Early Inflammatory Profiles Predict Maximal Disease Severity in Covid-19

Background: Better understanding of host inflammatory changes that precede development of severe COVID-19 could improve delivery of available antiviral and immunomodulatory therapies, and provide insights for the development of new therapies. Method(s): In plasma from individuals with COVID-19, sampled <=10 days from symptom onset from the All-Ireland Infectious Diseases Cohort study, we measured 61 biomarkers, including markers of innate immune and T cell activation, coagulation, tissue repair, lung injury, and immune regulation. We used principal component analysis (PCA) and k-means clustering to derive biomarker clusters, and univariate and multivariate ordinal logistic regression to explore association between cluster membership and maximal disease severity, adjusting for risk factors for severe COVID-19, including age, sex, ethnicity, BMI, hypertension and diabetes. Result(s): From March 2020-April 2021, we included 312 individuals, (median (IQR) age 62 (48-77) years, 7 (4-9) days from symptom onset, 54% male) in the analysis. PCA and clustering derived 4 clusters. Compared to cluster 1, clusters 2-4 were significantly older and of higher BMI but there were no significant differences in sex or ethnicity. Cluster 1 had low levels of inflammation, cluster 2 had higher levels of markers of tissue repair and endothelial activation (EGF, VEGF, PDGF, TGFalpha, serpin E1 and p-selectin). Cluster 3 and 4 were both characterised by higher overall inflammation, but compared to cluster 4, cluster 3 had downregulation of growth factors, markers of endothelial activation, and immune regulation (IL10, PDL1), but higher alveolar epithelial injury markers (RAGE, ST2). In univariate analysis, compared to cluster 1, cluster 3 had the highest odds of severe disease (OR (95% CI) 9.02 (4.62-18.31), followed by cluster 4: 5.59 (2.75-11.72) then cluster 2: 4.5 (2.38-8.81), all p < 0.05). Cluster 3 remained most strongly associated with severe disease in fully adjusted analyses;cluster 3: OR(95% CI) 5.99 (2.69-13.35), cluster 2: 3.14 (1.54-6.42), cluster 4: 3.13 (1.36-7.19), all p< 0.05). Conclusion(s): Distinct early inflammatory profiles predicted maximal disease severity independent of known risk factors for severe COVID-19. A cluster characterised by downregulation of growth factor and endothelial markers and early evidence of alveolar injury was associated with highest risk of developing severe COVID19. Whether this reflects a dysregulated inflammatory response that could improve targeted treatment requires further study. Heatmap of biomarker derived clusters and forest plot of association between clusters and disease severity. A: Heatmap demonstrating differences in biomarkers between clusters B: Forest plot demonstrating odds ratio of specific clusters for progressing to moderate or severe disease (reference Cluster 1), calculated using ordinal logistic regression. Odds ratio (95% CI) presented as unadjusted and fully adjusted (for age, sex, ethnicity, BMI, hypertension, diabetes, immunosuppression, smoking and baseline anticoagulant use). Maximal disease severity graded per the WHO severity scale.

Opportunities and challenges of COVID-19 therapy using mesenchymal stem cells and their exosomes.

BACKGROUND: Corona Virus Disease 2019 (COVID-19) is a highly contagious, rapidly variable, and dangerous infectious disease. However, no specific and effective treatment for COVID-19 is available until now. The safety and efficacy of mesenchymal stem cells and their exosomes have been well verified in numerous clinical trials. Their immunomodulatory and tissue regeneration capabilities may support them as a prospective therapy for COVID-19 application in the clinic. OBJECTIVE: To focus on the development, pathogenesis and the current treatment status of COVID-19, efficacy and possible immunomodulatory mechanisms of mesenchymal stem cells and their exosomes for COVID-19 so as to provide new insights into the clinical treatment for the disease in the future. METHODS: Articles were searched on PubMed and CNKI with the key words of "SARS-CoV-2, COVID-19, cytokine storm, acute respiratory distress syndrome, mesenchymal stem cells, exosomes, immune regulation, tissue repair” in Chinese and English. Finally, 64 articles were collected for this review. RESULTS AND CONCLUSION: Acute respiratory distress syndrome and acute lung injury caused by cytokine storm are the primary precipitating factors of death in individuals with COVID-19. Mesenchymal stem cells and their exosomes can effectively treat the symptoms of acute respiratory distress syndrome and repair the damaged lung tissue in COVID-19 patients by reducing the cytokine storm and promoting the regeneration of alveolar epithelial cells through the interaction with immune cells and their paracrine effects. All of these investigations confirmed that mesenchymal stem cells and their exosomes can fight the COVID-19 infection, and this might be a promising, safe and effective strategy. However, more preclinical studies and randomized, controlled clinical trials are needed to conduct the biodistribution, metabolic fate, and the potential treatment risks of mesenchymal stem cells and their derived exosomes in vivo to fully exploit their clinical efficacy. (English) [ FROM AUTHOR] 背景：2019 冠状病毒病 (Corona Virus Disease 2019，COVID-19) 的传播性强、变异速度快、且危害较大，目前没有针对 COVID-19 的特异治疗 策略。间充质干细胞及其外泌体的安全性和有效性已在众多临床试验中得到证实，其具有的免疫调节和组织修复能力，可作为COVID-19 前 瞻性疗法的主要应用依据，具有巨大的治疗潜力。 目的：重点阐述 COVID-19 的发生发展、致病机制、治疗现状，以及间充质干细胞与其衍生外泌体治疗 COVID-19 患者的有效性和可能的免疫 调控机制，为该疾病的临床治疗提供更多的理论参考。 方法：通过检索PubMed、中国知网数据库中收录的相关文献，英文搜索词为："SARS-CoV-2，COVID-19，cytokine storm，acute respiratory distress syndrome，mesenchymal stem cells，exosomes，immune regulation，tissue repair”，中文搜索词为："新型冠状病毒，2019 冠状病 毒病，细胞因子风暴，急性呼吸窘迫综合征，间充质干细胞，外泌体，免疫调节，组织修复”，最终对64篇文献进行归纳总结。 结果与结论：由细胞因子风暴所引起的急性呼吸窘迫综合征和急性肺损伤是导致 COVID-19 重症患者出现死亡的主要原因。间充质干细胞及 其外泌体通过与免疫细胞之间的相互作用及其旁分泌效应，降低 COVID-19 患者体内细胞因子风暴同时促进其肺泡上皮细胞再生，可有效治 疗急性呼吸窘迫综合征且能够修复其损伤肺组织，证明是一种能够对抗 COVID-19 感染且安全、有效的治疗策略。不过仍然需要更多的临床 前和随机对照临床试验对间充质干细胞及其外泌体移植后的生物分布、体内代谢命运、潜在风险进行更多的研究，以便于更充分发挥其临 床疗效。 (Chinese) [ FROM AUTHOR] Copyright of Chinese Journal of Tissue Engineering Research / Zhongguo zu zhi gong cheng yan jiu is the property of Chinese Journal of Tissue Engineering Research and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

