Effectiveness and tolerability of pegylated interferon alfa-2b in combination with ribavirin for treatment of chronic hepatitis C: the PegIntrust Study

Background and study aims : Large international clinical trials conducted in the past 5 years rapidly improved the treatment of chronic hepatitis C; however, it is unclear whether the advances seen in clinical trials are being paralleled by similar improvements in routine clinical practice. PegIntrust is a Belgian community-based trial evaluating the sustained virological response. Patients and Methods : Observational study of 219 patients receiving pegylated interferon alfa-2b (1.5 mu g/kg/wk) and weight. based ribavirin (800-1200 mg/day) for 48 weeks. Primary study end point was sustained virological response (SVR), defined as undetectable HCV RNA 6 months after the completion of treatment. Results : In total, 108 patients (49.3 %) had undetectable HCV RNA at the end of therapy, 91(41.6%) attaining SVR. Of the 111 patients without an end-of-treatment response, 28 were non-responders, and 21 had virological breakthrough. In total, 134 patients attained early virological response (EVR); 88 (65.7%) of those patients attained SVR. In contrast, 82 (96.5 %) of the 85 patients who did not attain EVR also did not attain SVR. Age, fibrosis score and baseline viral load were identified as important predictors of treatment outcome. The most frequently reported serious adverse events resulting in treatment discontinuation were anemia (n = 10), fatigue/asthenia/malaise (n = 6) and fever (n = 3). Conclusion : Our data indicate that treatment of chronic hepatitis C with PEG-IFN alfa-2b plus weight-based ribavirin results in favourable treatment outcomes in a Belgian cohort of patients treated in community-based clinical practice. (Ada gastroenterol. belg., 2010, 73, 5-11)

Risk factors for progression from severe maternal morbidity to death: a national cohort study.

Women continue to die unnecessarily during or after pregnancy in the developed world. The aim of this analysis was to compare women with severe maternal morbidities who survived with those who died, to quantify the risk associated with identified factors to inform policy and practice to improve survival

Ecological association between a deprivation index and mortality in France over the period 1997 – 2001: variations with spatial scale, degree of urbanicity, age, gender and cause of death

<p>Abstract</p> <p>Background</p> <p>Spatial health inequalities have often been analysed in terms of deprivation. The aim of this study was to create an ecological deprivation index and evaluate its association with mortality over the entire mainland France territory. More specifically, the variations with the degree of urbanicity, spatial scale, age, gender and cause of death, which influence the association between mortality and deprivation, have been described.</p> <p>Methods</p> <p>The deprivation index, 'FDep99', was developed at the '<it>commune</it>'(smallest administrative unit in France) level as the first component of a principal component analysis of four socioeconomic variables.</p> <p>Proxies of the Carstairs and Townsend indices were calculated for comparison.</p> <p>The spatial association between FDep99 and mortality was studied using five different spatial scales, and by degree of urbanicity (five urban unit categories), age, gender and cause of death, over the period 1997–2001.</p> <p>'Avoidable' causes of death were also considered for subjects aged less than 65 years. They were defined as causes related to risk behaviour and primary prevention (alcohol, smoking, accidents).</p> <p>Results</p> <p>The association between the FDep99 index and mortality was positive and quasi-log-linear, for all geographic scales. The standardized mortality ratio (SMR) was 24% higher for the <it>communes </it>of the most deprived quintile than for those of the least deprived quintile. The between-urban unit category and between-<it>région </it>heterogeneities of the log-linear associations were not statistically significant. The association was positive for all the categories studied and was significantly greater for subjects aged less than 65 years, for men, and for 'avoidable' mortality.</p> <p>The amplitude and regularity of the associations between mortality and the Townsend and Carstairs indices were lower.</p> <p>Conclusion</p> <p>The deprivation index proposed reflects a major part of spatial socioeconomic heterogeneity, in a homogeneous manner over the whole country. The index may be routinely used by healthcare authorities to observe, analyse, and manage spatial health inequalities.</p

Brain injury-associated biomarkers of TGF-beta1, S100B, GFAP, NF-L, tTG, AbetaPP, and tau were concomitantly enhanced and the UPS was impaired during acute brain injury caused by Toxocara canis in mice

BACKGROUND: Because the outcomes and sequelae after different types of brain injury (BI) are variable and difficult to predict, investigations on whether enhanced expressions of BI-associated biomarkers (BIABs), including transforming growth factor beta1 (TGF-beta1), S100B, glial fibrillary acidic protein (GFAP), neurofilament light chain( NF-L), tissue transglutaminases (tTGs), beta-amyloid precursor proteins (AbetaPP), and tau are present as well as whether impairment of the ubiquitin-proteasome system (UPS) is present have been widely used to help delineate pathophysiological mechanisms in various BIs. Larvae of Toxocara canis can invade the brain and cause BI in humans and mice, leading to cerebral toxocariasis (CT). Because the parasitic burden is light in CT, it may be too cryptic to be detected in humans, making it difficult to clearly understand the pathogenesis of subtle BI in CT. Since the pathogenesis of murine toxocariasis is very similar to that in humans, it appears appropriate to use a murine model to investigate the pathogenesis of CT. METHODS: BIAB expressions and UPS function in the brains of mice inoculated with a single dose of 250 T. canis embryonated eggs was investigated from 3 days (dpi) to 8 weeks post- infection (wpi) by Western blotting and RT-PCR. RESULTS: Results revealed that at 4 and 8 wpi, T. canis larvae were found to have invaded areas around the choroid plexus but without eliciting leukocyte infiltration in brains of infected mice; nevertheless, astrogliosis, an indicator of BI, with 78.9~142.0-fold increases in GFAP expression was present. Meanwhile, markedly increased levels of other BIAB proteins including TGF-beta1, S100B, NF-L, tTG, AbetaPP, and tau, with increases ranging 2.0~12.0-fold were found, although their corresponding mRNA expressions were not found to be present at 8 wpi. Concomitantly, UPS impairment was evidenced by the overexpression of conjugated ubiquitin and ubiquitin in the brain. CONCLUSION: Further studies are needed to determine whether there is an increased risk of CT progression into neurodegenerative disease because neurodegeneration-associated AbetaPP and phosphorylated tau emerged in the brain. DOI: 10.1186/1471-2334-8-8

