Effect of Helmet Noninvasive Ventilation vs Usual Respiratory Support on Mortality Among Patients With Acute Hypoxemic Respiratory Failure Due to COVID-19: The HELMET-COVID Randomized Clinical Trial.

Importance: Helmet noninvasive ventilation has been used in patients with COVID-19 with the premise that helmet interface is more effective than mask interface in delivering prolonged treatments with high positive airway pressure, but data about its effectiveness are limited. Objective: To evaluate whether helmet noninvasive ventilation compared with usual respiratory support reduces mortality in patients with acute hypoxemic respiratory failure due to COVID-19 pneumonia. Design, Setting, and Participants: This was a multicenter, pragmatic, randomized clinical trial that was conducted in 8 sites in Saudi Arabia and Kuwait between February 8, 2021, and November 16, 2021. Adult patients with acute hypoxemic respiratory failure (n = 320) due to suspected or confirmed COVID-19 were included. The final follow-up date for the primary outcome was December 14, 2021. Interventions: Patients were randomized to receive helmet noninvasive ventilation (n = 159) or usual respiratory support (n = 161), which included mask noninvasive ventilation, high-flow nasal oxygen, and standard oxygen. Main Outcomes and Measures: The primary outcome was 28-day all-cause mortality. There were 12 prespecified secondary outcomes, including endotracheal intubation, barotrauma, skin pressure injury, and serious adverse events. Results: Among 322 patients who were randomized, 320 were included in the primary analysis, all of whom completed the trial. Median age was 58 years, and 187 were men (58.4%). Within 28 days, 43 of 159 patients (27.0%) died in the helmet noninvasive ventilation group compared with 42 of 161 (26.1%) in the usual respiratory support group (risk difference, 1.0% [95% CI, -8.7% to 10.6%]; relative risk, 1.04 [95% CI, 0.72-1.49]; P = .85). Within 28 days, 75 of 159 patients (47.2%) required endotracheal intubation in the helmet noninvasive ventilation group compared with 81 of 161 (50.3%) in the usual respiratory support group (risk difference, -3.1% [95% CI, -14.1% to 7.8%]; relative risk, 0.94 [95% CI, 0.75-1.17]). There were no significant differences between the 2 groups in any of the prespecified secondary end points. Barotrauma occurred in 30 of 159 patients (18.9%) in the helmet noninvasive ventilation group and 25 of 161 (15.5%) in the usual respiratory support group. Skin pressure injury occurred in 5 of 159 patients (3.1%) in the helmet noninvasive ventilation group and 10 of 161 (6.2%) in the usual respiratory support group. There were 2 serious adverse events in the helmet noninvasive ventilation group and 1 in the usual respiratory support group. Conclusions and Relevance: Results of this study suggest that helmet noninvasive ventilation did not significantly reduce 28-day mortality compared with usual respiratory support among patients with acute hypoxemic respiratory failure due to COVID-19 pneumonia. However, interpretation of the findings is limited by imprecision in the effect estimate, which does not exclude potentially clinically important benefit or harm. Trial Registration: ClinicalTrials.gov Identifier: NCT04477668.

Critically ill patients with diabetes and Middle East respiratory syndrome: a multi-center observational study.

BACKGROUND: Diabetes is a risk factor for infection with coronaviruses. This study describes the demographic, clinical data, and outcomes of critically ill patients with diabetes and Middle East Respiratory Syndrome (MERS). METHODS: This retrospective cohort study was conducted at 14 hospitals in Saudi Arabia (September 2012-January 2018). We compared the demographic characteristics, underlying medical conditions, presenting symptoms and signs, management and clinical course, and outcomes of critically ill patients with MERS who had diabetes compared to those with no diabetes. Multivariable logistic regression analysis was performed to determine if diabetes was an independent predictor of 90-day mortality. RESULTS: Of the 350 critically ill patients with MERS, 171 (48.9%) had diabetes. Patients with diabetes were more likely to be older, and have comorbid conditions, compared to patients with no diabetes. They were more likely to present with respiratory failure requiring intubation, vasopressors, and corticosteroids. The median time to clearance of MERS-CoV RNA was similar (23 days (Q1, Q3: 17, 36) in patients with diabetes and 21.0 days (Q1, Q3: 10, 33) in patients with no diabetes). Mortality at 90 days was higher in patients with diabetes (78.9% versus 54.7%, p < 0.0001). Multivariable regression analysis showed that diabetes was an independent risk factor for 90-day mortality (odds ratio, 2.09; 95% confidence interval, 1.18-3.72). CONCLUSIONS: Half of the critically ill patients with MERS have diabetes; which is associated with more severe disease. Diabetes is an independent predictor of mortality among critically patients with MERS.

