Genetics of Neonatal Lupus Erythematosus Risk and Specific Manifestations.

OBJECTIVE: Neonatal lupus erythematosus (NLE) is a passively acquired autoimmune disease in infants born to anti-Ro and/or anti-La autoantibody-positive mothers. Genetics may affect NLE risk. We analyzed the genetics of infants and anti-Ro antibody-positive mothers, with NLE and NLE-specific manifestations. METHODS: Infants and mothers from a tertiary care clinic underwent genotyping on the Global Screening Array. We created additive non-HLA and HLA polygenic risk scores (PRS) for systemic lupus erythematosus (SLE), from one of the largest genome-wide association studies. Outcomes were any NLE manifestations, cardiac NLE, and cutaneous NLE. We tested the association between SLE-PRS in the infant, mother, and the PRS difference between the mother and infant with NLE outcomes, in logistic regression and generalized linear mixed models (Bonferroni P < 0.02). We also performed HLA-wide analyses for the outcomes (P < 5.00 × 10-8). RESULTS: The study included 332 infants, 270 anti-Ro antibody-positive mothers, and 253 mother-infant pairs. A large proportion of mothers (40.4%) and infants (41.3%) were European, and 50% of infants were female. More than half of the infants had NLE (53%), including 7.2% with cardiac NLE and 11.7% with cutaneous NLE. We did not identify significant associations between infant PRS, maternal PRS, or maternal-infant PRS difference and any NLE outcomes. HLA-wide analyses did not identify NLE risk alleles. CONCLUSION: In a multiethnic cohort of infants and anti-Ro antibody-positive mothers, we did not identify a significant association between SLE genetics and risk of NLE outcomes.

Nutrient Recovery from Algae Using Mild Oxidative Treatment and Ion Exchange.

Valorization of algal biomass to fuels and chemicals frequently requires pretreatment to lyse cells and extract lipids, leaving behind an extracted solid residue as an underutilized intermediate. Mild oxidative treatment (MOT) is a promising route to simultaneously convert nitrogen contained in these residues to easily recyclable ammonium and to convert carbon in the same fraction to biofuel precursor carboxylates. We show that for a Nannochloropsis algae under certain oxidation conditions, nearly all the nitrogen in the residues can be converted to ammonium and recovered by cation exchange, while up to ∼20% of the carbon can be converted to short chain carboxylates. At the same time, we also show that soluble phosphorus in the form of phosphate can be selectively recovered by anion exchange, leaving a clean aqueous carbon stream for further upgrading.

Point-of-Care Ultrasound-Guided Arthrocentesis of a Pediatric Septic Ankle.

ABSTRACT: Septic arthritis is one potential cause of pediatric joint effusion and pain that may lead to significant morbidity. We present a case where point-of-care ultrasound was used to identify and aspirate a joint effusion in a pediatric patient with septic arthritis of the ankle, facilitating timely diagnosis and care. We review the technique for arthrocentesis of the ankle and literature on point-of-care ultrasound in the diagnosis of pediatric septic arthritis.

Transmission disequilibrium analysis of whole genome data in childhood-onset systemic lupus erythematosus.

Childhood-onset systemic lupus erythematosus (cSLE) patients are unique, with hallmarks of Mendelian disorders (early-onset and severe disease) and thus are an ideal population for genetic investigation of SLE. In this study, we use the transmission disequilibrium test (TDT), a family-based genetic association analysis that employs robust methodology, to analyze whole genome sequencing data. We aim to identify novel genetic associations in an ancestrally diverse, international cSLE cohort. Forty-two cSLE patients and 84 unaffected parents from 3 countries underwent whole genome sequencing. First, we performed TDT with single nucleotide variant (SNV)-based (common variants) using PLINK 1.9, and gene-based (rare variants) analyses using Efficient and Parallelizable Association Container Toolbox (EPACTS) and rare variant TDT (rvTDT), which applies multiple gene-based burden tests adapted for TDT, including the burden of rare variants test. Applying the GWAS standard threshold (5.0 × 10-8) to common variants, our SNV-based analysis did not return any genome-wide significant SNVs. The rare variant gene-based TDT analysis identified many novel genes significantly enriched in cSLE patients, including HNRNPUL2, a DNA repair protein, and DNAH11, a ciliary movement protein, among others. Our approach identifies several novel SLE susceptibility genes in an ancestrally diverse childhood-onset lupus cohort.

