Journal of Internal Medicine

BackgroundCOVID-19 patients may experience long-lasting complications, particularly impairment of lung function. The persistence of inflammation may lead to tissue remodeling, but the impact on the lungs in these patients remains unclear. Research QuestionIs there evidence of neutrophil-mediated inflammation, tissue remodeling, and altered lung perfusion in individuals with long COVID-19 experiencing dyspnea and reduced diffusion capacity? Additionally, can the PET imaging findings be correlated with proteomic data reflecting inflammatory status and clinical information? Study Design and MethodsPatient experiencing persistent dyspnea and reduced diffusion capacity for carbon monoxide 20 to 30 months after severe COVID-19 illness were recruited and underwent sequential PET scans using [15O]water, [68Ga]Ga-FAPI-46, and [11C]NES. Clinical lung function and 6-minute walking tests were performed before the scans. Blood samples were collected for plasma analysis using proximity extension analysis, which enabled the measurement of 96 inflammation-related biomarkers. ResultsSix male patients were recruited (age 64 {+/-} 7 [median {+/-} range] years). Patients with known impaired lung function prior to COVID-19 illness were excluded. [15O]water did not show a clear reduction in areas with signs of inflammation or tissue remodeling. However, all patients showed uptake of [68Ga]Ga-FAPI-46 and [11C]NES in the lungs, especially in areas associated with inflammation and remodeling. Patients were categorized into two groups based on tracer uptake: a low-uptake group and a high-uptake group. While the plasma inflammatory profiles differed between long-COVID-19 patients and healthy individuals, there was no clear correlation between the lung uptake of [68Ga]Ga-FAPI-46 and [11C]NES in long-COVID-19 patients. Similar observations were made regarding clinical parameters. InterpretationSequential PET scans using [15O]water, [68Ga]Ga-FAPI-46, and [11C]NES, allowed observation of signs of neutrophil-mediated inflammation and tissue remodeling in patients with long-COVID-19. However, no association with lung perfusion was demonstrated. Additionally, the results from the PET scans could not be clearly associated with clinical parameters or inflammatory proteomics.

Background and PurposeTripartite motif-containing protein 72 (TRIM72) mediates tissue-repair following injury in several organs, including muscle and lung. Autoantibodies directed against TRIM72 (anti-TRIM72) have been identified in patients with idiopathic inflammatory myopathies (IIM) and disrupt TRIM72 function in vitro. We hypothesized that IIM patients positive for anti-TRIM72 antibodies would have a more severe clinical phenotype. MethodsSera from IIM patient (antisynthetase syndrome [ASyS], immune mediated necrotizing myopathy [IMNM], and dermatomyositis [DM]) and healthy controls (HC) were included. Anti-TRIM72 autoantibodies were tested using enzyme linked immunosorbent assay. Anti-TRIM72 testing was positive if value was >2 standard deviations above the mean for HC. Clinicodemographic features were identified through chart review and compared between anti-TRIM72 positive (anti-TRIM72[+]) and negative (anti-TRIM72[-]) groups. ResultsAnti-TRIM72 levels were significantly increased in patients with ASyS and IMNM when compared to patients with DM and healthy controls. Anti-TRIM72 levels were also increased in patients expressing anti-Jo-1, anti-PL7, anti-HMGCR, anti-SRP, and anti-MDA5. In ASyS, when anti-TRIM72(+) and anti-TRIM72(-) patients were compared, there were significantly more anti-TRIM72(+) ASyS patients with normal DLCO (>75%) when compared to anti-TRIM72(-); however, there were no differences in demographic features, CK levels or FVC. In anti-HMGCR(+) IMNM, anti-TRIM72(+) was associated with a lower proportion of females, as well as older age at time of diagnosis and at time of anti-TRIM72 testing; however, there was no significant difference in other clinicodemographic features in anti-HMGCR(+) IMNM patients when anti-TRIM72(+) and anti-TRIM72(-) groups were compared. ConclusionsAnti-TRIM72 antibody titres are increased in patients with ASyS and IMNM. The presence of anti-TRIM72 antibodies was not associated with a more severe phenotype in ASyS or anti-HMGCR(+) IMNM, and there were more ASyS patients with normal DLCO in the anti-TRIM72(+) group.

ObjectivesPatients with anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) are at increased long-term risk of cardiometabolic diseases. The prevalence of obesity in AAV has not been well documented. We aimed to characterise change in body weight following a diagnosis of active AAV and to determine the risk factors for this. MethodsWe examined data from a single-centre registry of patients with AAV, diagnosed between 2003 and 2023. We evaluated changes in body weight and BMI following diagnosis. Using linear regression, we identified factors contributing to an increase in BMI at six-months. Logistic regression was used to define predictors for obesity at six-months. ResultsTwo-hundred and fifteen patients with active AAV were included in the analysis. Patients experienced a mean gain in body weight of 5.2% in the first six-months; this was maintained for at least two-years. 64.1% of patients were overweight or obese at six-months. Weight gain was greater following first presentation of AAV compared to relapsing disease. Baseline factors associated with an increase in BMI at six-months included higher eGFR ({beta}=0.70 [0.36-1.03], P<0.001) and earlier year of presentation ({beta}=0.38 [0.08-0.69], P=0.008). Higher eGFR (aOR=1.36 (1.08-2.72), P<0.001) and baseline BMI (aOR=2.57 (1.81-3.64), P<0.001) were associated with an increased likelihood of obesity at six-months. ConclusionWeight gain is common following a diagnosis of active AAV. This is less pronounced than it was two-decades ago. Better kidney function and higher baseline BMI are associated with a greater risk of being obese at six-months. Management of AAV should include risk mitigation for developing an unhealthy high BMI. Key messagesO_LIWeight gain and an unhealthy high BMI are prevalent following diagnosis of active AAV. C_LIO_LIHigher baseline eGFR is associated with greater weight-gain in the first six-months following diagnosis. C_LIO_LIWeight gain is less pronounced following treatment of relapsing disease compared to initial presentation. C_LI

