis of three independent RNA-seq data verified the XIST-associated skewed AE on X chromosome in SLE. Integrative analyses of DNA methylation profiles showed an increased variability of DNA methylation levels at these AE-related X-linked genes. In cultured lymphoblastic cells, knockdown of XIST specifically altered allelic imbalance patterns between X chromosomes. Our study provides genetic evidence that upregulation of XIST accompanied with more skewed allelic expression on X chromosome is associated with the pathogenesis of SLE and may provide mechanistic insights into the increased incidence of SLE in females.

Relationships Between Pain, Life Stress, Sociodemographics, and Cortisol: Contributions of Pain Intensity and Financial Satisfaction.

OBJECTIVE: The relationship between psychosocial stress and chronic pain is bidirectional. An improved understanding regarding the relationships among chronic pain, life stress, and ethnicity/race will inform identification of factors contributing to health disparities in chronic pain and improve health outcomes. This study aims to assess relationships between measures of clinical pain, life stress, sociodemographics, and salivary cortisol levels. METHODS: A cross-sectional analysis involving data from 105 non-Hispanic White (NHW) and non-Hispanic Black (NHB) participants aged 45-85 years old with or at risk for knee osteoarthritis. Data included sociodemographics, clinical pain, psychosocial stress, and salivary cortisol across five time points over an approximate 12-hour period. Non-parametric correlation analysis, sociodemographic group comparisons, and regression analyses were performed. RESULTS: Clinical pain and psychosocial stress were associated with salivary cortisol levels, particularly morning waking and the evening to morning awakening slope. With the inclusion of recognized explanatory variables, the Graded Chronic Pain Scale characteristic pain intensity and financial satisfaction were identified as the primary pain and psychosocial measures associated with cortisol levels. Sociodemographic group differences were indicated such that NHB participants reported higher pain-related disability, higher levels of discrimination, lower financial and material satisfaction, and showed higher evening salivary cortisol levels compared to NHW participants. In combined pain and psychosocial stress analyses, greater financial satisfaction, lower pain intensity, and lower depression were associated with higher morning waking saliva cortisol levels while greater financial satisfaction was the only variable associated with greater evening to morning awakening slope. CONCLUSION: Our findings show relationships among clinical pain, psychosocial stress, sociodemographic factors, and salivary cortisol levels. Importantly, with inclusion of recognized explanatory variables, financial satisfaction remained the primary factor accounting for differences in morning waking cortisol and evening to morning awakening cortisol slope in an ethnic/racially diverse group of middle aged and older adults with or at risk for knee osteoarthritis.

Neuropathic-Like Pain Symptoms in a Community-Dwelling Sample with or at Risk for Knee Osteoarthritis.

OBJECTIVE: To characterize neuropathic-like pain among individuals with or at risk for knee osteoarthritis. SUBJECTS: One hundred eighty-four individuals who self-identified as non-Hispanic black or non-Hispanic white and presented with unilateral or bilateral knee pain. DESIGN: Neuropathic-like pain was assessed using the painDETECT, and those with high vs low neuropathic-like pain were compared on clinical pain, psychological symptoms, physical function, and quantitative sensory testing. Analyses were unadjusted, partially and fully adjusted for relevant covariates. RESULTS: Thirty-two (17.4%) participants reported experiencing neuropathic-like pain features above the painDETECT clinical cut-score. The neuropathic-like pain group reported significantly greater pain severity on all measures of clinical pain and higher levels of psychological symptoms when fully adjusted for covariates, but no differences emerged for disability and lower extremity function. The neuropathic-like pain group also reported greater overall heat pain ratings during the heat pain threshold and increased temporal summation of heat pain in the fully adjusted model. Additionally, those with neuropathic-like pain symptoms reported greater painful after-sensations following heat pain temporal summation in all analyses. No significant group differences in pressure pain threshold emerged at any of the testing sites. In contrast, temporal summation of mechanical pain was significantly greater at both the index knee and the ipsilateral hand for the neuropathic-like pain group in all analyses. CONCLUSIONS: Participants with or at risk for knee osteoarthritis who reported high neuropathic-like pain experienced significantly greater clinical pain and increased heat and mechanical temporal summation at the index knee and other body sites tested, suggesting central sensitization.

Race/Ethnicity Moderates the Association Between Psychosocial Resilience and Movement-Evoked Pain in Knee Osteoarthritis.