Nanomedicine and Drug Delivery Systems: Roles, Advantages and Disadvantages

Nanotechnology is a new and rapidly evolving subject in the pharmacological and therapeutic professions. Nanoparticles have many advantages as medication delivery systems, including increased efficacy and fewer adverse drug reactions. This study investigated the roles of nanomedicine and drug delivery systems in the pharmaceutical industry, as well as the advantages and disadvantages of nanotechnology. The study used a qualitative research technique, with online survey questionnaires sent to medical professionals and experts in the field of nanomedicine. These surveys comprised open-ended questions that enabled respondents to record their responses in whatever way they deemed fit. The ten respondents were from a variety of medical and health institutes, as well as medical consulting firms. In terms of results, the research established that nanomedicine had been used in medical care for therapy and diagnostic purposes. They are being explored in clinical trials for several reasons. Nanoparticles are used to treat renal disease, Tuberculosis, skin problems, Alzheimer's disease, and various types of cancer and to create COVID-19 vaccines. Further information about the study findings may be found in the results and discussion chapter.Copyright © 2022 Dr. Yashwant Research Labs Pvt. Ltd.. All rights reserved.

A Review: Zinc as an Antivirus Alternative Treatment for Herpes Simplex Virus Infection

This study aimed to review zinc's effectiveness as an antivirus in treating herpes simplex virus infection. The authors use international journals published from 2000-2022, and use search engines such as Google Scholar, PubMed, and Science Direct with the keywords "zinc and herpes simplex virus". The herpes simplex virus that often causes symptoms in humans are HSV type 1 and type 2. The lesions appear as vesicles which then rupture into ulcers. Zinc is one of the most abundant nutrients or metals in the human body besides iron. Studies about the effects of zinc on HSV have shown that it has the function of inhibiting the viral life cycle. HSV attaches to the host cells to replicate and synthesize new viral proteins. Zinc can inhibit this process by depositing on the surface of the virion and inactivating the enzymatic function which is required for the attachment to the host cell, disrupting the surface glycoprotein of the viral membrane so it could not adhere and carry out the next life cycle, it can also inhibit the function of DNA polymerase that works for viral replication in the host cell. This article showed that zinc has effectiveness as an antivirus against the herpes simplex virus, therefore, patients infected with HSV can be treated with zinc as an alternative to an antivirus drug.Copyright © 2022 The Authors. Published by Innovare Academic Sciences Pvt Ltd.

Opportunities and challenges of COVID-19 therapy using mesenchymal stem cells and their exosomes.

BACKGROUND: Corona Virus Disease 2019 (COVID-19) is a highly contagious, rapidly variable, and dangerous infectious disease. However, no specific and effective treatment for COVID-19 is available until now. The safety and efficacy of mesenchymal stem cells and their exosomes have been well verified in numerous clinical trials. Their immunomodulatory and tissue regeneration capabilities may support them as a prospective therapy for COVID-19 application in the clinic. OBJECTIVE: To focus on the development, pathogenesis and the current treatment status of COVID-19, efficacy and possible immunomodulatory mechanisms of mesenchymal stem cells and their exosomes for COVID-19 so as to provide new insights into the clinical treatment for the disease in the future. METHODS: Articles were searched on PubMed and CNKI with the key words of "SARS-CoV-2, COVID-19, cytokine storm, acute respiratory distress syndrome, mesenchymal stem cells, exosomes, immune regulation, tissue repair” in Chinese and English. Finally, 64 articles were collected for this review. RESULTS AND CONCLUSION: Acute respiratory distress syndrome and acute lung injury caused by cytokine storm are the primary precipitating factors of death in individuals with COVID-19. Mesenchymal stem cells and their exosomes can effectively treat the symptoms of acute respiratory distress syndrome and repair the damaged lung tissue in COVID-19 patients by reducing the cytokine storm and promoting the regeneration of alveolar epithelial cells through the interaction with immune cells and their paracrine effects. All of these investigations confirmed that mesenchymal stem cells and their exosomes can fight the COVID-19 infection, and this might be a promising, safe and effective strategy. However, more preclinical studies and randomized, controlled clinical trials are needed to conduct the biodistribution, metabolic fate, and the potential treatment risks of mesenchymal stem cells and their derived exosomes in vivo to fully exploit their clinical efficacy. (English) [ABSTRACT FROM AUTHOR] 背景：2019 冠状病毒病 (Corona Virus Disease 2019，COVID-19) 的传播性强、变异速度快、且危害较大，目前没有针对 COVID-19 的特异治疗 策略。间充质干细胞及其外泌体的安全性和有效性已在众多临床试验中得到证实，其具有的免疫调节和组织修复能力，可作为COVID-19 前 瞻性疗法的主要应用依据，具有巨大的治疗潜力。 目的：重点阐述 COVID-19 的发生发展、致病机制、治疗现状，以及间充质干细胞与其衍生外泌体治疗 COVID-19 患者的有效性和可能的免疫 调控机制，为该疾病的临床治疗提供更多的理论参考。 方法：通过检索PubMed、中国知网数据库中收录的相关文献，英文搜索词为："SARS-CoV-2，COVID-19，cytokine storm，acute respiratory distress syndrome，mesenchymal stem cells，exosomes，immune regulation，tissue repair”，中文搜索词为："新型冠状病毒，2019 冠状病 毒病，细胞因子风暴，急性呼吸窘迫综合征，间充质干细胞，外泌体，免疫调节，组织修复”，最终对64篇文献进行归纳总结。 结果与结论：由细胞因子风暴所引起的急性呼吸窘迫综合征和急性肺损伤是导致 COVID-19 重症患者出现死亡的主要原因。间充质干细胞及 其外泌体通过与免疫细胞之间的相互作用及其旁分泌效应，降低 COVID-19 患者体内细胞因子风暴同时促进其肺泡上皮细胞再生，可有效治 疗急性呼吸窘迫综合征且能够修复其损伤肺组织，证明是一种能够对抗 COVID-19 感染且安全、有效的治疗策略。不过仍然需要更多的临床 前和随机对照临床试验对间充质干细胞及其外泌体移植后的生物分布、体内代谢命运、潜在风险进行更多的研究，以便于更充分发挥其临 床疗效。 (Chinese) [ABSTRACT FROM AUTHOR] Copyright of Chinese Journal of Tissue Engineering Research / Zhongguo zu zhi gong cheng yan jiu is the property of Chinese Journal of Tissue Engineering Research and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Opportunities and challenges of COVID-19 therapy using mesenchymal stem cells and their exosomes

