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Additional baricitinib loading dose improves clinical outcome in COVID-19

  • Md Jahidul Hasan ORCID logo EMAIL logo , Raihan Rabbani ORCID logo , Ahmad Mursel Anam ORCID logo and Shihan Mahmud Redwanul Huq ORCID logo
Published/Copyright: December 5, 2020
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Open Medicine
From the journal Open Medicine Volume 16 Issue 1

Abstract

Pneumonia associated with coronavirus disease 2019 (COVID-19) has been accounted for high mortality rate in severe COVID-19 worldwide, and additional serious scarcity of standard and effective anti-inflammatory drug in COVID-19 pneumonia management is a big challenge. Baricitinib, a Janus kinase (JAK) inhibitor, is a promising drug in COVID-19 pneumonia. This study aims to compare the clinical outcome of moderate-to-severe COVID-19 pneumonia treated with baricitinib with or without a loading dose. This prospective case-control study enrolled 37 adult patients where 17 patients (control) received baricitinib at 4 mg oral daily dose and 20 patients (case) received an additional single 8 mg oral loading dose. The median day to gain blood oxygen saturation level ≥95% (in room air) and return in normal breathing function were lower in case group than the control group. The requirement of intensive care unit and mechanical ventilation support was higher in the control group than in the case group [29.4% (N = 17)/10% (N = 20), P < 0.05; 11.8% (N = 17)/5% (N = 20), P > 0.05), respectively]. Thus, an additional loading dose of baricitinib revealed better clinical outcome of patients with COVID-19 pneumonia.

Keywords: baricitinib; COVID-19 pneumonia; loading dose; maintenance dose

1 Introduction

The coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), first introduces to the world as an outbreak in Wuhan, China, in December 2019, was declared as a “global pandemic” by World Health Organization (WHO) on March 11, 2020 [1]. As of July 11, 2020, a total of 12,322,395 confirmed COVID-19 cases and 5,56,335 related deaths have been reported worldwide [2]. Acute respiratory distress syndrome (ARDS) due to hyperinflammation in the lungs and ultimately, respiratory failure from COVID-19 pneumonia has been reported as the prime cause of COVID-19-associated mortality [3,4] ranging from 1% to more than 7% [5]. Cytokine storm due to the overproduction of proinflammatory cytokines, including interleukin (IL)-6, IL-7, IL-8, etc. in critically ill patients with COVID-19 is a critical phase of the disease that may lead to acute respiratory failure or multiple organ dysfunction [6,7]. Therefore, early detection of the COVID-19 infection and prompt management to suppress the cytokine storm is equally important in patients with COVID-19 [8].

IL-6 plays a pivotal role in exacerbating the cytokine storm as a part of host’s innate immune response mechanism that is mostly activated by IL-1 beta, tumor necrosis factor (TNF-alfa), Toll-like receptors (TLRs), prostaglandins, adipokines, and other cytokines [9]. High levels of IL-6 and IL-8 were detected in patients with severe SARS-CoV-1 infection, where high-magnitude of innate inflammatory response in correspondence to SARS-CoV-1 invasion in the host’s respiratory tract was extensively induced by IL-6 [10]. Similarly, high plasma level of IL-6 along with other proinflammatory cytokines, such as IL-2, IL-7, IL-8, IL-10, macrophage inflammatory protein (MIP1A), monocyte chemoattractant protein (MCP1), and TNF-alfa have been found in critically ill patients with COVID-19 and these cytokines significantly contribute in the severity of the disease [5,6,8].

Receptor-mediated endocytosis is a process through which most viruses penetrate the host cells. AP2-associated protein kinase 1 (AAK1) is a regulator of this endocytosis and inactivation of this enzyme interrupts the entry of the virus into the host cells [11]. Baricitinib, a janus kinase (JAK) inhibitor, is an approved drug for rheumatoid arthritis (RA). In effect, baricitinib specifically prevents the expression of proinflammatory cytokines, including IL-6 by inhibiting JAK. Interestingly, among the six highly potent inhibitors of AAK1, baricitinib is one of them which works by binding with the cyclin G-associated kinase that disrupts endocytosis, competently leading to a reduction in viral load [11,12]. Nowadays, baricitinib at a 4 mg once daily oral dose has been highlighted as a promising investigational anti-inflammatory (IL-6 inhibitor) drug therapy in patients with COVID-19 pneumonia [4,11,12,14]. The pharmacokinetics, pharmacodynamics, and safety data of baricitinib at a 4 mg daily dose in COVID-19 are still under investigation and to date, no standard dosing of baricitinib in COVID-19 has yet been established worldwide [11,12,13,14,15]. The objective of this study was to compare the clinical outcomes of patients with moderate-to-severe COVID-19 pneumonia treated with baricitinib at a 4 mg once daily oral dose with or without a high oral loading dose.

