High prevalence of scrapie in a dairy goat herd: tissue distribution of disease-associated PrP and effect of PRNP genotype and age

Following a severe outbreak of clinical scrapie in 2006–2007, a large dairy goat herd was culled and 200 animals were selected for post-mortem examinations in order to ascertain the prevalence of infection, the effect of age, breed and PRNP genotype on the susceptibility to scrapie, the tissue distribution of diseaseassociated PrP (PrP$^{\rm d}$), and the comparative efficiency of different diagnostic methods. As determined by immunohistochemical (IHC) examinations with Bar224 PrP antibody, the prevalence of preclinical infection was very high (72/200; 36.0%), with most infected animals being positive for PrP$^{\rm d}$ in lymphoreticular system (LRS) tissues (68/72; 94.4%) compared to those that were positive in brain samples (38/72; 52.8%). The retropharyngeal lymph node and the palatine tonsil showed the highest frequency of PrP$^{\rm d}$ accumulation (87.3% and 84.5%, respectively), while the recto-anal mucosa-associated lymphoid tissue (RAMALT) was positive in only 30 (41.7%) of the infected goats. However, the efficiency of rectal and palatine tonsil biopsies taken shortly before necropsy was similar. The probability of brain and RAMALT being positive directly correlated with the spread of PrP$^{\rm d}$ within the LRS. The prevalence of infection was influenced by PRNP genetics at codon 142 and by the age of the goats: methionine carriers older than 60 months showed a much lower prevalence of infection (12/78; 15.4%) than those younger than 60 months (20/42; 47.6%); these last showed prevalence values similar to isoleucine homozygotes of any age (40/80; 50.0%). Two of seven goats with definite signs of scrapie were negative for PrP$^{\rm d}$ in brain but positive in LRS tissues, and one goat showed biochemical and IHC features of PrP$^{\rm d}$ different from all other infected goats. The results of this study have implications for surveillance and control policies for scrapie in goats

A Study of CO Emission in High Redshift QSOs Using the Owens Valley Millimeter Array

Searches for CO emission in high-redshift objects have traditionally suffered from the accuracy of optically-derived redshifts due to lack of bandwidth in correlators at radio observatories. This problem has motivated the creation of the new COBRA continuum correlator, with 4 GHz available bandwidth, at the Owens Valley Radio Observatory Millimeter Array. Presented here are the first scientific results from COBRA. We report detections of redshifted CO(J=3-2) emission in the QSOs SMM J04135+10277 and VCV J140955.5+562827, as well as a probable detection in RX J0911.4+0551. At redshifts of z=2.846, z=2.585, and z=2.796, we find integrated CO flux densities of 5.4 Jy km/s, 2.4 Jy km/s, and 2.9 Jy km/s for SMM J04135+10277, VCV J140955.5+562827, and RX J0911.4+0551, respectively, over linewidths of Delta(V_{FWHM}) ~ 350 km/s. These measurements, when corrected for gravitational lensing, correspond to molecular gas masses of order M(H_2) ~ 10^{9.6-11.1} solar masses, and are consistent with previous CO observations of high-redshift QSOs. We also report 3-sigma upper limits on CO(3-2) emission in the QSO LBQS 0018-0220 of 1.3 Jy km/s. We do not detect significant 3mm continuum emission from any of the QSOs, with the exception of a tentative (3-sigma) detection in RX J0911.4+0551 of S_{3mm}=0.92 mJy/beam.Comment: 18 pages, 5 figures, 2 tables, accepted to ApJ. Changes made for version 2: citations added, 2 objects added to Table 2 and Figure

Kinetics of active surface-mediated diffusion in spherically symmetric domains

We present an exact calculation of the mean first-passage time to a target on the surface of a 2D or 3D spherical domain, for a molecule alternating phases of surface diffusion on the domain boundary and phases of bulk diffusion. We generalize the results of [J. Stat. Phys. {\bf 142}, 657 (2011)] and consider a biased diffusion in a general annulus with an arbitrary number of regularly spaced targets on a partially reflecting surface. The presented approach is based on an integral equation which can be solved analytically. Numerically validated approximation schemes, which provide more tractable expressions of the mean first-passage time are also proposed. In the framework of this minimal model of surface-mediated reactions, we show analytically that the mean reaction time can be minimized as a function of the desorption rate from the surface.Comment: Published online in J. Stat. Phy

CHANGING NURSING CARE TIME AS AN EFFECT OF CHANGED CHARACTERISTICS OF THE DIALYSIS POPULATION

Background The population of dialysis patients is ageing. Dialysis nurses are confronted with geriatric patients with multiple comorbidities. Nurses are confronted with an increasing burden of care. Objectives The present study focused on the question of whether, over time, the increasing age and comorbidities of the haemodialysis population increased nursing care time. Furthermore, we studied potential changes in the predictors of the required nursing time. Design Observational study. Participants A total of 980 dialysis patients from 12 dialysis centres were included. Measurements Nurses filled out the classification tool for each patient and completed a form for reporting patient characteristics for groups of relevant haemodialysis patients at baseline and after 1 and four years. Changes in patient and dialysis characteristics were analysed, as well as the estimated nursing care time needed. Results An increase in the nursing time needed for dialysis was largely due to decreased mobility, closing of the vascular access and a greater need for psychosocial attention and was most strongly present in incident dialysis patients. The time needed for dialysis decreased as patient participation increased and vascular access changed from catheters to fistulae. Over the four-year period, the average overall needed nursing care time per haemodialysis session did not change. Conclusions Our study shows that the average nursing time needed per patient did not change in the four-year observation period. However, more time is required for incident patients; thus, if a centre has high patient turnover, more nursing care time is needed.</p

