Phage vB_Ec_ZCEC14 to treat antibiotic-resistant Escherichia coli isolated from urinary tract infections.

Escherichia coli is a commensal bacterial species in the human gastrointestinal tract; however, it could be pathogenic and cause severe infections in intra and extra-intestinal sites. Uropathogenic E. coli accounts for 80-90% of urinary tract infections that can result in urosepsis and septic shock. Consequently, multidrug-resistant uropathogenic E. coli poses a considerable risk to the healthcare system worldwide. Phage therapy is demonstrated as an optimistic solution to over-the-counter antibiotics that contribute to the global issue of multidrug-resistant bacteria. This study aims to isolate a novel phage that could be implemented to cure urinary tract infections mediated by multidrug-resistant E. coli. Twenty-seven E. coli isolates were collected from patients with urinary tract infections to assess the antibacterial efficacy of phage vB_Ec_ZCEC14. Phage kinetics were encountered against the E. coli strain (EC/4), in addition to evaluating phage stability under various temperatures, pH values, and UV exposure periods. Full genome sequencing and morphological analysis were conducted for further phage characterization, which revealed that phage vB_Ec_ZCEC14 belongs to the family Straboviridae. Phage vB_Ec_ZCEC14 showed thermal tolerance at 80 ℃, pH stability between pH 3 and pH 12, and endurance to UV exposure for 45 min. The phage-host interaction results revealed that phage vB_Ec_ZCEC14 has strong and steady antibacterial action at lower concentrations (MOI 0.1). The study findings strongly indicate that phage vB_Ec_ZCEC14 holds significant promise as a potential therapeutic alternative for treatment of antibiotic-resistant uropathogenic E. coli.

Synthesis, electrospinning, and molecular docking of poly(methyl methacrylate) Schiff bases and their applications as polymeric antimicrobial agents and for dye removal.

The antibacterial activity of a variety of modified poly(methyl methacrylate) Schiff bases against common microbial infections and removal of methylene blue (MB) dye were screened. The Schiff bases were synthesized from the reaction of the modified (PMMA) with vanillin (PMMA)Van and cinnamaldehyde (PMMA)Cin. By using Fourier transformer infrared (FT-IR), X-ray diffraction analysis (XRD), thermogravimetric analysis (TGA), and scanning electron microscopy (SEM), the structures of the nanofibers of the synthesized Schiff bases were confirmed. The modified Kirky-Bauer method was used to screen the antibacterial activities of all the obtained materials against various bacterial species, including gram-positive bacterial (Bacillus subtilis (4k1p), Staphylococcus aureus), Gram-negative bacteria (Escherichia coli (7ab3), Pseudomonas aeruginosa). Inhibition zones against gram-positive bacteria ranged in diameter from 7 to 14 mm, whereas for the Gram-negative bacteria, the inhibition zones found to be ranged between 6 and 13 mm. With a minimum bactericidal concentration (MBC) of 8 mg/mL and a minimum inhibitory concentration (MIC) of 2 mg/mL, (PMMA)Van shown the greatest antibacterial activity. Lastly, molecular docking research was done to better understand the interactions between this series' targets and inhibitors for (PMMA)Van and (PMMA)Cin (4k1p and 7ab3). Molecular modeling of these surface-adsorbed polymers indicated that (PMMA)Van binds more strongly with Nitrogen than does (PMMA)Cin through extra hydrogen-bonding interactions. All the developed materials were evaluated for the removal of 0.1 g/L methylene blue dye (MB) from an aqueous solution. The elimination percentage of MB dye ranged from 26.67% by using 0.05 g powder of (PMMA)Cin to 85.63% by employing 0.05 g nanofibers of (PMMA)Van.

Evaluation of chronic idiopathic tinnitus and its psychosocial triggers.