2 Materials and methods

2.1 Study design and data collection

This prospective case-control study was conducted in the “COVID-19 Unit” of Square Hospital Ltd, Dhaka, Bangladesh, on 37 adults (≥18 years) with moderate to severe COVID-19 symptoms admitted to this hospital from May 15 to June 13, 2020. All confirmed COVID-19 patients in this study were admitted to “COVID-19 unit” through a two-step triage system in the emergency department of the hospital. COVID-19 infection was confirmed in all patients by a positive reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay (instrument/device: Rotor Gene-Q/Cobas z480, and QIAGEN kits for real-time PCR, QIAGEN GmbH, Germany) of two specimens (nasal and oral swabs) in all patients collected by four trained phlebotomists following the hospital’s standard protocol of COVID-19 sample collection. All the patients were Bangladeshi citizens and older than 18 years. A combined dose of dexamethasone (corticosteroid) (10–20 mg/day, intravenously) and baricitinib was started on day 1 of admission for down-regulating the inflammatory processes in the lungs. Seventeen (N) patients in “no loading dose (LND) group” (control) received baricitinib 4 mg daily orally for 2 weeks, whereas 20 (N) patients in “loading dose (LD) group” (case) received baricitinib 8 mg single dose orally as a loading dose on day 1 and then 4 mg daily orally from days 2 to 14. The dose of baricitinib was taken on an empty stomach. Simple random sampling method was used in this study. The local brand “Baritor 2” (baricitinib 2 mg tablet) of Square Pharmaceuticals Ltd, Bangladesh, was used in this study. Data of this study were collected from online patient-wise data archive of this hospital and directly from patient-prescriptions on daily basis by participating doctors in COVID-19 unit. Adverse events were routinely monitored and reported by two clinical pharmacists.

The research related to human use has been complied with all the relevant national regulations, institutional policies, and in accordance with the tenets of the Declaration of Helsinki, and has been approved by the Research Ethics Committee, Square Hospitals Ltd, Dhaka, Bangladesh (no. 2004SH-OR024) on April 11, 2020. Written consent was taken from all participants in this study.

2.2 Inclusion criteria

Sample inclusion criteria were as follows:

  1. presence of SARS-CoV 2 in the nasal/oral swabs

  2. no previous history of COVID-19 infection

  3. having at least 3 of the following symptoms: fever, cough, tiredness, sore throat, anosmia, respiratory distress, and myalgia

  4. evidence of pneumonia in radiological diagnosis

2.3 Exclusion criteria

Sample exclusion criteria were as follows:

  1. more than 10 days from onset of symptoms

  2. patient with pregnancy

  3. any history of trauma or surgical procedure within the last 3 months of admission

  4. any history of acute/chronic autoimmune disease

  5. evidence of bacterial or fungal coinfection

2.4 Definition of moderate and severe COVID-19 pneumonia

Radiological evidence of bilateral pneumonia with clinical signs (fever, cough, difficulty breathing, tachypnea), no sign of severe stage of pneumonia, SpO2 (peripheral capillary blood oxygen saturation level) ≥90% on room air (RA), and ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2) 100–300 mmHg represents moderate COVID-19 pneumonia; radiological evidence of severe pneumonia with clinical signs (fever, cough, difficulty breathing, tachypnea) with at least one of the following signs: respiratory rate >30 breaths/min, severe respiratory distress, and SpO2 < 90% on room air represents severe COVID-19 pneumonia [16]. SpO2 ≥ 95% was considered as the targeted SpO2 in patients in this study. The severity of the disease and the progression of the symptoms of COVID-19 were measured on daily basis by assessing the physical condition of the patients and the laboratory investigations, including hematological tests, tests for liver and kidney functions, inflammation and infection markers, and arterial blood gas test.

