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

An ultrasonic sensor for monitoring wheel flange/rail gauge corner contact

Wheel/rail contact is critical to the successful operation of a railway network. Contact occurs at the wheel tread/rail head and wheel flange/rail gauge corner. Contact conditions are more severe in the latter, which occurs mainly at curves. The contact is small and supports large loads; therefore, high contact stresses are generated. These, combined with the slip in the contact, are primarily responsible for driving the processes that lead to wheel and rail damage, whether by deformation, wear or a fatigue process. Multi-body dynamics software is useful for predicting the wheel/rail contact characteristics; however, there is a shortage of experimental tools available. In this study, the feasibility of an approach based on an ultrasonic sensor mounted on the wheel is investigated. The sensor emits an ultrasonic pulse which is designed to impinge on the wheel flange. If there is no contact the pulse is fully reflected back at the flange and picked up by the same sensor. If flange contact takes place, a proportion of the pulse amplitude will be transmitted into the rail. The signal reflected back to the sensor is therefore reduced. The amount by which this signal reduces indicates how much flange contact has occurred. This work had two aspects. First, a standard ultrasonic ray-tracing software package was used to establish what it is possible to measure with sensors mounted in the wheel and to determine the best location and orientation. The second aspect was an experimental study to determine whether such measurements are feasible. Test specimens were cut from sections of wheel and rail, and a 2 MHz ultrasonic contact transducer was bonded onto the wheel in a position best suited to detect the flange contact. The specimens were pressed together in a bi-axial loading frame to generate differing degrees of rail head and flange contact. The reflected signal was monitored as the normal and lateral loads were varied. It proved possible not only to detect the onset of flanging, but also to record a signal that varied monotonically with both normal and lateral applied load. A map of reflected ultrasound against the applied loading is presented. The technology, while not currently suitable for full field implementation could be very useful in laboratory studies on, for example, a full-scale wheel/rail rig

Definitions of massive transfusion in adults with critical bleeding: a systematic review.

BACKGROUND: Definitions for massive transfusion (MT) vary widely between studies, contributing to challenges in interpretation of research findings and practice evaluation. In this first systematic review, we aimed to identify all MT definitions used in randomised controlled trials (RCTs) to date to inform the development of consensus definitions for MT. METHODS: We systematically searched the following databases for RCTs from inception until 11 August 2022: MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Cumulative Index to Nursing and Allied Health Literature, and Transfusion Evidence Library. Ongoing trials were sought from CENTRAL, ClinicalTrials.gov, and World Health Organisation International Clinical Trials Registry Platform. To be eligible for inclusion, studies had to fulfil all the following three criteria: (1) be an RCT; (2) include an adult patient population with major bleeding who had received, or were anticipated to receive, an MT in any clinical setting; and (3) specify a definition for MT as an inclusion criterion or outcome measure. RESULTS: Of the 8,458 distinct references identified, 30 trials were included for analysis (19 published, 11 ongoing). Trauma was the most common clinical setting in published trials, while for ongoing trials, it was obstetrics. A total of 15 different definitions of MT were identified across published and ongoing trials, varying greatly in cut-offs for volume transfused and time period. Almost all definitions specified the number of red blood cells (RBCs) within a set time period, with none including plasma, platelets or other haemostatic agents that are part of contemporary transfusion resuscitation. For completed trials, the most commonly used definition was transfusion of ≥ 10 RBC units in 24 h (9/19, all in trauma), while for ongoing trials it was 3-5 RBC units (n = 7), with the timing for transfusion being poorly defined, or in some trials not provided at all (n = 5). CONCLUSIONS: Transfusion of ≥ 10 RBC units within 24 h was the most commonly used definition in published RCTs, while lower RBC volumes are being used in ongoing RCTs. Any consensus definitions should reflect the need to incorporate different blood components/products for MT and agree on whether a 'one-size-fits-all' approach should be used across different clinical settings

The writing on the wall: the concealed communities of the East Yorkshire horselads

This paper examines the graffiti found within late nineteenth and early-twentieth century farm buildings in the Wolds of East Yorkshire. It suggests that the graffiti were created by a group of young men at the bottom of the social hierarchy - the horselads – and was one of the ways in which they constructed a distinctive sense of communal identity, at a particular stage in their lives. Whilst it tells us much about changing agricultural regimes and social structures, it also informs us about experiences and attitudes often hidden from official histories and biographies. In this way, the graffiti are argued to inform our understanding, not only of a concealed community, but also about their hidden histor

