Immunophenotyping characteristics of COVID-19 patients: Peripheral blood CD8+ HLA-DR+ T cells as a biomarker for mortality outcome.

INTRODUCTION: The goal of this study was to identify biomarker(s) to assign risk of mortality in COVID-19 patients to improve intensive care unit (ICU) and coronary care unit  management. A total of 100 confirmed COVID-19 patients admitted at Imam Khomeini Hospital in Tehran, were compared to 70 control subjects. Peripheral blood leukocyte was studied using staining reagents included CD3, CD4, CD8, HLA-DR, CD19, CD16, and CD56. The immunophenotyping analysis was evaluated using the FACSCalibur instrument. To investigate the cell density of lung infiltrating T cells, postmortem slides of needle necropsies taken from the lung tissue of 3 critical patients were evaluated by immunohistochemistry staining. The number of lymphocyte subpopulations was significantly lower in COVID-19 patients than in the control group. Regarding the disease severity, the absolute count of T, NK, and HLA-DR+ T cells were significantly reduced in severe patients compared to the moderate ones. The critical patients had a significantly lower count of CD8-HLA-DR+ T cells than the moderate cases. Regarding the disease mortality, based on univariate analysis, the count of HLA-DR+ T, CD8- HLA-DR+ T, and CD8+ HLA-DR+ T cells was associated with mortality in COVID-19 patients. Receiver operating characteristic curve analysis showed the count of CD8+ HLA-DR+ T cells is the best candidate as a biomarker for mortality outcome. Furthermore, pulmonary infiltration of T cells in the lung tissue showed only slight infiltrations of CD3+ T cells, with an equal percentage of CD4+ and CD8+ T cell subpopulation in the lung tissue. These findings suggest that close monitoring of the value of CD8+ HLA-DR+ T cells in COVID-19 patients may be helpful to identify high-risk patients. However, further studies with larger sample size are needed.

Effect of Intermediate-Dose vs Standard-Dose Prophylactic Anticoagulation on Thrombotic Events, Extracorporeal Membrane Oxygenation Treatment, or Mortality Among Patients With COVID-19 Admitted to the Intensive Care Unit: The INSPIRATION Randomized Clinical Trial.

Importance: Thrombotic events are commonly reported in critically ill patients with COVID-19. Limited data exist to guide the intensity of antithrombotic prophylaxis. Objective: To evaluate the effects of intermediate-dose vs standard-dose prophylactic anticoagulation among patients with COVID-19 admitted to the intensive care unit (ICU). Design, Setting, and Participants: Multicenter randomized trial with a 2 × 2 factorial design performed in 10 academic centers in Iran comparing intermediate-dose vs standard-dose prophylactic anticoagulation (first hypothesis) and statin therapy vs matching placebo (second hypothesis; not reported in this article) among adult patients admitted to the ICU with COVID-19. Patients were recruited between July 29, 2020, and November 19, 2020. The final follow-up date for the 30-day primary outcome was December 19, 2020. Interventions: Intermediate-dose (enoxaparin, 1 mg/kg daily) (n = 276) vs standard prophylactic anticoagulation (enoxaparin, 40 mg daily) (n = 286), with modification according to body weight and creatinine clearance. The assigned treatments were planned to be continued until completion of 30-day follow-up. Main Outcomes and Measures: The primary efficacy outcome was a composite of venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days, assessed in randomized patients who met the eligibility criteria and received at least 1 dose of the assigned treatment. Prespecified safety outcomes included major bleeding according to the Bleeding Academic Research Consortium (type 3 or 5 definition), powered for noninferiority (a noninferiority margin of 1.8 based on odds ratio), and severe thrombocytopenia (platelet count <20 ×103/µL). All outcomes were blindly adjudicated. Results: Among 600 randomized patients, 562 (93.7%) were included in the primary analysis (median [interquartile range] age, 62 [50-71] years; 237 [42.2%] women). The primary efficacy outcome occurred in 126 patients (45.7%) in the intermediate-dose group and 126 patients (44.1%) in the standard-dose prophylaxis group (absolute risk difference, 1.5% [95% CI, -6.6% to 9.8%]; odds ratio, 1.06 [95% CI, 0.76-1.48]; P = .70). Major bleeding occurred in 7 patients (2.5%) in the intermediate-dose group and 4 patients (1.4%) in the standard-dose prophylaxis group (risk difference, 1.1% [1-sided 97.5% CI, -∞ to 3.4%]; odds ratio, 1.83 [1-sided 97.5% CI, 0.00-5.93]), not meeting the noninferiority criteria (P for noninferiority >.99). Severe thrombocytopenia occurred only in patients assigned to the intermediate-dose group (6 vs 0 patients; risk difference, 2.2% [95% CI, 0.4%-3.8%]; P = .01). Conclusions and Relevance: Among patients admitted to the ICU with COVID-19, intermediate-dose prophylactic anticoagulation, compared with standard-dose prophylactic anticoagulation, did not result in a significant difference in the primary outcome of a composite of adjudicated venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days. These results do not support the routine empirical use of intermediate-dose prophylactic anticoagulation in unselected patients admitted to the ICU with COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04486508.

