Shear-Sensing by C-Reactive Protein: Linking Aortic Stenosis and Inflammation.

BACKGROUND: CRP (C-reactive protein) is a prototypical acute phase reactant. Upon dissociation of the pentameric isoform (pCRP [pentameric CRP]) into its monomeric subunits (mCRP [monomeric CRP]), it exhibits prothrombotic and proinflammatory activity. Pathophysiological shear rates as observed in aortic valve stenosis (AS) can influence protein conformation and function as observed with vWF (von Willebrand factor). Given the proinflammatory function of dissociated CRP and the important role of inflammation in the pathogenesis of AS, we investigated whether shear stress can modify CRP conformation and induce inflammatory effects relevant to AS. METHODS: To determine the effects of pathological shear rates on the function of human CRP, pCRP was subjected to pathophysiologically relevant shear rates and analyzed using biophysical and biochemical methods. To investigate the effect of shear on CRP conformation in vivo, we used a mouse model of arterial stenosis. Levels of mCRP and pCRP were measured in patients with severe AS pre- and post-transcatheter aortic valve implantation, and the presence of CRP was investigated on excised valves from patients undergoing aortic valve replacement surgery for severe AS. Microfluidic models of AS were then used to recapitulate the shear rates of patients with AS and to investigate this shear-dependent dissociation of pCRP and its inflammatory function. RESULTS: Exposed to high shear rates, pCRP dissociates into its proinflammatory monomers (mCRP) and aggregates into large particles. Our in vitro findings were further confirmed in a mouse carotid artery stenosis model, where the administration of human pCRP led to the deposition of mCRP poststenosis. Patients undergoing transcatheter aortic valve implantation demonstrated significantly higher mCRP bound to circulating microvesicles pre-transcatheter aortic valve implantation compared with post-transcatheter aortic valve implantation. Excised human stenotic aortic valves display mCRP deposition. pCRP dissociated in a microfluidic model of AS and induces endothelial cell activation as measured by increased ICAM-1 and P-selectin expression. mCRP also induces platelet activation and TGF-ß (transforming growth factor beta) expression on platelets. CONCLUSIONS: We identify a novel mechanism of shear-induced pCRP dissociation, which results in the activation of cells central to the development of AS. This novel mechanosensing mechanism of pCRP dissociation to mCRP is likely also relevant to other pathologies involving increased shear rates, such as in atherosclerotic and injured arteries.

Catheter-based renal denervation in patients with uncontrolled hypertension in the absence of antihypertensive medications (SPYRAL HTN-OFF MED): a randomised, sham-controlled, proof-of-concept trial.

BACKGROUND: Previous randomised renal denervation studies did not show consistent efficacy in reducing blood pressure. The objective of our study was to evaluate the effect of renal denervation on blood pressure in the absence of antihypertensive medications. METHODS: SPYRAL HTN-OFF MED was a multicentre, international, single-blind, randomised, sham-controlled, proof-of-concept trial. Patients were enrolled at 21 centres in the USA, Europe, Japan, and Australia. Eligible patients were drug-naive or discontinued their antihypertensive medications. Patients with an office systolic blood pressure (SBP) of 150 mm Hg or greater and less than 180 mm Hg, office diastolic blood pressure (DBP) of 90 mm Hg or greater, and a mean 24-h ambulatory SBP of 140 mm Hg or greater and less than 170 mm Hg at second screening underwent renal angiography and were randomly assigned to renal denervation or sham control. Patients, caregivers, and those assessing blood pressure were blinded to randomisation assignments. The primary endpoint, change in 24-h blood pressure at 3 months, was compared between groups. Drug surveillance was done to ensure patient compliance with absence of antihypertensive medication. The primary analysis was done in the intention-to-treat population. Safety events were assessed at 3 months. This study is registered with ClinicalTrials.gov, number NCT02439749. FINDINGS: Between June 25, 2015, and Jan 30, 2017, 353 patients were screened. 80 patients were randomly assigned to renal denervation (n=38) or sham control (n=42) and followed up for 3 months. Office and 24-h ambulatory blood pressure decreased significantly from baseline to 3 months in the renal denervation group: 24-h SBP -5·5 mm Hg (95% CI -9·1 to -2·0; p=0·0031), 24-h DBP -4·8 mm Hg (-7·0 to -2·6; p<0·0001), office SBP -10·0 mm Hg (-15·1 to -4·9; p=0·0004), and office DBP -5·3 mm Hg (-7·8 to -2·7; p=0·0002). No significant changes were seen in the sham-control group: 24-h SBP -0·5 mm Hg (95% CI -3·9 to 2·9; p=0·7644), 24-h DBP -0·4 mm Hg (-2·2 to 1·4; p=0·6448), office SBP -2·3 mm Hg (-6·1 to 1·6; p=0·2381), and office DBP -0·3 mm Hg (-2·9 to 2·2; p=0·8052). The mean difference between the groups favoured renal denervation for 3-month change in both office and 24-h blood pressure from baseline: 24-h SBP -5·0 mm Hg (95% CI -9·9 to -0·2; p=0·0414), 24-h DBP -4·4 mm Hg (-7·2 to -1·6; p=0·0024), office SBP -7·7 mm Hg (-14·0 to -1·5; p=0·0155), and office DBP -4·9 mm Hg (-8·5 to -1·4; p=0·0077). Baseline-adjusted analyses showed similar findings. There were no major adverse events in either group. INTERPRETATION: Results from SPYRAL HTN-OFF MED provide biological proof of principle for the blood-pressure-lowering efficacy of renal denervation. FUNDING: Medtronic.