The WD40 domain of FBXW7 is a poly(ADP-ribose)-binding domain that mediates the early DNA damage response.

FBXW7, a classic tumor suppressor, is a substrate recognition subunit of the Skp1-cullin-F-box (SCF) ubiquitin ligase that targets oncoproteins for ubiquitination and degradation. We recently found that FBXW7 is recruited to DNA damage sites to facilitate nonhomologous end-joining (NHEJ). The detailed underlying molecular mechanism, however, remains elusive. Here we report that the WD40 domain of FBXW7, which is responsible for substrate binding and frequently mutated in human cancers, binds to poly(ADP-ribose) (PAR) immediately following DNA damage and mediates rapid recruitment of FBXW7 to DNA damage sites, whereas ATM-mediated FBXW7 phosphorylation promotes its retention at DNA damage sites. Cancer-associated arginine mutations in the WD40 domain (R465H, R479Q and R505C) abolish both FBXW7 interaction with PAR and recruitment to DNA damage sites, causing inhibition of XRCC4 polyubiquitination and NHEJ. Furthermore, inhibition or silencing of poly(ADP-ribose) polymerase 1 (PARP1) inhibits PAR-mediated recruitment of FBXW7 to the DNA damage sites. Taken together, our study demonstrates that the WD40 domain of FBXW7 is a novel PAR-binding motif that facilitates early recruitment of FBXW7 to DNA damage sites for subsequent NHEJ repair. Abrogation of this ability seen in cancer-derived FBXW7 mutations provides a molecular mechanism for defective DNA repair, eventually leading to genome instability.

Ribavirin and Interferon Therapy for Critically Ill Patients With Middle East Respiratory Syndrome: A Multicenter Observational Study.

BACKGROUND: The objective of this study was to evaluate the effect of ribavirin and recombinant interferon (RBV/rIFN) therapy on the outcomes of critically ill patients with Middle East respiratory syndrome (MERS), accounting for time-varying confounders. METHODS: This is a retrospective cohort study of critically ill patients with laboratory-confirmed MERS from 14 hospitals in Saudi Arabia diagnosed between September 2012 and January 2018. We evaluated the association of RBV/rIFN with 90-day mortality and MERS coronavirus (MERS-CoV) RNA clearance using marginal structural modeling to account for baseline and time-varying confounders. RESULTS: Of 349 MERS patients, 144 (41.3%) patients received RBV/rIFN (RBV and/or rIFN-α2a, rIFN-α2b, or rIFN-ß1a; none received rIFN-ß1b). RBV/rIFN was initiated at a median of 2 days (Q1, Q3: 1, 3 days) from intensive care unit admission. Crude 90-day mortality was higher in patients with RBV/rIFN compared to no RBV/rIFN (106/144 [73.6%] vs 126/205 [61.5%]; P = .02]. After adjusting for baseline and time-varying confounders using a marginal structural model, RBV/rIFN was not associated with changes in 90-day mortality (adjusted odds ratio, 1.03 [95% confidence interval {CI}, .73-1.44]; P = .87) or with more rapid MERS-CoV RNA clearance (adjusted hazard ratio, 0.65 [95% CI, .30-1.44]; P = .29). CONCLUSIONS: In this observational study, RBV/rIFN (RBV and/or rIFN-α2a, rIFN-α2b, or rIFN-ß1a) therapy was commonly used in critically ill MERS patients but was not associated with reduction in 90-day mortality or in faster MERS-CoV RNA clearance.

Antimicrobial activity of green silver nanoparticles from endophytic fungi isolated from Calotropis procera (Ait) latex.