Effect of Magnesium Loading Dose on Insulin Resistance in Patients With Stress-Induced Hyperglycemia: A Randomized Clinical Trial.

OBJECTIVES: There is currently no evidence that whether magnesium supplementation would improve stress-induced hyperglycemia (SIH) in critically ill patients. In this study, effects of magnesium loading dose on insulin resistance (IR) indices were evaluated in critically ill patients without diabetes having SIH. METHODS: Seventy critically ill patients with SIH were assigned to receive a loading dose of magnesium (7.5 g of magnesium sulfate in 500 mL normal saline as intravenous infusion over an 8-hour period) or placebo. Changes in baseline of serum and intracellular magnesium and serum adiponectin (AD) levels, homeostasis model assessment of IR (HOMA-IR), and HOMA-AD ratio were assessed in this study. RESULTS: Serum and intracellular magnesium levels increased significantly in patients in the magnesium group (P < .001). At day 3, there were significant differences between the magnesium group and the placebo group in the mean changes from baseline in the HOMA (between-group difference: -0.11; 95% confidence interval [CI]: -0.19 to -0.01; P = .02), the AD (between-group difference: 0.94; 95% CI: 0.41-1.48; P = .04), and the HOMA-AD ratio (between-group difference: -0.03; 95% CI: -0.04 to -0.01; P < .001). CONCLUSION: In the present study, a single-loading dose of intravenous magnesium improved IR indices in critically ill patients with SIH.

Topical pentoxifylline for pressure ulcer treatment: a randomised, double-blind, placebo-controlled clinical trial.

OBJECTIVE: To evaluate the effectiveness of topical pentoxifylline (PTX) on pressure ulcer (PU) healing in critically ill patients. METHOD: In this randomised, double blind, placebo-controlled clinical trial, patients with category I or II PUs were randomly assigned to receive either topical PTX 5% or a placebo twice daily for 14 days. Changes in PU characteristics (category and size) were assessed. The category of the PU was determined by the Stirling Pressure Ulcer Severity Scale (two-digit) at baseline (day zero), day seven and day 14 of treatment. PU length and width was measured with a disposable ruler and expressed as cm2. RESULTS: A total of 112 adult patients were enrolled in the study. Median PU size and score at day zero were 32 (10.00-69.33)cm2 and 1(1.00-2.00) respectively. In the PTX group, the mean differences (95% confidence interval, CI) of all PU scores and sizes decreased significantly across the intervals (day seven versus day zero, day 14 versus day zero, and day 14 versus day seven), compared with the placebo group Conclusion: The severity and size of PUs improved significantly in patients who received topical PTX 5% ointment twice a day for 14 days compared with those in the placebo group. Topical PTX may be considered as a potential option in the treatment of categories I and II PUs in critically ill patients.

Effects of atorvastatin on biomarkers of acute kidney injury in amikacin recipients: A pilot, randomized, placebo-controlled, clinical trial.

