Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

The bioengineering development of a multi-channel, implantable hearing prosthesis for the profoundly deaf

© 1978 Dr. Ian Cameron ForsterThis thesis describes the bioengineering development of a sensory prosthesis system specifically dedicated to the multi-channel electrical stimulation of the terminations of the auditory nerve in the cochleae of profoundly deaf persons. By simulating the gross pattern of electrical activity that would exist in the auditory nerve of a person with normal hearing, it is hoped that the sensation of hearing may be restored, and in particular, speech comprehension and communication re-established. In order that the complications associated with a percutaneous connection to the intra-cochlear array may be avoided, a system has been devised which comprises an implantable stimulator controlled transcutaneously by an external transmitter. The implementation of this concept has established an interface between the electrode array and an external speech processor which is sufficiently transparent with respect to stimulus parameter control, to permit the investigation of coding schemes based on current auditory neurophysiological studies. In particular, control over both the amplitude and relative time of stimulation (or phase), as well as frequency of stimulation, of up to fifteen independent channels is possible. The phase control facility is considered a unique feature of the system for coding temporal data. Finally, the transcutaneous link has been realised using a novel, dual radio frequency coupling system to provide efficient transfer of both power and data to the implanted device. The realisation of this link has been based upon the results of basic studies concerning the properties of coupling networks, together with the development of a high efficiency switching mode power converter to effect transcutaneous power transfer

Correlation of pH response with protein expression level.

<p>Correlating sensor response with transport activity. a) Sensor response to proline superfusion of a representative oocyte (designated #4 in c) heterologously expressing PAT1. b) TEVC I-V data of the proline-dependent current of oocyte #4 in response to the addition of 3 mM proline solution to the 100 Na buffer. Inset shows the change in membrane potential induced by proline application for the same oocyte as in a. c) Correlation of ΔV_SG and the substrate-dependent current. Each point represents data from a single oocyte. Arrow marks the data point of oocyte #4 (−23 mV, −140 nA).</p

Design of the microdevice.

<p>a) Schematic view of the cross-section of the device (not drawn to scale). The height of the microperfusion channel is around 200 µm. A typical Xenopus oocyte would be 1000–1200 µm in diameter. b) Micrograph of the sensor as seen through the hole (ca. 800 µm in diameter) of the oocyte immobilization compartment. The oocyte membrane completely covers the active area of the sensor due to its deformability. c) Exploded view of the device using the original 3D CAD engineering data. d) Photograph of the assembled, but unconnected device.</p

Lateral proton diffusion model.

<p>Simplified cartoon of the proton-selective lateral diffusion model where the oocyte interfaces to the sensor element (not to scale). The vitelline layer of the (defolliculated) oocyte comprises a network of fibrous filaments that surround the cytoplasmic membrane, which itself is not smooth due to numerous microvilli protrusions (not shown). The total thickness of the vitelline layer is estimated to be 2–3 µm for stage VI oocytes. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0039238#pone.0039238-Dumont1" target="_blank">[39]</a> ([S]: concentration of substrate interacting with the membrane transport proteins. [H⁺]_D, [H⁺]_S, [H⁺]_B: Proton concentration at the detection site, membrane surface and in buffer, respectively.) We assume the diffusion barrier is narrow compared with the sensor area so that “edge effects” can be neglected and transporters within the sensor region do not “see” the substrate S.</p

Membrane transport experiments.

<p>Experiments conducted on oocytes heterologously expressing various membrane transport proteins indicated with their respective controls on non-injected (NI) oocytes showing sensor readout (V_SG) as a function of time. Only part of the initial stabilizing baseline region that preceded substrate application is shown (see Materials and Methods): a) PAT1, b) NaPi IIb, c) NaPi-IIc, d) PiT-2, e) Proline control, f) P_i control, g) GAT1, h) ENaC. In each case either the same or representative oocytes from the same batch were pretested using a two-electrode voltage clamp to confirm functional expression. The bars indicate the duration of application of the respective activating and blocking agents. Arrows indicate flux direction of substrate according to the assumed driving force conditions.</p

An integrated field-effect microdevice for monitoring membrane transport in Xenopus laevis oocytes via lateral proton diffusion

An integrated microdevice for measuring proton-dependent membrane activity at the surface of Xenopus laevis oocytes is presented. By establishing a stable contact between the oocyte vitelline membrane and an ion-sensitive field-effect (ISFET) sensor inside a microperfusion channel, changes in surface pH that are hypothesized to result from facilitated proton lateral diffusion along the membrane were detected. The solute diffusion barrier created between the sensor and the active membrane area allowed detection of surface proton concentration free from interference of solutes in bulk solution. The proposed sensor mechanism was verified by heterologously expressing membrane transport proteins and recording changes in surface pH during application of the specific substrates. Experiments conducted on two families of phosphate-sodium cotransporters (SLC20 & SLC34) demonstrated that it is possible to detect phosphate transport for both electrogenic and electroneutral isoforms and distinguish between transport of different phosphate species. Furthermore, the transport activity of the proton/amino acid cotransporter PAT1 assayed using conventional whole cell electrophysiology correlated well with changes in surface pH, confirming the ability of the system to detect activity proportional to expression level

Effect of Antiplatelet Therapy on Survival and Organ Support–Free Days in Critically Ill Patients With COVID-19

International audienc