Endophytes, a potential source of bioactive secondary metabolites, were isolated from the widely used medicinal plant Calotropis procera Ait. Approximately 675 segments from 15 Calotropis procera plants and 15 latex samples were assessed for the presence of endophytic fungi. Finally, eight fungal species were isolated and identified based on their macro- and micro-morphology. The endophytic fungal filtrates were screened for their antimicrobial activity against 11 important pathogenic micro-organisms. The filtrates of nanoparticles were from three of the eight isolated endophytic fungi, namely, Penicillium chrysogenum, Aspergillus fumigatus and Aspergillus flavus, and were highly effective against the tested bacteria, while the remaining endophytic fungal filtrates displayed low activity.

Corticosteroid Therapy for Critically Ill Patients with Middle East Respiratory Syndrome.

RATIONALE: Corticosteroid therapy is commonly used among critically ill patients with Middle East Respiratory Syndrome (MERS), but its impact on outcomes is uncertain. Analyses of observational studies often do not account for patients' clinical condition at the time of corticosteroid therapy initiation. OBJECTIVES: To investigate the association of corticosteroid therapy on mortality and on MERS coronavirus RNA clearance in critically ill patients with MERS. METHODS: ICU patients with MERs were included from 14 Saudi Arabian centers between September 2012 and October 2015. We performed marginal structural modeling to account for baseline and time-varying confounders. MEASUREMENTS AND MAIN RESULTS: Of 309 patients, 151 received corticosteroids. Corticosteroids were initiated at a median of 3.0 days (quartile 1 [Q1]-Q3, 1.0-7.0) from ICU admission. Patients who received corticosteroids were more likely to receive invasive ventilation (141 of 151 [93.4%] vs. 121 of 158 [76.6%]; P < 0.0001) and had higher 90-day crude mortality (112 of 151 [74.2%] vs. 91 of 158 [57.6%]; P = 0.002). Using marginal structural modeling, corticosteroid therapy was not significantly associated with 90-day mortality (adjusted odds ratio, 0.75; 95% confidence interval, 0.52-1.07; P = 0.12) but was associated with delay in MERS coronavirus RNA clearance (adjusted hazard ratio, 0.35; 95% CI, 0.17-0.72; P = 0.005). CONCLUSIONS: Corticosteroid therapy in patients with MERS was not associated with a difference in mortality after adjustment for time-varying confounders but was associated with delayed MERS coronavirus RNA clearance. These findings highlight the challenges and importance of adjusting for baseline and time-varying confounders when estimating clinical effects of treatments using observational studies.

Critically Ill Patients With the Middle East Respiratory Syndrome: A Multicenter Retrospective Cohort Study.

OBJECTIVES: To describe patient characteristics, clinical manifestations, disease course including viral replication patterns, and outcomes of critically ill patients with severe acute respiratory infection from the Middle East respiratory syndrome and to compare these features with patients with severe acute respiratory infection due to other etiologies. DESIGN: Retrospective cohort study. SETTING: Patients admitted to ICUs in 14 Saudi Arabian hospitals. PATIENTS: Critically ill patients with laboratory-confirmed Middle East respiratory syndrome severe acute respiratory infection (n = 330) admitted between September 2012 and October 2015 were compared to consecutive critically ill patients with community-acquired severe acute respiratory infection of non-Middle East respiratory syndrome etiology (non-Middle East respiratory syndrome severe acute respiratory infection) (n = 222). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Although Middle East respiratory syndrome severe acute respiratory infection patients were younger than those with non-Middle East respiratory syndrome severe acute respiratory infection (median [quartile 1, quartile 3] 58 yr [44, 69] vs 70 [52, 78]; p < 0.001), clinical presentations and comorbidities overlapped substantially. Patients with Middle East respiratory syndrome severe acute respiratory infection had more severe hypoxemic respiratory failure (PaO2/FIO2: 106 [66, 160] vs 176 [104, 252]; p < 0.001) and more frequent nonrespiratory organ failure (nonrespiratory Sequential Organ Failure Assessment score: 6 [4, 9] vs 5 [3, 7]; p = 0.002), thus required more frequently invasive mechanical ventilation (85.2% vs 73.0%; p < 0.001), oxygen rescue therapies (extracorporeal membrane oxygenation 5.8% vs 0.9%; p = 0.003), vasopressor support (79.4% vs 55.0%; p < 0.001), and renal replacement therapy (48.8% vs 22.1%; p < 0.001). After adjustment for potential confounding factors, Middle East respiratory syndrome was independently associated with death compared to non-Middle East respiratory syndrome severe acute respiratory infection (adjusted odds ratio, 5.87; 95% CI, 4.02-8.56; p < 0.001). CONCLUSIONS: Substantial overlap exists in the clinical presentation and comorbidities among patients with Middle East respiratory syndrome severe acute respiratory infection from other etiologies; therefore, a high index of suspicion combined with diagnostic testing is essential component of severe acute respiratory infection investigation for at-risk patients. The lack of distinguishing clinical features, the need to rely on real-time reverse transcription polymerase chain reaction from respiratory samples, variability in viral shedding duration, lack of effective therapy, and high mortality represent substantial clinical challenges and help guide ongoing clinical research efforts.

