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. OBJECTIVES: This study sought to test the association between the rs9349379 genotype and SCAD. METHODS: Results from case control studies from France, United Kingdom, United States, and Australia were analyzed to test the association with SCAD risk, including age at first event, pregnancy-associated SCAD (P-SCAD), and recurrent SCAD. RESULTS: The previously reported risk allele for FMD (rs9349379-A) was associated with a higher risk of SCAD in all studies. In a meta-analysis of 1,055 SCAD patients and 7,190 controls, the odds ratio (OR) was 1.67 (95% confidence interval [CI]: 1.50 to 1.86) per copy of rs9349379-A. In a subset of 491 SCAD patients, the OR estimate was found to be higher for the association with SCAD in patients without FMD (OR: 1.89; 95% CI: 1.53 to 2.33) than in SCAD cases with FMD (OR: 1.60; 95% CI: 1.28 to 1.99). There was no effect of genotype on age at first event, P-SCAD, or recurrence. CONCLUSIONS: The first genetic risk factor for SCAD was identified in the largest study conducted to date for this condition. This genetic link may contribute to the clinical overlap between SCAD and FMD.

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. First-degree relatives over age 40 provided serum samples for evaluation of MGUS (N = 1179). Age and sex specific rates of MGUS among first-degree relatives were compared to a population-based sample. Cytogenetic subtypes were classified by Fluorescence in situ hybridization. MGUS was detected in 75 first-degree relatives for an age- and sex- adjusted prevalence of 5.8% (95% CI: 4.5-7.2). Prevalence of MGUS in first-degree relatives was 2.4 fold (95% CI: 1.9-2.9) greater than expected rates. Familial risk did not differ by proband's age at diagnosis, gender, isotype, IgH translocation, or trisomy. This study confirms first-degree relatives of MM cases have a significantly higher risk of MGUS compared to the general population, regardless of age, gender, or tumor characteristics. In selected situations, such as multiple affected first-degree relatives, screening of first-degree relatives of MM cases could be considered for follow-up and prevention strategies.

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. METHODS: This retrospective study included 4907 patients who underwent 1 or more revision TKA between 1985 and 2015. Patients were grouped by surgical indications and followed until death or October 2017. The observed number of deaths was compared to the expected number of deaths using standardized mortality ratios (SMR) and Poisson regression models. RESULTS: Compared to the general population, patients who underwent revision TKA for infection (SMR, 1.45; 95% confidence interval [CI], 1.33-1.57; P < .0001) and fracture (SMR, 1.16; 95% CI, 1.00-1.34; P = .04) experienced a significantly higher mortality risk. Patients who underwent revision TKA for infection and fracture experienced excess mortality soon after surgery which became more pronounced over time. In contrast, the mortality risk among patients who underwent revision TKA for loosening and/or bearing wear was similar to the general population (SMR, 0.95; 95% CI, 0.89-1.02; P = .16). Aseptic loosening and/or wear and instability patients had improved mortality initially; however, there was a shift to excess mortality beyond 5 years among instability patients, and beyond 10 years among aseptic loosening and/or wear patients. CONCLUSION: Mortality is elevated soon after revision TKA for infection and fracture. Mortality is lower than the general population after revision TKA for loosening and/or bearing wear but gets worse than the general population beyond the first postoperative decade.

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. METHODS: Cone repair was performed in 235 consecutive patients with Ebstein anomaly, 134 children (57%) and 101 adults (43%), from June 2007 to October 2015. Median age was 15.6 years (range, 6 months to 73 years). Cone repair was the first operation in 192 patients (82%), the second in 41 (17%), and the third in 2 (1%). Previous tricuspid valve repair had been performed in 27 (12%). Echocardiograms were obtained preoperatively and at hospital dismissal for all patients and for a subgroup of patients at least 6 months after cone repair (n = 81). RESULTS: Leaflet augmentation was done in 67 patients (28%), Sebening stitch in 57 (24.2%), neochordae in 49 (21%), and annuloplasty band in 158 (67%). Bidirectional cavopulmonary shunt was performed in 46 patients (20%). There was 1 early death (0.4%). Early reoperation was required in 14 patients (5.9%); re-repair was possible in 7 (50%). The majority of early reoperations (11 of 14; 79%) occurred in the first third of the series. Mean follow-up was 3.5 ± 2.5 years. There was sustained reduction in tricuspid regurgitation (p < 0.0001), a progressive decline in right ventricle size (p < 0.0001), and late increase in right ventricle fractional area change after initial decline (p < 0.0001). Freedom from late reoperation was 97.9% at 6 years. CONCLUSIONS: Cone repair is safe, and the learning curve is significant. Sustained reduction in tricuspid regurgitation and favorable changes in the right ventricle at follow-up suggest that cone repair has an advantageous impact on right ventricular remodeling.