OBJECTIVE: Racial/ethnic disparities in pain are well-recognized, with non-Hispanic blacks (NHBs) experiencing greater pain severity and pain-related disability than non-Hispanic whites (NHWs). Although numerous risk factors are posited as contributors to these disparities, there is limited research addressing how resilience differentially influences pain and functioning across race/ethnicity. Therefore, this study examined associations between measures of psychosocial resilience, clinical pain, and functional performance among adults with knee osteoarthritis (OA), and assessed the moderating role of race/ethnicity on these relationships. METHODS: In a secondary analysis of the Understanding Pain and Limitations in Osteoarthritic Disease (UPLOAD-2) study, 201 individuals with knee OA (NHB = 105, NHW = 96) completed measures of resilience (ie, trait resilience, optimism, positive well-being, social support, positive affect) and clinical pain, as well as a performance-based measure assessing lower-extremity function and movement-evoked pain. RESULTS: Bivariate analyses showed that higher levels of psychosocial resilience were associated with lower clinical pain and disability and more optimal physical functioning. NHBs reported greater pain and disability, poorer lower-extremity function, and higher movement-evoked pain compared with NHWs; however, measures of psychosocial resilience were similar across race/ethnicity. In moderation analyses, higher optimism and positive well-being were protective against movement-evoked pain in NHBs, whereas higher levels of positive affect were associated with greater movement-evoked pain in NHWs. CONCLUSION: Our findings underscore the importance of psychosocial resilience on OA-related pain and function and highlight the influence of race/ethnicity on the resilience-pain relationship. Treatments aimed at targeting resilience may help mitigate racial/ethnic disparities in pain.

At the Intersection of Ethnicity/Race and Poverty: Knee Pain and Physical Function.

BACKGROUND: Knee osteoarthritis (OA) disproportionately affects racial and ethnic minorities. Non-Hispanic Blacks (NHB) report a higher prevalence and severity of knee OA symptoms than their non-Hispanic White (NHW) counterparts. The role of poverty in explaining this disparity remains unclear. OBJECTIVE: The overall aim of this cross-sectional study was to determine whether ethnic/racial differences in knee pain and physical function varied according to poverty status. DESIGN: NHB and NHW adults with or at risk of knee OA self-reported sociodemographic information, and completed the Western Ontario & McMaster Universities Osteoarthritis Index (WOMAC) and the Short Physical Performance Battery (SPPB). Annual income was adjusted for number of household occupants to determine poverty status (i.e., living above versus below poverty line). RESULTS: Findings revealed 120 individuals living above the poverty line (49% NHB, 77% NHW) and 71 individuals living below the poverty line (51% NHB, 23% NHW). Adjusted multivariable models revealed significant ethnic/race by poverty status interactions for knee pain (p = 0.036) and physical function (p = 0.032) on the WOMAC, as well as physical function on the SPPB (p = 0.042). Post hoc contrasts generally revealed that NHW adults living above the poverty line experienced the least severe knee pain and best physical function, while NHB adults living below the poverty line experienced the most severe knee pain and poorest physical function. CONCLUSIONS: Results of the present study add to the literature by emphasizing the importance of considering poverty and/or other indicators of socioeconomic status in studies examining ethnic/racial disparities in pain and physical function.

IFNγ induces epigenetic programming of human T-bethi B cells and promotes TLR7/8 and IL-21 induced differentiation.

Although B cells expressing the IFNγR or the IFNγ-inducible transcription factor T-bet promote autoimmunity in Systemic Lupus Erythematosus (SLE)-prone mouse models, the role for IFNγ signaling in human antibody responses is unknown. We show that elevated levels of IFNγ in SLE patients correlate with expansion of the T-bet expressing IgDnegCD27negCD11c+CXCR5neg (DN2) pre-antibody secreting cell (pre-ASC) subset. We demonstrate that naïve B cells form T-bethi pre-ASCs following stimulation with either Th1 cells or with IFNγ, IL-2, anti-Ig and TLR7/8 ligand and that IL-21 dependent ASC formation is significantly enhanced by IFNγ or IFNγ-producing T cells. IFNγ promotes ASC development by synergizing with IL-2 and TLR7/8 ligands to induce genome-wide epigenetic reprogramming of B cells, which results in increased chromatin accessibility surrounding IRF4 and BLIMP1 binding motifs and epigenetic remodeling of IL21R and PRDM1 loci. Finally, we show that IFNγ signals poise B cells to differentiate by increasing their responsiveness to IL-21.

