Admission Serum Magnesium Levels Is Associated with Short and Long-Term Clinical Outcomes in COVID-19 Patients.

BACKGROUND: In the face of the global pandemic that the coronavirus disease 2019 (COVID-19) has created, readily available prognostic markers may be of great use. OBJECTIVE: To evaluate the association between serum magnesium (sMg) levels on admission and clinical outcomes in hospitalized COVID-19 patients. METHODS: We retrospectively analyzed all patients admitted to a single tertiary center with a primary de novo diagnosis of COVID-19. Patients were followed for a mean of 10 ± 7 months. Demographic, clinical and laboratory data were collected and compared between five groups of patients according to sMg quintiles on hospital admission. RESULTS: The cohort included 1522 patients (58% male, 69 ± 17 years old). A low sMg level (1st quintile) was associated with higher rates of diabetes and steroid use, whereas a high sMg level (5th quintile) was associated with dyslipidemia, renal dysfunction, higher levels of inflammatory markers and stay in the intensive care unit. All-cause in-hospital and long-term mortality was higher in patients with both low and high sMg levels, compared with mid-range sMg levels (2nd, 3rd and 4th quintiles; 19% and 30% vs. 9.5%, 10.7% and 17.8% and 35% and 45.3% vs. 23%, 26.8% and 27.3% respectively; p < 0.001 for all). After adjusting for significant clinical parameters indicating severe disease and renal dysfunction, only low sMg state was independently associated with increased mortality (HR = 1.57, p < 0.001). CONCLUSIONS: Both low and high sMg levels were associated with increased mortality in a large cohort of hospitalized COVID-19 patients. However, after correction for renal dysfunction and disease severity, only low sMg maintained its prognostic ability.

Impact of Divalent Metal Ions on Regulation of Trans-Cleavage Activity of CRISPR-Cas13a: A Combined Experimental and Computational Study.

CRISPR-LbuCas13a has emerged as a revolutionary tool for in vitro diagnosis. Similar to other Cas effectors, LbuCas13a requires Mg2+ to maintain its nuclease activity. However, the effect of other divalent metal ions on its trans-cleavage activity remains less explored. Herein, we addressed this issue by combining experimental and molecular dynamics simulation analysis. In vitro studies showed that both Mn2+ and Ca2+ could replace Mg2+ as cofactors of LbuCas13a. In contrast, Ni2+ , Zn2+ , Cu2+ , or Fe2+ inhibits the cis- and trans-cleavage activity, while Pb2+ does not affect it. Importantly, molecular dynamics simulations confirmed that calcium, magnesium, and manganese hydrated ions have a strong affinity to nucleotide bases, thus stabilizing the conformation of crRNA repeat region and enhancing the trans-cleavage activity. Finally, we showed that combination of Mg2+ and Mn2+ can further enhance the trans-cleavage activity to allow amplified RNA detection, revealing its potential advantage for in vitro diagnosis.

Removal Performance and Mechanism of Emerging Pollutant Chloroquine Phosphate from Water by Iron and Magnesium Co-Modified Rape Straw Biochar.

Chloroquine phosphate (CQP) is effective in treating coronavirus disease 2019 (COVID-19); thus, its usage is rapidly increasing, which may pose a potential hazard to the environment and living organisms. However, there are limited findings on the removal of CQP in water. Herein, iron and magnesium co-modified rape straw biochar (Fe/Mg-RSB) was prepared to remove CQP from the aqueous solution. The results showed that Fe and Mg co-modification enhanced the adsorption efficiency of rape straw biochar (RSB) for CQP with the maximum adsorption capacity of 42.93 mg/g (at 308 K), which was about two times higher than that of RSB. The adsorption kinetics and isotherms analysis, as well as the physicochemical characterization analysis, demonstrated that the adsorption of CQP onto Fe/Mg-RSB was caused by the synergistic effect of pore filling, π-π interaction, hydrogen bonding, surface complexation, and electrostatic interaction. In addition, although solution pH and ionic strength affected the adsorption performance of CQP, Fe/Mg-RSB still had a high adsorption capability for CQP. Column adsorption experiments revealed that the Yoon-Nelson model better described the dynamic adsorption behavior of Fe/Mg-RSB. Furthermore, Fe/Mg-RSB had the potential for repeated use. Therefore, Fe and Mg co-modified biochar could be used for the remediation of CQP from contaminated water.