BACKGROUND: The tinnitus susceptibility patterns in relation to different psychological and life stressors are unknown in different cultures. AIM: To determine the comorbid psychosocial factors and behaviors associated with tinnitus and the predictors for the increase in its severity. METHODS: Participants were 230 adults (males = 70; females = 160; mean age = 38.6 ± 3.3). They underwent audiograms, speech discrimination and masking testing, and neuropsychiatric evaluation. Measures used for assessment included tinnitus handicap inventory, depression anxiety stress scale 21 (DASS-21), perceived stress scale (PSS), and insomnia severity index (ISI). RESULTS: Patients had mean duration of tinnitus of 11.5 ± 2.5 mo. They had intact hearing perception at 250-8000 Hz and 95 (41.3%) had aggravation of tinnitus loudness by masking noise. Decompensated tinnitus was reported in 77% (n = 177). The majority had clinically significant insomnia (81.3%), somatic symptoms (75%) other than tinnitus and perceived moderate (46.1%) and high (44.3%) stress to tinnitus. The severe/extremely severe symptoms of depression, anxiety and stress were reported in 17.4%, 35.7% and 44.3%, respectively. Patients with decom-pensated type had significantly higher scores for ISI (P = 0.001) and DASS-21 (depression = 0.02, anxiety = 0.01, stress = 0.001) compared to those with compensated tinnitus. Psychiatric interviewing showed that 35.7% had non-specific anxiety disorder, 17.4% had major depression, and 19.6% fulfilled the criteria of somatization disorder. Multivariate analysis showed that the only independent predictors for tinnitus severity were the duration of tinnitus [odd ratios (OR) = 0.832, 95%CI: 0.640-1.158; P = 0.001] and PSS (OR = 0.835, 95%CI: 0.540-1.125; P = 0.001) scores. CONCLUSION: To the best of our knowledge, this is the first study in our culture to evaluate the causal relationship between psychological factors and tinnitus onset, severity and persistence. Tinnitus could be the earliest and dominant somatic symptom induced by life stressors and psychological vulnerabilities. Therefore, multidisciplinary consultation (psychologists, psychiatrists, and neurologists) is important to acknowledge among the audiologists and otolaryngologists who primarily consult patients.

Expert consensus statement on venovenous extracorporeal membrane oxygenation ECMO for COVID-19 severe ARDS: an international Delphi study.

BACKGROUND: The high-quality evidence on managing COVID-19 patients requiring extracorporeal membrane oxygenation (ECMO) support is insufficient. Furthermore, there is little consensus on allocating ECMO resources when scarce. The paucity of evidence and the need for guidance on controversial topics required an international expert consensus statement to understand the role of ECMO in COVID-19 better. Twenty-two international ECMO experts worldwide work together to interpret the most recent findings of the evolving published research, statement formulation, and voting to achieve consensus. OBJECTIVES: To guide the next generation of ECMO practitioners during future pandemics on tackling controversial topics pertaining to using ECMO for patients with COVID-19-related severe ARDS. METHODS: The scientific committee was assembled of five chairpersons with more than 5 years of ECMO experience and a critical care background. Their roles were modifying and restructuring the panel's questions and, assisting with statement formulation in addition to expert composition and literature review. Experts are identified based on their clinical experience with ECMO (minimum of 5 years) and previous academic activity on a global scale, with a focus on diversity in gender, geography, area of expertise, and level of seniority. We used the modified Delphi technique rounds and the nominal group technique (NGT) through three face-to-face meetings and the voting on the statement was conducted anonymously. The entire process was planned to be carried out in five phases: identifying the gap of knowledge, validation, statement formulation, voting, and drafting, respectively. RESULTS: In phase I, the scientific committee obtained 52 questions on controversial topics in ECMO for COVID-19, further reviewed for duplication and redundancy in phase II, resulting in nine domains with 32 questions with a validation rate exceeding 75% (Fig. 1). In phase III, 25 questions were used to formulate 14 statements, and six questions achieved no consensus on the statements. In phase IV, two voting rounds resulted in 14 statements that reached a consensus are included in four domains which are: patient selection, ECMO clinical management, operational and logistics management, and ethics. CONCLUSION: Three years after the onset of COVID-19, our understanding of the role of ECMO has evolved. However, it is incomplete. Tota14 statements achieved consensus; included in four domains discussing patient selection, clinical ECMO management, operational and logistic ECMO management and ethics to guide next-generation ECMO providers during future pandemic situations.

Biocontrol of multi-drug resistant pathogenic bacteria in drainage water by locally isolated bacteriophage.