BACKGROUND: The most common clinical indication of aminoglycosides (AG) is the treatment of serious Gram-negative infections. The aim of this study was to evaluate plausible effects of atorvastatin on the biomarkers of acute kidney injury (AKI) in patients receiving amikacin. MATERIALS AND METHODS: In this double-blinded randomized clinical trial, fifty patients (25 in each group) receiving amikacin (15 mg/kg/day) were randomly assigned to either atorvastatin (40 mg/day) or placebo (40 mg/day) groups for 7 days. Blood urea nitrogen (BUN), serum creatinine (SCr), and urinary neutrophil gelatinase-associated lipocalin (NGAL) levels were measured at days 0, 1, and 7 of amikacin treatment. RESULTS: During the study period, 4 (8%) patients including two patients in each atorvastatin and placebo group experienced AKI. Urine NGAL/urine Cr did not change significantly between and within placebo and atorvastatin groups during the study period. Similarly, the mean changes in SCr, BUN, and urine NGAL/urine Cr values did not differ significantly between and within patients with and without AKI. CONCLUSION: Our data suggested that the changing pattern of urine NGAL/urine Cr ratio did not differ significantly between the atorvastatin and placebo groups during the early phase of amikacin treatment.

Hypertonic saline solution reduces the oxidative stress responses in traumatic brain injury patients.

BACKGROUND: Oxidative stress processes play an important role in the pathogenesis of secondary brain injury after traumatic brain injury (TBI). Hypertonic saline (HTS) has advantages as being preferred osmotic agent, but few studies investigated oxidant and antioxidant effects of HTS in TBI. This study was designed to compare two different regimens of HTS 5% with mannitol on TBI-induced oxidative stress. MATERIALS AND METHODS: Thirty-three adult patients with TBI were recruited and have randomly received one of the three protocols: 125 cc of HTS 5% every 6 h as bolus, 500 cc of HTS 5%as infusion for 24 h or 1 g/kg mannitol of 20% as a bolus, repeated with a dose of 0.25-0.5 g/kg every 6 h based on patient's response for 3 days. Serum total antioxidant power (TAP), reactive oxygen species (ROS) and nitric oxide (NO) were measured at baseline and daily for 3 days. RESULTS: Initial serum ROS and NO levels in patients were higher than control(6.86± [3.2] vs. 1.57± [0.5] picoM, P = 0.001, 14.6± [1.6] vs. 7.8± [3.9] mM, P = 0.001, respectively). Levels of ROS have decreased for all patients, but reduction was significantly after HTS infusion and mannitol (3. 08 [±3.1] to 1.07 [±1.6], P = 0.001, 5.6 [±3.4] to 2.5 [±1.8], P = 0.003 respectively). During study, NO levels significantly decreased in HTS infusion but significantly increased in mannitol. TAP Levels had decreased in all patients during study especially in mannitol (P = 0.004). CONCLUSION: Hypertonic saline 5% has significant effects on the oxidant responses compared to mannitol following TBI that makes HTS as a perfect therapeutic intervention for reducing unfavorable outcomes in TBI patients.

The effect of chamomile consumption on glycemic markers in humans and animals: a systematic review and meta-analysis.

Purpose: The use of natural and herbal products as alternative therapies, in conjunction with blood glucose-lowering medications, is on the rise for patients with diabetes. Our objective was to conduct a systematic review and comprehensive meta-analysis of both human and animal models to investigate the impact of chamomile consumption on glycemic control. Methods: A systematic search was conducted on all published papers from January 1990 up to January 2022 via Scopus, PubMed/Medline, Google Scholar, and ISI Web of Science. Human and animal articles evaluating the effect of chamomile on serum glycemic markers were included. We used the random-effects model to establish the pooled effect size. The dose-dependent effect was also assessed. Results: Overall, 4 clinical trials on human and 8 studies on animals met the inclusion criteria. With regard to RCTs, a favorable effect of chamomile consumption on serum fasting blood glucose (Standardized Mean Differences (SMD): -0.65, 95% CI: -1.00, -0.29, P < 0.001; I2 = 0%) and hemoglobin A1C (HbA1C) levels (SMD: -0.90, 95% CI: -1.39, -0.40, P < 0.001; I2 = 45.4%) was observed. Considering animal studies, consumption of chamomile extracts significantly reduced serum blood glucose (SMD: -4.37, 95% CI: -5.76, -2.98, P < 0.001; I2 = 61.2%). Moreover, each 100 mg/d increase in chamomile extract intervention resulted in a significantly declined blood glucose concentrations (MD: -54.35; 95% CI: -79.77, -28.93, P < 0.001; I2 = 94.8). Conclusion: The current meta-analysis revealed that chamomile consumption could exert favorable effects on serum blood glucose and HbA1C. However, additional randomized controlled trials are needed to further confirm these findings. Supplementary Information: The online version contains supplementary material available at 10.1007/s40200-023-01345-8.

