Percutaneous Coronary Revascularization Strategies After Myocardial Infarction: A Systematic Review and Network Meta-Analysis.

BACKGROUND: Complete revascularization with percutaneous coronary intervention improves outcomes compared with culprit revascularization following myocardial infarction (MI) with multivessel coronary artery disease. An all-cause mortality reduction has never been demonstrated. Debate also remains regarding the optimal timing of complete revascularization (immediate or staged), and method of evaluation of nonculprit lesions (physiology or angiography). OBJECTIVES: This study aims to perform an updated systematic review with frequentist and Bayesian network meta-analyses including the totality of randomized data investigating revascularization strategies in patients presenting with MI and multivessel coronary artery disease. METHODS: The primary comparison tested complete vs culprit revascularization. Timing and methods of achieving complete revascularization were assessed. The prespecified primary outcome was all-cause mortality. Outcomes were expressed as relative risk (RR) (95% CI). RESULTS: Twenty-four eligible trials randomized 16,371 patients (weighted mean follow-up: 26.4 months). Compared with culprit revascularization, complete revascularization reduced all-cause mortality in patients with any MI (RR: 0.85; 95% CI: 0.74-0.99; P = 0.04). Cardiovascular mortality, MI, major adverse cardiac events and repeat revascularization were also significantly reduced. In patients presenting with ST-segment elevation myocardial infarction, the point estimate for all-cause mortality with complete revascularization was RR: 0.91 (95% CI: 0.78-1.05; P = 0.18). Rates of stent thrombosis, major bleeding, and acute kidney injury were similar. Immediate complete revascularization ranked higher than staged complete revascularization for all endpoints. CONCLUSIONS: Complete revascularization following MI reduces all-cause mortality, cardiovascular mortality, MI, major adverse cardiac events, and repeat revascularization. There may be benefits to immediate complete revascularization, but additional head-to-head trials are needed.

Transcatheter Therapy for the Tricuspid Valve: A Focused Review of Edge-to-Edge Repair and Orthotopic Valve Replacement.

PURPOSE OF REVIEW: Patients with severe tricuspid regurgitation (TR) are at risk for significant morbidity and mortality. Transcatheter tricuspid valve interventions (TTVI) may offer patients less invasive treatment alternatives to surgery. This review evaluates the most common class of device currently used worldwide to treat TR, tricuspid transcatheter edge-to-edge repair (T-TEER) and orthotopic transcatheter tricuspid valve replacement (TTVR), both of which are now approved in the USA and Europe. RECENT FINDINGS: The first pivotal randomized clinical trial, TRILUMINATE, demonstrated that T-TEER can safely reduce TR and is associated with improved health status outcomes. However, results of this trial have raised questions about whether this device can provide sufficient TR reduction to impact clinical outcomes. Orthotopic TTVR has recently gained attention with initial data suggesting near-complete TR elimination. The current review examines the technical features and anatomic limitations of the most commonly used devices for T-TEER and orthotopic TTVR, discusses the current clinical data for these devices, and offers a theoretical construct for device selection.

Population analysis of ischemic stroke burden and risk factors in the United States in the pre- and post-mechanical thrombectomy eras.

