Platelets retain inducible alpha granule secretion by P‐selectin expression but exhibit mechanical dysfunction during trauma‐induced coagulopathy

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149281/1/jth14414.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149281/2/jth14414_am.pd

Factors Associated With Outcomes of Patients With Primary Sclerosing Cholangitis and Development and Validation of a Risk Scoring System.

We sought to identify factors that are predictive of liver transplantation or death in patients with primary sclerosing cholangitis (PSC), and to develop and validate a contemporaneous risk score for use in a real-world clinical setting. Analyzing data from 1,001 patients recruited to the UK-PSC research cohort, we evaluated clinical variables for their association with 2-year and 10-year outcome through Cox-proportional hazards and C-statistic analyses. We generated risk scores for short-term and long-term outcome prediction, validating their use in two independent cohorts totaling 451 patients. Thirty-six percent of the derivation cohort were transplanted or died over a cumulative follow-up of 7,904 years. Serum alkaline phosphatase of at least 2.4 × upper limit of normal at 1 year after diagnosis was predictive of 10-year outcome (hazard ratio [HR] = 3.05; C = 0.63; median transplant-free survival 63 versus 108 months; P < 0.0001), as was the presence of extrahepatic biliary disease (HR = 1.45; P = 0.01). We developed two risk scoring systems based on age, values of bilirubin, alkaline phosphatase, albumin, platelets, presence of extrahepatic biliary disease, and variceal hemorrhage, which predicted 2-year and 10-year outcomes with good discrimination (C statistic = 0.81 and 0.80, respectively). Both UK-PSC risk scores were well-validated in our external cohort and outperformed the Mayo Clinic and aspartate aminotransferase-to-platelet ratio index (APRI) scores (C statistic = 0.75 and 0.63, respectively). Although heterozygosity for the previously validated human leukocyte antigen (HLA)-DR*03:01 risk allele predicted increased risk of adverse outcome (HR = 1.33; P = 0.001), its addition did not improve the predictive accuracy of the UK-PSC risk scores. Conclusion: Our analyses, based on a detailed clinical evaluation of a large representative cohort of participants with PSC, furthers our understanding of clinical risk markers and reports the development and validation of a real-world scoring system to identify those patients most likely to die or require liver transplantation.Financial support has been received by National Institute of Health Research (RD-TRC and Birmingham Biomedical Research Centre), Isaac Newton Trust, Addenbrooke’s charitable trust, Norwegian PSC Research Center and PSC Support. GMH is supported by the Lily and Terry Horner Chair in Autoimmune Liver Disease Research, Toronto Centre for Liver Disease, Toronto

Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease

Primary sclerosing cholangitis (PSC) is a rare progressive disorder leading to bile duct destruction; ∼75% of patients have comorbid inflammatory bowel disease (IBD). We undertook the largest genome-wide association study of PSC (4,796 cases and 19,955 population controls) and identified four new genome-wide significant loci. The most associated SNP at one locus affects splicing and expression of UBASH3A, with the protective allele (C) predicted to cause nonstop-mediated mRNA decay and lower expression of UBASH3A. Further analyses based on common variants suggested that the genome-wide genetic correlation (rG) between PSC and ulcerative colitis (UC) (rG = 0.29) was significantly greater than that between PSC and Crohn's disease (CD) (rG = 0.04) (P = 2.55 × 10-15). UC and CD were genetically more similar to each other (rG = 0.56) than either was to PSC (P < 1.0 × 10-15). Our study represents a substantial advance in understanding of the genetics of PSC

Silencing Mediated by the Schizosaccharomyces pombe HIRA Complex Is Dependent upon the Hpc2-Like Protein, Hip4

HIRA (or Hir) proteins are conserved histone chaperones that function in multi-subunit complexes to mediate replication-independent nucleosome assembly. We have previously demonstrated that the Schizosaccharomyces pombe HIRA proteins, Hip1 and Slm9, form a complex with a TPR repeat protein called Hip3. Here we have identified a new subunit of this complex.To identify proteins that interact with the HIRA complex, rapid affinity purifications of Slm9 were performed. Multiple components of the chaperonin containing TCP-1 complex (CCT) and the 19S subunit of the proteasome reproducibly co-purified with Slm9, suggesting that HIRA interacts with these complexes. Slm9 was also found to interact with a previously uncharacterised protein (SPBC947.08c), that we called Hip4. Hip4 contains a HRD domain which is a characteristic of the budding yeast and human HIRA/Hir-binding proteins, Hpc2 and UBN1. Co-precipitation experiments revealed that Hip4 is stably associated with all of the other components of the HIRA complex and deletion of hip4(+) resulted in the characteristic phenotypes of cells lacking HIRA function, such as temperature sensitivity, an elongated cell morphology and hypersensitivity to the spindle poison, thiabendazole. Moreover, loss of Hip4 function alleviated the heterochromatic silencing of reporter genes located in the mating type locus and centromeres and was associated with increased levels of non-coding transcripts derived from centromeric repeat sequences. Hip4 was also found to be required for the distinct form of silencing that controls the expression of Tf2 LTR retrotransposons.Overall, these results indicate that Hip4 is an integral component of the HIRA complex that is required for transcriptional silencing at multiple loci

Initial Public Offerings and the Firm Location

The firm geographic location matters in IPOs because investors have a strong preference for newly issued local stocks and provide abnormal demand in local offerings. Using equity holdings data for more than 53,000 households, we show the probability to participate to the stock market and the proportion of the equity wealth is abnormally increasing with the volume of the IPOs inside the investor region. Upon nearly the universe of the 167,515 going public and private domestic manufacturing firms, we provide consistent evidence that the isolated private firms have higher probability to go public, larger IPO underpricing cross-sectional average and volatility, and less pronounced long-run under-performance. Similar but opposite evidence holds for the local concentration of the investor wealth. These effects are economically relevant and robust to local delistings, IPO market timing, agglomeration economies, firm location endogeneity, self-selection bias, and information asymmetries, among others. Findings suggest IPO waves have a strong geographic component, highlight that underwriters significantly under-estimate the local demand component thus leaving unexpected money on the table, and support state-contingent but constant investor propensity for risk

Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease.