2.5 Data analysis

Data were analyzed with SPSS version 22.0 statistical software (SPSS, Chicago, IL, USA). Descriptive statistics were presented through median value and interquartile range (IQR). Categorical variables were compared using Fisher’s exact test, and continuous variables were compared using Mann–Whitney U test. P values ≤ 0.05 were considered statistically significant.

3 Results

The number of male patients in both the groups was higher than the number of female patients with a median age of 52 (IQR: 50.5–62) and 59 (IQR: 49.8–69) in NLD and LD groups, respectively (P = 0.414). Fever [100 (IQR: 100–101.5)/100.5 (IQR: 100–101.75)], dry cough (100%, n = 17/100%, n = 20), generalized weakness (100%, n = 17/100%, n = 20), and sore throat (52.9%, n = 9/60%, n = 12) were significantly common in patients of NLD and LD groups (N = 17/20), respectively. Diabetes, hypertension, cardiovascular disease, bronchial asthma, chronic kidney disease, chronic obstructive pulmonary disease, obesity, malignancy, and Parkinson's disease were found as preexisting chronic diseases in patients with COVID-19 of NLD and LD groups (Table 1). Clinical characteristics, including blood-oxygen saturation profile, respiratory and cardiac functions, hematological components, and infection markers of all the patients in the two groups (NLD and LD) are given in Table 1 and compared, statistically.

Table 1

Baseline demographic, symptoms of COVID-19, comorbidity, and laboratory findings in patients treated with or without a loading dose of baricitinib

Characteristics NLD group (control) (N = 17) LD group (case) (N = 20) P value
Male/female, n (%) 13/4 (76/24) 16/4 (80/20) 0.617
Age (year), median (IQR) 52 (50.5–62) 59 (49.8–69) 0.414
Days from onset of symptoms-to-hospitalization, median (IQR) 7 (4.5–7.5) 6.5 (5–7) 0.185
Fever (°F), median (IQR) 101 (100–101.5) 100.5 (100–101.75) 0.012
Dry cough, n (%) 17 (100) 20 (100) 0.001
Shortness of breath, n (%) 14 (82.4) 16 (80) 0.855
Weakness, n (%) 17 (100) 20 (100) 0.001
Diarrhea, n (%) 3 (17.6) 5 (25) 0.289
Anosmia, n (%) 11 (64.7) 14 (70) 0.516
Sore throat, n (%) 9 (52.9) 12 (60) 0.043
Diabetes, n (%) 14 (82.4) 17 (85) 0.675
Hypertension, n (%) 13 (76.5) 12 (60) 0.043
CVD, n (%) 6 (35.3) 4 (20) 0.052
Bronchial asthma, n (%) 4 (23.5) 6 (30) 0.389
CKD, n (%) 2 (11.8) 3 (15) 0.577
COPD, n (%) 2 (11.8) 3 (15) 0.577
Obesity, n (%) 2 (11.8) 2 (10) 0.740
Malignancy, n (%) 1 (5.9) 3 (15) 0.075
PD, n (%) 0 (0) 2 (10) 0.005
SpO2 (%), median (IQR) 89 (87.5–90) 89.5 (88–90) 0.718
Respiratory rate, (breaths/min), median (IQR) 22 (20.5–24) 23 (21–24) 0.825
PaO2/FiO2 (mmHg), median (IQR) 240 (195.5–263.5) 245 (193.8–262.3) 0.010
Heart rate (beat/min), median (IQR) 98 (85.5–105.5) 94.5 (84.5–113) 0.174
CRP (mg/L), median (IQR) 43.5 (30–220) 77.1 (40.9–211.5) 0.946
Procalcitonin (ng/mL), median (IQR) 0.12 (0.06–0.49) 0.18 (0.07–0.86) 0.062
WBC (K/µL), median (IQR) 6.3 (4.7–10) 8 (6.3–14.3) 0.021
Neutrophils (%), median (IQR) 87.6 (79.4–92.1) 82.5 (76.8–88.1) 0.657
Lymphocytes (%), median (IQR) 13.9 (11.9–15.8) 12.2 (8.2–14.5) 0.006
Platelet (K/µL), median (IQR) 186 (128–255) 175 (133.3–245.3) 0.605
d-Dimer (mg/L FEU), median (IQR) 2.7 (1.7–7.6) 2 (1.5–3.2) 0.018
Serum ferritin (ng/mL), median (IQR) 434 (293.5–543.5) 470 (361.3–604.8) 0.227
LDH ((U/L), median (IQR) 272 (216–404.5) 334 (295–390.5) 0.009
Creatinine (mg/dL), median (IQR) 0.9 (0.8–1) 0.9 (0.7–1.1) 0.210
ALT (U/L), median (IQR) 34 (29–57) 44 (35–54) 0.13
AST (U/L), median (IQR) 35 (25.5–49) 40 (29.5–58.8) 0.349
MEWS, median (IQR) 3 (2–3) 3 (2–3) 0.476

