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Serum zinc associated with immunity and inflammatory markers in Covid-19

  • Hassan Joulaei , Parisa Keshani EMAIL logo , Zohre Foroozanfar , Daniel Zamanian , Amirhossein Hassani , Fateme Parvizi , Yasaman Khadem , Navid Omidifar and Mohammad Ali Davarpanah
Published/Copyright: April 7, 2022
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Open Medicine
From the journal Open Medicine Volume 17 Issue 1

Abstract

This study aimed to assess the association between serum zinc level with some inflammatory and immunity factors and the duration of hospitalization and mortality rate in patients diagnosed with Covid-19. In this cross-sectional study, blood samples were taken from polymerase chain reaction (PCR) positive patients. New patients diagnosed with Covid-19, admitted to different public hospital wards, were considered eligible for entering the study. The study was done on 179 hospitalized patients diagnosed with Covid-19. Fourteen patients died during the hospitalization and the in-hospital mortality rate was 7.8%, with 9.1% (13 patients) of patients with serum zinc level less than 70 mcg/dL and 3.4% (1 patient) of patients with zinc levels more than 70 mcg/dL. Higher levels of zinc were significantly associated with a higher and lower level of interferon-gamma (IFN-γ) (p-value = 0.035) and interleukin (IL)-6 (p-value = 0.004), respectively. The level of serum zinc did not have a significant association with mortality even after adjusting for confounding factors. The relationship between zinc level and the duration of hospitalization was also not significant. In conclusion, serum zinc level had an association with IL-6 and IFN-γ level, but it did not have any significant association with hospital duration or mortality.

Keywords: serum zinc; interleukin-6; interferon-gamma; duration of hospitalization; mortality rate; Covid-19

1 Introduction

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (Covid-19), was first reported in China in late 2019 from a zoonotic source [1]. The full spectrum of Covid-19 ranges from mild, self-limiting respiratory tract illness to severe progressive pneumonia, multi-organ failure, and death [2]. After an incubation period, the acute viral phase in patients with symptomatic Covid-19 usually manifests as influenza-like symptoms. In some persons, the illness progresses to hypoxemic respiratory failure [3]. Evidence suggests that the pathophysiological basis of this profound decline is a severe inflammatory response resembling cytokine release syndrome [4,5]. In this phase, patients have markedly abnormal inflammatory markers, including elevated serum interleukin (IL)-6, ferritin, and C-reactive protein (CRP) levels [6,7,8]. Zinc (Zn) is an essential micronutrient that is involved in the regulation of innate and adaptive immune responses [9]. Zn is involved in a variety of biological processes due to its function as a cofactor, signaling molecule, and structural element. The most critical role of Zn is demonstrated in the immune system. Zn regulates the proliferation, differentiation, maturation, and functioning of leukocytes and lymphocytes [9]. Zn also plays a signaling role involved in the modulation of inflammatory responses [9]. Having said the role of Zn in inflammatory responses, there must be an understanding of cytokines. Cytokines are one term for a group of protein cell regulators, variously called lymphokines, monokines, IL, and interferons (IFN), which are produced by a wide variety of cells in the body. They play an important role in many physiological responses, involved in the pathophysiology of a range of diseases, and have a therapeutic potential [10]. Evidence has shown the role of different types of cytokines in Covid-cytokine storm syndrome (COVID-CSS). In CSS, many inflammatory cytokines such as IL-1, IL-10, and tumor necrosis factor (TNF)-α are elevated, approximately 2–100 folds above normative values, whereas IL-6 demonstrates much larger increases, in some cases more than 1000 folds above normal [11]. Other cytokines such as interferon-gamma (IFN-γ) is capable of orchestrating numerous protective functions to heighten immune responses in infections and cancers [12]. Zn deficiency results in altered numbers and dysfunction of all immune cells, subjects with suboptimal Zn state have an increased risk of infectious diseases and autoimmune disorders [11,13,14,15]. Zn deficiency is responsible for 16% of all deep respiratory infections worldwide [16]. During chronic Zn deficiency, the production of pro-inflammatory cytokines increases, influencing the outcome of a large number of inflammatory, metabolic, neurodegenerative, and immune diseases [17]. Zn is essential to preserve natural tissue barriers such as the respiratory epithelium, preventing pathogen entry, for a balanced function of the immune and redox system. There are several data surrounding the association between Zn status and viral respiratory tract infections, but there is still more to know regarding its association with Covid-19. It has also been suggested that most Covid-19 symptoms are associated with altered Zn homeostasis and Zn might even prevent or attenuate those symptoms and thus should be regarded as a promising cost-effective, globally available therapeutic approach for Covid-19 patients [18]. Given all the data surrounding the role of minerals, especially Zn in the regulation of immune responses, especially against respiratory tract infections and the unprecedented situation we are living in, with a global pandemic affecting many lives and causing many more hospitalizations, without much effective prophylaxis or treatment against Covid-19, studying the concentration of Zn in individuals affected with this disease and its association with some immunological and inflammatory factors might help us develop more accurate treatments. Prophylaxis against this disease can help us get into a deeper understanding of the role of minerals, especially Zn in Covid-19 and other similar respiratory infections. This study aimed to assess the association between serum Zn levels and some inflammatory and immunity factors and also to evaluate the association between serum Zn level and the duration of hospitalization and mortality rate in patients diagnosed with Covid-19.

2 Methods

2.1 Participants

In this cross-sectional study blood samples were taken from 179 polymerase chain reaction (PCR)-positive patients. New patients diagnosed with Covid-19, admitted to different public hospital wards, were considered eligible for entering the study. Demographic and lab data were also collected at the time of admission. The duration of hospitalization and the mortality rate of these patients were also monitored. The patients were required to fill and sign in a consent form that explained the goal of the study. The information gathered from the patients included: name and address, telephone number, hospitalization document code, date and duration of hospital stay, date of death, sex and age, height and weight, educational status, job status, past medical history such as (hypertension, dyslipidemia, diabetes, underlying heart or vascular disease, chronic lung and airway diseases such as asthma, cancer, etc.), drug history (including the history of vitamin or mineral supplement intake), alcohol and smoking history, and hospital prescriptions (antibiotics, corticosteroids, respiratory drugs, etc.) were gathered by interviewing and using hospital documents. Biochemical parameters such as oxygen saturation (SpO2), complete blood count (CBC), erythrocyte sedimentation rate (ESR), CRP, liver and kidney function tests, ferritin, and lactate dehydrogenase (LDH) were also gathered from hospital documents at the time of admission, and serum Zn, IL-6, and IFN-γ level were measured.

2.2 Measurements

The samples were taken from patients hospitalized at the internal ward and emergency room (ER). 3cc of blood was drawn from each individual and was put in a clot activator tube. The tubes were then put in a centrifuge with a rotational speed of 4,000 rpm for 5 min. The residual plasma for each patient was transferred to a micro-tube and stored at −70°C until the end of the study.