Type 1 Diabetes Risk in African-Ancestry Participants and Utility of an Ancestry-Specific Genetic Risk Score.

OBJECTIVE: Genetic risk scores (GRS) have been developed that differentiate individuals with type 1 diabetes from those with other forms of diabetes and are starting to be used for population screening; however, most studies were conducted in European-ancestry populations. This study identifies novel genetic variants associated with type 1 diabetes risk in African-ancestry participants and develops an African-specific GRS. RESEARCH DESIGN AND METHODS: We generated single nucleotide polymorphism (SNP) data with the ImmunoChip on 1,021 African-ancestry participants with type 1 diabetes and 2,928 control participants. HLA class I and class II alleles were imputed using SNP2HLA. Logistic regression models were used to identify genome-wide significant (P < 5.0 × 10-8) SNPs associated with type 1 diabetes in the African-ancestry samples and validate SNPs associated with risk in known European-ancestry loci (P < 2.79 × 10-5). RESULTS: African-specific (HLA-DQA1*03:01-HLA-DQB1*02:01) and known European-ancestry HLA haplotypes (HLA-DRB1*03:01-HLA-DQA1*05:01-HLA-DQB1*02:01, HLA-DRB1*04:01-HLA-DQA1*03:01-HLA-DQB1*03:02) were significantly associated with type 1 diabetes risk. Among European-ancestry defined non-HLA risk loci, six risk loci were significantly associated with type 1 diabetes in subjects of African ancestry. An African-specific GRS provided strong prediction of type 1 diabetes risk (area under the curve 0.871), performing significantly better than a European-based GRS and two polygenic risk scores in independent discovery and validation cohorts. CONCLUSIONS: Genetic risk of type 1 diabetes includes ancestry-specific, disease-associated variants. The GRS developed here provides improved prediction of type 1 diabetes in African-ancestry subjects and a means to identify groups of individuals who would benefit from immune monitoring for early detection of islet autoimmunity.

Genetic influences on susceptibility to rheumatoid arthritis in African-Americans.

Large meta-analyses of rheumatoid arthritis (RA) susceptibility in European (EUR) and East Asian (EAS) populations have identified >100 RA risk loci, but genome-wide studies of RA in African-Americans (AAs) are absent. To address this disparity, we performed an analysis of 916 AA RA patients and 1392 controls and aggregated our data with genotyping data from >100 000 EUR and Asian RA patients and controls. We identified two novel risk loci that appear to be specific to AAs: GPC5 and RBFOX1 (PAA < 5 × 10-9). Most RA risk loci are shared across different ethnicities, but among discordant loci, we observed strong enrichment of variants having large effect sizes. We found strong evidence of effect concordance for only 3 of the 21 largest effect index variants in EURs. We used the trans-ethnic fine-mapping algorithm PAINTOR3 to prioritize risk variants in >90 RA risk loci. Addition of AA data to those of EUR and EAS descent enabled identification of seven novel high-confidence candidate pathogenic variants (defined by posterior probability > 0.8). In summary, our trans-ethnic analyses are the first to include AAs, identified several new RA risk loci and point to candidate pathogenic variants that may underlie this common autoimmune disease. These findings may lead to better ways to diagnose or stratify treatment approaches in RA.

Optimism and Psychological Resilience are Beneficially Associated With Measures of Clinical and Experimental Pain in Adults With or at Risk for Knee Osteoarthritis.

OBJECTIVES: This cross-sectional study examined the associations among optimism, psychological resilience, endogenous pain inhibition, and clinical knee pain severity. Two hypotheses were tested. First, we hypothesized that experimentally tested endogenous pain inhibition would mediate the relationship between optimism and clinical knee pain severity. Second, it was also hypothesized that optimism would moderate the relationships of psychological resilience with endogenous pain inhibition and clinical knee pain severity, particularly for individuals with high optimism. METHODS: A total of 150 individuals with or at risk for symptomatic knee osteoarthritis completed the Life Orientation Test-Revised, the Brief Resilience Scale, and the revised Short-Form McGill Pain Questionnaire-2 to assess optimism, psychological resilience, and clinical knee pain severity, respectively. Endogenous pain inhibition was examined experimentally using a conditioned pain modulation (CPM) protocol with algometry (test stimulus) and a cold pressor task (conditioning stimulus). RESULTS: As hypothesized, results showed that increased CPM significantly mediated the association between higher optimism and lower clinical knee pain severity. Further, optimism moderated the association between psychological resilience and CPM. However, contrary to our hypothesis, greater psychological resilience was associated with enhanced CPM in individuals with low optimism only. DISCUSSION: This study suggests that an optimistic outlook may beneficially impact clinical pain severity by altering endogenous pain modulatory capacity. Furthermore, individuals with low optimism (ie, pessimists) may be more adept at engaging resources that promote psychological resilience, which in turn, enhances endogenous pain modulatory capacity. Therefore, this study supports consideration of psychological resilience factors when evaluating experimental and clinical pain outcomes.

