Liver transplantation recovers hepatic N-glycosylation with persistent IgG glycosylation abnormalities: Three-year follow-up in a patient with phosphomannomutase-2-congenital disorder of glycosylation.

Phosphomannomutase-2-congenital disorder of glycosylation (PMM2-CDG) is the most common CDG and presents with highly variable features ranging from isolated neurologic involvement to severe multi-organ dysfunction. Liver abnormalities occur in in almost all patients and frequently include hepatomegaly and elevated aminotransferases, although only a minority of patients develop progressive hepatic fibrosis and liver failure. No curative therapies are currently available for PMM2-CDG, although investigation into several novel therapies is ongoing. We report the first successful liver transplantation in a 4-year-old patient with PMM2-CDG. Over a 3-year follow-up period, she demonstrated improved growth and neurocognitive development and complete normalization of liver enzymes, coagulation parameters, and carbohydrate-deficient transferrin profile, but persistently abnormal IgG glycosylation and recurrent upper airway infections that did not require hospitalization. Liver transplant should be considered as a treatment option for PMM2-CDG patients with end-stage liver disease, however these patients may be at increased risk for recurrent bacterial infections post-transplant.

NSUN2-mediated M5c methylation of IRF3 mRNA negatively regulates type I interferon responses during various viral infections.

5-Methylcytosine (m5C) is a widespread post-transcriptional RNA modification and is reported to be involved in manifold cellular responses and biological processes through regulating RNA metabolism. However, its regulatory role in antiviral innate immunity has not yet been elucidated. Here, we report that NSUN2, a typical m5C methyltransferase, negatively regulates type I interferon responses during various viral infections, including SARS-CoV-2. NSUN2 specifically mediates m5C methylation of IRF3 mRNA and accelerates its degradation, resulting in low levels of IRF3 and downstream IFN-ß production. Knockout or knockdown of NSUN2 enhanced type I interferon and downstream ISGs during various viral infection in vitro. And in vivo, the antiviral innate response is more dramatically enhanced in Nsun2+/- mice than in Nsun2+/+ mice. The highly m5C methylated cytosines in IRF3 mRNA were identified, and their mutation enhanced cellular IRF3 mRNA levels. Moreover, infection with Sendai virus (SeV), vesicular stomatitis virus (VSV), herpes simplex virus 1 (HSV-1), or Zika virus (ZIKV) resulted in a reduction of endogenous NSUN2 levels. Especially, SARS-CoV-2 infection (WT strain and BA.1 omicron variant) also decreased endogenous levels of NSUN2 in COVID-19 patients and K18-hACE2 KI mice, further increasing type I interferon and downstream ISGs. Together, our findings reveal that NSUN2 serves as a negative regulator of interferon response by accelerating the fast turnover of IRF3 mRNA, while endogenous NSUN2 levels decrease during SARS-CoV-2 and various viral infections to boost antiviral responses for effective elimination of viruses.

Shedding of SARS-CoV-2 for 85 Days in COVID-19 Patients With Type 2 Diabetes Mellitus and Lung Metastasis: A Case Report.

Background: COVID-19 (coronavirus disease 2019) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) seriously endangers people's lives. The variation in SARS-CoV-2 makes the research and development of vaccines and specific drugs particularly important. However, the prevention and diagnosis of COVID-19 cannot be underestimated in the control of the epidemic. Case Presentation: We introduced a 65-year-old female patient who was diagnosed with COVID-19. The SARS-CoV-2 nucleic acid test result of this patient was positive again during treatment. It took 85 days from the first symptom to the final cure. According to the known reports, she is currently the patient with the longest virus shedding in Sichuan Province, China. Due to the patient's special condition, she was treated in four hospitals before and after, and she was diagnosed with type 2 diabetes mellitus (T2DM) and right lung metastatic adenocarcinoma. We fully introduced the patient's epidemiological history, diagnosis, testing, and treatment process. The patient was finally discharged from the hospital under the treatment of antiviral, hypoglycaemic, anti-anxiety, and a combination of Chinese and Western medicine. Conclusions: The epidemic is still rampant, and we should not relax our efforts in the prevention and control of viruses. For the elderly, especially those who are suffering from complications or vulnerable to diseases, it is recommended to extend the observation time. Additionally, medical workers should pay attention to the mental state of patients.

Optimization of the Prodrug Moiety of Remdesivir to Improve Lung Exposure/Selectivity and Enhance Anti-SARS-CoV-2 Activity.

