Clearing up the hazy road from bench to bedside: A framework for integrating the fourth hurdle into translational medicine

<p>Abstract</p> <p>Background</p> <p>New products evolving from research and development can only be translated to medical practice on a large scale if they are reimbursed by third-party payers. Yet the decision processes regarding reimbursement are highly complex and internationally heterogeneous. This study develops a process-oriented framework for monitoring these so-called fourth hurdle procedures in the context of product development from bench to bedside. The framework is suitable both for new drugs and other medical technologies.</p> <p>Methods</p> <p>The study is based on expert interviews and literature searches, as well as an analysis of 47 websites of coverage decision-makers in England, Germany and the USA.</p> <p>Results</p> <p>Eight key steps for monitoring fourth hurdle procedures from a company perspective were determined: entering the scope of a healthcare payer; trigger of decision process; assessment; appraisal; setting level of reimbursement; establishing rules for service provision; formal and informal participation; and publication of the decision and supplementary information. Details are given for the English National Institute for Health and Clinical Excellence, the German Federal Joint Committee, Medicare's National and Local Coverage Determinations, and for Blue Cross Blue Shield companies.</p> <p>Conclusion</p> <p>Coverage determination decisions for new procedures tend to be less formalized than for novel drugs. The analysis of coverage procedures and requirements shows that the proof of patient benefit is essential. Cost-effectiveness is likely to gain importance in future.</p

Immunological reactivity of a human immunodeficiency virus type I derived peptide representing a consensus sequence of the GP120 major neutralizing region V3

To reduce the opportunities for human immunodeficiency virus type 1 (HIV-1) to evade vaccine induced immunity, the development of subunit vaccines must focus on the characterization of immunogenic epitopes, which are major targets for the immune system. The most dominant site for elicitation of neutralising immune response is located on the external envelope glycoprotein gp120 within the third variable domain (V3). To overcome virus type specificity of antibodies directed to the V3-domain we designed a 36 amino acids long gp120/V3-consensus peptide (V3-C36) based on published biological data and sequence comparisons of various HIV-1 virus isolates. This peptide contains a conserved core sequence which is suggested to form a surface-exposed beta-turn. This peptide also includes T-cell epitopes defined in mice and humans, an ADCC-epitope and two highly conserved cysteine residues which were oxidized to form a cystine derivate, thus allowing correct peptide folding. In ELISA-tests, this peptide reacts with at least 90% of randomly selected sera of European and African patients infected with HIV-1 and is recognized by three different HIV-1/V3 "type-specific" antisera (MN, RF, IIIB-strain). Using this peptide as immunogen in rabbits, antisera could be raised with highly cross-reactive and HIV-1/IIIB strain neutralizing properties. Moreover, HTLV/HIV-1/IIIB specific cytotoxic T-lymphocytes (CTLs) of BALB/c mice infected with a gp120 recombinant vaccinia virus recognized the central 16- and 12-mer peptides of the V3-C36 consensus peptide in cytolytic assays, indicating perfect compatibility of the consensus peptide with the IIIB-primed CTLs. The DNA-sequence encoding the V3-consensus loop region might be an important component in newly designed recombinant subunit vaccines. In addition, due to its broad serological reactivity, the V3-consensus peptide might play an important role in special diagnostic purposes

Occupation recorded on certificates of death compared with self-report: the Atherosclerosis Risk in Communities (ARIC) Study