Primary sclerosing cholangitis (PSC) is a rare progressive disorder leading to bile duct destruction; ∼75% of patients have comorbid inflammatory bowel disease (IBD). We undertook the largest genome-wide association study of PSC (4,796 cases and 19,955 population controls) and identified four new genome-wide significant loci. The most associated SNP at one locus affects splicing and expression of UBASH3A, with the protective allele (C) predicted to cause nonstop-mediated mRNA decay and lower expression of UBASH3A. Further analyses based on common variants suggested that the genome-wide genetic correlation (rG) between PSC and ulcerative colitis (UC) (rG = 0.29) was significantly greater than that between PSC and Crohn's disease (CD) (rG = 0.04) (P = 2.55 × 10-15). UC and CD were genetically more similar to each other (rG = 0.56) than either was to PSC (P < 1.0 × 10-15). Our study represents a substantial advance in understanding of the genetics of PSC

Measurement of Z0 decays to hadrons, and a precise determination of the number of neutrino species

We have made a precise measurement of the cross section for e+e---&gt;Z0--&gt;hadrons with the L3 detector at LEP, covering the range from 88.28 to 95.04 GeV. From a fit to the Z0 mass, total width, and the hadronic cross section to be MZ0=91.160 +/- 0.024 (experiment) +/-0.030(LEP) GeV, [Gamma]Z0=2.539+/-0.054 GeV, and [sigma]h(MZ0)=29.5+/-0.7 nb. We also used the fit to the Z0 peak cross section and the width todetermine [Gamma]invisible=0.548+/-0.029 GeV, which corresponds to 3.29+/-0.17 species of light neutrinos. The possibility of four or more neutrino flavors is thus ruled out at the 4[sigma] confidence level.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/28683/3/0000500.pd

Hand Surgery Fellowship Selection Criteria: A National Fellowship Director Survey

Background Candidate characteristics for hand surgery fellowship training remains unknown, as very little data is available in the literature. This study aims to provide information on the criteria that are employed to select candidates for the hand surgery fellowship match. Methods A 38-question survey was sent in April 2015 to all Accreditation Council for Graduate Medical Education recognized hand surgery fellowship program directors (n=81) involved in the U.S. match. The survey investigated factors used for the selection of applicants, including medical school, residency training, research experience, fellowship interview, and candidate characteristics. A 5-point Likert scale was used to grade 33 factors from “not at all important” (1) to “essential in making my decision” (5); or for five controversial factors from “very negative impact” (1) to “very positive impact in making my decision” (5). Results A total of 52% (42 out of 81) of responses were received from hand surgery fellowship program directors. The most important influential factors were interactions with faculty during interview and visit (4.6±0.6), interpersonal skills (4.6±0.5), overall interview performance in the selection process (4.6±0.6), professionalism and ethics (4.6±0.7), and letters of recommendation from hand surgeons (4.5±0.7). Factors that have a negative impact on the selection process include visa requirement (2.1±1.2), graduate of non-plastic surgery residency program (2.4±1.3), and graduate of a foreign medical school (2.4±1.1). Conclusions This study provides data on hand surgery fellowship directors’ perception on the criteria important for fellowship applicant selection, and showed that interview-related criteria and letters of recommendation are the important factors

Lateral Branch of the Thoracodorsal Nerve (LaT Branch) Transfer for Biceps Reinnervation

Summary:. In cases of significant upper extremity trauma, the thoracodorsal nerve is a reliable secondary option for the restoration of elbow flexion. In all previous descriptions, however, the entire nerve is transferred. We describe a case utilizing the lateral thoracodorsal nerve (LaT) branch for biceps reinnervation with an associated cadaver study. Transfer of the LaT branch to the biceps branch was performed on a patient who had sustained a traumatic brachial plexus injury that left him without elbow flexion. Also, 4 cadavers (8 upper extremities) were dissected to identify the bifurcation of the thoracodorsal nerve and confirm the feasibility of transferring the LaT branch to the biceps motor branch. Axon counts of the thoracodorsal proper, LaT branch, musculocutaneous proper, and the biceps branch were also obtained. A bifurcation of the thoracodorsal nerve was present in all cadaver specimens, with an average distance of 7.5 cm (range, 6.2–9.8 cm) from the insertion of the latissimus dorsi muscle. Axon counts revealed a donor-to-recipient ratio of 0.85:1. Follow-up of our patient at 1 year showed improvement of elbow flexion manual muscle testing grade from 0 to 4/5. Furthermore, electromyography at 1 year confirmed biceps reinnervation and showed normal readings of the latissimus compared with preoperative electromyography. Transfer of the LaT branch is a viable and minimally morbid option for biceps reinnervation after traumatic branchial plexus injury. Further follow-up of our patient and larger prospective studies are needed to understand the true potential of this nerve transfer