IMPORTANCEPericarditis is the most common cardiac manifestation of Systemic Lupus Erythematosus (SLE) and known to recur among patients. Yet, the prevalence and risk factors of recurrent pericarditis in SLE patients are unknown. OBJECTIVEDetermine the frequency and risk factors for the recurrence of pericarditis in patients with SLE. DESIGNRetrospective analysis of a well-characterized, prospective cohort of SLE patients enrolled between 1988 and 2023. SETTINGA single-center cohort study of a diverse group of SLE patients treated at a tertiary medical center. PARTICIPANTSPatients diagnosed with pericarditis (n=590) among those enrolled in the Hopkins Lupus Cohort (n=2931). MAIN OUTCOMERe-occurrence of pericarditis. The SELENA revision of the SLE Disease Activity Index (SLEDAI) was used to define pericarditis. Clinical information was examined for all follow-up encounters after the first episode of pericarditis. Pericarditis that occurred at least six weeks after the first recorded episode was defined as "Recurrent". RESULTSOf 2931 patients within the cohort, 590 had a history of pericarditis. In 3.4% of patients, the diagnosis of pericarditis was confirmed via electrocardiogram (EKG) or dedicated imaging, with 100% concordance between clinical and data-based diagnoses. During a median follow-up of 7 years (IQR: 3 - 14), 20% (n=120) of patients experienced recurrent pericarditis (recurrence rate {approx} 0.05 per person-year of follow-up). Most patients (51%) experienced only one recurrence, whereas 49% had [&ge;]2 recurrences. In multivariate analysis, predictors of recurrence included younger age ([&ge;]60 years vs. <40, RR 0.11 (0.04, 0.32), P <.001), treatment with prednisone ([&ge;]20 mg vs. 0, RR 1.99 (1.17, 3.40), P = 0.012), active SLE disease (SLEDAI [&ge;]3 vs. 0, RR 1.55 (1.21, 2.00), P <.001), and time since initial episode (3-10 years vs. <1, RR 0.32 (0.20, 0.52), P <.001). CONCLUSION AND RELEVANCERecurrence is more likely to occur within one year of the onset of pericarditis, and younger patients and those with uncontrolled disease are at greater risk of recurrence. As in the general population, oral prednisone therapy is associated with a higher chance of recurrence in SLE patients, with a dose-dependent effect. These findings set the basis for future studies to define optimal treatment for recurrent pericarditis in SLE patients and suggest that oral corticosteroids should be avoided when treating pericarditis.

ImportanceCongenital heart disease (CHD), especially the complex forms - such as hypoplastic left heart syndrome (HLHS) and transposition of the great arteries (TGA) - have been linked to neurodevelopmental deficits including impairments in gross cognitive functions, language abilities, and visuo-motor skills. The prognostic value of early infant brain trajectories and cumulative impact of demographic factors in relation to childhood neurodevelopmental outcomes is unknown. ObjectiveTo determine whether early structural brain trajectories predict early childhood neurodevelopmental deficits in complex CHD patients and to assess relative cumulative risk profiles of clinical, genetic, and demographic risk factors across early development. Design, Setting, and ParticipantsWe studied a prospective cohort study of term neonates with complex CHD (TGA and HLHS) were recruited at Texas Childrens Hospital between 2005-2011. Participants underwent structural MRI scans at three time points (one preoperative scan, one postoperative scan within 7 days of surgery, and one follow-up postoperative scan at 4 months). Participants also received three neurodevelopmental assessments at 1, 3, and 5 years of age. Main Outcomes and MeasuresBrain region volumes (macrostructure) and white matter tract (microstructure) fractional anisotropy (FA) and radial diffusivity (RD) were measured from the MRI scans acquired in the three neonatal time points. Three imaging trajectories - changes in volume, FA and RD, over time - corresponding to periods of brain changes were determined: perioperative (preoperative to postoperative #1), post-surgical (postoperative #1 to postoperative #2), and overall (preoperative #1 to postoperative #2). Gross cognitive, language, and visuo-motor outcomes were assessed with the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) at 1 and 3 years, and with the Wechsler Preschool and Primary Scale of Intelligence, Third Edition (WPPSI-III Full-Scale IQ and Verbal IQ, and Beery-Buktenica Developmental Test of Visual-Motor Integration (VMI)., 6th Edition at 5 years. The analysis included development of predictive multi-variable models incorporating other known risk factors (i.e., heart lesion type, microdeletion-related genetic abnormality, and maternal IQ) of poor neurodevelopmental outcomes in CHD. ResultsA total of 95 term (38.5{+/-}1.3 weeks gestational age) neonates with complex CHD (49 [51.6%] HLHS, 46 [48.4%] TGA; 42 [44.2%] girls) were analyzed. Reduced overall period trajectories predicted poor language outcomes: brainstem (p=0.0022) and white matter (p=0.0397) predicted poor 5-year verbal IQ; brainstem (p=0.0134), deep grey (p=0.0258), and FA of superior longitudinal fasciculus (SLF) (p=0.0256) predicted poor 3-year language; whole brain volume predicted poor performance on measures of language at 1 year. Maternal IQ was the strongest contributor to language outcome variance that increased from 37% at 1-year, up to 62% at 3-year, and up to 81% at 5-year testing. Genetic abnormality contribution to variance in these same models decreased from 41% in 1-year to about 25% at 3-year, and then to not significant in the 5-year assessments. Heart lesion type was found to be not significant in predicting outcomes in these models. Conclusion and RelevanceA dysmaturation pattern of reduced postnatal trajectories of subcortical-cerebral white matter MRI metrics predicted poor early childhood neurodevelopmental outcomes, despite the high relative contribution of maternal IQ. Maternal IQ was cumulative over time, exceeding the influence of known innate cardiac and genetic factors in complex CHD, underscoring the importance of both heritable factors and parent-based environmental factors. Key PointsO_ST_ABSQuestionC_ST_ABSDo early infant brain trajectories in congenital heart disease (CHD) patients predict early childhood neurodevelopmental (ND) outcomes adjusted for known genetic abnormalities and maternal intelligence (IQ)? FindingsAmong infants with, reduced brainstem and white matter volumetric trajectories in children with CHD predicted language outcomes at five years, adjusting for maternal IQ and known genetic abnormalities. At the same time, known genetic abnormalities exerted a maximum effect at 1-year relative to 5-year neurodevelopmental testing. Maternal IQ was the most substantial contributor to ND outcome variance, nearly doubling from 1-year relative to 5-year time points. MeaningPostnatal infant brain trajectories may aid in the prognostication of early childhood neurodevelopment outcomes in complex CHD. The influence of maternal IQ is cumulative and can exceed the influence of known innate cardiac and genetic factors in complex CHD, underscoring the importance of not only heritable factors but also parent-based environmental factors.