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. We studied twelve serum cytokines and the ALC/AMC ratios in 390 patients with untreated diffuse large B-cell, follicular, mantle cell, T-cell, and Hodgkin lymphoma. Different pre-treatment serum cytokine concentrations correlated with ALC, AMC, and ALC/AMC ratios depending on the lymphoma type. In the entire cohort (n = 390) lower ALC/AMC ratios modestly correlated with higher IL-2R (r = -0.36), IL-12 (r = -0.17), IP-10 (r = -0.23), and MIG (r = -0.32) concentrations (p < 0.001). Elevated IL-2R was independently associated with suppressed ALC (OR 2.69, 95% CI 1.77-4.07, p < 0.001), elevated AMC (OR 2.05, 95% CI 1.34-3.14, p < 0.001), and suppressed ALC/AMC ratios (OR 3.51, 95% CI 2.31-5.34, p < 0.001). Both elevated IL-2R (HR 2.27, 95% CI 1.48-3.49, p < 0.001) and suppressed ALC/AMC ratios (HR 1.53, 95% CI 1.03-2.28, p = 0.037) were independently associated with inferior overall survival. These data support the notion that elevated serum cytokines are immunosuppressive and provide further rationale to target the tumor microenvironment for therapeutic benefit.

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. All patients with VS with TN or neuropathy were included, with the exception of those patients with neurofibromatosis Type 2 and patients who elected observation. Patient demographic data, symptom evolution, and treatment outcomes were collected. Population data were summarized, and outcome comparisons between microsurgery and SRS were analyzed at last follow-up. RESULTS Sixty (2.2%) of 2771 total patients who had large VSs and either TN or neuropathy symptoms met inclusion criteria. The average age of trigeminal symptom onset was 53.6 years (range 24-79 years), the average age at VS diagnosis was 54.4 years (range 25-79 years), and the average follow-up for the microsurgery and SRS groups was 30 and 59 months, respectively (range 3-132 months). Of these patients, 50 (83%) had facial numbness, 16 (27%) had TN pain, and 13 (22%) had paresthesias (i.e., burning or tingling). Subsequently, 50 (83%) patients underwent resection and 10 (17%) patients received SRS. Treatment of VS with SRS did not improve trigeminal symptoms in any patient. This included 2 subjects with unimproved facial numbness and 4 patients with worsened numbness. Similarly, SRS worsened TN pain and paresthesias in 5 patients and failed to improve pain in 2 additional patients. The Barrow Neurological Institute neuralgia and hypesthesia scale scores were significantly worse for patients undergoing SRS compared with microsurgery. Resection alleviated facial numbness in 22 (50%) patients, paresthesias in 5 (42%) patients, and TN in 7 (70%) patients. In several patients, surgery was not successful in relieving facial numbness, which failed to improve in 17 (39%) cases and became worse in 5 (11%) cases. Also, surgery did not change the intensity of facial paresthesias or neuralgia in 6 (50%) and 3 (25%) patients, respectively. Microsurgery exacerbated facial paresthesias in 1 (8%) patient but, notably, did not aggravate TN in any patient. CONCLUSIONS Overall, resection of large VSs provided improved outcomes for patients with concomitant TN, facial paresthesia, and numbness compared with SRS. However, caution should be used when counseling surgical candidates because a number of patients did not experience improvement. This was especially true in patients with preoperative facial numbness and paresthesias, who frequently reported that these symptoms were unchanged following surgery.

