The cyclin-like protein SPY1 overrides reprogramming induced senescence through EZH2 mediated H3K27me3.

Fully differentiated cells can be reprogrammed through ectopic expression of key transcription factors to create induced pluripotent stem cells. These cells share many characteristics of normal embryonic stem cells and have great promise in disease modeling and regenerative medicine. The process of remodeling has its limitations, including a very low efficiency due to the upregulation of many antiproliferative genes, including cyclin dependent kinase inhibitors CDKN1A and CDKN2A, which serve to protect the cell by inducing apoptotic and senescent programs. Our data reveals a unique cell cycle mechanism enabling mouse fibroblasts to repress cyclin dependent kinase inhibitors through the activation of the epigenetic regulator EZH2 by a cyclin-like protein SPY1. This data reveals that the SPY1 protein is required for reprogramming to a pluripotent state and is capable of increasing reprogramming efficiency.

Comparing ultrafast excited state quenching of flavin 1,N6-ethenoadenine dinucleotide and flavin adenine dinucleotide by optical spectroscopy and DFT calculations.

Flavins are photoenzymatic cofactors often exploiting the absorption of light to energize photoinduced redox chemistry in a variety of contexts. Both flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) are used for this function. The study of these photoenzymes has been facilitated using flavin analogs. Most of these analogs involve modification of the flavin ring, and there is recent evidence that adenine (Ade)-modified FAD can affect enzyme turnover, but so far this has only been shown for enzymes where the adenine and flavin rings are close to each other in a stacked conformation. FAD is also stacked in aqueous solution, and its photodynamics are quite different from unstacked FAD or FMN. Oxidized photoexcited FAD decays rapidly, presumably through PET with Ade as donor and Fl* as acceptor. Definitive identification of the spectral signatures of Ade∙+ and Fl∙- radicals is elusive. Here we use the FAD analog Flavin 1,N6-Ethenoadenine Dinucleotide (εFAD) to study how different photochemical outcomes depend on the identity of the Ade moiety in stacked FAD and its analog εFAD. We have used UV-Vis transient absorption spectroscopy complemented by TD-DFT calculations to investigate the excited state evolution of the flavins. In FAD*, no radicals were observed, suggesting that FAD* does not undergo PET. εFAD* kinetics showed a broad absorption band that suggests a charge transfer state exists upon photoexcitation with evidence for radical pair formation. Surprisingly, significant triplet flavin was produced from εFAD* We hypothesize that the dipolar (ε)Ade moieties differentially modulate the singlet-triplet energy gap, resulting in different intersystem crossing rates. The additional electron density on the etheno group of εFAD supplies better orbital overlap with the flavin S1 state, accelerating charge transfer in that molecule.

Maternal and fetal incidental findings on antenatal magnetic resonance imaging.

BACKGROUND: Magnetic resonance imaging (MRI) examinations are increasingly used in antenatal clinical practice. Incidental findings are a recognized association with imaging and although in some circumstances their identification can alter management, they are often associated with increased anxiety, for both patient and clinician, as well as increased health care costs. OBJECTIVE: This study aimed to evaluate the incidence of unexpected findings in both the mother and fetus during antenatal MRI examinations. MATERIALS AND METHODS: A retrospective study was undertaken over a five-year period at St.. Thomas' Hospital in London. Maternal incidental findings were recorded from all clinical reports of all fetal MRIs performed (for clinical reasons and in healthy volunteers) during this period. Fetal incidental findings were recorded only in cases where women with uncomplicated pregnancies were participating as healthy volunteers. RESULTS: A total of 2,569 MRIs were included; 17% of women had maternal incidental findings. Of these, 1,099 were women with uncomplicated pregnancies who undertook research MRIs as healthy volunteers; fetal incidental findings were identified in 12.3%. CONCLUSION: Incidental findings are a common occurrence in antenatal MRI. Consideration should be given to counseling women appropriately before imaging and ensuring that robust local protocols are in place for follow-up and further management of such cases.

