Twenty Years of Hepatitis C in the Treviso District (Local Health Unit 2): Treatments, Clinical Management and Cost Analysis

Chronic hepatitis C virus (HCV) infection is a global health problem, and about 10-30% of patients develop cirrhosis or hepatocellular carcinoma several years after being infected. In past decades, treatment of HCV infection was based on peginterferon and ribavirin, which lead to a sustained virologic response (SVR) in only 50-60% of patients. Since 2014, direct acting antiviral (DAA) agents have been available. Patients administered DAA agents usually reach SVR in 12 weeks. The aim of this study was to estimate the cost analysis of these innovative drugs while also taking into account the total health expenditure for managing HCV infection. The pharmaceutical and hospitalisation databases of the Local Health Unit (ULSS2) of Treviso were retrospectively analysed between 1997 and 2016 for each HCV patient. During this twenty-year period, people affected by HCV totalled 2,949; 277 of these patients were treated with DAA and, of these, only 2% did not reach SVR. The HCV genotype 1b was the most common, accounting for 58% of the total patients. The treatment for HCV genotype 3 was associated with higher costs. The expenses for the new treatments were found to be significantly higher compared to those for the old ones (i.e., peginterferon and ribavirin). The average costs for a cycle of therapy were €8,000 and €24,000 for interferon and DAA therapy, respectively. Total health care costs associated with HCV (excluding DAA treatments) for an individual HCV infection patient were estimated to be €32,000. Our results confirm the high efficacy of DAA therapy. Furthermore, these agents improve the clinical conditions and reduce both the treatment cost and health care in patients with HCV infection

Lumbar spine and total-body dual-energy X-ray absorptiometry in children with severe neurological impairment and intellectual disability: a pilot study of artefacts and disrupting factors

Background Children with severe neurological impairment and intellectual disability (ID) are susceptible for developing low bone mineral density (BMD) and fractures. BMD is generally measured with dual-energy X-ray absorptiometry (DXA). Objective To describe the occurrence of factors that may influence the feasibility of DXA and the accuracy of DXA outcome in children with severe neurological impairment and ID. Materials and methods Based on literature and expert opinion, a list of disrupting factors was developed. Occurrence of these factors was assessed in 27 children who underwent DXA measurement. Results Disrupting factors that occurred most frequently were movement during measurement (82%), aberrant body composition (67%), small length for age (56%) and scoliosis (37%). The number of disrupting factors per child was mean 5.3 (range 1-8). No correlation was found between DXA outcomes and the number of disrupting factors. Conclusion Factors that may negatively influence the accuracy of DXA outcome are frequently present in children with severe neurological impairment and ID. No systematic deviation of DXA outcome in coherence with the amount of disrupting factors was found, but physicians should be aware of the possible influence of disrupting factors on the accuracy of DXA

Heterostructured electrode with concentration gradient shell for highly efficient oxygen reduction at low temperature

Heterostructures of oxides have been widely investigated in optical, catalytic and electrochemical applications, because the heterostructured interfaces exhibit pronouncedly different transport, charge, and reactivity characteristics compared to the bulk of the oxides. Here we fabricated a three-dimensional (3D) heterostructured electrode with a concentration gradient shell. The concentration gradient shell with the composition of Ba0.5-xSr0.5-yCo0.8Fe0.2O3-δ (BSCF-D) was prepared by simply treating porous Ba0.5Sr0.5Co0.8Fe0.2O3-δ (BSCF) backbone with microwave-plasma. Electrochemical impedance spectroscopy reveals that the oxygen surface exchange rate of the BSCF-D is enhanced by ~250% that of the pristine BSCF due to the appearance of the shell. The heterostructured electrode shows an interfacial resistance as low as 0.148 Ω cm2 at 550°C and an unchanged electrochemical performance after heating treatment for 200 h. This method offers potential to prepare heterostructured oxides not only for electrochemical devices but also for many other applications that use ceramic materials

Predictors of loss to follow up among patients with type 2 diabetes mellitus attending a private not for profit urban diabetes clinic in Uganda : a descriptive retrospective study