Impact of carbapenem restriction on the antimicrobial susceptibility pattern of Pseudomonas aeruginosa isolates in the ICU.

BACKGROUND: Rates of carbapenem-resistant Pseudomonas aeruginosa are increasing. Aggressive prevention strategies, including instituting antimicrobial stewardship programmes, are essential for combating antimicrobial resistance. OBJECTIVES: We conducted this study to compare the antimicrobial susceptibility pattern of P. aeruginosa before and after carbapenem restriction. METHODS: We conducted a two-phase retrospective study in an adult ICU. The first phase was from May until July 2016 (before carbapenem restriction), whereas the second phase was from September until November 2016 (while implementing carbapenem restriction). The antimicrobial susceptibility pattern of P. aeruginosa was reviewed in August and December 2016. The measure of carbapenem-resistant P. aeruginosa was the proportion of resistant isolates (percentage resistant). The measure of antibacterial consumption in the study phases was DDDs/1000 patient days. RESULTS: The overall carbapenem consumption decreased significantly in the second phase, from 28.44 to 11.67 DDDs/1000 patient days (P = 0.012). The resistance of P. aeruginosa to imipenem and meropenem decreased significantly from 76.0% to 38.5% (P = 0.019) and from 74.1% to 30.0% (P = 0.012), respectively. Susceptibility of P. aeruginosa to other antibacterials was not affected by carbapenem restriction. CONCLUSIONS: These data suggest that restricting carbapenems, even for a short duration, may be an effective strategy for managing the problem of carbapenem resistance in P. aeruginosa.

Wnt/ß-catenin signaling directs the regional expansion of first and second heart field-derived ventricular cardiomyocytes.

In mammals, cardiac development proceeds from the formation of the linear heart tube, through complex looping and septation, all the while increasing in mass to provide the oxygen delivery demands of embryonic growth. The developing heart must orchestrate regional differences in cardiomyocyte proliferation to control cardiac morphogenesis. During ventricular wall formation, the compact myocardium proliferates more vigorously than the trabecular myocardium, but the mechanisms controlling such regional differences among cardiomyocyte populations are not understood. Control of definitive cardiomyocyte proliferation is of great importance for application to regenerative cell-based therapies. We have used murine and human pluripotent stem cell systems to demonstrate that, during in vitro cellular differentiation, early ventricular cardiac myocytes display a robust proliferative response to ß-catenin-mediated signaling and conversely accelerate differentiation in response to inhibition of this pathway. Using gain- and loss-of-function murine genetic models, we show that ß-catenin controls ventricular myocyte proliferation during development and the perinatal period. We further demonstrate that the differential activation of the Wnt/ß-catenin signaling pathway accounts for the observed differences in the proliferation rates of the compact versus the trabecular myocardium during normal cardiac development. Collectively, these results provide a mechanistic explanation for the differences in localized proliferation rates of cardiac myocytes and point to a practical method for the generation of the large numbers of stem cell-derived cardiac myocytes necessary for clinical applications.

Cytotoxic cardenolides from the latex of Calotropis procera.