Pro-inflammatory cytokine profile of critically ill septic patients following therapeutic plasma exchange.

UNLABELLED: Severe sepsis involves a generalized inflammatory response, mediated by a number of various cytokines and factors. Plasma exchange (PE) has been proposed as a therapeutic approach to improve survival of patients with severe sepsis and septic shock. The theory is that removing harmful excessive endogenous inflammatory mediators is beneficial. Upon establishment of a diagnosis of severe sepsis, twelve patients received PE plus conventional sepsis treatment. Interleukin (IL)-6, IL-1ß and tumor necrosis factor (TNF)-α were assayed before and after each session of PE. RESULTS: There were no significant changes in cytokine plasma levels after each PE session compared to pre-procedure levels. Among measured pro-inflammatory cytokines, only the plasma levels of IL-6 before the 2nd and 3rd PE sessions were lower than baseline levels (p=0.011 and p=0.012, respectively). All patients tolerated PE therapy well without any adverse effects or homodynamic instability. The results of this study showed that PE does not have a direct and rapid effect on plasma level of TNF-α, IL-1ß and IL-6.

Safety and efficacy of pulmonary physiotherapy in hospitalized patients with severe COVID-19 pneumonia (PPTCOVID study): A prospective, randomised, single-blind, controlled trial.

BACKGROUND: Pulmonary physiotherapy (PPT) is an important treatment in the management of patients with different types of pulmonary disorders. We aimed to evaluate safety and efficacy of PPT in hospitalized patients with severe COVID-19 pneumonia. METHODS: In this randomised, single-blind, controlled trial, we enrolled hospitalized, non-intubated patients (18 to 75 years with oxygen saturation (Spo2) in free-air breathing ≤90%) with COVID-19 pneumonia at a referral hospital. Participants were randomly assigned (1:1) to receive PPT (six sessions PPT with breathing exercises and airway clearance techniques) or basic care. The primary outcomes were venous blood O2 (pO2) and CO2 (pCO2) pressures, Spo2, and three-minute walking test (3MWT) that were assessed before and end of sixth session. Secondary outcomes included level of dyspnea, venous blood PH, one-month mortality, three-month mortality and short form-36 (SF-36) after one and three months. The assessor was blinded to the assignment. This trial is registered with ClinicalTrials.gov (NCT04357340). FINDINGS: In April-May 2020, 40 participants were randomly assigned to PPT or basic care groups. While at the end of intervention, pO2 (adjusted mean difference to baseline measure (AMD) 6.43 mmHg [95%CI 2.8, 10.07], P<0.01), Spo2 (AMD 4.43% [95%CI 2.04, 6.83], P = 0.0011), and 3MTW (AMD 91.44 m [95%CI 68.88, 113.99], P<0.01) were higher in PPT group and basic care group, pCO2 was not improved (AMD -2.1 mmHg [95%CI-6.36, 2.21], P = 0.33). Based on the logistic model adjusted to baseline Spo2, the risks of mortality were reduced 81% ([95%CI: 97% reduction to 30% increase], P = .09) and 84% ([95%CI 74% reduction to 5% increase], P = .06) at one-month and three-month, respectively. There were no significant differences in most SF-36 domains scores after one and three months. No serious adverse event was observed during PPT sessions. CONCLUSION: Early PPT can be considered a safe and relatively effective therapeutic choice for patients with severe COVID-19.

Cannabidiol Anticonvulsant Effects Against Lithium-Pilocarpine-Induced Status Epilepticus in Male Rats Are Mediated by Neuroinflammation Modulation and Cannabinoids 1 (CB1), But Not CB2 and GABAA Receptors.