2.2.1 Serum Zn

Serum Zn was measured using AA500 Atomic Absorption Spectrometer. Given the lack of adequate data on the Zn deficiency status among Iranian individuals, the reference amount of Zn mentioned in the textbooks and articles which are between 70 and 120 mcg/dL were set as the normal range for individuals [19]. Those with serum Zn levels less than 70 mcg/dL were considered as Zn deficient.

2.2.2 Serum IL-6

The IMMULITE 2000 Systems Analyzer was used for the quantitative measurement of IL-6 in serum samples. IMMULITE 2000 IL-6 is a solid-phase, enzyme-labeled, chemiluminescent sequential immunometric assay. The absolute range was reported from nondetectable to 5.9 pg/mL for the procedure and analytical sensitivity was 2 pg/mL.

2.2.3 Serum IFN-γ

ZellBio ELIZA kit (Germany) was used for a quantitative assay of human IFN-γ on the basis of the Biotin double-antibody sandwich technology. Sensitivity was 1.5 ng/mL and the assay range was from 12.5 to 400 ng/mL.

2.3 Statistical analyses

Quantitative variables were reported as mean value ± standard deviation and qualitative variables were described in terms of number and percentage. Chi-square and t-tests were used to compare demographic and clinical characteristics in the Covid-19 Patients (alive or dead).

In order to determine the contribution of the Zn as a predictor of inflammatory factors (IFN-γ, IL-6, ESR, CRP, white blood cells (WBC), neutrophils, lymphocytes, SpO2, and LDH) in the Covid-19 patients, linear regression analysis was used. Logistic regression was used to determine the association between Zn and confounding variables with death outcome. Linear regression was also used to determine the relationship between Zn and confounding variables with the duration of hospitalization results.

Data were analyzed by SPSS software version 22 and GraphPad Prism software version 8. Also, p-value <0.05 was considered as the statistically significant level.

  1. Ethical standards disclosure: This study was conducted according to the guidelines laid down in the Declaration of Helsinki and all procedures involving research study participants were approved by the Shiraz University of Medical Sciences (SUMS) ethics board committee, reference number: IR.SUMS.REC.1399.836. Written informed consent was obtained from all participants and questionnaires were anonymous and encoded.

3 Results

In this study, 179 hospitalized patients diagnosed with Covid-19 participated. The mean age of the participants was 55.27 ± 16.23 in the total sample, with 54.30 ± 15.78 in survivor patients, and 66.79 ± 17.51 in non-survivor patients. This difference was statistically significant (p = 0.001). There were 108 (60.3%) male patients in the study. Among all the patients, 140 (81.9%) patients had Zn levels under 70 mcg/dL in which 83 (82.2%) of the male and 57 (81.4%) of the female population were Zn insufficient or deficient. Hypertension was the most common underlying disease in the participants (39.1% of patients reported a history of hypertension) and dyspnea was the most common presenting symptom in the patients diagnosed with Covid-19 (dyspnea has been reported in 78.2% of patients). About one-quarter of the patients had a history of vitamin use (50, 27.9%). Other demographic and clinical information of patients are reported in Table 1.

Table 1

Characteristics of patients with Covid-19 by survival status

Characteristics Patients (n = 179) Survived (n = 165) Non-survived (n = 14) p Value
Age mean value ± SD 55.27 ± 16.23 54.30 ± 15.78 66.79 ± 17.51 0.001*
BMI (kg/m2) mean value ± SD 27.54 ± 5.32 27.63 ± 5.46 26.37 ± 2.63 0.444
Sex N (%)
 Male 108 (60.3) 97 (58.8) 11 (78.6) 0.159
 Female 71 (39.7) 68 (41.2) 3 (21.4)
Education N (%)
 Illiterate 34 (19.0) 33 (19.4) 2 (14.3) 0.544
 Primary school 38 (21.2) 35 (21.2) 3 (21.4)
 Guidance school 13 (7.3) 10 (6.1) 3 (21.4)
 High school and diploma 30 (16.8) 30 (18.2) —
 Undergraduate 27 (15.1) 26 (15.8) 1 (7.1)
 Post graduate 13 (7.3) 12 (7.3) 1 (7.1)
Occupation N (%)
 Unemployed 4 (2.2) 4 (2.4) — 0.781
 House wife 59 (33.0) 56 (33.9) 3 (21.4)
 Worker 8 (4.5) 7 (4.2) 1 (7.1)
 Employed 28 (15.6) 26 (15.8) 2 (14.3)
 Self-employed 46 (25.7) 43 (26.1) 3 (21.4)
 Retired 19 (10.6) 16 (9.7) 3 (21.4)
 Student 1 (0.6) 1 (0.6) —
 Current smoking N (%) 39 (22.2) 38 (23.0) 1 (7.1) 0.190
 Alcohol consumer N (%) 15 (8.5) 15 (9.1) — 0.273
Place of residence N (%)
 Urban 147 (82.1) 135 (82.3) 12 (85.7) 0.691
 Rural 30 (16.8) 28 (17.1) 2 (14.3)
 Vitamin supplement consumption N (%) 50 (27.9) 47 (28.8) 47 (28.8) 0.557
 Vitamin C intake N (%) 16 (8.9) 15 (9.1) 15 (9.1) 0.807
 Vitamin D intake N (%) 27 (15.1) 25 (15.2) 25 (15.2) 0.931
 Zinc <70 mg/dL N (%) 142 (79.3) 130 (78.8) 12 (85.7) 0.316
History of underlying disease N (%)
 Diabetes 52 (29.2) 46 (28.0) 6 (42.9) 0.249
 Hypertension 70 (39.1) 62 (37.6) 8 (57.1) 0.158
 Cardiovascular disease 56 (31.3) 49 (29.7) 7 (50.0) 0.125
 Asthma and respiratory disease 22 (12.5) 20 (12.3) 2 (14.3) 0.827
 Cancer 7 (3.9) 6 (3.6) 1 (7.1) 0.618
 Autoimmune disease 16 (8.9) 9 (5.5) — 0.472
 HIV 2 (1.1) 2 (1.2) — 0.849
 Duration of hospitalization median (IQ) 3 (2–5) 3 (2–5) 2.50 (1.75–6.25) 0.838
Laboratory examinations mean value ± SD
 Zinc (mcg/dL) (n = 171) 58.65 ± 13.18 58.98 ± 13.38 54.61 ± 9.96 0.251
 IFN-γ (ng/mL) (n = 171) 19.04 ± 19.88 19.12 ± 20.4 18.11 ± 18.51 0.860
 IL-6 (pg/mL) (n = 170) 33.68 ± 40.21 32.80 ± 40.77 44.26 ± 31.99 0.330
 LDH (IU/L) (n = 153) 728.92 ± 397.74 720.15 ± 407.08 823.31 ± 271.67 0.376
 RBC (×106/µL) (n = 179) 4.73 ± 0.69 4.69 ± 0.69 5.14 ± 0.64 0.024*
 HB (g/dL) (n = 179) 13.15 ± 2.06 13.01 ± 2.01 14.77 ± 2.13 0.003*
 HCT (%) (n = 179) 40.73 ± 5.6 40.34 ± 5.48 45.32 ± 5.05 0.002*
 WBC (×1,000/µL) (n = 179) 6.85 ± 3.39 6.77 ± 3.47 7.76 ± 2.07 0.302
 PLT (×1,000/µL) (n = 179) 216.24 ± 118.72 218.21 ± 121.43 193.07 ± 79.73 0.437
 Neutrophils (%) (n = 176) 76.23 ± 57.17 75.87 ± 59.54 80.37 ± 8.08 0.781
 Lymphocytes (%) (n = 177) 20.74 ± 10.48 21.38 ± 10.47 13.22 ± 7.29 0.008*
 ESR (mm/h) (n = 128) 49.26 ± 26.53 49.04 ± 26.20 51.41 ± 30.66 0.767
 CRP (mg/L) (n = 164) 36.65 ± 32.97 35.64 ± 32.66 48.41 ± 35.57 0.186
 SpO2 (%) (n = 176) 86.48 ± 11.08 87.25 ± 10.19 77.64 ± 15.95 0.005*
 FBS (mg/dL) (n = 91) 146.12 ± 68.81 143.77 ± 67.19 161.58 ± 80.17 0.406
 BUN (mg/dL) (n = 179) 19.53 ± 10.96 19.29 ± 11.23 22.43 ± 6.84 0.309
 Creatinine (mg/dL) (n = 179) 1.26 ± 0.67 1.26 ± 0.69 1.31 ± 0.26 0.739
 Uric acid (mg/dL) (n = 80) 5.49 ± 2.55 5.69 ± 2.57 4.24 ± 2.10 0.081
 S.G.O.T (IU/L) (n = 164) 53.63 ± 54.74 53.43 ± 59.0 55.85 ± 21.04 0.874
 S.G.P.T (IU/L) (n = 164) 43.35 ± 36.40 44.11 ± 37.76 35.21 ± 13.73 0.388
 PTT (s) (n = 166) 37.94 ± 15.01 38.53 ± 15.50 31.57 ± 4.84 0.035*
 INR (n = 13) 1.22 ± 0.39 1.15 ± 0.15 1.14 ± 0.15 0.360
 D-dimer (ng/mL) (n = 79) 1,679.02 ± 1,850.33 1,699.43 ± 1,924.89 — 0.770
 Ferritin (ng/mL) (n = 36) 742.80 ± 694.65 731.74 ± 722.38 — 0.750
Treatments
 Covid-19 drug 153 (85.5) 139 (84.2) 14 (100.0) 0.101
 Other antibiotics 135 (85.5) 142 (86.1) 11 (78.6) 0.450
 Corticosteroids 122 (68.2) 111 (67.3) 11 (78.6) 0.389
 Respiratory drugs 100 (55.9) 90 (54.5) 10 (71.4) 0.231

