Can serum NSE predict and evaluate sepsis-associated encephalopathy: A protocol for a systematic review and meta-analysis.

INTRODUCTION: Brain dysfunction in sepsis is known as sepsis-associated encephalopathy (SAE), which often results in severe cognitive and neurological sequelae and increases the risk of death. Neuron specific enolase (NSE) may serve as an important neurocritical biomarker for detection and longitudinal monitoring in SAE patients. Our systematic review and meta-analysis will aim to explore the diagnostic and prognostic value of serum NSE in SAE patients. Currently, no systematic review and meta-analysis have been assessed that NSE as a biomarker of SAE. METHODS AND ANALYSIS: We will conduct a systematic review and meta-analysis of serum NSE for the diagnostic and prognostic value of SAE patients. The primary objective is to evaluate the diagnostic accuracy of serum NSE as an independent biomarker for SAE. The secondary objective is to determine the prognostic strength of serum NSE as an independent biomarker of mortality in septic patients determine. We will perform a systematic search and descriptive review using the MEDLINE database and the PubMed interface. We will assign two independent reviewers to review all collected titles and associated abstracts, review full articles, and extract study data. We will use the Quality Assessment of Diagnostic Accuracy Studies version 2 (QUADAS-2) assessment tool according to the recommendation by the Cochrane Collaboration to evaluate quality and risk of bias of the selected studies. Subgroup and sensitivity analyses will also be used to assess heterogeneity. Review Manager version 5.4 and Stata16.0. will be used for statistical analysis. ETHICS AND DISSEMINATION: The meta-analysis will provide ICU physicians with the most current information to predict which patients are at risk of SAE and take corresponding intervention measures to reduce morbidity and ameliorate neurological outcomes. There is no need for ethics approval for this review. The findings will be disseminated in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: CRD42023398736.

Demystifying COVID-19 mortality causes with interpretable data mining.

While COVID-19 becomes periodical, old individuals remain vulnerable to severe disease with high mortality. Although there have been some studies on revealing different risk factors affecting the death of COVID-19 patients, researchers rarely provide a comprehensive analysis to reveal the relationships and interactive effects of the risk factors of COVID-19 mortality, especially in the elderly. Through retrospectively including 1917 COVID-19 patients (102 were dead) admitted to Xiangya Hospital from December 2022 to March 2023, we used the association rule mining method to identify the risk factors leading causes of death among the elderly. Firstly, we used the Affinity Propagation clustering to extract key features from the dataset. Then, we applied the Apriori Algorithm to obtain 6 groups of abnormal feature combinations with significant increments in mortality rate. The results showed a relationship between the number of abnormal feature combinations and mortality rates within different groups. Patients with "C-reactive protein > 8 mg/L", "neutrophils percentage > 75.0 %", "lymphocytes percentage < 20%", and "albumin < 40 g/L" have a 2 × mortality rate than the basic one. When the characteristics of "D-dimer > 0.5 mg/L" and "WBC > 9.5 × 10 9 /L" are continuously included in this foundation, the mortality rate can be increased to 3 × or 4 × . In addition, we also found that liver and kidney diseases significantly affect patient mortality, and the mortality rate can be as high as 100%. These findings can support auxiliary diagnosis and treatment to facilitate early intervention in patients, thereby reducing patient mortality.

Association between segmental alterations of white matter bundles and cognitive performance in first-episode, treatment-naïve young adults with major depressive disorder.

BACKGROUND: Cumulative evidence has consistently shown that white matter (WM) disruption is associated with cognitive decline in geriatric depression. However, limited research has been conducted on the correlation between these lesions and cognitive performance in untreated young adults with major depressive disorder (MDD), particularly with the specific segmental alterations of the fibers. METHOD: Diffusion tensor images were performed on 60 first-episode, treatment-naïve young adult patients with MDD and 54 matched healthy controls (HCs). Automated fiber quantification was applied to calculate the tract profiles of fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) to evaluate the WM microstructural organization. Correlation analysis was performed to find the associations between the diffusion properties and cognitive performance. RESULTS: Compared with HCs, patients with MDD exhibited predominantly different diffusion properties in bilateral uncinate fasciculus (UF), corticospinal tracts (CSTs), left superior longitudinal fasciculus and anterior thalamic radiation. The FA of the temporal cortex portion of right UF was positively correlated with working memory. The MD of the temporal component of left UF was negatively correlated with working memory and positively correlated with symptom severity. Additionally, a positive correlation between the MD of left CST and the psychomotor speed, negative correlation between the MD of left CST and the executive functions and complex attentional processes were observed. CONCLUSIONS: Our study validated the alterations in spatial localization of WM microstructure and its correlations with cognitive performance in first-episode, treatment-naïve young adults with MDD. This study added to the knowledge of the neuropathological basis of MDD.