What is already known on this topic O_LIAconitate Decarboxylase 1 (ACOD1) is an enzyme involved in the synthesis of itaconate, a metabolite generated during the Krebs cycle. C_LIO_LIItaconate has been identified as an immunomodulatory molecule C_LIO_LIACOD1/Itaconate has been studied in the context of various inflammatory and autoimmune diseases, including sepsis, inflammatory bowel disease and rheumatoid arthritis. In these conditions, dysregulation of itaconate metabolism has been associated with altered immune responses and disease progression. C_LI What this study adds 1. Upon stimulation with lupus-relevant stimuli, ACOD1 expression is induced in myeloid cells. 2. IN an induced mouse model of lupus, ACOD1 knockout (Acod1-/-) mice exhibit exacerbated lupus-like symptoms, implicating dysregulation of this pathway in the induction and severity of autoimmunity features. 3. Itaconate serum levels are decreased in SLE patients, compared to healthy individuals. This decrease is associated with specific perturbed cardiometabolic parameters and subclinical atherosclerosis, indicating that modulating dysregulation of the itaconate pathway could have therapeutic benefits in this disease. How this study might affect research, practice or policy O_LIGiven its immunomodulatory effects, ACOD1/itaconate and its derivatives may have potential therapeutic benefit for the treatment of autoimmune diseases. They may also serve as putative biomarkers of cardiovascular risk in this disease. C_LI ObjectiveThe Krebs cycle enzyme Aconitate Decarboxylase 1 (ACOD1) mediates itaconate synthesis in myeloid cells.. Previously, we reported that administration of 4-octyl itaconate abrogated lupus phenotype in mice. Here, we explore the role of the endogenous ACOD1/itaconate pathway in the development of murine lupus as well as their relevance in premature cardiovascular damage in SLE. MethodsWe characterized Acod1 protein expression in bone marrow-derived macrophages and human monocyte-derived macrophages, following a TLR7 agonist (imiquimod, IMQ). Wild type and Acod1-/- mice were exposed to topical IMQ for 5 weeks to induce an SLE phenotype and immune dysregulation was quantified. Itaconate serum levels were quantified in SLE patients and associated to cardiometabolic parameters and disease activity. ResultsACOD1 was induced in mouse bone marrow-derived macrophages (BMDM) and human monocyte-derived macrophages following in vitro TLR7 stimulation. This induction was partially dependent on type I Interferon receptor signaling and specific intracellular pathways. In the IMQ-induced mouse model of lupus, ACOD1 knockout (Acod1-/-) displayed disruptions of the splenic architecture, increased serum anti-dsDNA and proinflammatory cytokine levels, enhanced kidney immune complex deposition and proteinuria, when compared to the IMQ-treated WT mice. Consistent with these results, Acod1-/- BMDM exposed to IMQ showed higher proinflammatory features in vitro. Itaconate levels were decreased in SLE serum compared to healthy control sera, in association with specific perturbed cardiometabolic parameters and subclinical vascular disease. ConclusionThese findings suggest that the ACOD1/itaconate pathway plays important immunomodulatory and vasculoprotective roles in SLE, supporting the potential therapeutic role of itaconate analogs in autoimmune diseases.

IntroductionMicrovascular abnormalities and impaired gas transfer have been observed in patients with COVID-19. The progression of pathophysiological pulmonary changes during the post-acute period in these patients remains unclear. MethodsPatients who were hospitalised due to COVID-19 pneumonia underwent a pulmonary 1H and 129Xe MRI protocol at 6, 12, 25 and 51 weeks after hospital admission. The imaging protocol included: ultra-short echo time, dynamic contrast enhanced lung perfusion, 129Xe lung ventilation, 129Xe diffusion weighted and 129Xe 3D spectroscopic imaging of gas exchange. Results9 patients were recruited and underwent MRI at 6 (n=9), 12 (n=9), 25 (n=6) and 51 (n=8) weeks after hospital admission. Patients with signs of interstitial lung damage at 3 months were excluded from this study. At 6 weeks after hospital admission, patients demonstrated impaired 129Xe gas transfer (RBC:M) but normal lung microstructure (ADC, LmD). Minor ventilation abnormalities present in four patients were largely resolved in the 6-25 week period. At 12 week follow up, all patients with lung perfusion data available (n=6) showed an increase in both pulmonary blood volume and flow when compared to 6 weeks, though this was not statistically significant. At 12 week follow up, significant improvements in 129Xe gas transfer were observed compared to 6-week examinations, however 129Xe gas transfer remained abnormally low at weeks 12, 25 and 51. Changes in 129Xe gas transfer correlated significantly with changes in pulmonary blood volume and TLCO Z-score. ConclusionsThis study demonstrates that multinuclear MRI is sensitive to functional pulmonary changes in the follow up of patients who were hospitalised with COVID-19. Impairment of xenon transfer may indicate damage to the pulmonary microcirculation.

