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Abstract: The variance analysis of actual loan sanctions with the non-documented method of loan allocation of the selected retail bank, over a period of 24 months, revealed that there is [...]

Introduction: Post-licensure surveillance of adverse events following vaccination or prescription drug use often relies on electronic healthcare data to efficiently detect and evaluate safety signals. The accuracy of seizure-related diagnosis codes in identifying true incident seizure events in vaccine safety studies is influenced by factors such as clinical setting of diagnosis and age. To date, most studies of post-vaccination seizure have focused on pediatric populations. More information is needed on how well seizure can be identified in adults and children using algorithms that rely on electronic healthcare data., Methods: This validation study was part of a larger safety study of influenza vaccination during the 2009-2010 and 2010-2011 influenza seasons. Children and adults receiving influenza vaccination were drawn from an administrative claims database of a large United States healthcare insurer. Potential seizure events were identified using an algorithm of ICD-9 diagnosis codes associated with an emergency department (ED) visit or hospitalization within pre-specified risk windows following influenza vaccination. Seizure events were confirmed through medical record review. The positive predictive value (PPV) of the algorithm was calculated within each diagnostic setting and stratified by age group, ICD-9 code group, and sex., Results: Review confirmed 113 out of 176 potential seizure events. The PPVs were higher in the ED setting (93.9%) than in the inpatient setting (38.3%). The PPVs by age varied within the ED setting (98.2% in <7 years, 76.9% in 7-24 years, 92.3% in ≥25 years) and within the inpatient setting (64.7% in <7 years, 33.3% in 7-24 years, 32.3% in ≥25 years)., Conclusions: Our algorithm for identification of seizure events using claims data had a high level of accuracy in the emergency department setting in young children and older adults and a lower, but acceptable, level of accuracy in older children and young adults., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Introduction: As part of the Centers for Disease Control and Prevention's monitoring and evaluation activities for influenza vaccines, we examined relationships between influenza vaccination and selected outcomes in the 2009-2010 and 2010-2011 influenza seasons in a claims-based data environment., Methods: We included patients with claims for trivalent influenza vaccine (TIV) and/or 2009 pandemic influenza A H1N1 vaccine (H1N1) during the 2009-2010 and 2010-2011 influenza seasons. Patients were followed for several pre-specified outcomes identified in claims. Seizures and Guillain-Barré Syndrome were selected a priori for medical record confirmation. We estimated incidence rate ratios (IRR) using a self-controlled risk interval (SCRI) or a historical comparison design. Outcomes with elevated IRRs, not selected a priori for medical record review, were further investigated with review of claims histories surrounding the outcome date to determine whether the potential event could be ruled-out or attributed to other causes based on the pattern of medical care., Results: In the 2009-2010 season, no significant increased risks for outcomes following H1N1 vaccination were observed. Following TIV administration, the IRR for peripheral nervous system disorders and neuropathy was slightly elevated (1.07, 95% CI: 1.01-1.13). The IRR for anaphylaxis following TIV was 28.55 (95% CI: 3.57-228.44). After further investigation of claims histories, the majority of potential anaphylaxis cases had additional claims around the time of the event indicating alternate explanatory factors or diagnoses. In the 2010-2011 season following TIV administration, a non-significant elevated IRR for anaphylaxis was observed with no other significant outcome findings., Conclusion: After claims history review, we ultimately found no increased outcome risk following administration of 998,881 TIV and 538,257 H1N1 vaccine doses in the 2009-2010 season, and 1,158,932 TIV doses in the 2010-2011 season., (Published by Elsevier Ltd.)

Objective: To estimate rates of all-cause mortality, fatal infection, and fatal malignancy in rheumatoid arthritis (RA) patients treated with anti-tumor necrosis factor-α (anti-TNF) biologics., Methods: A retrospective cohort study of RA patients initiating therapy with adalimumab, etanercept, or infliximab from January 2000 to December 2008 was conducted using an administrative database of a large health care insurer. Patients were followed for the occurrence of fatal events, which were identified using the National Death Index database. Overall and anti-TNF biologic-stratified incidence rates per 1000 person-years were calculated. Primary analyses were time-on-drug based on current anti-TNF biologic exposure on the outcome date for fatal infection and intent-to-treat based on the anti-TNF biologic initiated at cohort entry for fatal malignancy., Results: Seven thousand seven hundred thirty-four patients initiated an anti-TNF biologic with 13,296 person-years of observation. Seventy-one deaths were identified, including 12 fatal infections and 21 fatal malignancies. The all-cause mortality rate was 5.34 per 1000 person-years. Incidence rates for fatal infection were similar among anti-TNF biologic current exposure groups (0.78 to 0.88 per 1000 person-years). Incidence rates for fatal malignancy were similar among anti-TNF biologic initiator groups (1.24 to 1.84 per 1000 person-years)., Conclusions: The all-cause mortality rate in RA patients treated with anti-TNF biologics was lower than in previous studies in similar non-US populations, but comparable to mortality rates in the US general population. Fatal infection and fatal malignancy rates were similar across anti-TNF biologic groups. Further studies, designed to detect risk differences associated with anti-TNF biologic use and baseline risk factors, would provide additional information., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Single-center studies have shown acceptable long-term outcomes following orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC) when tumors are within the Milan criteria. However, the overall survival and waiting list removal rates have not been described at a national level with pooled registry data. To evaluate this, a retrospective cohort of patients listed for OLT with a diagnosis of HCC between January 1998 and March 2006 was identified from Organ Procurement Transplant Network data. Analysis was performed from the time of listing. Adjusted Cox models were used to assess the relative effect of potential confounders on removal from the waiting list as well as survival from the time of wait listing. A total of 4482 patients with HCC were placed on the liver waiting list during the study period. Of these, 65% underwent transplantation, and 18% were removed from the list because of tumor progression or death. The overall 1- and 5-year intent-to-treat survival for all patients listed was 81% and 51%, respectively. The 1- and 5-year survival was 89% and 61% for those listed with tumors meeting the Milan criteria versus 70% and 32% for those exceeding the Milan criteria (P < 0.0001). On multivariate analysis, advanced liver failure manifested by Child-Pugh class B or C increased the risk of death, while age < 55 years, meeting the Milan criteria, and obtaining a liver transplant were associated with better survival. The current criteria for liver transplantation of candidates with HCC lead to acceptable 5-year survival while limiting the dropout rate. Liver Transpl 15:859-868, 2009. (c) 2009 AASLD.

