Conservatism implications of shock test tailoring for multiple design environments

A method for analyzing shock conservation in test specifications that have been tailored to qualify a structure for multiple design environments is discussed. Shock test conservation is qualified for shock response spectra, shock intensity spectra and ranked peak acceleration data in terms of an Index of Conservation (IOC) and an Overtest Factor (OTF). The multi-environment conservation analysis addresses the issue of both absolute and average conservation. The method is demonstrated in a case where four laboratory tests have been specified to qualify a component which must survive seven different field environments. Final judgment of the tailored test specification is shown to require an understanding of the predominant failure modes of the test item

Entorhinal cortex volume is associated with episodic memory related brain activation in normal aging and amnesic mild cognitive impairment

The present study examined the relationship between entorhinal cortex and hippocampal volume with fMRI activation during episodic memory function in elderly controls with no cognitive impairment and individuals with amnesic mild cognitive impairment (aMCI). Both groups displayed limited evidence for a relationship between hippocampal volume and fMRI activation. Smaller right entorhinal cortex volume was correlated with reduced activation in left and right medial frontal cortex (BA 8) during incidental encoding for both aMCI and elderly controls. However, during recognition, smaller left entorhinal cortex volume correlated with reduced activation in right BA 8 for the control group, but greater activation for the aMCI group. There was no significant relationship between entorhinal cortex volume and activation during intentional encoding in either group. The recognition-related dissociation in structure/function relationships in aMCI paralleled our behavioral findings, where individuals with aMCI displayed poorer performance relative to controls during recognition, but not encoding. Taken together, these results suggest that the relationship between entorhinal cortex volume and fMRI activation during episodic memory function is altered in individuals with aMCI.Illinois. Department of Public HealthNational Institute on Aging (Grant P01 AG09466)National Institute on Aging (Grant P30 AG10161)National Institute on Aging (Grant R01 AG017917)National Institute on Aging (Grant T32 AG000257

Prospects for comparing European hospitals in terms of quality and safety

Purpose. Being able to compare hospitals in terms of quality and safety between countries is important for a number of reasons. For example, the 2011 European Union directive on patients’ rights to cross-border health care places a requirement on all member states to provide patients with comparable information on health-care quality, so that they can make an informed choice. Here, we report on the feasibility of using common process and outcome indicators to compare hospitals for quality and safety in five countries (England, Portugal, The Netherlands, Sweden and Norway). Main Challenges Identified. The cross-country comparison identified the following seven challenges with respect to comparing the quality of hospitals across Europe: different indicators are collected in each country; different definitions of the same indicators are used; different mandatory versus voluntary data collection requirements are in place; different types of organizations oversee data collection; different levels of aggregation of data exist (country, region and hospital); different levels of public access to data exist; and finally, hospital accreditation and licensing systems differ in each country. Conclusion. Our findings indicate that if patients and policymakers are to compare the quality and safety of hospitals across Europe, then further work is urgently needed to agree the way forward. Until then, patients will not be able to make informed choices about where they receive their health care in different countries, and some governments will remain in the dark about the quality and safety of care available to their citizens as compared to that available in neighbouring countries

Safety and Immunogenicity of the Live Attenuated Varicella Vaccine Following T Replete or T Cell-Depleted Related and Unrelated Allogeneic Hematopoietic Cell Transplantation (alloHCT)

There are limited studies assessing the live attenuated varicella vaccine following allogeneic hematopoietic cell transplantation (alloHCT). Because of the morbidity of varicella acquired after childhood, we immunized and retrospectively analyzed the safety and immunogenicity of this vaccine in 46 varicella zoster virus (VZV) seronegative patients <20 years old at HCT who achieved a CD4 cell count ≥200/μL, were off immunosuppression, and responded to ≥1 post-HCT vaccines. Two vaccinated patients lacking follow-up titers were excluded from analysis. Stem cells were derived from an HLA-matched sibling (n = 18) or an alternative (HLA mismatched related or unrelated) donor (n = 26). Median time to vaccination was 4 years. Sixty-four percent of patients seroconverted following 1 immunization. There was no significant difference in response between recipients of a matched related or alternative donor graft (P = .2) or between those given a T cell-depleted or T-replete alternative donor graft (P = .27). Three of 44 patients developed a self-limited varicella-like rash within 2.5 weeks of immunization. With a median follow-up of 29.1 (range: 6.9-167.1) months, there were no subsequent cases of varicella-like rashes. No patient developed shingles. This study suggests that this vaccine is safe and immunogenic when given according to preset clinical and immunologic milestones, warranting larger prospective studies in patients ≥24 months following HCT as outlined in current post-HCT vaccine guidelines