BACKGROUND: Corona Virus Disease 2019 (COVID-19) is a highly contagious, rapidly variable, and dangerous infectious disease. However, no specific and effective treatment for COVID-19 is available until now. The safety and efficacy of mesenchymal stem cells and their exosomes have been well verified in numerous clinical trials. Their immunomodulatory and tissue regeneration capabilities may support them as a prospective therapy for COVID-19 application in the clinic. OBJECTIVE: To focus on the development, pathogenesis and the current treatment status of COVID-19, efficacy and possible immunomodulatory mechanisms of mesenchymal stem cells and their exosomes for COVID-19 so as to provide new insights into the clinical treatment for the disease in the future. METHODS: Articles were searched on PubMed and CNKI with the key words of "SARS-CoV-2, COVID-19, cytokine storm, acute respiratory distress syndrome, mesenchymal stem cells, exosomes, immune regulation, tissue repair” in Chinese and English. Finally, 64 articles were collected for this review. RESULTS AND CONCLUSION: Acute respiratory distress syndrome and acute lung injury caused by cytokine storm are the primary precipitating factors of death in individuals with COVID-19. Mesenchymal stem cells and their exosomes can effectively treat the symptoms of acute respiratory distress syndrome and repair the damaged lung tissue in COVID-19 patients by reducing the cytokine storm and promoting the regeneration of alveolar epithelial cells through the interaction with immune cells and their paracrine effects. All of these investigations confirmed that mesenchymal stem cells and their exosomes can fight the COVID-19 infection, and this might be a promising, safe and effective strategy. However, more preclinical studies and randomized, controlled clinical trials are needed to conduct the biodistribution, metabolic fate, and the potential treatment risks of mesenchymal stem cells and their derived exosomes in vivo to fully exploit their clinical efficacy. (English) [ABSTRACT FROM AUTHOR] 背景：2019 冠状病毒病 (Corona Virus Disease 2019，COVID-19) 的传播性强、变异速度快、且危害较大，目前没有针对 COVID-19 的特异治疗 策略。间充质干细胞及其外泌体的安全性和有效性已在众多临床试验中得到证实，其具有的免疫调节和组织修复能力，可作为COVID-19 前 瞻性疗法的主要应用依据，具有巨大的治疗潜力。 目的：重点阐述 COVID-19 的发生发展、致病机制、治疗现状，以及间充质干细胞与其衍生外泌体治疗 COVID-19 患者的有效性和可能的免疫 调控机制，为该疾病的临床治疗提供更多的理论参考。 方法：通过检索PubMed、中国知网数据库中收录的相关文献，英文搜索词为："SARS-CoV-2，COVID-19，cytokine storm，acute respiratory distress syndrome，mesenchymal stem cells，exosomes，immune regulation，tissue repair”，中文搜索词为："新型冠状病毒，2019 冠状病 毒病，细胞因子风暴，急性呼吸窘迫综合征，间充质干细胞，外泌体，免疫调节，组织修复”，最终对64篇文献进行归纳总结。 结果与结论：由细胞因子风暴所引起的急性呼吸窘迫综合征和急性肺损伤是导致 COVID-19 重症患者出现死亡的主要原因。间充质干细胞及 其外泌体通过与免疫细胞之间的相互作用及其旁分泌效应，降低 COVID-19 患者体内细胞因子风暴同时促进其肺泡上皮细胞再生，可有效治 疗急性呼吸窘迫综合征且能够修复其损伤肺组织，证明是一种能够对抗 COVID-19 感染且安全、有效的治疗策略。不过仍然需要更多的临床 前和随机对照临床试验对间充质干细胞及其外泌体移植后的生物分布、体内代谢命运、潜在风险进行更多的研究，以便于更充分发挥其临 床疗效。 (Chinese) [ABSTRACT FROM AUTHOR] Copyright of Chinese Journal of Tissue Engineering Research / Zhongguo zu zhi gong cheng yan jiu is the property of Chinese Journal of Tissue Engineering Research and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Opportunities and challenges of COVID-19 therapy using mesenchymal stem cells and their exosomes.