Prognostic Value of Magnesium in COVID-19: Findings from the COMEPA Study.

Magnesium (Mg) plays a key role in infections. However, its role in coronavirus disease 2019 (COVID-19) is still underexplored, particularly in long-term sequelae. The aim of the present study was to examine the prognostic value of serum Mg levels in older people affected by COVID-19. Patients were divided into those with serum Mg levels ≤1.96 vs. >1.96 mg/dL, according to the Youden index. A total of 260 participants (mean age 65 years, 53.8% males) had valid Mg measurements. Serum Mg had a good accuracy in predicting in-hospital mortality (area under the curve = 0.83; 95% CI: 0.74-0.91). Low serum Mg at admission significantly predicted in-hospital death (HR = 1.29; 95% CI: 1.03-2.68) after adjusting for several confounders. A value of Mg ≤ 1.96 mg/dL was associated with a longer mean length of stay compared to those with a serum Mg > 1.96 (15.2 vs. 12.7 days). Low serum Mg was associated with a higher incidence of long COVID symptomatology (OR = 2.14; 95% CI: 1.30-4.31), particularly post-traumatic stress disorder (OR = 2.00; 95% CI: 1.24-16.40). In conclusion, low serum Mg levels were significant predictors of mortality, length of stay, and onset of long COVID symptoms, indicating that measuring serum Mg in COVID-19 may be helpful in the prediction of complications related to the disease.

Effect of serum magnesium levels on outcomes of patients hospitalized with COVID-19.

BACKGROUND:  The coronavirus disease 2019 (COVID-19) causes acute respiratory illness and multi-organ failure. The critical roles of magnesium in human health suggest that it could have an active role in the prevention and treatment of COVID-19. We measured magnesium levels in hospitalized COVID-19 patients concerning disease progression and mortality. MATERIALS AND METHODS:  This study was conducted in 2321 hospitalized COVID-19 patients. Clinical characteristics from each patient were recorded, and blood samples were collected from all patients upon their first admission to the hospital to determine serum magnesium levels. Patients were divided into two groups based on discharge or death. The effects of magnesium on death, severity, and hospitalization duration were estimated by crude and adjusted odds ratio using Stata Crop (version 12) software. RESULTS:  Mean magnesium levels in patients who died were higher than in discharged patients (2.10 vs 1.96 mg/dl, p 0.05). CONCLUSIONS: We found no relation between hypomagnesaemia on COVID-19 progression, although hypermagnesaemia could affect COVID-19 mortality (Tab. 4, Ref. 34).

The Significance of Low Magnesium Levels in COVID-19 Patients.

Magnesium is the fourth most common mineral in the human body and the second richest intracellular cation. This element is necessary for many physiological reactions, especially in the cardiovascular and respiratory systems. COVID-19 is an infectious disease caused by SARS-CoV-2. The majority of people who become ill as a result of COVID-19 have mild-to-moderate symptoms and recover without specific treatment. Moreover, there are people who develop severe forms of COVID-19, which require highly specialized medical assistance. Magnesium deficiency may play a role in the pathophysiology of infection with SARS-CoV-2. The primary manifestation of COVID-19 remains respiratory, but the virus can spread to other organs and tissues, complicating the clinical picture and culminating in multiorgan failure. The key mechanisms involved in the disease include direct viral cytotoxicity, endothelial dysfunction, and exaggerated release of inflammatory cytokines. The aim of this review was to summarize the available data regarding the role of magnesium in COVID-19 patients and its particularities in different clinical settings.