<p>Abstract</p> <p>Background</p> <p>Death certificates are a potential source of sociodemographic data for decedents in epidemiologic research. However, because this information is provided by the next-of-kin or other proxies, there are concerns about validity. Our objective was to assess the agreement of job titles and occupational categories derived from death certificates with that self-reported in mid and later life.</p> <p>Methods</p> <p>Occupation was abstracted from 431 death certificates from North Carolina Atherosclerosis Risk in Communities Study participants who died between 1987 and 2001. Occupations were coded according to 1980 Bureau of Census job titles and then grouped into six 1980 census occupational categories. This information was compared with the self-reported occupation at midlife as reported at the baseline examination (1987–89). We calculated percent agreement using standard methods. Chance-adjusted agreement was assessed by kappa coefficients, with 95% confidence intervals.</p> <p>Results</p> <p>Agreement between death certificate and self-reported job titles was poor (32%), while 67% of occupational categories matched the two sources. Kappa coefficients ranged from 0.53 for technical/sales/administrative jobs to 0.68 for homemakers. Agreement was lower, albeit nonsignificant, for women (kappa = 0.54, 95% Confidence Interval, CI = 0.44–0.63) than men (kappa = 0.62, 95% CI = 0.54–0.69) and for African-Americans (kappa = 0.47, 95% CI = 0.34–0.61) than whites (kappa = 0.63, 95% CI = 0.57–0.69) but varied only slightly by educational attainment.</p> <p>Conclusion</p> <p>While agreement between self- and death certificate reported job titles was poor, agreement between occupational categories was good. This suggests that while death certificates may not be a suitable source of occupational data where classification into specific job titles is essential, in the absence of other data, it is a reasonable source for constructing measures such as occupational SES that are based on grouped occupational data.</p

Comparison of the Effects of Early Pregnancy with Human Interferon, Alpha 2 (IFNA2), on Gene Expression in Bovine Endometrium

Interferon tau (IFNT), a type I IFN similar to alpha IFNs (IFNA), is the pregnancy recognition signal produced by the ruminant conceptus. To elucidate specific effects of bovine IFNT and of other conceptus-derived factors, endometrial gene expression changes during early pregnancy were compared to gene expression changes after intrauterine application of human IFNA2. In experiment 1, endometrial tissue samples were obtained on Day (D) 12, D15, and D18 postmating from nonpregnant or pregnant heifers. In experiment 2, heifers were treated from D14 to D16 of the estrous cycle with an intrauterine device releasing IFNA2 or, as controls, placebo lipid extrudates or PBS only. Endometrial biopsies were performed after flushing the uterus. All samples from both experiments were analyzed with an Affymetrix Bovine Genome Array. Experiment 1 revealed differential gene expression between pregnant and nonpregnant endometria on D15 and D18. In experiment 2, IFNA2 treatment resulted in differential gene expression in the bovine endometrium. Comparison of the data sets from both studies identified genes that were differentially expressed in response to IFNA2 but not in response to pregnancy on D15 or D18. In addition, genes were found that were differentially expressed during pregnancy but not after IFNA2 treatment. In experiment 3, spatiotemporal alterations in expression of selected genes were determined in uteri from nonpregnant and early pregnant heifers using in situ hybridization. The overall findings of this study suggest differential effects of bovine IFNT compared to human IFNA2 and that some pregnancy-specific changes in the endometrium are elicited by conceptus-derived factors other than IFNT

Association of Injury History and Incident Injury in Cadet Basic Military Training

To determine the association between injury history at enrollment and incident lower extremity (LE) injury during cadet basic training among first-year military cadets

Identification of a protein encoded in the EB-viral open reading frame BMRF2

Using monospecific rabbit sera against a peptide derived from a potential antigenic region of the Epstein-Barr viral amino acid sequence encoded in the open reading frame BMRF2 we could identify a protein-complex of 53/55 kDa in chemically induced B95-8, P3HR1 and Raji cell lines. This protein could be shown to be membrane-associated, as predicted by previous computer analysis of the secondary structure and hydrophilicity pattern, and may be a member of EBV-induced membrane proteins in lytically infected cells

Evidence for a regulatory role of Cullin-RING E3 ubiquitin ligase 7 in insulin signalling

