Response and survival of dogs with proteinuria (UPC > 2.0) treated with angiotensin converting enzyme inhibitors:Treatment of proteinuria (UPC>2.0) with ACEi

Background: Angiotensin-converting enzyme inhibitors (ACEi) are a recommended treatment for glomerular proteinuria. Frequency of response to ACEi and the association of achieving proposed urine protein-to-creatinine ratio (UPC) targets on survival is unknown. Objectives: To determine response rates to ACEi therapy and whether a positive response is associated with improved survival. Animals: Eighty-five dogs with proteinuria (UPC > 2.0). Methods: Retrospective study including dogs (UPC > 2.0) prescribed an ACEi for treatment of proteinuria. Baseline creatinine, albumin, cholesterol, UPC, and systolic blood pressure were recorded, and cases reviewed to track UPC. Treatment response was defined as achieving a UPC of <0.5 or reduction of ≥50% from baseline within 3 months. Outcome data were collected to determine overall and 12-month survival. Results: Thirty-five (41%) dogs responded to ACEi treatment. Treatment response was statistically associated with both median survival time (664 days [95% confidence interval (CI): 459-869] for responders compared to 177 [95% CI: 131-223] for non-responders) and 12-month survival (79% responders alive compared to 28% non-responders). Baseline azotemia or hypoalbuminemia were also associated with a worse prognosis, with odds ratios of death at 12 months of 5.34 (CI: 1.85-17.32) and 4.51 (CI: 1.66-13.14), respectively. In the 25 dogs with normal baseline creatinine and albumin, response to treatment was associated with 12-month survival (92% responders alive compared to 54% non-responders, P = .04). Conclusions and Clinical Importance: When the UPC is >2.0, achieving recommended UPC targets within 3 months appears to be associated with a significant survival benefit. Response to treatment is still associated with survival benefit in dogs with less severe disease (no azotemia or hypoalbuminemia)

Cost-effectiveness of paediatric central venous catheters in the UK:A secondary publication from the CATCH clinical trial

Background: Antibiotic-impregnated central venous catheters (CVCs) reduce the risk of bloodstream infections (BSIs) in patients treated in pediatric intensive care units (PICUs). However, it is unclear if they are cost-effective from the perspective of the National Health Service (NHS) in the UK.Methods: Economic evaluation alongside the CATCH trial (ISRCTN34884569) to estimate the incremental cost effectiveness ratio (ICER) of antibiotic-impregnated (rifampicin and minocycline), heparin-bonded and standard polyurethane CVCs. The 6-month costs of CVCs and hospital admissions and visits were determined from administrative hospital data and case report forms.Results: BSIs were detected in 3.59% (18/502) of patients randomized to standard, 1.44% (7/486) to antibiotic and 3.42% (17/497) to heparin CVCs. Lengths of hospital stay did not differ between intervention groups. Total mean costs (95% confidence interval) were: £45,663 (£41,647–£50,009) for antibiotic, £42,065 (£38,322–£46,110) for heparin, and £44,503 (£40,619–£48,666) for standard CVCs. As heparin CVCs were not clinically effective at reducing BSI rate compared to standard CVCs, they were considered not to be cost-effective. The ICER for antibiotic vs. standard CVCs, of £54,057 per BSI avoided, was sensitive to the analytical time horizon.Conclusions: Substituting standard CVCs for antibiotic CVCs in PICUs will result in reduced occurrence of BSI but there is uncertainty as to whether this would be a cost-effective strategy for the NHS

Urinary 11-dehydrothromboxane B₂ concentrations in 20 dogs with primary immune-mediated hemolytic anemia

Background: Thromboembolic disease is a major cause of mortality in dogs with immune-mediated hemolytic anemia (IMHA). At present, no reliable biomarkers of individual patient thrombotic risk are available. In human medicine, increased urinary thromboxane concentrations have utility as markers of prothrombotic tendency in various situations. Hypothesis/Objectives: First, to determine if urinary 11-dehydrothromboxane B2 (u11-dTXB) concentrations are increased in dogs with primary IMHA compared to normal dogs; second, to assess whether u11-dTXB concentration is associated with survival, known prognostic indicators, or frequency of thrombosis in dogs with IMHA. Animals: Twenty client-owned dogs diagnosed with primary IMHA and 17 healthy dogs volunteered by hospital staff. Methods: Prospective case-control study. A previously validated ELISA was used to measure urine 11-dTXB concentrations, which were normalized to urine creatinine concentration (u11-dTXB:Cr). Samples were obtained at presentation from patients with primary IMHA. Standard clincopathological data at baseline and survival data were collected. Urinary 11-dTXB:Cr was compared between outcome subgroups, and correlated with known markers of disease severity. Results: Baseline u11-dTXB:Cr was significantly higher in dogs with IMHA than in healthy dogs (median, 3.75; range, 0.83-25.36 vs 0.65; 0.24-2.57; P = .003) but did not differ between dogs with IMHA that survived and did not survive to 30 days after presentation, nor between dogs with and without clinical suspicion of thrombotic disease. Conclusions and Clinical Importance: Urinary 11-dTXB:Cr is increased in dogs with IMHA compared to healthy controls, consistent with a prothrombotic state. However, in this IMHA population u11-dTXB:Cr was not associated with survival or suspected thrombosis

