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Yuying Ge,1,* Yuepeng Xie,2,* Junlei Chai,3,* Weifeng Ji,4,* Xiulong Lou,1 Kun Tian,2 Ronghua Bao,3 Chengliang Wu,1 Hongfeng Ruan1 1Institute of Orthopaedics and Traumatology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, People’s Republic of China; 2The Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 3Hangzhou Fuyang Hospital of TCM Orthopedics and Traumatology, Hangzhou, People’s Republic of China; 4Department of Orthopaedics, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hongfeng Ruan; Chengliang Wu, Institute of Orthopaedics and Traumatology, The First Affiliated Hospital of Zhejiang Chinese Medical University, 548 Binwen Road, Hangzhou, 310053, People’s Republic of China, Fax +86 571 86613684, Email rhf@zcmu.edu.cn; wcl@zcmu.edu.cnBackground: Intervertebral disc (IVD) degeneration (IVDD) is highly prevalent among the elderly population and stands as a leading cause of low back pain. Our prior studies have highlighted the therapeutic potential of Liuwei Dihuang decoction (LWDHD) and its component Cornus officinalis (CO)-derived compounds in alleviating IVDD and osteoarthritis, suggesting beneficial effects of CO in treating degenerative osteoarthropathies. However, uncertainty remains regarding the optimal CO dosage within LWDHD and its potential mechanism for effectively treating IVDD.Objective: To ascertain the optimal dosage of CO within LWDHD for enhancing its therapeutic efficacy in treating IVDD, through a comparison of its effects across varied dosages using a mouse IVDD model.Methods: Eight-week-old male C57BL/6J mice were subjected to a lumbar spine instability surgery to induce an IVDD model and received a modified LWDHD formulation containing varied dosages of CO (original dose of CO, or 5- or 10-time dose of CO (referred to as 1 × CO, 5 × CO, and 10 × CO)) for 8 weeks. The therapeutic efficacy on IVDD was evaluated through changes in lumbar spine function, histopathological morphology, extracellular matrix metabolism, nucleus pulposus cell viability, sensory nerve ingrowth, and nucleus pulposus (NP) cell pyroptosis.Results: Augmenting CO levels in LWDHD led to a dose-dependent increase in the levels of CO-sourced active compounds in the plasma of mice. The modified LWDHD formulations, particularly the 5 × CO, exhibited a favorable pharmacological effect on lumbar function, structural integrity, ECM composition, NP cell viability, and sensory nerve ingrowth. Importantly, all 3 formulations notably mitigated NP cell pyroptosis by activating NRF2/KEAP1 pathway, with the 5 × CO formulation exhibiting superior efficacy. Additionally, a comprehensive score analysis indicated that 5 × CO formulation achieved the highest score.Conclusion: These data underscore that elevating the dosage of CO to a specific threshold can enhance the effectiveness of LWDHD in treating IVDD.Keywords: intervertebral disc degeneration, liuwei dihuang decoction, nucleus pulposus cell, pyroptosis, Cornus officinalis

Yuxi He,1,* Shike Geng,1,* Qing Mei,1,* Lei Zhang,1,* Tianjun Yang,1 Chunyan Zhu,1 Xiaoqin Fan,1 Yinzhong Wang,1 Fei Tong,1 Yu Gao,1 Xiaowei Fang,1 Renren Bao,2 Ximei Sheng,3 Aijun Pan1– 3 1Department of Intensive Care Unit, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, People’s Republic of China; 2Department of Intensive Care Unit, the Affiliated Provincial Hospital of Anhui Medical University, Hefei, Anhui, People’s Republic of China; 3Department of Intensive Care Unit, the Training Center of Anhui Provincial Hospital, Wannan Medical College, Wuhu, Anhui, People’s Republic of China*These authors contributed equally to this workCorrespondence: Aijun Pan; Qing Mei, Department of Intensive Care Unit, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, No. 17, Lu Jiang Road, Hefei, Anhui Province, People’s Republic of China, Tel +86-0551-62286175, Email aijunpan868@ustc.edu.cn; meiqing@ustc.edu.cnObjective: To evaluate the diagnostic value and clinical application of metagenomic next-generation sequencing (mNGS) for infections in critically ill patients.Methods: Comparison of diagnostic performance of mNGS and conventional microbiological testing for pathogens was analyzed in 234 patients. The differences between immunocompetent and immunocompromised individuals in mNGS-guided anti-infective treatment adjustment were also analyzed.Results: The sensitivity and specificity of mNGS for bacterial and fungal detection were 96.6% (95% confidence interval [CI], 93.5%– 99.6%) and 83.1% (95% CI, 75.2%– 91.1%), and 85.7% (95% CI, 71.9%– 99.5%) and 93.2% (95% CI, 89.7%– 96.7%), respectively. Overall, 152 viruses were detected by mNGS, but in which 28 viruses were considered causative agents. The proportion of mNGS-guided beneficial anti-infective therapy adjustments in the immunocompromised group was greater than in the immunocompetent group (48.5% vs 30.1%; P=0.008). In addition, mNGS-guided anti-infective regimens with peripheral blood and BALF specimens had the highest proportion (39.0%; 40.0%), but the proportion of patients not helpful due to peripheral blood mNGS was also as high as 22.0%.Conclusion: mNGS might be a promising technology to provide precision medicine for critically ill patients with infection.Keywords: next-generation sequencing, critically ill patients, community-acquired infection, hospital-acquired infection, immunosuppression