In areas with limited water resources, the reuse of treated drainage water for non-potable purposes is increasingly recognised as a valuable and sustainable water resource. Numerous pathogenic bacteria found in drainage water have a detrimental impact on public health. The emergence of antibiotic-resistant bacteria and the current worldwide delay in the production of new antibiotics may make the issue of this microbial water pollution even more challenging. This challenge aided the resumption of phage treatment to address this alarming issue. In this study, strains of Escherichia coli and Pseudomonas aeruginosa and their phages were isolated from drainage and surface water from Bahr El-Baqar and El-Manzala Lake in Damietta governorate, Egypt. Bacterial strains were identified by microscopical and biochemical examinations which were confirmed by 16 S rDNA sequencing. The susceptibility of these bacteria to several antibiotics revealed that most of the isolates had multiple antibiotic resistances (MAR). The calculated MAR index values (> 0.25) categorized study sites as potentially hazardous to health. Lytic bacteriophages against these multidrug-resistant strains of E. coli and P. aeruginosa were isolated and characterized. The isolated phages were found to be pH and heat stable and were all members of the Caudovirales order as recognized by the electron microscope. They infect 88.9% of E. coli strains and 100% of P. aeruginosa strains examined. Under laboratory conditions, the use of a phage cocktail resulted in a considerable reduction in bacterial growth. The removal efficiency (%) for E. coli and P. aeruginosa colonies increased with time and maximized at 24 h revealing a nearly 100% reduction after incubation with the phage mixture. The study candidates new phages for detecting and controlling other bacterial pathogens of public health concern to limit water pollution and maintain adequate hygiene.

Tocilizumab Outcomes in Critically Ill COVID-19 Patients Admitted to the ICU and the Role of Non-Tocilizumab COVID-19-Specific Medical Therapeutics.

BACKGROUND: Tocilizumab is a monoclonal antibody proposed to manage cytokine release syndrome (CRS) associated with severe COVID-19. Previously published reports have shown that tocilizumab may improve the clinical outcomes of critically ill patients admitted to the ICU. However, no precise data about the role of other medical therapeutics concurrently used for COVID-19 on this outcome have been published. OBJECTIVES: We aimed to compare the overall outcome of critically ill COVID-19 patients admitted to the ICU who received tocilizumab with the outcome of matched patients who did not receive tocilizumab while controlling for other confounders, including medical therapeutics for critically ill patients admitted to ICUs. METHODS: A prospective, observational, multicenter cohort study was conducted among critically ill COVID-19 patients admitted to the ICU of 14 hospitals in Saudi Arabia between 1 March 2020, and October 31, 2020. Propensity-score matching was utilized to compare patients who received tocilizumab to patients who did not. In addition, the log-rank test was used to compare the 28 day hospital survival of patients who received tocilizumab with those who did not. Then, a multivariate logistic regression analysis of the matched groups was performed to evaluate the impact of the remaining concurrent medical therapeutics that could not be excluded via matching 28 day hospital survival rates. The primary outcome measure was patients' overall 28 day hospital survival, and the secondary outcomes were ICU length of stay and ICU survival to hospital discharge. RESULTS: A total of 1470 unmatched patients were included, of whom 426 received tocilizumab. The total number of propensity-matched patients was 1278. Overall, 28 day hospital survival revealed a significant difference between the unmatched non-tocilizumab group (586; 56.1%) and the tocilizumab group (269; 63.1%) (p-value = 0.016), and this difference increased even more in the propensity-matched analysis between the non-tocilizumab group (466.7; 54.6%) and the tocilizumab group (269; 63.1%) (p-value = 0.005). The matching model successfully matched the two groups' common medical therapeutics used to treat COVID-19. Two medical therapeutics remained significantly different, favoring the tocilizumab group. A multivariate logistic regression was performed for the 28 day hospital survival in the propensity-matched patients. It showed that neither steroids (OR: 1.07 (95% CI: 0.75-1.53)) (p = 0.697) nor favipiravir (OR: 1.08 (95% CI: 0.61-1.9)) (p = 0.799) remained as a predictor for an increase in 28 day survival. CONCLUSION: The tocilizumab treatment in critically ill COVID-19 patients admitted to the ICU improved the overall 28 day hospital survival, which might not be influenced by the concurrent use of other COVID-19 medical therapeutics, although further research is needed to confirm this.

Machine learning decision tree algorithm role for predicting mortality in critically ill adult COVID-19 patients admitted to the ICU.