Background: Status epilepticus (SE) is a series of seizures that can lead to serious neurological damages. Cannabidiol (CBD) is extracted from the cannabis plant, which has been approved as an antiseizure medication. This study aimed to determine the efficacy of various doses of CBD on lithium-pilocarpine-induced SE in rats and possible involvement of multiple pharmacological pathways. We hypothesized that cannabinoid receptors type 1 (CB1) and CB2, as well as GABAA receptors, might have important roles in the anticonvulsant effects of CBD against SE by its anti-inflammatory effects. Methods: SE was induced by intraperitoneal (i.p.) injection of lithium (127 mg/kg, i.p.) and pilocarpine (60 mg/kg, i.p., 20 h after lithium). Forty-two male rats were divided into seven groups (including control and sham groups), and the treated groups received different doses of CBD (1, 3, 5, 10, and 25 mg/kg, i.p.). SE score was recorded over the next 2 h following pilocarpine injection. Then, we measured the levels of pro-inflammatory cytokines, including interleukin (IL)-lß and tumor necrosis factor (TNF)-α, using ELISA kits. Also we analyzed the expression of CB1, CB2, and GABAA receptors using the Western blot technique. Results: CBD at 5 mg/kg significantly reduced Racine's scale and duration of seizures, and increased the onset time of seizure. Moreover, CBD 5 mg/kg caused significant reductions in the elevated levels of IL-lß and TNF-α, as well as a significant increase in the decreased level of CB1 receptor expression compared to the control group. In other word, CBD reverted the effects of SE in terms of neuroinflammation and CB1 receptor. Based on the obtained results, CBD was not able to restore the declined levels of CB2 or GABAA receptors. Conclusion: Our study found anticonvulsant effects of CBD on the SE rat model induced by lithium-pilocarpine with probable involvement of CB1 receptors and anti-inflammatory effects by reducing IL-1ß and TNF-α markers independent of CB2 and GABAA receptors.

Effects of nebulized hypertonic saline on inflammatory mediators in patients with severe COVID-19 pneumonia: A double-blinded randomized controlled trial.

INTRODUCTION: An exaggerated immune response is considered the most important aspect of COVID-19 pathogenesis. Hypertonic saline (HS) has shown promise in combating inflammation in several respiratory diseases. We investigated the effects of nebulized HS on clinical symptoms and inflammatory status in patients with severe novel coronavirus infection (COVID-19) pneumonia. MATERIALS AND METHODS: We randomly assigned 60 adults admitted to the intensive care unit (ICU) due to severe COVID-19 pneumonia to the experimental (received nebulized 5% saline) and control (received nebulized distilled water) groups. All interventions were applied 4 times daily for 5 days. The levels of tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), and other clinical factors from venous blood were evaluated before and after intervention application. Mortality rate, intubation rate, and durations of ICU and hospital stay were also compared between groups. RESULTS: The levels of TNF-α (MD: -21.35 [-32.29, -10.40], P = 0.000) and IL-6 (-9.94 [-18.86, -1.02], P = 0.003) were lower in the experimental group compared to the control group after applying the interventions. The levels of white blood cell count, PO2, and serum sodium were also statistically significant differences between groups. However, we did not observe significant differences in terms of hospitalization durations and mortality rates. CONCLUSION: Nebulization of HS in patients with severe COVID-19 pneumonia appears to be effective in reducing inflammation, but does not appear to affect intubation rates, mortality, hospitalization, or length of stay in ICU.

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

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

Gargle test for successful extubation in critically ill patients underwent head and neck surgeries: A new test.

Background: Improvement of predictive tools for recognition of airway edema is crucial for safe extubation and patient safety. This study aimed to evaluate the diagnostic accuracy of the Gargle test (GT) as a new test for assessing airway edema and predicting successful extubation in patients admitted to the intensive care unit (ICU). Method: In this prospective observational study, patients underwent head and neck surgeries and admitted to ICU included. All the patients were weaned based on the same protocol.Quantitative Cuff Leak Test (CLT) and qualitative CLTwere first applied followed by GT with normal saline 0.9%. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were calculated. Results: One hundred and eighteen (male 67, female 51) participated in this study. The agreement between GT and CLT was low (Kappa: quantitative CLT 0.07, qualitative CLT 0.21). The GT compared to CLT had higher sensitivity (33.3% vs 16.6%), specificity (96.3% vs qualitative CLT 92.8%, quantitative CLT 79.4%), PPV (33.3% vs qualitative CLT 11.11%, quantitative CLT 4.0%), NPV (96.3% vs qualitative CLT 95.4%, quantitative CLT 94.6%), and accuracy (92.92% vs qualitative CLT 88.98%, quantitative CLT 76.27%. The cut-off value for GT was estimated 16.5% (sensitivity 74.1% and specificity 60%). Conclusion: The GT is a simple accurate test and can be used as a new test in the ICU for recognition of airway edema and prediction of safe extubation in patients with head and neck surgeries.