*p < 0.05. # Covid-19 drugs include: favipiravir, efavirence, zidovudine, lamivudine, lopinavir, ritonavir, atazanavir, kaletra, remdesivir, linezolid, IFN-beta, ivermectin, HCQ. Other antibiotics include: imipenem, meropenem, tavanex, ampibactam, vancomycin, azithromycin, clexane, ceftriaxone, clindamycin, metronidazole, coamoxiclav, ampisulbactam, ampicillin, sulbactam. Corticosteroids include: dexamethasone, prednisolone, methylprednisolone, hydrocortisone, triamcinolone, pulmicort neb. Respiratory drugs include: salbutamol, atrovent, seroflo, guaifenesin, carnitine, bromhexine, dextromethorphan, theophylline, pirfenidone, tiova. BMI, body mass index; BUN, blood urea nitrogen; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; FBS, fasting blood sugar; HB, hemoglobin; HCT, hematocrit; HIV, human immunodeficiency virus, IFN-γ, interferon-gamma; IL-6, interleukin-6; INR, international normalized ratio; IQ, interquartile; IU, international unit; LDH, lactate dehydrogenase; PLT, platelets; PTT, partial thromboplastin time; RBC, red blood cells; S.G.O.T, serum glutamic-oxaloacetic transaminase; S.G.P.T, serum glutamic-pyruvic transaminase; SpO2, oxygen saturation; WBC, white blood cells.

Fourteen patients died during the hospitalization and the in-hospital mortality rate was calculated as 7.8%, and 9.1% (13 patients) of patients had serum Zn level less than 70 mcg/dL and 3.4% (1 patient) of patients had serum Zn level more than 70 mcg/dL; however, this difference was not statistically significant (p = 0.331). The median duration of hospitalization was 3 days (2–5 days) which happened to be the same for patients with Zn levels lower or higher than 70 mcg/dL. According to the results, there was a significant association between serum Zn and IFN-γ (p-value = 0.035), a higher level of Zn was significantly associated with a higher level of IFN-γ. A significant association was also found between Zn level and IL-6 (p-value = 0.004). Higher levels of serum Zn were significantly associated with a lower level of IL-6. There was no significant association between Zn level and other inflammatory factors (Table 2). Zn did not have a significant association with death. Even after adjustment for confounding factors such as age as well as history of underlying disease, there still happened to be no significant association between Zn and mortality rate. The relationship between serum Zn level and the duration of hospitalization was not significant either. Even after adjusting for confounding factors (age and history of underlying disease), there was still no significant association between serum Zn level and the duration of hospitalization (Table 3).

Table 2

Association between zinc and inflammatory factors

Independent variable and outcome B SE p-value
Zinc and IFN-γ 0.25 0.12 0.035*
Zinc and IL-6 −0.70 0.24 0.004*
Zinc and ESR 1.53 0.79 0.084
Zinc and CRP 1.61 0.98 0.131
Zinc and WBC −0.04 0.06 0.501
Zinc and neutrophils 0.12 0.25 0.628
Zinc and lymphocytes −0.02 0.23 0.934
Zinc and SpO2 0.001 0.48 0.999
Zinc and LDH 0.84 0.50 0.745

*Significant at 0.05 level; zinc is considered as an independent variable. B, linear regression coefficient; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; IFN-γ, interferon-gamma; IL-6, interleukin-6; LDH, lactate dehydrogenase; SE, standard error; SpO2, oxygen saturation; WBC, white blood cells.

Table 3

Factors associated with duration of hospitalization and survival

Duration of hospitalization Death
B SE p value OR 95% CI p value
Model 1 (simple model)
 Zinc −0.01 0.01 0.541 0.97 0.93–1.02 0.251
Model 2 (multiple model)
 Zinc −0.01 0.01 0.845 0.97 0.93–1.03 0.406
 Age 0.02 0.01 0.041* 1.06 1.01–1.10 0.010*
History of underlying disease
 No Ref. — — Ref. — —
 Yes 0.61 0.41 0.132 1.71 0.19–14.86 0.626

*Significant at 0.05 level; CI: confidence interval. B, regression coefficient; OR, odds ratio; SE, standard error.