IntroductionPregnant women with systemic lupus erythematosus (SLE) have an increased risk of maternal complications and adverse fetal outcomes. These include preeclampsia, preterm birth and fetal growth restriction. Interestingly, this increased risk persists in subsequent pregnancies, whereas it decreases in healthy women due to the development of maternal-fetal tolerance. As maternal-fetal tolerance is crucial for a healthy pregnancy, we hypothesize that its failure contributes to the increased risk of pregnancy complications in women with SLE. Therefore, we initiated the FaMaLE study to investigate the failure of maternal-fetal tolerance in pregnant women with SLE. Methods and analysisIn the FaMaLE study, women with SLE and healthy women are included in their first trimester of pregnancy (< 14 weeks gestational age (GA)) at Amsterdam UMC. Throughout the pregnancy, data on SLE disease activity, pregnancy course, and medication use are collected. Peripheral blood is collected once per trimester, within 48 hours before delivery and 5-12 weeks post-partum. In addition, the placenta is collected after delivery. Whole blood, peripheral blood mononuclear cells (PBMC) and placenta samples are freshly analyzed by flow cytometry to assess immune cell composition. The resulting data are analyzed in relation to SLE disease course, pregnancy course and pregnancy outcomes. Ethics and disseminationThe study has been approved by the Amsterdam UMC Medical Ethics Committee and all participating women will be asked to provide informed consent. The findings will be disseminated through peer-reviewed publications, presentations at scientific meetings and via patient organizations. STRENGTHS AND WEAKNESSES- A unique prospective longitudinal study design, featuring the collection of serum, plasma and PBMC throughout and after pregnancy, alongside placental cells and biopsies from the same participants. This is complemented by detailed clinical data on SLE disease course and pregnancy course, and outcomes. - Fresh flow cytometry analyses allow immediate assessment of cell composition in blood and placenta, without freeze/thawing effects - The study does not include pre-pregnancy collection of serum, plasma and PBMC; however detailed clinical data are collected during this period.

BackgroundTwo risk variants in the apolipoprotein L1 gene (APOL1) have been associated with increased susceptibility to sepsis in Black patients. However, it remains unclear whether APOL1 high-risk genotypes are associated with occurrence of either sepsis or sepsis-related phenotypes in patients hospitalized with infections, independent of their association with pre-existing severe renal disease. MethodsA retrospective cohort study of 2,242 Black patients hospitalized with infections. We assessed whether carriage of APOL1 high-risk genotypes was associated with the risk of sepsis and sepsis-related phenotypes in patients hospitalized with infections. The primary outcome was sepsis; secondary outcomes were short-term mortality and organ failure related to sepsis. ResultsOf 2,242 Black patients hospitalized with infections, 565 developed sepsis. Patients with high-risk APOL1 genotypes had a significantly increased risk of sepsis (odds ratio [OR]=1.29 [95% CI, 1.00-1.67; p=0.047]); however, this association was not significant after adjustment for pre-existing severe renal disease (OR=1.14 [95% CI, 0.88-1.48; p=0.33]), nor after exclusion of those patients with pre-existing severe renal disease (OR=0.99 [95% CI, 0.70-1.39; p=0.95]. APOL1 high-risk genotypes were significantly associated with the renal dysfunction component of the Sepsis-3 criteria (OR=1.64 [95% CI, 1.21-2.22; p=0.001], but not with other sepsis-related organ dysfunction or short-term mortality. The association between high-risk APOL1 genotypes and sepsis-related renal dysfunction was markedly attenuated by adjusting for pre-existing severe renal disease (OR=1.36 [95% CI, 1.00-1.86; p=0.05]) and was nullified after exclusion of patients with pre-existing severe renal disease (OR=1.16 [95% CI, 0.74-1.81; p=0.52]). ConclusionAPOL1 high-risk genotypes were associated with an increased risk of sepsis; however, this increased risk was attributable predominantly to pre-existing severe renal disease. FundingThis study was supported by R01GM120523 (Q.F.), R01HL163854 (Q.F.), R35GM131770 (C.M.S.), HL133786 (W.Q.W.), and Vanderbilt Faculty Research Scholar Fund (Q.F.). The dataset(s) used for the analyses described were obtained from Vanderbilt University Medical Centers BioVU which is supported by institutional funding, the 1S10RR025141-01 instrumentation award, and by the CTSA grant UL1TR0004from NCATS/NIH. Additional funding provided by the NIH through grants P50GM115305 and U19HL065962. The authors wish to acknowledge the expert technical support of the VANTAGE and VANGARD core facilities, supported in part by the Vanderbilt-Ingram Cancer Center (P30 CA068485) and Vanderbilt Vision Center (P30 EY08126). The funders had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