BACKGROUND: Corona Virus Disease 2019 (COVID-19) is a highly contagious, rapidly variable, and dangerous infectious disease. However, no specific and effective treatment for COVID-19 is available until now. The safety and efficacy of mesenchymal stem cells and their exosomes have been well verified in numerous clinical trials. Their immunomodulatory and tissue regeneration capabilities may support them as a prospective therapy for COVID-19 application in the clinic. OBJECTIVE: To focus on the development, pathogenesis and the current treatment status of COVID-19, efficacy and possible immunomodulatory mechanisms of mesenchymal stem cells and their exosomes for COVID-19 so as to provide new insights into the clinical treatment for the disease in the future. METHODS: Articles were searched on PubMed and CNKI with the key words of "SARS-CoV-2, COVID-19, cytokine storm, acute respiratory distress syndrome, mesenchymal stem cells, exosomes, immune regulation, tissue repair” in Chinese and English. Finally, 64 articles were collected for this review. RESULTS AND CONCLUSION: Acute respiratory distress syndrome and acute lung injury caused by cytokine storm are the primary precipitating factors of death in individuals with COVID-19. Mesenchymal stem cells and their exosomes can effectively treat the symptoms of acute respiratory distress syndrome and repair the damaged lung tissue in COVID-19 patients by reducing the cytokine storm and promoting the regeneration of alveolar epithelial cells through the interaction with immune cells and their paracrine effects. All of these investigations confirmed that mesenchymal stem cells and their exosomes can fight the COVID-19 infection, and this might be a promising, safe and effective strategy. However, more preclinical studies and randomized, controlled clinical trials are needed to conduct the biodistribution, metabolic fate, and the potential treatment risks of mesenchymal stem cells and their derived exosomes in vivo to fully exploit their clinical efficacy. (English) [ABSTRACT FROM AUTHOR] 背景：2019 冠状病毒病 (Corona Virus Disease 2019，COVID-19) 的传播性强、变异速度快、且危害较大，目前没有针对 COVID-19 的特异治疗 策略。间充质干细胞及其外泌体的安全性和有效性已在众多临床试验中得到证实，其具有的免疫调节和组织修复能力，可作为COVID-19 前 瞻性疗法的主要应用依据，具有巨大的治疗潜力。 目的：重点阐述 COVID-19 的发生发展、致病机制、治疗现状，以及间充质干细胞与其衍生外泌体治疗 COVID-19 患者的有效性和可能的免疫 调控机制，为该疾病的临床治疗提供更多的理论参考。 方法：通过检索PubMed、中国知网数据库中收录的相关文献，英文搜索词为："SARS-CoV-2，COVID-19，cytokine storm，acute respiratory distress syndrome，mesenchymal stem cells，exosomes，immune regulation，tissue repair”，中文搜索词为："新型冠状病毒，2019 冠状病 毒病，细胞因子风暴，急性呼吸窘迫综合征，间充质干细胞，外泌体，免疫调节，组织修复”，最终对64篇文献进行归纳总结。 结果与结论：由细胞因子风暴所引起的急性呼吸窘迫综合征和急性肺损伤是导致 COVID-19 重症患者出现死亡的主要原因。间充质干细胞及 其外泌体通过与免疫细胞之间的相互作用及其旁分泌效应，降低 COVID-19 患者体内细胞因子风暴同时促进其肺泡上皮细胞再生，可有效治 疗急性呼吸窘迫综合征且能够修复其损伤肺组织，证明是一种能够对抗 COVID-19 感染且安全、有效的治疗策略。不过仍然需要更多的临床 前和随机对照临床试验对间充质干细胞及其外泌体移植后的生物分布、体内代谢命运、潜在风险进行更多的研究，以便于更充分发挥其临 床疗效。 (Chinese) [ABSTRACT FROM AUTHOR] Copyright of Chinese Journal of Tissue Engineering Research / Zhongguo zu zhi gong cheng yan jiu is the property of Chinese Journal of Tissue Engineering Research and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Nutritional Intervention for the Treatment and Prevention Against Novel Coronavirus-19

Introduction: The ongoing pandemic of Severe Acute Respiratory Syndrome coronavirus-2 (SARS COV-2) has jeopardized people's health and the global economy. The infection caused by these viruses inflicts immunosuppression and an unprecedented range of symptoms leading to mortality. At this stage, there are no countermeasures or medicines to overcome rapid disease proliferation and aberrant immunological response. Objective(s): The study aims to determine different immunomodulatory therapeutics that could be potential agents to alleviate viral and other lethal infections and possibly rejuvenate immunological and tissue repair response against this disease. Method(s): A review of the literature was performed by screening different scientific databases to procure various immunomodulatory therapies for the treatment of SAR COV-2. Result(s): A comprehensive literature review indicated that different foods rich in vitamins (A-D), selenium and iron can enhance immunological response against various deleterious infections, whereas different nutritious drinks that include hydrogen-enriched water and green tea alleviate inflammation and elicit wound healing properties. Black cumin seeds and Garlic have a myriad of biological activities due to abundant bioactive phytochemicals that play an important role in the elimination of various bacterial and viral infections. Conclusion(s): These foods/supplements are relatively safe to consume and possess high toxicity profile and could be a potential nutritional intervention in order to create adequate immunity within a population to fight against this prevailing infection.Copyright © 2021 Bentham Science Publishers.

Joint Distraction Using An Intended Device For Knee Osteoarthritis: A Prospective Two-Year Follow-Up