The patients were divided into two groups based on their Zn status (less and more than 70 mcg/dL). The inflammatory factors in the two subgroups are shown in Figure 1. According to the results, there was no significant difference in inflammatory factors between the two subgroups based on serum Zn (less and more than 70 mcg/dL) except for IL-6 (p-value = 0.014). The amount of IL-6 in patients with serum Zn levels less than 70 mcg/dL was significantly higher than patients with Zn levels more than 70 mcg/dL. Correlation between serum Zn level and duration of hospitalization is shown in Figure 2.

Figure 1 Comparison of inflammatory factors in two subgroups of serum zinc (less and more than 70 mcg/dL). (a) Serum zinc and IL-6 (pg/mL. (b) Serum zinc and neutrophils (%). (c) Serum zinc and lymphocytes (%). (d) Serum zinc and ESR (mm/h). (e) Serum zinc and WBC (×1,000/µL). (f) Serum zinc and IFN-γ (ng/mL). (g) Serum zinc and CRP (mg/L). (h) Serum zinc and SpO2 (%). (i) Serum zinc and LDH (IU/L).
Figure 1

Comparison of inflammatory factors in two subgroups of serum zinc (less and more than 70 mcg/dL). (a) Serum zinc and IL-6 (pg/mL. (b) Serum zinc and neutrophils (%). (c) Serum zinc and lymphocytes (%). (d) Serum zinc and ESR (mm/h). (e) Serum zinc and WBC (×1,000/µL). (f) Serum zinc and IFN-γ (ng/mL). (g) Serum zinc and CRP (mg/L). (h) Serum zinc and SpO2 (%). (i) Serum zinc and LDH (IU/L).

Figure 2 Correlation between serum zinc level and duration of hospitalization.
Figure 2

Correlation between serum zinc level and duration of hospitalization.

4 Discussion

Given the novelty of the SARS-CoV-2 disease, not many studies have been reported regarding the measurement of serum Zn level and comparing it with inflammatory factors such as IL-6 or IFN-γ in patients diagnosed with Covid-19, but the role of Zn in inflammation and immunity has been presented in previous studies. Proliferation, differentiation, maturation, and functioning of leukocytes including lymphocytes are all regulated by Zn [7]. Chronic inflammation is characterized by an increased level of inflammatory cytokine production and Zn deficiency could cause altered production of cytokines which could lead to inflammation [20]. Lower circulating Zn level correlates with increased IL-6, IL-8, and TNF-α, in addition, cytokine signaling pathways are influenced by Zn status [21]. Cytokines are produced by different types of cells, primarily by T-lymphocytes and macrophages and the influence of Zn on these cells may explain the observed effect Zn has on cytokine production [22,23]. Zn deficiency is associated with downregulation of IFN-γ, resulting in severe impairment of cell-mediated immunity [15]. As mentioned, regarding the association between Zn and inflammatory factors in our study, 2 inflammatory factors had a significant association (p-value <0.05) with increased Zn level, higher level of Zn were significantly associated with a lower level of IL-6 (p-value = 0.004) and a higher level of IFN-γ (p-value = 0.035) which are in accordance with the previous studies. Other inflammatory factors that we studied were: ESR, CRP, WBC, neutrophils, lymphocytes, SpO2, and LDH. The association of all these other factors with increased serum Zn level was not statistically significant (p > 0.05). We also divided the patients into two groups regarding their Zn status and set the Zn level of 70 mcg/dL [24] as the cutoff value. In this division, the only inflammatory factor which was different between Zn sufficient and deficient groups was IL-6 (p-value = 0.014). Other factors that were measured and compared in these two groups were: WBC, lymphocytes, ESR, CRP, SpO2, and IFN-γ. Patients with Zn sufficient status (Zn > 70 mcg/dL) had a higher SpO2, lymphocytes, and IFN-γ but lower CRP and lower ESR compared to the Zn-deficient group. However, none of these differences were statistically significant. Serum Zn level did not have a statistically significant effect on mortality and hospitalization duration (p = 0.251). The only factor that had an effect on hospitalization and mortality was age with a p-value of 0.010. Thomas et al. conducted a randomized clinical trial study published in JAMA which recently concluded that the initiation of high-dose Zn gluconate, ascorbic acid, or a combination of the two supplements did not significantly decrease the duration of the symptoms or mortality compared with standard of care. This study also indicated that there was no significant difference in any secondary outcome such as number of days to reach no presence of fever, cough, shortness of breath, or fatigue in patients who received high dose Zn and ascorbic acid [25]. Based on our findings and a previous article, it seems that Zn levels do not have an effect on mortality and duration of hospitalization. The percentage of patients who died in this study was 7.8% with 9.1% being the mortality rate of patients with serum Zn levels less than 70 mcg/dL and 3.4% being the mortality rate of the patients with serum Zn levels higher than 70 mcg/dL. Although the mortality rate was higher in patients with serum Zn level less than 70 mcg/dL, the results were not statistically significant and the reason could be because of the disproportionate number of patients with serum Zn level less than 70 mcg/dL compared to those with serum Zn level higher than 70 mcg/dL. A study conducted by Nasrollahzadeh and colleagues in 2020 showed that the mortality percentage in their study was 21.9% but the study was done on Covid-19 patients who had an underlying disease [26] and it can explain the higher mortality rate reported in their study compared to this one. Our study has shown that there is an association between serum inflammatory markers and Zn level especially cytokine level such as IL-6 in patients with Covid-19. This association has been seen in other studies as mentioned above. Whether serum Zn level can have a subsequent effect on conditions such as cytokine storm in patients with Covid-19 warrants for further investigation and more study needs to be done on the relationship between serum Zn level in patients diagnosed with Covid-19 and other factors.