Relativistic suppression of Auger recombination in Weyl semimetals

Auger recombination (AR) being electron-hole annihilation with energy-momentum transfer to another carrier is believed to speed up in materials with small band gap. We theoretically show that this rule is violated in gapless three-dimensional materials with ultra-relativistic electron-hole dispersion, Weyl semimetals (WSM). Namely, AR is prohibited by energy-momentum conservation laws in prototypical WSM with a single Weyl node, even in the presence of anisotropy and tilt. In real multi-node WSM, the geometric dissimilarity of nodal dispersions enables weak inter-node AR, which is further suppressed by strong screening due to large number of nodes. While partial AR rates between the nodes of the same node group are mutually equal, the inter-group processes are non-reciprocal, so that one of groups is geometrically protected from AR. Our calculations show that geometrical protection can help prolonging AR lifetime by the two orders of magnitude, up to the level of nanoseconds.Comment: 6 pages + 10 pages of supporting informatio

Lower NPAS3 expression during the later stages of abnormal lung development in rat congenital diaphragmatic hernia

Purpose Congenital diaphragmatic hernia (CDH) is characterized by a developmental defect in the diaphragm, pulmonary hypoplasia and pulmonary hypertension. NPAS3 is a PAS domain transcription factor regulating Drosophila tracheogenesis. NPAS3 null mice develop pulmonary hypoplasia in utero and die after birth due to respiratory failure. We aimed to evaluate NPAS3 expres- sion during normal and abnormal lung development due to CDH. Methods CDH was induced by administering 100 mg/ml nitrofen to time-pregnant dams on embryonic day (E) 9 of gestation. Lungs were isolated on E15, E18 and E21 and NPAS3 localization was determined by immunohisto- chemistry and quantified using Western blotting. Results We found that only E21 hypoplastic CDH lungs have reduced expression of NPAS3 in the terminal sac- cules. Western blotting confirmed the down-regulation of NPAS3 protein in the nitrofen-induced hypoplastic lungs. Conclusions We demonstrate for the first time that ni- trofen-induced hypoplastic CDH lungs have reduced NPAS3 expression in the terminal saccules during the later stages of abnormal lung development. Our findings suggest that NPAS3 is associated with pulmonary hypoplasia in CDH.Supported by the Children’s Hospital Research Institute of Manitoba; RK is the recipient of a Career Enhancement Award from the Canadian Child Health Clinician Scientist Program and a New Investigator Salary Award from the Canadian Institutes of Health Research, Manitoba Lung Association and the Children’s Hospital Research Institute

Outcomes valued by people living with dementia and their care partners: protocol for a qualitative systematic review and synthesis

IntroductionGrowing numbers of interventions are being developed to support people and families living with dementia, but the extent to which they address the areas of most importance to the intended recipients is unclear. This qualitative review will synthesise outcomes identified as important from the perspectives of people living with dementia and their care partners, both for themselves and each other.Methods and analysisThe review will employ thematic synthesis methodology. Studies from 1990 or later will be eligible if they include qualitative data on the views of people living with dementia or their care partners on valued outcomes or the lived experience of dementia. Databases to be searched include MEDLINE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycInfo and Social Sciences Premium Collection, in addition to systematically gathered grey literature. Rayyan QCRI software will be used to manage the screening processes, and NVivo software will be used to manage data extraction and analysis. The review will also critically evaluate the extent to which international recommendations address the areas of importance to people living with dementia and their families. The findings will be of relevance to researchers, policy makers and providers and commissioners of dementia services. The protocol is written in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols guidelines.Ethics and disseminationAs the methodology of this study consists of collecting data from publicly available articles, it does not require ethical approval. We will share the results through conference presentations and an open-access publication in a peer-reviewed journal. Our mixed stakeholder involvement group will advise on dissemination to non-academic audiences.PROSPERO registration numberCRD42020219274.</jats:sec

A comparison of HIV outpatient care in primary and secondary healthcare-level settings in Zimbabwe.

SETTING: Decentralisation of HIV care to nurse-led primary care services is being implemented across low- and middle-income countries in sub-Saharan Africa. OBJECTIVE: To compare services offered to clients attending for HIV care at a physician-led and a nurse-led service in Harare, Zimbabwe. DESIGN: A cross-sectional study was performed at Harare Central Hospital (HCH) and Budiriro Primary Care Clinic (PCC) from June to August 2018. An interviewer-administered questionnaire was used to collect sociodemographics, HIV treatment and clinical history from clients attending for routine HIV care. The Mann-Whitney U-test was used to evaluate for differences between groups for continuous variables. For categorical variables, the χ2 test was used. RESULTS: The median age of the 404 participants recruited was 38 years (IQR 28-47); 69% were female. Viral suppression was comparable between sites (HCH, 70% vs. PCC, 80%; P = 0.07); however, screening for comorbidities such as cervical cancer screening (HCH, 61% vs. PCC, 41%; P = 0.001) and provision of referral services (HCH, 23% vs. PCC, 13%; P = 0.01) differed between sites. CONCLUSION: Efforts to improve service provision in primary care settings are needed to ensure equity for users of health services