A Microelectrode Array with Reproducible Performance Shows Loss of Consistency Following Functionalization with a Self-Assembled 6-Mercapto-1-hexanol Layer.

For analytical applications involving label-free biosensors and multiple measurements, i.e., across an electrode array, it is essential to develop complete sensor systems capable of functionalization and of producing highly consistent responses. To achieve this, a multi-microelectrode device bearing twenty-four equivalent 50 µm diameter Pt disc microelectrodes was designed in an integrated 3-electrode system configuration and then fabricated. Cyclic voltammetry and electrochemical impedance spectroscopy were used for initial electrochemical characterization of the individual working electrodes. These confirmed the expected consistency of performance with a high degree of measurement reproducibility for each microelectrode across the array. With the aim of assessing the potential for production of an enhanced multi-electrode sensor for biomedical use, the working electrodes were then functionalized with 6-mercapto-1-hexanol (MCH). This is a well-known and commonly employed surface modification process, which involves the same principles of thiol attachment chemistry and self-assembled monolayer (SAM) formation commonly employed in the functionalization of electrodes and the formation of biosensors. Following this SAM formation, the reproducibility of the observed electrochemical signal between electrodes was seen to decrease markedly, compromising the ability to achieve consistent analytical measurements from the sensor array following this relatively simple and well-established surface modification. To successfully and consistently functionalize the sensors, it was necessary to dilute the constituent molecules by a factor of ten thousand to support adequate SAM formation on microelectrodes. The use of this multi-electrode device therefore demonstrates in a high throughput manner irreproducibility in the SAM formation process at the higher concentration, even though these electrodes are apparently functionalized simultaneously in the same film formation environment, confirming that the often seen significant electrode-to-electrode variation in label-free SAM biosensing films formed under such conditions is not likely to be due to variation in film deposition conditions, but rather kinetically controlled variation in the SAM layer formation process at these microelectrodes.

Advances in electroanalysis, sensing and monitoring in molten salts.

Microelectrodes have a number of advantages over macroelectrodes for quantitative electroanalysis and monitoring, including reduced iR drop, a high signal-to-noise ratio and reduced sensitivity to convection. Their use in molten salts has been generally precluded by the combined materials challenges of stresses associated with thermal cycling and physical and corrosive chemical degradation at the relatively high temperatures involved. We have shown that microfabrication, employing high precision photolithographic patterning in combination with the controlled deposition of materials, can be used to successfully address these challenges. The resulting molten salt compatible microelectrodes (MSMs) enable prolonged quantitative microelectrode measurements in molten salts (MSs). This paper reports the fabrication of novel MSM disc electrodes, chosen because they have an established ambient analytical response. It includes a detailed set of electrochemical characterisation studies which demonstrate both their enhanced capability over macroelectrodes and over commercial glass pulled microelectrodes, and their ability to extract quantitative electroanalytical information from MS systems. MSM measurements are then used to demonstrate their potential for shedding new light on the fundamental properties of, and processes in, MSs, such as mass transport, charge transfer reaction rates and the selective plating/stripping and alloying reactions of liquid Bi and other metals; this will underpin the development of enhanced MS industrial processes, including pyrochemical spent nuclear fuel reprocessing.