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, 14.7 to 16.6 years). Scores from the MMPI Optimism-Pessimism (PSM) scale were used to categorize patients as pessimistic (t-score >60) or non-pessimistic (t score ≤60). Outcomes were self-reported: (a) moderate-severe pain, (b) absence of "much better" improvement compared to preoperative hip function, and (c) moderate-severe activity limitation. Multivariable logistic regression was adjusted for gender, age and other covariates. Odds ratios (OR) with 95 % confidence intervals (CI) are presented. RESULTS: We identified 507 patients with 565 primary THAs with an MMPI prior to primary THA, of whom 441 patients with 488 primary THAs had responded to hip pain and function follow-up surveys at 2-years post-surgery. Similarly, 202 patients with 235 revision THAs had an MMPI prior to surgery, of whom 172 patients with 196 revision THAs completed 2-year surveys. Among those with primary THA, pessimists reported (a) a non-significant trend toward more moderate-severe pain at 2-years with OR (95 % CI; p-value), 2.16 (0.90, 5.20; p = 0.08; reference, none-mild pain),; (b) no significant difference for absence of "much better" improvement in hip function at 2-years, 1.87 (0.77, 4.52; p = 0.16; reference, much better hip function); and (c) significantly higher rate of moderate-severe activity limitation at 2-years, 2.90 (1.25, 6.70; p = 0.01). Among revision THA cohort, pessimists reported no significant differences from non-pessimists in moderate-severe pain, improvement in hip function or moderate-severe functional limitation at 2-years. CONCLUSIONS: A pessimistic explanatory style was associated with moderate-severe activity limitation and a non-significant trend towards moderate-severe pain post-THA.

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. Because direct IRF4 inhibitors are not clinically available, we sought to characterize the mechanism by which IRF4 expression is regulated in PTCLs. We demonstrated that IRF4 is constitutively expressed in PTCL cells and drives Myc expression and proliferation. Using an inhibitor screen, we identified nuclear factor κB (NF-κB) as a candidate regulator of IRF4 expression and cell proliferation. We then demonstrated that the NF-κB subunits p52 and RelB were transcriptional activators of IRF4. Further analysis showed that activation of CD30 promotes p52 and RelB activity and subsequent IRF4 expression. Finally, we showed that IRF4 transcriptionally regulates CD30 expression. Taken together, these data demonstrate a novel positive feedback loop involving CD30, NF-κB, and IRF4; further evidence for this mechanism was demonstrated in human PTCL tissue samples. Accordingly, NF-κB inhibitors may represent a clinical means to disrupt this feedback loop in IRF4-positive PTCLs.

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. PARTICIPANTS: Patients (N=311) with late-stage lung cancer (LC). INTERVENTIONS: Monthly assessments for up to 2 years. Disease progression was determined via record abstraction. Anchor-based responsiveness techniques were used to compare AM-PAC-CAT score changes between global rating of change (GRC) question response levels, as well as between intervals when adverse clinical events or symptom worsening did and did not occur. Distribution-based responsiveness assessments included calculation of the standardized effect size (SES) and standardized response mean (SRM). MAIN OUTCOME MEASURES: AM-PAC-CAT, symptom numerical rating scales, and a GRC. RESULTS: Administration time averaged 112 seconds over 2543 interviews. AM-PAC-CAT score changes became more positive as GRC responses reflected more improved states: a lot worse (-11.62), a little worse (-1.92), the same (-.10), a little better (1.01), and a lot better (2.82). Score changes were negative when associated with adverse clinical events. The SES and SRM for score differences between 1 to 2 and 9 to 10 months prior to death were -.87 and -1.13, respectively. The minimally important difference estimate was defined by the mean CAT session SE at 2.0. CONCLUSIONS: The AM-PAC-CAT imposes a low, <2-minute, respondent burden, and distribution- and anchor-based methods suggest that is moderately responsive in patients with late-stage LC.