Protocol to monitor cardiac function and hemodynamics in septic rodents.

Septic cardiomyopathy is associated with high mortality in septic patients, characterized by reversible systolic and diastolic dysfunction. It is essential to monitor cardiac function and hemodynamic changes in septic animals. Here, we present a protocol to monitor cardiac function and hemodynamics in septic rodents. We describe steps for performing cecal ligation and puncture on rodents to induce sepsis, acquiring two-dimensional echocardiographic and M-mode ultrasonic images, and assessing mean arterial pressure in septic animals. For complete details on the use and execution of this protocol, please refer to Zhang et al.1.

Meta-analysis of evaluating neuron specific enolase as a serum biomarker for sepsis-associated encephalopathy.

INTRODUCTION: Brain dysfunction in sepsis is known as Sepsis-associated encephalopathy (SAE), which often results in severe cognitive and neurological sequelae and increases the risk of death. Neuron specific enolase (NSE) may serve as an important neurocritical biomarker for detection and longitudinal monitoring in SAE patients. Our Meta-analysis aimed to explore the diagnostic and prognostic value of serum NSE in SAE patients. Currently, no systematic Review and Meta-analysis have been assessed that NSE as a biomarker of SAE. METHODS: The study protocol was registered in the PROSPERO database (CRD42023398736) and adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We conducted a systematic review and Meta-analysis to evaluate the serum NSE's diagnostic accuracy for SAE and prognostic strength for probability of death of septic patients. We systematic searched electronic bibliographic databases from PubMed, MEDLINE, Web of Science, Embase, Cochrane databases, CNKI, CQVIP, and WFSD. QUADAS-2 assessment tool was used to evaluate quality and risk of bias of the selected studies. Subgroup analyses, funnel plots, sensitivity analyses were also carried out. Review Manager version 5.4 and Stata16.0. was used for statistical analysis. RESULTS: This Meta-analysis included 22 studies with 1361 serum samples from SAE patients and 1580 serum samples from no-encephalopathy septic (NE) patients. The Meta-analysis showed that individuals with SAE had higher serum NSE level than NE controls (SMD 1.93 (95 % CI 1.51-2.35), P < 0.00001). In addition, there are 948 serum samples from survival septic patients and 446 serum samples from non-survival septic patients, septic patients with survival outcomes had lower serum NSE levels than those with death outcomes (SMD -1.87 (95 % CI -2.43 to -1.32), P < 0.00001). CONCLUSION: Our Meta-analysis reveals a significant association between elevated NSE concentrations and the increased likelihood of concomitant SAE and mortality during septic patients. This comprehensive analysis will equip ICU physicians with up-to-date insights to accurately identify patients at risk of SAE and implement appropriate intervention strategies to mitigate morbidity and improve neurological outcomes. However, it is important to note that the presence of substantial heterogeneity among studies poses challenges in determining the most effective discrimination cutoff values and optimal sampling collection time.

Decoding molecular signature on heart of septic mice with distinct left ventricular ejection fraction.

Dysregulated cardiac function after sepsis in intensive care unit is known to predict poor long-term outcome and increase mortality. Their pathological feature and molecular mechanism remain unclear. We observed that septic patients with depressed left ventricular ejection fraction (LVEF) have the highest in-hospital and 28 days mortality comparing to patients with hyperdynamic LVEF or with heart failure with preserved LVEF. Echocardiograms reveal that survivors post cecum ligation and puncture (CLP) on rodents have stable LVEF and non-survivors have fluctuated LVEF at CLP early phase. CLP-induced mice fall into three groups based on LVEF 24 h post-surgery: high-, low-, and normal-LVEF. Transcriptomic and proteomic analyses identify jointly and distinctively changed genes, proteins and biologically essential pathways in left ventricles from three CLP groups. Notably, transmission electron microscopy shows different mitochondrial and sarcomere defects associated with LVEF variances. Together, this study systematically characterizes the molecular, morphological, and functional alterations in CLP-induced cardiac injury.