Magnesemia in COVID-19 ICU patients: the relationship between serum magnesium level and mortality

Objective: This study aimed to investigate the relationship between serum magnesium (Mg) levels at the time of admission and survival in COVID-19 patients followed in the intensive care unit (ICU). Methods: In total, 461 patients over the age of 18 diagnosed with the COVID-19, followed in the COVID-19 ICU of our hospital, were included. Patients whose files could not be accessed were excluded. Data on patients' demographics, clinical features, and laboratory data were compared according to the Mg levels measured during their admission to the ICU. The patients were divided into five groups according to their Mg level: Group 1 (<1.8 mg/dL), Group 2 (1.8-<2 mg/dL), Group 3 (2-<2.2 mg/dL), Group 4 (2.2-<2.4 mg/dL), and Group 5 (>2.4 mg/dL). Results: For patients with Mg value of <2 mg/dL, the proportion of males to females was roughly equal, however, the proportion of males was higher in other groups (p = 0.004). Overall, hypertension was the most common comorbid disease in patients, followed by diabetes mellitus in 32.1%. The latter was observed more frequently in Group 1 (<1.8 mg/dL) compared to the other groups (51.3%, p = 0.008). No significant difference was determined between the groups regarding laboratory values and treatments administered. Requirement of mechanical ventilation was significantly higher in Groups 1 (<1.8 mg/dL) and 5 (>2.4 mg/dL) than in other groups (p = 0.008). However, although mortality was also high in these groups, the difference was not statistically significant (p = 0.067). Conclusion: A correlation between serum Mg levels and mortality was not observed, but mortality and the need for mechanical ventilation were higher in groups with Mg levels <1.8 mg/dL and >2.4 mg/dL compared to other groups. We believe that it is critical to measure serum Mg levels while supporting COVID-19 patients with Mg in the ICU.

The effect of vitamin D and magnesium supplementation on clinical symptoms and serum inflammatory and oxidative stress markers in patients with COVID-19: a structured summary of a study protocol for a randomized controlled trial.

OBJECTIVES: This study aims to evaluate the effect of vitamin D and magnesium supplementation on clinical symptoms and serum inflammatory and oxidative stress markers in patients with COVID-19. TRIAL DESIGN: This study is a 4-arm randomized, double-blind, placebo-controlled clinical trial with a factorial design and the intervention period is 3 weeks. PARTICIPANTS: This study is conducted on COVID-19 patients admitted to the Shahid Mohammadi hospital in Bandar Abbas, Iran, who are eligible for inclusion in the study. Patients are included only if they meet all of the following criteria: (1) aged from 18 to 65 years old; (2) confirmation of COVID-19 by RT-PCR test; (3) completing informed consent; (4) passing less than 48 h since the patient's hospitalization; (5) no skin or gastrointestinal allergies due to taking multivitamin supplements, vitamin D, and magnesium; and (6) having more than 30 breaths per minute and less than 93% oxygen saturation in room air and sea level. Patients are excluded if they have any of the following conditions: (1) pregnancy or lactation; (2) taking a daily multivitamin or take a vitamin D or magnesium supplement in the last month; (3) participating in other clinical trials; (4) renal failure or dialysis, severe liver disease or cirrhosis; (5) known diagnosis of hypercalcemia; (6) discharging from the hospital less than 24 h after the start of the intervention; (7) history of kidney stones in the last year; (8) transfer the patient to the ICU; (9) baseline vitamin D levels above 80 ng/ml; (10) baseline magnesium levels above 2.6 mg/dl; and (11) unwillingness of the patient to continue the study. INTERVENTION AND COMPARATOR: Participants will be randomly allocated to one of the four following groups: (A) vitamin D (two 50,000 IU capsules at the beginning of the study, two 50,000 IU capsules on the 4th day, one 50,000 IU capsule on the 11th day, and one 50,000 IU capsule on the 17th day) and magnesium supplement (300 mg/day); (B) vitamin D capsule and magnesium placebo; (C) magnesium supplement and vitamin D placebo; and (D) vitamin D placebo and magnesium placebo. MAIN OUTCOMES: The resolution of clinical symptoms (fever, dry cough, shortness of breath, headache, myalgia, oxygen saturation, and mortality rate) and interpretation of laboratory assays (CRP, MDA, TAC, WBC, neutrophils count, lymphocytes count, ratio of neutrophils to lymphocytes, levels of 25 hydroxyvitamin D and magnesium) will be assessed in the study groups. RANDOMIZATION: A computer-generated block randomization list is used for randomization. BLINDING (MASKING): Investigators and patients are blinded to group allocation and treatment. A double-blind design is achieved using matched placebos. NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): A total of 104 eligible patients are randomized into four groups of 26 subjects (1:1:1:1 allocation ratio). DISCUSSION: With the rapid prevalence of COVID-19 in recent years, more attention has been paid to effective dietary supplementation to improve clinical symptoms and biochemical parameters in these patients. To our knowledge, this is the first study to evaluate the effects of vitamin D supplementation in combination with magnesium or alone with respect to this infectious disease. The findings of the current RCT will provide evidence regarding the effectiveness of dietary supplementation strategies to improve COVID-19 outcomes. TRIAL STATUS: Ethical approval of the first version of the study protocol was obtained from the medical ethics committee of Hormozgan University of Medical Sciences, Bandar Abbas, Iran on May 30, 2021 (IR.HUMS.REC.1400.085). Currently, the recruitment phase is ongoing since August 23, 2021, and is anticipated to be complete by the end of August 2022. TRIAL REGISTRATION: The study protocol was registered in the Iranian Registry of Clinical Trials ( https://www.irct.ir ; IRCT20210702051763N1) on August 14, 2021. https://www.irct.ir/trial/57413 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this letter serves as a summary of the key elements of the full protocol.

