Mapping the 17q12-21.1 Locus for Variants Associated with Early-Onset Asthma in African Americans.

Rationale: The 17q12-21.1 locus is one of the most highly replicated genetic associations with asthma. Individuals of African descent have lower linkage disequilibrium in this region, which could facilitate identifying causal variants.Objectives: To identify functional variants at 17q12-21.1 associated with early-onset asthma among African American individuals.Methods: We evaluated African American participants from SAPPHIRE (Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-Ethnicity) (n = 1,940), SAGE II (Study of African Americans, Asthma, Genes and Environment) (n = 885), and GCPD-A (Study of the Genetic Causes of Complex Pediatric Disorders-Asthma) (n = 2,805). Associations with asthma onset at ages under 5 years were meta-analyzed across cohorts. The lead signal was reevaluated considering haplotypes informed by genetic ancestry (i.e., African vs. European). Both an expression-quantitative trait locus analysis and a phenome-wide association study were performed on the lead variant.Measurements and Main Results: The meta-analyzed results from SAPPHIRE, SAGE II, and the GCPD-A identified rs11078928 as the top association for early-onset asthma. A haplotype analysis suggested that the asthma association partitioned most closely with the rs11078928 genotype. Genetic ancestry did not appear to influence the effect of this variant. In the expression-quantitative trait locus analysis, rs11078928 was related to alternative splicing of GSDMB (gasdermin-B) transcripts. The phenome-wide association study of rs11078928 suggested that this variant was predominantly associated with asthma and asthma-associated symptoms.Conclusions: A splice-acceptor polymorphism appears to be a causal variant for asthma at the 17q12-21.1 locus. This variant appears to have the same magnitude of effect in individuals of African and European descent.

Integrative approach identifies corticosteroid response variant in diverse populations with asthma.

BACKGROUND: Although inhaled corticosteroid (ICS) medication is considered the cornerstone treatment for patients with persistent asthma, few ICS pharmacogenomic studies have involved nonwhite populations. OBJECTIVE: We sought to identify genetic predictors of ICS response in multiple population groups with asthma. METHODS: The discovery group comprised African American participants from the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-Ethnicity (SAPPHIRE) who underwent 6 weeks of monitored ICS therapy (n = 244). A genome-wide scan was performed to identify single nucleotide polymorphism (SNP) variants jointly associated (ie, the combined effect of the SNP and SNP × ICS treatment interaction) with changes in asthma control. Top associations were validated by assessing the joint association with asthma exacerbations in 3 additional groups: African Americans (n = 803 and n = 563) and Latinos (n = 1461). RNA sequencing data from 408 asthmatic patients and 405 control subjects were used to examine whether genotype was associated with gene expression. RESULTS: One variant, rs3827907, was significantly associated with ICS-mediated changes in asthma control in the discovery set (P = 7.79 × 10-8) and was jointly associated with asthma exacerbations in 3 validation cohorts (P = .023, P = .029, and P = .041). RNA sequencing analysis found the rs3827907 C-allele to be associated with lower RNASE2 expression (P = 6.10 × 10-4). RNASE2 encodes eosinophil-derived neurotoxin, and the rs3827907 C-allele appeared to particularly influence ICS treatment response in the presence of eosinophilic inflammation (ie, high pretreatment eosinophil-derived neurotoxin levels or blood eosinophil counts). CONCLUSION: We identified a variant, rs3827907, that appears to influence response to ICS treatment in multiple population groups and likely mediates its effect through eosinophils.

SOC bioavailability significantly correlated with the microbial activity mediated by size fractionation and soil morphology in agricultural ecosystems.