Utility of rotational atherectomy and outcomes over an eight-year period.

OBJECTIVES: To evaluate outcomes of patients undergoing rotational atherectomy (RA) in a multicenter percutaneous coronary intervention (PCI) registry. BACKGROUND: RA remains an important technique for plaque modification in PCI, particularly with complex calcification. METHODS: The study population consisted of consecutive patients undergoing PCI in nine major Australian hospitals, who were treated over an 8-year period (June 2004 to June 2012). RESULTS: Of 16,577 PCI's, 1.0% of patients n = 167 (214 lesions) underwent RA. Patients undergoing RA were more likely to be older (71.0 ± 9.7 vs. 64.4 ±11.9 years, P < 0.01), with greater incidence of diabetes (37.7% vs. 23.8%, P < 0.01) and renal impairment. There was no significant difference in procedural success (94.6% vs. 95.5%, P = 0.57), dissection (6.1% vs. 4.8%, P = 0.39), transient no reflow (4.4% vs. 2.8%, P = 0.23), or persistent no reflow (0% RA vs. 0.7% non-RA, P = 0.23). Those undergoing RA had a low but increased risk of death at 12 months (6.6 vs. 3.6%, P = 0.04). There was no significant difference in 12 month major adverse cardiovascular outcomes (MACE) between groups following adjustment for univariate predictors (OR 1.00, 95%CI; 0.93-1.08). Additionally, there was no significant difference in 30-day MACE (6.0% vs. 5.1%, P = 0.62) or 30-day mortality (2.4% vs. 1.8%, P = 0.54) between groups. CONCLUSIONS: In this large multicenter registry, RA continues to be used to treat complex lesions with low procedural complications and MACE rates. It is essential for interventional cardiologists to maintain skills in RA to enable effective percutaneous treatment of certain complex lesions.

Enhanced electroanalysis in lithium potassium eutectic (LKE) using microfabricated square microelectrodes.

Molten salts (MSs) are an attractive medium for chemical and electrochemical processing and as a result there is demand for MS-compatible analysis technologies. However, MSs containing redox species present a challenging environment in which to perform analytical measurements because of their corrosive nature, significant thermal convection and the high temperatures involved. This paper outlines the fabrication and characterization of microfabricated square microelectrodes (MSMs) designed for electrochemical analysis in MS systems. Their design enables precise control over electrode dimension, the minimization of stress because of differential thermal expansion through design for high temperature operation, and the minimization of corrosive attack through effective insulation. The exemplar MS system used for characterization was lithium chloride/potassium chloride eutectic (LKE), which has potential applications in pyrochemical nuclear fuel reprocessing, metal refining, molten salt batteries and electric power cells. The observed responses for a range of redox ions between 400 and 500 °C (673 and 773 K) were quantitative and typical of microelectrodes. MSMs also showed the reduced iR drop, steady-state diffusion-limited response, and reduced sensitivity to convection seen for microelectrodes under ambient conditions and expected for these electrodes in comparison to macroelectrodes. Diffusion coefficients were obtained in close agreement with literature values, more readily and at greater precision and accuracy than both macroelectrode and previous microelectrode measurements. The feasibility of extracting individual physical parameters from mixtures of redox species (as required in reprocessing) and of the prolonged measurement required for online monitoring was also demonstrated. Together, this demonstrates that MSMs provide enhanced electrode devices widely applicable to the characterization of redox species in a range of MS systems.

Comparison of the performance of an array of nanoband electrodes with a macro electrode with similar overall area.

The performance of two electrode architectures with broadly similar overall active electrode areas are examined. The first is an electrode comprising a single contiguous area (a disc) and the second is an electrode in which the cumulative electrode area is dispersed over a wide area as a 50 nm thickness platinum nanoband. A direct comparison of the electrochemical performance of these two electrodes has been made. The relatively simple nanoband electrode architecture is shown to have benefits, including two orders of magnitude greater mass transport limited currents, the ability to measure faster electrode kinetics (by a similar factor), a three orders of magnitude lowering of the Limit of Detection and a significantly reduced susceptibility to hydrodynamic perturbations. The consequences and implications of these performance characteristics on the uses of such a nanoband electrode have been considered.