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 ß (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. RESULTS: The RARB haplotype (rs6800566/rs6550976/rs9834818) was significantly associated with variations in both measles antibody (global, P=0.013) and cytokine secretion levels, such as interleukin (IL)-10 (global, P=0.006), interferon (IFN)-α (global, P=0.008), and tumor necrosis factor-α (global, P=0.039) in the Caucasian subgroup. Specifically, the RARB haplotype, AAC, was associated with higher (t-statistic: 3.27, P=0.001) measles antibody levels. At the other end of the spectrum, haplotype GG for rs6550978/rs6777544 was associated with lower antibody levels (t-statistic: -2.32, P=0.020) in the Caucasian subgroup. In a sensitivity analysis, the RARB haplotype, CTGGGCAA, remained marginally significant (P<0.02) when the single SNP rs12630816 was included in the model for IL-10 secretion levels. A significant association was found between lower measles-specific IFN-γ Enzyme-linked immunosorbent spot responses and haplotypes rs11102986/rs11103473/rs11103482/rs10776909/rs12004589/rs35780541/rs2266677/rs875444 (global, P=0.004) and rs6537944/rs3118571 (global, P<0.001) in the RXRA gene for Caucasians. We also found associations between multiple RARB, VDR, and RXRA SNPs/haplotypes and measles-specific IL-2, IL-6, IL-10, IFN-α, IFN-γ, IFNλ-1, and TNF-α cytokine secretions. CONCLUSION: Our results suggest that specific allelic variations and haplotypes in the vitamin A receptor and VDR genes may influence adaptive immune responses to measles vaccine.

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. RESULTS: A previously detected association of the CD46 SNP rs2724384 with measles-specific antibodies was successfully replicated in this study. Increased representation of the minor allele G for an intronic CD46 SNP was associated with an allele dose-related decrease (978 vs. 522 mIU/ml, p = 0.0007) in antibody levels. This polymorphism rs2724384 also demonstrated associations with IL-6 (p = 0.02), IFN-α (p = 0.007) and TNF-α (p = 0.0007) responses. Two polymorphisms (coding rs164288 and intronic rs11265452) in the SLAM gene that were associated with measles antibody levels in our previous study were associated with IFN-γ Elispot (p = 0.04) and IL-10 responses (p = 0.0008), respectively, in this study. We found associations between haplotypes, AACGGAATGGAAAG (p = 0.009) and GGCCGAGAGGAGAG (p < 0.001), in the CD46 gene and TNF-α secretion. CONCLUSION: Understanding the functional and mechanistic consequences of these genetic polymorphisms on immune response variations could assist in directing new measles and potentially other viral vaccine design, and in better understanding measles immunogenetics.

Risk factors for splenic injury during colectomy: a matched case-control study.

PURPOSE: We assessed risk factors for splenic injury during colectomy and associated outcomes for a 15-year period at a single institution. METHODS: All adult general surgery patients who sustained a splenic injury during colectomy at our institution from 1992 to 2007 were retrospectively identified and matched 1:1 to controls without splenic injury. Putative risk factors were assessed using paired univariate analysis and conditional logistic regression. Differences in short- and long-term mortality were assessed using the log-rank test. Results are reported as a proportion, median, or odds ratio [OR (95% confidence intervals)]. RESULTS: A total of 118 patients were included: 59 patients with splenic injury and 59 control patients. Statistically significant risk factors for splenic injury during colectomy found on univariate analysis included: splenic flexure mobilization, OR 21.00 (2.82-156.12); Charlson comorbidity index≥5, OR 3.17 (1.26-7.93); ASA class≥3, OR 5.33 (1.55-18.3); and nonelective surgery, OR 5.00 (1.1-22.82). On multivariate analysis, only splenic flexure mobilization was independently associated with increased risk of splenic injury (OR 18.4 (2.1-161); p=0.0085). Splenic injured patients trended toward decrease survival both at 30 days (98 vs. 88%; p=0.06) and at 5 years (58 vs. 55%), with a hazard ratio of 1.6 (1.0, 2.6; p=0.05). CONCLUSIONS: Splenic flexure mobilization is the primary risk factor for splenic injury during colectomy, independent of other factors, such as higher ASA class, Charlson score, and nonelective surgery. Splenic injury during colectomy has an increased risk of death in both the short- and long-term.