Three new cardenolides (3, 9 and 10), along with eight known ones, were isolated from the latex of Calotropis procera. The structural determination was accomplished by the 1D- and 2D-NMR spectra as well as HRESIMS analysis. The growth inhibitory activity of the latex and its sub-fractions as well as isolated compounds was evaluated against human A549 and Hela cell lines. The results exhibited that latex had strong growth inhibitory activity with IC50s of (3.37 µM, A-549) and (6.45 µM, Hela). Among the four extracts (hexane, chloroform, ethyl acetate and aqueous), chloroform extract displayed the highest potential cytotoxic activity, with IC50s of (0.985 µM, A-549) and (1.471 µM, Hela). All the isolated compounds displayed various degrees of cytotoxic activity and the highest activity was observed by calactin (1) with IC50s values of (0.036 µM, A-549) and (0.083 µM, Hela). None of these isolated compounds exhibited good antimicrobial activity evaluated by determination of their MICs using the broth microdilution method against various infectious pathogens. The structure-activity relationships for cytotoxic activity were also discussed.

Saudi expert consensus on acquired hemophilia A diagnosis and management.

Objectives: Acquired hemophilia affects approximately one in 1 million people. Timely diagnosis is key to appropriate disease management and the prevention of life-threatening complications. Patients with this condition may initially be seen by inexperienced physicians and remain underdiagnosed for several years. This consensus statement is aimed at providing guidelines for all practitioners in the Kingdom of Saudi Arabia (KSA) to diagnose and manage acquired hemophilia A. Methods: This consensus statement reflects the opinions drafted by a group of hematology specialists, who used an explicit systematic process to identify areas of agreement and disagreement. Results: This consensus statement provides a guide for all practitioners in the KSA regarding the diagnosis of clinical presentation, relevance, characteristics of bleeding symptoms, and case management; it additionally provides guidance for non-specialists. All management aspects, including diagnosis and treatment modalities, are discussed. Conclusions: Patients with acquired hemophilia may initially be seen by physicians who lack appropriate expertise in diagnosing and managing this condition. This consensus statement from the premier experts on the disease in the KSA provides details for diagnosing and managing acquired hemophilia.

Validity of Pleuroscopy in Evaluating Pleural Effusions of Uncertain Etiology at the Cardiothoracic Unit of Minia University Hospital, Egypt.

INTRODUCTION: Pleural effusion is a medical condition where an excessive amount of fluid accumulates in the pleural space. This can be caused by inflammation or malignant growth in the body. Doctors use medical thoracoscopy for both diagnostic and therapeutic purposes. This technique allows them to view the internal pleural surfaces and take biopsies of any abnormal lesions within the pleural cavity. OBJECTIVE: This work aimed to evaluate the diagnostic value of pleuroscopy in patients with undiagnosed exudative pleural effusion. PATIENTS AND METHODS: A study was conducted on 61 patients who had undiagnosed exudative pleural effusion and were admitted to the chest department at the cardiothoracic unit of the Minia University Hospital. All patients provided written consent and underwent a complete history and clinical examination. Standard laboratory tests, including routine liver and kidney function tests, a complete blood count, and a coagulation profile, were conducted on all patients, along with chest X-rays. If necessary, a chest CT scan was also performed. Diagnostic thoracentesis was done, and the pleural fluid was analyzed for sugar, protein, and lactate dehydrogenase and sent for bacteriological analysis (Gram stain, culture, and acid-fast bacilli smear) and cytopathological examination. Medical thoracoscopy was performed in cases where an etiological diagnosis was not established. RESULTS: A total of 61 patients with undiagnosed exudative pleural effusions were included. A definitive etiological diagnosis was reached in 58 (95%) patients. In 47 (77%) of the studied group, malignant etiology was confirmed; nine (14.8%) had tuberculous pleurisy, one (1.6%) had empyema, and one (1.6%) had inflammatory/autoimmune pleurisy. A definite diagnosis was not reached in three (5%) patients. The malignant pathology was caused by bronchogenic carcinoma in 20 (42.5%) cases, malignant mesothelioma in 10 (21.3%) cases, metastatic malignant deposits from other organs in six (12.7%) cases, and lymphoma in three (6.5%) cases. No serious adverse events related to the procedure were recorded. The most common minor complications were transient chest pain in 34 (55.7%) patients, followed by surgical emphysema in 10 (16.4%) patients. CONCLUSION: Pleuroscopy is an effective diagnostic tool for identifying the cause of pleural effusion when it is unclear. It is a minimally invasive and straightforward procedure associated with high diagnostic accuracy and low complication rates.

Middle Eastern Expert Opinion: Strategies for Successful Antifungal Stewardship Program Implementation in Invasive Fungal Infections.

