Effects of different ACE inhibitor combinations on albuminuria: results of the GUARD study

Clinical practice guidelines recommend blockers of the renin-angiotensin system alone or in combination with other agents to reduce blood pressure and albuminuria in patients with type 2 diabetes. Dihydropyridine calcium channel blockers, however, may lower blood pressure but not albuminuria in these patients. Here we tested the hypothesis that combining an ACE inhibitor with either a thiazide diuretic or a calcium channel blocker will cause similar reductions in blood pressure and albuminuria in hypertensive type 2 diabetics. We conducted a double blind randomized controlled trial on 332 hypertensive, albuminuric type 2 diabetic patients treated with benazepril with either amlodipine or hydrochlorothiazide for 1 year. The trial employed a non-inferiority design. Both combinations significantly reduced the urinary albumin to creatinine ratio and sitting blood pressure of the entire cohort. The percentage of patients progressing to overt proteinuria was similar for both groups. When we examined patients who had only microalbuminuria and hypertension we found that a larger percentage of the diuretic and ACE inhibitor normalized their albuminuria. We conclude that initial treatment using benzaepril with a diuretic resulted in a greater reduction in albuminuria compared to the group of ACE inhibitor and calcium channel blocker. In contrast, blood pressure reduction, particularly the diastolic component, favored the combination with amilodipine. The dissociation between reductions in blood pressure and albuminuria may be related to factors other than blood pressure

The effect of current inhomogeneity on the performance and degradation of Li-S batteries

The effect of thermal gradients on the performance and cycle life of Li-S batteries is studied using bespoke single-layer Li-S cells, with isothermal boundary conditions maintained by Peltier elements. A temperature difference is shown to cause significant current imbalance between parallel connected single-layer cells, causing the hotter cell to provide more charge and discharge capacities during cycling. During charge, significant shuttle is induced in the hotter Li-S cell, causing accelerated degradation of it. A bespoke multi-tab cell in which the inner layers are electrically connected to different tabs versus the outer layers, is used to demonstrate that noticeable current inhomogeneity occurs during the operation of practical multilayer Li-S pouch cells, which is expected to affect their performance and degradation. The observed thermal and current inhomogeneity should have a direct consequence on battery pack and thermal management system design for real world Li-S battery packs

A Versatile Computational Pipeline for Bacterial Genome Annotation Improvement and Comparative Analysis, with \u3cem\u3eBrucella\u3c/em\u3e as a Use Case

We present a bacterial genome computational analysis pipeline, called GenVar. The pipeline, based on the program GeneWise, is designed to analyze an annotated genome and automatically identify missed gene calls and sequence variants such as genes with disrupted reading frames (split genes) and those with insertions and deletions (indels). For a given genome to be analyzed, GenVar relies on a database containing closely related genomes (such as other species or strains) as well as a few additional reference genomes. GenVar also helps identify gene disruptions probably caused by sequencing errors. We exemplify GenVar’s capabilities by presenting results from the analysis of four Brucella genomes. Brucella is an important human pathogen and zoonotic agent. The analysis revealed hundreds of missed gene calls, new split genes and indels, several of which are species specific and hence provide valuable clues to the understanding of the genome basis of Brucella pathogenicity and host specificity

Switching the stereochemical outcome of 6-endo-trig cyclizations; Synthesis of 2,6-Cis-6-substituted 4-oxopipecolic acids

A base-mediated 6-endo-trig cyclization of readily accessible enone-derived α-amino acids has been developed for the direct synthesis of novel 2,6-cis-6- substituted-4-oxo-L-pipecolic acids. A range of aliphatic and aryl side chains were tolerated by this mild procedure to give the target compounds in good overall yields. Molecular modeling of the 6-endo-trig cyclization allowed some insight as to how these compounds were formed, with the enolate intermediate generated via an equilibrium process, followed by irreversible tautomerization/neutralization providing the driving force for product formation. Stereoselective reduction and deprotection of the resulting 2,6-cis-6-substituted 4-oxo-L-pipecolic acids to the corresponding 4-hydroxy-L-pipecolic acids was also performed

Thermoregulatory, metabolic, and cardiovascular responses during 88 min of full-body ice immersion - A case study.

Exposure to extreme cold environments is potentially life-threatening. However, the world record holder of full-body ice immersion has repeatedly demonstrated an extraordinary tolerance to extreme cold. We aimed to explore thermoregulatory, metabolic, and cardiovascular responses during 88 min of full-body ice immersion. We continuously measured gastrointestinal temperature (Tgi ), skin temperature (Tskin), blood pressure, and heart rate (HR). Oxygen consumption (VO2 ) was measured at rest, and after 45 and 88 min of ice immersion, in order to calculate the metabolic heat production. Tskin dropped significantly (28-34°C to 4-15°C) and VO2 doubled (5.7-11.3 ml kg-1  min-1 ), whereas Tgi (37.6°C), HR (72 bpm), and mean arterial pressure (106 mmHg) remained stable during the first 30 min of cold exposure. During the remaining of the trial, Tskin and VO2 remained stable, while Tgi gradually declined to 37.0°C and HR and mean arterial blood pressure increased to maximum values of 101 bpm and 115 mmHg, respectively. Metabolic heat production in rest was 169 W and increased to 321 W and 314 W after 45 and 80 min of ice immersion. Eighty-eight minutes of full-body ice immersion resulted in minor changes of Tgi and cardiovascular responses, while Tskin and VO2 changed markedly. These findings may suggest that our participant can optimize his thermoregulatory, metabolic, and cardiovascular responses to challenge extreme cold exposure