COVID-19 patients with severe symptoms still lack antiviral treatment options. Although remdesivir is the only FDA-approved drug for those patients, its efficacy is limited by premature hydrolysis to nucleoside (NUC), low accumulation in the disease-targeted tissue (lungs), and low antiviral potency. In this study, we synthesized a new series of remdesivir analogues by modifying the ProTide moiety. In comparison with remdesivir, the lead compound MMT5-14 showed 2- to 7-fold higher antiviral activity in four variants of SARS-CoV-2. By reducing premature hydrolysis in hamsters, MMT5-14 increased the prodrug concentration by 200- to 300-fold in the plasma and lungs but also enhanced lung accumulation of the active metabolite triphosphate nucleosides (NTP) by 5-fold. Compared to remdesivir, MMT5-14 also increased the intracellular uptake and activation in lung epithelial cells by 4- to 25-fold. These data suggest that MMT5-14 could be a potential antiviral drug to treat COVID-19 patients with severe symptoms.

Shedding of SARS-CoV-2 for 85 Days in COVID-19 Patients With Type 2 Diabetes Mellitus and Lung Metastasis: A Case Report

Background COVID-19 (coronavirus disease 2019) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) seriously endangers people's lives. The variation in SARS-CoV-2 makes the research and development of vaccines and specific drugs particularly important. However, the prevention and diagnosis of COVID-19 cannot be underestimated in the control of the epidemic. Case Presentation We introduced a 65-year-old female patient who was diagnosed with COVID-19. The SARS-CoV-2 nucleic acid test result of this patient was positive again during treatment. It took 85 days from the first symptom to the final cure. According to the known reports, she is currently the patient with the longest virus shedding in Sichuan Province, China. Due to the patient's special condition, she was treated in four hospitals before and after, and she was diagnosed with type 2 diabetes mellitus (T2DM) and right lung metastatic adenocarcinoma. We fully introduced the patient's epidemiological history, diagnosis, testing, and treatment process. The patient was finally discharged from the hospital under the treatment of antiviral, hypoglycaemic, anti-anxiety, and a combination of Chinese and Western medicine. Conclusions The epidemic is still rampant, and we should not relax our efforts in the prevention and control of viruses. For the elderly, especially those who are suffering from complications or vulnerable to diseases, it is recommended to extend the observation time. Additionally, medical workers should pay attention to the mental state of patients.

Efficacy and safety of short-wave diathermy treatment for moderate COVID-19 patients: a prospective, double-blind, randomized controlled clinical study.

BACKGROUND: Millions of human beings have suffered in the epidemic of Coronavirus disease 2019 (COVID-19), but until now the effective treatment methods have been limited. AIM: This study aimed to evaluate the efficacy and safety of short-wave diathermy (SWD) treatment for moderate COVID-19 patients. DESIGN: A prospective, double-blind, randomized controlled clinical study. SETTING: Inpatients Unit of a COVID-19 specialized hospital. POPULATION: Forty-two patients with moderate COVID-19 were randomly allocated at a 2:1 ratio to two groups: the SWD group and the control group. METHODS: Participants of the SWD group received SWD treatment, and participants of the control group received placebo SWD treatment for one session per day, 10 minutes per session, for no more than 14 days. Both groups were given standard care treatment. Primary outcome was the rate of clinical improvement according to a seven-category ordinal scale. Secondary outcomes included the rate of computed tomography (CT) improvement and the rate of potential adverse events. RESULTS: Clinical improvement occurred in 92.6% of patients in the SWD group by day 14 compared with 69.2% of patients in the control group (P=0.001). The Cox model indicated that the SWD group had a higher clinical improvement probability than the control group (hazard ratio: 3.045; 95% CI: 1.391-6.666; P=0.005). Similarly, CT improvement occurred in 85.2% of patients in the SWD group and 46.2% of patients in the control group respectively by day 14 (P=0.001). The Cox model indicated SWD group had a higher CT improvement probability than control group (hazard ratio: 3.720; 95% CI: 1.486-9.311; P=0.005). There was no significant difference in adverse events between the SWD group and the control group (2 of 27 [7.4%] SWD vs. 1 of 13 [7.7%] control, P=1.000), the most frequent of which were headache (1 of 27 [3.7%] SWD vs. 1 of 13 [7.7%] control patients) and dizziness (1 of 27 [3.7%] SWD vs. 0 of 13 [0%] control patients). CONCLUSIONS: SWD is a valid and reliable adjuvant therapy with a favorable safety profile for moderate COVID-19 patients. CLINICAL REHABILITATION IMPACT: Clinically relevant information is lacking regarding the efficacy and safety of SWD for patients with COVID-19. This study provides the first evidence that SWD is a promising adjuvant therapy for COVID-19.