ObjectiveTracheobronchial stenosis (TBS) occurs in 13-27% of patients with granulomatosis with polyangiitis (GPA) and may cause life-threatening airway compromise. Despite advances in treatment, TBS remains difficult to manage, with frequent relapses and high procedural burden. The objective of this study was to evaluate the relationship between immunosuppressant use and frequency of relapse in patients with TBS-GPA. MethodsWe performed retrospective review of patients with TBS-GPA seen at Johns Hopkins Medical Institutions between 2013-2024. Baseline demographic and clinical characteristics, immunosuppressant exposure, and tracheal dilation procedure dates were abstracted. A multivariate mixed effects Poisson regression model was used to assess the association between immunosuppressant exposures (rituximab, cyclophosphamide, methotrexate, azathioprine, leflunomide, and mycophenolate) and tracheal dilation incidence, adjusting for age, years since TBS diagnosis, anti-neutrophil cytoplasmic antibody (ANCA) status, GPA disease severity, and concomitant treatment with glucocorticoid injections. ResultsA total of 56 patients with TBS-GPA were included in the analysis, with a mean follow-up duration of 9.9 years. In the adjusted mixed-effects Poisson model, patient-years on leflunomide were associated with a 64% lower incidence of tracheal dilations compared to periods off leflunomide (IRR 0.36, p = 0.002). No statistically significant associations were observed for the other immunosuppressants measured. Among other tested covariates, age under 40, severe GPA, and concomitant glucocorticoid injections were associated with higher dilation frequency. ConclusionLeflunomide use was associated with a lower frequency of tracheal dilations in patients with TBS-GPA. These findings support the need for further evaluation of leflunomide as a treatment option in this population.

ObjectivesCritically ill patients with COVID-19 may suffer from a cytokine release syndrome (CRS) characterized by remarkably high levels of interleukin 6 (IL-6). We assessed the effects of tocilizumab, an IL-6 receptor antagonist, on intra-hospital mortality and development of positive cultures in patients with COVID-19 admitted to the ICU. DesignPatients with COVID 19 admitted in the ICU who were treated with tocilizumab plus standard care were enrolled and compared to controls. SettingCOVID-19 severe disease PatientsPatients with severe COVID-19 disease admitted in the ICU. InterventionsTocilizumab 400 mg IV two doses. Standard and intensive medical care as per institutional clinical protocol. Measures and Main ResultsMain outcome: 1) intra-hospital mortality; Secondary Outcomes: 1) the need for renal replacement therapy, 2) use of antibiotics and positive culture, and 3) inflammatory and oxygenation markers. There was no difference in mortality, need for renal replacement therapy, use of antibiotics or positive cultures between the two groups. The use of corticosteroids was more frequent in the treatment group. Levels of C-reactive protein (CRP) and WBC (white blood cells) counts declined significantly faster in the treatment group. Oxygenation markers rose significantly higher in patients in the tocilizumab group as compared to controls. ConclusionTocilizumab was associated with rapid improvement in oxygenation and a faster decrease of CRP and WBC counts in patients with COVID-19 and should be evaluated as rescue therapy for patients with progressive disease

ObjectivesTo appraise the causal effect of systemic lupus erythematosus (SLE) for risk of Coronary heart disease (CHD). MethodsWe selected single nucleotide polymorphisms (SNPs) associated with SLE as instrumental variables (IVs) from three independent genome-wide association studies (GWAS), the three largest to date for SLE of European ancestry. Then we conducted two-sample Mendelian randomization (2SMR) analyses to estimate the effects of IVs on the odds of CHD and traditional coronary risk factors (including high LDL cholesterol levels, low HDL cholesterol levels, Apolipoprotein A-I, Apolipoprotein B, diabetes mellitus, and hypertension). Additionally, we searched for common risk loci between SLE and premature coronary atherosclerosis. Furthermore, we retrospectively reviewed the lipid profile of treatment-naive SLE patients and age-matched healthy controls. ResultsGenetically predicted SLE did not increase the odds of CHD. Nevertheless, we found mild causal relationships between SLE and decreased HDL cholesterol levels, and between SLE and decreased apolipoprotein A-I. There was one common risk locus (rs597808) between SLE and premature coronary atherosclerosis at a genome-wide significance level (P<5 x 10-8). Retrospective analysis showed decreased HDL-cholesterol (0.98{+/-}0.516mmol/L vs. 1.46{+/-}0.307mmol/L in female, 0.76{+/-}0.199mmol/L vs. 1.19{+/-}0.257mmol/L in male; both P<0.001) and apolipoprotein A-I (1.06{+/-}0.314g/L vs. 1.37{+/-}0.205g/L in female, 0.87{+/-}0.174g/L vs. 1.24{+/-}0.200g/L in male; both P<0.001) in naive SLE patients. ConclusionSLE may accelerate coronary atherosclerosis in young patients by reducing HDL cholesterol and apolipoprotein A-I intrinsically, but it seems not to play a predominant role in CHD development in old patients.

ImportanceStudies have suggested intra-pulmonary shunts may contribute to hypoxemia in COVID-19 ARDS and may be associated with worse outcomes. ObjectiveTo evaluate the presence of right-to-left (R-L) shunts in COVID-19 and non-COVID ARDS patients using a comprehensive hypoxemia work-up for shunt etiology and associations with mortality. Design, Setting, ParticipantsWe conducted a multi-centre (4 Canadian hospitals), prospective, observational cohort study of adult critically ill, mechanically ventilated, ICU patients admitted for ARDS from both COVID-19 or non-COVID (November 16, 2020-September 1, 2021). InterventionContrast-enhanced agitated-saline bubble studies with transthoracic echocardiography/transcranial Doppler (TTE/TCD) {+/-} transesophageal echocardiography (TEE) assessed for the presence of R-L shunts. Main Outcomes and MeasuresPrimary outcomes were shunt incidence and association with hospital mortality. Logistic regression analysis was used to determine association of shunt presence/absence with covariables. ResultsThe study enrolled 226 patients (182 COVID-19 vs. 42 non-COVID). Median age was 58 years (interquartile range [IQR]: 47-67) and APACHE II scores of 30 (IQR: 21-36). In COVID-19 patients, the incidence of R-L shunt was 31/182 patients (17.0%; intra-pulmonary: 61.3%; intra-cardiac: 38.7%) versus 10/44 (22.7%) non-COVID patients. No evidence of difference was detected between the COVID-19 and non-COVID-19 shunt rates (risk difference [RD]: -5.7%, 95% CI: -18.4-7.0, p=0.38). In the COVID-19 group, hospital mortality was higher for those with R-L shunt compared to those without (54.8% vs 35.8%, RD: 19.0%, 95% CI 0.1-37.9, p=0.05). But this did not persist at 90-day mortality, nor after regression adjustments for age and illness severity. ConclusionsThere was no evidence of increased R-L shunt rates in COVID-19 compared to non-COVID controls. Right-to-left shunt was associated with increased in-hospital mortality for COVID-19 patients, but this did not persist at 90-day mortality or after adjusting using logistic regression. Key Points QuestionDoes right-to-left shunt incidence increase with COVID-19 ARDS compared to non-COVID, and is there association with shunt incidence and mortality? FindingsIn this prospective, observational cohort study, we showed no statistically significant difference in shunt prevalence between COVID-19 ARDS patients (17.0%) and non-COVID patients (22.7%). However, in COVID-19 patients, there was a difference in hospital mortality for those with shunt (54.8%) compared to those without shunt (35.8%), but this difference did not persist at 90-day mortality, nor after regression adjustments for age and illness severity. MeaningThere was no evidence of increased R-L shunt rates in COVID-19 compared to non-COVID or historical controls. Right-to-left shunt presence was associated with increased hospital mortality for COVID-19 patients, but this did not persist for 90-day mortality or after adjustment using logistic regression.

