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Background Aspartate aminotransferase (AST) is often increased in COVID-19 and, in some studies, AST abnormalities were associated with mortality risk. Methods 2054 hospitalized COVID-19 patients were studied. To identify sources of AST release, correlations between AST peak values and other biomarkers of tissue damage, i.e., alanine aminotransferase (ALT) for hepatocellular damage, creatine kinase (CK) for muscle damage, lactate dehydrogenase for multiorgan involvement, alkaline phosphatase and γ-glutamyltransferase for cholestatic injury, and C-reactive protein (CRP) for systemic inflammation, were performed and coefficients of determination estimated. The role of AST to predict death and intensive care unit admission during hospitalization was also evaluated. All measurements were performed using standardized assays. Results AST was increased in 69% of patients. Increases could be fully explained by summing the effects of hepatocellular injury [AST dependence from ALT, 66.8% [95% confidence interval (CI): 64.5–69.1)] and muscle damage [AST dependence from CK, 42.6% (CI: 39.3–45.8)]. We were unable to demonstrate an independent association of AST increases with worse outcomes. Conclusion The mechanisms for abnormal AST in COVID-19 are likely multifactorial and a status related to tissue suffering could play a significant role. The clinical significance of AST elevations remains unclear.

A 79-year-old man with chest pain and dyspnea underwent emergency percutaneous coronary intervention for acute myocardial infarction. However, he died 17 days later due to refractory heart failure. An autopsy revealed cardiac strangulation caused by herniation of the apical heart through a pericardial defect due to partial absence of the pericardium. (Level of Difficulty: Advanced.), Central Illustration

Background: Invasive mechanical ventilation is the treatment of choice in COVID-19 patients when hypoxemia persists, despite maximum conventional oxygen administration. Some frail patients with severe hypoxemic respiratory failure are deemed not eligible for invasive mechanical ventilation. Objectives: To investigate whether High-flow nasal cannula (HFNC) in the wards could serve as a rescue therapy in these frail patients. Methods: This retrospective cohort study included frail COVID-19 patients admitted to the hospital between March 9th and May 1st 2020. HFNC therapy was started in the wards. The primary endpoint was the survival rate at hospital discharge. Results: Thirty-two patients with a median age of 79.0 years (74.5–83.0) and a Clinical Frailty Score of 4 out of 9 (3–6) were included. Only 6% reported HFNC tolerability issues. The overall survival rate was 25% at hospital discharge. Conclusions: This study suggests that, when preferred, HFNC in the wards could be a potential rescue therapy for respiratory failure in vulnerable COVID-19 patients.

COVID-19, caused by SARS-CoV-2, is a highly infectious disease, and clinical laboratory detection has played important roles in its diagnosis and in evaluating progression of the disease. Nucleic acid amplification testing or gene sequencing can serve as pathogenic evidence of COVID-19 diagnosing for clinically suspected cases, and dynamic monitoring of specific antibodies (IgM, IgA, and IgG) is an effective complement for false-negative detection of SARS-CoV-2 nucleic acid. Antigen tests to identify SARS-CoV-2 are recommended in the first week of infection, which is associated with high viral loads. Additionally, many clinical laboratory indicators are abnormal as the disease evolves. For example, from moderate to severe and critical cases, leukocytes, neutrophils, and the neutrophil-lymphocyte ratio increase; conversely, lymphocytes decrease progressively but are over activated. LDH, AST, ALT, CK, high-sensitivity troponin I, and urea also increase progressively, and increased D-dimer is an indicator of severe disease and an independent risk factor for death. Severe infection leads to aggravation of inflammation. Inflammatory biomarkers and cytokines, such as CRP, SAA, ferritin, IL-6, and TNF-α, increase gradually. High-risk COVID-19 patients with severe disease, such as the elderly and those with underlying diseases (cardiovascular disease, diabetes, chronic respiratory disease, hypertension, obesity, and cancer), should be monitored dynamically, which will be helpful as an early warning of serious diseases.

Hepatocellular carcinoma (HCC) has been known as the second common leading cancer worldwide, as it responds poorly to both chemotherapy and medication. Triptolide (TP), a diterpenoid triepoxide, is a promising treatment agent for its effective anticancer effect on multiple cancers including HCC. However, its clinical application has been limited owing to its severe systemic toxicities, low solubility, and fast elimination in the body. Therefore, to overcome the above obstacles, photo-activatable liposomes (LP) integrated with both photosensitizer Ce6 and chemotherapeutic drug TP (TP/Ce6-LP) was designed in the pursuit of controlled drug release and synergetic photodynamic therapy in HCC therapy. The TP encapsulated in liposomes accumulated to the tumor site due to the enhanced permeability and retention (EPR) effect. Under laser irradiation, the photosensitizer Ce6 generated reactive oxygen species (ROS) and further oxidized the unsaturated phospholipids. In this way, the liposomes were destroyed to release TP. TP/Ce6-LP with NIR laser irradiation (TP/Ce6-LP+L) showed the best anti-tumor effect both in vitro and in vivo on a patient derived tumor xenograft of HCC (PDXHCC). TP/Ce6-LP significantly reduced the side effects of TP. Furthermore, TP/Ce6-LP+L induced apoptosis through a caspase-3/PARP signaling pathway. Overall, TP/Ce6-LP+L is a novel potential treatment option in halting HCC progression with attenuated toxicity., Graphical abstract Photo-activatable liposomes incorporating Ce6 and triptolide (TP/Ce6-LP) for hepatocellular carcinoma (HCC) therapy were designed. Photodynamic therapy (PDT) and TP possibly induced cell apoptosis via a caspase-3/PARP signaling pathway in PDXHCC model.Image 1

Current research in structural biology 3, 121-132 (2021). doi:10.1016/j.crstbi.2021.05.001, Calmodulin (CaM) is a ubiquitous Ca$^{2+}$ sensing protein that binds to and modulates numerous target proteins and enzymes during cellular signaling processes. A large number of CaM-target complexes have been identified and structurally characterized, revealing a wide diversity of CaM-binding modes. A newly identified target is creatine kinase (CK), a central enzyme in cellular energy homeostasis. This study reports two high-resolution X-ray structures, determined to 1.24 ����� and 1.43 ����� resolution, of calmodulin in complex with peptides from human brain and muscle CK, respectively. Both complexes adopt a rare extended binding mode with an observed stoichiometry of 1:2 CaM:peptide, confirmed by isothermal titration calorimetry, suggesting that each CaM domain independently binds one CK peptide in a Ca$^{2+}$-depended manner. While the overall binding mode is similar between the structures with muscle or brain-type CK peptides, the most significant difference is the opposite binding orientation of the peptides in the N-terminal domain. This may extrapolate into distinct binding modes and regulation of the full-length CK isoforms. The structural insights gained in this study strengthen the link between cellular energy homeostasis and Ca$^{2+}$-mediated cell signaling and may shed light on ways by which cells can ���fine tune��� their energy levels to match the spatial and temporal demands., Published by Elsevier, Amsterdam

Graphical abstract, Severity prediction of COVID-19 remains one of the major clinical challenges for the ongoing pandemic. Here, we have recruited a 144 COVID-19 patient cohort, resulting in a data matrix containing 3,065 readings for 124 types of measurements over 52 days. A machine learning model was established to predict the disease progression based on the cohort consisting of training, validation, and internal test sets. A panel of eleven routine clinical factors constructed a classifier for COVID-19 severity prediction, achieving accuracy of over 98% in the discovery set. Validation of the model in an independent cohort containing 25 patients achieved accuracy of 80%. The overall sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 0.70, 0.99, 0.93, and 0.93, respectively. Our model captured predictive dynamics of lactate dehydrogenase (LDH) and creatine kinase (CK) while their levels were in the normal range. This model is accessible at https://www.guomics.com/covidAI/ for research purpose.