Phase II randomized, double-blind, placebo-controlled study of tivantinib in men with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC)

Background Tivantinib is a non-ATP competitive inhibitor of c-MET receptor tyrosine kinase that may have additional cytotoxic mechanisms including tubulin inhibition. Prostate cancer demonstrates higher c-MET expression as the disease progresses to more advanced stages and to a castration resistant state. Methods 80 patients (pts) with asymptomatic or minimally symptomatic mCRPC were assigned (2:1) to either tivantinib 360 mg PO BID or placebo (P). The primary endpoint was progression free survival (PFS). Results Of the 80 pts. enrolled, 78 (52 tivantinib, 26 P) received treatment and were evaluable. Median follow up is 8.9 months (range: 2.3 to 19.6 months). Patients treated with tivantinib had significantly better PFS vs. those treated with placebo (medians: 5.5 mo vs 3.7 mo, respectively; HR = 0.55, 95% CI: 0.33 to 0.90; p = 0.02). Grade 3 febrile neutropenia was seen in 1 patient on tivantinib while grade 3 and 4 neutropenia was recorded in 1 patient each on tivantinib and placebo. Grade 3 sinus bradycardia was recorded in two men on the tivantinib arm. Conclusions Tivantinib has mild toxicity and improved PFS in men with asymptomatic or minimally symptomatic mCRPC

The HLA class II allele DRB1*1501 is over-represented in patients with idiopathic pulmonary fibrosis

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive and medically refractory lung disease with a grim prognosis. Although the etiology of IPF remains perplexing, abnormal adaptive immune responses are evident in many afflicted patients. We hypothesized that perturbations of human leukocyte antigen (HLA) allele frequencies, which are often seen among patients with immunologic diseases, may also be present in IPF patients. Methods/Principal Findings: HLA alleles were determined in subpopulations of IPF and normal subjects using molecular typing methods. HLA-DRB1*15 was over-represented in a discovery cohort of 79 Caucasian IPF subjects who had lung transplantations at the University of Pittsburgh (36.7%) compared to normal reference populations. These findings were prospectively replicated in a validation cohort of 196 additional IPF subjects from four other U.S. medical centers that included both ambulatory patients and lung transplantation recipients. High-resolution typing was used to further define specific HLA-DRB1*15 alleles. DRB1*1501 prevalence in IPF subjects was similar among the 143 ambulatory patients and 132 transplant recipients (31.5% and 34.8%, respectively, p = 0.55). The aggregate prevalence of DRB1*1501 in IPF patients was significantly greater than among 285 healthy controls (33.1% vs. 20.0%, respectively, OR 2.0; 95%CI 1.3-2.9, p = 0.0004). IPF patients with DRB1*1501 (n = 91) tended to have decreased diffusing capacities for carbon monoxide (DLCO) compared to the 184 disease subjects who lacked this allele (37.8±1.7% vs. 42.8±1.4%, p = 0.036). Conclusions/Significance: DRB1*1501 is more prevalent among IPF patients than normal subjects, and may be associated with greater impairment of gas exchange. These data are novel evidence that immunogenetic processes can play a role in the susceptibility to and/or manifestations of IPF. Findings here of a disease association at the HLA-DR locus have broad pathogenic implications, illustrate a specific chromosomal area for incremental, targeted genomic study, and may identify a distinct clinical phenotype among patients with this enigmatic, morbid lung disease