Purpose: Knee distraction (KD) treatment for young (<65) patients with end-stage knee osteoarthritis (OA) has previously been shown to successfully postpone a knee arthroplasty for years by reducing pain, improving function, and inducing joint tissue repair. During KD treatment, the tibia and femur are separated ~5 mm for ~6 weeks using an external fixation device. The studies performed thus far have used proof-of-concept medical devices intended for other applications than KD. Recently, the first device specifically designed and intended for KD treatment has been developed. The purpose of the current study was to evaluate the clinical efficacy of this intended device. Method(s): In 5 hospitals, 65 patients with end-stage knee OA, in general practice considered for arthroplasty or high tibial osteotomy, were offered KD treatment by their orthopedic surgeon. Inclusion criteria were judged by the orthopedic surgeon and included age <=65 years, BMI <35 kg/m2 with weight <=110 kg, sufficient knee stability and physical condition, KL grade >=2, malalignment <=10 degrees, no history of inflammatory or septic arthritis. KD was performed according to a standardized protocol. Before and 1 and 2 years after treatment, standardized knee radiographs were performed and patients filled out WOMAC (for pain and function, 0-100, primary clinical outcome) and SF-36 (for quality of life, 0-100, secondary outcome) questionnaires. From the radiographs, minimum joint space width (JSW, mm, primary structural outcome) was measured by one experienced observer and KL grade at baseline was determined. Use of self-reported pain medication (paracetamol, opioids, NSAIDs) and intra-articular injections were registered as well, as were adverse events. Changes over 2 years were evaluated for statistical significance with paired t-tests for continuous variables and McNemar's tests for categorical variables. For the primary clinical outcome (WOMAC), clinical significance was evaluated as well, on group level defined as an increase of >=15 points and on individual level using OARSI-OMERACT response criteria. The influence of adverse effects on 2-year changes in primary outcomes was analyzed with independent t-tests. Result(s): Of the 65 treated patients (age: 53.3+/-6.7;BMI: 28.0+/-3.2;sex: 38 (55%) male;KL grade 0/1/2/3/4: 0 (0%) / 7 (11%) / 26 (40%) / 23 (36%) / 9 (14%)), 50 patients completed 2 years follow-up: 6 patients received partial or total arthroplasty (of which 3 in the 1st year) and 8 patients were lost to follow-up in the 2nd year (primarily due to COVID restrictions). The total WOMAC score (Figure 1A/B) showed a statistically and clinically significant improvement over 1 (+28.4 points;p<0.001) and 2 (+26.2 points;p<0.001) years, as did all the subscales (all p<0.001). After 1 year 72% of patients were OARSI-OMERACT responders, while after 2 years this was 51%. The minimum JSW (Figure 1C/D) significantly improved over 1 (+0.5 mm;p<0.001) and 2 (+0.4 mm;p=0.015) years as well. The physical component scale of the SF36 (Figure 2A/B) showed statistically significant improvement over 1 (+10.5 points;p<0.001) and 2 (+9.8;p<0.001) years, while the mental component scale (Figure 2C/D) did not (both p>0.26). The most common adverse event (Table 1) was pin tract skin infections, experienced by 46 (71%) of patients. In most cases (36;78% of cases) they could be treated with oral antibiotics, while in 3 of the cases (5% of treated patients) hospitalization and/or intravenous antibiotics were needed. Also, 8 (12%) of patients experienced device related complications. Experiencing pin tract infections or device complications did not significantly influence 2-year changes in primary outcomes in these patients (both p>0.05). Before treatment, 39 (60%) of patients used pain medication (Table 2), most often paracetamol (20;31%) or NSAIDs (16;25%). Around half used them daily. After treatment, significantly less patients used pain medication (p<0.001), with 35% at 1 year and 36% at 2 years. In total 12 (18%) patients had received an intra-arti ular injection before KD treatment, of whom 5 (8%) steroids and 3 (5%) hyaluronic acid. Both in the 1st and 2nd year after treatment, 1 patient (2%) received an injection. Conclusion(s): Patients treated with the first device intended for KD treatment showed significant clinical and structural improvement after 1 and 2 years. Importantly, the effect was clinically relevant, as a majority of patients were clinical responders and pain medication use decreased. Long-term evaluation will show whether arthroplasty can be postponed successfully as well. [Formula presented] [Formula presented] [Formula presented] [Formula presented]Copyright © 2023

Lesion Sterilization and Tissue Repair of Laterally Luxated Primary Mandibular Incisor: A Case Report

Lateral luxation injuries are common during childhood and in young adolescence. These injuries involve the surrounding tissues that could lead to extensive clinical treatment problems with a risk of pulpal complications such as pulp necrosis. A case of a healthy 4-year-old Malay boy visiting the paediatric dental clinic after seven months of laterally luxated injury on the lower right lateral incisor (tooth 82) was reported. The traumatic tooth was splinted by a private practitioner three days after the trauma, however, the splint dislodged less than 24-hour after placement. In view of the mother's fear of bringing her child to the dentist due to the COVID-19, no follow-up and further treatment were carried out. This has resulted in the development of discolouration and pulpal necrosis to the injured tooth. Lesion sterilization and tissue repair technique (LSTR) was performed. This report highlights the rare occurrence of lateral luxation injury on tooth 82 and the management of pulp necrosis as a complication via lesion sterilization and tissue repair technique due to the uncooperative behaviour of the child.Copyright © 2022, Faculty of Medicine, University of Malaya. All rights reserved.

Challenges and strategies: Scalable and efficient production of mesenchymal stem cells-derived exosomes for cell-free therapy.

Exosomes are small membrane vesicles secreted by most cell types, and widely exist in cell supernatants and various body fluids. They can transmit numerous bioactive elements, such as proteins, nucleic acids, and lipids, to affect the gene expression and function of recipient cells. Mesenchymal stem cells (MSCs) have been confirmed to be a potentially promising therapy for tissue repair and regeneration. Accumulating studies demonstrated that the predominant regenerative paradigm of MSCs transplantation was the paracrine effect but not the differentiation effect. Exosomes secreted by MSCs also showed similar therapeutic effects as their parent cells and were considered to be used for cell-free regenerative medicine. However, the inefficient and limited production has hampered their development for clinical translation. In this review, we summarize potential methods to efficiently promote the yield of exosomes. We mainly focus on engineering the process of exosome biogenesis and secretion, altering the cell culture conditions, cell expansion through 3D dynamic culture and the isolation of exosomes. In addition, we also discuss the application of MSCs-derived exosomes as therapeutics in disease treatment.

The Role of Vitamin C in Human Immunity and Its Treatment Potential Against COVID-19: A Review Article.

The outbreak of the COVID-19 pandemic has left clinicians around the world searching for viable prevention and treatment options to use against the virus. The important physiologic properties of vitamin C have been well documented regarding its use by immune cells and its role as an antioxidant. It has previously shown potential as a prophylactic and treatment option for other respiratory viruses, and because of this, there has been intrigue into whether these positive outcomes translate into a cost-effective prevention and treatment option for COVID-19. To this point, there have only been a few clinical trials performed to assess the validity of this notion, with very few showing definitive positive outcomes when vitamin C has been incorporated into prophylactic or treatment protocols to use against coronavirus. When being used to specifically treat the severe complications that arise from COVID-19, vitamin C is a reliable option to treat COVID-19-induced sepsis but not pneumonia or acute respiratory distress syndrome (ARDS). As a treatment option, high-dose therapy has shown flashes of promise in a few studies although investigators in these studies often subject the testing group to multimodal therapies that include vitamin C as opposed to just vitamin C alone. Given the role that vitamin C has shown to uphold regarding the human immune response, it is currently advised for all individuals to maintain a normal physiologic range of plasma vitamin C through diet or supplements for adequate prophylactic protection against the virus. More research with definitive outcomes will be needed before it is recommended to provide high-dose vitamin C therapy to prevent or treat COVID-19.