A 47-year-old woman presented with atypical chest pain and a troponin level of 30.15 ng/dl. A detailed diagnostic work-up did not detect an acute myocardial infarction but revealed the presence of heterophile antibodies. Laboratory values need to be interpreted in the context of the clinical picture when test results do not correspond to clinical findings. (Level of Difficulty: Beginner.), Graphical abstract, A 47-year-old woman presented with atypical chest pain and a troponin level of 30.15 ng/dl. A detailed diagnostic work-up did not detect an acute…

A young man presented with syncope. He was diagnosed with triglyceride deposit cardiomyovasculopathy and skeletal myopathy secondary to adipose triglyceride lipase (ATGL) deficiency. Despite optimal medical therapy, he required heart transplantation to treat his heart failure. Five years post-transplant, the graft function was normal with no evidence of triglyceride deposits. (Level of Difficulty: Intermediate.), Graphical abstract, A young man presented with syncope. He was diagnosed with triglyceride deposit cardiomyovasculopathy and skeletal myopathy secondary to adipose…

We present the case of a female patient who developed persistently elevated levels of cardiac troponin (cTn) after a previous episode of clinically presumed myocarditis. Extensive investigation concluded that the presence of heterophile antibodies was causing false positive cTn elevation. (Level of Difficulty: Intermediate.), Graphical abstract, We present the case of a female patient who developed persistently elevated levels of cardiac troponin (cTn) after a previous episode of clinically…

Graphical abstract, Highlights • Ursolic acid was administered at a dose of 100, 300 or 1000 mg/kg/day. • No Ursolic acid related effects were found after administrating orally for 90 days. • The no observed adverse effect level is likely to be higher than 1000 mg/kg/day., Background Ursolic acid (UA) has been used in alternative medicine for decades, and there has been a great interest in its medicinal properties. Despite this increased interest, a detailed long-term toxicity study has not been performed. The objective of this study was to determine the long-term toxic effect of UA on clinical chemistry, haematology, coagulation, pathology/morphology, behaviour and motor skills in rats. Methods A solution was made by dissolving UA in a mixture of 0.1% Tween 80 and 0.5% hydroxypropyl methylcellulose in Milli-Q Water. The control group received the vehicle, and the test groups received a dose up to 1000 mg/kg/day via oral gavage. The solution was administered to both male and female (Han-Wistar) rats for 90 consecutive days. Results UA did not cause any deaths, abnormal body weights or abnormal pathology at all test doses. In addition to that, no toxicological changes were observed in behaviour, neurotoxicity, coagulation, haematology or clinical chemistry that are related to the administration of UA. Conclusion This study indicates that oral dosing of UA for 90 consecutive days does not lead to toxic effects at any of the doses. Therefore, the NOAEL for UA is likely to be higher than 1000 mg/kg/day.

Introduction Amyotrophic lateral sclerosis (ALS) is an intractable and incurable neurological disease. It is a progressive disease characterized by muscle atrophy and weakness caused by selective vulnerability of upper and lower motor neurons. In disease research, it has been common to use mouse models carrying mutations in responsible genes for familial ALS as pathological models of ALS. However, there is no model that has reproduced the actual conditions of human spinal cord pathology. Thus, we developed a method of producing human spinal motor neurons using human induced pluripotent stem cells (iPSCs) and an innovative experimental technique for drug screening. As a result, ropinirole hydrochloride was eventually discovered after considering such results as its preferable transitivity in the brain and tolerability, including possible adverse reactions. Therefore, we explore the safety, tolerability and efficacy of ropinirole hydrochloride as an ALS treatment in this clinical trial. Methods The ROPALS trial is a single-center double-blind randomized parallel group-controlled trial of the safety, tolerability, and efficacy of the ropinirole hydrochloride extended-release tablet (Requip CR) at 2- to 16-mg doses in patients with ALS. Twenty patients will be recruited for the active drug group (fifteen patients) and placebo group (five patients). All patients will be able to receive the standard ALS treatment of riluzole if not changed the dosage during this trial. The primary outcome will be safety and tolerability at 24 weeks, defined from the date of randomization. Secondary outcome will be the efficacy, including any change in the ALS Functional Rating Scale-Revised (ALSFRS-R), change in the Combined Assessment of Function and Survival (CAFS), and the composite endpoint as a sum of Z-transformed scores on various clinical items. Notably, we will perform an explorative search for a drug effect evaluation using the patient-derived iPSCs to prove this trial concept. Eligible patients will have El Escorial Possible, clinically possible and laboratory-supported, clinically probable, or clinically definite amyotrophic lateral sclerosis with disease duration less than 60 months (inclusive), an ALSFRS-R score ≥2 points on all items and age from 20 to 80 years. Conclusion Patient recruitment began in December 2018 and the last patient is expected to complete the trial protocol in November 2020. Trial registration Current controlled trials UMIN000034954 and JMA-IIA00397 Protocol version version 1.6 (Date; 5/Apr/2019)., Highlights • ALS is a progressive neurodegenerative disease caused by selective vulnerability of upper and lower motor neurons. • ALS patients have no radical treatment. • The ROPALS trial reveals the safety, tolerability, and efficacy of the ropinirole hydrochloride in patients with ALS. • This trial is the pioneering clinical trial for ALS based on iPSCs-drug discovery in Japan.

Background COVID-19 is diagnosed using RT-PCR assays of samples from nasal and oropharyngeal swabs. People with negative RT-PCR often presented with clinical manifestations of COVID-19. The data on such patients are lacking. The present study aims to characterize the patients who were suspected COVID-19 cases and tested negative in RT-PCR compared to patients who had been tested RT-PCR positive. Methods This is a retrospective, observational study of adult suspected and confirmed patients of COVID-19 admitted to King Saud University Medical City, Riyadh, Saudi Arabia, from 1st March 2020 until 30th November 2020. Laboratory confirmation is done through nasal/pharyngeal swab specimens, tested positive in RT-PCR assay. Patients with initial negative RT-PCR test results were assessed again within 48−72 h to avoid false-negative results. Patient data were extracted from the electronic medical files of each included patient using a predesigned case report form. Results The study included 488 (80.93%) patients with RT-PCR swab results positive, and 115 (19.07%) patients who were negative. Respiratory rate and diastolic blood pressure were higher among the swab-positive cases. More number of swab-negative patients had comorbidities such as coronary heart disease, chronic kidney disease, and carcinoma. Fever, cough, and shortness of breath were reported higher among the swab-positive cases. ALT and AST, and LDH levels were found higher among RT-PCR-positive patients. Serum creatinine, blood urea nitrogen and troponin were more elevated in RT-PCR-negative patients. Antibiotics, anticoagulants, and corticosteroids were used more by swab-positive patients. Significantly higher number of RT-PCR-positive patients required proning, high-flow nasal cannula, non-invasive mechanical ventilation, and invasive mechanical ventilation. Acute cardiac ischemia and death were found to be similar among the patients. However, deaths occurred significantly earlier among the swab-positive cases when compared to the swab-negative group. Conclusion Distinctive symptoms and markers of COVID-19 are more frequent among patients who had RT-PCR-positive results.

Purpose of review: Although the respiratory system is the main target of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), it is evident from recent data that other systems, especially cardiovascular and hematological, are also significantly affected. In fact, in severe form, COVID-19 causes a systemic illness with widespread inflammation and cytokine flood, resulting in severe cardiovascular injury. Therefore, we reviewed cardiac injury biomarkers' role in various cardiovascular complications of COVID 19 in recent studies. Recent findings: Cardiac injury biomarkers were elevated in most of the complicated cases of COVID-19, and their elevation is directly proportional to the worst outcome. Evaluation of cardiac biomarkers with markers of other organ damage gives a more reliable tool for case fatalities and future outcome. Summary: Significant association of cardiac biomarkers in COVID-19 cases helps disease management and prognosis, especially in severely ill patients.