Reduction in Serum Magnesium Levels and Renal Function Are Associated with Increased Mortality in Obese COVID-19 Patients.

Several studies provide evidence that obesity is a significant risk factor for adverse outcomes in coronavirus disease 2019 (COVID-19). Altered renal function and disturbances in magnesium levels have been reported to play important pathophysiological roles in COVID-19. However, the relationship between obesity, renal function, circulating magnesium levels, and mortality in patients with COVID-19 remains unclear. In this retrospective cohort study, we characterized 390 hospitalized patients with COVID-19 that were categorized according to their body mass index (BMI). Patients were clinically characterized and biochemical parameters, renal function, and electrolyte markers measured upon admission. We found that in patients who died, BMI was associated with reduced estimated glomerular filtration rate (eGFR, Rho: -0.251, p = 0.001) and serum magnesium levels (Rho: -0.308, p < 0.0001). Multiple linear regression analyses showed that death was significantly associated with obesity (p = 0.001). The Cox model for obese patients showed that magnesium levels were associated with increased risk of death (hazard ratio: 0.213, 95% confidence interval: 0.077 to 0.586, p = 0.003). Thus, reduced renal function and lower magnesium levels were associated with increased mortality in obese COVID-19 patients. These results suggest that assessment of kidney function, including magnesium levels, may assist in developing effective treatment strategies to reduce mortality among obese COVID-19 patients.

A potential protective role of magnesium in neuroCOVID

Several recent studies support a role of dysregulated magnesium homeostasis in COVID-19. In the present narrative review, we focus on the neurological aspects of this disease, collectively known as neuroCOVID, and we propose some mechanisms by which alterations of magnesium may contribute to the involvement of the nervous system in the context of SARS-CoV-2 infection. Further fundamental, translational, and clinical research is needed to underpin the potential relationships between altered magnesium status and neuro-COVID, with potentially novel therapeutic implications.

Therapeutic potential of metal ions for COVID-19: insights from the papain-like protease of SARS-CoV-2.