IQR = interquartile range; n = number; % = percentage; °F = grade Fahrenheit; CVD = cardiovascular disease; CKD = chronic kidney disease; COPD = chronic obstructive pulmonary disease; PD = Parkinson’s disease; SpO2 = peripheral capillary oxygen saturation; min = minute; PaO2/FiO2 = ratio of arterial oxygen partial pressure to fractional inspired oxygen; mmHg = millimetre of mercury; CRP = C-reactive protein; mg = milligram; L = liter; FEU = fibrinogen equivalent units; ng = nanogram; WBC = white blood cells; K/µL = thousand cells per micro liter; LDH = lactate dehydrogenase; U/L = units per liter; dL = deciliter; ALT = alanine aminotransferase; AST = aspartate aminotransferase; MEWS = Modified Early Warning Score.

All patients in both the groups tolerated baricitinib therapy well with no mild-to-serious adverse events (AEs) during the study period. No bacterial or fungal or any other opportunistic infections, hepatic or hematological toxicity were observed in the groups.

The median day to reach the targeted SpO2 (≥95% in RA) was less in the LD group (case) [3 (IQR: 2–8)] than that in the NLD group (control) [4 (IQR: 4–5)] (P = 0.180), and the median day to return in normal breathing function was significantly less in the LD group [5 (IQR: 4–5)] than that in the NLD group [8 (IQR: 7–10)]. ICU support was required higher in the NLD group with more requirement of mechanical ventilation support than that in the LD group [29.4% (N = 17)/10% (N = 20), P < 0.05; 11.8% (N = 17)/5% (N = 20), P = 0.141, respectively] (Table 2). The median day of hospitalization was lower in the LD group [12 (IQR: 10–14)] than that in the NLD group [15 (IQR: 9–18.5)] and this was statistically significant. The 30-day all-cause mortality rate was similar in NLD and LD groups [5.9%, n = 1 (N = 17)/5%, n = 1 (N = 20), respectively].

Table 2

Clinical outcomes in patients with COVID-19 treated with baricitinib with or without a loading dose

Parameters NLD group (control) (N = 17) LD group (case) (N = 20) P value
Days required to increase SpO2 ≥ 95% in RA, median (IQR) 4 (4–5) 3 (2–8) 0.180
Days required to stop the need of supplement oxygen, median (IQR) 8 (7–10) 5 (4–5) 0.001
Patients required ICU support, n (%) 5 (29.4) 2 (10) 0.005
Patients intubated on ventilator, n (%) 2 (11.8) 1 (5) 0.141
Length of hospital stay (day), median (IQR) 15 (9–18.5) 12 (10–14) 0.028
30-day mortality, n (%) 1 (5.9) 1 (5) 0.906

NLD = no loading dose; LD = loading dose; SpO2 = peripheral capillary oxygen saturation; RA = rheumatoid arthritis; IQR = interquartile range; ICU = intensive care unit; n = number; % = percentage.

4 Discussion

This study found that a single 8 mg oral loading dose of baricitinib added to its daily 4 mg maintenance dose for up to 2 weeks exhibited better clinical outcomes in patients with moderate-to-severe COVID-19 than 4 mg daily oral dose regimen without having a loading dose. The targeted SpO2 (≥95%) was gained earlier in patients who received an early 8 mg of loading dose of baricitinib than the patients treated without a loading dose of baricitinib. Similarly, the requirement of supplement oxygen support was significantly reduced earlier in patients treated with an extra 8 mg of loading dose of baricitinib that the patients received only 4 mg daily maintenance dose.

