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

Rerun: Exploiting Episodes for Lightweight Memory Race Recording

Multiprocessor deterministic replay has many potential uses in the era of multicore computing, including enhanced debugging, fault tolerance, and intrusion detection. While sources of nondeterminism in a uniprocessor can be recorded efficiently in software, it seems likely that hardware support will be needed in a multiprocessor environment where the outcome of memory races must also be recorded. We develop a memory race recording mechanism, called Rerun, that uses small hardware state (~166 bytes/core), writes a small race log (~4 bytes/kiloinstruction), and operates well as the number of cores per system scales (e.g., to 16 cores). Rerun exploits the dual of conventional wisdom in race recording: Rather than record information about individual memory accesses that conflict, we record how long a thread executes without conflicting with other threads. In particular, Rerun passively creates atomic episodes. Each episode is a dynamic instruction sequence that a thread happens to execute without interacting with other threads. Rerun uses Lamport Clocks to order episodes and enable replay of an equivalent execution. 1

FreshCache: Statically and Dynamically Exploiting Dataless Ways

Last level caches (LLCs) account for a substantial fraction of the area and power budget in many modern processors. Two recent trends ? dwindling die yield that falls off sharply with larger chips and increasing static power ? make a strong case for a fresh look at LLC design. Inclusive caches are particularly interesting because many, if not most, commercially successful processors use inclusion to ease coherence at a cost of some data being stale or redundant. LLC designs can be improved statically (at design time) or dynamically (at runtime). The "static dataless ways," removes the data?but not tag?from some cache ways to save energy and area without complicating inclusive-LLC coherence. A dynamic version ("dynamic dataless ways") could dynamically turn off data, but not tags, effectively adapting the classic selective cache ways idea to save energy in LLC but not area. Our data show that (a) all our benchmarks benefit from dataless ways, but (b) the best number of dataless ways varies by workload. Thus, a pure static dataless design leaves energy-saving opportunity on the table, while a pure dynamic dataless design misses area-saving opportunity. To surpass both pure static and dynamic approaches, we develop the FreshCache LLC design that both statically and dynamically exploits dataless ways, including repurposing a predictor to adapt the number of dynamic dataless ways as well as detailed cache management policies. Results show that FreshCache saves more energy than static dataless ways alone (e.g., 72% vs. 9% of LLC) and more area by dynamic dataless ways only (e.g., 8% vs. 0% of LLC)

Calvin: Deterministic or Not? Free Will to Choose

Most shared memory systems maximize performance by unpredictably resolving memory races. Unpredictable memory races can lead to nondeterminism in parallel programs, which can suffer from hard-toreproduce hiesenbugs. We introduce Calvin, a shared memory model capable of executing in a conventional nondeterministic mode when performance is paramount and a deterministic mode when execution repeatability is important. Unlike prior hardware proposals for deterministic execution, Calvin exploits the flexibility of a memory consistency model weaker than sequential consistency. Specifically, Calvin logically orders memory operations into strata that are compatible with the Total Store Order (TSO). Calvin is also designed with the needs of future power-aware processors in mind, and does not require any speculation support. We develop a Calvin-MIST implementation that uses an unordered coalescing write cache, multiplewrite coherence protocol, and delayed (timebomb) invalidations while maintaining TSO compatibility. Results show that Calvin-MIST can execute workloads in conventional mode at speeds comparable to a conventional system (providing compatibility) or execute deterministically for a modest average slowdown of less than 20 % (when determinism is valued). 1

Self-Checking and Self-Diagnosing 32-bit Microprocessor Multiplier ∗

In this paper, we propose a low-cost fault tolerance technique for microprocessor multipliers, both non-pipelined (NP) and pipelined (P). Our fault tolerant multiplier designs are capable of detecting and correcting errors, diagnosing hard faults, and reconfiguring to take the faulty subunit off-line. We utilize the branch misprediction recovery mechanism in the microprocessor core to take the error detection process off the critical path. Our analysis shows that our scheme provides 99 % fault security and, compared to a baseline unprotected multiplier, achieves this fault tolerance with low performance overhead (5 % for NP and 2.5 % for P multiplier) and reasonably low area (38 % NP and 26 % P) and power consumption (36 % NP and 28.5 % P) overheads.