Background About 10–20% of patients with Coronavirus disease 2019 (COVID-19) infection progressed to severe illness within a week or so after initially diagnosed as mild infection. Identification of this subgroup of patients was crucial for early aggressive intervention to improve survival. The purpose of this study was to evaluate whether computer tomography (CT) - derived measurements of body composition such as myosteatosis indicating fat deposition inside the muscles could be used to predict the risk of transition to severe illness in patients with initial diagnosis of mild COVID-19 infection. Methods Patients with laboratory-confirmed COVID-19 infection presenting initially as having the mild common-subtype illness were retrospectively recruited between January 21, 2020 and February 19, 2020. CT-derived body composition measurements were obtained from the initial chest CT images at the level of the twelfth thoracic vertebra (T12) and were used to build models to predict the risk of transition. A myosteatosis nomogram was constructed using multivariate logistic regression incorporating both clinical variables and myosteatosis measurements. The performance of the prediction models was assessed by receiver operating characteristic (ROC) curve including the area under the curve (AUC). The performance of the nomogram was evaluated by discrimination, calibration curve, and decision curve. Results A total of 234 patients were included in this study. Thirty-one of the enrolled patients transitioned to severe illness. Myosteatosis measurements including SM-RA (skeletal muscle radiation attenuation) and SMFI (skeletal muscle fat index) score fitted with SMFI, age and gender, were significantly associated with risk of transition for both the training and validation cohorts (P

Aims Type 2 diabetes is considered to be one of the essential risks of adverse outcomes in coronavirus disease 2019 (COVID-19).1 Metformin and insulin were suggested to affect the outcomes. However, divergent views are still expressed. We aim to gain further insight into metformin and insulin in both pre-admission and in-hospital usage in COVID-19 patients with pre-existed type 2 diabetes. Main methods This is a multicentral retrospective study of the hospital confirmed COVID-19 patients between January 19 to April 09, 2020, who admitted to 3 main hospitals in Xiangyang city, China. The effect of type 2 diabetes, metformin, and insulin on COVID-19 were analyzed, respectively. Clinical characteristics, blood laboratory indices, clinical observational indices, and outcomes of these cases were collected. Key findings A total of 407 confirmed COVID-19 patients (including 50 pre-existed type 2 diabetes) were eligible in our study. COVID-19 patients with type 2 diabetes had more adverse outcomes than non-diabetes (OR2: mortality: 1.46 [95% CI3 1.11, 1.93]; P, Graphical abstract Unlabelled Image

Coronavirus disease 2019 (COVID-19) is associated with considerable morbidity and mortality. The number of confirmed cases of infection with SARS-CoV-2, the virus causing COVID-19 continues to escalate with over 70 million confirmed cases and over 1.6 million confirmed deaths. Severe-to-critical COVID-19 is associated with a dysregulated host immune response to the virus, which is thought to lead to pathogenic immune dysregulation and end-organ damage. Presently few effective treatment options are available to treat COVID-19. Leronlimab is a humanized IgG4, kappa monoclonal antibody that blocks C–C chemokine receptor type 5 (CCR5). It has been shown that in patients with severe COVID-19 treatment with leronlimab reduces elevated plasma IL-6 and chemokine ligand 5 (CCL5), and normalized CD4/CD8 ratios. We administered leronlimab to 4 critically ill COVID-19 patients in intensive care. All 4 of these patients improved clinically as measured by vasopressor support, and discontinuation of hemodialysis and mechanical ventilation. Following administration of leronlimab there was a statistically significant decrease in IL-6 observed in patient A (p=0.034) from day 0–7 and patient D (p=0.027) from day 0–14. This corresponds to restoration of the immune function as measured by CD4+/CD8+ T cell ratio. Although two of the patients went on to survive the other two subsequently died of surgical complications after an initial recovery from SARS-CoV-2 infection., Highlights • Leronlimab is a monoclonal antibody in clinical trials to treat the cytokine storm. • Critically ill patients received leronlimab through compassionate use and had remarkable recoveries measured objectively. • The CCR5 receptor is important in recruiting inflammatory cells mainly T cells and macrophages. • Leronlimab disrupted this signal and may have been responsible for restoration of the immune system, improved survival and decrease in IL-6.

Hypervirulent Klebsiella pneumoniae (hvKP) with a high mucus phenotype, can cause liver abscess and extrahepatic invasive infection. The morbidity of hvKP infections has increased recently. Here we describe a case report of septicemia caused by hvKP due to the term septic arthritis of right knee joint in a 29-year-old male. The patient was persistent fever with a peak temperature at 40.6 °C. However, based on the drug sensitivity, the treatment failed frequently. The patient did not improve clinically on susceptible monotherapy antimicrobial. Combination therapy with meropenem and rifampicin (RFP) lead to clinical improvement and discharge.

Coronavirus disease 2019 (COVID-19), a new type and rapidly spread viral pneumonia, is now producing an outbreak of pandemic proportions. The clinical features and laboratory results of different age groups are different due to the general susceptibility of the disease. The laboratory findings of COVID-19 in pregnant women are also conflicting. Para-clinical investigations including laboratory tests and radiologic findings play an important role in early diagnosis and treatment monitoring of COVID-19. The majority of previous reports on the COVID-19 laboratory results were based on data from the general population and limited information is available based on age difference and pregnancy status. This review aimed to describe the COVID-19 laboratory findings in neonates, children, adults, elderly and pregnant women altogether for the first time. The most attracting and reliable markers of COVID-19 in patients were: normal C-reactive protein (CRP) and very different and conflicting laboratory results regardless of clinical symptoms in neonates, normal or temporary elevated CRP, conflicting WBC count results and procalcitonin elevation in children, lymphopenia and elevated lactate dehydrogenase (LDH) in adult patients, lymphopenia and elevated CRP and LDH in the elderly people and high CRP, leukocytosis and elevated neutrophil ratio in pregnant women., Highlights The most attracting and reliable markers of COVID-19 in patients were as follows:•Normal C-reactive protein (CRP) and very different and conflicting laboratory results regardless of clinical symptoms in neonates•Normal or temporary elevated CRP, conflicting WBC count results and procalcitonin elevation in children•Lymphopenia and elevated lactate dehydrogenase (LDH) in adult patients•Lymphopenia and elevated CRP and LDH in the elderly people and high CRP•Leukocytosis and elevated neutrophil ratio in pregnant women.

Introduction Mitochondrial fatty acid oxidation disorders (FAODs) are a heterogeneous group of hereditary autosomal recessive diseases included in newborn screening (NBS) program in Italy. The aim of this study was to analyse FAODs cases, identified either clinically or by NBS,for clinical and genetic characterization and to evaluate a five years' experience of NBS, in the attempt to figure out the complexity of genotype-phenotype correlation and to confirm the clinical impact of NBS in our centre experience. Materials and methods We analysed FAODs patients diagnosed either by NBS or clinically, followed since February 2014 to April 2019 at the Regional Screening Centre and Inherited Metabolic Diseases Unit of Verona. Diagnosis was confirmed by plasma acylcarnitines, urinary organic acids, enzymatic and genetic testing. For not clear genotypes due to the presence of variants of uncertain significance, in silico predictive tools have been used as well as enzymatic activity assays. Patients underwent clinical, nutritional and biochemical follow up. Results We diagnosed 30 patients with FAODs. 20 by NBS: 3 CUD, 6 SCADD, 5 MCADD, 4 VLCADD, 2 MADD. Overall incidence of FAODs diagnosed by NBS was 1:4316 newborns. No one reported complications during the follow up period. 10 patients were diagnosed clinically: 2 CUD, 2 CPT2D, 1 VLCADD, 5 MADD. Mean age at diagnosis was 29.3 years. Within this group, complications or symptoms were reported at diagnosis, but not during follow-up. 12 mutations not previously reported in literature were found, all predicted as pathogenic or likely pathogenic. Discussion and conclusions Our study highlighted the great phenotypic variability and molecular heterogeneity of FAODs and confirmed the importance of a tailored follow up and treatment. Despite the short duration of follow up, early identification by NBS prevented diseases related complications and resulted in normal growth and psycho-motor development as well., Highlights • Early identification by newborn screening prevents disease related complications. • Newborn screening is changing prevalence clinical and molecular heterogeneity of FAODs. • Genotype-phenotype correlation helps to achieve personalized follow-up and treatment. • Enzymatic assay may be pivotal in predicting phenotype and symptoms severity. • Diagnosis on clinical grounds is anyway important to change disease course.