High-sensitivity cardiac troponin T in infants exposed to anti-Ro antibodies.

OBJECTIVES: Cardiac involvement in neonatal lupus erythematosis (NLE) can present as myocarditis/endocardial fibroelastosis (EFE). It is unknown whether high-sensitivity cardiac troponin T (hs-cTnT) is useful in identifying subclinical myocardial inflammation in infants exposed prenatally to anti-Ro antibodies. This study reports hs-cTnT levels in infants exposed to anti-Ro antibodies with/without cardiac NLE and reports cardiac MRI (CMR) findings in a subset of these children. METHODS: The study included 45 consecutive infants exposed prenatally to anti-Ro antibodies with (n = 7) or without (n = 38) cardiac NLE, who were seen at the SickKids NLE Clinic between 2012 and 2014. Hs-cTnT levels were measured at least once, and those infants with values of ≥30 ng/l were offered the opportunity to undergo CMR. Descriptive statistics were performed. RESULTS: Of 38 infants without cardiac NLE, 25 had a hs-cTnT level of ≥30 ng/l (including 1 of >113 ng/l); of these, 8 underwent CMR (all without myocarditis/EFE). All 7 infants with cardiac NLE had at least one hs-cTnT level of ≥30 ng/l, but only 2/7 had a level of >113 ng/l; 4/7 infants with cardiac NLE had CMR (all without myocarditis/EFE); 6/7 infants with cardiac NLE had their steroid treatment adjusted based on the trend in their hs-cTnT levels. CONCLUSION: Only 3/45 anti-Ro antibodies-exposed infants had hs-cTnT values outside the reference range reported in healthy infants. None of 12 infants who had CMR had subclinical myocarditis/EFE. Routine measurement of hs-cTnT in every anti-Ro antibody-exposed infant is not indicated. Further studies are needed to define the role of hs-cTnT as a biomarker for cardiac NLE.

Maternal Anti-Ro Antibody Titers Obtained With Commercially Available Immunoassays Are Strongly Associated With Immune-Mediated Fetal Heart Disease.

OBJECTIVE: Anti-Ro antibody-positive mothers are frequently referred for serial echocardiography due to the fetal risk of developing heart block and endocardial fibroelastosis. Little is known why only some and not all offspring develop these cardiac manifestations of neonatal lupus (CNL). This prospective study examined associations between anti-Ro antibody titers and fetal CNL. METHODS: Antibody-positive mothers referred since 2018 for fetal echocardiography at risk of CNL (group 1; n = 240) or with CNL (group 2; n = 18) were included. Maternal antibody titers were measured with a chemiluminescent immunoassay (CIA). Additional testing on diluted serum samples was used to quantify anti-Ro 60 antibody titers above the analytical measuring range (AMR) of the standard CIA (≥1,375 chemiluminescent units [CU]). RESULTS: Among 27 total mothers with a fetal diagnosis of CNL, all displayed anti-Ro 60 antibody titers that exceeded the AMR of the CIA at least 10-fold. Of 122 mothers in group 1 who underwent additional anti-Ro 60 antibody testing, event rates of CNL (n = 9) were 0% (0 of 45) among mothers with anti-Ro 60 antibody titers from 1,375-10,000 CU, 5% (3 of 56) among mothers with titers from 10,000-50,000 CU, but 29% (6 of 21) among mothers with titers >50,000 CU (odds ratio 13.1, P = 0.0008). Of mothers in group 2 with a primary diagnosis of CNL, 0% (0 of 18 mothers) had anti-Ro 60 antibody titers <10,000 CU, 44% (8 of 18 mothers) had titers from 10,000-50,000 CU, and 56% (10 of 18 mothers) had titers >50,000 CU. CONCLUSION: CNL is associated with substantially higher anti-Ro antibody titers than are obtained using a standard CIA. Enhancing the assay measuring range allows an improved specificity of identifying pregnancies at risk of CNL.

