Randomized multicentre pilot study of sacubitril/valsartan versus irbesartan in patients with chronic kidney disease: United Kingdom Heart and Renal Protection (HARP)- III—rationale, trial design and baseline data

BACKGROUND: Patients with chronic kidney disease (CKD) are at risk of progression to end-stage renal disease and cardiovascular disease. Data from other populations and animal experiments suggest that neprilysin inhibition (which augments the natriuretic peptide system) may reduce these risks, but clinical trials among patients with CKD are required to test this hypothesis. METHODS: UK Heart and Renal Protection III (HARP-III) is a multicentre, double-blind, randomized controlled trial comparing sacubitril/valsartan 97/103 mg two times daily (an angiotensin receptor-neprilysin inhibitor) with irbesartan 300 mg one time daily among 414 patients with CKD. Patients ≥18 years of age with an estimated glomerular filtration rate (eGFR) of ≥45 but <60 mL/min/1.73 m2 and urine albumin:creatinine ratio (uACR) >20 mg/mmol or eGFR ≥20 but <45 mL/min/1.73 m2 (regardless of uACR) were invited to be screened. Following a 4- to 7-week pre-randomization single-blind placebo run-in phase (during which any current renin-angiotensin system inhibitors were stopped), willing and eligible participants were randomly assigned either sacubitril/valsartan or irbesartan and followed-up for 12 months. The primary aim was to compare the effects of sacubitril/valsartan and irbesartan on measured GFR after 12 months of therapy. Important secondary outcomes include effects on albuminuria, change in eGFR over time and the safety and tolerability of sacubitril/valsartan in CKD. RESULTS: Between November 2014 and January 2016, 620 patients attended a screening visit and 566 (91%) entered the pre-randomization run-in phase. Of these, 414 (73%) participants were randomized (mean age 63 years; 72% male). The mean eGFR was 34.0 mL/min/1.73 m2 and the median uACR was 58.5 mg/mmol. CONCLUSIONS: UK HARP-III will provide important information on the short-term effects of sacubitril/valsartan on renal function, tolerability and safety among patients with CKD

Informative censoring in transplantation statistics

Observations are informatively censored when there is dependence between the time to the event of interest and time to censoring. When considering the time to death of patients on the waiting list for a transplant, particularly a liver transplant, patients that are removed for transplantation are potentially informatively censored, as generally the most ill patients are transplanted. If this censoring is assumed to be non-informative then any inferences may be misleading.The existing methods in the literature that account for informative censoring are applied to data to assess their suitability for the liver transplantation setting. As the amount of dependence between the time to failure and time to censoring variables cannot be identified from the observed data, estimators that give bounds on the marginal survival function for a given range of dependence values are considered. However, the bounds are too wide to be of use in practice. Sensitivity analyses are also reviewed as these allow us to assess how inferences are affected by assuming differing amounts of dependence and whether methods that account for informative censoring are necessary. Of the other methods considered IPCW estimators were found to be the most useful in practice.Sensitivity analyses for parametric models are less computationally intensive than those for Cox models, although they are not suitable for all sets of data. Therefore, we develop a sensitivity analysis for piecewise exponential models that is still quick to apply. These models are flexible enough to be suitable for a wide range of baseline hazards. The sensitivity analysis suggests that for the liver transplantation setting the inferences about time to failure are sensitive to informative censoring. A simulation study is carried out that shows that the sensitivity analysis is accurate in many situations, although not when there is a large proportion of censoring in the data set. Finally, a method to calculate the survival benefit of liver transplantation is adapted to make it more suitable for UK data. This method calculates the expected change in post-transplant mortality relative to waiting list mortality. It uses IPCW methods to account for the informative censoring encountered when estimating waiting list mortality to ensure the estimated survival benefit is as accurate as possible

Analysis of ribosomal subunit association using mutations at position 790 of Escherichia coli 16S rRNA.