Alzheimer disease models and human neuropathology: similarities and differences

Animal models aim to replicate the symptoms, the lesions or the cause(s) of Alzheimer disease. Numerous mouse transgenic lines have now succeeded in partially reproducing its lesions: the extracellular deposits of Aβ peptide and the intracellular accumulation of tau protein. Mutated human APP transgenes result in the deposition of Aβ peptide, similar but not identical to the Aβ peptide of human senile plaque. Amyloid angiopathy is common. Besides the deposition of Aβ, axon dystrophy and alteration of dendrites have been observed. All of the mutations cause an increase in Aβ 42 levels, except for the Arctic mutation, which alters the Aβ sequence itself. Overexpressing wild-type APP alone (as in the murine models of human trisomy 21) causes no Aβ deposition in most mouse lines. Doubly (APP × mutated PS1) transgenic mice develop the lesions earlier. Transgenic mice in which BACE1 has been knocked out or overexpressed have been produced, as well as lines with altered expression of neprilysin, the main degrading enzyme of Aβ. The APP transgenic mice have raised new questions concerning the mechanisms of neuronal loss, the accumulation of Aβ in the cell body of the neurons, inflammation and gliosis, and the dendritic alterations. They have allowed some insight to be gained into the kinetics of the changes. The connection between the symptoms, the lesions and the increase in Aβ oligomers has been found to be difficult to unravel. Neurofibrillary tangles are only found in mouse lines that overexpress mutated tau or human tau on a murine tau −/− background. A triply transgenic model (mutated APP, PS1 and tau) recapitulates the alterations seen in AD but its physiological relevance may be discussed. A number of modulators of Aβ or of tau accumulation have been tested. A transgenic model may be analyzed at three levels at least (symptoms, lesions, cause of the disease), and a reading key is proposed to summarize this analysis

Laddered motivations of external whistleblowers: The truth about attributes, consequences, and values

The purpose of this study was to explore the motivational structures of external whistleblowers involved in the decision to blow the whistle by applying MEC theory and the laddering technique. Using both soft and hard laddering methods, data were collected from 37 Korean external whistleblowers. Results revealed that the means-end chain of external whistleblow-ers was the hierarchical linkage among two concrete attributes (the power of external whistleblowing to make changes and its warning about the seriousness of wrongdoing to the public), two functional consequences (correcting a wrongdoing and making those who violated laws admit their offenses), and one terminal value (the truth). The extant whistleblowing literature has either made assumptions about whistleblowers’ motivations when developing models or has drawn indirect inferences from measures of other variables. Our study is the first with an explicit and empirical focus on whistleblowers’ motivations. The findings provide evidence of the motivational structures of external whistleblowers that consist of a set of complex paths linked by multi-layered motivators. This research will be helpful in designing and reviewing whistleblowing programs for organizations, regulatory agencies, and journalists

The broad-lined Type-Ic supernova SN 2022xxf and its extraordinary two-humped light curves: I. Signatures of H/He-free interaction in the first four months

We report on our study of supernova (SN) 2022xxf based on observations obtained during the first four months of its evolution. The light curves (LCs) display two humps of similar maximum brightness separated by 75 days, unprecedented for a broad-lined (BL) Type Ic supernova (SN IcBL). SN 2022xxf is the most nearby SN IcBL to date (in NGC 3705, z = 0.0037, at a distance of about 20 Mpc). Optical and near-infrared photometry and spectroscopy are used to identify the energy source powering the LC. Nearly 50 epochs of high signal-to-noise-ratio spectroscopy were obtained within 130 days, comprising an unparalleled dataset for a SN IcBL, and one of the best-sampled SN datasets to date. The global spectral appearance and evolution of SN 2022xxf points to typical SN Ic/IcBL, with broad features (up to ~1400 km s-1 and a gradual transition from the photospheric to the nebular phase. However, narrow emission lines (corresponding to ~1000-2500 km s-1 are present in the spectra from the time of the second rise, suggesting slower-moving circumstellar material (CSM). These lines are subtle, in comparison to the typical strong narrow lines of CSM-interacting SNe, for example, Type IIn, Ibn, and Icn, but some are readily noticeable at late times such as in Mg I \5170 and [O I] \l5577. Unusually, the near-infrared spectra show narrow line peaks in a number of features formed by ions of O and Mg. We infer the presence of CSM that is free of H and He. We propose that the radiative energy from the ejecta-CSM interaction is a plausible explanation for the second LC hump. This interaction scenario is supported by the color evolution, which progresses to the blue as the light curve evolves along the second hump, and the slow second rise and subsequent rapid LC drop. SN2022xxf may be related to an emerging number of CSM-interacting SNeIc, which show slow, peculiar LCs, bluecolors,and subtle CSM interaction lines.The progenitor stars of these SNe likely experienced an episode of mass loss consistingof H/He-free material shortly prio rto explosion