Despite the fact that physical and chemical processes have been widely proposed to explicate the stabilization mechanisms of soil organic carbon (SOC), thebioavailability of SOC linked to soil physical structure, microbial community structure, and functional genes remains poorly understood. This study aims to investigate the SOC division based on bioavailability differences formed by physical isolation, and to clarify the relationships of SOC bioavailability with soil elements, pore characteristics, and microbial activity. Results revealed that soil element abundances such as SOC, TN, and DOC ranked in the same order as the soil porosity as clay > silt ≥ coarse sand > fine sand in both top and sub soil. In contrast to silt and clay, which had reduced SOC bioavailability, fine sand and coarse sand had dramatically enhanced SOC bioavailability compared to the bulk soil. The bacterial and fungal community structure was significantly influenced by particle size, porosity, and soil elements. Copiotrophic bacteria and functional genes were more prevalent in fine sand than clay, which also contained more oligotrophic bacteria. The SOC bioavailability was positively correlated with abundances of functional genes, C degradation genes, and copiotrophic bacteria, but negatively correlated with abundances of soil elements, porosity, oligotrophic bacteria, and microbial biomass (p < 0.05). This indicated that the soil physical structure divided SOC into pools with varying levels of bioavailability, with sand fractions having more bioavailable organic carbon than finer fractions. Copiotrophic Proteobacteria and oligotrophic Acidobacteria, Firmicutes, and Gemmatimonadetes made up the majority of the bacteria linked to SOC mineralization. Additionally, the fungi Mortierellomycota and Mucoromycota, which are mostly involved in SOC mineralization, may have the potential for oligotrophic metabolism. Our results indicated that particle-size fractionation could influence the SOC bioavailability by restricting SOC accessibility and microbial activity, thus having a significant impact on sustaining soil organic carbon reserves in temperate agricultural ecosystems, and provided a new research direction for organic carbon stability.

Genome-Wide Association Study Identifies Pharmacogenomic Variants Associated With Metformin Glycemic Response in African American Patients With Type 2 Diabetes.

OBJECTIVE: Metformin is the most common treatment for type 2 diabetes (T2D). However, there have been no pharmacogenomic studies for T2D in which a population of color was used in the discovery analysis. This study sought to identify genomic variants associated with metformin response in African American patients with diabetes. RESEARCH DESIGN AND METHODS: Patients in the discovery set were adult, African American participants from the Diabetes Multi-omic Investigation of Drug Response (DIAMOND), a cohort study of patients with T2D from a health system serving southeast Michigan. DIAMOND participants had genome-wide genotype data and longitudinal electronic records of laboratory results and medication fills. The genome-wide discovery analysis identified polymorphisms correlated to changes in glycated hemoglobin (HbA1c) levels among individuals on metformin monotherapy. Lead associations were assessed for replication in an independent cohort of African American participants from Kaiser Permanente Northern California (KPNC) and in European American participants from DIAMOND. RESULTS: The discovery set consisted of 447 African American participants, whereas the replication sets included 353 African American KPNC participants and 466 European American DIAMOND participants. The primary analysis identified a variant, rs143276236, in the gene ARFGEF3, which met the threshold for genome-wide significance, replicated in KPNC African Americans, and was still significant in the meta-analysis (P = 1.17 × 10-9). None of the significant discovery variants replicated in European Americans DIAMOND participants. CONCLUSIONS: We identified a novel and biologically plausible genetic variant associated with a change in HbA1c levels among African American patients on metformin monotherapy. These results highlight the importance of diversity in pharmacogenomic studies.

Differences in Self-Reported Food Allergy and Food-Associated Anaphylaxis by Race and Ethnicity Among SAPPHIRE Cohort Participants.

BACKGROUND: Although food allergies are considered common, relatively little is known about disparities in food allergy by race in the United States. OBJECTIVE: To evaluate differences in reported food allergy and food-associated anaphylaxis among individuals enrolled in a longitudinal cohort study from metropolitan Detroit, Michigan. METHODS: Participants in the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-Ethnicity (SAPPHIRE) were asked about food allergies, including the inciting food and associated symptoms. Individuals were considered to have food-associated anaphylaxis if symptoms coincided with established clinical criteria. Logistic regression was used to assess whether race difference persisted after adjusting for and stratifying by potential confounders. African genetic ancestry was individually estimated among African American SAPPHIRE participants to assess whether ancestry was associated with food allergy. RESULTS: Within the SAPPHIRE cohort, African American participants were significantly more likely to report food allergy (26.1% vs 17%; P = 3.47 × 10-18) and have food-associated anaphylactic symptoms (12.7% vs 7%; P = 4.65 × 10-14) when compared with European American participants. Allergy to seafood accounted for the largest difference (13.1% vs 4.6%; P = 1.38 × 10-31). Differences in food allergy by race persisted after adjusting for potential confounders including asthma status. Among African American participants, the proportion of African ancestry was not associated with any outcome evaluated. CONCLUSION: Compared with European Americans, African Americans appear to be at higher risk for developing food allergy and food-associated anaphylaxis, particularly with regard to seafood allergy. The lack of association with genetic ancestry suggests that socioenvironmental determinants may play a role in these disparities.