ObjectivesAnti-type I interferon (IFN) autoantibodies have been reported in patients with systemic lupus erythematosus (SLE). Recently, an association of these autoantibodies with severe COVID-19 was reported in the general population. We assessed whether having pre-existing anti-IFN autoantibodies was associated with COVID-19 infection in SLE patients. MethodsPatients with SLE who developed COVID-19 between April 1st to October 1st, 2020 were studied. Biobanked pre-COVID-19 plasma from these SLE subjects and healthy controls were tested for anti-IFN IgG autoantibodies by ELISA. The ability of plasma anti-IFN autoantibodies to block signal transducer and activator of transcription 1 (STAT1) phosphorylation by recombinant human IFN in vitro was assessed by flow cytometry. ResultsTen SLE subjects with COVID-19 were identified. A 40% of these subjects had stable autoantibodies against IFN for up to three years preceding COVID-19 diagnosis. A 50% of the subjects with these autoantibodies neutralized IFN induced STAT1 phosphorylation.None of the other SLE samples blocked IFN signaling. ConclusionsWe noted an increased prevalence of pre-existing anti-IFN autoantibodies in SLE patients with COVID-19 compared to the reported prevalence in lupus patients and the general population with severe COVID-19. Autoantibodies against IFN in SLE patients may be pathogenic and patients with them maybe at-risk of developing COVID-19. Key MessagesO_ST_ABSWhat is already known about this subject?C_ST_ABS- Anti-type I interferon (IFN) autoantibodies have been reported in patients with systemic lupus erythematosus (SLE) and have recently been associated with severe COVID-19 in the general population. What does this study add?- SLE subjects with COVID-19 had an increased prevalence of pre-existing anti-IFN autoantibodies compared to the reported prevalence in lupus patients and the general population with severe COVID-19. - Plasma from 50% of subjects with these autoantibodies were able to block in vitro activity of IFN. - SLE patients with pre-existing anti-IFN autoantibodies had more severe COVID-19 manifestations. How might this impact on clinical practice or future developments?- Anti-IFN autoantibodies may be pathogenic and could prove to be a helpful prognostic marker to predict which SLE patient may develop COVID-19 and inform preventive measures and management of this subset of patients.

BackgroundMost patients with systemic sclerosis (SSc) experience gastrointestinal (GI) dysmotility. The enteric nervous system (ENS) regulates GI motility, and its dysfunction causes dysmotility. A subset of SSc patients harbor autoantibodies against the M2 mitochondrial antigen (AM2A). Here, we investigate whether M2 is expressed by specific ENS cells, and if AM2A associate with GI dysmotility in SSc patients. MethodsSera from 154 well-characterized patients with SSc were screened for AM2A by ELISA. Clinical features and GI transit data were compared between AM2A-positive and negative patients. HepG2 cells were cultured with these sera and co-stained with AM2A. ResultsNineteen of 147 patients (12.9%) were AM2A positive. AM2A positivity was significantly associated with slower transit in the esophagus ({beta} -14.4, 95%CI -26.2, -2.6) and stomach ({beta} -7.9, 95% CI -14.1, -1.6). Immunostaining demonstrated pan-mitochondrial antigens TOM-20 and M2 enrichment in human ENS neurons, specifically in mesoderm- derived enteric neurons (MENS). HepG2 cells cultured with SSc sera showed that SSc autoantibodies penetrate live cells and that AM2A and other SSc autoantibodies are localized to subcellular compartments containing target antigens. ConclusionAM2A in SSc patients associate with slower GI transit. MENs are enriched in mitochondria, suggesting enhanced susceptibility to mitochondrial dysfunction and associated GI dysmotility in SSc. Our finding that SSc autoantibodies penetrate live cells in vitro suggests that SSc-AM2A may penetrate MENs in vivo, driving ENS and GI dysfunction. Further studies are warranted to understand whether AM2As contribute to mitochondrial dysfunction, and whether mitochondrial dysfunction contributes to GI dysmotility in SSc. Key messagesO_LIWhat is already known on this topic O_LIsubset of SSc patients have autoantibodies against the M2 mitochondrial antigen (AM2A). Whether AM2A antibodies inform the presence or severity of GI dysfunction in SSc is unknown. C_LI C_LI O_LIWhat this study adds: O_LIAM2A antibodies in SSc patients associate with slower upper GI transit. C_LIO_LIMitochondria are enriched in a recently identified mesoderm-derived lineage of enteric neurons (MENs), which play a major role in GI motility. This suggests that MENS may be more mitochondrial-dependent than other cell types, and thus more susceptible to mitochondrial dysfunction. This may contribute to dysmotility in AM2A-positive SSc patients. C_LIO_LISSc autoantibodies penetrate live cells in vitro and bind to their target antigens intracellularly. C_LI C_LI O_LIHow this study might affect research, practice or policy O_LIAM2A antibodies in SSc patients may penetrate MENs in vivo, driving ENS dysfunction and subsequent GI dysmotility C_LIO_LIThis potentially novel mechanism in SSc GI disease could inform our current approach to diagnosing and managing these patients. C_LI C_LI

