Non-linear control of a hydraulic piezo-valve using a generalized Prandtl-Ishlinskii hysteresis model

The potential to actuate proportional flow control valves using piezoelectric ceramics or other smart materials has been investigated for a number of years. Although performance advantages compared to electromagnetic actuation have been demonstrated, a major obstacle has proven to be ferroelectric hysteresis, which is typically 20% for a piezoelectric actuator. In this paper, a detailed study of valve control methods incorporating hysteresis compensation is made for the first time. Experimental results are obtained from a novel spool valve actuated by a multi-layer piezoelectric ring bender. A generalized Prandtl-Ishlinskii model, fitted to experimental training data from the prototype valve, is used to model hysteresis empirically. This form of model is analytically invertible and is used to compensate for hysteresis in the prototype valve both open loop, and in several configurations of closed loop real time control system. The closed loop control configurations use PID (Proportional Integral Derivative) control with either the inverse hysteresis model in the forward path or in a command feedforward path. Performance is compared to both open and closed loop control without hysteresis compensation via step and frequency response results. Results show a significant improvement in accuracy and dynamic performance using hysteresis compensation in open loop, but where valve position feedback is available for closed loop control the improvements are smaller, and so conventional PID control may well be sufficient. It is concluded that the ability to combine state-of-the-art multi-layer piezoelectric bending actuators with either sophisticated hysteresis compensation or closed loop control provides a route for the creation of a new generation of high performance piezoelectric valves.<br/

Effect of large weight reductions on measured and estimated kidney function

BACKGROUND: When patients experience large weight loss, muscle mass may be affected followed by changes in plasma creatinine (pCr). The MDRD and CKD-EPI equations for estimated GFR (eGFR) include pCr. We hypothesised that a large weight loss reduces muscle mass and pCr causing increase in eGFR (creatinine-based equations), whereas measured GFR (mGFR) and cystatin C-based eGFR would be unaffected if adjusted for body surface area. METHODS: Prospective, intervention study including 19 patients. All attended a baseline visit before gastric bypass surgery followed by a visit six months post-surgery. mGFR was assessed during four hours plasma (51)Cr-EDTA clearance. GFR was estimated by four equations (MDRD, CKD-EPI-pCr, CKD-EPI-cysC and CKD-EPI-pCr-cysC). DXA-scans were performed at baseline and six months post-surgery to measure changes in lean limb mass, as a surrogate for muscle mass. RESULTS: Patients were (mean ± SD) 40.0 ± 9.3 years, 14 (74%) were female and 5 (26%) had type 2 diabetes, baseline weight was 128 ± 19 kg, body mass index 41 ± 6 kg/m2 and absolute mGFR 122 ± 24 ml/min. Six months post-surgery weight loss was 27 (95% CI: 23; 30) kg, mGFR decreased by 9 (−17; −2) from 122 ± 24 to 113 ± 21 ml/min (p = 0.024), but corrected for current body surface area (BSA) mGFR was unchanged by 2 (−5; 9) ml/min/1.73 m(2) (p = 0.52). CKD-EPI-pCr increased by 12 (6; 17) and MDRD by 13 (8; 18) (p < 0.001 for both), while CKD-EPI-cysC was unchanged by 2 (−8; 4) ml/min/1.73 m(2) (p = 0.51). Lean limb mass was reduced by 3.5 (−4.4;−2.6; p < 0.001) kg and change in lean limb mass correlated with change in plasma creatinine (R (2) = 0.28, p = 0.032). CONCLUSIONS: Major weight reductions are associated with a reduction in absolute mGFR, which may reflect resolution of glomerular hyperfiltration, while mGFR adjusted for body surface area was unchanged. Estimates of GFR based on creatinine overestimate renal function likely due to changes in muscle mass, whereas cystatin C based estimates are unaffected. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02138565. Date of registration: March 24, 2014

Urinary albumin and 8-oxo-7,8-dihydroguanosine as markers of mortality and cardiovascular disease during 19 years after diagnosis of type 2 diabetes:A comparative study of two markers to identify high risk patients