Identification of Genetic Variation Influencing Metformin Response in a Multiancestry Genome-Wide Association Study in the Diabetes Prevention Program (DPP).

Genome-wide significant loci for metformin response in type 2 diabetes reported elsewhere have not been replicated in the Diabetes Prevention Program (DPP). To assess pharmacogenetic interactions in prediabetes, we conducted a genome-wide association study (GWAS) in the DPP. Cox proportional hazards models tested associations with diabetes incidence in the metformin (MET; n = 876) and placebo (PBO; n = 887) arms. Multiple linear regression assessed association with 1-year change in metformin-related quantitative traits, adjusted for baseline trait, age, sex, and 10 ancestry principal components. We tested for gene-by-treatment interaction. No significant associations emerged for diabetes incidence. We identified four genome-wide significant variants after correcting for correlated traits (P < 9 × 10-9). In the MET arm, rs144322333 near ENOSF1 (minor allele frequency [MAF]AFR = 0.07; MAFEUR = 0.002) was associated with an increase in percentage of glycated hemoglobin (per minor allele, ß = 0.39 [95% CI 0.28, 0.50]; P = 2.8 × 10-12). rs145591055 near OMSR (MAF = 0.10 in American Indians) was associated with weight loss (kilograms) (per G allele, ß = -7.55 [95% CI -9.88, -5.22]; P = 3.2 × 10-10) in the MET arm. Neither variant was significant in PBO; gene-by-treatment interaction was significant for both variants [P(G×T) < 1.0 × 10-4]. Replication in individuals with diabetes did not yield significant findings. A GWAS for metformin response in prediabetes revealed novel ethnic-specific associations that require further investigation but may have implications for tailored therapy.

Gene expression in African Americans, Puerto Ricans and Mexican Americans reveals ancestry-specific patterns of genetic architecture.

We explored ancestry-related differences in the genetic architecture of whole-blood gene expression using whole-genome and RNA sequencing data from 2,733 African Americans, Puerto Ricans and Mexican Americans. We found that heritability of gene expression significantly increased with greater proportions of African genetic ancestry and decreased with higher proportions of Indigenous American ancestry, reflecting the relationship between heterozygosity and genetic variance. Among heritable protein-coding genes, the prevalence of ancestry-specific expression quantitative trait loci (anc-eQTLs) was 30% in African ancestry and 8% for Indigenous American ancestry segments. Most anc-eQTLs (89%) were driven by population differences in allele frequency. Transcriptome-wide association analyses of multi-ancestry summary statistics for 28 traits identified 79% more gene-trait associations using transcriptome prediction models trained in our admixed population than models trained using data from the Genotype-Tissue Expression project. Our study highlights the importance of measuring gene expression across large and ancestrally diverse populations for enabling new discoveries and reducing disparities.

MRE11-RAD50-NBS1 and ATM function as co-mediators of TRF1 in telomere length control.

Human telomeres are associated with ATM and the protein complex consisting of MRE11, RAD50 and NBS1 (MRN), which are central to maintaining genomic stability. Here we show that when targeted to telomeres, wild-type RAD50 downregulates telomeric association of TRF1, a negative regulator of telomere maintenance. TRF1 binding to telomeres is upregulated in cells deficient in NBS1 or under ATM inhibition. The TRF1 association with telomeres induced by ATM inhibition is abrogated in cells lacking MRE11 or NBS1, suggesting that MRN and ATM function in the same pathway controlling TRF1 binding to telomeres. The ability of TRF1 to interact with telomeric DNA in vitro is impaired by ATM-mediated phosphorylation. We propose that MRN is required for TRF1 phosphorylation by ATM and that such phosphorylation results in the release of TRF1 from telomeres, promoting telomerase access to the ends of telomeres.