Graphical abstract, Highlights • Qingfeng Paidu decoction + Western medicine are beneficial for COVID-19. • Combined therapy improves anti-inflammation in patients with COVID-19. • Combined therapy may mitigate the extent of multi-organ impairment in COVID-19. • Mortality rate and length of stay were unaffected by Qingfeng Paidu decoction., Background Coronavirus disease 2019 (COVID-19)2 has emerged as a global pandemic. However, as effective treatments for this disease are still unclear, safe and efficient therapies are urgently needed. Qingfei Paidu decoction (QPD)3 is strongly recommended in the Chinese Novel Coronavirus Pneumonia Diagnosis and Treatment Plan (Provisional 6th Edition). However, clinical research data on the effects of QPD on COVID-19 are scarce. Our study aimed to explore the effects of combined treatment with QPD and Western medicine on COVID-19. Methods In this study, 63 patients with confirmed COVID-19 were analyzed. During the first 14 days of hospitalization, patients with deteriorating symptoms were administered QPD along with Western medicine therapy (the antiviral medicine selected from interferon, lopinavir, or arbidol). The clinical characteristics and blood laboratory indices (blood routine, inflammatory factors, and multi-organ biochemical indices) were examined, and the total lung severity scores were evaluated in each patient by reviewing chest computed tomography before treatment and at the end of treatment. Results Before QPD treatment, the combined treatment group showed higher blood C-reactive protein levels and more severe pulmonary inflammation and clinical symptoms than the Western medicine treatment group. Both groups met the discharge criteria after a similar length of hospitalization. At the end of treatment, circulating white blood cells, total lymphocyte count, and glutamic-oxaloacetic transaminase levels improved dramatically in both groups (P 0.05). Conclusion The combination of QPD with Western medicine demonstrated significant anti-inflammatory effects compared with those of only Western medicine in patients with mild and moderate COVID-19; however, neither mortality nor length of hospitalization was affected. Moreover, the combined treatment tended to mitigate the extent of multi-organ impairment. Long-term randomized controlled trials with follow-up evaluations are required to confirm the results presented here.

Mitochondrial trifunctional protein (TFP) deficiency is a rare inherited metabolic disorder caused by defects in fatty acid β-oxidation (FAO) of long-chain fatty acids, leading to impaired energy production. Fasting avoidance, fatty acid-restricted diets, and supplementation with medium-chain triglycerides are recommended as a treatment, but there are no pharmaceutical treatments available with strong evidence of efficacy. Bezafibrate, which enhances the transcription of FAO enzymes, is a promising therapeutic option for FAO disorders (FAODs). The effectiveness of bezafibrate for FAODs has been reported in some clinical trials, but few clinical studies have investigated its in vivo efficacy toward TFP deficiency. Herein, we describe two Japanese patients with TFP deficiency. Patient 1 presented with recurrent myalgia since the age of 5 years. Laboratory findings showed increased serum levels of long-chain fatty acids and reduced expression of TFPα and TFPβ in his skin fibroblasts. Based on these findings, he was diagnosed with the myopathic type of TFP deficiency. Patient 2 suddenly exhibited cardiopulmonary arrest one day after birth. Elevated levels of creatine kinase and long-chain acylcarnitines were observed. Genetic analysis identified compound heterozygous variants in HADHB (c.1175C>T/c.1364T>G). He was diagnosed with the lethal type of TFP deficiency. Although both patients were treated with dietary therapy and l -carnitine supplementation, they experienced frequent myopathic attacks associated with respiratory infections and exercise. After the initiation of bezafibrate, their myopathic manifestations were markedly reduced, leading to an improvement in quality of life without any side effects. Our clinical findings indicate that bezafibrate combined with other treatments such as dietary therapy may be effective in improving myopathic manifestations in TFP deficiency.

Nemaline myopathy is a heterogeneous disorder of skeletal muscle, and histologically characterized by the presence of nemaline bodies in muscle fibers. Patients with typical congenital form of nemaline myopathy initially present with proximal but later also distal muscle weakness, mostly involving facial and respiratory muscle. Cardiac involvement has been rarely observed especially in nebulin-related nemaline myopathy and there have been only two reports about nebulin-related nemaline myopathy patients with cardiac involvement. We present here the case of a 65-year-old woman manifesting slowly progressive distal myopathy with respiratory and heart failure. She harbored two variants in the nebulin gene, c.20131C > T (p.Arg6711Trp) and c.674C > T (p.Pro225Leu), and one of them, c.674C > T, was a novel variant. In this report, we discuss the pathogenicity of the novel variant and its association with clinical phenotypes including cardiac involvement., Highlights • A NEB-related nemaline myopathy patient developed distal myopathy, respiratory and heart failure. • Two variants in NEB were noted and one of them was a novel variant. • The novel variant might be associated with the clinical symptoms including heart failure.

The expression and localization of different isoforms of creatine kinase in Pelodiscus sinensis (PSCK) were studied to reveal the role of PSCK isozymes (PSCK-B, PSCK-M, PSCK-S) under bacterial infection-induced immunologic stress. The computational molecular dynamics simulations predicted that PSCK-S would mostly possess a kinase function in a structural aspect when compared to PSCK-B and PSCK-M. The assay of biochemical parameters such as total superoxide dismutase (T-SOD), lactate dehydrogenase (LDH), malondialdehyde (MDA), catalase (CAT), and the content of ATP were measured along with total PSCK activity in different tissue samples under bacterial infection. The expression detections of PSCK isozymes in vitro and in vivo were overall well-matched where PSCK isozymes were expressed differently in P. sinensis tissues. The results showed that PSCK-B mostly contributes to the spleen, followed by the liver and myocardium; PSCK-M mostly contributes to the liver, followed by the myocardium and skeletal muscle, while PSCK-S contributes to the spleen and is uniquely expressed in skeletal muscle. Our study suggests that the various alterations of PSCK isozymes in tissues of P. sinensis are prone to defense the bacterial infection and blocking energetic imbalance before severe pathogenesis turned on in P. sinensis.

Now 15-year-old girl with glycogen storage disease (GSD) type IIIa (OMIM 232400 ) developed severe left ventricular obstructive hypertrophy and hepatomegaly while treated with frequent cornstarch meals. Subsequently, she was introduced the ketogenic diet; continuous ketosis has been maintained for over the last 4 years. After the introduction of ketogenic diet, a normalization of the cardiomyopathy and improvement of hepatopathy was achieved, with enhanced overall quality of life.

Dermatomyositis, one of the subtypes of idiopathic inflammatory myopathies, presents with a prominent skin rash in up to 80% of patients with or without proximal muscle weakness.1 Dermatomyositis treatment can be very challenging. In particular, cutaneous disease is usually refractory and impacts the quality of life in patients with dermatomyositis.2 Systemic steroids are still considered first-line treatment; however, their chronic use should be limited.3 Many steroid-sparing agents have been used with variable outcomes.3 Currently used immunomodulators include antimalarials, azathioprine, methotrexate, mycophenolate mofetil, intravenous immunoglobulin, rituximab, and oral calcineurin inhibitors.4Apremilast is a phosphodiesterase-4 (PDE-4) inhibitor recently used in the treatment of several inflammatory diseases including psoriasis, psoriatic arthritis, and Behcet disease.5, 6 Apremilast was not previously reported in the treatment of patients with dermatomyositis. We report the efficacy of off-label use of apremilast in the treatment of 3 patients with recalcitrant dermatomyositis.

Objective Enzyme replacement therapy (ERT), the only approved therapy for infantile-onset Pompe disease (IOPD), had heterogeneous clinical effects due to factors such as severity, age at first treatment, dosage, and dosing regimens. We report the clinical and biochemical outcomes of a cohort of IOPD patients identified through newborn screening, and evaluating the dosage effect. Study design A retrospective observational study was designed to describe the long-term clinical and biochemical outcomes of a uniform cohort of IOPD patients who have been treated with high-dosage of ERT. Results Twenty-eight patients received alglucosidase alpha at either the labeled dosage followed by a high dosage (n = 23) or a high dosage exclusively (n = 5). At a median age of 8.3 years (0.8–17.3), 15 patients were walkers, 8 were weak walkers, and 5 were nonwalkers. The three groups exhibited a significant difference in the age of gross motor decline (p, Highlights • CK and uGlc4 levels were correlated with favorable response to ERT in IOPD patients. • Once these biomarkers rose, they never returned to normal. • High-dose ERT instituted immediately at newborn screening seems to give the best outcome.