A recent study showed that around 80% of patients with COVID-19 develop acute lung inflammation due to massive cytokine storm [3,5,6,7] resulting in hypoxemia, impaired hypoxic pulmonary vasoconstriction, and high altitude pulmonary edema leading to ARDS [3,8,17], which may result in death in 2–7% of patients with COVID-19 pneumonia [18]. Janus kinases, a tyrosine kinase, play its major anti-inflammatory role in the cytokine signaling pathways by constitutively binding to cytokine receptors. To potentiate a cytokine storm, proinflammatory cytokines need to transmit more signals through signaling pathways. In-role, more than 40 different types of cytokines transmit signals through JAKs, including JAK1, JAK2, JAK3, and tyrosine kinase-2 (TyK2) [13,18]. Baricitinib has an oral bioavailability of approximately 79%, plasma protein binding ability up to 50%, mean half-life of approximately 12.5 h (in RA), and shows serum drug level of approximately 100–300 nM following a 4 mg oral dose [13,19]. The low molecular weight baricitinib concentration-dependently inhibits JAK1 and JAK2 with high target specificity [13].

In addition, baricitinib suppresses the production of Type-I interferons (IFNs) from plasmacytoid dendritic cells (pDCs), inhibits the synthesis of interleukin (IL)-6 from B cells [20], and possesses strong anti-viral property by inhibiting endocytosis [21]. Therefore, down-regulation of signal transmission of proinflammatory cytokines through JAKs, and suppression of other intrinsic inflammatory pathways makes baricitinib a suitable anti-inflammatory drug therapy in the treatment of COVID-19 pneumonia. The additional strong anti-viral property of baricitinib along with its selective anti-inflammatory ability has attributed its superiority to other oral investigational anti-inflammatory drugs in the treatment of COVID-19 pneumonia.

The plasma drug concentration of baricitinib at 2–4 mg daily oral dose is sufficient to exhibit its anti-inflammatory role (JAKs inhibition) in RA [11,12], but, a standard dose of baricitinib to achieve its optimum therapeutic outcome in COVID-19 pneumonia is still under investigation. In a recent study with a small sample size showed an improved clinical outcome of patients with COVID-19 with baricitinib at 4 mg per day of oral dose for 2 weeks [14]. In this study, a 2-fold higher (2 × 4 mg) single loading dose of baricitinib followed by 4 mg daily dose showed better therapeutic response in the management of moderate-to-severe COVID-19 pneumonia, and a superior clinical outcome was attributed in patients (case group) within 2 weeks of therapy with reduced hospitalization time and mortality rate. The major limitation of this study was small study sample size, short duration of the study, no proven justification of using 8 mg loading dose of baricitinib, and unavailability of serum cytokines monitoring facility in the study setup.

5 Conclusion

Severe pneumonia associated with COVID-19 is a major cause of mortality in COVID-19 infection. No anti-inflammatory drug, including baricitinib for the treatment of COVID-19 pneumonia has yet been recommended. In this study, 2-week-long 4 mg once daily oral maintenance therapy of baricitinib following a single 8 mg loading dose in moderate-to-severe COVID-19 pneumonia showed faster return to normal respiratory function with reduced requirement of ICU and ventilator support, length of hospital stay, and mortality rate than a loading dose less than 4 mg once daily oral dose of baricitinib.

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Acknowledgments

The authors of this study are very grateful to the authority of the Square hospital for their ethical permission for this study and also grateful to the participated patients for their consent for this study.

  1. Competing interests: Authors state no conflict of interest.

  2. Funding source: No external funding source for this study.

  3. Author's contribution: The authors confirm that the Principal Investigator for this paper is Raihan Rabbani, MD, Consultant, Internal Medicine and ICU, Square Hospitals Ltd., Dhaka, Bangladesh, and that he had direct clinical responsibility for patients.