A Highly Efficient Ion and Electron Conductive Interlayer To Achieve Low Self-Discharge of Lithium-Sulfur Batteries.

The practical use of lithium-sulfur (Li-S) batteries is limited by serious self-discharge, fast capacity loss, and severe lithium anode erosion due to the shuttling of lithium polysulfides (LiPSs). Herein, we developed a highly efficient ion and electron conductive interlayer composed of Ti2(SO4)3/carbon composite layer-coated Li1.3Al0.3Ti1.7(PO4)3 (CLATP) and graphene to effectively block the diffusion of polysulfide anions but allow rapid Li ion transfer, therefore significantly inhibiting the self-discharge and boosting the cyclic stability of Li-S batteries. The Ti2(SO4)3/carbon thin protective layer endows an optimized adsorption ability toward LiPSs and avoids the side reactions between LATP and LiPSs. The high electronic conductivity of graphene and high ionic conductivity of CLATP ensures the hybrid interlayer rapid electron and fast Li ion transport. As a result, the Li-S battery with the hybrid interlayer shows a high discharge capacity of 671 mAh g-1 after 500 cycles with an extremely low capacity fading of 0.022% per cycle at 1 C. Moreover, the battery shows no self-discharge even after rest for 12 days. This work opens up a new way for the design of functional separators to significantly improve the electrochemical performance of Li-S batteries.

Overexpression of pdeR promotes biofilm formation of Paracoccus denitrificans by promoting ATP production and iron acquisition.

Bacterial biofilms are ubiquitous in natural environments and play an essential role in bacteria's environmental adaptability. Quorum sensing (QS), as the main signaling mechanism bacteria used for cell-to-cell communication, plays a key role in bacterial biofilm formation. However, little is known about the role of QS circuit in the N-transformation type strain, Paracoccus denitrificans, especially for the regulatory protein PdeR. In this study, we found the overexpression of pdeR promoted bacterial aggregation and biofilm formation. Through RNA-seq analysis, we demonstrated that PdeR is a global regulator which could regulate 656 genes expression, involved in multiple metabolic pathways. Combined with transcriptome as well as biochemical experiments, we found the overexpressed pdeR mainly promoted the intracellular degradation of amino acids and fatty acids, as well as siderophore biosynthesis and transportation, thus providing cells enough energy and iron for biofilm development. These results revealed the underlying mechanism for PdeR in biofilm formation of P. denitrificans, adding to our understanding of QS regulation in biofilm development.

Antimicrobial peptide antibiotics inhibit aerobic denitrification via affecting electron transportation and remolding carbon metabolism.

The harmful effects of antibiotics on biological denitrification have attracted widespread attention due to their excessive usage. Polymyxin B (PMB) as the typical antimicrobial peptides having been regarded as the "last hope" for treatment of multidrug-resistance bacteria, has also been detected in wastewater. However, little is known about the influence of PMB on aerobic denitrification. In this study, the impact of PMB on aerobic denitrification performance was investigated. Results showed 0.50 mg/L PMB decreased nitrate removal efficiency from 97.4% to 85.3%, and drove denitrifiers to transform more nitrate to biomass instead of producing gas-N. The live/dead staining method showed PMB damaged bacterial membrane. Transcriptome analysis further indicated the key enzymes participating in denitrification and aerobic respiratory chains were suppressed by PMB. To resist the PMB stress, denitrifiers formed thicker biofilm to protect cells from PMB damaging and thus remodeling the central carbon metabolism. Further investigation revealed denitrifiers have different preference on various carbon sources when PMB is present. Subsequently, the underlying mechanism of the distinctive carbon sources preference was explored by the combination of transcriptome and metabolism analysis. Overall, our data suggested denitrifiers have distinctive carbon sources preference under PMB treatment conditions, reminding us that carbon source selection should be cautious in practical applications.