Clinical application of doxorubicin (DOX) is limited because of its cardiotoxicity. Thus, exploration of effective lead compounds against DOX-induced cardiotoxicity is necessary. The aim of the present study was to investigate the effects and possible mechanisms of dioscin against DOX-induced cardiotoxicity. The in vitro model of DOX- treated H9C2 cells and the in vivo models of DOX-treated rats and mice were used in this study. The results showed that discoin markedly increased H9C2 cell viability, decreased the levels of CK, LDH, and improved histopathological and electrocardio- gram changes in rats and mice to protect DOX-induced cardiotoxicity. Furthermore, dioscin significantly inhibited myocardial oxidative insult through adjusting the levels of intracellular ROS, MDA, SOD, GSH and GSH-Px in vitro and in vivo. Our data also indicated that dioscin activated Nrf2 and Sirt2 signaling pathways, and thereby affected the expression levels of HO-1, NQO1, Gst, GCLM, Keap1 and FOXO3a through decreasing miR-140-5p expression level. In addition, the level of intracellular ROS was significantly increased in H9C2 cells treated by DOX after miR-140-5p mimic transfection, as well as the down-regulated expression levels of Nrf2 and Sirt2, which were markedly reversed by dioscin. In conclusion, our data suggested that dioscin alleviated DOX-induced cardiotoxicity through modulating miR-140-5p-mediated myocardial oxidative stress. This natural product should be developed as a new candidate to alleviate cardiotoxicity caused by DOX in the future., Graphical abstract fx1, Highlights • Dioscin significantly alleviated DOX-induced cardiotoxicity. • Dioscin markedly inhibited myocardial oxidative stress. • Dioscin significantly decreased the levels of miR-140-5p in vitro and in vivo. • Dioscin activated Nrf2 and Sirt2 signal pathways in vitro and in vivo. • Dioscin may be a new potential candidate for DOX-induced cardiotoxicity.

Introduction and Objectives In many studies, varying degrees of liver damage have been reported in more than half of the COVID-19 patients. The aim of this study is to determine the effect of liver biochemical parameters abnormality on mortality in critical COVID-19 patients who have been followed in the ICU since the beginning of the pandemic process. Materials and Methods In this study 533 critical patients who admitted to the ICU due to COVID-19 were included. The patients were divided into three groups according to their ALT, AST, and total bilirubin levels at their admission to the ICU. Group 1 was formed of patients with normal liver biochemical parameters values; Group 2 was formed of patients with liver biochemical parameters abnormality; Group 3 was formed of patients with liver injury. Results 353 (66.2%) of all patients died. Neutrophil, aPTT, CRP, LDH, CK, ALT, AST, bilirubin, procalcitonin and ferritin values in Group 2 and Group 3 were found to be statistically significantly higher than Group 1. It was detected that the days of stay in ICU of the patients in Group 1 was statistically significantly longer than others group. It was found that the patients in Groups 2 and 3 had higher total, 7-day, and 28-day mortality rates than expected. Conclusions The study showed that liver disfunction was associated with higher mortality and shorter ICU occupation time.

Background Exercise-induced muscle damage (EIMD) commonly occurs following intense resistance exercise and is associated with decrements in exercise performance and delayed muscle recovery. Thus, practical methods to attenuate EIMD would prove useful to both training and athletic populations. Omega-3 (n-3) supplementation has been shown to mitigate EIMD with evidence of increasing efficacy at higher doses (up to 6 g/day). However, data of its efficacy in trained individuals is limited. Therefore, this study investigated the effects of 6 and 8 g of n-3 supplementation on markers of muscle damage and muscle recovery after eccentric resistance exercise in resistance-trained males. Methods Using a double-blind, randomized, placebo-controlled design, 26 resistance trained males (23 ± 4 years; 173.6 ± 20.5 cm; 81.9 ± 9.7 kg; 14.2 ± 3.7% body fat) supplemented with 6 (n=10) or 8 g (n=7) of n-3 polyunsaturated fatty acids, or placebo (n=9) for 33 days. On day 30, participants performed a lower body muscle-damaging eccentric resistance exercise bout. Measures of muscle performance, soreness, and damage were taken pre-exercise on day 30 as well as on days 31–33, including vertical jump height (VJH), perceived muscle soreness (PMS), hip and knee range of motion (ROM), repetitions to fatigue (RTF) at 70% 1-RM, and serum creatine kinase (CK) while participants continued to supplement until day 33. Results There were significant differences in VJH, PMS, and serum CK following the muscle-damaging exercise bout compared to pre-exercise (p0.05) differences between supplementation groups (6 g, 8 g, and placebo) at any time point post-exercise (day 31–33). There were no changes in hip and knee ROM or RTF at any time point or between groups. Vertical jump height and PMS returned to pre-exercise levels despite CK remaining elevated post-exercise. Conclusions Thirty-three days of 6 and 8 g of n-3 supplementation did not attenuate EIMD or enhance muscle recovery following muscle-damaging eccentric resistance exercise in resistance-trained males. Further research using various n-3 supplementation durations, doses, and eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) concentrations may be needed to establish its efficacy in attenuating EIMD, which may vary between trained and untrained individuals. Furthermore, while circulating CK is commonly used to assess muscle damage, elevated CK levels may not reflect muscle recovery status following muscle-damaging exercise., Highlights • Intense exercise produces exercise-induced muscle damage (EIMD). • Omega-3 polyunsaturated fatty acid (n-3) supplementation may ameliorate EIMD and promote muscle recovery. • Thirty-three days of 6 and 8 g of n-3 did not reduce EIMD or increase muscle recovery in trained males. • Muscle performance recovered while circulating creatine kinase remained elevated. • Thirty-three days of high daily n-3 intake may be insufficient dosing in trained males.

Background This study utilized a comprehensive nomogram to evaluate the prognosis of patients with COVID-19 pneumonia. Methods: COVID-19 pneumonia data was divided into training set (256 of 321, 80%), internal validation set (65 of 321, 20%) and independent external validation set (n =188). After image processing, lesion segmentation, feature extraction and feature selection, radiomics signatures and clinical indicators were used to develop a radiomics model and a clinical model respectively. Combining radiomics signatures and clinical indicators, a radiomics nomogram was built. The performance of proposed models was evaluated by the receiver operating characteristic curve (AUC). Calibration curves and decision curve analysis were used to assess the performance of the radiomics nomogram. Results: Two clinical indicators that were age and chronic lung disease or asthma and 21 radiomics features were selected to build the radiomics nomogram. The radiomics nomogram yielded an Area Under The Curve1 (AUC) of 0.88 and accuracy of 0.80 in the training set, an AUC of 0.85 and accuracy of 0.77 in internal testing validation set and an AUC of 0.84 and accuracy of 0.75 in independent external validation set. The performance of radiomics nomogram was better than clinical model (AUC = 0.77, p

Introduction and importance Well-leg compartment syndrome (WLCS) develops from abnormal positioning of the limb during surgery. There have been few reports of WLCS in rectal cancer patients, although the lithotomy position, which is widely applied for rectal surgery, is a risk factor for WLCS. Case presentation A 56-year-old man with rectal cancer underwent laparoscopic low anterior resection of the rectum, left lateral lymph node dissection and diverting ileostomy. The operation time was 393 min. The patient was in the head-down tilt lithotomy position and rotated to the right side. Postoperatively, he complained of left lower leg pain and swelling and difficulty moving his legs. The compartment pressure of his right and left lower legs was 80 mmHg and 120 mmHg, respectively. A diagnosis of bilateral WLCS was made, and fasciotomy of both lower legs was performed 2 h after surgery. Although he was able to live his daily life, mild numbness remained in his toes one year after surgery. Clinical discussion In addition to risk factors previously reported for WLCS, our review shows that the male sex and left side are associated with a greater risk of WLCS, especially in rectal surgery. Additionally, our review reveals that the type of rectal surgery leading to WLCS is almost always laparoscopic surgery. Conclusion Surgeons should be especially vigilant for WLCS when they encounter patients, especially males, who complain of left lower leg pain after laparoscopic rectal surgery., Highlights • Male sex, left leg, and laparoscopic are key factors for WLCS in rectal cancer. • Leveling the patient every 3 h is important for prevention of WLCS. • Surgeon's vigilance is vital for early diagnosis and resolution without sequela.