In recent years, global public health efforts have increasingly emphasized the critical role of antimicrobial stewardship (AMS) in improving outcomes, reducing costs, and combating the growing threat of antimicrobial resistance. However, antifungal stewardship (AFS) has remained relatively overlooked despite the staggering impact of invasive fungal infections (IFIs). This burden is particularly pronounced in hospitals worldwide, with the Middle East facing significant unmet needs. The rising population of immunocompromised individuals vulnerable to IFI has prompted an increased reliance on antifungal agents for both prevention and treatment. Given the considerable mortality associated with IFIs and the emergence of antifungal resistance, implementing AFS programs in hospital settings is becoming increasingly urgent. In this article, we offer expert insights into the strategies that can be used for successful antifungal stewardship program implementation in IFI. Drawing upon the extensive clinical experience of a multinational and multidisciplinary panel, we present recommendations for optimizing AFS practices. We delve into the challenges and practical considerations of tailoring local AFS initiatives to the evolving landscape of fungal infections. Additionally, we provide actionable recommendations and position statements for the effective implementation of AFS programs, informed by the collective clinical experiences of panel members across their respective countries of practice.

Diagnostic accuracy of ePOS score in predicting DNR labeling after ICU admission: A prospective observational study (ePOS-DNR).

Background: Resuscitation can sometimes be futile and making a do-not-resuscitate (DNR) decision is in the best interest of the patient. The electronic poor outcome screening (ePOS) score was developed to predict 6-month poor outcomes of critically ill patients. We explored the diagnostic accuracy of the ePOS score in predicting DNR decisions in the intensive care unit (ICU). Methods: This study was conducted at the ICU of a tertiary referral hospital in Saudi Arabia between March and May 2023. Prospectively, we calculated ePOS scores for all eligible consecutive admissions after 48 h in the ICU and recorded the DNR orders. The ability of the score to predict DNR was explored using logistic regression. Youden's ideal cut-off value was calculated using the DeLong method, and different diagnostic accuracy measures were generated with corresponding 95 % confidence intervals (CIs). Results: We enrolled 857 patients, 125 received a DNR order and 732 did not. The average ePOS score of DNR and non-DNR patients was 28.2±10.7 and 15.2±9.7, respectively. ePOS score, as a predictor of DNR order, had an area under receiver operator characteristic (AUROC) curve of 81.8 % (95% CI: 79.0 to 84.3, P <0.001). Youden's ideal cut-off value >17 was associated with a sensitivity of 87.2 (95% CI: 80.0 to 92.5, P <0.001), specificity of 63.9 (95% CI: 60.3 to 67.4, P <0.001), positive predictive value of 29.2 (95% CI: 24.6 to 33.8, P <0.001), negative predictive value of 96.7 (95% CI: 95.1 to 98.3, P <0.001), and diagnostic odds ratio 12.1 (95% CI: 7.0 to 20.8, P <0.001). Conclusions: In this study, the ePOS score performed well as a diagnostic test for patients who will be labeled as DNR during their ICU stay. A cut-off score >17 may help guide clinical decisions to withhold or commence resuscitative measures.

Statistical analysis plan for the replacing protein via enteral nutrition in a stepwise approach in critically ill patients (REPLENISH) randomized clinical trial.

BACKGROUND: The optimal amount and timing of protein intake in critically ill patients are unknown. REPLENISH (Replacing Protein via Enteral Nutrition in a Stepwise Approach in Critically Ill Patients) trial evaluates whether supplemental enteral protein added to standard enteral nutrition to achieve a high amount of enteral protein given from ICU day five until ICU discharge or ICU day 90 as compared to no supplemental enteral protein to achieve a moderate amount of enteral protein would reduce all-cause 90-day mortality in adult critically ill mechanically ventilated patients. METHODS: In this multicenter randomized trial, critically ill patients will be randomized to receive supplemental enteral protein (1.2 g/kg/day) added to standard enteral nutrition to achieve a high amount of enteral protein (range of 2-2.4 g/kg/day) or no supplemental enteral protein to achieve a moderate amount of enteral protein (0.8-1.2 g/kg/day). The primary outcome is 90-day all-cause mortality; other outcomes include functional and health-related quality-of-life assessments at 90 days. The study sample size of 2502 patients will have 80% power to detect a 5% absolute risk reduction in 90-day mortality from 30 to 25%. Consistent with international guidelines, this statistical analysis plan specifies the methods for evaluating primary and secondary outcomes and subgroups. Applying this statistical analysis plan to the REPLENISH trial will facilitate unbiased analyses of clinical data. CONCLUSION: Ethics approval was obtained from the institutional review board, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia (RC19/414/R). Approvals were also obtained from the institutional review boards of each participating institution. Our findings will be disseminated in an international peer-reviewed journal and presented at relevant conferences and meetings. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04475666 . Registered on July 17, 2020.