Cultural adaptation and psychometric assessment of the Persian version of the lumbar spine instability questionnaire.

BACKGROUND: The Lumbar Spine Instability Questionnaire (LSIQ) is a self-reported measure of clinical instability of the lumbar spine. This study aimed to translate and culturally adapt the LSIQ into Persian language (LSIQ-P) and to evaluate its reliability and validity in a sample of patients with chronic non-specific low back pain (LBP). METHODS: In a cross-sectional study, the LSIQ was translated using guidelines. Participants with chronic non-specific LBP, aged ≥ 18 years old, answered an online survey consisting of LSIQ-P, the Persian Functional Rating Index (FRI), and the pain Numeric Rating Scale (NRS). Construct validity, internal consistency reliability, test-retest reliability, standard error of measurement (SEM), smallest detectable change (SDC), discriminant validity, and factor analysis were evaluated. RESULTS: The LSIQ was successfully adapted into Persian. A sample of 100 participants with LBP and 100 healthy subjects completed the survey. Floor and ceiling effects were not observed. Cronbach's alpha = 0.767 and ICCagreement = 0.78 indicated good internal consistency and test-retest reliability. The SEM and SDC were 1.53 and 4.24, respectively. Construct validity of LSIQ-P was confirmed with significant correlation with Persian FRI (r = 0.44, p < 0.001) and pain NRS (r = 0.30, p = 0.003). An evidence of discriminant validity was demonstrated by significant difference in LSIQ-P total scores between the patients with LBP and healthy subjects, and between the patients with high total score ≥ 9 and those with low total score < 9 on the LSIQ-P. The LSIQ-P was found a multidimensional instrument with eight items appeared being redundant. CONCLUSIONS: The Persian LSIQ showed satisfactory metric characteristics of reliability and validity. Further studies are required to elucidate the internal structure of the LSIQ-P.

The effect of Vitamin C and Zn supplementation on the immune system and clinical outcomes in COVID-19 patients.

SARS-CoV-2 (Severe Acute Respiratory Syndrome-Coronavirus-2) is the most dangerous form of the coronavirus, which causes COVID-19. In patients with severe COVID-19, the immune system becomes markedly overactive. There is evidence that supplementation with select micronutrients may play a role in maintaining immune system function in this patient population. Throughout the COVID-19 pandemic, significant emphasis has been placed on the importance of supplementing critical micronutrients such as Vitamin C and Zinc (Zn) due to their immunomodulatory effects. Viral infections, like COVID-19, increase physiological demand for these micronutrients. Therefore, the purpose of this review was to provide comprehensive information regarding the potential effectiveness of Vitamin C and Zn supplementation during viral infection and specifically COVID-19. This review demonstrated a relation between Vitamin C and Zn deficiency and a reduction in the innate immune response, which can ultimately make patients with COVID-19 more vulnerable to viral infection. As such, adequate intake of Vitamin C and Zn, as an adjunctive therapeutic approach with any necessary pharmacological treatment(s), may be necessary to mitigate the adverse physiological effects of COVID-19. To truly clarify the role of Vitamin C and Zn supplementation in the management of COVID-19, we must wait for the results of ongoing randomized controlled trials. The toxicity of Vitamin C and Zn should also be considered to prevent over-supplementation. Over-supplementation of Vitamin C can lead to oxalate toxicity, while increased Zn intake can reduce immune system function. In summary, Vitamin C and Zn supplementation may be useful in mitigating COVID-19 symptomology.

The role of saliva PCR assay in the diagnosis of COVID-19.