Objectives: When laboratory Reference Ranges (RR) do not reflect analytical methodology, result interpretation can cause misclassification of patients and inappropriate management. This can be mitigated by determining and implementing method-specific RRs, which was the main objective of this study. Design and methods: Serum was obtained from healthy volunteers (Male + Female, n > 120) attending hospital health-check sessions during June and July 2011. Pseudo-anonymised aliquots were stored (at − 70 °C) prior t° analysis on Abbott ARCHITECT c16000 chemistry and i2000SR immunoassay analysers. Data were stratified by gender where appropriate. Outliers were excluded statistically (Tukey method) to generate non-parametric RRs (2.5th + 97.5th percentiles). RRs were compared to those quoted by Abbott and UK Pathology Harmony (PH) where possible. For 7 selected tests, RRs were verified using a data mining approach. Results: For chemistry tests (n = 23), Upper or Lower Reference Limits (LRL or URL) were > 20% different from Abbott ranges in 25% of tests (11% from PH ranges) but in 38% for immunoassay tests (n = 13). RRs (mmol/L) for sodium (138−144), potassium (3.8–4.9) and chloride (102−110) were considerably narrower than PH ranges (133–146, 3.5–5.0 and 95–108, respectively). The gender difference for ferritin (M: 29–441, F: 8–193 ng/mL) was more pronounced than reported by Abbott (M: 22–275, F: 5–204 ng/mL). Verification studies showed good agreement for chemistry tests (mean [SD] difference = 0.4% [1.2%]) but less so for immunoassay tests (27% [29%]), particularly for TSH (LRL). Conclusion: Where resource permits, we advocate using method-specific RRs in preference to other sources, particularly where method bias and lack of standardisation limits RR transferability and harmonisation. Keywords: Reference Ranges, Method-specific, Harmonisation

Reperfusion of ischemic myocardium is crucial for salvaging myocardial cells from ischemic cell death. However, reperfusion itself induces various deleterious effects on the ischemic myocardium. These effects, known collectively as reperfusion injury, comprise stunned myocardium, reperfusion-induced arrhythmia, microvascular reperfusion injury, and lethal reperfusion injury. No approach has proven successful in preventing any of these injuries in the clinical setting. My colleagues and I recently proposed a new postconditioning protocol, postconditioning with lactate-enriched blood (PCLeB), for the prevention of reperfusion injury. This new approach consists of intermittent reperfusion and timely coronary injections of lactated Ringer's solution, aiming to achieve controlled reperfusion with cellular oxygenation and minimal lactate washout from the cells. This approach appeared to be effective in preventing all types of reperfusion injury in patients with ST-segment elevation myocardial infarction (STEMI), and we have already reported excellent in-hospital outcomes of patients with STEMI treated using PCLeB. In this review article, I discuss a possible mechanism of reperfusion injury, which we believe to be valid and which we targeted using this new approach, and I report how the approach worked in preventing each type of reperfusion injury., Highlights • Postconditioning with lactate-enriched blood (PCLeB) targets hypercontracture. • PCLeB employs lactate as an inherent contractile activity blocker. • PCLeB appears to be effective in preventing all four types of reperfusion injury. • PCLeB may also suppress early inflammation after myocardial infarction. • PCLeB may improve outcomes of patients with acute myocardial infarction.

Background Early initiation of enzyme replacement therapy (ERT) with recombinant human acid alpha-glucosidase is an effective treatment for patients with infantile-onset Pompe disease (IOPD) but cannot prevent a slow progression of myopathy. Albuterol has been shown to be helpful in adult patients with Pompe disease, and therefore, we administered an open-label adjunctive therapy with albuterol in IOPD patients undergoing ERT. Methods Fourteen patients, aged 2 to 12 years, were enrolled in this study; all of them had a disease onset before 12 months of life, and 13 of them were ambulatory because of early initiation of ERT. All patients received albuterol (also referred to as salbutamol) 12 mg daily for 26 weeks. The outcome measurements included a 6-minute walk test, four-stair climb test (SCT), the standing/walking/running/jumping domains of Gross Motor Function Measure-88, speech quality, serum creatine kinase, and urinary glucose tetrasaccharide. Outcome and safety measurements were evaluated at baseline, and at 1, 3, and 6 months (26 weeks) after entering the trial. Results After a period of 26 weeks, among the 12 patients who were able to complete the SCT, the median time needed decreased by 22% (p = 0.034). Other parameters inconsistently improved in a variety of individuals. Eleven adverse events, including nausea, urinary frequency, and tachycardia, were potentially related to the study drug, but all were mild and disappeared after a brief drug withdrawal. One patient was actively withdrawn from the trial because of poor compliance. Conclusions The results of our study suggest that albuterol showed a good safety profile as an adjunctive treatment in our IOPD cohort, although the benefits are limited., Highlights • Albuterol may benefit some children with infantile-onset Pompe disease. • Albuterol is safe as an adjunctive treatment to enzyme replacement therapy in children with Pompe disease. • Adverse events associated with albuterol are usually manageable.

Highlights • The research of this paper showed that some suspected SFTS cases are confused with HV infection due to similar symptoms. • No case of simultaneous infection with two or more pathogens was found. • The distribution of SFTSV has a marked regional aggregation in Hubei Province. • Combining qPCR and ELISA can increase sensitivity markedly for diagnosis of SFTSV infection., To evaluate the aetiological agents and epidemiologic features of severe fever with thrombocytopenia syndrome (SFTS) in Hubei province, China, sera from patients were collected from January to December 2011. All cases occurred from April to December, and the epidemic peaked from May to August. The ages of patients ranged from 10 to 86 years (median = 55 years), and the incidence of SFTS increased with age. The female:male ratio of cases was 1.008:1, and 54.6% (77/141) and 1.4% (2/141) of the cases were confirmed by qPCR to be SFTSV and Hantavirus (HV) infection, respectively. No case of simultaneous infection with two or more pathogens was found. The research in this paper showed that some suspected SFTS cases are confused with HV infection due to similar symptoms. The analysis showed that the distribution of SFTSV has a marked regional aggregation in Hubei province.

Terbinafine is a common antifungal medication taken orally to treat onychomycosis. This drug is considered a first-line agent for this disease and has a better cure rate than other antifungal drugs.1 Terbinafine functions as an allylamine agent, which inhibits squalene epoxidase, a key enzyme of ergosterol biosynthesis. The increase in concentration of extracellular squalene is thought to result in toxic levels that kill fungal cells.2 Side effects of terbinafine include gastrointestinal disturbances, dysgeusia, headache, and rash.1 Hepatotoxicity is a less frequent adverse effect of terbinafine that has an incidence of 2.5 cases/100,000.3 Because of the potential for this feared adverse event, some physicians have chosen to monitor liver enzymes during the course of terbinafine treatment. Rhabdomyolysis is another rare side effect that has been associated with terbinafine use. Many occurrences have been reported by physicians in adverse drug reaction reporting databases; however, there have been few published cases of this association.4, 5 Because rhabdomyolysis is not a well-known side effect of terbinafine, patients might not readily discuss symptoms of weakness, myalgia, or darkened urine. Elevated liver enzymes found on routine monitoring might also mistakenly be attributed to terbinafine-induced hepatotoxicity. As a result, it is important to have rhabdomyolysis as a differential diagnosis when monitoring patients on terbinafine.

Polymyositis (PM) and dermatomyositis (DM) are different disease subtypes of idiopathic inflammatory myopathies (IIMs). The main clinical features of PM and DM include progressive symmetric, predominantly proximal muscle weakness. Laboratory findings include elevated creatine kinase (CK), autoantibodies in serum, and inflammatory infiltrates in muscle biopsy. Dermatomyositis can also involve a characteristic skin rash. Both polymyositis and dermatomyositis can present with extramuscular involvement. The causative factor is agnogenic activation of immune system, leading to immunologic attacks on muscle fibers and endomysial capillaries. The treatment of choice is immunosuppression. PM and DM can be distinguished from other IIMs and myopathies by thorough history, physical examinations and laboratory evaluation and adherence to specific and up-to-date diagnosis criteria and classification standards. Treatment is based on correct diagnosis of these conditions., High lights • Challenges of diagnosis and management influences the clinical research and practice of Polymyositis and dermatomyositis. • Diagnostic criteria have been updated and novel therapies have been developed in PM/DM. • Pathogenesis investigation and diagnosis precision improvement may help to guide future treatment strategies.

