The impact of control strategies and behavioural changes on the elimination of Ebola from Lofa County, Liberia.

The Ebola epidemic in West Africa was stopped by an enormous concerted effort of local communities and national and international organizations. It is not clear, however, how much the public health response and behavioural changes in affected communities, respectively, contributed to ending the outbreak. Here, we analyse the epidemic in Lofa County, Liberia, lasting from March to November 2014, by reporting a comprehensive time line of events and estimating the time-varying transmission intensity using a mathematical model of Ebola transmission. Model fits to the epidemic show an alternation of peaks and troughs in transmission, consistent with highly heterogeneous spread. This is combined with an overall decline in the reproduction number of Ebola transmission from early August, coinciding with an expansion of the local Ebola treatment centre. We estimate that healthcare seeking approximately doubled over the course of the outbreak, and that isolation of those seeking healthcare reduced their reproduction number by 62% (mean estimate, 95% credible interval (CI) 59-66). Both expansion of bed availability and improved healthcare seeking contributed to ending the epidemic, highlighting the importance of community engagement alongside clinical intervention.This article is part of the themed issue 'The 2013-2016 West African Ebola epidemic: data, decision-making and disease control'

Analysis of Global Sumoylation Changes Occurring during Keratinocyte Differentiation

Sumoylation is a highly dynamic process that plays a role in a multitude of processes ranging from cell cycle progression to mRNA processing and cancer. A previous study from our lab demonstrated that SUMO plays an important role in keratinocyte differentiation. Here we present a new method of tracking the sumoylation state of proteins by creating a stably transfected HaCaT keratinocyte cell line expressing an inducible SNAP-SUMO3 protein. The SNAP-tag allows covalent fluorescent labeling that is denaturation resistant. When combined with two-dimensional gel electrophoresis, the SNAP-tag technology provides direct visualization of sumoylated targets and can be used to follow temporal changes in the global cohort of sumoylated proteins during dynamic processes such as differentiation. HaCaT keratinocyte cells expressing SNAP-SUMO3 displayed normal morphological and biochemical features that are consistent with typical keratinocyte differentiation. SNAP-SUMO3 also localized normally in these cells with a predominantly nuclear signal and some minor cytoplasmic staining, consistent with previous reports for untagged SUMO2/3. During keratinocyte differentiation the total number of proteins modified by SNAP-SUMO3 was highest in basal cells, decreased abruptly after induction of differentiation, and slowly rebounded beginning between 48 and 72 hours as differentiation progressed. However, within this overall trend the pattern of change for individual sumoylated proteins was highly variable with both increases and decreases in amount over time. From these results we conclude that sumoylation of proteins during keratinocyte differentiation is a complex process which likely reflects and contributes to the biochemical changes that drive differentiation

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

Vascular function and glucose variability improve transiently following initiation of continuous subcutaneous insulin infusion in children with type 1 diabetes

ObjectiveThe effect of continuous subcutaneous insulin infusion (CSII) and glucose variability on vascular health in type 1 diabetes (T1D) is not known. We aimed to determine whether initiation of CSII improves vascular function and reduces glucose variability, independent of changes in HbA1c.MethodsTwenty-two children with T1D (12.5 ± 2.9 yr) were reviewed immediately prior, 3 wk, and 12 months after initiation of CSII. Vascular function [flow-mediated dilatation (FMD), glyceryl trinitrate-mediated dilatation (GTN)], glucose variability [mean of daily differences (MODD), mean amplitude of glycaemic excursions (MAGE) and continuous overlapping net glycaemic action (CONGA)], and clinical and biochemical data were measured at each visit. Results for the first two visits were compared to a previously studied cohort of 31 children with T1D who remained on multiple daily injections (MDI).ResultsFMD, GTN, blood pressure, HbA1c, fructosamine, and glucose variability significantly improved 3 wk after CSII commencement (all p ConclusionsInitiation of CSII rapidly improves vascular function in association with decreased glucose variability; however, the effects are not sustained with deterioration of metabolic control and glucose variability.Jennifer Harrington, Alexia S Peña, Louise Wilson, Roger Gent, Kate Dowling, Peter Baghurst and Jennifer Coupe