Predictors of moderate-severe functional limitation 2 and 5 years after revision total knee arthroplasty.

In patients who underwent revision TKA from 1993 to 2005 and responded to follow-up questionnaires 2 or 5 years postrevision TKA, we studied whether body mass index (BMI), comorbidity (measured by validated Deyo-Charlson index), sex, and age predict activity limitation 2 and 5 years after revision TKA. Overall moderate-severe activity limitation was defined as 2 or more activities (walking, stairs, rising chair) with moderate-severe limitation. Multivariable logistic regressions also adjusted for income, diagnosis, and distance from medical center and American Society of Anesthesiologists physical status score. The prevalence of overall moderate-severe activity limitation was high: 46.5% (677/1456) at 2 years and 50.5% (420/832) at 5 years postrevision TKA. At both 2 and 5 years of follow-up, BMI of 40 or higher, higher Deyo-Charlson score, female sex, and age greater than 80 years, each significantly predicted higher odds of moderate-severe overall activity limitation.

Associations between SNPs in candidate immune-relevant genes and rubella antibody levels: a multigenic assessment.

BACKGROUND: The mechanisms of immune response are structured within a highly complex regulatory system. Genetic associations with variation in the immune response to rubella vaccine have typically been assessed one locus at a time. We simultaneously assessed the associations between 726 SNPs tagging 84 candidate immune response genes and rubella-specific antibody levels. Blood samples were obtained from 714 school-aged children who had received two doses of MMR vaccine. Associations between rubella-specific antibody levels and 726 candidate tagSNPs were assessed both one SNP at a time and in a variety of multigenic analyses. RESULTS: Single-SNP assessments identified 4 SNPs that appeared to be univariately associated with rubella antibody levels: rs2844482 (p = 0.0002) and rs2857708 (p = 0.001) in the 5'UTR of the LTA gene, rs7801617 in the 5'UTR of the IL6 gene (p = 0.0005), and rs4787947 in the 5'UTR of the IL4R gene (p = 0.002). While there was not significant evidence in favor of epistatic genetic associations among the candidate SNPs, multigenic analyses identified 29 SNPs significantly associated with rubella antibody levels when selected as a group (p = 0.017). This collection of SNPs included not only those that were significant univariately, but others that would not have been identified if only considered in isolation from the other SNPs. CONCLUSIONS: For the first time, multigenic assessment of associations between candidate SNPs and rubella antibody levels identified a broad number of genetic associations that would not have been deemed important univariately. It is important to consider approaches like those applied here in order to better understand the full genetic complexity of response to vaccination.

A qualitative and quantitative comparison of two rubella virus-specific IgG antibody immunoassays.

Monitoring circulating rubella IgG antibody concentration in children and in women of child-bearing age is an important step in maintaining high levels of rubella immunity and preventing congenital rubella syndrome. The objective of this study was to evaluate the Beckman Coulter Access Rubella IgG assay against the Dade Behring Enzygnost Anti-Rubella-Virus/IgG EIA assay in serum of children (n = 342) immunized with two doses of measles-mumps-rubella-II (MMR-II) vaccine. We found that the two assays had a high qualitative (96%), and quantitative correlation 0.93 (0.92, 0.95), based on a protective antibody concentration of > or =15 IU/mL. The mean rubella antibody concentration measured by both assays was >37 IU/mL; however, 10% of our study participants had low concentrations of circulating rubella-specific antibodies. These findings might indicate a need for additional monitoring of antibody levels as these children reach child-bearing age, or potentially a need for a third dose of vaccine to increase seroconversion.

SNP/haplotype associations in cytokine and cytokine receptor genes and immunity to rubella vaccine.