Background Coronavirus disease 2019 (COVID-19) is still a pandemic, with a high mortality rate in severe/critical cases. Therapies based on the Shenghuang Granule have proved helpful in viral infection and septic shock. Hypothesis/Purpose The objective of the current study was to compare the efficacy and safety of the traditional Chinese medicine, Shenhuang Granule, with standard care in hospitalized patients with severe/critical COVID-19. Study Design and Methods This was an open-label, multicenter, randomized, controlled clinical trial. At 4 medical centers, a total of 111 severe/critical patients were randomly assigned to receive Shenhuang Granule (SHG group) twice a day for 14 days, in addition to standard care, or to receive standard care alone (Control group). The maximal follow up time was 75 days. The clinical endpoint was clinical improvement and mortality. Results 54 patients were assigned to the control group and 57 to the SHG group. The overall mortality was 75.9% (41/54) in the control group, and 38.6% (22/57) in the SHG group (p, Graphical abstract Image, graphical abstract

Very long-chain acyl-coenzyme A dehydrogenase deficiency (VLCADD, OMIM 201475) is a congenital fatty acid oxidation disorder. Individuals with VLCADD should avoid catabolic states, including strenuous exercise and long-term fasting; however, such conditions are required when undergoing surgery. The perioperative management of VLCADD in infants has rarely been reported and details regarding the transition of serum biomarkers reflecting catabolic status have not been disclosed. Herein, we present the perioperative clinical and biological data of cryptorchidism in a 1.5-year-old boy with VLCADD. The patient was diagnosed through newborn screening and his clinical course was very stable. Genetic testing of ACADVL revealed compound heterozygous variants c.506 T > C (p.Met169Thr) and c.606-609delC (p.L216*). The enzyme activity of the patient with VLCAD was only 20% compared to that of healthy control. Left orchiopexy for the pediatric cryptorchidism was planned and performed at 1 and a half year of age. Induction anesthesia involved thiopental, fentanyl and rocuronium. The glucose infusion rate was maintained above 6.6 mg/kg/min starting the day before surgery until the operation was completed. Anesthesia was maintained with sevoflurane at approximately 2%. The serum concentration of tetradecenoylcarnitine were stable during the operation, ranging between 0.08 and 0.19 μM (cutoff, Highlights • Catabolic biomarker status details during surgery in infants with VLCADD is lacking. • We performed uneventful surgical intervention in a 1.5-year-old patient with VLCADD. • Serum levels of tetradecenoyl carnitine remained stable during the operation. • Serum biomarkers creatine kinase, 3-hydroxybutyrate, and free fatty acid remained similarly unchanged. • These findings will be beneficial in the management of VLCADD.

Aims Triglycerides droplets are massively stored in muscle in Lipid Storage Myopathies (LSM). We studied in muscle regulators of lipophagy, the expression of the transcription factor-EB (TFEB) (a master regulator of lysosomal biogenesis), and markers of autophagy which are induced by starvation and exert a transcriptional control on lipid catabolism. Methods We investigated the factors that regulate lipophagy in muscle biopsies from 6 patients with different types of LSM: 2 cases of riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency (MADD), 1 case of primary carnitine deficiency (CD), 2 cases of neutral lipid storage myopathy (NLSD-M), 1 case of carnitine–palmitoyl-transferase-II (CPT) deficiency. Results Conventional morphology and electron microscopy documented the lipid accumulation and its dramatic resolution after treatment. Muscle immunofluorescence showed that while in MADD and NLSD-M there was a co-localized expression of TFEB and p62-SQSTM1 (marker of protein aggregates) in some atrophic fibers, in CD and CPT-II deficiency the reaction was almost normal. In regenerating fibers, TFEB localized in the cytoplasm (inactive form), whereas in atrophic fibers it localized in the nuclei (active form). Lipid-accumulated/atrophic fibers did not display p62-positive protein aggregates, indicating, together with the LC3-II (marker of autophagosomes) and p62-SQSTM1 analysis, that the autophagic flux is often preserved and lipophagy occurs. Conclusion In atrophic and regenerating fibers of patients with NLSD-M we observed TFEB over-expression; in other conditions autophagy markers are increased, suggesting lipophagy active role on human lipid metabolism., Highlights • Fatty acid disorders are due to defective oxidation or transport in mitochondria. • Lipophagy mobilizes fatty acids from lipid droplets within muscle fibers. • Lipophagy has a role in utilization of triglycerides from lipid droplets. • LC3-II and p62-SQSTM1 accumulate in atrophic fibers in lipid storage myopathies. • TFEB, a regulator of lipophagy, is increased when lipophagy or oxidation is blocked.

Introduction Hypotonia is a common presentation that child neurologists encounter daily. The hypotonic neonate represents a diagnostic challenge as a lesion at any level in the neuro-axis may cause hypotonia. In this paper, we study the diagnostic yield of investigations commonly used as part of a hypotonia work-up. Methods A 12-year retrospective cohort study was conducted at a tertiary care center in Saudi Arabia from 2007 to 2018. Final diagnoses, clinical presentations, laboratory tests, imaging and genetic studies were reviewed from the patient's electronic health records. Results 164 patients were identified as fitting the inclusion criteria of the study. 50% had central hypotonia, 18% peripheral hypotonia and 32% mixed hypotonia. Molecular testing was performed for 82% (74) of patients. 65 Microarray studies were done; 27% abnormal and 9% diagnostic. 55 gene panels were done; 58% abnormal and 30% diagnostic. 53 single-gene tests were done; 57% abnormal and 40% diagnostic. 61 whole exome sequences were done; 72% positive and 59% diagnostic. 126 MRIs were reviewed; 56% abnormal and 33% contributed to the diagnosis. Conclusion Molecular genetic testing is our recommended next step in the diagnosis of patients with hypotonia after careful phenotyping. Neuroimaging is helpful to guide further costly workup of patients with hypotonia.

Creatine kinase (CK) is an energy storage enzyme that plays an important role in energy metabolism. CK/phosphocreatine functions as an energy buffer and links ATP production sites with ATP utilization sites. Several key mutations in the αA-crystallin (cryaa) and αB-crystallin (cryab) genes have been linked with autosomal-dominant, hereditary human cataracts. The cryaa-R49C mutation was identified in a four-generation Caucasian family. We previously identified an increase in the quantity of CK complexed with α-crystallin in the lenses of knock-in mice expressing the cryaa-R49C mutation using proteomic analyses. Increased levels of CK in postnatal cataractous lenses may indicate increased ATP requirements during early cataract development. To gain a further understanding of the relationship between CK and α-crystallin, we investigated whether α-crystallin interacts with and forms complexes with CK, in vitro. Isothermal titration calorimetry (ITC) showed that each CK dimer bound to 28 α-crystallin subunits, with a Kd of 3.3 × 10−7 M, and that the interaction between α-crystallin and CK was endothermic, thermodynamically favorable, and entropy-driven. High-salt concentrations did not affect the interaction between CK and α-crystallin, suggesting that the interaction between CK and α-crystallin is primarily hydrophobic. Gel permeation chromatography (GPC) detected water-soluble α-crystallin and CK complexes, as determined by increased light scattering after complex formation. In addition, CK and α-crystallin formed partially-water-insoluble, high-molecular-mass complexes. Enzyme-linked immunosorbent assay (ELISA)-based enzymatic activity analyses of lens homogenates showed a 17-fold increase in CK activity in the postnatal lenses of cryaa-R49C knock-in mice. These studies indicate that the interaction between α-crystallin and CK is functionally important and that increased CK levels may be necessary to meet the increased ATP demands of ATP-dependent functions in cataractous lenses., Highlights • Cataract model α-crystallin mutant mice exhibit upregulated creatine kinase. • Isothermal titration calorimetry detected creatine kinase/α-crystallin interaction. • The protein-protein interaction is thermodynamically favorable and entropy driven.