Dysfunctional regulation of signalling pathways downstream of the insulin receptor plays a pivotal role in the pathogenesis of insulin resistance and type 2 diabetes. In this study we report both in vitro and in vivo experimental evidence for a role of Cullin-RING E3 ubiquitin ligase 7 (CRL7) in the regulation of insulin signalling and glucose homeostasis. We show that Cul7−/− mouse embryonic fibroblasts displayed enhanced AKT and Erk MAP kinase phosphorylation upon insulin stimulation. Depletion of CUL7 by RNA interference in C2C12 myotubes led to increased activation of insulin signalling pathways and cellular glucose uptake, as well as a reduced capacity of these cells to execute insulin-induced degradation of insulin receptor substrate 1 (IRS1). In vivo, heterozygosity of either Cul7 or Fbxw8, both key components of CRL7, resulted in elevated PI3 kinase / AKT activation in skeletal muscle tissue upon insulin stimulation when compared to wild-type controls. Finally, Cul7+/− or Fbxw8+/− mice exhibited enhanced insulin sensitivity and plasma glucose clearance. Collectively, our findings point to a yet unrecognized role of CRL7 in insulin-mediated control of glucose homeostasis by restraining PI3 kinase / AKT activities in skeletal muscle cells

Hourly Exposure to Ultrafine Particle Metrics and the Onset of Myocardial Infarction in Augsburg, Germany

BACKGROUND: Epidemiological evidence on the health effects of ultrafine particles (UFP) remains insufficient to infer a causal relationship that is largely due to different size ranges and exposure metrics examined across studies. Moreover, evidence regarding the association between UFP and cardiovascular disease at a sub-daily timescale is lacking. OBJECTIVE: We investigated the relationship between different particle metrics, including particle number (PNC), length (PLC), and surface area (PSC) concentrations, and myocardial infarction (MI) at an hourly timescale. METHODS: We collected hourly air pollution and meteorological data from fixed urban Background: monitoring sites and hourly nonfatal MI cases from a MI registry in Augsburg, Germany, during 2005-2015. We conducted a time-stratified case-crossover analysis with conditional logistic regression to estimate the association between hourly particle metrics and MI cases, adjusted for air temperature and relative humidity. We also examined the independent effects of a certain particle metric in two-pollutant models by adjusting for copollutants, including particulate matter (PM) with an aerodynamic diameter of >= 10 mu m or 2.5 mu m (PM10 and PM2.5, respectively), nitrogen dioxide, ozone, and black carbon. RESULTS: Overall, a total of 5,898 cases of nonfatal MI cases were recorded. Exploratory analyses showed similar associations across particle metrics in the first 6-12 h. For example, interquartile range increases in PNC within the size range of 10-100 nm, PLC, and PSC were associated with an increase of MI 6 h later by 3.27% [95% confidence interval (CI): 0.27, 6.37], 5.71% (95% CI: 1.79, 9.77), and 5.84% (95% CI: 1.04, 10.87), respectively. Positive, albeit imprecise, associations were observed for PNC within the size range of 10-30 nm and 100-500 nm. Effect estimates for PLC and PSC remained similar after adjustment for PM and gaseous pollutants. CONCLUSIONS: Transient exposure to particle number, length, and surface area concentrations or other potentially related exposures may trigger the onset of nonfatal myocardial infraction

The WISDOM Radar: Unveiling the Subsurface Beneath the ExoMars Rover and Identifying the Best Locations for Drilling

The search for evidence of past or present life on Mars is the principal objective of the 2020 ESA-Roscosmos ExoMars Rover mission. If such evidence is to be found anywhere, it will most likely be in the subsurface, where organic molecules are shielded from the destructive effects of ionizing radiation and atmospheric oxidants. For this reason, the ExoMars Rover mission has been optimized to investigate the subsurface to identify, understand, and sample those locations where conditions for the preservation of evidence of past life are most likely to be found. The Water Ice Subsurface Deposit Observation on Mars (WISDOM) ground-penetrating radar has been designed to provide information about the nature of the shallow subsurface over depth ranging from 3 to 10 m (with a vertical resolution of up to 3 cm), depending on the dielectric properties of the regolith. This depth range is critical to understanding the geologic evolution stratigraphy and distribution and state of subsurface H2O, which provide important clues in the search for life and the identification of optimal drilling sites for investigation and sampling by the Rover's 2-m drill. WISDOM will help ensure the safety and success of drilling operations by identification of potential hazards that might interfere with retrieval of subsurface samples