An effective immune response to vaccination is, in part, a complex interaction of alleles of multiple genes regulating cytokine networks. We conducted a genotyping study of Th1/Th2/inflammatory cytokines/cytokine receptors in healthy children (n = 738, 11-19 years) to determine associations between individual single-nucleotide polymorphisms (SNPs)/haplotypes and immune outcomes after two doses of rubella vaccine. SNPs (n = 501) were selected using the ldSelect-approach and genotyped using Illumina GoldenGate and TaqMan assays. Rubella-IgG levels were measured by immunoassay and secreted cytokines by ELISA. Linear regression and post hoc haplotype analyses were used to determine associations between single SNPs/haplotypes and immune outcomes. Increased carriage of minor alleles for the promoter SNPs (rs2844482 and rs2857708) of the TNFA gene were associated with dose-related increases in rubella antibodies. IL-6 secretion was co-directionally associated (p < or = 0.01) with five intronic SNPs in the TNFRSF1B gene in an allele dose-related manner, while five promoter/intronic SNPs in the IL12B gene were associated with variations in IL-6 secretion. TNFA haplotype AAACGGGGC (t-statistic = 3.32) and IL12B promoter haplotype TAG (t-statistic = 2.66) were associated with higher levels of (p < or = 0.01) rubella-IgG and IL-6 secretion, respectively. We identified individual SNPs/haplotypes in TNFA/TNFRSF1B and IL12B genes that appear to modulate immunity to rubella vaccination. Identification of such "genetic fingerprints" may predict the outcome of vaccine response and inform new vaccine strategies.

Failure of institutionally derived predictive models of conversion in laparoscopic colorectal surgery to predict conversion outcomes in an independent data set of 998 laparoscopic colorectal procedures.

OBJECTIVE: The aim of this study was to perform an external validation of 2 institutionally derived predictive models of laparoscopic conversion in colorectal surgery using the Mayo Clinic, Rochester (MCR) laparoscopic colon and rectal surgery experience. SUMMARY OF BACKGROUND DATA: Two different predictive scoring systems of conversion in laparoscopic colorectal surgery were developed and published based upon single institution experiences. Neither model was validated on an independent data set. Thus, the utility of these models outside of their respective institutions is unknown. METHODS: A prospectively collected data set of 998 laparoscopic colorectal procedures from MCR was analyzed. All patient-, procedure-, and surgeon-related factors used in both models were present in our data set. Logistic regression was used to evaluate their ability to predict conversion in our cohort. Model effectiveness was assessed by area under the curve from the logistic regression model, 95% confidence intervals for the observed number of conversions, and a goodness-of-fit test to compare the observed number of conversions with the predicted conversion rates for each score. RESULTS: The cohort mean age of 552 women was 53, with a median body mass index of 25.2 kg/m. There were 382 right-sided, 251 left-sided, 46 rectal resections, and 151 proctocolectomies. Major diagnoses were inflammatory bowel disease 34%, cancer 18%, polyps 17%, and diverticular disease 13%. The overall MCR conversion rate was 15%. Several variables from the models were statistically significant predictors of conversion in our data set. However, both models performed similarly with an area under the curve of 0.62, suggesting that these models are of limited predictive value in our independent cohort with a performance closer to chance. The numbers of actual conversions were significantly different from the predicted number for both scoring systems. CONCLUSION: Patient and clinical factors associated with laparoscopic conversion in colorectal surgery may be institution dependent. This finding cautions surgeons on the applicability of institution-based surgical predictive models. Independent data set validation is recommended before surgical predictive models are applied to general clinical practice.

Polymorphisms in the vitamin A receptor and innate immunity genes influence the antibody response to rubella vaccination.

BACKGROUND: Genetic polymorphisms play an important role in rubella vaccine-induced immunity. METHODS: We genotyped 714 healthy children after 2 age-appropriate doses of rubella-containing vaccine for 142 potential single-nucleotide polymorphisms (SNPs). RESULTS: Specific polymorphisms in the vitamin A receptor, retinoic acid-inducible gene I (RIG-I), and tripartite motif 5 and 22 (TRIM5 and TRIM22) genes were significantly associated with rubella vaccine humoral immunity. The minor allele of the rs4416353 in the vitamin A receptor gene was associated with an allele dose-related decrease (P = .019) in rubella antibody response. The minor allele of rs6793694, in the vitamin A receptor gene, was associated with an allele dose-related antibody decrease (p = .039). The minor variant of nonsynonymous SNP rs10813831 (Arg7Cys) in the RIG-I gene was associated with an allele dose-related decrease in rubella antibody level from 37.4 to 28.0 IU/mL (P = .035), whereas increased representation of the minor allele of the 5'UTR SNP (rs3824949, P = .015) in the antiretroviral TRIM5 gene was associated with an allele dose-related increase in rubella antibody. It is of particular interest that the nonsynonymous SNP rs3740996 (His43Tyr) in the TRIM5 gene was associated with variations in rubella antibody response (P = .016) after having been previously found to play a significant functional role. CONCLUSIONS: These findings further expand our immunogenetic understanding of mechanisms of rubella vaccine-induced immunity.

