A 7-year follow-up of sacral anterior root stimulation for bladder control in patients with a spinal cord injury: quality of life and users' experiences\ud

Study design: Cross-sectional descriptive study.\ud \ud Objectives: To assess long-term effects and quality of life (QoL) of using sacral anterior root stimulation (SARS) in spinal cord injured patients.\ud \ud Setting: Neurosurgical and Urological Departments of a large teaching hospital and a large rehabilitation centre in the Netherlands.\ud \ud Methods: In all, 42 patients with complete spinal cord injury (SCI) implanted between 1987 and 2000 were included. A questionnaire was constructed to determine complications, technical failures and personal experiences of the patients. The Qualiveen questionnaire was used and the outcome was compared with data obtained from a reference group of 400 SCI patients with neurogenic bladder problems not using the bladder controller. The Qualiveen questionnaire measures disease-specific aspects in four domains with respect to limitations, constraints, fears and feelings and general QoL aspects, suitable for use in SCI patients with urinary disorders.\ud \ud Results: The results of 37 patients are presented. Our results with the bladder controller with respect to medical and technical complications and infection rates are similar to the results presented by others. From users' experiences, the most important advantages reported were a decreased infection rate (68%), improved social life (54%) and continence (54%). Comparison of the obtained results of our patient group with the Qualiveen questionnaire with a reference group not using the bladder controller indicates that the specific impact of urinary disorders in the four domains on QoL is reduced and that general QoL is improved.\ud \ud Conclusion: SARS is effective and safe for neurogenic bladder management in patients with complete SCI. Users' experiences are positive. Furthermore, this therapy seems to reduce the effects of urinary-disorder-specific QoL aspects, and to increase the QoL in general\u

Minimum target prices for production of direct acting antivirals and associated diagnostics to combat Hepatitis C Virus

Combinations of direct-acting antivirals (DAAs) can cure hepatitis C virus (HCV) in the majority of treatment-naïve patients. Mass treatment programs to cure HCV in developing countries are only feasible if the costs of treatment and laboratory diagnostics are very low. This analysis aimed to estimate minimum costs of DAA treatment and associated diagnostic monitoring. Clinical trials of HCV DAAs were reviewed to identify combinations with consistently high rates of sustained virological response across hepatitis C genotypes. For each DAA, molecular structures, doses, treatment duration, and components of retrosynthesis were used to estimate costs of large-scale, generic production. Manufacturing costs per gram of DAA were based upon treating at least 5 million patients per year and a 40% margin for formulation. Costs of diagnostic support were estimated based on published minimum prices of genotyping, HCV antigen tests plus full blood count/clinical chemistry tests. Predicted minimum costs for 12-week courses of combination DAAs with the most consistent efficacy results were: US$122 per person for sofosbuvir+daclatasvir; US$152 for sofosbuvir+ribavirin; US$192 for sofosbuvir+ledipasvir; and US$115 for MK-8742+MK-5172. Diagnostic testing costs were estimated at US$90 for genotyping US$34 for two HCV antigen tests and US$22 for two full blood count/clinical chemistry tests. Conclusions: Minimum costs of treatment and diagnostics to cure hepatitis C virus infection were estimated at US$171-360 per person without genotyping or US$261-450 per person with genotyping. These cost estimates assume that existing large-scale treatment programs can be established. (Hepatology 2015;61:1174–1182

HOXA10 controls osteoblastogenesis by directly activating bone regulatory and phenotypic genes

HOXA10 is necessary for embryonic patterning of skeletal elements, but its function in bone formation beyond this early developmental stage is unknown. Here we show that HOXA10 contributes to osteogenic lineage determination through activation of Runx2 and directly regulates osteoblastic phenotypic genes. In response to bone morphogenic protein BMP2, Hoxa10 is rapidly induced and functions to activate the Runx2 transcription factor essential for bone formation. A functional element with the Hox core motif was characterized for the bone-related Runx2 P1 promoter. HOXA10 also activates other osteogenic genes, including the alkaline phosphatase, osteocalcin, and bone sialoprotein genes, and temporally associates with these target gene promoters during stages of osteoblast differentiation prior to the recruitment of RUNX2. Exogenous expression and small interfering RNA knockdown studies establish that HOXA10 mediates chromatin hyperacetylation and trimethyl histone K4 (H3K4) methylation of these genes, correlating to active transcription. HOXA10 therefore contributes to early expression of osteogenic genes through chromatin remodeling. Importantly, HOXA10 can induce osteoblast genes in Runx2 null cells, providing evidence for a direct role in mediating osteoblast differentiation independent of RUNX2. We propose that HOXA10 activates RUNX2 in mesenchymal cells, contributing to the onset of osteogenesis, and that HOXA10 subsequently supports bone formation by direct regulation of osteoblast phenotypic genes. <br/

The colonization history of British water vole (Arvicola amphibius (Linnaeus, 1758)): origins and development of the Celtic fringe.