BACKGROUND: Coronavirus disease-19 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is currently a major cause of intensive care unit (ICU) admissions globally. The role of machine learning in the ICU is evolving but currently limited to diagnostic and prognostic values. A decision tree (DT) algorithm is a simple and intuitive machine learning method that provides sequential nonlinear analysis of variables. It is simple and might be a valuable tool for bedside physicians during COVID-19 to predict ICU outcomes and help in critical decision-making like end-of-life decisions and bed allocation in the event of limited ICU bed capacities. Herein, we utilized a machine learning DT algorithm to describe the association of a predefined set of variables and 28-day ICU outcome in adult COVID-19 patients admitted to the ICU. We highlight the value of utilizing a machine learning DT algorithm in the ICU at the time of a COVID-19 pandemic. METHODS: This was a prospective and multicenter cohort study involving 14 hospitals in Saudi Arabia. We included critically ill COVID-19 patients admitted to the ICU between March 1, 2020, and October 31, 2020. The predictors of 28-day ICU mortality were identified using two predictive models: conventional logistic regression and DT analyses. RESULTS: There were 1468 critically ill COVID-19 patients included in the study. The 28-day ICU mortality was 540 (36.8 %), and the 90-day mortality was 600 (40.9 %). The DT algorithm identified five variables that were integrated into the algorithm to predict 28-day ICU outcomes: need for intubation, need for vasopressors, age, gender, and PaO2/FiO2 ratio. CONCLUSION: DT is a simple tool that might be utilized in the ICU to identify critically ill COVID-19 patients who are at high risk of 28-day ICU mortality. However, further studies and external validation are still required.

Early Outcomes of Emergency Surgery for Left-Sided Mechanical Valve Thrombosis.

BACKGROUND: Valve thrombosis is a potentially lethal complication of mechanical cardiac valves. We examined the clinical characteristics as well as the early outcomes of patients undergoing emergency surgery for left-sided mechanical valve thrombosis. METHODS: Between January 2012 and May 2020, 104 consecutive patients were offered an emergency redo surgery for acute mechanical valve thrombosis. Ninety-seven of these patients were included in the current study. RESULTS: The mean age was 34.2 ± 10.3 years. Most of the patients were females (61 patients), and 27 patients (27.8%) were pregnant. The mitral valve was the site of thrombosis in 81 patients. Inadequate anticoagulation was found in 60.8% of patients. The overall early mortality was 32.9% (32 patients) with an operative mortality of 25.7%. Outcomes in the pregnant subgroup tended to be worst with a maternal mortality in the range of 37%, and with fetal and neonatal survival as low as 33.3%. CONCLUSION: The overall mortality in cases of mechanical valve thrombosis warranting surgery remains high. Since inadequate anticoagulation seems to be one of the major precipitating factors, the current study highlights the need for improvements in anticoagulation practices. The use of tissue valves should also be contemplated more seriously in some younger patients, especially females expressing the desire for future pregnancies.

Implementation of new ECMO centers during the COVID-19 pandemic: experience and results from the Middle East and India.

PURPOSE: Extracorporeal membrane oxygenation (ECMO) use for severe coronavirus disease 2019 (COVID-19) patients has increased during the course of the pandemic. As uncertainty existed regarding patient's outcomes, early guidelines recommended against establishing new ECMO centers. We aimed to explore the epidemiology and outcomes of ECMO for COVID-19 related cardiopulmonary failure in five countries in the Middle East and India and to evaluate the results of ECMO in 5 new centers. METHODS: This is a retrospective, multicenter international, observational study conducted in 19 ECMO centers in five countries in the Middle East and India from March 1, 2020, to September 30, 2020. We included patients with COVID-19 who received ECMO for refractory hypoxemia and severe respiratory acidosis with or without circulatory failure. Data collection included demographic data, ECMO-related specific data, pre-ECMO patient condition, 24 h post-ECMO initiation data, and outcome. The primary outcome was survival to home discharge. Secondary outcomes included mortality during ECMO, survival to decannulation, and outcomes stratified by center type. RESULTS: Three hundred and seven COVID-19 patients received ECMO support during the study period, of whom 78 (25%) were treated in the new ECMO centers. The median age was 45 years (interquartile range IQR 37-52), and 81% were men. New center patients were younger, were less frequently male, had received higher PEEP, more frequently inotropes and prone positioning before ECMO and were less frequently retrieved from a peripheral center on ECMO. Survival to home discharge was 45%. In patients treated in new and established centers, survival was 55 and 41% (p = 0.03), respectively. Multivariable analysis retained only a SOFA score < 12 at ECMO initiation as associated with survival (odds ratio, OR 1.93 (95% CI 1.05-3.58), p = 0.034), but not treatment in a new center (OR 1.65 (95% CI 0.75-3.67)). CONCLUSIONS: During pandemics, ECMO may provide favorable outcomes in highly selected patients as resources allow. Newly formed ECMO centers with appropriate supervision of regional experts may have satisfactory results.

