Patient-specific genomics and cross-species functional analysis implicate LRP2 in hypoplastic left heart syndrome.

Congenital heart diseases (CHDs), including hypoplastic left heart syndrome (HLHS), are genetically complex and poorly understood. Here, a multidisciplinary platform was established to functionally evaluate novel CHD gene candidates, based on whole-genome and iPSC RNA sequencing of a HLHS family-trio. Filtering for rare variants and altered expression in proband iPSCs prioritized 10 candidates.

Does Shorter Time to Treatment of Pediatric Femur Shaft Fractures Impact Clinical Outcomes?

Background: Annual rankings by US News and World Report are a widely utilized metric by both health care leaders and patients. One longstanding measure is time to treatment of femur shaft fractures. Hospitals able to provide at least 80% of pediatric patients with an operating room start time within 18 hours of admission to the emergency department score better as part of the overall pediatric orthopaedic ranking.

Identification of Susceptibility Loci for Spontaneous Coronary Artery Dissection.

Importance: Spontaneous coronary artery dissection (SCAD), an idiopathic disorder that predominantly affects young to middle-aged women, has emerged as an important cause of acute coronary syndrome, myocardial infarction, and sudden cardiac death.

Objective: To identify common single-nucleotide variants (SNVs) associated with SCAD susceptibility.

Design, Setting, And Participants: This single-center genome-wide association study examined approximately 5 million genotyped and imputed SNVs and subsequent SNV-targeted replication analysis results in individuals enrolled in the Mayo Clinic SCAD registry from August 30, 2011, to August 2, 2018.

Rare Missense Variants in TLN1 Are Associated With Familial and Sporadic Spontaneous Coronary Artery Dissection.

Background: Spontaneous coronary artery dissection (SCAD) is an uncommon idiopathic disorder predominantly affecting young, otherwise healthy women. Rare familial cases reveal a genetic predisposition to disease. The aim of this study was to identify a novel susceptibility gene for SCAD.

Association of the PHACTR1/EDN1 Genetic Locus With Spontaneous Coronary Artery Dissection.

Background: Spontaneous coronary artery dissection (SCAD) is an increasingly recognized cause of acute coronary syndromes (ACS) afflicting predominantly younger to middle-aged women. Observational studies have reported a high prevalence of extracoronary vascular anomalies, especially fibromuscular dysplasia (FMD) and a low prevalence of coincidental cases of atherosclerosis. PHACTR1/EDN1 is a genetic risk locus for several vascular diseases, including FMD and coronary artery disease, with the putative causal noncoding variant at the rs9349379 locus acting as a potential enhancer for the endothelin-1 (EDN1) gene.

Long-Term Mortality Trends After Revision Total Knee Arthroplasty.

Background: Long-term mortality following primary total knee arthroplasty (TKA) is lower than the general population. However, it is unknown whether this is true in the setting of revision TKA. We examined long-term mortality trends following revision TKA.

Prognostic and therapeutic significance of phosphorylated STAT3 and protein tyrosine phosphatase-6 in peripheral-T cell lymphoma.

Peripheral T cell lymphomas (PTCL) is a heterogenous group of non-Hodgkin lymphoma and many patients remain refractory to the frontline therapy. Identifying new prognostic markers and treatment is an unmet need in PTCL. We analyzed phospho-STAT3 (pSTAT3) expression in a cohort of 169 PTCL tumors and show overall 38% positivity with varied distribution among PTCL subtypes with 27% (16/59) in PTCL-NOS; 29% (11/38) in AITL, 57% (13/28) in ALK-negative ALCL, and 93% in ALK-pos ALCL (14/15), respectively.

Risk of MGUS in relatives of multiple myeloma cases by clinical and tumor characteristics.

We and others have shown increased risk of monoclonal gammopathy of undetermined significance (MGUS) in first-degree relatives of patients with multiple myeloma (MM). Whether familial risk of MGUS differs by the MM proband's age at onset, tumor or clinical characteristics is unknown. MM and smoldering MM (SMM) cases (N = 430) were recruited from the Mayo Clinic in Rochester, Minnesota between 2005-2015.

Improving Results of Surgery for Ebstein Anomaly: Where Are We After 235 Cone Repairs?

Background: Ebstein anomaly has heterogeneous anatomy and numerous operative techniques are described. Cone repair provides a near anatomic tricuspid valve repair. The purpose of this study was to examine our experience with cone repair.

Associations between elevated pre-treatment serum cytokines and peripheral blood cellular markers of immunosuppression in patients with lymphoma.