The terminal Pleistocene and Early Holocene, a period from 15 000 to 18 000 Before Present (BP), was critical in establishing the current Holarctic fauna, with temperate-climate species largely replacing cold-adapted ones at mid-latitudes. However, the timing and nature of this process remain unclear for many taxa, a point that impacts on current and future management strategies. Here, we use an ancient DNA dataset to test more directly postglacial histories of the water vole (Arvicola amphibius, formerly A terrestris), a species that is both a conservation priority and a pest in different parts of its range. We specifically examine colonization of Britain, where a complex genetic structure can be observed today. Although we focus on population history at the limits of the species' range, the inclusion of additional European samples allows insights into European postglacial colonization events and provides a molecular perspective on water vole taxonomy

Effective Field Theory for Few-Nucleon Systems

We review the effective field theories (EFTs) developed for few-nucleon systems. These EFTs are controlled expansions in momenta, where certain (leading-order) interactions are summed to all orders. At low energies, an EFT with only contact interactions allows a detailed analysis of renormalization in a non-perturbative context and uncovers novel asymptotic behavior. Manifestly model-independent calculations can be carried out to high orders, leading to high precision. At higher energies, an EFT that includes pion fields justifies and extends the traditional framework of phenomenological potentials. The correct treatment of QCD symmetries ensures a connection with lattice QCD. Several tests and prospects of these EFTs are discussed.Comment: 55 pages, 18 figures, to appear in Ann. Rev. Nucl. Part. Sci. 52 (2002

Measurement of sedentary time and physical activity in rheumatoid arthritis: an ActiGraph and activPAL™ validation study

© 2020 The Authors. Published by Springer. This is an open access article available under a Creative Commons licence. The published version can be accessed at the following link on the publisher’s website: https://doi.org/10.1007/s00296-020-04608-2© 2020, The Author(s). Accurate measurement of sedentary time and physical activity (PA) is essential to establish their relationships with rheumatoid arthritis (RA) outcomes. Study objectives were to: (1) validate the GT3X+ and activPAL3μ™, and develop RA-specific accelerometer (count-based) cut-points for measuring sedentary time, light-intensity PA and moderate-intensity PA (laboratory-validation); (2) determine the accuracy of the RA-specific (vs. non-RA) cut-points, for estimating free-living sedentary time in RA (field-validation). Laboratory-validation: RA patients (n = 22) were fitted with a GT3X+, activPAL3μ™ and indirect calorimeter. Whilst being video-recorded, participants undertook 11 activities, comprising sedentary, light-intensity and moderate-intensity behaviours. Criterion standards for devices were indirect calorimetry (GT3X+) and direct observation (activPAL3μ™). Field-validation: RA patients (n = 100) wore a GT3X+ and activPAL3μ™ for 7 days. The criterion standard for sedentary time cut-points (RA-specific vs. non-RA) was the activPAL3μ™. Results of the laboratory-validation: GT3X—receiver operating characteristic curves generated RA-specific cut-points (counts/min) for: sedentary time = ≤ 244; light-intensity PA = 245–2501; moderate-intensity PA ≥ 2502 (all sensitivity ≥ 0.87 and 1-specificity ≤ 0.11). ActivPAL3μ™—Bland–Altman 95% limits of agreement (lower–upper [min]) were: sedentary = (− 0.1 to 0.2); standing = (− 0.7 to 1.1); stepping = (− 1.2 to 0.6). Results of the field-validation: compared to the activPAL3μ™, Bland–Altman 95% limits of agreement (lower–upper) for sedentary time (min/day) estimated by the RA-specific cut-point = (− 42.6 to 318.0) vs. the non-RA cut-point = (− 19.6 to 432.0). In conclusion, the activPAL3μ™ accurately quantifies sedentary, standing and stepping time in RA. The RA-specific cut-points offer a validated measure of sedentary time, light-intensity PA and moderate-intensity PA in these patients, and demonstrated superior accuracy for estimating free-living sedentary time, compared to non-RA cut-points.Published versio