Genetics of longitudinal kidney function in children and adults with systemic lupus erythematosus.

OBJECTIVES: Genome-wide association studies (GWAS) have identified loci associated with estimated glomerular filtration rate (eGFR). Few LN risk loci have been identified to date. We tested the association of SLE and eGFR polygenic risk scores (PRS) with repeated eGFR measures from children and adults with SLE. METHODS: Patients from two tertiary care lupus clinics that met ≥4 ACR and/or SLICC criteria for SLE were genotyped on the Illumina MEGA or Omni1-Quad arrays. PRSs were calculated for SLE and eGFR, using published weighted GWA-significant alleles. eGFR was calculated using the CKD-EPI and Schwartz equations. We tested the effect of eGFR- and SLE-PRSs on eGFR mean and variance, adjusting for age at diagnosis, sex, ancestry, follow-up time, and clinical event flags. RESULTS: We included 1158 SLE patients (37% biopsy-confirmed LN) with 36 733 eGFR measures over a median of 7.6 years (IQR: 3.9-15.3). LN was associated with lower within-person mean eGFR [LN: 93.8 (s.d. 26.4) vs non-LN: 101.6 (s.d. 17.7) mL/min per 1.73 m2; P < 0.0001] and higher variance [LN median: 157.0 (IQR: 89.5, 268.9) vs non-LN median: 84.9 (IQR: 46.9, 138.2) (mL/min per 1.73 m2)2; P < 0.0001]. Increasing SLE-PRSs were associated with lower mean eGFR and greater variance, while increasing eGFR-PRS was associated with increased eGFR mean and variance. CONCLUSION: We observed significant associations between SLE and eGFR PRSs and repeated eGFR measurements, in a large cohort of children and adults with SLE. Longitudinal eGFR may serve as a powerful alternative outcome to LN categories for discovery of LN risk loci.

Genetics of osteonecrosis in children and adults with systemic lupus erythematosus.

OBJECTIVES: Genetics plays an important role in SLE risk, as well as osteonecrosis (ON), a significant and often debilitating complication of SLE. We aimed to identify genetic risk loci for ON in people with childhood-onset (cSLE) and adult-onset (aSLE) SLE. METHODS: We enrolled participants from two tertiary care centres who met classification criteria for SLE. Participants had prospectively collected clinical data and were genotyped on a multiethnic array. Un-genotyped single nucleotide polymorphisms (SNPs) were imputed, and ancestry was inferred using principal components (PCs). Our outcome was symptomatic ON confirmed by imaging. We completed time-to-ON and logistic regression of ON genome-wide association studies (GWASs) with covariates for sex, age of SLE diagnosis, five PCs for ancestry, corticosteroid use and selected SLE manifestations. We conducted separate analyses for cSLE and aSLE and meta-analysed results using inverse-variance weighting. Genome-wide significance was P < 5 × 10-8. RESULTS: The study included 940 participants with SLE, 87% female and 56% with cSLE. ON was present in 7.6% (n = 71). Median age of SLE diagnosis was 16.9 years (interquartile range [IQR]: 13.5, 29.3), with median follow-up of 8.0 years (IQR: 4.2, 15.7). Meta-GWAS of cSLE and aSLE time-to-ON of 4 431 911 SNPs identified a significant Chr.2 SNP, rs34118383 (minor allele frequency = 0.18), intronic to WIPF1 (hazard ratio = 3.2 [95% CI: 2.2, 4.8]; P = 1.0 × 10-8). CONCLUSION: We identified an intronic WIPF1 variant associated with a 3.2 times increased hazard for ON (95% CI: 2.2, 4.8; P = 1.0 × 10-8) during SLE follow-up, independent of corticosteroid exposure. The effect of the SNP on time-to-ON was similar in cSLE and aSLE. This novel discovery represents a potential ON risk locus. Our results warrant replication.

Regional analysis of planting date and cultivar maturity recommendations that improve soybean oil yield and meal protein concentration.