Characterizing distinct profiles of immune and inflammatory response with age to Omicron infection.

Background: Understanding inflammatory and immune responses to Omicron infection based on age is crucial when addressing this global health threat. However, the lacking of comprehensive elucidation hinders the development of distinct treatments tailored to different age populations. Methods: 1299 cases of Omicron infection in Shanghai were enrolled between April 10, 2022 and June 3, 2022, dividing into three groups by ages: Adult group (18-59 years), Old group (60-79 years), and Elder group (≥ 80 years). Laboratory data including inflammatory cytokines, cellular, and humoral immunity were collected and analyzed. Results: The mean age of Adult, Old, and Elder groups were 44.14, 69.98, and 89.35 years, respectively, with 40.9% being men. The Elder group patients exhibited higher white blood cell (WBC) counts and elevated levels of inflammatory cytokines, but their lymphocyte counts were relatively lower. In comparison to the Old group patients, the Elder group patients demonstrated significantly lower CD3+ T-cell counts, CD3+ T-cell proportion, CD4+ T-cell counts, CD8+ T-cell counts, and CD19+ B-cell counts, while the NK-cell counts were higher. Omicron negative patients displayed a higher proportion of CD19+ B-cells and higher levels of Complement-3 and IL-17 compared to the positive patients in the Old group. Omicron negative patients had lower WBC counts, CD3+CD8+ T-cells proportion, and the levels of serum amyloid A and IgA in the Elder group, but the CD4+/CD8+ ratio was higher. Conclusions: Our study identified the distinct profiles of inflammatory and immune responses to Omicron infection varying with age and highlighted the diverse correlations between the levels of various biomarkers and Omicron infected/convalescent patients.

Predictive value of immunoglobulin G, activated partial thromboplastin time, platelet, and indirect bilirubin for delayed viral clearance in patients infected with the Omicron variant.

Background: Omicron is the recently emerged highly transmissible severe acute respiratory syndrome coronavirus 2 variant that has caused a dramatic increase in coronavirus disease-2019 infection cases worldwide. This study was to investigate the association between demographic and laboratory findings, and the duration of Omicron viral clearance. Methods: Approximately 278 Omicron cases at the Ruijin Hospital Luwan Branch, Shanghai Jiaotong University School of Medicine were retrospectively analyzed between August 11 and August 31, 2022. Demographic and laboratory data were also collected. The association between demographics, laboratory findings, and duration of Omicron viral clearance was analyzed using Pearson correlation analysis and univariate and multivariate logistic regression. Results: Univariate logistic regression analyses showed that a prolonged viral clearance time was significantly associated with older age and lower immunoglobulin (Ig) G and platelet (PLT) levels. Using multinomial logistic regression analyses, direct bilirubin, IgG, activated partial thromboplastin time (APTT), and PLT were independent factors for longer viral shedding duration. The model combining direct bilirubin, IgG, APTT, and PLT identifies patients infected with Omicron whose viral clearance time was ≥7 days with 62.7% sensitivity and 83.4% specificity. Conclusion: These findings suggest that direct bilirubin, IgG, PLT, and APTT are significant risk factors for a longer viral shedding duration in patients infected with Omicron. Measuring levels of direct bilirubin, IgG, PLT, and APTT is advantageous to identify patients infected with Omicron with longer viral shedding duration.

Regional disparities and influencing factors of high quality medical resources distribution in China.