Voltage-gated sodium channel alpha and beta subunits expressed in mammalian heart are differentially localized to t-tubules and intercalated disks. Sodium channel beta subunits are multifunctional molecules that participate in channel modulation and cell adhesion. Reversible, receptor-mediated changes in beta1 tyrosine phosphorylation modulate its ability to recruit and associate with ankyrin. The purpose of the present study was to test our hypothesis that tyrosine-phosphorylated beta1 (pYbeta1) and nonphosphorylated beta1 subunits may be differentially localized in heart and thus interact with different cytoskeletal and signaling proteins. We developed an antibody that specifically recognizes pYbeta1 and investigated the differential subcellular localization of beta1 and pYbeta1 in mouse ventricular myocytes. We found that pYbeta1 colocalized with connexin-43, N-cadherin, and Nav1.5 at intercalated disks but was not detected at the t-tubules. Anti-pYbeta1 immunoprecipitates N-cadherin from heart membranes and from cells transfected with beta1 and N-cadherin in the absence of other sodium channel subunits. pYbeta1 does not associate with ankyrinB in heart membranes. N-cadherin and connexin-43 associate with Nav1.5 in heart membranes as assessed by co-immunoprecipitation assays. We propose that sodium channel complexes at intercalated disks of ventricular myocytes are composed of Nav1.5 and pYbeta1 and that these complexes are in close association with both N-cadherin and connexin-43. beta1 phosphorylation appears to regulate its localization to differential subcellular domains., (Copyright 2004 American Society for Biochemistry and Molecular Biology, Inc.)

Voltage-gated sodium channels are composed of a pore-forming alpha subunit and at least one auxiliary beta subunit. Both beta1 and beta2 are cell adhesion molecules that interact homophilically, resulting in ankyrin recruitment. In contrast, beta1, but not beta2, interacts heterophilically with contactin, resulting in increased levels of cell surface sodium channels. We took advantage of these results to investigate the molecular basis of beta1-mediated enhancement of sodium channel cell surface density, including elucidating structure-function relationships for beta1 association with contactin, ankyrin, and Nav1.2. beta1/beta2 subunit chimeras were used to assign putative sites of contactin interaction to two regions of the beta1 Ig loop. Recent studies have shown that glutathione S-transferase fusion proteins containing portions of Nav1.2 intracellular domains interact directly with ankyrinG. We show that native Nav1.2 associates with ankyrinG in cells in the absence of beta subunits and that this interaction is enhanced in the presence of beta1 but not beta1Y181E, a mutant that does not interact with ankyrinG. beta1Y181E does not modulate Nav1.2 channel function despite efficient association with Nav1.2 and contactin. beta1Y181E increases Nav1.2 cell surface expression, but not as efficiently as wild type beta1. beta1/beta2 chimeras exchanging various regions of the beta1 Ig loop were all ineffective in increasing Nav1.2 cell surface density. Our results demonstrate that full-length beta1 is required for channel modulation and enhancement of sodium channel cell surface expression.

Generalized epilepsy with febrile seizures plus type 1 is an inherited human epileptic syndrome, associated with a cysteine-to-tryptophan (C121W) mutation in the extracellular immunoglobin domain of the auxiliary beta1 subunit of the voltage-gated sodium channel. The mutation disrupts beta1 function, but how this leads to epilepsy is not understood. In this study, we make several observations that may be relevant for understanding why this beta1 mutation results in seizures. First, using electrophysiological recordings from mammalian cell lines, coexpressing sodium channel alpha subunits and either wild-type beta1 or C121Wbeta1, we show that loss of beta1 functional modulation, caused by the C121W mutation, leads to increased sodium channel availability at hyperpolarized membrane potentials and reduced sodium channel rundown during high-frequency channel activity, compared with channels coexpressed with wild-type beta1. In contrast, neither wild-type beta1 nor C121Wbeta1 significantly affected sodium current time course or the voltage dependence of channel activation. We also show, using a Drosophila S2 cell adhesion assay, that the C121W mutation disrupts beta1-beta1 homophilic cell adhesion, suggesting that the mutation may alter the ability of beta1 to mediate protein-protein interactions critical for sodium channel localization. Finally, we demonstrate that neither functional modulation nor cell adhesion mediated by wild-type beta1 is occluded by coexpression of C121Wbeta1, arguing against the idea that the mutant beta1 acts as a dominant-negative subunit. Together, these data suggest that C121Wbeta1 causes subtle effects on channel function and subcellular distribution that bias neurons toward hyperexcitabity and epileptogenesis.