Genome-wide association study in minority children with asthma implicates DNAH5 in bronchodilator responsiveness.

Variability in response to short-acting ß2-agonists (e.g., albuterol) among patients with asthma from diverse racial/ethnic groups may contribute to asthma disparities. We sought to identify genetic variants associated with bronchodilator response (BDR) to identify potential mechanisms of drug response and risk factors for worse asthma outcomes. Genome-wide association studies of bronchodilator response (BDR) were performed using TOPMed Whole Genome Sequencing data of the Asthma Translational Genomic Collaboration (ATGC), which corresponded to 1136 Puerto Rican, 656 Mexican and 4337 African American patients with asthma. With the population-specific GWAS results, a trans-ethnic meta-analysis was performed to identify BDR-associated variants shared across the three populations. Replication analysis was carried out in three pediatric asthma cohorts, including CAMP (Childhood Asthma Management Program; n = 560), GACRS (Genetics of Asthma in Costa Rica Study; n = 967) and HPR (Hartford-Puerto Rico; n = 417). A genome-wide significant locus (rs35661809; P = 3.61 × 10-8) in LINC02220, a non-coding RNA gene, was identified in Puerto Ricans. While this region was devoid of protein-coding genes, capture Hi-C data showed a distal interaction with the promoter of the DNAH5 gene in lung tissue. In replication analysis, the GACRS cohort yielded a nominal association (1-tailed P < 0.05). No genetic variant was associated with BDR at the genome-wide significant threshold in Mexicans and African Americans. Our findings help inform genetic underpinnings of BDR for understudied minority patients with asthma, but the limited availability of genetic data for racial/ethnic minority children with asthma remains a paramount challenge.

Predicting death from COVID-19 using pre-existing conditions: implications for vaccination triage.

INTRODUCTION: Global shortages in the supply of SARS-CoV-2 vaccines have resulted in campaigns to first inoculate individuals at highest risk for death from COVID-19. Here, we develop a predictive model of COVID-19-related death using longitudinal clinical data from patients in metropolitan Detroit. METHODS: All individuals included in the analysis had a laboratory-confirmed SARS-CoV-2 infection. Thirty-six pre-existing conditions with a false discovery rate p<0.05 were combined with other demographic variables to develop a parsimonious prediction model using least absolute shrinkage and selection operator regression. The model was then prospectively validated in a separate set of individuals with confirmed COVID-19. RESULTS: The study population consisted of 15 502 individuals with laboratory-confirmed SARS-CoV-2. The main prediction model was developed using data from 11 635 individuals with 709 reported deaths (case fatality ratio 6.1%). The final prediction model consisted of 14 variables with 11 comorbidities. This model was then prospectively assessed among the remaining 3867 individuals (185 deaths; case fatality ratio 4.8%). When compared with using an age threshold of 65 years, the 14-variable model detected 6% more of the individuals who would die from COVID-19. However, below age 45 years and its risk equivalent, there was no benefit to using the prediction model over age alone. DISCUSSION: Using a prediction model, such as the one described here, may help identify individuals who would most benefit from COVID-19 inoculation, and thereby may produce more dramatic initial drops in deaths through targeted vaccination.

Evolution of a Record-Setting AT-Rich Genome: Indel Mutation, Recombination, and Substitution Bias.

Genome-wide nucleotide composition varies widely among species. Despite extensive research, the source of genome-wide nucleotide composition diversity remains elusive. Yeast mitochondrial genomes (mitogenomes) are highly A + T rich, and they provide a unique opportunity to study the evolution of AT-biased landscape. In this study, we sequenced ten complete mitogenomes of the Saccharomycodes ludwigii yeast with 8% G + C content, the lowest genome-wide %(G + C) in all published genomes to date. The S. ludwigii mitogenomes have high densities of short tandem repeats but severely underrepresented mononucleotide repeats. Comparative population genomics of these record-setting A + T-rich genomes shows dynamic indel mutations and strong mutation bias toward A/T. Indel mutations play a greater role in genomic variation among very closely related strains than nucleotide substitutions. Indels have resulted in presence-absence polymorphism of tRNAArg (ACG) among S. ludwigii mitogenomes. Interestingly, these mitogenomes have undergone recombination, a genetic process that can increase G + C content by GC-biased gene conversion. Finally, the expected equilibrium G + C content under mutation pressure alone is higher than observed G + C content, suggesting existence of mechanisms other than AT-biased mutation operating to increase A/T. Together, our findings shed new lights on mechanisms driving extremely AT-rich genomes.