OBJECTIVES: To provide an updated analysis of the burden of ischemic stroke in the United States. MATERIALS AND METHODS: Using the Global Burden of Disease database, we estimated age-standardized, population-adjusted rates of incidence, prevalence, mortality, and disability-adjusted life years from 2010 to 2019, with regional comparisons. Deaths and disability-adjusted life years were compared in 2010-2014 and 2015-2019 to assess the potential effect of increased mechanical thrombectomy use. The attributable, disability-adjusted life years for twenty risk factors were estimated, ranked, and trended. RESULTS: Incident ischemic strokes decreased by 11.4 % across the study period from 65.7 (55.9-77.3) to 58.2 (49.0-69.5) per 100,000. Prevalence (-8.2 %), mortality (-1.9 %), and disability-adjusted life years (-4.4 %) all declined. All regions showed reductions in all burden measures, with the South consistently having the highest burden yet the largest reduction in incidence (-12.6 %) and prevalence (-10.5 %). Deaths (p < 0.0001) and DALYs (p < 0.0001) significantly differed between the pre- and post-mechanical thrombectomy eras. Total attributable disability-adjusted life years for all risk factors decreased from 304.7 (258.5-353.2) in 2010 to 288.9 (242.2-337.2) in 2019. In 2019, the risk factors with the most disability-adjusted life years were hypertension, hyperglycemia, and obesity with no state-based differences. Across the study period, disability-adjusted life years attributable to leading risk factors decreased among men but decreased less or increased among women. CONCLUSIONS: The burden of ischemic stroke decreased during the study period. Declines in deaths and disability-adjusted life years suggest a mitigating impact of mechanical thrombectomy. While disability-adjusted life years attributable to leading risk factors decreased, sex-based disparities were observed.

User authentication system based on human exhaled breath physics.

This work, in a pioneering approach, attempts to build a biometric system that works purely based on the fluid mechanics governing exhaled breath. We test the hypothesis that the structure of turbulence in exhaled human breath can be exploited to build biometric algorithms. This work relies on the idea that the extrathoracic airway is unique for every individual, making the exhaled breath a biomarker. Methods including classical multi-dimensional hypothesis testing approach and machine learning models are employed in building user authentication algorithms, namely user confirmation and user identification. A user confirmation algorithm tries to verify whether a user is the person they claim to be. A user identification algorithm tries to identify a user's identity with no prior information available. A dataset of exhaled breath time series samples from 94 human subjects was used to evaluate the performance of these algorithms. The user confirmation algorithms performed exceedingly well for the given dataset with over 97% true confirmation rate. The machine learning based algorithm achieved a good true confirmation rate, reiterating our understanding of why machine learning based algorithms typically outperform classical hypothesis test based algorithms. The user identification algorithm performs reasonably well with the provided dataset with over 50% of the users identified as being within two possible suspects. We show surprisingly unique turbulent signatures in the exhaled breath that have not been discovered before. In addition to discussions on a novel biometric system, we make arguments to utilise this idea as a tool to gain insights into the morphometric variation of extrathoracic airway across individuals. Such tools are expected to have future potential in the area of personalised medicines.

Epidemiology of healthcare-associated Pseudomonas aeruginosa in intensive care units: are sink drains to blame?

BACKGROUND: Pseudomonas aeruginosa (PA) is a common cause of healthcare-associated infection (PA-HAI) in the intensive care unit (ICU). AIM: To describe the epidemiology of PA-HAI in ICUs in Ontario, Canada, and to identify episodes of sink-to-patient PA transmission. METHODS: This was a prospective cohort study of patients in six ICUs from 2018 to 2019, with retrieval of PA clinical isolates, and PA-screening of antimicrobial-resistant organism surveillance rectal swabs, and of sink drain, air, and faucet samples. All PA isolates underwent whole-genome sequencing. PA-HAI was defined using US National Healthcare Safety Network criteria. ICU-acquired PA was defined as PA isolated from specimens obtained ≥48 h after ICU admission in those with prior negative rectal swabs. Sink-to-patient PA transmission was defined as ICU-acquired PA with close genomic relationship to isolate(s) previously recovered from sinks in a room/bedspace occupied 3-14 days prior to collection date of the relevant patient specimen. FINDINGS: Over ten months, 72 PA-HAIs occurred among 60/4263 admissions. The rate of PA-HAI was 2.40 per 1000 patient-ICU-days; higher in patients who were PA-colonized on admission. PA-HAI was associated with longer stay (median: 26 vs 3 days uninfected; P < 0.001) and contributed to death in 22/60 cases (36.7%). Fifty-eight admissions with ICU-acquired PA were identified, contributing 35/72 (48.6%) PA-HAIs. Four patients with five PA-HAIs (6.9%) had closely related isolates previously recovered from their room/bedspace sinks. CONCLUSION: Nearly half of PA causing HAI appeared to be acquired in ICUs, and 7% of PA-HAIs were associated with sink-to-patient transmission. Sinks may be an under-recognized reservoir for HAIs.