Design and Fabrication of a Fully-Integrated, Miniaturised Fluidic System for the Analysis of Enzyme Kinetics.

The lab-on-a-chip concept, enabled by microfluidic technology, promises the integration of multiple discrete laboratory techniques into a miniaturised system. Research into microfluidics has generally focused on the development of individual elements of the total system (often with relatively limited functionality), without full consideration for integration into a complete fully optimised and miniaturised system. Typically, the operation of many of the reported lab-on-a-chip devices is dependent on the support of a laboratory framework. In this paper, a demonstrator platform for routine laboratory analysis is designed and built, which fully integrates a number of technologies into a single device with multiple domains such as fluidics, electronics, pneumatics, hydraulics, and photonics. This facilitates the delivery of breakthroughs in research, by incorporating all physical requirements into a single device. To highlight this proposed approach, this demonstrator microsystem acts as a fully integrated biochemical assay reaction system. The resulting design determines enzyme kinetics in an automated process and combines reservoirs, three-dimensional fluidic channels, optical sensing, and electronics in a low-cost, low-power and portable package.

In vivo application of an implantable tri-anchored methylene blue-based electrochemical pH sensor.

The development of robust implantable sensors is important in the successful advancement of personalised medicine as they have the potential to provide in situ real-time data regarding the status of health and disease and the effectiveness of treatment. Tissue pH is a key physiological parameter and herein, we report the design, fabrication, functionalisation, encapsulation and protection of a miniaturised, self-contained, electrochemical pH sensor system and characterisation of sensor performance. Notably for the first time in this environment the pH sensor was based on a methylene blue redox reporter which showed remarkable robustness, accuracy and sensitivity. This was achieved by encapsulation of a self-assembled monolayer containing methylene blue entrapped within a Nafion layer. Another powerful feature was the incorporation, within the same implanted device, of a fabricated on-chip Ag/AgCl reference electrode - vital in any electrochemical sensor, but often ignored. When utilised in vivo, the sensor allowed accurate tracking of externally induced pH changes within a naturally occurring ovine lung cancer model, and correlated well with single point laboratory measurements made on extracted arterial blood, whilst enabling in vivo time-dependent measurements. The sensors functioned robustly whilst implanted, and maintained in vitro function once extracted and together, these results demonstrate proof-of-concept of the ability to sense real-time intratumoral tissue pH changes in vivo.

Physician-directed patient self-management of left atrial pressure in advanced chronic heart failure.

BACKGROUND: Previous studies suggest that management of ambulatory hemodynamics may improve outcomes in chronic heart failure. We conducted a prospective, observational, first-in-human study of a physician-directed patient self-management system targeting left atrial pressure. METHODS AND RESULTS: Forty patients with reduced or preserved left ventricular ejection fraction and a history of New York Heart Association class III or IV heart failure and acute decompensation were implanted with an investigational left atrial pressure monitor, and readings were acquired twice daily. For the first 3 months, patients and clinicians were blinded as to these readings, and treatment continued per usual clinical assessment. Thereafter, left atrial pressure and individualized therapy instructions guided by these pressures were disclosed to the patient. Event-free survival was determined over a median follow-up of 25 months (range 3 to 38 months). Survival without decompensation was 61% at 3 years, and events tended to be less frequent after the first 3 months (hazard ratio 0.16 [95% confidence interval 0.04 to 0.68], P=0.012). Mean daily left atrial pressure fell from 17.6 mm Hg (95% confidence interval 15.8 to 19.4 mm Hg) in the first 3 months to 14.8 mm Hg (95% confidence interval 13.0 to 16.6 mm Hg; P=0.003) during pressure-guided therapy. The frequency of elevated readings (>25 mm Hg) was reduced by 67% (P<0.001). There were improvements in New York Heart Association class (-0.7+/-0.8, P<0.001) and left ventricular ejection fraction (7+/-10%, P<0.001). Doses of angiotensin-converting enzyme/angiotensin-receptor blockers and beta-blockers were uptitrated by 37% (P<0.001) and 40% (P<0.001), respectively, whereas doses of loop diuretics fell by 27% (P=0.15). CONCLUSIONS: Physician-directed patient self-management of left atrial pressure has the potential to improve hemodynamics, symptoms, and outcomes in advanced heart failure. Clinical Trial Registration Information- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00547729.