Efficacy and Tolerability of 5-Year Adjuvant Imatinib Treatment for Patients With Resected Intermediate- or High-Risk Primary Gastrointestinal Stromal Tumor: The PERSIST-5 Clinical Trial

Importance: Three years of adjuvant imatinib mesylate therapy is associated with reduced recurrence rates and improved overall survival in patients with high-risk primary gastrointestinal stromal tumor (GIST) compared with patients who receive 1 year of treatment. The impact of a longer duration of therapy is unknown. Objective: To determine whether adjuvant treatment for primary GIST with imatinib for 5 years is tolerable and efficacious. Design, Setting, and Participants: This prospective, single-arm, phase 2 clinical trial (Postresection Evaluation of Recurrence-free Survival for Gastrointestinal Stromal Tumors With 5 Years of Adjuvant Imatinib [PERSIST-5]) included adult patients with primary GIST (expressing KIT) at 21 US institutions who underwent a macroscopically complete resection and were at intermediate or high risk of recurrence, defined as primary GIST at any site measuring 2 cm or larger with 5 or more mitoses per 50 high-power field or nongastric primary GIST measuring 5 cm or larger. Data were collected from August 5, 2009, through December 20, 2016. Interventions: Imatinib, 400 mg once daily, orally for 5 years or until discontinuation of therapy because of progression or intolerance. Main Outcomes and Measures: The primary end point was recurrence-free survival (RFS). The secondary end point was overall survival. Results: Of the 91 patients enrolled, 48 (53%) were men with a median age of 60 years (range, 30-90 years). Median tumor size was 6.5 cm (range, 2.3-30.0 cm). Median treatment duration was 55.1 months (range, 0.5-60.6 months); 46 patients (51%) completed 5 years of imatinib therapy. Estimated 5-year RFS was 90% (95% CI, 80%-95%), and overall survival was 95% (95% CI, 86%-99%). Recurrence was noted in 7 patients: 1 had disease recur while receiving imatinib (PDGFRA D842V mutation) and died; 6 had disease recur after discontinuation of imatinib therapy. Two additional deaths were unrelated to treatment or tumor progression. Forty-five patients (49%) stopped treatment early because of patient choice (10 [21%]), adverse events (15 [16%]), or other (11 [12%]). All 91 patients experienced at least 1 adverse event, and 17 (19%) experienced grade 3 or 4 adverse events. Conclusions and Relevance: In this first adjuvant trial, to our knowledge, of patients with resected primary GIST who received 5 years of imatinib therapy, no patient with imatinib-sensitive mutations had disease recur during therapy. For patients in whom disease recurred, recurrence was within 2 years of discontinuation of imatinib therapy. Approximately half of the patients discontinued treatment early, most commonly because of patient choice, thus emphasizing the importance of close clinical monitoring to continue imatinib treatment for patients at appropriate risk. Trial Registration: ClinicalTrials.gov identifier: NCT00867113

Tracking physical activity using smart phone apps: assessing the ability of a current app and systematically collecting patient recommendations for future development

Background Within the United Kingdom’s National Health System (NHS), patients suffering from obesity may be provided with bariatric surgery. After receiving surgery many of these patients require further support to continue to lose more weight or to maintain a healthy weight. Remotely monitoring such patients’ physical activity and other health-related variables could provide healthworkers with a more ‘ecologically valid’ picture of these patients’ behaviours to then provide more personalised support. The current study assesses the feasibility of two smartphone apps to do so. In addition, the study looks at the barriers and facilitators patients experience to using these apps effectively. Methods Participants with a BMI > 35 kg/m2 being considered for and who had previously undergone bariatric surgery were recruited. Participants were asked to install two mobile phone apps. The ‘Moves’ app automatically tracked participants’ physical activity and the ‘WLCompanion’ app prompted participants to set goals and input other health-related information. Then, to learn about participants’ facilitators and barriers to using the apps, some participants were asked to complete a survey informed by the Theoretical Domains Framework. The data were analysed using regressions and descriptive statistics. Results Of the 494 participants originally enrolled, 274 participants data were included in the analyses about their activity pre- and/or post-bariatric surgery (ages 18–65, M = 44.02, SD ± 11.29). Further analyses were performed on those 36 participants whose activity was tracked both pre- and post-surgery. Participants’ activity levels pre- and post-surgery did not differ. In addition, 54 participants’ survey responses suggested that the main facilitator to their continued use of the Moves app was its automatic nature, and the main barrier was its battery drain. Conclusions The current study tracked physical activity in patients considered for and who had previously undergone bariatric surgery. The results should be interpreted with caution because of the small number of participants whose data meet the inclusion criteria and the barriers participants encountered to using the apps. Future studies should take note of the barriers to develop more user-friendly apps.Engineering and Physical Sciences Research Council; National Institute for Health Research; Applied Research Centre West Midland