Opportunities and challenges of COVID-19 therapy using mesenchymal stem cells and their exosomes

BACKGROUND: Corona Virus Disease 2019 (COVID-19) is a highly contagious, rapidly variable, and dangerous infectious disease. However, no specific and effective treatment for COVID-19 is available until now. The safety and efficacy of mesenchymal stem cells and their exosomes have been well verified in numerous clinical trials. Their immunomodulatory and tissue regeneration capabilities may support them as a prospective therapy for COVID-19 application in the clinic. OBJECTIVE: To focus on the development, pathogenesis and the current treatment status of COVID-19, efficacy and possible immunomodulatory mechanisms of mesenchymal stem cells and their exosomes for COVID-19 so as to provide new insights into the clinical treatment for the disease in the future. METHODS: Articles were searched on PubMed and CNKI with the key words of "SARS-CoV-2, COVID-19, cytokine storm, acute respiratory distress syndrome, mesenchymal stem cells, exosomes, immune regulation, tissue repair” in Chinese and English. Finally, 64 articles were collected for this review. RESULTS AND CONCLUSION: Acute respiratory distress syndrome and acute lung injury caused by cytokine storm are the primary precipitating factors of death in individuals with COVID-19. Mesenchymal stem cells and their exosomes can effectively treat the symptoms of acute respiratory distress syndrome and repair the damaged lung tissue in COVID-19 patients by reducing the cytokine storm and promoting the regeneration of alveolar epithelial cells through the interaction with immune cells and their paracrine effects. All of these investigations confirmed that mesenchymal stem cells and their exosomes can fight the COVID-19 infection, and this might be a promising, safe and effective strategy. However, more preclinical studies and randomized, controlled clinical trials are needed to conduct the biodistribution, metabolic fate, and the potential treatment risks of mesenchymal stem cells and their derived exosomes in vivo to fully exploit their clinical efficacy. © 2023, Publishing House of Chinese Journal of Tissue Engineering Research. All rights reserved.

Opportunities and challenges of COVID-19 therapy using mesenchymal stem cells and their exosomes

BACKGROUND: Corona Virus Disease 2019 (COVID-19) is a highly contagious, rapidly variable, and dangerous infectious disease. However, no specific and effective treatment for COVID-19 is available until now. The safety and efficacy of mesenchymal stem cells and their exosomes have been well verified in numerous clinical trials. Their immunomodulatory and tissue regeneration capabilities may support them as a prospective therapy for COVID-19 application in the clinic. OBJECTIVE: To focus on the development, pathogenesis and the current treatment status of COVID-19, efficacy and possible immunomodulatory mechanisms of mesenchymal stem cells and their exosomes for COVID-19 so as to provide new insights into the clinical treatment for the disease in the future. METHODS: Articles were searched on PubMed and CNKI with the key words of "SARS-CoV-2, COVID-19, cytokine storm, acute respiratory distress syndrome, mesenchymal stem cells, exosomes, immune regulation, tissue repair” in Chinese and English. Finally, 64 articles were collected for this review. RESULTS AND CONCLUSION: Acute respiratory distress syndrome and acute lung injury caused by cytokine storm are the primary precipitating factors of death in individuals with COVID-19. Mesenchymal stem cells and their exosomes can effectively treat the symptoms of acute respiratory distress syndrome and repair the damaged lung tissue in COVID-19 patients by reducing the cytokine storm and promoting the regeneration of alveolar epithelial cells through the interaction with immune cells and their paracrine effects. All of these investigations confirmed that mesenchymal stem cells and their exosomes can fight the COVID-19 infection, and this might be a promising, safe and effective strategy. However, more preclinical studies and randomized, controlled clinical trials are needed to conduct the biodistribution, metabolic fate, and the potential treatment risks of mesenchymal stem cells and their derived exosomes in vivo to fully exploit their clinical efficacy. (English) [ FROM AUTHOR]

Endogenous reparative pluripotent Muse cells with a unique immune privilege system: Hint at a new strategy for controlling acute and chronic inflammation.

Multilineage-differentiating stress enduring (Muse) cells, non-tumorigenic endogenous pluripotent stem cells, reside in the bone marrow (BM), peripheral blood, and connective tissue as pluripotent surface marker SSEA-3(+) cells. They express other pluripotent markers, including Nanog, Oct3/4, and Sox2 at moderate levels, differentiate into triploblastic lineages, self-renew at a single cell level, and exhibit anti-inflammatory effects. Cultured mesenchymal stromal cells (MSCs) and fibroblasts contain several percent of SSEA-3(+)-Muse cells. Circulating Muse cells, either endogenous or administered exogenously, selectively accumulate at the damaged site by sensing sphingosine-1-phosphate (S1P), a key mediator of inflammation, produced by damaged cells and replace apoptotic and damaged cells by spontaneously differentiating into multiple cells types that comprise the tissue and repair the tissue. Thus, intravenous injection is the main route for Muse cell treatment, and surgical operation is not necessary. Furthermore, gene introduction or cytokine induction are not required for generating pluripotent or differentiated states prior to treatment. Notably, allogenic and xenogenic Muse cells escape host immune rejection after intravenous injection and survive in the tissue as functioning cells over 6 and ∼2 months, respectively, without immunosuppressant treatment. Since Muse cells survive in the host tissue for extended periods of time, therefore their anti-inflammatory, anti-fibrotic, and trophic effects are long-lasting. These unique characteristics have led to the administration of Muse cells via intravenous drip in clinical trials for stroke, acute myocardial infarction, epidermolysis bullosa, spinal cord injury, neonatal hypoxic ischemic encephalopathy, amyotrophic lateral sclerosis, and COVID-19 acute respiratory distress syndrome without HLA-matching or immunosuppressive treatment.