In this study, we also assessed several other laboratory data in the patients, such as WBC, red blood cells (RBC), hematocrit (HCT), platelets (PLT), neutrophil, lymphocyte, and SpO2. Among the factors mentioned above, four factors were statistically significant between the patients who lived and those who died as an endpoint for the study; RBC and HCT were higher in the patients who died and lymphocytes and SpO2 were higher in the patients who lived. Most Covid-19 fatalities experienced greater lymphopenia. Decreased lymphocytes accompanied by mild thrombocytopenia were among the most common abnormal findings attracting attention in the CBC of Covid-19 patients [27]. The lymphocyte count is an important parameter to directly discriminate between Covid-19 patients with and without the severe disease [22]. Other studies have also shown a higher level of neutrophils in patients with severe Covid-19 disease [27]. Our study demonstrated a statistically significant association between lymphocyte counts and mortality, with these counts being lower in patients who passed away, which is in line with the mentioned previous findings, but with regard to the platelet counts and neutrophils, we found no statistically significant association. With regards to the SpO2 level, patients who lived had higher SpO2 levels. This association was also demonstrated in another study conducted by Jiang Xie and coworkers in 2020. In this cohort of patients with Covid-19, hypoxemia was independently associated with in-hospital mortality [23]. Another study conducted by Celine Renoux and colleagues showed that RBC and HCT levels were higher in Covid patients compared to non-Covid sepsis but the results were not statistically significant. But the study showed a statistically significant association between RBC rheological properties in Covid-19 infected patients. A statistically significant association was found between RBC and HCT levels in this study [28]. We should also note that a correlation between serum Zn level and Covid-19 outcome has been demonstrated in a recent study by Vogel-González et al. There were 249 participants in this study and serum Zn levels lower than 50 µg/dL at admission correlated with worse clinical presentation, longer time to recovery, and higher mortality. This study also demonstrated a higher level of inflammatory markers, such as IL-6 and CRP, in patients with low serum Zn levels [29]. Relative to hospitalization duration and mortality rates, our study has shown otherwise, with no association between serum Zn level and these two factors in patients diagnosed with Covid-19. There were some limitations in the study. The number of patients who were considered Zn deficient was disproportionate compared to those regarded as Zn sufficient, thus this could have probably been the limitation of the study and the reasons for not finding statistically significant associations. The study also had its strengths, the hospital where our research was conducted is one of the main hospitals for admitting patients diagnosed with Covid-19 in a city with a population of roughly 2 million. The criteria for admission for all the patients were the same and the same guidelines were followed.

5 Conclusion

In summary, serum Zn level had an association with IL-6 and IFN-γ levels but no significant association between serum Zn level and hospital duration or mortality was found. Although higher mortality rates were reported among patients considered to have inadequate serum Zn levels, this result was not considered to be statistically significant. We believe that further studies still have to be conducted in order to bring us more solid evidence with regards to the association between serum Zn level and hospitalization duration and mortality. In measuring other factors in patients infected with Covid-19, our study demonstrated a significant association between RBC, HCT, lymphocytes, and SpO2 in the patients who lived and those who died. Although the association between Zn and inflammatory markers and its outcome on non-Covid sepsis and other infections has been demonstrated in numerous studies, the effect of Zn on these factors and other factors in patients diagnosed with Covid-19 warrants for further investigation.

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Acknowledgments

The authors are grateful for the supports of participants in this study and administrative support of hospitals’ managers, supervisors, and nurses.

  1. Funding information: This study was funded by Vise Chancellor of Research, Shiraz University of Medical Sciences, Shiraz, Iran.

  2. Author contributions: H.J. was responsible for the study concept and design, critical revision of the manuscript for intellectual content, and administrative support. P.K. was responsible for the study concept and design, administrative, technical support, study supervision, drafting the manuscript, and critical revision of the manuscript. Z.F. was responsible for analysis and interpretation of the data, drafting the manuscript, and critical revision of the manuscript. H.R.S. was responsible for analysis and interpretation of data, statistical analysis, and critical revision of the manuscript for important intellectual content. D.Z. was responsible for the study design, drafting the manuscript, and critical revision of the manuscript. A.H., F.P., and Y.K. were responsible for data gathering, preparing blood samples for laboratory testing, and critical revision of the manuscript. N.O. and M.D. administrative, technical support and supervision, interpretation of the data, and critical revision of the manuscript.

  3. Conflict of interest: There is no conflict of interest to be disclosed.

  4. Data availability statement: The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Received: 2021-08-28
Revised: 2022-01-01
Accepted: 2022-03-09
Published Online: 2022-04-07

© 2022 Hassan Joulaei et al., published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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https://doi.org/10.1515/med-2022-0469
Keywords for this article
serum zinc; interleukin-6; interferon-gamma; duration of hospitalization; mortality rate; Covid-19
Creative Commons
BY 4.0

