IMPORTANCEOveractivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19.ObjectiveTo determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19.DESIGN, SETTING, AND PARTICIPANTSIn 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).INTERVENTIONSPatients 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 MEASURESThe 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.RESULTSOn 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 RELEVANCEIn 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 REGISTRATIONClinicalTrials.gov Identifier: NCT02735707

Numerical constraint solving techniques operate in a branch& prune fashion, using consistency enforcement techniques to prune the search space and splitting operations to explore it. Extensions address disjunctions of constraints as well, but usually in a restrictive case and not tting well the branch&prune scheme. On the other hand, Ratschan has recently proposed a general framework for rst-order formulas whose atoms are numerical constraints. It extends the notion of consistency to logical terms, but little is done with respect to the splitting operation. In this paper, we explore the potential of splitting heuristics that exploit the logical structure of disjunctive numerical constraint problems in order to simplify the problem along the search. First experiments on CNF formulas show that interesting solving time gains can be achieved by choosing the right splitting points.

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Intrathecal Drug Delivery Systems are invasive pain treatment techniques that require bypassing the blood-brain barrier in order to implant a catheter inside the CSF. Imaging is a key element before and during implantation as well as in the diagnosis of complications. The understanding of delivery mechanisms has been greatly improved using MRI. Drug diffusion can now be modeled according to infusion level and flow rate for each individual patient. MRI and CT are useful in diagnosing the patient, targeting spinal level, and accurately evaluating implantation concerns or contraindications. Imaging is a key tool during the implantation of the device. Catheter positioning is essential as the treatment diffusion is limited, and the tip of the catheter must be set behind the spinal cord. Currently, fluoroscopy is the gold standard for catheter placement. Biplane Interventional Imaging and surgical CT scan will soon be able to help with more accurate positioning. An ultrasoundguided technique is helpful to localize a recessed septum in challenging pump refill procedures where pumps are deeply situated. Imaging is also essential for device malfunction diagnosis. Plain radiology is currently limited as new catheters have a poor opacity, but it remains useful for confirming motor stall of the peristaltic pump and is appropriate for the diagnosis of pump rotation. High-resolution threedimensional Computer Tomography reconstruction allows accurate control of catheter positioning and the diagnosis of dislodgment, kinking, and breaking. MRI is the most accurate imagery to diagnose spinal cord injuries following implantation or as an adverse effect of IT treatment such as granuloma. Diffusion control requires dynamic imaging which can be performed by TC99 scintigraphy. This allows for the visualization of drug diffusion and velocity. In the near future, novel techniques such as PET-CT scan could be useful for testing the distribution of intrathecal drugs