BACKGROUND: With the gradual increase of residents' income and the continuous improvement of medical security system, people's demand for pursuing higher quality and better medical and health services has been released. However, so far little research has been published on China's high quality medical resources (HQMR). This study aims to understand the spatiotemporal variation trend of HQMR from 2006 to 2020, analyze regional disparity of HQMR in 2020, and further explore the main factors influencing the distribution of HQMR in China. METHODS: The study selected Class III level A hospitals (the highest level medical institutions in China) to represent HQMR. Descriptive statistical methods were used to address the changes in the distribution of HQMR from 2006 to 2020. Lorentz curve, Gini coefficient (G), Theil index (T) and High-quality health resource density index (HHRDI) were used to calculate the degree of inequity. The geographical detector method was used to reveal the key factors influencing the distribution of HQMR. RESULTS: The total amount of HQMR in China had increased year by year, from 647 Class III level A hospitals in 2006 to 1580 in 2020. In 2020, G for HQMR by population was 0.166, while by geographic area was 0.614. T was consistent with the results for G, and intra-regional contribution rates were higher than inter-regional contribution rates. HHRDI showed that Beijing, Shanghai, and Tianjin had the highest allocated amounts of HQMR. The results of the geographical detector showed that total health costs, government health expenditure, size of resident populations, GDP, number of medical colleges had a significant impact on the spatial distribution of HQMR and the q values were 0.813, 0.781, 0.719, 0.661, 0.492 respectively. There was an interaction between the influencing factors. CONCLUSIONS: China's total HQMR is growing rapidly but is relatively inadequate. The distribution of HQMR by population is better than by geography, and the distribution by geography is less equitable. Population size and geographical area both need to be taken into account when formulating policies, rather than simply increasing the number of HQMR.

Economic impact of powered stapler in video-assisted thoracic surgery lobectomy for lung Cancer in a Chinese tertiary hospital: a cost-minimization analysis.

BACKGROUND: To assess the economic impact of powered stapler use in video-assisted thoracic surgery (VATS) lobectomy for lung cancer in a Chinese tertiary care hospital. METHODS: This study identified 388 patients who received VATS lobectomy using the ECHELON powered stapler (n = 296) or the ECHELON manual stapler (n = 92) for lung cancer in a Chinese tertiary hospital. Multiple generalized linear regression analyses were conducted using data on hospital costs and patient characteristics to develop predictive equations for hospital costs in a cost-minimization analysis (CMA) model comparing hospital costs associated with the ECHELON powered stapler and the ECHELON manual stapler. CMA model was used to conduct scenario analysis to compare the ECHELON powered stapler with another manual stapler (Victor Medical). RESULTS: The multiple generalized linear regression analyses identified that using the ECHELON powered stapler in VATS lobectomy for lung cancer was associated with significantly lower drug costs than using the ECHELON manual stapler (coefficient - 0.256, 95% confidence interval: - 0.375 to - 0.139). The CMA model estimated that the ECHELON powered stapler could save hospital costs by ¥1653 when compared with the ECHELON manual stapler (¥65,531 vs. ¥67,184). The use of the ECHELON powered stapler also saved hospital costs by ¥4411 when compared with the Victor Medical manual stapler (¥65,531 vs. ¥69,942) in the scenario analysis. CONCLUSIONS: Compared to the two manual staplers used for VATS lobectomy for lung cancer in a Chinese tertiary hospital, the ECHELON powered stapler had 100% probability to save total hospital costs under present prices of the three staplers according to the CMA.

Clinical outcomes of powered and manual staplers in video-assisted thoracic surgery lobectomy for lung cancer.

Methods: This retrospective cohort study identified patients who underwent video-assisted thoracic surgery (VATS) lobectomy for lung cancer from January 2016 to December 2018 in a Chinese tertiary general hospital. The electronic hospital medical records associated with the VATS lobectomy for lung cancer were the data sources. Results: Based on the analysis of 433 patients with the utilization of staplers in their VATS lobectomy for lung cancer, using powered stapler was associated with significantly shorter operation time and postsurgery hospital stay length than using the manual stapler in the multivariable generalized linear regression analyses with the adjustment of patient characteristics. However, no other significant differences were observed for other clinical outcomes between the two staplers.

18 F-2-fluoro-2-deoxy-D-glucose-positron emission tomography metabolic pattern assessment in the brain of betel quid dependent individuals.