Changing perceptions: a multicentre survey of final-year medical students' and junior doctors' perceptions of diabetes and endocrinology.

PURPOSE OF THE STUDY: The National Health Service is experiencing a recruitment crisis across many medical specialties. Diabetes and endocrinology (D&E) is failing to fill training posts with only 77%, 83% and 73% of posts filled overall in 2016, 2017 and 2018, respectively. STUDY DESIGN: We surveyed 316 final-year medical students and undifferentiated trainees (from foundation programme doctors to core medical trainees), across the South Thames, Northern and West Midlands deaneries in England to gain an understanding of perceptions of the specialty. RESULTS: 9% of respondents were considering a career in D&E. Factors such as 'being the medical registrar' (27%), being a 'non-procedural specialty' (23%) and 'looking after majority of general medical admissions' (22%) were cited as the most common reasons why D&E is an unattractive career choice. 51% reported inadequate exposure to D&E. Factors that made respondents more likely to want to pursue a career in D&E included having undertaken a placement in the specialty and having exposure to outpatient clinics. Methods to improve awareness and uptake, such as increased teaching and clinical exposure, and the opportunity to attend taster events were frequently highlighted. CONCLUSIONS: The results from this survey, the first of its kind on perceptions of D&E as a career pathway, reveal a worrying lack of interest in, and exposure to, D&E among current final-year medical students and undifferentiated trainees. These issues must be addressed in order to improve D&E recruitment rates.

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. Therefore, it is important to determine whether the 18-hour treatment time for pediatric femur shaft fractures is a clinically meaningful metric. METHODS: A retrospective review of clinical outcomes of 174 pediatric patients (aged below 16 y) with isolated femur shaft fractures (Injury Severity Score=9) was conducted from 1997 to 2017 at a single level I pediatric trauma center. The 2 comparison groups were patients receiving fracture reduction within 18 hours of emergency department admission (N=87) or >18 hours (N=87). RESULTS: Patient, injury, and surgical characteristics were similar between the 2 groups. Both groups had a similar mean age (treatment <18 h=7.5 y; treatment >18 h=8.1 y). Patients who received treatment within 18 hours were more often immobilized postoperatively (70.1% vs. 53.5%; P=0.0362) and had a shorter median hospital length of stay (2 vs. 3 d; P=0.0047). There were no statistically significant differences in any outcomes including surgical site infection, time to weight-bearing (treatment <18 h mean=48.1 d vs. 52.5 d), time to complete radiographic fracture healing (treatment <18 h mean=258.9 d vs. 232.0 d), decreased range of motion, genu varus/valgus, limb length discrepancy, loss of reduction, or persistent pain. CONCLUSIONS: Treatment of pediatric femur shaft fractures within 18 hours does not impact clinical outcomes. National quality measures should therefore use evidence-based metrics to help improve the standard of care. LEVEL OF EVIDENCE: Therapeutic level III.

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.

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.

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.

Lessons from in-home air filtration intervention trials to reduce urban ultrafine particle number concentrations.

BACKGROUND: Exposure to airborne ultrafine particle (UFP; <100 nm in aerodynamic diameter) is an emerging public health problem. Nevertheless, the benefit of using high efficiency particulate arrestance (HEPA) filtration to reduce UFP concentrations in homes is not yet clear. METHODS: We conducted a randomized crossover study of HEPA filtration without a washout period in 23 homes of low-income Puerto Ricans in Boston and Chelsea, MA (USA). Most participants were female, older adults who were overweight or obese. Particle number concentrations (PNC, a proxy for UFP) were measured indoors and outdoors at each home continuously for six weeks. Homes received both HEPA filtration and sham filtration for three weeks each in random order. RESULTS: Median PNC under HEPA filtration was 50-85% lower compared to sham filtration in most homes, but we found no benefit in terms of reduced inflammation; associations between hsCRP, IL-6, or TNFRII in blood samples and indoor PNC were inverse and not statistically significant. CONCLUSIONS: Limitations to our study design likely contributed to our findings. Limitations included carry-over effects, a population that may have been relatively unresponsive to UFP, reduction in PNC even during sham filtration that limited differences between HEPA and sham filtration, window opening by participants, and lack of fine-grained (room-specific) participant time-activity information. Our approach was similar to other recent HEPA intervention studies of particulate matter exposure and cardiovascular risk, suggesting that there is a need for better study designs.