Role of Macrophage Migration Inhibitory Factor in Granulomatosis With Polyangiitis.

OBJECTIVE: To examine the association between macrophage migration inhibitory factor (MIF) promoter polymorphisms and granulomatosis with polyangiitis (GPA) in human subjects, and to assess the role of MIF in a murine model of granulomatous vasculitis. METHODS: The human study involved 1,077 patients with GPA and healthy controls whose serum was genotyped by capillary electrophoresis for the MIF -794 CATT5-8 promoter microsatellite (rs5844572). MIF promoter, CATT-length-dependent gene expression in response to ß-glucan was assessed by gene reporter assays. In mouse studies, granulomatous disease was induced by injection of Candida albicans ß-glucan into wild-type (WT) or Mif-knockout (Mif-KO) C57BL/6 mice and C57BL/6 mice transgenically overexpressing Mif in lung epithelium (Mif lung-Tg2.1). Mice were treated with a neutralizing anti-MIF antibody and analyzed for the density of pulmonary granulomas, expression of inflammatory chemokines, and frequency of mortality. RESULTS: The percentage of human subjects carrying >5 CATT repeats in each MIF allele (high genotypic MIF expressers) was 60.2% among patients with GPA and 53.9% among healthy controls (adjusted P = 0.049). In response to granulomatous stimulation, human MIF gene expression increased proportionally with CATT length. Mif lung-Tg2.1 mice exhibited more pulmonary granulomas than WT mice, which in turn showed more granulomas than Mif-KO mice. A significantly higher percentage of Mif lung-Tg2.1 mice, compared to Mif-KO or WT mice, died when injected with Candida albicans ß-glucan, and treatment of these mice with an anti-MIF monoclonal antibody protected against a lethal outcome. Levels of MIF-dependent neutrophil/macrophage chemokines were elevated in the bronchoalveolar lavage fluid or plasma of Mif lung-Tg2.1 mice. CONCLUSION: Patients with GPA have an increased frequency of high MIF expression CATT alleles. Higher Mif expression increases the incidence of mortality and pulmonary granulomas in Mif lung-Tg2.1 mice, while anti-MIF treatment protects these mice against death. Blockade of MIF in high genotypic MIF expressers may therefore offer a selective pharmacologic therapy for GPA.

Genome-wide association studies suggest that APOL1-environment interactions more likely trigger kidney disease in African Americans with nondiabetic nephropathy than strong APOL1-second gene interactions.

African Americans carrying two apolipoprotein L1 gene (APOL1) renal risk variants have a high risk for nephropathy. However, only a minority develops end-stage renal disease (ESRD). Hence, modifying factors likely contribute to initiation of kidney disease such as endogenous (HIV infection) or exogenous (interferon treatment) environmental modifiers. In this report, genome-wide association studies and a meta-analysis were performed to identify novel loci for nondiabetic ESRD in African Americans and to detect genetic modifiers in APOL1-associated nephropathy. Two African American cohorts were analyzed, 1749 nondiabetic ESRD cases and 1136 controls from Wake Forest and 901 lupus nephritis (LN)-ESRD cases and 520 controls with systemic lupus erythematosus but lacking nephropathy from the LN-ESRD Consortium. Association analyses adjusting for APOL1 G1/G2 renal-risk variants were completed and stratified by APOL1 risk genotype status. Individual genome-wide association studies and meta-analysis results of all 2650 ESRD cases and 1656 controls did not detect significant genome-wide associations with ESRD beyond APOL1. Similarly, no single nucleotide polymorphism showed significant genome-wide evidence of an interaction with APOL1 risk variants. Thus, although variants with small individual effects cannot be ruled out and are likely to exist, our results suggest that APOL1-environment interactions may be of greater clinical importance in triggering nephropathy in African Americans than APOL1 interactions with other single nucleotide polymorphisms.