Coronaviruses have been responsible for multiple challenging global pandemics, including coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Papain-like protease (PLpro), one of two cysteine proteases responsible for the maturation and infectivity of SARS-CoV-2, processes and liberates functional proteins from the viral polyproteins and cleaves ubiquitin and ISG15 modifications to inhibit innate immune sensing. Consequently, PLpro is an attractive target for developing COVID-19 therapies. PLpro contains a zinc-finger domain important for substrate binding and structural stability. However, the impact of metal ions on the activity and biophysical properties of SARS-CoV-2 PLpro has not been comprehensively studied. Here, we assessed the impacts of metal ions on the catalytic activity of PLpro. Zinc had the largest inhibitory effect on PLpro, followed by manganese. Calcium, magnesium, and iron had smaller or no effects on PLpro activity. EDTA at a concentration of 0.5 mM was essential for PLpro activity, likely by chelating trace metals that inhibit PLpro. IC50 values for ZnCl2, ZnSO4, and MnCl2 of 0.42 ± 0.02 mM, 0.35 ± 0.01 mM, and 2.6 ± 0.3 mM were obtained in the presence of 0.5 mM EDTA; in the absence of EDTA, the estimated IC50 of ZnCl2 was 14 µM. Tryptophan intrinsic fluorescence analysis confirmed the binding of zinc and manganese to PLpro, and differential scanning calorimetry revealed that zinc but not manganese reduced ΔHcal of PLpro. The results of this study provide a reference for further work targeting PLpro to prevent and treat COVID-19.

SARS-COV-ATE risk assessment model for arterial thromboembolism in COVID-19.

Patients with SARS-CoV-2 infection are at an increased risk of cardiovascular and thrombotic complications conferring an extremely poor prognosis. COVID-19 infection is known to be an independent risk factor for acute ischemic stroke and myocardial infarction (MI). We developed a risk assessment model (RAM) to stratify hospitalized COVID-19 patients for arterial thromboembolism (ATE). This multicenter, retrospective study included adult COVID-19 patients admitted between 3/1/2020 and 9/5/2021. Among 3531 patients from the training cohort, 15.5% developed acute in-hospital ATE, including stroke, MI, and other ATE, compared to 13.4% in the validation cohort. The 16-item final score was named SARS-COV-ATE (Sex: male = 1, Age [40-59 = 2, > 60 = 4], Race: non-African American = 1, Smoking = 1 and Systolic blood pressure elevation = 1, Creatinine elevation = 1; Over the range: leukocytes/lactate dehydrogenase/interleukin-6, B-type natriuretic peptide = 1, Vascular disease (cardiovascular/cerebrovascular = 1), Aspartate aminotransferase = 1, Troponin-I [> 0.04 ng/mL = 1, troponin-I > 0.09 ng/mL = 3], Electrolytes derangement [magnesium/potassium = 1]). RAM had a good discrimination (training AUC 0.777, 0.756-0.797; validation AUC 0.766, 0.741-0.790). The validation cohort was stratified as low-risk (score 0-8), intermediate-risk (score 9-13), and high-risk groups (score ≥ 14), with the incidence of ATE 2.4%, 12.8%, and 33.8%, respectively. Our novel prediction model based on 16 standardized, commonly available parameters showed good performance in identifying COVID-19 patients at risk for ATE on admission.

Reply to Scarpati, G.; Piazza, O. Comment on "Guerrero-Romero et al. Magnesium-to-Calcium Ratio and Mortality from COVID-19. Nutrients 2022, 14, 1686".

We thank Dr. Scarpati and Dr. Piazza for their interest and comments [...].

Comment on Guerrero-Romero et al. Magnesium-to-Calcium Ratio and Mortality from COVID-19. Nutrients 2022, 14, 1686.

We read with great interest the article by Romero et al. [...].

Caged Dexamethasone/Quercetin Nanoparticles, Formed of the Morphogenetic Active Inorganic Polyphosphate, are Strong Inducers of MUC5AC.