Urinary albumin is an important biomarker used to identify high risk patients with diabetes, but there is a need for new biomarkers that alone or in combination with urinary albumin could give an even better prediction of clinical patient outcomes. One promising biomarker is 8-oxo-7,8-dihydroguanosine (8-oxoGuo) that represents intracellular oxidative stress. We investigated the ability of microalbuminuria (MA) and urinary 8-oxoGuo, alone and in combination, to predict mortality and cardiovascular disease (CVD) in patients with type 2 diabetes. We used data from 1381 newly diagnosed diabetes patients, and urinary albumin and 8-oxoGuo were assessed in morning urine collected at the time of diabetes diagnosis and at a follow-up visit 6 years later. Associations between the urinary markers and mortality and CVD were assessed in Cox proportional hazards regression models. Test performance was assessed using sensitivity, specificity, positive predictive value and negative predictive value for 10-year mortality and 10-year incidence of CVD. Both 8-oxoGuo and urinary albumin were statistically significantly associated with all-cause mortality at diagnosis as well as at 6-year follow-up. At diagnosis only urinary albumin was associated with CVD. In contrast, only 8-oxoGuo was associated with CVD at 6-year follow-up. When investigating test performance, we found that by combining information from MA and 8-oxoGuo the ability to correctly identify patients at risk could be improved. The findings suggest that measurement of urinary 8-oxoGuo provides additional information about risk to that obtained from urinary albumin, and that the combined use of 8-oxoGuo and urinary albumin could be useful for a better identification of patients at risk of CVD and death

Proteomic prediction and Renin angiotensin aldosterone system Inhibition prevention Of early diabetic nephRopathy in TYpe 2 diabetic patients with normoalbuminuria (PRIORITY): essential study design and rationale of a randomised clinical multicentre trial

Introduction: Diabetes mellitus affects 9% of the European population and accounts for 15% of healthcare expenditure, in particular, due to excess costs related to complications. Clinical trials aiming for earlier prevention of diabetic nephropathy by renin angiotensin system blocking treatment in normoalbumuric patients have given mixed results. This might reflect that the large fraction of normoalbuminuric patients are not at risk of progression, thereby reducing power in previous studies. A specific risk classifier based on urinary proteomics (chronic kidney disease (CKD)273) has been shown to identify normoalbuminuric diabetic patients who later progressed to overt kidney disease, and may hold the potential for selection of high-risk patients for early intervention. Combining the ability of CKD273 to identify patients at highest risk of progression with prescription of preventive aldosterone blockade only to this high-risk population will increase power. We aim to confirm performance of CKD273 in a prospective multicentre clinical trial and test the ability of spironolactone to delay progression of early diabetic nephropathy. Methods and analysis: Investigator-initiated, prospective multicentre clinical trial, with randomised double-masked placebo-controlled intervention and a prospective observational study. We aim to include 3280 type 2 diabetic participants with normoalbuminuria. The CKD273 classifier will be assessed in all participants. Participants with high-risk pattern are randomised to treatment with spironolactone 25 mg once daily, or placebo, whereas, those with low-risk pattern will be observed without intervention other than standard of care. Treatment or observational period is 3 years. The primary endpoint is development of confirmed microalbuminuria in 2 of 3 first morning voids urine samples. Ethics and dissemination: The study will be conducted under International Conference on Harmonisation – Good clinical practice (ICH-GCP) requirements, ethical principles of Declaration of Helsinki and national laws. This first new biomarker-directed intervention trial aiming at primary prevention of diabetic nephropathy may pave the way for personalised medicine approaches in treatment of diabetes complications

Impact of random variation in albuminuria and estimated glomerular filtration rate on patient enrolment and duration of clinical trials in nephrology

Aim To test whether a screening approach with more flexible urinary albumin creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) thresholds would decrease screen failure rate without negatively impacting on the event rate and overall study duration. Methods We performed a post-hoc analysis of the ALTITUDE trial. We selected participants randomized to placebo with a UACR of >300 mg/g and an eGFR between 30 mL/min/1.73 m(2) and 60 mL/min/1.73 m(2) at the first visit (pre-screening) for the trial. We then used less stringent lower UACR and higher eGFR thresholds for the following qualifying visit. For each scenario we calculated the number of eligible participants, the number of renal and cardiovascular endpoints, and the event rates. Based on this, we performed simulations for a future trial and estimated the duration of enrolment and total duration of this trial. Results The base scenario consisted of 848 participants (median UACR 1239 mg/g; median eGFR 44 mL/min/1.73 m(2)). Lowering the UACR and/or raising eGFR qualification thresholds increased the number of eligible participants, decreased screen failures and resulted in only a modest decrease in renal and cardiovascular event rates. For example, relaxing the UACR criterion from 300 mg/g to 210 mg/g at the qualifying visit, increased the number of eligible patients from 848 to 923, and increased the number of renal events from 117 to 122 events. The event rate showed a moderate decrease from 5.6 (4.6-6.7) events per 100 patient-years to 5.3 (4.4-6.4) events per 100 patient-years. In simulations, lowering the UACR and raising eGFR thresholds for inclusion accelerated patient enrolment and did not increase in the overall trial duration. Conclusion More flexible albuminuria and eGFR-based inclusion criteria, in participants who met the inclusion criteria of a trial based on pre-screening values prior to the clinical trial, decreases screen failure rates and accelerated patient enrolment leading to more efficient trial conduct without impacting the overall trial duration