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

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Received: 2020-08-07
Revised: 2020-10-02
Accepted: 2020-10-06
Published Online: 2020-12-05

© 2021 Md Jahidul Hasan et al., published by De Gruyter

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

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  80. Knockdown of lncRNA TapSAKI alleviates LPS-induced injury in HK-2 cells through the miR-205/IRF3 pathway
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  95. Prognostic value of preoperative inflammation-based predictors in patients with bladder carcinoma after radical cystectomy
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  106. lncRNA MALAT1 regulated ATAD2 to facilitate retinoblastoma progression via miR-655-3p
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  108. Analysis of COVID-19 outbreak origin in China in 2019 using differentiation method for unusual epidemiological events
  109. Laparoscopic versus open major liver resection for hepatocellular carcinoma: A case-matched analysis of short- and long-term outcomes
  110. Travelers’ vaccines and their adverse events in Nara, Japan
  111. Association between Tfh and PGA in children with Henoch–Schönlein purpura
  112. Can exchange transfusion be replaced by double-LED phototherapy?
  113. circ_0005962 functions as an oncogene to aggravate NSCLC progression
  114. Circular RNA VANGL1 knockdown suppressed viability, promoted apoptosis, and increased doxorubicin sensitivity through targeting miR-145-5p to regulate SOX4 in bladder cancer cells
  115. Serum intact fibroblast growth factor 23 in healthy paediatric population
  116. Algorithm of rational approach to reconstruction in Fournier’s disease
  117. A meta-analysis of exosome in the treatment of spinal cord injury
  118. Src-1 and SP2 promote the proliferation and epithelial–mesenchymal transition of nasopharyngeal carcinoma
  119. Dexmedetomidine may decrease the bupivacaine toxicity to heart
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  121. Long noncoding RNA XIST knockdown relieves the injury of microglia cells after spinal cord injury by sponging miR-219-5p
  122. External fixation via the anterior inferior iliac spine for proximal femoral fractures in young patients
  123. miR-128-3p reduced acute lung injury induced by sepsis via targeting PEL12
  124. HAGLR promotes neuron differentiation through the miR-130a-3p-MeCP2 axis
  125. Phosphoglycerate mutase 2 is elevated in serum of patients with heart failure and correlates with the disease severity and patient’s prognosis
  126. Cell population data in identifying active tuberculosis and community-acquired pneumonia
  127. Prognostic value of microRNA-4521 in non-small cell lung cancer and its regulatory effect on tumor progression
  128. Mean platelet volume and red blood cell distribution width is associated with prognosis in premature neonates with sepsis
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  130. Association of gene polymorphisms with women urinary incontinence
  131. Influence of COVID-19 pandemic on stress levels of urologic patients
  132. miR-496 inhibits proliferation via LYN and AKT pathway in gastric cancer
  133. miR-519d downregulates LEP expression to inhibit preeclampsia development
  134. Comparison of single- and triple-port VATS for lung cancer: A meta-analysis
  135. Fluorescent light energy modulates healing in skin grafted mouse model
  136. Silencing CDK6-AS1 inhibits LPS-induced inflammatory damage in HK-2 cells
  137. Predictive effect of DCE-MRI and DWI in brain metastases from NSCLC
  138. Severe postoperative hyperbilirubinemia in congenital heart disease
  139. Baicalin improves podocyte injury in rats with diabetic nephropathy by inhibiting PI3K/Akt/mTOR signaling pathway
  140. Clinical factors predicting ureteral stent failure in patients with external ureteral compression
  141. Novel H2S donor proglumide-ADT-OH protects HUVECs from ox-LDL-induced injury through NF-κB and JAK/SATA pathway
  142. Triple-Endobutton and clavicular hook: A propensity score matching analysis
  143. Long noncoding RNA MIAT inhibits the progression of diabetic nephropathy and the activation of NF-κB pathway in high glucose-treated renal tubular epithelial cells by the miR-182-5p/GPRC5A axis
  144. Serum exosomal miR-122-5p, GAS, and PGR in the non-invasive diagnosis of CAG
  145. miR-513b-5p inhibits the proliferation and promotes apoptosis of retinoblastoma cells by targeting TRIB1
  146. Fer exacerbates renal fibrosis and can be targeted by miR-29c-3p