Predictors of Mortality in Adults With Sickle Cell Disease Admitted to the Intensive Care Unit in King Saud Medical City, Saudi Arabia.

Background Sickle cell disease (SCD) is the most common genetic blood disorder in Saudi Arabia. A limited number of studies have been conducted on SCD patients regarding their intensive care unit (ICU) admissions. We aimed to identify the cause of ICU admission in SCD patients and to identify predictors of mortality. Methodology We identified 64 patients with SCD, aged 14 years and older, who were admitted to the ICU of King Saud Medical City, Riyadh, Kingdom of Saudi Arabia, from January 1, 2017, to December 31, 2020. Results Acute chest syndrome was the most frequent primary diagnosis for ICU admission in 29 (45.3%) patients followed by vaso-occlusive crisis in 23 (35.9%) patients. Pregnancy in eight (12.5%) patients was the most prevalent co-existing condition. The median age was 29 years, with males comprising 45.3% and females comprising 54.7% of the study population. Arterial blood gas pH less than 7.2 on ICU admission (p= <0.001), hemodialysis support (p= 0.049), the use of vasopressors (p= 0.016), intubation (p= <0.001), and being intubated within the first 24 hours of ICU stay (p= 0.04) had a statistically significant association with mortality at ICU discharge out of all the variables tested. Mortality on ICU discharge was 7 (10.9%). Conclusion This was a retrospective study carried out in King Saud Medical City. Comparing the results of the study to those of similar ones conducted around the world revealed a low SCD ICU mortality rate. This low mortality may be a result of improved overall ICU care. We recommend a multi-center, prospective study in future.

The relationship between asymptomatic atherosclerosis and hepcidin-25 in chronic kidney disease patients.

BACKGROUND: The most common and lethal consequence of chronic kidney disease (CKD) is atherosclerotic cardiovascular disease. The persistent inflammation present in CKD increases hepcidin levels. Iron accumulates in the arterial wall in atherosclerosis. Hepcidin-25 was thought to accelerate the development of atherosclerotic plaques by blocking iron release from macrophages. Therefore, we sought to determine the relationship between hepcidin-25 and asymptomatic atherosclerosis in non-dialysis CKD patients. OBJECTIVES: Investigate the relationship between hepcidin-25 and subclinical atherosclerosis in non-dialysis CKD patients. DESIGN: Cross-sectional SETTINGS: Outpatient clinic for urology and nephrology at a university hospital SUBJECTS AND METHODS: Participants above the age of 18 years included a group of healthy controls and a group of CKD patients who were not routinely maintained on hemodialysis. The latter group was further divided according to eGFR into CKD-3, CKD-4 and CKD-5 subgroups. We excluded patients with comorbidities, patients with chronic liver disease, and other conditions or habits. CBC, kidney function tests, and serum levels of hepcidin-25 (SH-25), TNF-α, IL-6, high-sensitivity C-reactive protein (hs-CRP), TC, TG, LDL-C and HDL-C were assessed. To measure carotid intima media thickness (CIMT) and determine presence of plaques, carotid ultrasonography was performed. The near or far walls of common carotid artery, bulb, and internal carotid artery were used to measure CIMT. MAIN OUTCOME MEASURES: SH-25 association and indicators of subclinical atherosclerosis. SAMPLE SIZE: 128 participants, the control group (n=25) and the non-hemodialysis CKD patients (n=103) RESULTS: The CKD patients had significantly higher serum levels of markers of inflammation including IL-6, TNF-α, and hs-CRP (P<.001 for each) compared to the controls. There was a significantly higher level of TC, TG and LDL-C (P<.001 for each) and a lower level of HDL-C (P<.001) in the CDK patients compared to controls. SH-25 was considerably higher in all CKD subgroups, especially with progression of CKD. CIMT was increased in CKD patients especially CKD-4 and CKD-5 subgroups when compared to healthy participants (P<.001 for each). In the patient group, CIMT showed a positive correlation with SH-25, (r=.65 and P<.001), IL-6 (r=.65, P<.001), TNF-α (r=.71, P<.001), and hs-CRP (r=.52, P<.001). The ROC curve study showed that SH-25 (AUC=.86, P<.001), IL-6 (AUC=.83, P<.001), hs-CRP (AUC=.72, P<.001), TNF-α (AUC=.82, P<.001) were strong predictors of subclinical atherosclerosis in the CKD patients. CONCLUSIONS: SH-25 and CIMT had a positive relationship in CKD patients. The ROC curve showed that SH-25 is a reliable predictor of carotid atherosclerosis. Therefore, we suggest that SH-25 is a vital biomarker of asymptomatic atherosclerosis. LIMITATIONS: Single-center.