Higher ratios of the pre-treatment peripheral blood absolute lymphocyte (ALC) to absolute monocyte counts (AMC) are associated with improved outcomes in lymphoma. Conversely, elevated pre-treatment serum cytokines are associated with inferior outcomes. The relationship between pre-treatment serum cytokines and ALC/AMC ratios remains unknown.

Trigeminal neuralgia and neuropathy in large sporadic vestibular schwannomas.

OBJECTIVE The aim of this study was to evaluate the incidence, presentation, and treatment outcomes of trigeminal nerve-mediated symptoms secondary to large vestibular schwannomas (VSs) with trigeminal nerve contact. Specifically, the symptomatic results of pain, paresthesias, and numbness after microsurgical resection or stereotactic radiosurgery (SRS) were examined. METHODS The authors conducted a retrospective review of a database for concomitant diagnosis of trigeminal neuralgia (TN) or trigeminal neuropathy and VS between 1994 and 2014 at a tertiary academic center.

Do pessimists report worse outcomes after total hip arthroplasty?

Background: Seligman's theory of causal attribution predicts that patients with a pessimistic explanatory style will have less favorable health outcomes. We investigated this hypothesis using self-reported hip pain and hip function 2- years after total hip arthroplasty (THA).

Methods: Most THA patients had completed the Minnesota Multiphasic Personality Inventory (MMPI) during their usual clinical care long before THA (median, 14.

Compound heterozygous NOTCH1 mutations underlie impaired cardiogenesis in a patient with hypoplastic left heart syndrome.

Hypoplastic left heart syndrome (HLHS) is a severe congenital heart defect (CHD) that necessitates staged, single ventricle surgical palliation. An increased frequency of bicuspid aortic valve (BAV) has been observed among relatives. We postulated number of mutant alleles as a molecular basis for variable CHD expression in an extended family comprised of an HLHS proband and four family members who underwent echocardiography and whole-genome sequencing (WGS).

The oncogenic transcription factor IRF4 is regulated by a novel CD30/NF-κB positive feedback loop in peripheral T-cell lymphoma.

Peripheral T-cell lymphomas (PTCLs) are generally aggressive non-Hodgkin lymphomas with poor overall survival rates following standard therapy. One-third of PTCLs express interferon regulatory factor-4 (IRF4), a tightly regulated transcription factor involved in lymphocyte growth and differentiation. IRF4 drives tumor growth in several lymphoid malignancies and has been proposed as a candidate therapeutic target.

Genetic variation in IL18R1 and IL18 genes and Inteferon γ ELISPOT response to smallpox vaccination: an unexpected relationship.

Background: Genetic association studies demonstrated a role for cytokine proteins and cytokine or cytokine receptor gene polymorphisms in smallpox vaccine-induced adaptive immunity.

Methods: We examined the association of genetic polymorphisms with cellular (interferon [IFN] γ enzyme-linked immunospot assay [ELISPOT]) immune response to smallpox vaccine in 1076 immunized individuals.

Results: The majority of significant associations were discovered between single-nucleotide polymorphisms/haplotypes in IL18R1 and IL18 genes, in which we previously reported an association with vaccinia virus-induced neutralizing antibody titers in this study cohort.

Associations between polymorphisms in the antiviral TRIM genes and measles vaccine immunity.

The role of polymorphisms within the antiviral tripartite motif (TRIM) genes in measles vaccine adaptive immune responses was examined. A limited association was found between TRIM5 (rs7122620) and TRIM25 (rs205499) gene polymorphisms and measles-specific antibody levels. However, many associations were found between TRIM gene SNPs and variations in cellular responses (IFN-γ Elispot and secreted cytokines IL-2, IL-6, IL-10, IFN-γ, and TNF-α).

Drivers of cost after surgical and medical therapy for chronic ulcerative colitis: a nested case-cohort study in Olmsted County, Minnesota.

Background: We previously reported the costs associated with surgery for chronic ulcerative colitis in the Olmsted County population and found that direct medical costs after surgery were significantly reduced compared with before surgery. However, in that study, costs associated with chronic medical therapy for ulcerative colitis were not assessed in nonsurgical patients.

Objective: To gain insight into the drivers of costs of treatment for chronic ulcerative colitis, we assessed direct costs after surgical and medical therapy in 120 patients in the Rochester Epidemiology Project database.

A clinical deterioration prediction tool for internal medicine patients.