The Preoperative Risks and Two-Year Sequelae of Postoperative Urinary Retention: Analysis of the Michigan Spine Surgery Improvement Collaborative (MSSIC).

OBJECTIVE: Although postoperative urinary retention (POUR) is common after spine surgery, the association of this adverse event with other morbidities and patient-reported outcomes is not fully understood. We sought to examine the sequelae of POUR after lumbar spine surgery. METHODS: The Michigan Spine Surgery Improvement Collaborative (MSSIC) is a large prospective multicenter registry. MSSIC was queried with multivariate analysis for factors that are associated with POUR, the association of POUR with 90-day adverse events, and the effect of POUR on 2-year patient-reported outcomes and satisfaction. RESULTS: Multivariate analysis identified hardware revision (odds ratio [OR], 0.61), 1 operative level (OR, 0.74), and ambulation on postoperative day zero (OR, 0.65) to be protective for POUR. Factors associated with POUR included age (OR, 1.19), male gender (OR, 1.58), body mass index <25 (OR, 1.22), diabetes (OR, 1.28), coronary artery disease (OR, 1.20), fusion surgery (OR, 1.27), and longer surgery (OR, 1.11). Patients who had POUR were more likely to be readmitted, develop a urinary tract infection, and develop an infection (P < 0.001). POUR was associated with decreased likelihood of achieving Oswestry Disability Index minimal clinically important difference at 90 days (P < 0.001), but not at 1 year after surgery. POUR was associated with dissatisfaction with surgery at 90 days (P < 0.001), 1 year (P = 0.004), and 2 years after surgery (P = 0.011). CONCLUSIONS: POUR is common after lumbar spine surgery, and the demographic, diagnostic, and surgical factors that are associated with POUR are identified. POUR is associated with several adverse events, and patients who have POUR were less likely to be satisfied with surgery up to 2 years after surgery.

Unsaturated Single Atoms on Monolayer Transition Metal Dichalcogenides for Ultrafast Hydrogen Evolution.

Large-scale implementation of electrochemical water splitting for hydrogen evolution requires cheap and efficient catalysts to replace expensive platinum. However, catalysts that work well at high current densities with ultrafast intrinsic activities is still the central challenge for hydrogen evolution. An ideal case is to use single atoms on monolayer two-dimensional (2D) materials, which simplifies the system and in turn benefits the mechanism study, but is a grand challenge to synthesize. Here, we report a universal cold hydrogen plasma reduction method for synthesizing different single atoms sitting on 2D monolayers. In the case of molybdenum disulfide, we design and identify a type of active site, i.e., unsaturated Mo single atoms on cogenetic monolayer molybdenum disulfide. The catalyst shows exceptional intrinsic activity with a Tafel slope of 36.4 mV dec-1 in 0.5 M H2SO4 and superior performance at a high current density of 400 mA cm-2 with an overpotential of ∼260 mV, based on single flake microcell measurements. Theoretical studies indicate that coordinately unsaturated Mo single atoms sitting on molybdenum disulfide increase the bond strength between adsorbed hydrogen atoms and the substrates through hybridization, leading to fast hydrogen adsorption/desorption kinetics and superior hydrogen evolution activity. This work shines fresh light on preparing highly efficient electrocatalysts for water splitting and other electrochemical processes, as well as provides a general method to synthesize single atoms on two-dimensional monolayers.

Asthma and its relationship to mitochondrial copy number: Results from the Asthma Translational Genomics Collaborative (ATGC) of the Trans-Omics for Precision Medicine (TOPMed) program.