The primary objective of this study was to identify the metabolic pattern in the brains of betel quid dependent (BQD) individuals using 18 F-2-fluoro-2-deoxy-D-glucose-positron emission tomography (18 F-FDG-PET). A total of 42 individuals (16 BQD individuals and 26 healthy controls, HCs) enrolled at the Department of Nuclear Medicine of Xiangya Hospital underwent brain 18 F-FDG-PET. Group comparisons using statistical parametric mapping (SPM) were performed to identify the 18 F-FDG-PET patterns. Standardized uptake value ratios of anterior cingulate, frontal, thalamus, parietal, occipital, temporal and cerebellum were calculated by SPM. The characteristics of abnormal metabolism in brain regions were quantified using the xjView toolbox, and a 3-D brain map was drawn using BrainNet Viewer. We found significant metabolic reduction in the bilateral middle prefrontal cortex (PFC) and the left orbital frontal gyrus (OFC). In contrast, hypermetabolism was observed in the inferior cerebellum, fusiform, superior cerebellum, parahippocampal, vermis, lingual and thalamus. However, we found no significant difference between the BQD and HC group in the anterior cingulate, thalamus, cerebellum and frontal, temporal, parietal and occipital lobes. In summary, we found abnormal 18 F-FDG-PET metabolic pattern in BQD individuals, and this pattern may help the treatment of BQD.

Differences in clinical characteristics between younger and older patients with COVID-19 and their relationship with the length of hospital stay.

Background: The coronavirus disease 2019 (COVID-19) pandemic is currently threatening the health of individuals worldwide. We compared the clinical characteristics between younger patients (aged <60 years) and older patients (aged ≥60 years) with COVID-19, detected the risk factors associated with a prolonged hospital stay, and examined the treatments commonly used with a particular focus on antiviral therapies. Methods: This retrospective study was conducted at the West Campus, Union Hospital affiliated to Tongji Medical College of Huazhong University of Science and Technology (Wuhan, China). The sample consisted of 123 patients admitted to the hospital between 9th February, 2020, and 3rd March, 2020. The data related to the demographics, laboratory findings, and treatment were analyzed to identify discrepancies between younger and older patients and those with and without primary diseases. The risk factors that contribute to a prolonged hospital stay were subsequently identified. Results: Patients aged ≥60 years required longer hospital stay than younger patients (P=0.001). The percentage of lymphocytes was significantly lower in older patients and those with primary diseases (P=0.016 and P=0.042, respectively). The findings revealed that the risk factors that contributed to the length of hospital stay were age, the number of days of illness before hospitalization, white blood cell (WBC) count and albumin levels at admission, a neutrophil fraction at discharge, and antibiotic treatment. Analysis using a model that consisted of the above five risk factors for predicting prolonged hospital stay (>14 days) yielded an area under the ROC (AuROC) curve of 0.716. Antiviral and antibiotic treatments were administered to 97.6% and 39.0% of patients, respectively. The antiviral drugs most commonly administered were traditional Chinese medicine (83.7%) and arbidol (75.6%). Conclusions: In this study, older patients and those with primary diseases were at a higher risk of worse clinical manifestations. The physicians who treat the patients should pay close attention to the risk factors that contribute to the length of hospital stay, which could be used for predicting prolonged hospital stay. Traditional Chinese medicine and arbidol were the most frequently used antiviral drugs. Nevertheless, the extent to which these medications can effectively treat COVID-19 warrants further investigation.

Higher Trait Impulsivity and Altered Frontostriatal Connectivity in Betel-Quid Dependent Individuals.

Objective: Betel quid dependency (BQD) is characterized by functional and structural brain alterations. Trait impulsivity may influence substance dependence by impacting its neurobiological underpinnings in the frontostriatal circuit. However, little is known about the trait impulsivity and its neural correlates in individuals with BQD. Methods: Forty-eight participants with BQD and 22 normal controls (NCs) were recruited and scanned on a 3T MRI scanner. Barratt impulsiveness scale (BIS) was used to measure trait impulsivity: motor, attention, and no plan impulsivity. We used voxel-based morphometry (VBM) to assess the relationship between trait impulsivity and gray matter volumes. The relevant clusters identified were served as regions of interest (ROI) seeds. The whole-volume psycho-physiological interactions (PPI) analysis was used to investigate the changes of functional connectivity related to ROI seeds in the cue-reactivity task condition (BQ and control images). Results: Behaviorally, the BQD group showed significantly higher trait impulsivity including motor and no plan impulsivity than the NCs group. VBM analyses showed that motor impulsivity was negatively associated with gray matter volume of right caudate in the whole sample. No difference in gray matter volume between the two groups was observed. PPI analyses showed that there was a significantly decreased functional connectivity between the right caudate and right dorsolateral prefrontal cortex (DLPFC) when watching BQ related images than control images in individuals with BQD. Furthermore, functional connectivity between the right caudate and right DLPFC was negatively correlated with BQ dependency scores. Conclusions: Our study demonstrated the structural basis of trait impulsivity in the caudate and provided evidence for abnormal interactions within frontostriatal circuitsin individuals with BQD, which may provide insight into the selection of potential novel therapeutic targets for the treatment of BQ dependency.