Many early warning models for hospitalized patients use variables measured on admission to the hospital ward; few have been rigorously derived and validated. The objective was to create and validate a clinical deterioration prediction tool using routinely collected clinical and nursing measurements. Multivariate regression analysis was used to determine clinical variables statistically associated with clinical deterioration; subsequently, the model tool was retrospectively validated using a different cohort of medical inpatients.

Performance of an item response theory-based computer adaptive test in identifying functional decline.

Objective: To achieve a low respondent burden and increase the responsiveness of functional measurement by using an item response theory-based computer adaptive test (CAT), the Activity Measure for Post-Acute Care (AM-PAC) CAT.

Design: Two-year prospective cohort study.

Setting: Telephonic assessments from a quaternary medical center.

Genome-wide association study of antibody response to smallpox vaccine.

We performed a genome-wide association study (GWAS) of antibody levels in a multi-ethnic group of 1071 healthy smallpox vaccine recipients. In Caucasians, the most prominent association was found with promoter SNP rs10489759 in the LOC647132 pseudogene on chromosome 1 (p=7.77×10(-8)).

Replication of associations between cytokine and cytokine receptor single nucleotide polymorphisms and measles-specific adaptive immunophenotypic extremes.

Our objective was to replicate previously reported associations between cytokine and cytokine receptor SNPs and humoral and CMI (cell-mediated immune) responses to measles vaccine. All subjects (n=758) received two doses of MMR (measles/mumps/rubella) vaccine. From these subjects, candidate cytokine and cytokine receptor SNPs were genotyped and analyzed in 29-30 subjects falling into one of four "extreme" humoral (Ab(high/low)) and CMI (CMI(high/low)) response quadrants.

Multigenic control of measles vaccine immunity mediated by polymorphisms in measles receptor, innate pathway, and cytokine genes.

Measles infection and vaccine response are complex biological processes that involve both viral and host genetic factors. We have previously investigated the influence of genetic polymorphisms on vaccine immune response, including measles vaccines, and have shown that polymorphisms in HLA, cytokine, cytokine receptor, and innate immune response genes are associated with variation in vaccine response but do not account for all of the inter-individual variance seen in vaccinated populations. In the current study we report the findings of a multigenic analysis of measles vaccine immunity, indicating a role for the measles virus receptor CD46, innate pattern-recognition receptors (DDX58, TLR2, 4, 5, 7 and 8) and intracellular signaling intermediates (MAP3K7, NFKBIA), and key antiviral molecules (VISA, OAS2, MX1, PKR) as well as cytokines (IFNA1, IL4, IL6, IL8, IL12B) and cytokine receptor genes (IL2RB, IL6R, IL8RA) in the genetic control of both humoral and cellular immune responses.

The association of CD46, SLAM and CD209 cellular receptor gene SNPs with variations in measles vaccine-induced immune responses: a replication study and examination of novel polymorphisms.

Background: The measles virus (MV) interacts with two known cellular receptors: CD46 and SLAM. The transmembrane receptor CD209 interacts with MV and augments dendritic cell infection.

Methods: 764 subjects previously immunized with measles-mumps-rubella vaccine were genotyped for 66 candidate SNPs in the CD46, SLAM and CD209 genes as part of a larger study.

Effects of vitamin A and D receptor gene polymorphisms/haplotypes on immune responses to measles vaccine.

Objective: Vitamins A and D, and their receptors, are important regulators of the immune system, including vaccine immune response. We assessed the association between polymorphisms in the vitamin A receptors [retinoic acid receptor α, retinoic acid receptor β (RARB), and retinoic acid receptor γ] and vitamin D receptor (VDR)/retinoid X receptor α (RXRA) genes and interindividual variations in immune responses after two doses of measles vaccine in 745 children.

Methods: Using a tag single nucleotide polymorphism (SNP) approach, we genotyped 745 healthy children for the 391 polymorphisms in vitamin A receptor and VDR genes.

Common SNPs/haplotypes in IL18R1 and IL18 genes are associated with variations in humoral immunity to smallpox vaccination in Caucasians and African Americans.

Background: Identifying genetic factors that influence poxvirus immunity across races may assist in the development of better vaccines and approaches for vaccine development.

Methods: We performed an extensive candidate-gene genetic screen (across 32 cytokine and cytokine receptor genes) in a racially diverse cohort of 1056 healthy adults after a single dose of smallpox vaccine. Associations between single-nucleotide polymorphisms (SNPs)/haplotypes and vaccinia virus-specific neutralizing antibodies were assessed using linear regression methodologies.