BACKGROUND: Although the prevalence of type 2 diabetes mellitus is increasing in Uganda, data on loss to follow up (LTFU) of patients in care is scanty. We aimed to estimate proportions of patients LTFU and document associated factors among patients attending a private not for profit urban diabetes clinic in Uganda. METHODS: We conducted a descriptive retrospective study between March and May 2017. We reviewed 1818 out-patient medical records of adults diagnosed with type 2 diabetes mellitus registered between July 2003 and September 2016 at St. Francis Hospital - Nsambya Diabetes clinic in Uganda. Data was extracted on: patients' registration dates, demographics, socioeconomic status, smoking, glycaemic control, type of treatment, diabetes mellitus complications and last follow-up clinic visit. LTFU was defined as missing collecting medication for six months or more from the date of last clinic visit, excluding situations of death or referral to another clinic. We used Kaplan-Meier technique to estimate time to defaulting medical care after initial registration, log-rank test to test the significance of observed differences between groups. Cox proportional hazards regression model was used to determine predictors of patients' LTFU rates in hazard ratios (HRs). RESULTS: Between July 2003 and September 2016, one thousand eight hundred eighteen patients with type 2 diabetes mellitus were followed for 4847.1 person-years. Majority of patients were female 1066/1818 (59%) and 1317/1818 (72%) had poor glycaemic control. Over the 13 years, 1690/1818 (93%) patients were LTFU, giving a LTFU rate of 34.9 patients per 100 person-years (95%CI: 33.2-36.6). LTFU was significantly higher among males, younger patients (< 45 years), smokers, patients on dual therapy, lower socioeconomic status, and those with diabetes complications like neuropathy and nephropathy. CONCLUSION: We found high proportions of patients LTFU in this diabetes clinic which warrants intervention studies targeting the identified risk factors and strengthening follow up of patients

White matter changes in microstructure associated with a maladaptive response to stress in rats

In today's society, every individual is subjected to stressful stimuli with different intensities and duration. This exposure can be a key trigger in several mental illnesses greatly affecting one's quality of life. Yet not all subjects respond equally to the same stimulus and some are able to better adapt to them delaying the onset of its negative consequences. The neural specificities of this adaptation can be essential to understand the true dynamics of stress as well as to design new approaches to reduce its consequences. In the current work, we employed ex vivo high field diffusion magnetic resonance imaging (MRI) to uncover the differences in white matter properties in the entire brain between Fisher 344 (F344) and Sprague-Dawley (SD) rats, known to present different responses to stress, and to examine the effects of a 2-week repeated inescapable stress paradigm. We applied a tract-based spatial statistics (TBSS) analysis approach to a total of 25 animals. After exposure to stress, SD rats were found to have lower values of corticosterone when compared with F344 rats. Overall, stress was found to lead to an overall increase in fractional anisotropy (FA), on top of a reduction in mean and radial diffusivity (MD and RD) in several white matter bundles of the brain. No effect of strain on the white matter diffusion properties was observed. The strain-by-stress interaction revealed an effect on SD rats in MD, RD and axial diffusivity (AD), with lower diffusion metric levels on stressed animals. These effects were localized on the left side of the brain on the external capsule, corpus callosum, deep cerebral white matter, anterior commissure, endopiriform nucleus, dorsal hippocampus and amygdala fibers. The results possibly reveal an adaptation of the SD strain to the stressful stimuli through synaptic and structural plasticity processes, possibly reflecting learning processes.We thank Neurospin (high field MRI center CEA Saclay) for providing its support for MRI acquisition. JB was supported by grants from Fondation pour la Recherche Médicale (FRM) and Groupe Pasteur Mutualité (GPM). This work was supported by a grant from ANR (SIGMA). This work was performed on a platform of France Life Imaging (FLI) network partly funded by the grant ANR-11-INBS-0006. This work and RM were supported by a fellowship of the project FCT-ANR/NEU-OSD/0258/2012 founded by FCT/MEC (www.fct.pt) and by Fundo Europeu de Desenvolvimento Regional (FEDER). AC was supported by a grant from the Fondation NRJ.info:eu-repo/semantics/publishedVersio

Detection of partial-thickness supraspinatus tendon tears: is a single direct MR arthrography series in ABER position as accurate as conventional MR arthrography?

The purpose of this study was to retrospectively evaluate sensitivity and specificity of a single magnetic resonance (MR) arthrography series in abduction external rotation (ABER) position compared with conventional MR arthrography for detection of supraspinatus tendon tears, with arthroscopy as gold standard, and to assess interobserver variability. Institutional review board approval was obtained; informed consent was waived. MR arthrograms of 250 patients (170 men and 80 women; mean age, 36 years) were retrospectively and independently evaluated by three observers. Oblique coronal T1-weighted fat-suppressed images, proton density, and T2-weighted images and axial T1-weighted images and oblique sagittal T1-weighted fat-suppressed images were analyzed to detect supraspinatus tendon tears. Separately, a single T1-weighted fat-suppressed oblique axial series in ABER position was evaluated. Both protocols were scored randomly without knowledge of patients' clinical history and arthroscopy results. Tears were subclassified, based on articular surface integrity and extension (Lee classification). Interobserver agreement was assessed by kappa statistics for all patients. Ninety-two of 250 patients underwent arthroscopy; sensitivity and specificity of ABER and conventional MR arthrography were calculated and compared using paired McNemar test. Weighted kappa values of ABER and conventional MR arthrography were 0.48-0.65 and 0.60-0.67, respectively. According to arthroscopy, 69 of 92 patients had an intact cuff, and 23 patients had a cuff tear (16 partial thickness and seven full thickness). There were no statistically significant differences between ABER and conventional MR arthrography regarding sensitivity (48-61% and 52-70%, respectively) and specificity (80-94% and 91-95%). Sensitivity and specificity of a single T1-weighted series in ABER position and conventional MR arthrography are comparable for assessment of rotator cuff tear