Multiple acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive disorder of fatty acid, amino acid, and choline metabolism caused by mutations in EFTA, EFTB, or ETFDH. Many MADD patients are responsive to treatment with riboflavin, termed riboflavin-responsive MADD (RR-MADD). Here, we report three novel mutations and one previously reported mutation in ETFDH in four RR-MADD patients who presented at various ages, and characterize the corresponding changes in ETF-QO protein structure. Clinicians should consider MADD in the differential diagnosis when patients present with muscle weakness and biochemical abnormalities. Gene testing plays a critical role in confirming the diagnosis of MADD, and may not only prevent patients from invasive testing, but also allow timely initiation of riboflavin treatment. The novel variants in ETFDH and the corresponding clinical features reported here enrich the allelic heterogeneity of RR-MADD and provide insight into genotype-phenotype relationships.

Study objectives: Severe acute respiratory syndrome (SARS) is a rapidly progressive disease caused by a novel coronavirus (CoV) infection. However, the disease presentation is nonspecific. The aim of this study was to define clearly the presentation, clinical progression, and laboratory data in a group of patients who had SARS. Design: Retrospective observational study. Setting: A tertiary care medical center with 51 negative-pressure isolation rooms in Taipei, Taiwan. Patients: Fifty-three patients with SARS seen between April 27 and June 16, 2003. Results: Fever ( ie , temperature > 38°C) was the most common symptom (98%) and the earliest. When admitted to the isolation unit of the hospital for observation, most patients reported nonspecific symptoms associated with their fever. Only two patients with preexisting illnesses had cough on the same day the fever began. Eventually, 39 patients (74%) developed cough, beginning at a mean (± SD) time of 4.5 ± 1.9 days after fever onset, and 35 patients (66%) had diarrhea beginning at a mean time of 6.0 ± 3.3 days after fever onset. Thirty-one patients (59%) had abnormal findings on chest radiographs on hospital admission, and all but 1 patient (98%) eventually developed lung infiltrates that were consistent with pneumonia. The majority of patients (63%) first developed unifocal infiltrates at a mean time of 4.5 ± 2.1 days after fever onset, while in 37% of patients the initial infiltrates were multifocal, appearing at a mean time of 5.8 ± 1.3 days after fever onset. Common laboratory findings included lymphopenia (on hospital admission, 70%; during hospitalization, 95%), thrombocytopenia (on hospital admission, 28%; during hospitalization, 40%), elevated lactate dehydrogenase (on hospital admission, 58%; during hospitalization, 88%), creatine kinase (on hospital admission, 18%; during hospitalization, 32%), and aspartate aminotransferase or alanine aminotransferase levels (on hospital admission, 27%; during hospitalization, 62%). Throat or nasopharyngeal swab for SARS-CoV by reverse transcriptase polymerase chain reaction (PCR) and real-time PCR was positive in 40 of the 47 patients (85%) in whom the test was performed. Conclusions: None of the presenting symptoms or laboratory findings are pathognomonic for SARS. Even though cough developed in a majority of patients, it did not occur until later in the disease course, suggesting that a cough preceding or concurrent with the onset of fever is less likely to indicate SARS. While PCR for SARS-CoV appears to be the best early diagnostic test currently available, it is clear that better methods are needed to differentiate between SARS and non-SARS illness on initial presentation.

Fatty acid oxidation disorders and lipin-1 deficiency are the commonest genetic causes of rhabdomyolysis in children. We describe a lipin-1-deficient boy with recurrent, severe rhabdomyolytic episodes from the age of 4 years. Analysis of the LPIN1 gene that encodes lipin-1 revealed a novel homozygous frameshift mutation in exon 9, c.1381delC (p.Leu461SerfsX47), and complete uniparental isodisomy of maternal chromosome 2. This mutation is predicted to cause complete lipin-1 deficiency. The patient had six rhabdomyolytic crises, with creatine kinase (CK) levels up to 300,000 U/L (normal, 30 to 200). Plasma CK remained elevated between crises. A treatment protocol was instituted, with early aggressive monitoring, hydration, electrolyte replacement and high caloric, high carbohydrate intake. The patient received dexamethasone during two crises, which was well-tolerated and in these episodes, peak CK values were lower than in preceding episodes. Studies of anti-inflammatory therapy may be indicated in lipin-1 deficiency.

In Alzheimer's disease (AD), defects in essential metabolic processes for energy supply and phospholipid membrane function have been implicated in the pathological process. However, post-mortem investigations are generally limited to late stage disease and prone to tissue decay artifacts. In vivo assessments of high energy phosphates, tissue pH and phospholipid metabolites are possible by phosphorus MR spectroscopy (31P–MRS), but so far only small studies, mostly focusing on single brain regions, have been performed. Therefore, we assessed phospholipid and energy metabolism in multiple brain regions of 31 early stage AD patients and 31 age- and gender-matched controls using 31P–MRS imaging. An increase of phosphocreatine (PCr) was found in AD patients compared with controls in the retrosplenial cortex, and both hippocampi, but not in the anterior cingulate cortex. While PCr/inorganic phosphate and pH were also increased in AD, no changes were found for phospholipid metabolites. This study showed that PCr levels are specifically increased in regions that show early degeneration in AD. Together with an increased pH, this indicates an altered energy metabolism in mild AD., Highlights • Phosphocreatine and pH are increased in mild Alzheimer's disease. • Phosphocreatine increase occurs in early affected brain regions. • Brain energy metabolism may be altered in mild Alzheimer's disease. • Phospholipid and energy metabolites as well as pH, differ across brain regions.

Chaperone-assisted selective autophagy (CASA) is a tension-induced degradation pathway essential for muscle maintenance. Impairment of CASA causes childhood muscle dystrophy and cardiomyopathy. However, the importance of CASA for muscle function in healthy individuals has remained elusive so far. Here we describe the impact of strength training on CASA in a group of healthy and moderately trained men. We show that strenuous resistance exercise causes an acute induction of CASA in affected muscles to degrade mechanically damaged cytoskeleton proteins. Moreover, repeated resistance exercise during 4 wk of training led to an increased expression of CASA components. In human skeletal muscle, CASA apparently acts as a central adaptation mechanism that responds to acute physical exercise and to repeated mechanical stimulation.

Clinical application of doxorubicin (DOX), an anthracycline antibiotic with potent anti- tumor effects, is limited because of its cardiotoxicity. However, its pathogenesis is still not entirely understood. The aim of this paper was to explore the mechanisms and new drug targets to treat DOX-induced cardiotoxicity. The in vitro model on H9C2 cells and the in vivo models on rats and mice were developed. The results showed that DOX markedly decreased H9C2 cell viability, increased the levels of CK, LDH, caused histopathological and ECG changes in rats and mice, and triggered myocardial oxidative damage via adjusting the levels of intracellular ROS, MDA, SOD, GSH and GSH-Px. Total of 18 differentially expressed microRNAs in rat heart tissue caused by DOX were screened out using microRNA microarray assay, especially showing that miR-140-5p was significantly increased by DOX which was selected as the target miRNA. Double-luciferase reporter assay showed that miR-140-5p directly targeted Nrf2 and Sirt2, as a result of affecting the expression levels of HO-1, NQO1, Gst, GCLM, Keap1 and FOXO3a, and thereby increasing DOX-caused myocardial oxidative damage. In addition, the levels of intracellular ROS were significantly increased or decreased in H9C2 cells treated with DOX after miR-140-5p mimic or miR-140-5p inhibitor transfection, respectively, as well as the changed expression levels of Nrf2 and Sirt2. Furthermore, DOX- induced myocardial oxidative damage was worsened in mice treated with miR-140-5p agomir, and however the injury was alleviated in the mice administrated with miR-140-5p antagomir. Therefore, miR-140-5p plays an important role in DOX-induced cardiotoxicity by promoting myocardial oxidative stress via targeting Nrf2 and Sirt2. Our data provide novel insights for investigating DOX-induced heart injury. In addition, miR-140-5p/ Nrf2 and miR-140-5p/Sirt2 may be the new targets to treat DOX-induced cardiotoxicity., Graphical abstract fx1, Highlights • DOX significantly increased the levels of miR-140-5p in vitro and in vivo. • MiR-140-5p aggravated DOX-induced cardiotoxicity. • MiR-140-5p promoted myocardial oxidative stress. • MiR-140-5p directly targeted Nrf2 and Sirt2. • MiR-140-5p may be the new target of DOX-induced cardiotoxicity.