Dysfunction of the Prefrontal Cortex in Betel-Quid-Dependent Chewers.

Betel quid is the fourth most popular psychoactive agent worldwide. Imaging studies have found altered brain structure in prefrontal cortex (PFC) in betel-quid dependent (BQD) chewers. However, the brain function in PFC associated with BQ use still remains unclear. The present study aimed to examine brain functional activity in PFC in individuals with BQD. This study recruited 48 participants with BQD and 22 normal controls (NCs). Both BQ-specific cue reactivity and Go/NoGo tasks were administered with functional magnetic resonance imaging (fMRI). Behavioral results showed a deficit in the choice reaction time task in BQD group. The fMRI results of the cue reactivity task suggested that, individuals with BQD exhibited responses in right ventromedial PFC, left posterior cingulate cortex (PCC), left lateral parietal lobe (LPL), left middle temporal gyrus and left visual cortex, when seeing BQ images compared with control images. In the Go/NoGo task, relative to NCs group, individuals with BQD showed higher activity in right dorsolateral PFC, right PCC and bilateral LPL between NoGo and Go trials. Across these two tasks, we consistently found disrupted function in PFC in individuals with BQD, which might lead to impaired craving and response inhibition in BQ addiction. Results of current study might shed light on the neural mechanisms involved in BQ use, which could be used as potential guidelines for diagnosis and treatment of BQ dependence.

Clinical and economic impact of oxidized regenerated cellulose for surgeries in a Chinese tertiary care hospital.

Aim: To assess the impact of oxidized regenerated cellulose (ORC) on blood transfusion and hospital costs associated with surgeries. Patients & methods: This retrospective cohort study selected ten surgeries to create propensity-score matching groups to compare ORC versus nonORC (conventional hemostatic techniques such as manual pressure, ligature and electrocautery). Results: NonORC was associated with both higher blood transfusion volume and higher hospital costs than ORC in endoscopic transnasal sphenoidal surgery, nonskull base craniotomy, hepatectomy, cholangiotomy, gastrectomy and lumbar surgery. However, nonORC was associated with better outcomes than ORC in open colorectal surgery, mammectomy and hip arthroplasty surgery. Conclusion: When compared with conventional hemostatic technique, using ORC could impact blood transfusion and hospital costs differently by surgical settings.

Care for Critical Ill Patients With COVID-19: Establishment of a Temporary Intensive Care Unit in an Isolated Hospital.

The current global spread of COVID-19, a highly contagious disease, has challenged healthcare systems, and placed immense burdens on medical staff globally. With a sharp increase in the number of newly confirmed cases and the rapid progression of the disease into a critically ill state, overstretched critical care units have had to contend with a shortage of beds, specialist personnel, and medical resources. Temporary intensive care units (ICUs) were therefore set up in isolated hospitals to provide the required standardized care for all severe cases. The current paper describes the authors' experience of setting up and managing such an ICU in Wuhan, Hubei Province, China, from the identification of critically ill COVID-19 patients through to the arranging and equipping of the unit, providing training and protection for staff, and standardizing all aspects of care.

Accumulated Clinical Experiences from Successful Treatment of 1377 Severe and Critically Ill COVID-19 Cases.

In late December 2019, COVID-19 was firstly recognized in Wuhan, China and spread rapidly to all of the provinces of China. The West Campus of Wuhan Union Hospital, the designated hospital to admit and treat the severe and critically ill COVID-19 cases, has treated a large number of such patients with great success and obtained lots of valuable experiences based on the Chinese guideline (V7.0). To standardize and share the treatment procedures of severe and critically ill cases, Wuhan Union Hospital has established a working group and formulated an operational recommendation, including the monitoring, early warning indicators, and several treatment principles for severe and critically ill cases. The treatment experiences may provide some constructive suggestions for treating the severe and critically ill COVID-19 cases all over the world.