Awake Extracorporeal Membrane Oxygenation in Coronavirus Disease 2019 Patients Without Invasive Mechanical Ventilation.

OBJECTIVES/BACKGROUND: Extracorporeal membrane oxygenation is used as rescue therapy for patients with acute respiratory distress syndrome in whom conventional therapy has failed prior to an Extra Corporeal Membrane Oxygenator to rescue Lung Injury in Severe Acute Respiratory Distress Syndrome trial. Since then, extracorporeal membrane oxygenation has been incorporated as part of the standard treatment algorithm in many centers for patients with severe acute respiratory distress syndrome. Since the emergence of coronavirus disease 2019 in early 2020, extracorporeal membrane oxygenation has been used effectively as rescue therapy and as a bridge to recovery in some patients with refractory respiratory failure. DESIGN SUBJECT AND INTERVENTION: We present a 38-year-old male healthcare worker diagnosed with coronavirus disease 2019 and progressed to critical condition with severe surgical emphysema on a high-flow nasal cannula with Fio2 100%, a flow of 40 L/min, and a maximum oxygen saturation of 88%. He was successfully treated by applying awake extracorporeal membrane oxygenation, without a need for invasive mechanical ventilation, to avoid worsening barotrauma and hemodynamic compromise potentially induced by positive pressure ventilation. MAIN RESULTS AND CONCLUSIONS: To our knowledge, this is one of the first cases to be reported in the literature on the use of awake extracorporeal membrane oxygenation as a "treatment" for barotrauma due to severe acute respiratory distress syndrome in a coronavirus disease 2019 patient, without the need for invasive mechanical ventilation. In selected patients with severe respiratory failure, awake extracorporeal membrane oxygenation can be used as a salvage treatment and obviate the need for invasive mechanical ventilation.

Knowledge Exchange Between Domain-Adversarial and Private Networks Improves Open Set Image Classification.

Both target-specific and domain-invariant features can facilitate Open Set Domain Adaptation (OSDA). To exploit these features, we propose a Knowledge Exchange (KnowEx) model which jointly trains two complementary constituent networks: (1) a Domain-Adversarial Network (DAdvNet) learning the domain-invariant representation, through which the supervision in source domain can be exploited to infer the class information of unlabeled target data; (2) a Private Network (PrivNet) exclusive for target domain, which is beneficial for discriminating between instances from known and unknown classes. The two constituent networks exchange training experience in the learning process. Toward this end, we exploit an adversarial perturbation process against DAdvNet to regularize PrivNet. This enhances the complementarity between the two networks. At the same time, we incorporate an adaptation layer into DAdvNet to address the unreliability of the PrivNet's experience. Therefore, DAdvNet and PrivNet are able to mutually reinforce each other during training. We have conducted thorough experiments on multiple standard benchmarks to verify the effectiveness and superiority of KnowEx in OSDA.

The Saudi Critical Care Society extracorporeal life support chapter guidance on utilization of veno-venous extracorporeal membrane oxygenation in adults with acute respiratory distress syndrome and special considerations in the era of coronavirus disease 2019.