Effect of training of all staff and influencing factors in Huangshi, Hubei Province during prevention and control of COVID-19 in March 2020

Objective: To understand the status of acquisition of knowledge of infection control and observe the effect of training and influencing factors in Huangshi, Hubei province during prevention and control of COVID-19.

Case Report: Genomic Characteristics of the First Known Case of SARS-CoV-2 Imported From Spain to Sichuan, China.

The pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been basically under control in China since March 2020, but the import of domestic SARS-CoV-2 has begun to increase. This study reported the first case of asymptomatic SARS-CoV-2 infection imported from Spain into Sichuan Province, China, on March 11, 2020. The infected male had a body temperature of 37.5°C, normal blood oxygen saturation levels, and a computed tomography (CT) examination showed that his lungs had no shadows. However, a throat swab from the subject tested positive for SARS-CoV-2 using qPCR assay. In this study, we conducted transcriptome sequencing on respiratory throat swabs from the subject and found that the dominant SARS-CoV-2 sequence (Gene Bank ID: MW301121) was a spike protein D614G mutant strain, which is currently popular throughout world. We downloaded and analyzed SARS-CoV-2 sequences collected from cases in China and Spain for comparison and tracing purposes. After March 11, 2020, the Chinese domestic clade was naturally divided into the imported SARS-CoV-2 D614G mutant strain and evolutionarily-related similar sequences and that of sequences collected in the original Wuhan area. The sequence reported in this study was located on a small branch, far from the evolution of Wuhan sequences. As expected, the identified sequence was closely related to the evolution of the SARS-CoV-2 D614G mutant strain circulating in Spain.

Remote clinical training practice in the neurology internship during the COVID-19 pandemic.

Background: During the current COVID-19 pandemic, offline clinical education was mandated to suspend at the neurology department of many teaching hospitals globally, yet there is insufficient evidence regarding the preferred practice and methods for online neurology intern training course.Objective: The investigation aimed to examine whether the online neurology training course based on Small Private Online Course (SPOC) and blending learning mode can achieve a good effect and cater for interns from different medical programs and whether the learning group size affects the teaching effect.Design: The subjects were 92 students enrolled in the neurology internship at the Second Xiangya Hospital of China from 9 March to 9 August 2020. After completing the online course, the final scores and evaluation results were compared among different groups of interns, and their preference to distinct contents of the course was analyzed. Statistical analysis was performed using the SPSS program (version 22.0).Results: Our online course received consistent positive recognition from the interns. Ninety-nine percent of the interns recommended incorporating the online course into the conventional offline training program after the pandemic. There was no significant difference between interns from different programs concerning the final scores and course evaluation. A smaller learning group size (<15 students) could achieve a better teaching effect than a larger group size (p < 0.05). The interns preferred interactive discussions, and course contents that they can get practice and feedback from, rather than video watching and didactic lectures.Conclusions: The online neurology intern training course based on SPOC and blending learning mode is worthy of popularization in a large student base. The teaching effect of an online intern training program may be improved by limiting the group size to less than 15 students and encouraging more interactive discussion, more practice and feedback.

Comparison of lung image quality between CT Ark and Brilliance 64 CT during COVID-19.

AIM: This study is to compare the lung image quality between shelter hospital CT (CT Ark) and ordinary CT scans (Brilliance 64) scans. METHODS: The patients who received scans with CT Ark or Brilliance 64 CT were enrolled. Their lung images were divided into two groups according to the scanner. The objective evaluation methods of signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were used. The subjective evaluation methods including the evaluation of the fine structure under the lung window and the evaluation of the general structure under the mediastinum window were compared. Kappa method was used to assess the reliability of the subjective evaluation. The subjective evaluation results were analyzed using the Wilcoxon rank sum test. SNR and CNR were tested using independent sample t tests. RESULTS: There was no statistical difference in somatotype of enrolled subjects. The Kappa value between the two observers was between 0.68 and 0.81, indicating good consistency. For subjective evaluation results, the rank sum test P value of fine structure evaluation and general structure evaluation by the two observers was ≥ 0.05. For objective evaluation results, SNR and CNR between the two CT scanners were significantly different (P<0.05). Notably, the absolute values ​​of SNR and CNR of the CT Ark were larger than Brilliance 64 CT scanner. CONCLUSION: CT Ark is fully capable of scanning the lungs of the COVID-19 patients during the epidemic in the shelter hospital.