BackgroundAcute respiratory distress syndrome (ARDS) is associated with high mortality in Intensive Care Units (ICU). A previous genome-wide association study (GWAS) identified the vascular endothelial growth factor receptor 1 (VEGFR1) gene in ARDS risk. We performed a GWAS on soluble VEGFR1 (sVEGFR1) levels to identify protein quantitative trait loci (pQTLs) and genes of interest for ARDS. MethodsSerum samples (n=292) within the first 24 (T1), 72 hours (T2), and 7 days (T7) after sepsis diagnosis were collected while in the ICU. sVEGFR1 levels were measured and tested for association. We combined fine mapping, colocalisation and gene-set mapping analyses to prioritise genes and test low-frequency variation association with ARDS (n=822). We analysed the association of sVEGFR1 pQTLs with mortality and ARDS susceptibility using polygenic scores (PGS). Finally, the causality of VEGFR1 in ARDS was assessed using two-sample Mendelian randomisation (MR) analyses. ResultsWe found a pQTL for T2 sVEGFR1 levels at TCF20 (rs134871, p=4.66x10-8). Fine mapping prioritised rs762995 as a likely pathogenic variant and CYP2D6 as the most likely functional gene. The locus colocalised with eQTLs for TCF20 and CYP2D6. Low-frequency missense variation in TCF20 was associated with sepsis-associated ARDS susceptibility (p=3.0x10-3). sVEGFR1 levels PGS were associated with decreased ARDS susceptibility and mortality. MR analyses did not evidence causality. ConclusionsWe identified biologically relevant pQTLs of VEGFR1 levels during sepsis in TCF20 and identified CYP2D6 as the gene more biologically implicated. Low frequency missense variation in TCF20 and sVEGFR1 levels PGS models were associated with sepsis outcomes. What is already known on this topicAcute respiratory distress syndrome (ARDS) is an acute condition, characterised by respiratory failure, an acute inflammatory response and the development of non-cardiogenic oedema. There is a need for target pharmacological strategies and advances in the risk stratification methods that can improve patient management. What this study addsWe performed the first GWAS of sVEGFR1 levels in patients with sepsis. The integration of different complementary genomic approaches has allowed us to reveal a regulatory variant of sVEGFR1 during sepsis, suggesting a role in ARDS susceptibility and mortality. In exome-wide low-frequency variation analyses, we identified TCF20 as a novel gene of interest for ARDS. How this study might affect research, practice or policyThis study emphasises the value of proteogenomic approaches in improving our understanding of ARDS pathogenesis and detecting novel risk genes to advance patient risk stratification.

BackgroundHigh resolution computed tomography (HRCT) of the chest is increasingly used in clinical practice for sarcoidosis. Visual assessment of chest HRCTs in patients with sarcoidosis has high inter- and intra-rater variation. Radiomics offers a reproducible quantitative assessment of HRCT lung parenchyma and could be useful as an additional summary measure of disease. We develop radiomic profiles on HRCT and map them to radiologic, clinical, and patient reported outcomes. Research QuestionCan radiomic analysis of chest HRCT cluster patients into groups that are related to radiologic, clinical, and patient reported outcomes? Study Design and MethodsThree-dimensional radiomic features were calculated on chest HRCT for both lungs from sarcoidosis cases enrolled in the Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) study (N=320). Robust and sparse K-means was used to cluster sarcoidosis cases using their radiomic profiles. Differences in patterns on visual assessment (VAS) by cluster were identified using chi-squared tests. Linear regression investigated how pulmonary function tests and patient reported outcomes differed between clusters with and without adjustment for other radiologic quantification. ResultsRadiomic-based clustering identified four clusters associated with both Scadding stage and Oberstein score (P<0.001). One of the clusters had markedly few abnormalities. Another cluster had consistently more abnormalities along with more Scadding stage IV. Average pulmonary function testing (PFT) differed between clusters, even after accounting for Scadding stage and Oberstein score (P <0.001), with one cluster having more obstructive disease. The most discriminative radiomic measures explained 10-15% of the variation in PFT beyond demographic variables. Shortness of breath, fatigue, and physical health differed by cluster (P <0.014). InterpretationRadiomic quantification of sarcoidosis identifies new subtypes representative of existing radiologic assessment and more predictive of pulmonary function. These findings provide evidence that radiomics may be useful for identifying new imaging-based disease phenotypes.