Planting date and cultivar maturity group (MG) are major management factors affecting soybean [Glycine max (L.) Merr.] yield, but their effect on seed oil and protein concentration, and in particular meal protein concentration, is less understood. We quantified changes in seed oil and protein, and estimated meal protein concentration, and total oil and protein yield in response to planting date and cultivar MG ranging from 3 to 6 and across locations comprising a 8.3° range in latitude in the U.S. Midsouth. Our results show that delayed planting date and later cultivar maturity reduced oil concentration, and this was partially associated with a decrease in temperature during the seed fill phase. Thus, optimum cultivar MG recommendations to maximize total oil yield (in kg ha-1) for planting dates in May and June required relatively earlier cultivar MGs than those recommended to maximize seed yield. For planting dates in April, short-season MG 3 cultivars did not increase oil yield compared to full-season MG 4 or 5 cultivars due to a quadratic yield response to planting date at most locations. Planting date and cultivar maturity effects on seed protein concentration were not always consistent with the effects on estimated meal protein concentration after oil extraction. Meal protein concentration decreased with lower temperatures during seed fill, and when the start of seed fill occurred after August 15, but relatively short-season cultivar MGs reduced the risk of low meal protein concentration. Meal protein concentration is a trait of interest for the feed industry that would be beneficial to report in future studies evaluating genetic, management, and environmental effects on seed protein concentration.

Screening and evaluation of biomass upgrading strategies for sustainable transportation fuel production with biomass-derived volatile fatty acids.

Biomass conversion to fuels and chemicals is crucial to decarbonization, but choosing an advantageous upgrading pathway out of many options is challenging. Rigorously evaluating all candidate pathways (process simulation, product property testing) requires a prohibitive amount of research effort; even simple upgrading schemes have hundreds of possible permutations. We present a method enabling high-throughput screening by approximating upgrading unit operations and drop-in compatibility of products (e.g., fuel properties) and apply it to volatile fatty acid (VFA) conversion to liquid transportation fuels via a MATLAB script, VFA Upgrading to Liquid Transportation fUels Refinery Estimation (VULTURE). VULTURE selects upgrading configurations that maximize fuel blend bio-derived content. We validate VULTURE's approximations through surrogate fuel property testing and process simulation. Techno-economic and life cycle analyses suggest that VFA upgrading processes down-selected by VULTURE are profitable and have low carbon intensities, demonstrating the potential for the strategy to accelerate process development timelines at decreased costs.

The deformity angular ratio: can three-dimensional computed tomography improve prediction of intraoperative neuromonitoring events?

PURPOSE: Assess whether a novel deformity angular ratio (DAR) calculated using preoperative three-dimensional computed tomography (3D CT) is more accurate than total DAR (T-DAR) radiographic measurements at predicting intraoperative neuromonitoring (IONM) events during vertebral column resection (VCR). METHODS: Consecutive, unique patients undergoing thoracic VCR by a single surgeon from 2015 to 2021 were identified. The T-DAR was calculated by dividing the total radiographic Cobb angle by the number of vertebral segments the angle subtends. 3D CT DAR was calculated for each patient from a preoperative CT scan by finding the maximum angle subtended by three contiguous vertebral segments. All patients were assessed for IONM events. A binary threshold of 25 was used for T-DAR and 3D CT DAR measurements for predictive analysis. p < 0.05 indicated significance. RESULTS: In total, 68 patients were identified. Mean age was 28 years. Mean levels fused was 15. Twenty-one patients (31%) had IONM events. In patients, with and without an IONM event, mean T-DAR was 26.6 ± 9.8 and 21.5 ± 8.8 (p = 0.04), respectively. 3D CT DAR mean values were 26.4 ± 10.8 and 18.4 ± 5.6, respectively (p < 0.001). 3D CT DAR accurately classified 81% of patients with a positive predictive value (PPV) of 75%. In comparison, T-DAR accurately classified 60% of patients with a PPV of 39%. CONCLUSION: 3D CT substantially improves preoperative IONM event prediction when compared to traditional radiographic measurements. A 3D CT DAR of 25 or greater was correlated with an increased rate of IONM events. 3D CT reconstructions are a useful adjunct for planning prior to a VCR.