Articles in the same Issue

  1. Research Articles
  2. AMBRA1 attenuates the proliferation of uveal melanoma cells
  3. A ceRNA network mediated by LINC00475 in papillary thyroid carcinoma
  4. Differences in complications between hepatitis B-related cirrhosis and alcohol-related cirrhosis
  5. Effect of gestational diabetes mellitus on lipid profile: A systematic review and meta-analysis
  6. Long noncoding RNA NR2F1-AS1 stimulates the tumorigenic behavior of non-small cell lung cancer cells by sponging miR-363-3p to increase SOX4
  7. Promising novel biomarkers and candidate small-molecule drugs for lung adenocarcinoma: Evidence from bioinformatics analysis of high-throughput data
  8. Plasmapheresis: Is it a potential alternative treatment for chronic urticaria?
  9. The biomarkers of key miRNAs and gene targets associated with extranodal NK/T-cell lymphoma
  10. Gene signature to predict prognostic survival of hepatocellular carcinoma
  11. Effects of miRNA-199a-5p on cell proliferation and apoptosis of uterine leiomyoma by targeting MED12
  12. Does diabetes affect paraneoplastic thrombocytosis in colorectal cancer?
  13. Is there any effect on imprinted genes H19, PEG3, and SNRPN during AOA?
  14. Leptin and PCSK9 concentrations are associated with vascular endothelial cytokines in patients with stable coronary heart disease
  15. Pericentric inversion of chromosome 6 and male fertility problems
  16. Staple line reinforcement with nebulized cyanoacrylate glue in laparoscopic sleeve gastrectomy: A propensity score-matched study
  17. Retrospective analysis of crescent score in clinical prognosis of IgA nephropathy
  18. Expression of DNM3 is associated with good outcome in colorectal cancer
  19. Activation of SphK2 contributes to adipocyte-induced EOC cell proliferation
  20. CRRT influences PICCO measurements in febrile critically ill patients
  21. SLCO4A1-AS1 mediates pancreatic cancer development via miR-4673/KIF21B axis
  22. lncRNA ACTA2-AS1 inhibits malignant phenotypes of gastric cancer cells
  23. circ_AKT3 knockdown suppresses cisplatin resistance in gastric cancer
  24. Prognostic value of nicotinamide N-methyltransferase in human cancers: Evidence from a meta-analysis and database validation
  25. GPC2 deficiency inhibits cell growth and metastasis in colon adenocarcinoma
  26. A pan-cancer analysis of the oncogenic role of Holliday junction recognition protein in human tumors
  27. Radiation increases COL1A1, COL3A1, and COL1A2 expression in breast cancer
  28. Association between preventable risk factors and metabolic syndrome
  29. miR-29c-5p knockdown reduces inflammation and blood–brain barrier disruption by upregulating LRP6
  30. Cardiac contractility modulation ameliorates myocardial metabolic remodeling in a rabbit model of chronic heart failure through activation of AMPK and PPAR-α pathway
  31. Quercitrin protects human bronchial epithelial cells from oxidative damage
  32. Smurf2 suppresses the metastasis of hepatocellular carcinoma via ubiquitin degradation of Smad2
  33. circRNA_0001679/miR-338-3p/DUSP16 axis aggravates acute lung injury
  34. Sonoclot’s usefulness in prediction of cardiopulmonary arrest prognosis: A proof of concept study
  35. Four drug metabolism-related subgroups of pancreatic adenocarcinoma in prognosis, immune infiltration, and gene mutation
  36. Decreased expression of miR-195 mediated by hypermethylation promotes osteosarcoma
  37. LMO3 promotes proliferation and metastasis of papillary thyroid carcinoma cells by regulating LIMK1-mediated cofilin and the β-catenin pathway
  38. Cx43 upregulation in HUVECs under stretch via TGF-β1 and cytoskeletal network
  39. Evaluation of menstrual irregularities after COVID-19 vaccination: Results of the MECOVAC survey
  40. Histopathologic findings on removed stomach after sleeve gastrectomy. Do they influence the outcome?
  41. Analysis of the expression and prognostic value of MT1-MMP, β1-integrin and YAP1 in glioma
  42. Optimal diagnosis of the skin cancer using a hybrid deep neural network and grasshopper optimization algorithm
  43. miR-223-3p alleviates TGF-β-induced epithelial-mesenchymal transition and extracellular matrix deposition by targeting SP3 in endometrial epithelial cells
  44. Clinical value of SIRT1 as a prognostic biomarker in esophageal squamous cell carcinoma, a systematic meta-analysis
  45. circ_0020123 promotes cell proliferation and migration in lung adenocarcinoma via PDZD8
  46. miR-22-5p regulates the self-renewal of spermatogonial stem cells by targeting EZH2
  47. hsa-miR-340-5p inhibits epithelial–mesenchymal transition in endometriosis by targeting MAP3K2 and inactivating MAPK/ERK signaling
  48. circ_0085296 inhibits the biological functions of trophoblast cells to promote the progression of preeclampsia via the miR-942-5p/THBS2 network
  49. TCD hemodynamics findings in the subacute phase of anterior circulation stroke patients treated with mechanical thrombectomy
  50. Development of a risk-stratification scoring system for predicting risk of breast cancer based on non-alcoholic fatty liver disease, non-alcoholic fatty pancreas disease, and uric acid
  51. Tollip promotes hepatocellular carcinoma progression via PI3K/AKT pathway
  52. circ_0062491 alleviates periodontitis via the miR-142-5p/IGF1 axis
  53. Human amniotic fluid as a source of stem cells
  54. lncRNA NONRATT013819.2 promotes transforming growth factor-β1-induced myofibroblastic transition of hepatic stellate cells by miR24-3p/lox
  55. NORAD modulates miR-30c-5p-LDHA to protect lung endothelial cells damage
  56. Idiopathic pulmonary fibrosis telemedicine management during COVID-19 outbreak
  57. Risk factors for adverse drug reactions associated with clopidogrel therapy
  58. Serum zinc associated with immunity and inflammatory markers in Covid-19
  59. The relationship between night shift work and breast cancer incidence: A systematic review and meta-analysis of observational studies
  60. LncRNA expression in idiopathic achalasia: New insight and preliminary exploration into pathogenesis
  61. Notoginsenoside R1 alleviates spinal cord injury through the miR-301a/KLF7 axis to activate Wnt/β-catenin pathway
  62. Moscatilin suppresses the inflammation from macrophages and T cells
  63. Zoledronate promotes ECM degradation and apoptosis via Wnt/β-catenin
  64. Epithelial-mesenchymal transition-related genes in coronary artery disease
  65. The effect evaluation of traditional vaginal surgery and transvaginal mesh surgery for severe pelvic organ prolapse: 5 years follow-up
  66. Repeated partial splenic artery embolization for hypersplenism improves platelet count
  67. Low expression of miR-27b in serum exosomes of non-small cell lung cancer facilitates its progression by affecting EGFR
  68. Exosomal hsa_circ_0000519 modulates the NSCLC cell growth and metastasis via miR-1258/RHOV axis
  69. miR-455-5p enhances 5-fluorouracil sensitivity in colorectal cancer cells by targeting PIK3R1 and DEPDC1
  70. The effect of tranexamic acid on the reduction of intraoperative and postoperative blood loss and thromboembolic risk in patients with hip fracture
  71. Isocitrate dehydrogenase 1 mutation in cholangiocarcinoma impairs tumor progression by sensitizing cells to ferroptosis
  72. Artemisinin protects against cerebral ischemia and reperfusion injury via inhibiting the NF-κB pathway
  73. A 16-gene signature associated with homologous recombination deficiency for prognosis prediction in patients with triple-negative breast cancer
  74. Lidocaine ameliorates chronic constriction injury-induced neuropathic pain through regulating M1/M2 microglia polarization
  75. MicroRNA 322-5p reduced neuronal inflammation via the TLR4/TRAF6/NF-κB axis in a rat epilepsy model
  76. miR-1273h-5p suppresses CXCL12 expression and inhibits gastric cancer cell invasion and metastasis