  147. The diagnostic and prognostic value of miR-92a in gastric cancer: A systematic review and meta-analysis
  148. Prognostic value of α2δ1 in hypopharyngeal carcinoma: A retrospective study
  149. No significant benefit of moderate-dose vitamin C on severe COVID-19 cases
  150. circ_0000467 promotes the proliferation, metastasis, and angiogenesis in colorectal cancer cells through regulating KLF12 expression by sponging miR-4766-5p
  151. Downregulation of RAB7 and Caveolin-1 increases MMP-2 activity in renal tubular epithelial cells under hypoxic conditions
  152. Educational program for orthopedic surgeons’ influences for osteoporosis
  153. Expression and function analysis of CRABP2 and FABP5, and their ratio in esophageal squamous cell carcinoma
  154. GJA1 promotes hepatocellular carcinoma progression by mediating TGF-β-induced activation and the epithelial–mesenchymal transition of hepatic stellate cells
  155. lncRNA-ZFAS1 promotes the progression of endometrial carcinoma by targeting miR-34b to regulate VEGFA expression
  156. Anticoagulation is the answer in treating noncritical COVID-19 patients
  157. Effect of late-onset hemorrhagic cystitis on PFS after haplo-PBSCT
  158. Comparison of Dako HercepTest and Ventana PATHWAY anti-HER2 (4B5) tests and their correlation with silver in situ hybridization in lung adenocarcinoma
  159. VSTM1 regulates monocyte/macrophage function via the NF-κB signaling pathway
  160. Comparison of vaginal birth outcomes in midwifery-led versus physician-led setting: A propensity score-matched analysis
  161. Treatment of osteoporosis with teriparatide: The Slovenian experience
  162. New targets of morphine postconditioning protection of the myocardium in ischemia/reperfusion injury: Involvement of HSP90/Akt and C5a/NF-κB
  163. Superenhancer–transcription factor regulatory network in malignant tumors
  164. β-Cell function is associated with osteosarcopenia in middle-aged and older nonobese patients with type 2 diabetes: A cross-sectional study
  165. Clinical features of atypical tuberculosis mimicking bacterial pneumonia
  166. Proteoglycan-depleted regions of annular injury promote nerve ingrowth in a rabbit disc degeneration model
  167. Effect of electromagnetic field on abortion: A systematic review and meta-analysis
  168. miR-150-5p affects AS plaque with ASMC proliferation and migration by STAT1
  169. MALAT1 promotes malignant pleural mesothelioma by sponging miR-141-3p
  170. Effects of remifentanil and propofol on distant organ lung injury in an ischemia–reperfusion model
  171. miR-654-5p promotes gastric cancer progression via the GPRIN1/NF-κB pathway
  172. Identification of LIG1 and LIG3 as prognostic biomarkers in breast cancer
  173. MitoQ inhibits hepatic stellate cell activation and liver fibrosis by enhancing PINK1/parkin-mediated mitophagy
  174. Dissecting role of founder mutation p.V727M in GNE in Indian HIBM cohort
  175. circATP2A2 promotes osteosarcoma progression by upregulating MYH9
  176. Prognostic role of oxytocin receptor in colon adenocarcinoma
  177. Review Articles
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  199. Sonazoid-enhanced ultrasonography and pathologic characters of CD68 positive cell in primary hepatic perivascular epithelioid cell tumors: A case report and literature review
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  210. Chondroblastoma of mandibular condyle: Case report and literature review
  211. Trauma-induced complete pacemaker lead fracture 8 months prior to hospitalization: A case report
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  213. Computer-assisted preoperative planning of reduction of and osteosynthesis of scapular fracture: A case report
  214. High quality of 58-month life in lung cancer patient with brain metastases sequentially treated with gefitinib and osimertinib
  215. Rapid response of locally advanced oral squamous cell carcinoma to apatinib: A case report
  216. Retrieval of intrarenal coiled and ruptured guidewire by retrograde intrarenal surgery: A case report and literature review
  217. Usage of intermingled skin allografts and autografts in a senior patient with major burn injury
  218. Retraction
  219. Retraction on “Dihydromyricetin attenuates inflammation through TLR4/NF-kappa B pathway”
  220. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part I
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https://doi.org/10.1515/med-2021-0010
Keywords for this article
baricitinib; COVID-19 pneumonia; loading dose; maintenance dose
Creative Commons
BY 4.0