Fast DNA and protein microarray tests for the diagnosis of hepatitis C virus infection on a single platform.

Hepatitis C virus (HCV) is a major cause of chronic liver disease and liver cancer, and remains a large health care burden to the world. In this study we developed a DNA microarray test to detect HCV RNA and a protein microarray to detect human anti-HCV antibodies on a single platform. A main focus of this study was to evaluate possibilities to reduce the assay time, as a short time-to-result (TTR) is a prerequisite for a point-of-care test. Significantly reducing hybridisation and washing times did not impair the assay performance. This was confirmed first using artificial targets and subsequently using clinical samples from an HCV seroconversion panel derived from a HCV-infected patient. We were able to reduce the time required for the detection of human anti-HCV antibodies to only 14 min, achieving nanomolar sensitivity. The protein microarray exhibited an analytical sensitivity comparable to that of commercial systems. Similar results were obtained with the DNA microarray using a universal probe which covered all different HCV genotypes. It was possible to reduce the assay time after PCR from 150 min to 16 min without any loss of sensitivity. Taken together, these results constitute a significant step forward in the design of rapid, microarray-based diagnostics for human infectious disease, and show that the protein microarray is currently the most favourable candidate to fill this role.

Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study.

BACKGROUND: Renal sympathetic hyperactivity is associated with hypertension and its progression, chronic kidney disease, and heart failure. We did a proof-of-principle trial of therapeutic renal sympathetic denervation in patients with resistant hypertension (ie, systolic blood pressure >/=160 mm Hg on three or more antihypertensive medications, including a diuretic) to assess safety and blood-pressure reduction effectiveness. METHODS: We enrolled 50 patients at five Australian and European centres; 5 patients were excluded for anatomical reasons (mainly on the basis of dual renal artery systems). Patients received percutaneous radiofrequency catheter-based treatment between June, 2007, and November, 2008, with subsequent follow-up to 1 year. We assessed the effectiveness of renal sympathetic denervation with renal noradrenaline spillover in a subgroup of patients. Primary endpoints were office blood pressure and safety data before and at 1, 3, 6, 9, and 12 months after procedure. Renal angiography was done before, immediately after, and 14-30 days after procedure, and magnetic resonance angiogram 6 months after procedure. We assessed blood-pressure lowering effectiveness by repeated measures ANOVA. This study is registered in Australia and Europe with ClinicalTrials.gov, numbers NCT 00483808 and NCT 00664638. FINDINGS: In treated patients, baseline mean office blood pressure was 177/101 mm Hg (SD 20/15), (mean 4.7 antihypertensive medications); estimated glomerular filtration rate was 81 mL/min/1.73m(2) (SD 23); and mean reduction in renal noradrenaline spillover was 47% (95% CI 28-65%). Office blood pressures after procedure were reduced by -14/-10, -21/-10, -22/-11, -24/-11, and -27/-17 mm Hg at 1, 3, 6, 9, and 12 months, respectively. In the five non-treated patients, mean rise in office blood pressure was +3/-2, +2/+3, +14/+9, and +26/+17 mm Hg at 1, 3, 6, and 9 months, respectively. One intraprocedural renal artery dissection occurred before radiofrequency energy delivery, without further sequelae. There were no other renovascular complications. INTERPRETATION: Catheter-based renal denervation causes substantial and sustained blood-pressure reduction, without serious adverse events, in patients with resistant hypertension. Prospective randomised clinical trials are needed to investigate the usefulness of this procedure in the management of this condition.

The development and characterisation of square microfabricated electrode systems.

This paper outlines the systematic production and characterisation of biocompatible square microfabricated electrode systems for electroanalysis. In contrast to previous results, a combination of simulation, theoretical analysis and measurement has established that there is an enhanced current density for a microsquare electrode under mass transport limiting current conditions when compared to a microdisc of equivalent size. This is not simply due to a difference in the effective areas of the electrodes as the difference is frequency (diffusion layer thickness) dependent; it can instead be attributed to the effects of enhanced diffusion at the corners of the microsquares on the growing diffusion layer.

A DNA nanoswitch incorporating the fluorescent base analogue 2-aminopurine detects single nucleotide mismatches in unlabelled targets.