  77. Clinical characteristics of pneumonia patients of long course of illness infected with SARS-CoV-2
  78. circRNF20 aggravates the malignancy of retinoblastoma depending on the regulation of miR-132-3p/PAX6 axis
  79. Linezolid for resistant Gram-positive bacterial infections in children under 12 years: A meta-analysis
  80. Rack1 regulates pro-inflammatory cytokines by NF-κB in diabetic nephropathy
  81. Comprehensive analysis of molecular mechanism and a novel prognostic signature based on small nuclear RNA biomarkers in gastric cancer patients
  82. Smog and risk of maternal and fetal birth outcomes: A retrospective study in Baoding, China
  83. Let-7i-3p inhibits the cell cycle, proliferation, invasion, and migration of colorectal cancer cells via downregulating CCND1
  84. β2-Adrenergic receptor expression in subchondral bone of patients with varus knee osteoarthritis
  85. Possible impact of COVID-19 pandemic and lockdown on suicide behavior among patients in Southeast Serbia
  86. In vitro antimicrobial activity of ozonated oil in liposome eyedrop against multidrug-resistant bacteria
  87. Potential biomarkers for inflammatory response in acute lung injury
  88. A low serum uric acid concentration predicts a poor prognosis in adult patients with candidemia
  89. Antitumor activity of recombinant oncolytic vaccinia virus with human IL2
  90. ALKBH5 inhibits TNF-α-induced apoptosis of HUVECs through Bcl-2 pathway
  91. Risk prediction of cardiovascular disease using machine learning classifiers
  92. Value of ultrasonography parameters in diagnosing polycystic ovary syndrome
  93. Bioinformatics analysis reveals three key genes and four survival genes associated with youth-onset NSCLC
  94. Identification of autophagy-related biomarkers in patients with pulmonary arterial hypertension based on bioinformatics analysis
  95. Protective effects of glaucocalyxin A on the airway of asthmatic mice
  96. Overexpression of miR-100-5p inhibits papillary thyroid cancer progression via targeting FZD8
  97. Bioinformatics-based analysis of SUMOylation-related genes in hepatocellular carcinoma reveals a role of upregulated SAE1 in promoting cell proliferation
  98. Effectiveness and clinical benefits of new anti-diabetic drugs: A real life experience
  99. Identification of osteoporosis based on gene biomarkers using support vector machine
  100. Tanshinone IIA reverses oxaliplatin resistance in colorectal cancer through microRNA-30b-5p/AVEN axis
  101. miR-212-5p inhibits nasopharyngeal carcinoma progression by targeting METTL3
  102. Association of ST-T changes with all-cause mortality among patients with peripheral T-cell lymphomas
  103. LINC00665/miRNAs axis-mediated collagen type XI alpha 1 correlates with immune infiltration and malignant phenotypes in lung adenocarcinoma
  104. The perinatal factors that influence the excretion of fecal calprotectin in premature-born children
  105. Effect of femoral head necrosis cystic area on femoral head collapse and stress distribution in femoral head: A clinical and finite element study
  106. Does the use of 3D-printed cones give a chance to postpone the use of megaprostheses in patients with large bone defects in the knee joint?
  107. lncRNA HAGLR modulates myocardial ischemia–reperfusion injury in mice through regulating miR-133a-3p/MAPK1 axis
  108. Protective effect of ghrelin on intestinal I/R injury in rats
  109. In vivo knee kinematics of an innovative prosthesis design
  110. Relationship between the height of fibular head and the incidence and severity of knee osteoarthritis
  111. lncRNA WT1-AS attenuates hypoxia/ischemia-induced neuronal injury during cerebral ischemic stroke via miR-186-5p/XIAP axis
  112. Correlation of cardiac troponin T and APACHE III score with all-cause in-hospital mortality in critically ill patients with acute pulmonary embolism
  113. LncRNA LINC01857 reduces metastasis and angiogenesis in breast cancer cells via regulating miR-2052/CENPQ axis
  114. Endothelial cell-specific molecule 1 (ESM1) promoted by transcription factor SPI1 acts as an oncogene to modulate the malignant phenotype of endometrial cancer
  115. SELENBP1 inhibits progression of colorectal cancer by suppressing epithelial–mesenchymal transition
  116. Visfatin is negatively associated with coronary artery lesions in subjects with impaired fasting glucose
  117. Treatment and outcomes of mechanical complications of acute myocardial infarction during the Covid-19 era: A comparison with the pre-Covid-19 period. A systematic review and meta-analysis
  118. Neonatal stroke surveillance study protocol in the United Kingdom and Republic of Ireland
  119. Oncogenic role of TWF2 in human tumors: A pan-cancer analysis
  120. Mean corpuscular hemoglobin predicts the length of hospital stay independent of severity classification in patients with acute pancreatitis
  121. Association of gallstone and polymorphisms of UGT1A1*27 and UGT1A1*28 in patients with hepatitis B virus-related liver failure
  122. TGF-β1 upregulates Sar1a expression and induces procollagen-I secretion in hypertrophic scarring fibroblasts
  123. Antisense lncRNA PCNA-AS1 promotes esophageal squamous cell carcinoma progression through the miR-2467-3p/PCNA axis
  124. NK-cell dysfunction of acute myeloid leukemia in relation to the renin–angiotensin system and neurotransmitter genes
  125. The effect of dilution with glucose and prolonged injection time on dexamethasone-induced perineal irritation – A randomized controlled trial
  126. miR-146-5p restrains calcification of vascular smooth muscle cells by suppressing TRAF6
  127. Role of lncRNA MIAT/miR-361-3p/CCAR2 in prostate cancer cells
  128. lncRNA NORAD promotes lung cancer progression by competitively binding to miR-28-3p with E2F2
  129. Noninvasive diagnosis of AIH/PBC overlap syndrome based on prediction models
  130. lncRNA FAM230B is highly expressed in colorectal cancer and suppresses the maturation of miR-1182 to increase cell proliferation
  131. circ-LIMK1 regulates cisplatin resistance in lung adenocarcinoma by targeting miR-512-5p/HMGA1 axis
  132. LncRNA SNHG3 promoted cell proliferation, migration, and metastasis of esophageal squamous cell carcinoma via regulating miR-151a-3p/PFN2 axis
  133. Risk perception and affective state on work exhaustion in obstetrics during the COVID-19 pandemic
  134. lncRNA-AC130710/miR-129-5p/mGluR1 axis promote migration and invasion by activating PKCα-MAPK signal pathway in melanoma
  135. SNRPB promotes cell cycle progression in thyroid carcinoma via inhibiting p53
  136. Xylooligosaccharides and aerobic training regulate metabolism and behavior in rats with streptozotocin-induced type 1 diabetes
  137. Serpin family A member 1 is an oncogene in glioma and its translation is enhanced by NAD(P)H quinone dehydrogenase 1 through RNA-binding activity
  138. Silencing of CPSF7 inhibits the proliferation, migration, and invasion of lung adenocarcinoma cells by blocking the AKT/mTOR signaling pathway
  139. Ultrasound-guided lumbar plexus block versus transversus abdominis plane block for analgesia in children with hip dislocation: A double-blind, randomized trial
  140. Relationship of plasma MBP and 8-oxo-dG with brain damage in preterm
  141. Identification of a novel necroptosis-associated miRNA signature for predicting the prognosis in head and neck squamous cell carcinoma
  142. Delayed femoral vein ligation reduces operative time and blood loss during hip disarticulation in patients with extremity tumors
  143. The expression of ASAP3 and NOTCH3 and the clinicopathological characteristics of adult glioma patients
  144. Longitudinal analysis of factors related to Helicobacter pylori infection in Chinese adults
  145. HOXA10 enhances cell proliferation and suppresses apoptosis in esophageal cancer via activating p38/ERK signaling pathway