Metabolic Engineering of Cofactor F420 Production in Mycobacterium smegmatis

Cofactor F420 is a unique electron carrier in a number of microorganisms including Archaea and Mycobacteria. It has been shown that F420 has a direct and important role in archaeal energy metabolism whereas the role of F420 in mycobacterial metabolism has only begun to be uncovered in the last few years. It has been suggested that cofactor F420 has a role in the pathogenesis of M. tuberculosis, the causative agent of tuberculosis. In the absence of a commercial source for F420, M. smegmatis has previously been used to provide this cofactor for studies of the F420-dependent proteins from mycobacterial species. Three proteins have been shown to be involved in the F420 biosynthesis in Mycobacteria and three other proteins have been demonstrated to be involved in F420 metabolism. Here we report the over-expression of all of these proteins in M. smegmatis and testing of their importance for F420 production. The results indicate that co–expression of the F420 biosynthetic proteins can give rise to a much higher F420 production level. This was achieved by designing and preparing a new T7 promoter–based co-expression shuttle vector. A combination of co–expression of the F420 biosynthetic proteins and fine-tuning of the culture media has enabled us to achieve F420 production levels of up to 10 times higher compared with the wild type M. smegmatis strain. The high levels of the F420 produced in this study provide a suitable source of this cofactor for studies of F420-dependent proteins from other microorganisms and for possible biotechnological applications

Atomic-Resolution Simulations Predict a Transition State for Vesicle Fusion Defined by Contact of a Few Lipid Tails

Membrane fusion is essential to both cellular vesicle trafficking and infection by enveloped viruses. While the fusion protein assemblies that catalyze fusion are readily identifiable, the specific activities of the proteins involved and nature of the membrane changes they induce remain unknown. Here, we use many atomic-resolution simulations of vesicle fusion to examine the molecular mechanisms for fusion in detail. We employ committor analysis for these million-atom vesicle fusion simulations to identify a transition state for fusion stalk formation. In our simulations, this transition state occurs when the bulk properties of each lipid bilayer remain in a lamellar state but a few hydrophobic tails bulge into the hydrophilic interface layer and make contact to nucleate a stalk. Additional simulations of influenza fusion peptides in lipid bilayers show that the peptides promote similar local protrusion of lipid tails. Comparing these two sets of simulations, we obtain a common set of structural changes between the transition state for stalk formation and the local environment of peptides known to catalyze fusion. Our results thus suggest that the specific molecular properties of individual lipids are highly important to vesicle fusion and yield an explicit structural model that could help explain the mechanism of catalysis by fusion proteins

Effects of Heparin and Enoxaparin on APP Processing and Aβ Production in Primary Cortical Neurons from Tg2576 Mice

Alzheimer's disease (AD) is caused by accumulation of Aβ, which is produced through sequential cleavage of β-amyloid precursor protein (APP) by the β-site APP cleaving enzyme (BACE1) and γ-secretase. Enoxaparin, a low molecular weight form of the glycosaminoglycan (GAG) heparin, has been reported to lower Aβ plaque deposition and improve cognitive function in AD transgenic mice

How Noisy Adaptation of Neurons Shapes Interspike Interval Histograms and Correlations

Channel noise is the dominant intrinsic noise source of neurons causing variability in the timing of action potentials and interspike intervals (ISI). Slow adaptation currents are observed in many cells and strongly shape response properties of neurons. These currents are mediated by finite populations of ionic channels and may thus carry a substantial noise component. Here we study the effect of such adaptation noise on the ISI statistics of an integrate-and-fire model neuron by means of analytical techniques and extensive numerical simulations. We contrast this stochastic adaptation with the commonly studied case of a fast fluctuating current noise and a deterministic adaptation current (corresponding to an infinite population of adaptation channels). We derive analytical approximations for the ISI density and ISI serial correlation coefficient for both cases. For fast fluctuations and deterministic adaptation, the ISI density is well approximated by an inverse Gaussian (IG) and the ISI correlations are negative. In marked contrast, for stochastic adaptation, the density is more peaked and has a heavier tail than an IG density and the serial correlations are positive. A numerical study of the mixed case where both fast fluctuations and adaptation channel noise are present reveals a smooth transition between the analytically tractable limiting cases. Our conclusions are furthermore supported by numerical simulations of a biophysically more realistic Hodgkin-Huxley type model. Our results could be used to infer the dominant source of noise in neurons from their ISI statistics