Technique and impact on first pass effect primary results of the ASSIST global registry.

BACKGROUND: Patients treated with mechanical thrombectomy (MT) for acute ischemic strokes from large vessel occlusion (LVO) have better outcomes with effective reperfusion. However, it is unknown which technique leads to better technical and clinical success. We aimed to determine which technique yields the most effective first pass reperfusion during MT. METHODS: In a prospective, multicenter global registry we enrolled patients treated with operator preferred MT technique at 71 hospitals from January 2019 to January 2022. Three techniques were assessed: SR Classic with stent retriever (SR) and balloon guide catheter (BGC); SR Combination which employed SR with contact aspiration with or without BGC; and direct aspiration (DA) with or without BGC. The primary outcome was achieving an expanded Thrombolysis In Cerebral Infarction (eTICI) score of 2c or 3 on the first pass, with the primary technique as adjudicated by core lab. The primary clinical outcome measure was a 90-day modified Rankin Scale (mRS) score of 0-2. RESULTS: A total of 1492 patients were enrolled. Patients treated with SR Classic or SR Combination were more likely to achieve first pass eTICI 2c or 3 reperfusion (P=0.01). There was no significant difference in mRS 0-2 (P=0.46) or safety endpoints. CONCLUSIONS: The use of SR Classic or SR Combination was more likely to achieve first pass eTICI 2c or 3 reperfusion. There were no significant differences in clinical outcomes and safety endpoints.

Transcending the challenge of evolving resistance mechanisms in Pseudomonas aeruginosa through ß-lactam-enhancer-mechanism-based cefepime/zidebactam.

Multi-drug resistant (MDR) Pseudomonas aeruginosa harbor a complex array of ß-lactamases and non-enzymatic resistance mechanisms. In this study, the activity of a ß-lactam/ß-lactam-enhancer, cefepime/zidebactam, and novel ß-lactam/ß-lactamase inhibitor combinations was determined against an MDR phenotype-enriched, challenge panel of P. aeruginosa (n = 108). Isolates were multi-clonal as they belonged to at least 29 distinct sequence types (STs) and harbored metallo-ß-lactamases, serine ß-lactamases, penicillin binding protein (PBP) mutations, and other non-enzymatic resistance mechanisms. Ceftazidime/avibactam, ceftolozane/tazobactam, imipenem/relebactam, and cefepime/taniborbactam demonstrated MIC90s of >128 mg/L, while cefepime/zidebactam MIC90 was 16 mg/L. In a neutropenic-murine lung infection model, a cefepime/zidebactam human epithelial-lining fluid-simulated regimen achieved or exceeded a translational end point of 1-log10 kill for the isolates with elevated cefepime/zidebactam MICs (16-32 mg/L), harboring VIM-2 or KPC-2 and alterations in PBP2 and PBP3. In the same model, to assess the impact of zidebactam on the pharmacodynamic (PD) requirement of cefepime, dose-fractionation studies were undertaken employing cefepime-susceptible P. aeruginosa isolates. Administered alone, cefepime required 47%-68% fT >MIC for stasis to ~1 log10 kill effect, while cefepime in the presence of zidebactam required just 8%-16% for >2 log10 kill effect, thus, providing the pharmacokinetic/PD basis for in vivo efficacy of cefepime/zidebactam against isolates with MICs up to 32 mg/L. Unlike ß-lactam/ß-lactamase inhibitors, ß-lactam enhancer mechanism-based cefepime/zidebactam shows a potential to transcend the challenge of ever-evolving resistance mechanisms by targeting multiple PBPs and overcoming diverse ß-lactamases including carbapenemases in P. aeruginosa.IMPORTANCECompared to other genera of Gram-negative pathogens, Pseudomonas is adept in acquiring complex non-enzymatic and enzymatic resistance mechanisms thus remaining a challenge to even novel antibiotics including recently developed ß-lactam and ß-lactamase inhibitor combinations. This study shows that the novel ß-lactam enhancer approach enables cefepime/zidebactam to overcome both non-enzymatic and enzymatic resistance mechanisms associated with a challenging panel of P. aeruginosa. This study highlights that the ß-lactam enhancer mechanism is a promising alternative to the conventional ß-lactam/ß-lactamase inhibitor approach in combating ever-evolving MDR P. aeruginosa.