BACKGROUND: Mitochondria support critical cellular functions, such as energy production through oxidative phosphorylation, regulation of reactive oxygen species, apoptosis, and calcium homeostasis. OBJECTIVE: Given the heightened level of cellular activity in patients with asthma, we sought to determine whether mitochondrial DNA (mtDNA) copy number measured in peripheral blood differed between individuals with and without asthma. METHODS: Whole genome sequence data was generated as part of the Trans-Omics for Precision Medicine (TOPMed) Program on participants from the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-ethnicity (SAPPHIRE) and the Study of African Americans, Asthma, Genes, & Environment II (SAGE II). We restricted our analysis to individuals who self-identified as African American (3,651 asthma cases and 1,344 controls). Mitochondrial copy number was estimated using the sequencing read depth ratio for the mitochondrial and nuclear genomes. Respiratory complex expression was assessed using RNA-sequencing. RESULTS: Average mitochondrial copy number was significantly higher among individuals with asthma when compared with controls (SAPPHIRE: 218.60 vs. 200.47, P<0.001; SAGE II: 235.99 vs. 223.07, P<0.001). Asthma status was significantly associated with mitochondrial copy number after accounting for potential explanatory variables, such as participant age, sex, leukocyte counts, and mitochondrial haplogroup. Despite the consistent relationship between asthma status and mitochondrial copy number, the latter was not associated with time-to-exacerbation or patient-reported asthma control. Mitochondrial respiratory complex gene expression was disproportionately lower in individuals with asthma when compared with individuals without asthma and other protein-encoding genes. CONCLUSIONS: We observed a robust association between asthma and higher mitochondrial copy number. Asthma having an effect on mitochondria function was also supported by lower respiratory complex gene expression in this group.

Lung Function in African American Children with Asthma Is Associated with Novel Regulatory Variants of the KIT Ligand KITLG/SCF and Gene-By-Air-Pollution Interaction.

Baseline lung function, quantified as forced expiratory volume in the first second of exhalation (FEV1), is a standard diagnostic criterion used by clinicians to identify and classify lung diseases. Using whole-genome sequencing data from the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine project, we identified a novel genetic association with FEV1 on chromosome 12 in 867 African American children with asthma (P = 1.26 × 10-8, ß = 0.302). Conditional analysis within 1 Mb of the tag signal (rs73429450) yielded one major and two other weaker independent signals within this peak. We explored statistical and functional evidence for all variants in linkage disequilibrium with the three independent signals and yielded nine variants as the most likely candidates responsible for the association with FEV1 Hi-C data and expression QTL analysis demonstrated that these variants physically interacted with KITLG (KIT ligand, also known as SCF), and their minor alleles were associated with increased expression of the KITLG gene in nasal epithelial cells. Gene-by-air-pollution interaction analysis found that the candidate variant rs58475486 interacted with past-year ambient sulfur dioxide exposure (P = 0.003, ß = 0.32). This study identified a novel protective genetic association with FEV1, possibly mediated through KITLG, in African American children with asthma. This is the first study that has identified a genetic association between lung function and KITLG, which has established a role in orchestrating allergic inflammation in asthma.

Predictors of patient dissatisfaction at 1 and 2 years after lumbar surgery.