  146. Meta-analysis of early-life antibiotic use and allergic rhinitis
  147. Marital status and its correlation with age, race, and gender in prognosis of tonsil squamous cell carcinomas
  148. HPV16 E6E7 up-regulates KIF2A expression by activating JNK/c-Jun signal, is beneficial to migration and invasion of cervical cancer cells
  149. Amino acid profiles in the tissue and serum of patients with liver cancer
  150. Pain in critically ill COVID-19 patients: An Italian retrospective study
  151. Immunohistochemical distribution of Bcl-2 and p53 apoptotic markers in acetamiprid-induced nephrotoxicity
  152. Estradiol pretreatment in GnRH antagonist protocol for IVF/ICSI treatment
  153. Long non-coding RNAs LINC00689 inhibits the apoptosis of human nucleus pulposus cells via miR-3127-5p/ATG7 axis-mediated autophagy
  154. The relationship between oxygen therapy, drug therapy, and COVID-19 mortality
  155. Monitoring hypertensive disorders in pregnancy to prevent preeclampsia in pregnant women of advanced maternal age: Trial mimicking with retrospective data
  156. SETD1A promotes the proliferation and glycolysis of nasopharyngeal carcinoma cells by activating the PI3K/Akt pathway
  157. The role of Shunaoxin pills in the treatment of chronic cerebral hypoperfusion and its main pharmacodynamic components
  158. TET3 governs malignant behaviors and unfavorable prognosis of esophageal squamous cell carcinoma by activating the PI3K/AKT/GSK3β/β-catenin pathway
  159. Associations between morphokinetic parameters of temporary-arrest embryos and the clinical prognosis in FET cycles
  160. Long noncoding RNA WT1-AS regulates trophoblast proliferation, migration, and invasion via the microRNA-186-5p/CADM2 axis
  161. The incidence of bronchiectasis in chronic obstructive pulmonary disease
  162. Integrated bioinformatics analysis shows integrin alpha 3 is a prognostic biomarker for pancreatic cancer
  163. Inhibition of miR-21 improves pulmonary vascular responses in bronchopulmonary dysplasia by targeting the DDAH1/ADMA/NO pathway
  164. Comparison of hospitalized patients with severe pneumonia caused by COVID-19 and influenza A (H7N9 and H1N1): A retrospective study from a designated hospital
  165. lncRNA ZFAS1 promotes intervertebral disc degeneration by upregulating AAK1
  166. Pathological characteristics of liver injury induced by N,N-dimethylformamide: From humans to animal models
  167. lncRNA ELFN1-AS1 enhances the progression of colon cancer by targeting miR-4270 to upregulate AURKB
  168. DARS-AS1 modulates cell proliferation and migration of gastric cancer cells by regulating miR-330-3p/NAT10 axis
  169. Dezocine inhibits cell proliferation, migration, and invasion by targeting CRABP2 in ovarian cancer
  170. MGST1 alleviates the oxidative stress of trophoblast cells induced by hypoxia/reoxygenation and promotes cell proliferation, migration, and invasion by activating the PI3K/AKT/mTOR pathway
  171. Bifidobacterium lactis Probio-M8 ameliorated the symptoms of type 2 diabetes mellitus mice by changing ileum FXR-CYP7A1
  172. circRNA DENND1B inhibits tumorigenicity of clear cell renal cell carcinoma via miR-122-5p/TIMP2 axis
  173. EphA3 targeted by miR-3666 contributes to melanoma malignancy via activating ERK1/2 and p38 MAPK pathways
  174. Pacemakers and methylprednisolone pulse therapy in immune-related myocarditis concomitant with complete heart block
  175. miRNA-130a-3p targets sphingosine-1-phosphate receptor 1 to activate the microglial and astrocytes and to promote neural injury under the high glucose condition
  176. Review Articles
  177. Current management of cancer pain in Italy: Expert opinion paper
  178. Hearing loss and brain disorders: A review of multiple pathologies
  179. The rationale for using low-molecular weight heparin in the therapy of symptomatic COVID-19 patients
  180. Amyotrophic lateral sclerosis and delayed onset muscle soreness in light of the impaired blink and stretch reflexes – watch out for Piezo2
  181. Interleukin-35 in autoimmune dermatoses: Current concepts
  182. Recent discoveries in microbiota dysbiosis, cholangiocytic factors, and models for studying the pathogenesis of primary sclerosing cholangitis
  183. Advantages of ketamine in pediatric anesthesia
  184. Congenital adrenal hyperplasia. Role of dentist in early diagnosis
  185. Migraine management: Non-pharmacological points for patients and health care professionals
  186. Atherogenic index of plasma and coronary artery disease: A systematic review
  187. Physiological and modulatory role of thioredoxins in the cellular function
  188. Case Reports
  189. Intrauterine Bakri balloon tamponade plus cervical cerclage for the prevention and treatment of postpartum haemorrhage in late pregnancy complicated with acute aortic dissection: Case series
  190. A case of successful pembrolizumab monotherapy in a patient with advanced lung adenocarcinoma: Use of multiple biomarkers in combination for clinical practice
  191. Unusual neurological manifestations of bilateral medial medullary infarction: A case report
  192. Atypical symptoms of malignant hyperthermia: A rare causative mutation in the RYR1 gene
  193. A case report of dermatomyositis with the missed diagnosis of non-small cell lung cancer and concurrence of pulmonary tuberculosis
  194. A rare case of endometrial polyp complicated with uterine inversion: A case report and clinical management
  195. Spontaneous rupturing of splenic artery aneurysm: Another reason for fatal syncope and shock (Case report and literature review)
  196. Fungal infection mimicking COVID-19 infection – A case report
  197. Concurrent aspergillosis and cystic pulmonary metastases in a patient with tongue squamous cell carcinoma
  198. Paraganglioma-induced inverted takotsubo-like cardiomyopathy leading to cardiogenic shock successfully treated with extracorporeal membrane oxygenation
  199. Lineage switch from lymphoma to myeloid neoplasms: First case series from a single institution
  200. Trismus during tracheal extubation as a complication of general anaesthesia – A case report
  201. Simultaneous treatment of a pubovesical fistula and lymph node metastasis secondary to multimodal treatment for prostate cancer: Case report and review of the literature
  202. Two case reports of skin vasculitis following the COVID-19 immunization
  203. Ureteroiliac fistula after oncological surgery: Case report and review of the literature
  204. Synchronous triple primary malignant tumours in the bladder, prostate, and lung harbouring TP53 and MEK1 mutations accompanied with severe cardiovascular diseases: A case report
  205. Huge mucinous cystic neoplasms with adhesion to the left colon: A case report and literature review
  206. Commentary
  207. Commentary on “Clinicopathological features of programmed cell death-ligand 1 expression in patients with oral squamous cell carcinoma”
  208. Rapid Communication
  209. COVID-19 fear, post-traumatic stress, growth, and the role of resilience
  210. Erratum
  211. Erratum to “Tollip promotes hepatocellular carcinoma progression via PI3K/AKT pathway”
  212. Erratum to “Effect of femoral head necrosis cystic area on femoral head collapse and stress distribution in femoral head: A clinical and finite element study”
  213. Erratum to “lncRNA NORAD promotes lung cancer progression by competitively binding to miR-28-3p with E2F2”
  214. Retraction
  215. Expression and role of ABIN1 in sepsis: In vitro and in vivo studies
  216. Retraction to “miR-519d downregulates LEP expression to inhibit preeclampsia development”
  217. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part II
  218. Usefulness of close surveillance for rectal cancer patients after neoadjuvant chemoradiotherapy
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