Extracorporeal membrane oxygenation (ECMO) is considered as a supportive treatment that provides circulatory and ventilatory support and can be thought off as a bridge to organ recovery. Since 2009, it has been applied as a rescue treatment for patients with severe adult respiratory distress syndrome (ARDS) mainly due to viral causes. In December 2019, several patients presented with a constellation of symptoms of viral pneumonia in China. A new strain of the corona virus family, called COVID-19, has been discovered to be the cause of this severe mysterious illness that was named severe acute respiratory syndrome coronavirus 2 (SARS­CoV­2). This new virus continued to spread across the globe leading to the World Health Organization announcing it as a pandemic in the early 2020. By the end of March 2021, the number of COVID-19 cases worldwide exceeded 126 million cases. In Saudi Arabia, the first confirmed case of COVID-19 was reported in the 2nd March 2020. By the end of March 2021, the total number of confirmed COVID-19 cases in Saudi Arabia is just above 360,000. In anticipation of the need of ECMO for the treatment of patients with SARS­CoV­2 based on the previous Middle East respiratory syndrome coronavirus pandemic experience, the Saudi Extra-Corporeal Life Support (ECLS) chapter that is under the umbrella of the Saudi Critical Care Society (SCCS) convened a working group of ECMO experts. The mission of this group was to formulate a guidance for the use of ECMO as a last resort for patients with severe ARDS, especially with COVID-19 based on available evidence. The ECLS-SCCS chapter wanted to generate a document that can be used to simple guide, with a focus on safety, to provide ECMO service for patients with severe ARDS with a special focus on SARS­CoV­2.

Beyond Frontiers: Feasibility and Outcomes of Prolonged Veno-Venous Extracorporeal Membrane Oxygenation in Severe Acute Respiratory Distress Syndrome.

Extracorporeal membrane oxygenation (ECMO) use in acute respiratory failure is increasing. We aim to compare characteristics and outcomes of patients with prolonged (≥21 days) veno-venous (VV) ECMO runs (pECMO), to patients with short (<21 days) VV ECMO runs (sECMO). The observational retrospective single-center study compared patients who received VV ECMO from January 2018 to June 2019 at Prince Mohamed Bin Abdulaziz Center in Riyadh, Saudi Arabia. Forty-three patients were supported with VV ECMO during the study period, of whom 37 are included as six patients were still receiving ECMO at time of data collection: 24 sECMO and 13 pECMO patients. Baseline characteristics and comorbidities were similar except pECMO patients were older and had a lower P/F ratio (61 [58-68] vs. 71[58-85.5], p = 0.05). Survival to hospital discharge (69% vs. 83%, p = 0.32; pECMO vs. sECMO) and 90 day survival (62% vs. 75%, p = 0.413; pECMO vs. sECMO) were similar among groups. At 1 year follow-up, all patients were still alive and independently functioning except for one patient in the pECMO group who required a walking aid related to trauma. In this single-center study, patients requiring pECMO had similar short- and long-term survival to those requiring sECMO duration.

Interferon Beta-1b and Lopinavir-Ritonavir for Middle East Respiratory Syndrome.

BACKGROUND: Whether combined treatment with recombinant interferon beta-1b and lopinavir-ritonavir reduces mortality among patients hospitalized with Middle East respiratory syndrome (MERS) is unclear. METHODS: We conducted a randomized, adaptive, double-blind, placebo-controlled trial that enrolled patients at nine sites in Saudi Arabia. Hospitalized adults with laboratory-confirmed MERS were randomly assigned to receive recombinant interferon beta-1b plus lopinavir-ritonavir (intervention) or placebo for 14 days. The primary outcome was 90-day all-cause mortality, with a one-sided P-value threshold of 0.025. Prespecified subgroup analyses and safety analyses were conducted. Because of the pandemic of coronavirus disease 2019, the data and safety monitoring board requested an unplanned interim analysis and subsequently recommended the termination of enrollment and the reporting of the results. RESULTS: A total of 95 patients were enrolled; 43 patients were assigned to the intervention group and 52 to the placebo group. A total of 12 patients (28%) in the intervention group and 23 (44%) in the placebo group died by day 90. The analysis of the primary outcome, with accounting for the adaptive design, yielded a risk difference of -19 percentage points (upper boundary of the 97.5% confidence interval [CI], -3; one-sided P = 0.024). In a prespecified subgroup analysis, treatment within 7 days after symptom onset led to lower 90-day mortality than use of placebo (relative risk, 0.19; 95% CI, 0.05 to 0.75), whereas later treatment did not. Serious adverse events occurred in 4 patients (9%) in the intervention group and in 10 (19%) in the placebo group. CONCLUSIONS: A combination of recombinant interferon beta-1b and lopinavir-ritonavir led to lower mortality than placebo among patients who had been hospitalized with laboratory-confirmed MERS. The effect was greatest when treatment was started within 7 days after symptom onset. (Funded by the King Abdullah International Medical Research Center; MIRACLE ClinicalTrials.gov number, NCT02845843.).