ObjectivTo assess the associations between gout, brain structure, and neurodegenerative disease incidence. MethodsUsing observational and Mendelian randomization analyses we investigated causal relationships between gout and brain health. Exposures included gout diagnosis (from self-report, linked health records and death records) and genetically proxied gout and serum urate. Outcomes were neuroimaging markers of brain structure and neurodegenerative disease incidence (ascertained through self-report, health records and death reports). Cox proportional hazards models were used to examine time to neurodegenerative disease diagnosis. Results11,735 UK Biobank participants (mean age 55.5{+/-}8.0 years and 50.5% female) had a diagnosis of gout (n=1165 in MRI subset). Dementia was ascertained in 3126 individuals over a mean follow-up time of 12.4{+/-}1.9 years. Gout patients had smaller global and regional brain volumes and higher brain iron markers. Genetic associations mirrored observational associations. Genetically proxied gout associated with lower global grey matter volume (beta= -0.05[-0.08 to -0.01]). Participants with gout had higher incidence of all-cause dementia (hazard ratio (HR)=1.60, 95% confidence interval (CI) [1.38-1.85]), Parkinsons disease (HR=1.43[1.15 to 1.79]), and probable essential tremor (HR=6.75[5.69 to 8.00]). Risks were strongly time dependent, whereby associations with incident dementia were highest in the first 3 years after gout diagnosis (HR=7.40[4.95 to 11.07]). ConclusionsThese findings suggest gout is causally related to several measures of brain structure. Lower brain reserve amongst gout patients may explain their higher vulnerability to multiple neurodegenerative diseases. Key pointsO_ST_ABSWhat is already known on this topic?C_ST_ABSO_LIStudies of neurodegenerative disease risk in gout are contradictory. C_LIO_LIRelationships with neuroimaging markers of brain structure, which may offer insights, are uncertain. C_LI What this study adds?O_LIIn this prospective cohort study gout was associated with smaller brain volumes and higher incidence of multiple neurodegenerative diseases. C_LIO_LIMendelian randomization analyses suggested gout is causally related to brain structure. C_LI How might this study affect research, practice or policy?O_LIOur findings emphasise the importance for clinicians of assessing for motor and cognitive impairments amongst gout patients, particularly in early years after diagnosis. C_LI

Background and PurposeCommon sequelae for patients with congenital heart disease (CHD) are neurodevelopmental disabilities including executive function, attention, and socio-emotional deficits. Although these are common diagnoses for patients with CHD, limited research has investigated the mechanistic underpinnings of these findings. Our previous research examined the association between abnormal respiratory ciliary motion and brain abnormalities in infants with CHD. Results suggested that abnormal ciliary motion correlated to a spectrum of subtle dysplasia, notably within the olfactory bulb (OB)1. Our current study investigates whether OB anomalies predict neurodevelopmental outcomes for pediatric patients with CHD. We hypothesize that adolescents with CHD who exhibit aberrant morphological measurements in the OB are more likely to suffer from executive functional deficits. Materials and MethodsA prospective, observational study of 54 CHD and 75 healthy subjects, ages 6-25 years old, was completed under the supervision of a senior pediatric neuroradiologist. T2 3D Space and T2 Blade 2MM MRI images were manually segmented to extract volumetric bilateral regions of the OB and cerebrospinal fluid (CSF) using ITK-SNAP. Imaging metrics were correlated to OB asymmetry, CSF to OB ratio, total CSF volume, total OB volume, and independent left and right CSF and OB volumes. Linear regression was used to evaluate MRI morphologic measurements with co-variates: CHD status, sex, MRI age, and segmenter. Executive function was determined by the Behavioral Rating Inventory of Executive Function (BRIEF) Parent Report and Delis-Kaplan Executive Function System (D-KEFS) for subjects ages 6-16. Cognition and olfactory function were measured with the NIH Toolbox Cognitive Battery and Odor Identification Test, respectively. ResultsNo statistically significant results were reported between cohorts for asymmetry of OB, CSF to OB ratio, total CSF volume, total OB volume, nor between independent left and right CSF and OB volumes. Increased OB volume was associated with worse outcomes on the BRIEF Parent Report (p[&le;]0.03). Asymmetry of OB predicted poorer executive functioning as reported by parents on the BRIEF (p[&le;]0.05). Overall, the CHD cohort demonstrated worse scores on the BRIEF Parent Report compared to controls. Across groups, no significant association was reported for olfaction function measured by the NIH Toolbox Odor Identification Test on a limited subset of participants. ConclusionAs survival rates for CHD improve, there is an increased risk of long-term neurodevelopmental impairments. Our findings identify adolescents who are at risk for executive dysfunction, particularly those showing increased OB volume and/or asymmetry of the OB. This is particularly concerning for the CHD population with atypical OB morphology, who also exhibit significantly poorer outcomes on the BRIEF Parent Report and face a higher overall risk. Increased OB volume and OB asymmetry are olfactory-based biomarkers that may help identify at-risk CHD patients earlier, enabling more timely intervention and support.

BackgroundPatients with AL amyloidosis present sustained paradoxical vasodilation in response to sympathetic stimulation by cold pressor test (CPT). The clinical relevance of this finding is unknown. We investigated the clinical role of CPT induced vascular and hemodynamic responses. MethodsWe prospectively recruited 113 treatment-naive AL amyloidosis patients. High resolution ultrasonography was used to measure the peak percent change of the brachial artery during CPT and 3 minutes after its withdrawal (postCPT), defined as sustained response. Peripheral and aortic (central) systolic (SBP) and diastolic blood pressure (DBP) were measured at the same timepoints before and 12 months after treatment initiation. All-cause and cardiovascular mortality were recorded (median follow-up 26 months). The same tests were performed in ten healthy volunteers. ResultsSustained vasodilation and reductions in central systolic (%CSBP_post) and peripheral diastolic BP were observed in AL as compared to controls (p<0.01 for all) and were associated with all-cause and cardiovascular death after adjustment for disease-related risk factors (p<0.05 for all). %CSBP_post provided incremental value over Mayo stage. Mechanistic analyses revealed associations of %CSBP_post with markers of neurological and cardiac dysfunction and of myocardial infiltration. Longitudinally, at 12 months, %CSBP_post further decreased in patients with earlier poor hematologic response to disease-specific treatment. ConclusionsUsing a noninvasive readily available method in treatment-naive AL amyloidosis patients, sustained reduction of central SBP after sympathetic stimulation was associated with cardiac dysfunction, poor survival and response to treatment.