Outcomes of SAPIEN 3 Transcatheter Aortic Valve Replacement Compared With Surgical Valve Replacement in Intermediate-Risk Patients.

BACKGROUND: Previous studies demonstrated transcatheter aortic valve replacement (TAVR) with an earlier generation balloon-expandable valve to be noninferior to surgical aortic valve replacement (SAVR) for death and disabling stroke in intermediate-risk patients with symptomatic, severe aortic stenosis at 5 years. However, limited long-term data are available with the more contemporary SAPIEN 3 (S3) bioprosthesis. OBJECTIVES: The aim of this study was to compare 5-year risk-adjusted outcomes in intermediate-risk patients undergoing S3 TAVR vs SAVR. METHODS: Propensity score matching was performed to account for baseline differences in intermediate-risk patients undergoing S3 TAVR in the PARTNER 2 (Placement of Aortic Transcatheter Valves) S3 single-arm study and SAVR in the PARTNER 2A randomized clinical trial. The primary composite endpoint consisted of 5-year all-cause death and disabling stroke. RESULTS: A total of 783 matched pairs of intermediate-risk patients with severe aortic stenosis were studied. There were no differences in the primary endpoint between S3 TAVR and SAVR at 5 years (40.2% vs 42.7%; HR: 0.87; 95% CI: 0.74-1.03; P = 0.10). The incidence of mild or greater paravalvular regurgitation was more common after S3 TAVR. There were no differences in structural valve deterioration-related stage 2 and 3 hemodynamic valve deterioration or bioprosthetic valve failure. CONCLUSIONS: In this propensity-matched analysis of intermediate-risk patients, 5-year rates of death and disabling stroke were similar between S3 TAVR and SAVR. Rates of structural valve deterioration-related hemodynamic valve deterioration were similar, but paravalvular regurgitation was more common after S3 TAVR. Longer-term follow-up is needed to further evaluate differences in late adverse clinical events and bioprosthetic valve durability. (PII S3i [PARTNER II Trial: Placement of Aortic Transcatheter Valves II - S3 Intermediate], NCT03222128; PII A (PARTNER II Trial: Placement of Aortic Transcatheter Valves II - XT Intermediate and High Risk], NCT01314313).

Cerebral Embolic Protection in Transcatheter Aortic Valve Replacement.

Transcatheter aortic valve replacement (TAVR) is a treatment option for patients with symptomatic severe aortic stenosis across the entire spectrum of surgical risk. Recent trial data have led to the expansion of TAVR into lower-risk patients. With iterative technological advances and successive increases in procedural experience, the occurrence of complications following TAVR has declined. One of the most feared complications remains stroke, and patients consider stroke a worse outcome than death. There has therefore been great interest in strategies to mitigate the risk of stroke in patients undergoing TAVR. In this paper, we will discuss mechanisms and predictors of stroke after TAVR and describe the currently available cerebral embolic protection devices, including their design and relevant clinical studies pertaining to their use. We will also review the current overall evidence base for cerebral embolic protection during TAVR and ongoing randomized controlled trials. Finally, we will discuss our pragmatic recommendations for the use of cerebral embolic protection devices in patients undergoing TAVR.