Inorganic polyphosphate (polyP) is a widely distributed polymer found from bacteria to animals, including marine species. This polymer exhibits morphogenetic as well as antiviral activity and releases metabolic energy after enzymatic hydrolysis also in human cells. In the pathogenesis of the coronavirus disease 2019 (COVID-19), the platelets are at the frontline of this syndrome. Platelets release a set of molecules, among them polyP. In addition, the production of airway mucus, the first line of body defense, is impaired in those patients. Therefore, in this study, amorphous nanoparticles of the magnesium salt of polyP (Mg-polyP-NP), matching the size of the coronavirus SARS-CoV-2, were prepared and loaded with the secondary plant metabolite quercetin or with dexamethasone to study their effects on the respiratory epithelium using human alveolar basal epithelial A549 cells as a model. The results revealed that both compounds embedded into the polyP nanoparticles significantly increased the steady-state-expression of the MUC5AC gene. This mucin species is the major mucus glycoprotein present in the secreted gel-forming mucus. The level of gene expression caused by quercetin or with dexamethasone, if caged into polyP NP, is significantly higher compared to the individual drugs alone. Both quercetin and dexamethasone did not impair the growth-supporting effect of polyP on A549 cells even at concentrations of quercetin which are cytotoxic for the cells. A possible mechanism of the effects of the two drugs together with polyP on mucin expression is proposed based on the scavenging of free oxygen species and the generation of ADP/ATP from the polyP, which is needed for the organization of the protective mucin-based mucus layer.

Essential oil-mediated biocompatible magnesium nanoparticles with enhanced antibacterial, antifungal, and photocatalytic efficacies.

Emergent application of antimicrobial strategies as symptomatic treatment in coronavirus disease (COVID-19) and linkage of severe acute respiratory syndrome coronavirus2 with microbial infections, has created colossal demand for antimicrobials. For the first time, this communication explore the physicochemical, antifungal, antibacterial, and photocatalytic properties of biogenic magnesium nanoparticles (MgNPs), synthesized using essential oil of Cymbopogon flexuosus's as an efficient multifunctional reducing and stabilizing/capping reagent. It is observed that MgNPs (ranging in size: 8-16 nm) of varying phytochemical compositions (MgS1, MgS2, MgS3) exhibited various useful physicochemical, antimicrobial, and photocatalytic properties. FTIR outcomes highlight the functional biomolecules-assisted reduction of Mg from Mg+ to Mg0. Among all, MgS3-Nps owing to the smallest particle size exhibited superior photocatalytic efficacy (91.2%) for the methylene blue degradation upon direct exposure to the sunlight for 3 h without using any reducing agents. Fabricated MgNPs also exhibited excellent antifungal (against Fusarium oxysporum) and antibacterial (versus Staphylococcus aureus and Escherichia coli) efficacies compared to state-of-the-art antimicrobial agents deployed for the treatment of infectious diseases. Based on this investigated greener approach, imperative from economic and environmental viewpoint, such essential oil based-MgNPs can be a potential nanosystem for various industrial applications where photocatalytic, and biomedical attributes are the key requirements.

Hypermagnesemia and hyperphosphatemia are highly prevalent in patients with COVID-19 and increase the risk of death.

OBJECTIVES: Nonrespiratory manifestations of COVID-19 include endocrine disorders, among which are calcium-magnesium-phosphate homeostasis abnormalities, which seem to influence the disease severity and patient outcome. The aim of this study was to evaluate the prevalence and impact of calcium-magnesium-phosphate and vitamin D3 disorders on survival in patients hospitalized for COVID-19 depending on the severity of the disease and kidney function. DESIGN OR METHODS: The study was conducted between April 2020 and May 2021 at Central Clinical Hospital in Warsaw, Poland. A total of 146 patients who had tested concentration of at least one of the studied elements, estimated glomerular filtration ratio, creatinine levels, and blood saturation, and were diagnosed with COVID-19 disease were included in the analysis. RESULTS: We found that hypermagnesemia was common and associated with a 1.5-fold increased risk of death in the whole cohort. Hyperphosphatemia also increased the risk of death, exactly 2.4-fold. Furthermore, we found a statistically significant association between increased mortality in the whole cohort and hypovitaminosis D3 (P <0.05). Serum creatinine concentration and estimated glomerular filtration ratio significantly correlated with serum magnesium and phosphate levels. CONCLUSION: Hypermagnesemia, hyperphosphatemia, and hypovitaminosis D but not hypocalcemia influence the mortality of patients with COVID-19. These parameters should be monitored routinely in this group of patients, especially in those with decreased kidney function.