Several phylogenetically conserved single-stranded regions within the secondary structure of 16S ribosomal RNA exhibit essential functional roles in protein synthesis. These dynamic residues adopt several three-dimensional conformations, as they interact with the 50S subunit another intercellular components. The central domain region of 16S ribosomal RNA plays a major role in this process by providing several single-stranded loop regions. The largest and most active of these loop regions surrounds position 790. The 790 loop is universally conserved amongst all sequenced species in specific residues have proven to be highly active. For example, a large body of evidence supports a direct role for the 790 loop in the initiation of protein synthesis. In this study, position 790 was investigated for its role in subunit association. Single base subunits changing 790A to C, G and U were constructed in the Escherichia coli rrnB operon on a multi-copy plasmid. The effects of the mutations on subunit association was monitored by both in vitro and in vivo assays. Cells containing 790C, 790 G, and 790U all displayed an increase in generation time. In fact, the 790G substitution resulted in a mutant ribosome that were unable to support cell growth. In vivo subunit association was dramatically reduced for cells containing 790C and 790U. This was confirmed when in vitro subunit association assays showed distinct depletions in 70S ribosomal pools. In vitro subunit association identified a pronounced increase in the affinity between subunits with the 790G mutation. All evidence suggests that position 790 plays a vitally important role in subunit association and sequence initiation of protein synthesis

Effect of simplicity and attractiveness on route selection for different journey types

This study investigated the effects of six attributes, associated with simplicity or attractiveness, on route preference for three pedestrian journey types (everyday, leisure and tourist). Using stated choice preference experiments with computer generated scenes, participants were asked to choose one of a pair of routes showing either two levels of the same attribute (experiment 1) or different attributes (experiment 2). Contrary to predictions, vegetation was the most influential for both everyday and leisure journeys, and land use ranked much lower than expected in both cases. Turns ranked higher than decision points for everyday journeys as predicted, but the positions of both were lowered by initially unranked attributes. As anticipated, points of interest were most important for tourist trips, with the initially unranked attributes having less influence. This is the first time so many attributes have been compared directly, providing new information about the importance of the attributes for different journeys. © 2014 Springer International Publishing

The Role of Simulation in a Staged Learning Model for Novice Driver Situational Awareness Training

This paper theorizes that an optimal strategy for training novice drivers to acquire situational awareness skills will rely on a hierarchical approach consistent with traditional models of cognitive development. The success of applying such models hinges upon information presentation techniques that can maximize depth of processing, and hence comprehension and retention, at a specific stage of learning. Our general discussion argues that the appropriate use of simulation is uniquely suited to meet this need

Randomized multicentre pilot study of sacubitril/valsartan versus irbesartan in patients with chronic kidney disease: United Kingdom Heart and Renal Protection (HARP)- III-rationale, trial design and baseline data

Background Patients with chronic kidney disease (CKD) are at risk of progression to end-stage renal disease and cardiovascular disease. Data from other populations and animal experiments suggest that neprilysin inhibition (which augments the natriuretic peptide system) may reduce these risks, but clinical trials among patients with CKD are required to test this hypothesis. Methods UK Heart and Renal Protection III (HARP-III) is a multicentre, double-blind, randomized controlled trial comparing sacubitril/valsartan 97/103 mg two times daily (an angiotensin receptor–neprilysin inhibitor) with irbesartan 300 mg one time daily among 414 patients with CKD. Patients ≥18 years of age with an estimated glomerular filtration rate (eGFR) of ≥45 but 20 mg/mmol or eGFR ≥20 but <45 mL/min/1.73 m2 (regardless of uACR) were invited to be screened. Following a 4- to 7-week pre-randomization single-blind placebo run-in phase (during which any current renin–angiotensin system inhibitors were stopped), willing and eligible participants were randomly assigned either sacubitril/valsartan or irbesartan and followed-up for 12 months. The primary aim was to compare the effects of sacubitril/valsartan and irbesartan on measured GFR after 12 months of therapy. Important secondary outcomes include effects on albuminuria, change in eGFR over time and the safety and tolerability of sacubitril/valsartan in CKD. Results Between November 2014 and January 2016, 620 patients attended a screening visit and 566 (91%) entered the pre-randomization run-in phase. Of these, 414 (73%) participants were randomized (mean age 63 years; 72% male). The mean eGFR was 34.0 mL/min/1.73 m2 and the median uACR was 58.5 mg/mmol. Conclusions UK HARP-III will provide important information on the short-term effects of sacubitril/valsartan on renal function, tolerability and safety among patients with CKD

Effects of sodium glucose co-transporter-2 inhibitors by diabetes status and level of albuminuria: a collaborative meta-analysis