DRUG-INDUCED PNEUMONITIS IN THE SETTING OF SARS-COV-2 INFECTION

SESSION TITLE: Drug-Induced and Associated Critical Care Cases Posters 1 SESSION TYPE: Case Report Posters PRESENTED ON: 10/19/2022 12:45 pm - 01:45 pm INTRODUCTION: Interstitial pneumonitis (ILD) is inflammation of lung interstitium leading to scarring and pulmonary fibrosis. Various etiologies include idiopathic, connective tissue disorders, sarcoidosis and drug induced1. Many chemotherapy agents have been implicated in drug related ILD such as bleomycin, taxanes. However, newer chemotherapeutic drugs such as molecular agents such as anti-VEGF, anti-EGFR (panitumumab) could be causative of drug induced ILD. CASE PRESENTATION: A 75-year-old female with stage IV sigmoid colon cancer treated with surgery, adjuvant FOLFOX chemotherapy and Panitumumab. She presented to the emergency department with shortness of breath and hypoxia after known COVID-19 exposure. Initial imaging with chest radiography showed bilateral ground glass opacities. A chest CT pulmonary embolism protocol was negative for pulmonary embolism but showed bilateral ground glass opacities (GGOs) and some interstitial thickening (L>R) not typical of COVID-19 infection. She was treated with remdesivir and dexamethasone, however her oxygen requirements continued to rapidly escalate. A repeat CT chest without contrast showed bilateral asymmetric interstitial thickening and GGOs. Given persistence of CT chest abnormalities, workup for interstitial lung disease was initiated. The results include ANA titer 1:80, otherwise negative ANCA profile, rheumatoid factor, anti-CCP, Scl-70, Sjogren antibodies. Given clinical history and imaging findings, diagnosis of ILD was suspected, and she was started on solumedrol 1 mg/kg. Her oxygen requirements decreased significantly over the next 2 days, and she was discharged home on oral steroid taper and pneumocystis pneumonia prophylaxis. DISCUSSION: Panitumumab is a fully humanized monoclonal antibody against EGFR. Approved by the US Food and Drug Administration in 2006 for advanced or recurrent colorectal cancer exhibiting wild-type KRAS mutation.2 ILD is rarely reported with panitumumab monotherapy, but higher incidence when used as a combination treatment such as with FOLFOX or FOLFIRI. A Japanese post-marketing surveillance study from 2010-2015 showed an ILD incidence of 1.3% but mortality rates of 51.3%.2 EGFR is expressed on basal cells and non-cilia cells of the bronchioles and type II cells of the alveolus. EGFR mediated mechanisms are important in tissue repair.3 Therefore inhibition of this pathway has been postulated to play a role in development of ILD. Another mechanism was decreased surfactant production by type II cells in pre-clinical study.4,5 ILD secondary to Panitumumab can occur at any point during therapy and up to 1 year after administration of drug.6 The role of infectious processes, in this case, COVID-19 pneumonia, could synergistically worsen ILD presentation. CONCLUSIONS: Although the incidence of ILD is low, the mortality rate is high, therefore early recognition and treatment is associated with improved clinical outcomes. Reference #1: Mudawi D, Heyes K, Hastings R, Rivera-Ortega P, Chaudhuri N. An update on interstitial lung disease. Br J Hosp Med (Lond). Jul 2 2021;82(7):1-14. Reference #2: Osawa M, Kudoh S, Sakai F, et al. Clinical features and risk factors of panitumumab-induced interstitial lung disease: a postmarketing all-case surveillance study. Int J Clin Oncol. Dec 2015;20(6):1063-1071. Reference #3: The FASEB Journal - 2000 - Puddicombe - Involvement of the epidermal growth factor receptor in epithelial repair in asthma.pdf. DISCLOSURES: No relevant relationships by Navitha Ramesh No relevant relationships by Uba Udeh

Conventional and pathogenic Th2 cells in inflammation, tissue repair, and fibrosis.

Type 2 helper T (Th2) cells, a subset of CD4+ T cells, play an important role in the host defense against pathogens and allergens by producing Th2 cytokines, such as interleukin-4 (IL-4), IL-5, and IL-13, to trigger inflammatory responses. Emerging evidence reveals that Th2 cells also contribute to the repair of injured tissues after inflammatory reactions. However, when the tissue repair process becomes chronic, excessive, or uncontrolled, pathological fibrosis is induced, leading to organ failure and death. Thus, proper control of Th2 cells is needed for complete tissue repair without the induction of fibrosis. Recently, the existence of pathogenic Th2 (Tpath2) cells has been revealed. Tpath2 cells produce large amounts of Th2 cytokines and induce type 2 inflammation when activated by antigen exposure or tissue injury. In recent studies, Tpath2 cells are suggested to play a central role in the induction of type 2 inflammation whereas the role of Tpath2 cells in tissue repair and fibrosis has been less reported in comparison to conventional Th2 cells. In this review, we discuss the roles of conventional Th2 cells and pathogenic Th2 cells in the sequence of tissue inflammation, repair, and fibrosis.

Opportunities and challenges of COVID-19 therapy using mesenchymal stem cells and their exosomes.