Rubella vaccine-induced cellular immunity: evidence of associations with polymorphisms in the Toll-like, vitamin A and D receptors, and innate immune response genes.

Toll-like, vitamin A and D receptors and other innate proteins participate in various immune functions. We determined whether innate gene-sequence variations are associated with rubella vaccine-induced cytokine immune responses. We genotyped 714 healthy children (11-19 years of age) after two doses of rubella-containing vaccine for 148 candidate SNP markers. Rubella virus-induced cytokines were measured by ELISA. Twenty-two significant associations (range of P values 0.002-0.048) were found between SNPs in the vitamin A receptor family (RARA, RARB, TOP2B and RARG), vitamin D receptor and downstream mediator of vitamin D signaling (RXRA) genes and rubella virus-specific (IFN-gamma, IL-2, IL-10, TNF-alpha, and GM-CSF) cytokine immune responses. A TLR3 gene promoter region SNP (rs5743305, -8441A > T) was associated with rubella-specific GM-CSF secretion. Importantly, SNPs in the TRIM5 gene coding regions, rs3740996 (His43Tyr) and rs10838525 (Gln136Arg), were associated with an allele dose-related secretion of rubella virus-specific TNF-alpha and IL-2/GM-CSF, respectively, and have been previously shown to have functional consequences regarding the antiviral activity and susceptibility to HIV-1 infection. We identified associations between individual SNPs and haplotypes in, or involving, the RIG-I (DDX58) gene and rubella-specific TNF-alpha secretion. This is the first paper to present evidence that polymorphisms in the TLR, vitamin A, vitamin D receptor, and innate immunity genes can influence adaptive cytokine responses to rubella vaccination.

Splenic salvage after intraoperative splenic injury during colectomy.

OBJECTIVE: To determine the optimal surgical management of splenic injury encountered during colectomy. DESIGN: Retrospective review from 1992 to 2007. SETTING: Mayo Clinic in Rochester, Minnesota, a tertiary care center. PATIENTS: A cohort of patients who sustained splenic injury during colectomy from 1992 to 2007. MAIN OUTCOME MEASURES: Overall 30-day major morbidity and mortality and overall 5-year survival. RESULTS: Of 13,897 colectomies, we identified 59 splenic injuries (0.42%). Of these, 33 (56%) were in men; there was a median age of 68 years (range, 30-93 years) and a median body mass index of 25.5 (range, 15-54). Thirty-seven injuries (63%) occurred during elective surgery, 6 (10%) occurred without splenic flexure mobilization, and 5 (8.4%) occurred during minimally invasive surgery. Injury was successfully managed by primary repair in 10 (17%), splenorrhaphy in 4 (7%), and splenectomy in 45 cases (76%). Four injuries (7%) were unrecognized and resulted in reoperation and splenectomy. Multiple attempts at splenic salvage were performed in 30 (51%); of these, 21 (70%) required splenectomy. More than 2 attempts at salvage was associated with splenectomy (P = .03). The 30-day major morbidity and mortality rates were 34% and 17%, respectively. Sepsis was the most common complication, with no confirmed episodes of postsplenectomy sepsis. Median survival after splenic injury was 7.25 years. There was no significant association between the surgical management of splenic injuries and short- or long-term outcomes. CONCLUSIONS: Splenic injury is an infrequent but morbid complication. Splenic salvage is frequently unsuccessful; our data suggest that surgeons should not be reluctant to perform splenectomy when initial repair attempts fail.