Mortality Rates in Early versus Late Intensive Care Unit Readmission.

Background: ICU readmission is associated with poor outcomes. Few studies have directly compared the outcomes of early versus late readmissions, especially in Saudi Arabia. Objective: To compare the outcomes between early and late ICU readmissions, mainly with regards to hospital mortality. Methods: This retrospective study included unique patients who, within the same hospitalization, were admitted to the ICU, discharged to the general wards, and then readmitted to the ICU of King Saud Medical City, Riyadh, Saudi Arabia, between January 01, 2015, and June 30, 2022. Patients readmitted within 2 calendar days were grouped into the Early readmission group, while those readmitted after 2 calendar days were in the Late readmission group. Results: A total of 997 patients were included, of which 753 (75.5%) belonged to the Late group. The mortality rate in the Late group was significantly higher than that in the Early group (37.6% vs. 29.5%, respectively; 95% CI: 1%-14.8%; P = 0.03). The readmission length of stay (LOS) and severity score of both groups were similar. The odds ratio of mortality for the Early group was 0.71 (95% CI: 0.51-0.98, P = 0.04); other significant risk factors were age (OR = 1.023, 95% CI: 1.016-1.03; P < 0.001) and readmission LOS (OR = 1.017, 95% CI: 1.009-1.026; P < 0.001). The most common reason for readmission in the Early group was high Modified Early Warning Score, while in the Late group, it was respiratory failure followed by sepsis or septic shock. Conclusion: Compared with late readmission, early readmission was associated with lower mortality, but not with lower LOS or severity score.

Deferoxamine in the management of COVID-19 adult patients admitted to ICU: a prospective observational cohort study.

COVID-19 infection is associated with high mortality, and despite extensive studying the scientific society is still working to find a definitive treatment. Some experts postulated a beneficial role of Deferoxamine. Aim: The aim of this study was to compare the outcomes of COVID-19 adult patients admitted to the ICU who received deferoxamine to those who received standard of care. Methods: Prospective observational cohort study, in the ICU of a tertiary referral hospital in Saudi Arabia to compare all-cause hospital mortality between COVID-19 patients who received deferoxamine and standard of care. Results: A total of 205 patients were enrolled, with an average age of 50.1±14.3, 150 patients received standard of care only, and 55 patients received deferoxamine additionally. Hospital mortality was lower in deferoxamine group (25.5 vs. 40.7%, 95% CI=1.3-29.2%; P=0.045). Clinical status score upon discharge was lower in deferoxamine group (3.6±4.3 vs. 6.2±4, 95% CI: 1.4-3.9; P<0.001), as was the difference between discharge score and admission score (indicating clinical improvement). More patients admitted with mechanical ventilation were successfully extubated in the deferoxamine group (61.5 vs. 14.3%, 95% CI: 15-73%; P=0.001), with a higher median ventilator-free days. There were no differences between groups in adverse events. Deferoxamine group was associated with hospital mortality [odds ratio=0.46 (95% CI: 0.22-0.95); P=0.04]. Conclusions: Deferoxamine may have mortality and clinical improvement benefits in COVID-19 adults admitted to ICU. Further powered and controlled studies are required.

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.