DNA nanoswitches can be designed to detect unlabelled nucleic acid targets and have been shown to discriminate between targets which differ in the identity of only one base. This paper demonstrates that the fluorescent base analogue 2-aminopurine (AP) can be used to discriminate between nanoswitches with and without targets and to discriminate between matched and mismatched targets. In particular, we have used both steady-state and time-resolved fluorescence spectroscopy to determine differences in AP environment at the branchpoint of nanoswitches assembled using complementary targets and targets which incorporate single base mismatches.

Fluorescence lifetime imaging of quantum dot labeled DNA microarrays.

Quantum dot (QD) labeling combined with fluorescence lifetime imaging microscopy is proposed as a powerful transduction technique for the detection of DNA hybridization events. Fluorescence lifetime analysis of DNA microarray spots of hybridized QD labeled target indicated a characteristic lifetime value of 18.8 ns, compared to 13.3 ns obtained for spots of free QD solution, revealing that QD labels are sensitive to the spot microenvironment. Additionally, time gated detection was shown to improve the microarray image contrast ratio by 1.8, achieving femtomolar target sensitivity. Finally, lifetime multiplexing based on Qdot525 and Alexa430 was demonstrated using a single excitation-detection readout channel.

Aortic balloon valvuloplasty--review and case series.

Aortic balloon valvuloplasty (BAV) was initially devised in the 1980s as an alternative procedure to the surgical treatment of aortic stenosis, with the theory behind it being both minimally invasive as well as having a lower complication rate [Hara H, et al. Percutaneous balloon aortic valvuloplasty revisited: time for a renaissance? Circulation 2007 March;115(12):e334-8]. In practice however, the procedure was found to have a higher complication rate with only a modest haemodynamic improvement compared to the surgical approach. Most important of all it had an unacceptably high restenosis rate as a substitute for surgery [Otto CM, et al. 3-year outcome after balloon aortic balloon valvuloplasty: insights into prognosis of valvular aortic stenosis. Circulation 1994;89:642-50]. As a result, the procedure has fallen out of favour and has been abandoned at many health care facilities [Hara H, et al. Percutaneous balloon aortic valvuloplasty revisited: time for a renaissance? Circulation 2007 March;115(12):e334-8]. This article will review the management of patients with severe aortic stenosis that are unsuitable to undergo surgery.

Matrix metalloproteinase-3 and coronary remodelling: implications for unstable coronary disease.

OBJECTIVES: Matrix metalloproteinases (MMPs) are plausible candidates for prediction of unstable coronary syndromes. We hypothesised that the MMP-3 polymorphism (- 1171, 5A/6A) would relate to coronary plaque characteristics and unstable clinical presentation. METHODS AND RESULTS: Forty patients with de novo presentation of coronary artery disease (CAD) were classified into unstable coronary syndrome (n=19) or stable angina pectoris (n=21). On coronary intravascular ultrasound, patients with unstable disease had a greater plaque burden, more positive (outward) coronary remodelling, and all but one were MMP-3 6A allele carriers (p=0.027 compared with stable). The relationship between the 6A allele and unstable presentation was substantiated in a validation cohort of 161 CAD patients (58 stable and 103 unstable) and in the total population of 201 CAD patients (79 stable and 122 unstable, p=0.007), and was independent of conventional risk factors. Furthermore, 6A allele carriers had a higher plasma MMP-3 concentration (15.8+/-12.5 versus 11.7+/-7.2 ng/mL, p=0.01), maximum coronary stenosis on angiography (89+/-15% versus 80+/-23%, p=0.02), plaque area (12.0+/-5.2 versus 7.5+/-3.6 mm(2), p=0.03), percentage plaque burden (82+/-7 versus 71+/-13%, p=0.003), and remodelling ratio (1.03+/-0.23 versus 0.83+/-0.12, p=0.003). CONCLUSIONS: The MMP-3 6A allele promotes positive coronary remodelling, greater plaque burden, and increased susceptibility to unstable coronary syndromes in humans.

One-Year Safety and Clinical Outcomes of a Transcatheter Interatrial Shunt Device for the Treatment of Heart Failure With Preserved Ejection Fraction in the Reduce Elevated Left Atrial Pressure in Patients With Heart Failure (REDUCE LAP-HF I) Trial: A Randomized Clinical Trial.