INTRODUCTION: The introduction of a self-collection sampling method with less discomfort would be of great benefit in reducing the risk of medical provider's contamination and patient's acceptance. The aim of the present study was to investigate saliva samples' diagnostic performance for the COVID-19 RT-PCR test compared to pharyngeal swabs. METHODOLOGY: From individuals referred to a medical center with presentations compatible with COVID-19 who were eligible for molecular diagnostic tests, 80 cases were selected. Nasopharyngeal and oropharyngeal swabs (placed into the same transport tube) along with self-collected saliva sample were taken from each participant for COVID-19 RT-PCR assay. The results of pharyngeal swabs and saliva sample were compared. RESULTS: Sixty-two (78%) infected cases were detected, of whom 31 (39%) cases tested positive for both pharyngeal swab and saliva samples. 24 (30%) and 7 (9%) cases tested positive only for pharyngeal or saliva samples, respectively. The overall percentage of agreement between pharyngeal swab and saliva sample was 61%, with a kappa value of 0.24 (p-value = 0.019, 95% CI: 0.04-0.44), showing a fair level of agreement. The diagnostic sensitivity of pharyngeal swabs was 88.71% (95% CI: 78.11-95.34), and the diagnostic sensitivity of saliva samples was 61.29% (95% CI: 48.07-73.40). Compared to pharyngeal swabs (oropharyngeal and nasopharyngeal swabs in the same collection tube), an important observation was that seven more positive cases were detected among saliva samples. CONCLUSIONS: The findings of the present study indicated that self-collected saliva samples cannot replace pharyngeal swabs. Still, saliva samples significantly increased the case detection rate and can be used along with pharyngeal swabs.

Mortality Predictive Value of APACHE II and SOFA Scores in COVID-19 Patients in the Intensive Care Unit.

Background: COVID-19 pandemic has become a global dilemma since December 2019. Are the standard scores, such as acute physiology and chronic health evaluation (APACHE II) and sequential organ failure assessment (SOFA) score, accurate for predicting the mortality rate of COVID-19 or the need for new scores? We aimed to evaluate the mortality predictive value of APACHE II and SOFA scores in critically ill COVID-19 patients. Methods: In a cohort study, we enrolled 204 confirmed COVID-19 patients admitted to the intensive care units at the Imam Khomeini hospital complex. APACHE II on the first day and daily SOFA scoring were performed. The primary outcome was the mortality rate in the nonsurvived and survived groups, and the secondary outcome was organ dysfunction. Two groups of survived and nonsurvived patients were compared by the chi-square test for categorical variables and an independent sample t-test for continuous variables. We used logistic regression models to estimate the mortality risk of high APACHE II and SOFA scores. Result: Among 204 severe COVID-19 patients, 114 patients (55.9%) expired and 169 patients (82.8%) had at least one comorbidity that 103 (60.9%) of them did not survive (P=0.002). Invasive mechanical ventilation and its duration were significantly different between survived and nonsurvived groups (P ≤ 0.001 and P=0.002, respectively). Mean APACHE II and mean SOFA scores were significantly higher in the nonsurvived than in the survived group (14.4 ± 5.7 vs. 9.5 ± 5.1, P ≤ 0.001, 7.3 ± 3.1 vs. 3.1 ± 1.1, P ≤ 0.001, respectively). The area under the curve was 89.5% for SOFA and 73% for the APACHE II score. Respiratory diseases and malignancy were risk factors for the mortality rate (P=0.004 and P=0.007, respectively) against diabetes and hypertension. Conclusion: The daily SOFA was a better mortality predictor than the APACHE II in critically ill COVID-19 patients. But they could not predict death with high accuracy. We need new scoring with consideration of the prognostic factors and daily evaluation of changes in clinical conditions.

Effects of Melatonin and Propolis Supplementation on Inflammation, Oxidative Stress, and Clinical Outcomes in Patients with Primary Pneumosepsis: A Randomized Controlled Clinical Trial.

BACKGROUND AND OBJECTIVE: The present study aimed to investigate the effects of propolis and melatonin supplementation on inflammation, clinical outcomes, and oxidative stress markers in patients with primary pneumosepsis. MATERIALS AND METHODS: This pilot randomized controlled trial was conducted on 55 patients with primary pneumosepsis who were randomly assigned to the intervention and control groups. In the three intervention groups, the patients received propolis alone (1,000 mg/day), propolis (1,000 mg/day) plus melatonin (20 mg/day), and melatonin alone (20 mg/day). The control group received placebo. The inflammatory and oxidative stress markers as well as clinical outcomes were evaluated before and after the intervention, and the 28-day survival rate was also recorded. RESULTS: After the intervention, the combination of propolis and melatonin significantly reduced interleukin-6 (-55.282 pg/mL) and C-reactive protein (-21.656 mg/L) levels, while increasing gavage intake (326.680 mL/day) and improving some clinical outcomes (APACHE II, SOFA, and NUTRIC scores) compared to the control group. However, no significant difference was observed between the groups in terms of oxidative stress and hematological indices. In addition, there was no significant difference in the 28-day survival rate between the groups (p = 0.07). CONCLUSION: Supplementation with propolis and melatonin may improve clinical outcomes by reducing inflammation. Further investigations are required to confirm these findings.