OBJECTIVE: As compensation transitions from a fee-for-service to pay-for-performance healthcare model, providers must prioritize patient-centered experiences. Here, the authors' primary aim was to identify predictors of patient dissatisfaction at 1 and 2 years after lumbar surgery. METHODS: The Michigan Spine Surgery Improvement Collaborative (MSSIC) was queried for all lumbar operations at the 1- and 2-year follow-ups. Predictors of patients' postoperative contentment were identified per the North American Spine Surgery (NASS) Patient Satisfaction Index, wherein satisfied patients were assigned a score of 1 ("the treatment met my expectations") or 2 ("I did not improve as much as I had hoped, but I would undergo the same treatment for the same outcome") and unsatisfied patients were assigned a score of 3 ("I did not improve as much as I had hoped, and I would not undergo the same treatment for the same outcome") or 4 ("I am the same or worse than before treatment"). Multivariable Poisson generalized estimating equation models were used to report adjusted risk ratios (RRadj). RESULTS: Among 5390 patients with a 1-year follow-up, 22% reported dissatisfaction postoperatively. Dissatisfaction was predicted by higher body mass index (RRadj =1.07, p < 0.001), African American race compared to white (RRadj = 1.51, p < 0.001), education level less than high school graduation compared to a high school diploma or equivalent (RRadj = 1.25, p = 0.008), smoking (RRadj = 1.34, p < 0.001), daily preoperative opioid use > 6 months (RRadj = 1.22, p < 0.001), depression (RRadj = 1.31, p < 0.001), symptom duration > 1 year (RRadj = 1.32, p < 0.001), previous spine surgery (RRadj = 1.32, p < 0.001), and higher baseline numeric rating scale (NRS)-back pain score (RRadj = 1.04, p = 0.002). Conversely, an education level higher than high school graduation, independent ambulation (RRadj = 0.90, p = 0.039), higher baseline NRS-leg pain score (RRadj = 0.97, p = 0.013), and fusion surgery (RRadj = 0.88, p = 0.014) decreased dissatisfaction.Among 2776 patients with a 2-year follow-up, 22% reported dissatisfaction postoperatively. Dissatisfaction was predicted by a non-white race, current smoking (RRadj = 1.26, p = 0.004), depression (RRadj = 1.34, p < 0.001), symptom duration > 1 year (RRadj = 1.47, p < 0.001), previous spine surgery (RRadj = 1.28, p < 0.001), and higher baseline NRS-back pain score (RRadj = 1.06, p = 0.003). Conversely, at least some college education (RRadj = 0.87, p = 0.035) decreased the risk of dissatisfaction. CONCLUSIONS: Both comorbid conditions and socioeconomic circumstances must be considered in counseling patients on postoperative expectations. After race, symptom duration was the strongest predictor of dissatisfaction; thus, patient-centered measures must be prioritized. These findings should serve as a tool for surgeons to identify at-risk populations that may need more attention regarding effective communication and additional preoperative counseling to address potential barriers unique to their situation.

Risk Factors Associated With 90-Day Readmissions After Degenerative Lumbar Fusion: An Examination of the Michigan Spine Surgery Improvement Collaborative (MSSIC) Registry.

BACKGROUND: Most studies have evaluated 30-d readmissions after lumbar fusion surgery. Evaluation of the 90-d period, however, allows a more comprehensive assessment of factors associated with readmission. OBJECTIVE: To assess the reasons and risk factors for 90-d readmissions after lumbar fusion surgery. METHODS: The Michigan Spine Surgery Improvement Collaborative (MSSIC) registry is a prospective, multicenter, and spine-specific database of patients surgically treated for degenerative disease. MSSIC data were retrospectively analyzed for causes of readmission, and independent risk factors impacting readmission were found by multivariate logistic regression. RESULTS: Of 10 204 patients who underwent lumbar fusion, 915 (9.0%) were readmitted within 90 d, most commonly for pain (17%), surgical site infection (16%), and radicular symptoms (10%). Risk factors associated with increased likelihood of readmission were other race (odds ratio [OR] 1.81, confidence interval [CI] 1.22-2.69), coronary artery disease (OR 1.57, CI 1.25-1.96), ≥4 fused levels (OR 1.41, CI 1.06-1.88), diabetes (OR 1.34, CI 1.10-1.63), and surgery length (OR 1.09, CI 1.03-1.16). Factors associated with decreased risk were discharge to home (OR 0.63, CI 0.51-0.78), private insurance (OR 0.79, CI 0.65-0.97), ambulation same day of surgery (OR 0.81, CI 0.67-0.97), and spondylolisthesis diagnosis (OR 0.82, CI 0.68-0.97). Of those readmitted, 385 (42.1%) patients underwent another surgery. CONCLUSION: Ninety-day readmission occurred in 9.0% of patients, mainly for pain, wound infection, and radicular symptoms. Increased focus on postoperative pain may decrease readmissions. Among factors impacting the likelihood of 90-d readmission, early postoperative ambulation may be most easily modifiable. Optimization of preexisting medical conditions could also potentially decrease readmission risk.