Comparative Dosimetric Analysis and Normal Tissue Complication Probability Modelling of Four-Dimensional Computed Tomography Planning Scans Within the UK NeoSCOPE Trial

Aims: NeoSCOPE is a trial of two different neoadjuvant chemoradiotherapy regimens for resectable oesophageal cancer and was the first multicentre trial in the UK to incorporate four-dimensional computed tomography (4D-CT) into radiotherapy planning. Despite 4D-CT being increasingly accepted as a standard of care for lower third and junctional oesophageal tumours, there is limited evidence of its benefit over standard three-dimensional computed tomography (3D-CT). // Materials: Using NeoSCOPE 4D-CT cases, we undertook a dosimetric comparison study of 3D-CT versus 4D-CT plans comparing target volume coverage and dose to organs at risk. We used established normal tissue complication probability models to evaluate the potential toxicity reduction of using 4D-CT plans in oesophageal cancer. // Results: 4D-CT resulted in a smaller median absolute PTV volume and lower dose levels for all reported constraints with comparable target volume coverage. NTCP modelling suggests a significant relative risk reduction of cardiac and pulmonary toxicity endpoints with 4D-CT. // Conclusion: Our work shows that incorporating 4D-CT into treatment planning may significantly reduce the toxicity burden from this treatment

Renal Transplant Outcomes in Amyloidosis

Background: Outcomes after renal transplantation have traditionally been poor in systemic amyloid A (AA) amyloidosis and systemic light chain (AL) amyloidosis, with high mortality and frequent recurrent disease. We sought to compare outcomes with matched transplant recipients with autosomal dominant polycystic kidney disease (ADPKD) and diabetic nephropathy (DN), and identify factors predictive of outcomes. Methods: We performed a retrospective cohort study of 51 systemic AL and 48 systemic AA amyloidosis patients undergoing renal transplantation. Matched groups were generated by propensity score matching. Patient and death-censored allograft survival were compared via Kaplan–Meier survival analyses, and assessment of clinicopathological features predicting outcomes via Cox proportional hazard analyses. Results: One-, 5- and 10-year death-censored unadjusted graft survival was, respectively, 94, 91 and 78% for AA amyloidosis, and 98, 93 and 93% for AL amyloidosis; median patient survival was 13.1 and 7.9 years, respectively. Patient survival in AL and AA amyloidosis was comparable to DN, but poorer than ADPKD [hazard ratio (HR) = 3.12 and 3.09, respectively; P 12 mm (HR = 26.58; P = 0.03), while survival was predicted by haematologic response (very good partial or complete response; HR = 0.07; P = 0.018). In AA amyloidosis, recurrent amyloid was associated with elevated serum amyloid A concentration but not with outcomes. Conclusions: Renal transplantation outcomes for selected patients with AA and AL amyloidosis are comparable to those with DN. In AL amyloidosis, IVSd thickness and achievement of deep haematologic response pre-transplant profoundly impact patient survival

Braneworld Cosmology in (Anti)--de Sitter Einstein--Gauss--Bonnet--Maxwell Gravity

Braneworld cosmology for a domain wall embedded in the charged (Anti)-de Sitter-Schwarzschildblack hole of the five--dimensional Einstein-Gauss-Bonnet-Maxwell theory is considered. The effective Friedmann equation for the brane is derived by introducing the necessary surface counterterms required for a well-defined variational principlein the Gauss--Bonnet theory and for the finiteness of the bulk space. The asymptotic dynamics of the brane cosmology is determined and it is found that solutions with vanishingly small spatial volume are unphysical. The finiteness of the bulk action is related to the vanishing of the effective cosmological constant on the brane. An analogy between the Friedmann equation and a generalized Cardy--Verlinde formula is drawn.Comment: LaTex file 28 pages, typos corrected, one reference is adde

Estimating the Value of New Antimicrobials in the Context of Antimicrobial Resistance: Development and Application of a Dynamic Disease Transmission Model

Objectives Antimicrobial resistance (AMR) represents a significant threat to patient and population health. The study aim was to develop and validate a model of AMR that defines and quantifies the value of new antibiotics. Methods A dynamic disease transmission and cost-effectiveness model of AMR consisting of three components (disease transmission, treatment pathway and optimisation) was developed to evaluate the health economic value of new antibiotics. The model is based on the relationship between AMR, antimicrobial availability and consumption. Model analysis explored the impact of different antibiotic treatment strategies on the development of AMR, patient and population estimates of health benefit, across three common treatment indications and pathogens in the UK. Results Population-level resistance to existing antimicrobials was estimated to increase from 10.3 to 16.1% over 10 years based on current antibiotic availability and consumption. In comparison, the diversified use of a new antibiotic was associated with significant reduction in AMR (12.8% vs. 16.1%) and quality-adjusted life year (QALY) gains at a patient (7.7–10.3, dependent on antimicrobial efficacy) and population level (3657–8197, dependent on antimicrobial efficacy and the prevalence of AMR). Validation across several real-world data sources showed that the model output does not tend to systematically under- or over-estimate observed data. Conclusions The development of new antibiotics and the appropriate use of existing antibiotics are key to addressing the threat of AMR. This study presents a validated model that quantifies the value of new antibiotics through clinical and economic outcomes of relevance, and accounts for disease transmission of infection and development of AMR. In this context, the model may be a useful tool that could contribute to the decision-making process alongside other potential models and expert advice