Biocompatibility of Ajwain Oil Combined with Eugenol and Zinc Oxide as a Deciduous Root Canal Obturating Material: An In Vivo Study.

Aim and objectives: The present study was intended to assess the biocompatibility of newly formulated materials such as zinc oxide (ZO) admixed with ajwain oil (A) as well as ajwain eugenol (E) (1:1 ratio) against ZOE through an animal model as root canal obturating materials in deciduous teeth. Materials and methods: The study involved randomly selected 24 albino rats, which were divided into three groups based on test materials. Two polyethylene tubes (PETT) (8 mm long × 1 mm internal diameter) were inserted into connective tissues of the dorsal side on either side of each rat viz empty tube (negative control) and another containing test material (test group). Animals were sacrificed at the end of the 7th and 21st days. PETT with surrounding connective tissues were excised. Histopathological evaluations of the material's biocompatibility were done by determining inflammatory tissue responses. Non-parametric tests such as Kruskal-Wallis and Mann-Whitney U were used for statistical analysis (p < 0.05). Results: Histopathological examination on the 7th day showed increased polymorphonuclear cells for all test materials compared to the negative control (p = 0.92), suggesting acute inflammation. The inflammation subsided gradually after 21 days (p = 0.48). The lymphocytes increased after 21 days for all the materials indicating chronic inflammation (p = 0.79), as well as fibroblasts (p = 0.34) and capillaries (p = 0.35), indicating healing and repair. Conclusion: The newly formulated obturating materials were found to be biocompatible compared to ZOE. How to cite this article: Dahake PT, Joshi SS, Kale YJ, et al. Biocompatibility of Ajwain Oil Combined with Eugenol and Zinc Oxide as a Deciduous Root Canal Obturating Material: An In Vivo Study. Int J Clin Pediatr Dent 2023;16(3):431-436.

Impact of Malnutrition in Patients With Heart Failure and Secondary Mitral Regurgitation: The COAPT Trial.

BACKGROUND: Although malnutrition is associated with poor prognosis in several diseases, its prognostic impact in patients with heart failure (HF) and secondary mitral regurgitation (SMR) is not understood. OBJECTIVES: The purpose of this study was to assess the prevalence and impact of malnutrition in HF patients with severe SMR randomized to transcatheter edge-to-edge repair (TEER) with the MitraClip plus guideline-directed medical therapy (GDMT) vs GDMT alone in the COAPT trial. METHODS: Baseline malnutrition risk was calculated using the validated geriatric nutritional risk index (GNRI) score. Patients were categorized as having "malnutrition" (GNRI ≤98) vs "no malnutrition" (GNRI >98). Outcomes were assessed through 4 years. The primary endpoint of interest was all-cause mortality. RESULTS: Among 552 patients, median baseline GNRI was 109 (IQR: 101-116); 94 (17.0%) had malnutrition. All-cause mortality at 4 years was greater in patients with vs those without malnutrition (68.3% vs 52.8%; P = 0.001). Using multivariable analysis, both baseline malnutrition (adjusted-HR [adj-HR]: 1.37; 95% CI: 1.03-1.82; P = 0.03) and randomization to TEER plus GDMT compared with GDMT alone (adj-HR: 0.65; 95% CI: 0.51-0.82; P = 0.0003) were independent predictors of 4-year mortality. In contrast, GNRI was unrelated to the 4-year rate of heart failure hospitalization (HFH), although TEER treatment reduced HFH (adj-HR: 0.46; 95% CI: 0.36-0.56). The reductions in death (adj-Pinteraction = 0.46) and HFH (adj-Pinteraction = 0.67) with TEER were consistent in patients with and without malnutrition. CONCLUSIONS: Malnutrition was present in 1 of 6 patients with HF and severe SMR enrolled in COAPT and was independently associated with increased 4-year mortality (but not HFH). TEER reduced mortality and HFH in patients with and without malnutrition. (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation [The COAPT Trial] and COAPT CAS [COAPT]; NCT01626079).