Yedong Yu,1 Ruijie Bao,1 Junhao Lyu,1– 4 Jianyong Wu,1– 4 Jianghua Chen,1– 4 Wenhan Peng1– 4 1Department of Kidney Disease Center, The First Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 2Department of Kidney Disease Immunology Laboratory, State Administration of Traditional Chinese Medicine of China, Hangzhou, People’s Republic of China; 3Department of Key Laboratory of Multiple Organ Transplantation, Ministry of Health of China, Hangzhou, People’s Republic of China; 4Institute of Nephropathy, Zhejiang University, Hangzhou, People’s Republic of ChinaCorrespondence: Wenhan PengKidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310003, People’s Republic of ChinaTel +86 571-87236871Email 1198027@zju.edu.cnBackground: Parvovirus B19-associated pure red cell aplasia (PVB19-PRCA) is an uncommon but serious complication after kidney transplantation. Currently, intravenous immunoglobulin (IVIG) is preferred as the first-line treatment for PVB19-PRCA, but presents with disadvantages of disease recurrence and expensive cost. In this context, we propose that foscarnet therapy for kidney transplantation recipients (KTR) with PVB19-PRCA may be an alternative scenario. No related study has been reported, and we performed this study to assess the efficacy and safety of foscarnet for PVB19-associated PRCA in KTR.Methods: We conducted a retrospective review of PVB19-PRCA in KTR at our center over 9-year period. The data on therapy and outcomes in all cases treated with foscarnet are detailed records and summarized.Results: Among our 68 patients, PVB19-PRCA was confirmed in 50 based on inclusion/exclusion criteria. All patients presented with refractory anemia and low reticulocyte percentage (< 0.5%), the mean hemoglobin of patients was 79.8± 12.6g/L at the time of PVB19-PRCA was identified. The median serum genome copy number of parvovirus B19 at diagnosis was 9.6 log10 copies per milliliter. A total of 11 patients received foscarnet therapy, of 10 patients responded well to the treatment and maintained no recurrence. But 1 patient had a poor response to foscarnet therapy. Except for this patient, the mean hemoglobin level gradually increased from 68.5± 9.3 g/L to 73.2± 8.8 g/L, and the mean percentage of reticulocytes steadily increased from 0.1± 0.0% to 7.6± 2.9% after foscarnet therapy. The median serum genome copy number of parvovirus B19 decreased from 9.8 log10 to 6.1 log10 copies per milliliter. There was no significant difference (P=0.61, 0.60) in serum creatinine and glomerular filtration rate before and after foscarnet treatment. At the latest follow-up, the mean hemoglobin was 131.5± 12.5 g/L and the hemoglobin correction occurred in all patients.Conclusion: Foscarnet therapy doesn’t seem to be worse than IVIG for PVB19-PRCA in KTR, and it can be an alternative option.Keywords: human parvovirus B19, pure red cell aplasia, foscarnet therapy, kidney transplantation

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Lijiang Ma,1,* Ruijun Bao2,*1Department of Pediatrics and Medicine, Division of Molecular Genetics, Columbia University Medical Center, New York, NY, 2The Children's IBD Center, Mount Sinai Hospital, New York, NY, USA *These authors contributed equally to this work Abstract: Pulmonary capillary hemangiomatosis (PCH) is a pulmonary vascular disease that mainly affects small capillaries in the lung, and is often misdiagnosed as pulmonary arterial hypertension or pulmonary veno-occlusive disease due to similarities in their clinical presentations, prognosis, and management. In patients who are symptomatic, there is a high mortality rate with median survival of 3 years after diagnosis. Both idiopathic and familial PCH cases are being reported, indicating there is genetic component in disease etiology. Mutations in the eukaryotic translation initiation factor 2α kinase 4 (EIF2AK4) gene were identified in familial and idiopathic PCH cases, suggesting EIF2AK4 is a genetic risk factor for PCH. EIF2AK4 mutations were identified in 100% (6/6) of autosomal recessively inherited familial PCH and 20% (2/10) of sporadic PCH cases. EIF2AK4 is a member of serine/threonine kinases. It downregulates protein synthesis in response to a variety of cellular stress such as hypoxia, viral infection, and amino acid deprivation. Bone morphogenetic protein receptor 2 (BMPR2) is a major genetic risk factor in pulmonary arterial hypertension and EIF2AK4 potentially connects with BMPR2 to cause PCH. L-Arginine is substrate of nitric oxide synthase, and L-arginine is depleted during the production of nitric oxide, which may activate EIF2AK4 to inhibit protein synthesis and negatively regulate vasculogenesis. Mammalian target of rapamycin and EIF2α kinase are two major pathways for translational regulation. Mutant EIF2AK4 could promote proliferation of small pulmonary arteries by crosstalk with mammalian targets of the rapamycin signaling pathway. EIF2AK4 may regulate angiogenesis by modulating the immune system in PCH pathogenesis. The mechanisms of abnormal capillary angiogenesis are suggested to be similar to that of tumor vascularization. Specific therapies were developed according to pathogenesis and are proved to be effective in reported cases. Targeting the EIF2AK4 pathway may provide a novel therapy for PCH. Keywords: EIF2AK4, genetics, pulmonary arterial hypertension, pulmonary veno-occlusive disease