Importance: In patients with heart failure (HF) and left ventricular ejection fraction (LVEF) equal to or greater than 40%, a transcatheter interatrial shunt device (IASD; Corvia Medical) reduces exercise pulmonary capillary wedge pressure (PCWP) and is safe compared with sham control treatment at 1 month of follow-up. The longer-term safety and patency of the IASD has not yet been demonstrated in the setting of a randomized clinical trial (RCT). Objective: To evaluate the 1-year safety and clinical outcomes of the IASD compared with a sham control treatment. Design, Setting, and Participants: This phase 2, double-blind, 1-to-1 sham-controlled multicenter RCT of IASD implantation vs a sham procedure (femoral venous access and imaging of the interatrial septum without IASD) was conducted in 22 centers in the United States, Europe, and Australia on patients with New York Heart Association (NYHA) class III or ambulatory class IV HF, LVEF equal to or greater than 40%, exercise PCWP equal to or greater than 25 mm Hg, and PCWP-right atrial pressure gradient equal to or greater than 5 mm Hg. Main Outcomes and Measures: Safety was assessed by major adverse cardiac, cerebrovascular, or renal events (MACCRE). Exploratory outcomes evaluated at 1 year were hospitalizations for HF, NYHA class, quality of life, a 6-minute walk test, and device patency. Results: After 1 year, shunts were patent in all IASD-treated patients; MACCRE did not differ significantly in the IASD arm (2 of 21 [9.5%]) vs the control arm (5 of 22 [22.7%]; P = .41), and no strokes occurred. The yearly rate of hospitalizations for HF was 0.22 in the IASD arm and 0.63 in the control arm (P = .06). Median improvement in NYHA class was 1 class in the IASD arm (IQR, -1 to 0) vs 0 in the control arm (IQR, -1 to 0; P = .08). Quality of life and 6-minute walk test distance were similar in both groups. At 6 months, there was an increase in right ventricular size in the IASD arm (mean [SD], 7.9 [8.0] mL/m2) vs the control arm (-1.8 [9.6] mL/m2; P = .002), consistent with left-to-right shunting through the device; no further increase occurred in the IASD arm at 12 months. Conclusions and Relevance: The REDUCE LAP-HF I phase 2, sham-controlled RCT confirms the longer-term patency of the IASD. Through 1 year of follow-up, IASD treatment appears safe, with no significant differences in MACCRE in patients receiving IASD compared with those who received sham control treatment. Trial Registration: ClinicalTrials.gov identifier: NCT02600234.

Electrical and optical measurements on the first SCUBA-2 prototype 1280 pixel submillimeter superconducting bolometer array.

SCUBA-2 is a submillimeter camera being built for the James Clerk Maxwell Telescope in Hawaii. Bringing CCD style imaging to the submillimeter for the first time, with over 10000 pixels, it will provide a revolutionary improvement in sensitivity and mapping speed. We present results of the first tests on a prototype 1280 pixel SCUBA-2 subarray; the full instrument will be made up of eight such subarrays. The array is made up of transition edge sensor (TES) detectors, with Mo/Cu bilayers as the sensing element. To keep the number of wires reasonable, a multiplexed readout is used. Unlike previous TES arrays, an in-focal plane multiplexer configuration is used, in which the multiplexing elements are located beneath each pixel. To achieve the required performance, the detectors are operated at a temperature of approximately 120 mK. We describe the results of a basic electrical and optical characterization of the array, demonstrating that it is fully operational. Noise measurements were made on several pixels and gave a noise equivalent power below 2.5 x 10(-17) W HZ(-0.5), within the requirements for SCUBA-2. The construction of the testbed used to carry out these measurements is also described.

Integration of Electrodeposited Ni-Fe in MEMS with Low-Temperature Deposition and Etch Processes.

This article presents a set of low-temperature deposition and etching processes for the integration of electrochemically deposited Ni-Fe alloys in complex magnetic microelectromechanical systems, as Ni-Fe is known to suffer from detrimental stress development when subjected to excessive thermal loads. A selective etch process is reported which enables the copper seed layer used for electrodeposition to be removed while preserving the integrity of Ni-Fe. In addition, a low temperature deposition and surface micromachining process is presented in which silicon dioxide and silicon nitride are used, respectively, as sacrificial material and structural dielectric. The sacrificial layer can be patterned and removed by wet buffered oxide etch or vapour HF etching. The reported methods limit the thermal budget and minimise the stress development in Ni-Fe. This combination of techniques represents an advance towards the reliable integration of Ni-Fe components in complex surface micromachined magnetic MEMS.