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  60. Fatal immune-related hepatitis with intrahepatic cholestasis and pneumonia associated with camrelizumab: A case report and literature review
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  65. Ratios between circulating myeloid cells and lymphocytes are associated with mortality in severe COVID-19 patients
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  68. Surgical myocardial revascularization outcomes in Kawasaki disease: systematic review and meta-analysis
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  74. Prognostic significance of TRIM28 expression in patients with breast carcinoma
  75. Integrative bioinformatics analysis of KPNA2 in six major human cancers
  76. Exosomal-mediated transfer of OIP5-AS1 enhanced cell chemoresistance to trastuzumab in breast cancer via up-regulating HMGB3 by sponging miR-381-3p
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  96. Sublingual immunotherapy increases Treg/Th17 ratio in allergic rhinitis
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  120. Hypoxia stimulates the migration and invasion of osteosarcoma via up-regulating the NUSAP1 expression
  121. Long noncoding RNA XIST knockdown relieves the injury of microglia cells after spinal cord injury by sponging miR-219-5p
  122. External fixation via the anterior inferior iliac spine for proximal femoral fractures in young patients
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  127. Prognostic value of microRNA-4521 in non-small cell lung cancer and its regulatory effect on tumor progression
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  132. miR-496 inhibits proliferation via LYN and AKT pathway in gastric cancer
  133. miR-519d downregulates LEP expression to inhibit preeclampsia development
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  136. Silencing CDK6-AS1 inhibits LPS-induced inflammatory damage in HK-2 cells
  137. Predictive effect of DCE-MRI and DWI in brain metastases from NSCLC
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  139. Baicalin improves podocyte injury in rats with diabetic nephropathy by inhibiting PI3K/Akt/mTOR signaling pathway
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  141. Novel H2S donor proglumide-ADT-OH protects HUVECs from ox-LDL-induced injury through NF-κB and JAK/SATA pathway
  142. Triple-Endobutton and clavicular hook: A propensity score matching analysis
  143. Long noncoding RNA MIAT inhibits the progression of diabetic nephropathy and the activation of NF-κB pathway in high glucose-treated renal tubular epithelial cells by the miR-182-5p/GPRC5A axis
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  146. Fer exacerbates renal fibrosis and can be targeted by miR-29c-3p
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  151. Downregulation of RAB7 and Caveolin-1 increases MMP-2 activity in renal tubular epithelial cells under hypoxic conditions
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  155. lncRNA-ZFAS1 promotes the progression of endometrial carcinoma by targeting miR-34b to regulate VEGFA expression
  156. Anticoagulation is the answer in treating noncritical COVID-19 patients
  157. Effect of late-onset hemorrhagic cystitis on PFS after haplo-PBSCT
  158. Comparison of Dako HercepTest and Ventana PATHWAY anti-HER2 (4B5) tests and their correlation with silver in situ hybridization in lung adenocarcinoma
  159. VSTM1 regulates monocyte/macrophage function via the NF-κB signaling pathway
  160. Comparison of vaginal birth outcomes in midwifery-led versus physician-led setting: A propensity score-matched analysis
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  164. β-Cell function is associated with osteosarcopenia in middle-aged and older nonobese patients with type 2 diabetes: A cross-sectional study
  165. Clinical features of atypical tuberculosis mimicking bacterial pneumonia
  166. Proteoglycan-depleted regions of annular injury promote nerve ingrowth in a rabbit disc degeneration model
  167. Effect of electromagnetic field on abortion: A systematic review and meta-analysis
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  169. MALAT1 promotes malignant pleural mesothelioma by sponging miR-141-3p
  170. Effects of remifentanil and propofol on distant organ lung injury in an ischemia–reperfusion model
  171. miR-654-5p promotes gastric cancer progression via the GPRIN1/NF-κB pathway
  172. Identification of LIG1 and LIG3 as prognostic biomarkers in breast cancer
  173. MitoQ inhibits hepatic stellate cell activation and liver fibrosis by enhancing PINK1/parkin-mediated mitophagy
  174. Dissecting role of founder mutation p.V727M in GNE in Indian HIBM cohort
  175. circATP2A2 promotes osteosarcoma progression by upregulating MYH9
  176. Prognostic role of oxytocin receptor in colon adenocarcinoma
  177. Review Articles
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