Clinical Research on Transcatheter Aortic Valve Replacement for Bicuspid Aortic Valve Disease: Principles, Challenges, and an Agenda for the Future.

Bicuspid aortic valve disease (BAVD) is present in up to half of all patients referred for surgical aortic valve replacement (SAVR) yet was an exclusion criterion for all randomized controlled trials (RCTs) comparing transcatheter aortic valve replacement (TAVR) to SAVR. Nonetheless, approximately 10% of patients currently treated with TAVR have BAVD and available observational data for performing TAVR in these patients are limited by selection bias. Many in the cardiovascular community have advocated for RCTs in this population, but none have been performed. The Heart Valve Collaboratory (HVC) is a multidisciplinary community of stakeholders with the aim of creating significant advances in valvular heart disease by stimulating clinical research, engaging in educational activities, and advancing regulatory science. In December 2020, the HVC hosted a Global Multidisciplinary workshop involving over 100 international experts in the field. Following this 2-day symposium, working groups with varied expertise were convened to discuss BAVD, including the need for and design of RCTs. This review, conducted under the auspices of the HVC, summarizes available data and knowledge gaps regarding procedural therapy for BAVD, outlining specific challenges for trials in this population. We also propose several potential studies that could be performed and discuss respective strengths and weaknesses of each approach. Finally, we present a roadmap for future directions in clinical research in TAVR for BAVD with an emphasis both on RCTs and also prospective registries focused on disease phenotyping to develop parameters and risk scores that could ultimately be applied to patients to inform clinical decision-making.

Long-Term Outcomes of Randomized Controlled Trials Comparing Percutaneous Left Atrial Appendage Closure to Oral Anticoagulation for Nonvalvular Atrial Fibrillation: A Meta-Analysis.

Background: Oral anticoagulation (OAC) has been considered the standard of care for stroke prophylaxis for patients with nonvalvular atrial fibrillation; however, many individuals are unable or unwilling to take long-term OAC. The safety and efficacy of percutaneous left atrial appendage closure (LAAC) have been controversial, and new trial data have recently emerged. We therefore sought to perform an updated meta-analysis of randomized clinical trials (RCTs) comparing OAC to percutaneous LAAC, focusing on individual clinical endpoints. Methods: We performed a systematic search of the MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials from January 2000 through December 2021 for all RCTs comparing percutaneous LAAC to OAC in patients with nonvalvular atrial fibrillation. Fixed and random effects meta-analyses of hazard ratios (HRs) were performed using the longest follow-up duration available by intention-to-treat. The prespecified primary endpoint was all-cause mortality. Results: Three RCTs enrolling 1516 patients were identified. The weighted mean follow-up was 54.7 months. LAAC was associated with a reduced risk of all-cause mortality (HR 0.76; 95% confidence interval [CI], 0.59-0.96; p = 0.023), hemorrhagic stroke (HR 0.24; 95% CI, 0.09-0.61; p = 0.003), and major nonprocedural bleeding (HR 0.52; 95% CI, 0.37-0.74; p < 0.001). There was no significant difference between LAAC and OAC for any other endpoints. Conclusions: The available evidence from RCTs suggests LAAC therapy is associated with reduced long-term risk of death compared with OAC. This may be driven by reductions in hemorrhagic stroke and major nonprocedural bleeding. There were no significant differences in the risk of all stroke. Further large-scale clinical trials are needed to validate these findings.

Asymmetric lung increases particle filtration by deposition.