Corticosteroids Treatment of Patients with Coronavirus Disease 2019: A Propensity Score Matching Study.

The role of corticosteroids in the treatment of Coronavirus disease 2019 (COVID-19) is controversial. In the present study, we evaluated the effects of adjuvant corticosteroids treatment on the outcome of patients with COVID-19 (n=966), using Propensity Score Matching to adjust for potential differences between the corticosteroids group (n=289) and the non-corticosteroids group (n=677). Analysis of data without adjusting differences in baseline characteristics indicated that the proportion of mechanical ventilation and the mortality was higher in the corticosteroids treatment group in total or severe/critical patients. The duration of viral shedding was longer in the non-corticosteroids treatment group in total or general/mild patients. After adjusting the difference between the corticosteroids and non-corticosteroids treatment group, the analysis revealed that the use of corticosteroids had no effect on the duration of viral shedding, in-hospital mortality or 28-day mortality.

Novel risk scoring system for predicting acute respiratory distress syndrome among hospitalized patients with coronavirus disease 2019 in Wuhan, China.

BACKGROUND: The mortality rate from acute respiratory distress syndrome (ARDS) is high among hospitalized patients with coronavirus disease 2019 (COVID-19). Hence, risk evaluation tools are required to immediately identify high-risk patients upon admission for early intervention. METHODS: A cohort of 220 consecutive patients with COVID-19 were included in this study. To analyze the risk factors of ARDS, data obtained from approximately 70% of the participants were randomly selected and used as training dataset to establish a logistic regression model. Meanwhile, data obtained from the remaining 30% of the participants were used as test dataset to validate the effect of the model. RESULTS: Lactate dehydrogenase, blood urea nitrogen, D-dimer, procalcitonin, and ferritin levels were included in the risk score system and were assigned a score of 25, 15, 34, 20, and 24, respectively. The cutoff value for the total score was > 35, with a sensitivity of 100.00% and specificity of 81.20%. The area under the receiver operating characteristic curve and the Hosmer-Lemeshow test were 0.967 (95% confidence interval [CI]: 0.925-0.989) and 0.437(P Value = 0.437). The model had excellent discrimination and calibration during internal validation. CONCLUSIONS: The novel risk score may be a valuable risk evaluation tool for screening patients with COVID-19 who are at high risk of ARDS.

Analysis of the Risk Factors for Nosocomial Bacterial Infection in Patients with COVID-19 in a Tertiary Hospital.

BACKGROUND: Infection surveillance and risk factor analysis are among the most important prerequisites for the prevention and treatment of nosocomial bacteria infections, which are the demands for both infected and non-infected patients. PURPOSE: To explore the risk factors for nosocomial bacterial infection of patients with COVID-19, and further to provide a theoretical basis for scientific prevention and control of nosocomial bacterial infection. METHODS: Between 10 January 2020 and 9 March 2020, we collected data of 212 patients with COVID-19 and then explored the influence of age, gender, length of stay, use of ventilator, urinary catheterization, central venous catheterization, white blood cell (WBC) count and procalcitonin on the nosocomial bacterial infection of patients with COVID-19 by a retrospective study. RESULTS: There were 212 confirmed cases of COVID-19, of which 31 cases had nosocomial bacterial infections, with an incidence of 14.62%. The most common types of nosocomial bacterial infections were lower respiratory tract (12 cases, 38.71%), which was the most frequent site, followed by urinary tract (10 cases, 32.26%), blood stream (7 cases, 22.58%), upper respiratory tract (1 case, 3.23%) and gastrointestinal tract infection (1 case, 3.23%). The incidence of nosocomial bacterial infection was significantly correlated with age, arteriovenous catheterization, urinary catheterization, WBC count and procalcitonin. Moreover, multivariate analysis confirmed that WBC (OR 8.38, 95% CI 1.07 to 65.55), procalcitonin (OR 4.92, 95% CI 1.39 to 17.33) and urinary catheterization (OR 25.38, 95% CI 5.09 to 126.53) were independent risk factors for the nosocomial bacterial infection of patients with COVID-19. CONCLUSION: Understanding the risk factors for nosocomial bacterial infection of patients with COVID-19 and strengthening the monitoring of various susceptible factors are helpful to control the occurrence of nosocomial bacterial infection in the COVID-19 isolation wards.

Risk factors for depression and anxiety in healthcare workers deployed during the COVID-19 outbreak in China.