BACKGROUND: Corona Virus Disease 2019 (COVID-19) is a highly contagious, rapidly variable, and dangerous infectious disease. However, no specific and effective treatment for COVID-19 is available until now. The safety and efficacy of mesenchymal stem cells and their exosomes have been well verified in numerous clinical trials. Their immunomodulatory and tissue regeneration capabilities may support them as a prospective therapy for COVID-19 application in the clinic. OBJECTIVE: To focus on the development, pathogenesis and the current treatment status of COVID-19, efficacy and possible immunomodulatory mechanisms of mesenchymal stem cells and their exosomes for COVID-19 so as to provide new insights into the clinical treatment for the disease in the future. METHODS: Articles were searched on PubMed and CNKI with the key words of “SARS-CoV-2, COVID-19, cytokine storm, acute respiratory distress syndrome, mesenchymal stem cells, exosomes, immune regulation, tissue repair” in Chinese and English. Finally, 64 articles were collected for this review. RESULTS AND CONCLUSION: Acute respiratory distress syndrome and acute lung injury caused by cytokine storm are the primary precipitating factors of death in individuals with COVID-19. Mesenchymal stem cells and their exosomes can effectively treat the symptoms of acute respiratory distress syndrome and repair the damaged lung tissue in COVID-19 patients by reducing the cytokine storm and promoting the regeneration of alveolar epithelial cells through the interaction with immune cells and their paracrine effects. All of these investigations confirmed that mesenchymal stem cells and their exosomes can fight the COVID-19 infection, and this might be a promising, safe and effective strategy. However, more preclinical studies and randomized, controlled clinical trials are needed to conduct the biodistribution, metabolic fate, and the potential treatment risks of mesenchymal stem cells and their derived exosomes in vivo to fully exploit their clinical efficacy. (English) [ FROM AUTHOR] 背景：2019 冠状病毒病 (Corona Virus Disease 2019，COVID-19) 的传播性强、变异速度快、且危害较大，目前没有针对 COVID-19 的特异治疗 策略。间充质干细胞及其外泌体的安全性和有效性已在众多临床试验中得到证实，其具有的免疫调节和组织修复能力，可作为COVID-19 前 瞻性疗法的主要应用依据，具有巨大的治疗潜力。 目的：重点阐述 COVID-19 的发生发展、致病机制、治疗现状，以及间充质干细胞与其衍生外泌体治疗 COVID-19 患者的有效性和可能的免疫 调控机制，为该疾病的临床治疗提供更多的理论参考。 方法：通过检索PubMed、中国知网数据库中收录的相关文献，英文搜索词为：“SARS-CoV-2，COVID-19，cytokine storm，acute respiratory distress syndrome，mesenchymal stem cells，exosomes，immune regulation，tissue repair”，中文搜索词为：“新型冠状病毒，2019 冠状病 毒病，细胞因子风暴，急性呼吸窘迫综合征，间充质干细胞，外泌体，免疫调节，组织修复”，最终对64篇文献进行归纳总结。 结果与结论：由细胞因子风暴所引起的急性呼吸窘迫综合征和急性肺损伤是导致 COVID-19 重症患者出现死亡的主要原因。间充质干细胞及 其外泌体通过与免疫细胞之间的相互作用及其旁分泌效应，降低 COVID-19 患者体内细胞因子风暴同时促进其肺泡上皮细胞再生，可有效治 疗急性呼吸窘迫综合征且能够修复其损伤肺组织，证明是一种能够对抗 COVID-19 感染且安全、有效的治疗策略。不过仍然需要更多的临床 前和随机对照临床试验对间充质干细胞及其外泌体移植后的生物分布、体内代谢命运、潜在风险进行更多的研究，以便于更充分发挥其临 床疗效。 (Chinese) [ FROM AUTHOR] Copyright of Chinese Journal of Tissue Engineering Research / Zhongguo zu zhi gong cheng yan jiu is the property of Chinese Journal of Tissue Engineering Research and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

COST ANALYSIS OF MINIMALLY-INVASIVE SACROCOLPOPEXY COMPARED TO NATIVE TISSUE VAGINAL REPAIR IN THE ERA OF ERAS

Introduction: Minimally invasive sacrocolpopexy (SCP) is the gold-standard treatment for patients with apical prolapse and is increasingly used as a primary intervention in women with uterovaginal prolapse. There is a lack of comparative data evaluating costs between SCP versus native tissue vaginal repair in the post-ERAS implementation era. Objective: The primary aim was to determine the cost difference between performing hysterectomy and minimally-invasive sacrocolpopexy as compared to vaginal hysterectomy with native tissue vaginal repair for uterovaginal prolapse. We hypothesized that minimally-invasive sacral colpopexy has a higher cost when compared to native tissue repair but when failure rates of native tissue repair approach 15%, costs equilibrate. Methods: This was a retrospective cohort study at a tertiary care center. The electronic medical record system was queried for women who underwent native tissue vaginal repair or minimally invasive SCP with concomitant hysterectomy for uterovaginal prolapse in calendar year 2021 (post-COVID enhanced recovery after surgery implementation). We excluded all patients who had concomitant colorectal procedures and where billing was not complete or re-imbursement was not received. Hospital charges, direct and indirect costs and operating margin (net revenue minus all costs) were obtained from Strata Jazz and were compared using R statistical program. Net revenue (reimbursement) was directly obtained from the record as the total payment received by the hospital from the payor. Results: A total of 81 women were included, (33 SCP (25 robotic and 8 laparoscopic) versus 48 native tissue). Payor mix included 27% Medicare, 5% medicaid, 61% employer-based and 7% private insurance. Demographic and surgical data is presented in Table 1. The mean total charge per case for services was higher in the SCP group compared to the vaginal repair group ($119,863 vs. $82,205, P < 0.01). Cost of supplies was more in the SCP group ($4429 vs. $2108, P < 0.01), but the cost of operating room time and staff was similar ($7926 vs. $7216, P = 0.06). Controlling for surgeon, age and BMI, the direct and indirect costs were also higher in the SCP group ($13,649 vs. $10,168, P < 0.01 and $5068 vs. $3685, P < 0.01, respectively). Net revenue was lower for the vaginal repair group compared to the SCP group ($14,614 vs. $31,618, P < 0.01). The operating margin was significantly higher in the SCP group ($11,770 vs. $ 517, P < 0.01). Additionally, there were no significant differences in the net revenue between different payors (P = 0.8997). Same-day discharge and EBL were similar among both groups with operative time being higher in the SCP group (204 vs. 161, P < 0.01). Using the means of the direct costs between groups, a re-operation rate of 25.5% would be needed for the native tissue repair costs to equilibrate to the SCP group. From a hospital perspective, due to the low operating margins experienced with native tissue vaginal repair, 227 native tissue vaginal repairs would need to be performed for the same net return as 10 minimally-invasive SCP's. Conclusions: Vaginal hysterectomy with native tissue repair had lower direct and indirect costs compared to minimally-invasive SCP. However, operating margins are significantly higher for SC P due to net revenue received. (Table Presented).