Human lung is known to be an asymmetric dichotomously branched network of bronchioles. Existing literature on the relation between anatomy and air-flow physics in the tracheobronchial trees has discussed the results of asymmetry. We discuss a secondary (but an important) lung function to seek asymmetry: to protect the acinus from a high pathogen load. We build morphometric parameter-based mathematical models of realistic bronchial trees to explore the structure-function relationship. We observe that maximum surface area for gas exchange, minimum resistance and minimum volume are obtained near the symmetry condition. In contrast, we show that deposition of inhaled foreign particles in the non-terminal airways is enhanced by asymmetry. We show from our model, that the optimal value of asymmetry for maximum particle filtration is within 10% of the experimentally measured value in human lungs. This structural trait of the lung aids in self-defence of the host against pathogen laden aerosols. We explain how natural asymmetric design of typical human lungs makes a sacrifice away from gas exchange optimality to gain this protection. In a typical human lung, when compared to most optimal condition (which is associated with symmetric branching), the fluidic resistance is 14% greater, the gas exchange surface area is about 11% lower, the lung volume is about 13% greater to gain an increase of 4.4% protection against foreign particles. This afforded protection is also robust to minor variations in branching ratio or variation in ventilation, which are both crucial to survival.

Atorvastatin versus Placebo in ICU Patients with COVID-19: Ninety-day Results of the INSPIRATION-S Trial.

BACKGROUND: In the INSPIRATION-S trial, atorvastatin versus placebo was associated with a nonsignificant 16% reduction in 30-day composite of venous/arterial thrombosis or death in intensive care unit (ICU) patients with COVID-19. Thrombo-inflammatory response in coronavirus disease 2019 (COVID-19) may last beyond the first 30 days. METHODS: This article reports the effects of atorvastatin 20 mg daily versus placebo on 90-day clinical and functional outcomes from INSPIRATION-S, a double-blind multicenter randomized trial of adult ICU patients with COVID-19. The main outcome for this prespecified study was a composite of adjudicated venous/arterial thrombosis, treatment with extracorporeal membrane oxygenation (ECMO), or all-cause mortality. Functional status was assessed with the Post-COVID-19 Functional Scale. RESULTS: In the primary analysis, 587 patients were included (age: 57 [Q1-Q3: 45-68] years; 44% women). By 90-day follow-up, the main outcome occurred in 96 (33.1%) patients assigned to atorvastatin and 113 (38.0%) assigned to placebo (hazard ratio [HR]: 0.80, 95% confidence interval [CI]: 0.60-1.05, p = 0.11). Atorvastatin in patients who presented within 7 days of symptom onset was associated with reduced 90-day hazard for the main outcome (HR: 0.60, 95% CI: 0.42-0.86, p interaction = 0.02). Atorvastatin use was associated with improved 90-day functional status, although the upper bound CI crossed 1.0 (ORordinal: 0.64, 95% CI: 0.41-1.01, p = 0.05). CONCLUSION: Atorvastatin 20 mg compared with placebo did not significantly reduce the 90-day composite of death, treatment with ECMO, or venous/arterial thrombosis. However, the point estimates do not exclude a potential clinically meaningful treatment effect, especially among patients who presented within 7 days of symptom onset (NCT04486508).

Inhalation of virus-loaded droplets as a clinically plausible pathway to deep lung infection.

Respiratory viruses, such as SARS-CoV-2, preliminarily infect the nasopharyngeal mucosa. The mechanism of infection spread from the nasopharynx to the deep lung-which may cause a severe infection-is, however, still unclear. We propose a clinically plausible mechanism of infection spread to the deep lung through droplets, present in the nasopharynx, inhaled and transported into the lower respiratory tract. A coupled mathematical model of droplet, virus transport and virus infection kinetics is exercised to demonstrate clinically observed times to deep lung infection. The model predicts, in agreement with clinical observations, that severe infection can develop in the deep lung within 2.5-7 days of initial symptom onset. Results indicate that while fluid dynamics plays an important role in transporting the droplets, infection kinetics and immune responses determine infection growth and resolution. Immune responses, particularly antibodies and T-lymphocytes, are observed to be critically important for preventing infection severity. This reinforces the role of vaccination in preventing severe infection. Managing aerosolization of infected nasopharyngeal mucosa is additionally suggested as a strategy for minimizing infection spread and severity.