Effects of receptor clustering on ligand dissociation: Theory and simulations

Receptor-ligand binding is a critical first step in signal transduction and the duration of the interaction can impact signal generation. In mammalian cells, clustering of receptors may be facilitated by heterogeneous zones of lipids, known as lipid rafts. In vitro experiments show that disruption of rafts significantly alters the dissociation of fibroblast growth factor-2 (FGF-2) from heparan sulfate proteoglycans, co-receptors for FGF-2. In this paper, we develop a continuum stochastic formalism in order to (i) study how rebinding affects the dissociation of ligands from a planar substrate, and (ii) address the question of how receptor clustering influences ligand rebinding. We find that clusters reduce the effective dissociation rate dramatically when the clusters are dense and the overall surface density of receptors is low. The effect is much less pronounced in the case of high receptor density and shows non-monotonic behavior with time. These predictions are verified via lattice Monte Carlo simulations. Comparison with experimental results suggests that the theory does not capture the complete biological system. We speculate that additional co-operative mechanisms might be present in order to increase ligand retention, and present one possible ``internal diffusion'' model.Comment: Expanded text and added figures, revised version to appear in Biophys.

Predicting Outcome in dogs with Primary Immune-Mediated Hemolytic Anemia: Results of a Multicenter Case Registry

BACKGROUND: Outcome prediction in dogs with immune‐mediated hemolytic anemia (IMHA) is challenging and few prognostic indicators have been consistently identified. OBJECTIVES: An online case registry was initiated to: prospectively survey canine IMHA presentation and management in the British Isles; evaluate 2 previously reported illness severity scores, Canine Hemolytic Anemia Score (CHAOS) and Tokyo and to identify independent prognostic markers. ANIMALS: Data from 276 dogs with primary IMHA across 10 referral centers were collected between 2008 and 2012. METHODS: Outcome prediction by previously reported illness‐severity scores was tested using univariate logistic regression. Independent predictors of death in hospital or by 30‐days after admission were identified using multivariable logistic regression. RESULTS: Purebreds represented 89.1% dogs (n = 246). Immunosuppressive medications were administered to 88.4% dogs (n = 244), 76.1% (n = 210) received antithrombotics and 74.3% (n = 205) received packed red blood cells. Seventy‐four per cent of dogs (n = 205) were discharged from hospital and 67.7% (n = 187) were alive 30‐days after admission. Two dogs were lost to follow‐up at 30‐days. In univariate analyses CHAOS was associated with death in hospital and death within 30‐days. Tokyo score was not associated with either outcome measure. A model containing SIRS‐classification, ASA classification, ALT, bilirubin, urea and creatinine predicting outcome at discharge was accurate in 82% of cases. ASA classification, bilirubin, urea and creatinine were independently associated with death in hospital or by 30‐days. CONCLUSIONS AND CLINICAL IMPORTANCE: Markers of kidney function, bilirubin concentration and ASA classification are independently associated with outcome in dogs with IMHA. Validation of this score in an unrelated population is now warranted

Confidence of UK Ophthalmology Registrars in Managing Posterior Capsular Rupture: Results from a National Trainee Survey

Introduction: To establish the level of confidence amongst UK ophthalmology specialist registrars (residents) in managing posterior capsule rupture (PCR) during cataract surgery. / Methods: An online nine-item questionnaire was distributed to all registrars, recruited nationwide via regional representatives. Data collected included stage of training, number of completed cataract operations, cumulative PCR rate, number of PCRs independently managed, understanding of vitrectomy settings and fluidic parameters and access to simulation. Respondents self-evaluated their confidence in managing PCR with vitreous loss. / Results: Complete responses were obtained from 248 registrars (35% response rate). Mean number of phacoemulsification procedures performed was 386. For senior registrars (OST 6–7), 35 out of 70 (50%) felt confident to manage PCR independently and 55 out of 70 (78.6%) were either quite confident or very confident at deciding when to implant an intraocular lens during PCR management. Lower confidence levels were noted for junior trainees (OST 1–2). Over 65% of survey respondents had access to relevant simulation. / Conclusions: Our results represent the largest UK survey analysing the confidence of PCR management amongst registrars. Confidence improves with duration of training and increased exposure to management of PCR. However, 50% of senior registrars still lacked confidence to independently manage PCR and vitreous loss. A specific competency-based framework, potentially using a simulator or simulating a PCR event, incorporated into the curriculum may be desirable