Intermediate-Dose versus Standard-Dose Prophylactic Anticoagulation in Patients with COVID-19 Admitted to the Intensive Care Unit: 90-Day Results from the INSPIRATION Randomized Trial.

BACKGROUND: Thrombotic complications are considered among the main extrapulmonary manifestations of coronavirus disease 2019 (COVID-19). The optimal type and duration of prophylactic antithrombotic therapy in these patients remain unknown. METHODS: This article reports the final (90-day) results of the Intermediate versus Standard-dose Prophylactic anticoagulation In cRitically-ill pATIents with COVID-19: An opeN label randomized controlled trial (INSPIRATION) study. Patients with COVID-19 admitted to intensive care were randomized to intermediate-dose versus standard-dose prophylactic anticoagulation for 30 days, irrespective of hospital discharge status. The primary efficacy outcome was a composite of adjudicated venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation (ECMO), or all-cause death. The main safety outcome was major bleeding. RESULTS: Of 600 randomized patients, 562 entered the modified intention-to-treat analysis (median age [Q1, Q3]: 62 [50, 71] years; 237 [42.2%] women), of whom 336 (59.8%) survived to hospital discharge. The primary outcome occurred in 132 (47.8%) of patients assigned to intermediate dose and 130 (45.4%) patients assigned to standard-dose prophylactic anticoagulation (hazard ratio [HR]: 1.21, 95% confidence interval [CI]: 0.95-1.55, p = 0.11). Findings were similar for other efficacy outcomes, and in the landmark analysis from days 31 to 90 (HR: 1.59, 95% CI: 0.45-5.06). There were 7 (2.5%) major bleeding events in the intermediate-dose group (including 3 fatal events) and 4 (1.4%) major bleeding events in the standard-dose group (none fatal) (HR: 1.82, 95% CI: 0.53-6.24). CONCLUSION: Intermediate-dose compared with standard-dose prophylactic anticoagulation did not reduce a composite of death, treatment with ECMO, or venous or arterial thrombosis at 90-day follow-up.

The effect of supplementation with vitamins A, B, C, D, and E on disease severity and inflammatory responses in patients with COVID-19: a randomized clinical trial.

BACKGROUND AND OBJECTIVE: Because of the effect of vitamins on modulating the immune system function, we have evaluated the effect of supplementation with vitamins A, B, C, D, and E in ICU-admitted patients with COVID-19. METHODS: This study was a randomized and single-blinded clinical trial in which 60 subjects were randomly assigned to two groups. The intervention group (n=30) received vitamins, and the control group did not receive any vitamin or placebo. The intervention was included 25,000 IU daily of vitamins A, 600,000 IU once during the study of D, 300 IU twice daily of E, 500 mg four times daily of C, and one amp daily of B complex for 7 days. At baseline and after the 7-day intervention, the serum levels of inflammatory markers, vitamins, and the SOFA score were assessed. In addition, the mortality rate and duration of hospitalization were evaluated after the intervention (IRCT registration number: IRCT20200319046819N1/registration date: 2020-04-04, https://www.irct.ir/trial/46838 ). RESULTS: Significant changes were detected in serum levels of vitamins (p < 0.001 for all vitamins), ESR (p < 0.001), CRP (p = 0.001), IL6 (p = 0.003), TNF-a (p = 0.001), and SOFA score (p < 0.001) after intervention compared with the control group. The effect of vitamins on the mortality rate was not statistically significant (p=0.112). The prolonged hospitalization rate to more than 7 days was significantly lower in the intervention group than the control group (p=0.001). Regarding the effect size, there was a significant and inverse association between receiving the intervention and prolonged hospitalization (OR = 0.135, 95% CI 0.038-0.481; p=0.002); however, after adjusting for confounders, it was not significant (OR=0.402, 95% CI 0.086-1.883; p=0.247). CONCLUSION: Supplementation with vitamins A, B, C, D, and E could improve the inflammatory response and decrease the severity of disease in ICU-admitted patients with COVID-19.