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.

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). Dermal fibroblast-derived induced pluripotent stem cells (iPSC) were procured from the proband-parent trio and bioengineered into cardiomyocytes. Cardiac phenotyping revealed aortic valve atresia and a slit-like left ventricular cavity in the HLHS proband, isolated bicuspid pulmonary valve in his mother, BAV in a maternal 4° relative, and no CHD in his father or sister. Filtering of WGS for rare, functional variants that segregated with CHD and were compound heterozygous in the HLHS proband identified NOTCH1 as the sole candidate gene. An unreported missense mutation (P1964L) in the cytoplasmic domain, segregating with semilunar valve malformation, was maternally inherited and a rare missense mutation (P1256L) in the extracellular domain, clinically silent in the heterozygous state, was paternally inherited. Patient-specific iPSCs exhibited diminished transcript levels of NOTCH1 signaling pathway components, impaired myocardiogenesis, and a higher prevalence of heterogeneous myofilament organization. Extended, phenotypically characterized families enable WGS-derived variant filtering for plausible Mendelian modes of inheritance, a powerful strategy to discover molecular underpinnings of CHD. Identification of compound heterozygous NOTCH1 mutations and iPSC-based functional modeling implicate mutant allele burden and impaired myogenic potential as mechanisms for HLHS.

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. A functional coding IL18R1 polymorphism (rs1035130/Phe251Phe; P = .01) was significantly associated with an allele dose-related increase in IFN-γ production and was also associated with vaccinia-specific neutralizing antibody titers. Significant associations were also found between IL18R1 haplotypes and variations in IFN-γ ELISPOT responses (global P < .0001). CONCLUSIONS: Our data suggest the importance of variants in the IL18R1 and IL18 genetic loci for broad-based smallpox vaccine-induced adaptive immunity.

Active film packaging based on bio-nanocomposite TiO2 and cinnamon essential oil for enhanced preservation of cheese quality.

This study involves the preparation of PLA/PBAT composite blend films incorporated with TiO2 and varying concentrations of cinnamon essential oil. The films were characterised for optical and mechanical properties, chemical composition, thermo-stability, surface hydrophobicity, inhibition of biofilm formation, anti-microbial efficiency against S. aureus and E. coli, and application on cheese. The thickness of the films increased with the increase in cinnamon oil concentration along with the water contact angle degree and highest UV-barrier properties with the PLA-PBAT-TiO2-7 %Cinn film. The best anti-bacterial activity was seen in the PLA-PBAT-TiO2-7 %Cinn film against S. aureus and E. coli. The cheese packed in PLA-PBAT-TiO2-7 %Cinn film has shown the least weight loss and enhanced antibacterial activity against E. coli for 12 days of storage. The use of cinnamon oil-loaded TiO2 incorporated in films showed positive effects on the shelf life, quality, and safety of a food product and has a high potential for use commercially.

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.

Epidemiology and genotypic characteristics of methicillin-resistant Staphylococcus aureus strains of porcine origin.