PURPOSE: This study was conducted to evaluate the status of depression and anxiety of healthcare workers and to explore the risk factors during the outbreak of COVID-19 in China. METHODS: A cross-sectional study was designed using convenience sampling to obtain a sample of healthcare workers. A structured questionnaire was designed to collect the information of the basic characteristics, workload, and the health condition. Burnout, coping style, anxiety, and depression were measured by specific scales. Multiple logistic regression model was performed to explore the risk factors of anxiety or depression. RESULTS: There were 902 questionnaires received between February 9, 2020 and February 11, 2020. The proportion of healthcare workers with symptoms of moderate/severe anxiety and moderate/severe depression were 16.63% and 18.29%, respectively. There were 24.50% healthcare workers experiencing moderate/severe anxiety and depression at the same time. The increased workload, respiratory symptoms, digestive symptoms, having done specific test(s) related to COVID-19, having family member needs to be taken care of, negative coping style, and job burnout were the independent risk factors of anxiety. Furthermore, the increased workload, respiratory symptoms, digestive symptoms, having done specific test(s) related to COVID-19, negative coping style, and job burnout were the independent risk factors of depression. CONCLUSION: More attention should be paid to the mental health of frontline healthcare workers at the outbreak of COVID-19 in China. Taking steps to reduce the intensity of the work and burnout will be effective to stabilize the mental state of them.

Public health initiatives from hospitalized patients with COVID-19, China.

BACKGROUND: Since December 2019, when it first occurred in Wuhan, China, coronavirus disease 2019 (COVID-19) has spread rapidly worldwide via human-to-human transmission. We aimed to describe the epidemiological and demographic features of COVID-19 outside Wuhan. METHODS: A single-center case series of 136 consecutive (from January 16 to February 17, 2020) patients with confirmed COVID-19 hospitalized in The First People's Hospital of Jingzhou, China, was retrospectively analyzed. Outcomes were followed up until February 19, 2020. RESULTS: Of the 136 patients (median age, 49 years; interquartile range [IQR], 33-63 years; range, 0.3-83 years), 91 (67%) had been to Wuhan or contacted persons from Wuhan. Forty-five (33.1%) were familial clusters. The median incubation period was 6 days (IQR: 4-11 days). All children had an exact exposure history, family members with COVID-19, and "Mild/Moderate" symptoms at admission. Among the 64 elderly patients, 14 (21.9%) had no exposure history, and 43 (67.2%) had a chronic illness. All 11 (8.1%) "Severe/very severe" illness at onset cases and 5 (3.7%) fatal cases were elderly patients. The duration from symptom onset to admission was positively correlated with the duration from symptom onset to endpoint. Overall, patients with a longer incubation period had more severe outcomes. CONCLUSION: As high-risk susceptible groups, strong protection should be implemented for children and the elderly. Universal screening should be performed for people with a clear exposure history, even lacking apparent symptoms. Given the rapid progression of COVID-19, people should be admitted quickly following symptom onset.

Impact of temperature on the dynamics of the COVID-19 outbreak in China.

A COVID-19 outbreak emerged in Wuhan, China at the end of 2019 and developed into a global pandemic during March 2020. The effects of temperature on the dynamics of the COVID-19 epidemic in China are unknown. Data on COVID-19 daily confirmed cases and daily mean temperatures were collected from 31 provincial-level regions in mainland China between Jan. 20 and Feb. 29, 2020. Locally weighted regression and smoothing scatterplot (LOESS), distributed lag nonlinear models (DLNMs), and random-effects meta-analysis were used to examine the relationship between daily confirmed cases rate of COVID-19 and temperature conditions. The daily number of new cases peaked on Feb. 12, and then decreased. The daily confirmed cases rate of COVID-19 had a biphasic relationship with temperature (with a peak at 10 °C), and the daily incidence of COVID-19 decreased at values below and above these values. The overall epidemic intensity of COVID-19 reduced slightly following days with higher temperatures with a relative risk (RR) was 0.96 (95% CI: 0.93, 0.99). A random-effect meta-analysis including 28 provinces in mainland China, we confirmed the statistically significant association between temperature and RR during the study period (Coefficient = -0.0100, 95% CI: -0.0125, -0.0074). The DLNMs in Hubei Province (outside of Wuhan) and Wuhan showed similar patterns of temperature. Additionally, a modified susceptible-exposed-infectious-recovered (M-SEIR) model, with adjustment for climatic factors, was used to provide a complete characterization of the impact of climate on the dynamics of the COVID-19 epidemic.