Importance: There is uncertainty about the effects of SGLT2 inhibitors (SGLT2i) in certain types of patients with chronic kidney disease (CKD), with international guidelines offering different strengths of recommendation based on diabetes status and urine albumin:creatinine ratio (uACR) of ≥200 mg/g or <200 mg/g. Objective: To assess the relative and absolute effects of SGLT2i in participants across the full range of efficacy and serious safety outcomes stratified by diabetes status and uACR. Data sources: Eight large placebo control trials providing analyses to SMART-C. Study selection: Trials were included if they: studied an SGLT2i with label indication for use in kidney disease, and reported longitudinal kidney outcomes and baseline data on albuminuria. Data extraction and synthesis: Data were combined using inverse variance-weighted meta-analysis. Group-specific absolute effects were estimated by applying relevant subgroup-specific relative risks to the event rates in placebo groups. Main outcomes and measures: We assessed effects on clinical efficacy and safety outcomes, including kidney outcomes, heart failure and other hospitalization, and mortality. We assessed heterogeneity by baseline uACR <200 versus ≥200mg/g separately by diabetes status. Results: A total of 58,816 participants (mean [SD] age, 64 [10] years; 20,543 (35%) female; 48,946 with diabetes and 9870 without diabetes) were included from 8 large randomized trials of an SGLT2i versus placebo. Allocation to SGLT2i reduced risk of kidney disease progression (33 vs 48 per 1000 patient-years [1000py], hazard ratio [HR] 0.65, 95% confidence interval 0.60-0.70 in those with diabetes; and 32 vs 46/1000py, HR 0.74, 0.63-0.85 in those without diabetes), acute kidney injury (14 vs 18/1000py, HR 0.77, 0.69-0.87 in diabetes; and 13 vs 18/1000py, HR 0.72, 0.56-0.92 without diabetes), any hospitalization (202 vs 231/1000py, HR 0.90, 0.87-0.92 with diabetes; and 203 vs 237/1000py, HR 0.89, 0.83-0.95 without diabetes), and any death (42 vs 47/1000py, HR 0.86, 0.80-0.91 with diabetes; and 42 vs 48/1000py, HR 0.91, 0.78-1.05 without diabetes). In analyses further stratified by uACR, diabetes-specific hazard ratios were generally similar in participants with uACR ≥200 mg/g versus 0.10). Higher absolute risk at uACR ≥200 mg/g meant larger estimated absolute benefits on kidney disease progression were evident in this subgroup. Net absolute benefits were evident for other efficacy outcomes, and particularly hospitalization, in participants with uACR <200 mg/g. Net benefits were clear in analyses restricted to non-heart failure populations and when estimated glomerular filtration rate was <60 mL/min/1.73m2. Conclusions and relevance: Within the studied participants, there were clear net absolute benefits of SGLT2i on kidney, hospitalization, and mortality outcomes irrespective of diabetes status and level of uACR

Mortality risks in different subtypes of masked hypertension in the Spanish ambulatory blood pressure monitoring registry

Objective: We aimed to evaluate the risks of death and cardiovascular death of different subtypes of masked hypertension, defined by either isolated daytime or nighttime blood pressure (BP) elevation, or both, compared with patients with normal both office and 24-h BP. Methods: We selected 4999 patients with masked hypertension (normal office BP and elevated 24-h BP). They were divided in three different categories: isolated daytime masked hypertension (elevated daytime BP and normal nighttime BP, 800 patients), isolated nighttime masked hypertension (elevated nighttime BP and normal daytime BP, 1069 patients) and daytime and nighttime masked hypertension (elevation of both daytime and nighttime BP, 2989). All-cause and cardiovascular death (median follow-up 9.7 years) were assessed in each of these subtypes in comparison to 10 006 patients with normal both office and 24-h BP. Hazard ratios from Cox models after adjustment for clinical confounders were used for such comparisons. Results: Compared with patients with normal both office and 24-h BP, isolated daytime masked hypertension was not associated with an increased risk of death in models adjusted for clinical confounders [hazard ratio 1.07; 95% confidence interval (CI): 0.80–1.43]. In contrast, isolated nighttime masked hypertension (hazard ratio: 1.39; 95% CI 1.19–1.63) and daytime and nighttime masked hypertension (hazard ratio: 1.22; 95% CI 1.08–1.37) had an increased risk of death in comparison to patients with BP in the normal range. Similar results were observed for cardiovascular death. Conclusion: The risk of death in masked hypertension is not homogeneous and requires nocturnal BP elevation, either isolated or with daytime elevation. Isolated daytime masked hypertension is not associated with an increased risk of death