The main goal of this study was to determine the prevalence of methicillin-resistant Staphylococcus aureus (MRSA), particularly livestock-associated MRSA (LA-MRSA) in pigs and pork. The genotypic relatedness of isolates on the farm, at slaughter, and at the retail level was assessed. Paired nasal and perianal swab samples were collected from 10 cohorts of market-age pigs (24 pigs per cohort) and carcasses at slaughterhouse, and pork samples were collected at retail. Staphylococci were isolated using selective enrichment method. Isolates were tested for antimicrobial resistance by broth microdilution. Duplex PCR was used to confirm MRSA using species-specific (nuc) and methicillin resistance (mecA) genes. The clonal relatedness of isolates was determined using pulsed-field gel electrophoresis (PFGE), Staphylococcus protein A (spa) typing, multilocus sequence typing (MLST), and staphylococcal cassette chromosome mec element (SCCmec) typing. MRSA was detected in 5 of the 10 cohorts (50%), with the prevalence ranging from 0% to 12.5% per cohort. Of all the pigs sampled on the farm before they went to market, 3% (7/240) were MRSA positive. A higher prevalence of MRSA was detected at holding pens at the slaughterhouse (11% [27/240]). MRSA was also detected in 2% (4/235) of the carcasses and 4% (5/135) of the retail pork. While the isolates appear predominantly to be highly clonal, PFGE had a relatively higher discriminatory power (discriminatory index [DI] = 0.624). Four genotypic clusters were identified by PFGE; of the four clusters, clonal type B was predominant across the farm-to-retail continuum. MLST findings revealed that sequence type 5 (ST5) was the most predominant subtype (32/50). The livestock-associated MRSA (clonal complex 398 [CC398] or sequence type 398 [ST398]) was the second common type (12/50) and was detected at all stages from farm to retail. Nine of the 50 (18%) MRSA isolates belonged to spa type 539/t034 that were of ST398 based on MLST. The results of this study confirm that MRSA, including LA-MRSA, is common in herds of swine in Ohio and hereby shown to persist in the farm to processing and retail continuum.

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. METHODS: A cohort of 60 patients who recovered from surgery for ulcerative colitis from 1988 to 2006 were 1:1 matched by age, sex, and referent year to medically managed patients. Direct health care costs were estimated from an institutional database, and observed cost differences over a 2-year period were calculated. Statistical significance was assessed by paired t tests and bootstrapping; mean costs are adjusted 2009 constant dollars. RESULTS: Two-year direct health care costs in the surgical and medical cohorts were $10,328 vs $6,586 (p = 0.19). In the surgical cohort, Brooke ileostomy patients were observed to have higher costs than patients with ileal pouches ([INCREMENT]$8187, p = 0.04), and after ileal pouch, pouchitis was associated with increased costs ([INCREMENT]$12,763, p < 0.01). In the medical cohort, disease extent ([INCREMENT]$6059, p = 0.04) but not disease severity was associated with increased costs. LIMITATIONS: This study was limited by the relatively small population size and by its performance in a county with a tertiary referral center. CONCLUSIONS: Before the introduction of biologic therapies for ulcerative colitis, patients were observed to have similar health care costs after surgical and medical therapy. In medically treated patients, disease extent was associated with increased costs, whereas in surgically treated patients, permanent ileostomy and pouchitis were observed to be associated with increased costs.

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.

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.

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. RESULTS: The combined analysis identified 63 associations between candidate SNPs and antibody levels after smallpox vaccination with P < .05. Thirty-one of these were within the IL18R1 and IL18 genes. Five IL18R1 SNPs, including a coding synonymous polymorphism rs1035130 (Phe251Phe) and 2 promoter SNPs (rs6710885, rs2287037), all in linkage disequilibrium, were associated with significant variations in antibody levels in both Caucasians (P ≤ .016) and African Americans (P ≤ .025). Similarly, associations with 2 intronic IL18 SNPs (rs2043055 and rs5744280) were consistent in the Caucasian (P ≤ .023) and African American samples (P ≤ .014). Haplotype analysis revealed highly significant associations between IL18R1 haplotypes and vaccinia virus-specific antibody levels (P < .001, by combined analysis) that were consistent across races. CONCLUSIONS: Our study provides evidence for IL18 and IL18R1 genes as plausible genes regulating the humoral immune response to smallpox vaccine in both Caucasians and African Americans.