Major Organ Damage Research Articles

Lipid Nanoparticle-Mediated Oip5-as1 Delivery Preserves Mitochondrial Function in Myocardial Ischemia/Reperfusion Injury by Inhibiting the p53 Pathway.

Myocardial ischemia/reperfusion (MI/R) injury, a major contributor to poor prognosis in patients with acute myocardial infarction, currently lacks effective therapeutic strategies in clinical practice. The long noncoding RNA (lncRNA) Oip5-as1 can regulate various cellular processes, such as cell proliferation, differentiation, and survival. Oip5-as1 may have potential as a therapeutic target for MI/R injury as its upregulated expression has been associated with reduced infarct size and improved cardiac function in animal models, although how to effectively and safely overexpress Oip5-as1 in vivo remains unclear. Lipid nanoparticles (LNPs) are a versatile technology for targeted drug delivery in numerous therapeutic applications. Herein, we aimed to assess the therapeutic efficacy and safety of LNPs coloaded with Oip5-as1 and a cardiomyocyte-specific binding peptide (LNP@Oip5-as1@CMP) in a murine model of MI/R injury. To achieve this, LNP@Oip5-as1@CMP was synthesized via ethanol injection method. The structural components of LNP@Oip5-as1@CMP were physicochemically analyzed. A hypoxia/reoxygenation (H/R) model in HL-1 cells and coronary artery ligation in mice were used to simulate MI/R injury. Our results demonstrated that LNPs designed for cardiomyocyte targeting and efficient Oip5-as1 delivery were successfully synthesized. In HL-1 cells, LNP@Oip5-as1@CMP treatment significantly reduced mitochondrial apoptosis caused by H/R injury. In the murine MI/R model, the intravenous administration of LNP@Oip5-as1@CMP significantly decreased myocardial infarct size and improved cardiac function. Mechanistic investigations revealed that Oip5-as1 delivery inhibited the p53 signaling pathway. However, the cardioprotective effects of Oip5-as1 were abrogated by administrating Nutlin-3a, a p53 activator. Furthermore, no signs of major organ damage were detected after LNP@Oip5-as1@CMP injection. Our study reveals the therapeutic potential of LNPs for targeted Oip5-as1 delivery in mitigating MI/R injury. These findings pave the way for advanced targeted treatments in cardiovascular diseases, emphasizing the promise of lncRNA-based therapies.

A novel mechanism of major ginsenosides from Panax ginseng against multiple organ aging in middle-aged mice: Phosphatidylcholine-myo-inositol metabolism based on metabolomic analysis

Aging is a complex, degenerative process associated with various metabolic abnormalities. Ginsenosides (GS) is the main active components of Panax ginseng, which has anti-aging effects and improves metabolism. However, the anti-aging effect and the mechanism of GS in middle-aged mice has not been elucidated. In this study, GS after 3-month treatment significantly improved the grip strength, fatigue resistance, cognitive indices, and cardiac function of 15-month-old mice. Meanwhile, GS treatment reduced the fat content and obviously inhibited histone H2AX phosphorylation at Ser 139 (γ-H2AX), a marker of DNA damage in major organs, especially in the heart and liver. Further, the correlation analysis of serum metabolomics combined with aging phenotype suggested that myo-inositol (MI) upregulated by GS was positively correlated with left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS), the main indicators of cardiac function. More importantly, liver tissue metabolomic analysis showed that GS increased MI content by promoting the synthesis pathway from phosphatidylcholine (PC) to MI for the inhibition of liver aging. Finally, we proved that MI reduced the percentage of senescence-associated β-galactosidase staining, γ-H2AX immunofluorescence staining, p21 expression, and the production of reactive oxygen species in H2O2-induced cardiomyocytes. These results suggest that GS can enhance multiple organ functions, especially cardiac function for promoting the healthspan of aging mice, which is mediated by the conversion of PC to MI in the liver and the increase of MI level in the serum. Our study might provide new insights into the potential mechanisms of ginsenosides for prolonging the healthspan of natural aging mice.

Early prediction of Sepsis: A comparative assessment on patients’ covariates

The early prediction of Sepsis is a highly important task regarding its impact on the mortality ratio for ICU patients. The earlier the Sepsis occurrence is foreseen, the sooner the patient can have the chance to be intervened and the patient can be prevented from getting major organ damage. However, it is a challenging task for healthcare professionals even though they have expert knowledge and standardized prediction scoring systems. Therefore the machine learning models that evaluate the patients’ regularly measured covariates as features, and make predictions by utilizing them have been acknowledged and have gathered attention to automatize and improve the early prediction process. However, the nature of the problem of early prediction of Sepsis requires patients to make an estimation based on past measurements, and reliable estimation cannot be made with the use of instant measurement results alone. To this end, additional features obtained by recent measurements have been proposed to be involved in the machine learning model’s estimation process by basing a specific dataset with a specific definition of the illness. This study broadly evaluates the previously proposed features to measure the effectiveness of their single and joint use. Unlike the previous research, this evaluation was done by multiple datasets, different types of additional features, and various machine learning methods for validation purposes. Experimental results have proved that the proposed machine learning model has a significant effect on early prediction, and the best improvement is obtained with the XGBoost classifier. However, it should be noted that quantity, especially the quality of the features used to feed the model has a critical effect on the model’s performance. Consequently, using additional features enhances the model’s performance dramatically.

Biogenic crocetin-crosslinked chitosan nanoparticles with high stability and drug loading for efficient radioprotection

The risk of radiation exposure increases with the development of nuclear energy and technology, and radiation protection receives more and more attention from public health and safety. However, the numerous adverse effects and low drug utilization limit the practical applications of radioprotective agents. In this study, we developed a biogenic crocetin-crosslinked chitosan nanoparticle with high stability and drug loading for efficient radioprotection. In detail, the nanoparticles were prepared using the natural antioxidant crocetin as a cross-linking reagent in amidation reactions of chitosan and mPEG-COOH. The nanoparticles exhibit a quick scavenging ability for common reactive oxygen species and reactive nitrogen in vitro. Meanwhile, cellular experiments demonstrate the good biocompatibility of the nanoparticles and the alleviation of radiation damage by scavenging reactive oxygen species, reducing apoptosis, and inhibiting DNA damage, etc. Importantly, the nanoparticles are effective in mitigating oxidative damage in major organs and maintaining peripheral blood cell content. In addition, they perform better radioprotective properties than free drug due to the significant extension of the blood half-life of crocetin in vivo from 10 min to 5 h. This work proposes a drug-crosslinking strategy for the design of a highly efficient radioprotective agent, which exhibits a promising prospect in the fields of nuclear emergency and public health.

Avacopan's potential to decrease MPO-ANCA titres concurrent with ameliorated activity in ANCA-associated vasculitis.

Avacopan, an orally administered C5a receptor antagonist, is effective in microscopic polyangiitis via the inhibition of neutrophil priming induced by C5a. However, the exact effect of avacopan on the production of myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA) is yet to be clearly established. This report presents a microscopic polyangiitis patient without major organ damage where high levels of MPO-ANCA persisted with high-dose steroid therapy and azathioprine, but the addition of avacopan led to a reduction in MPO-ANCA titres. The present case implies that avacopan-mediated inhibition of C5a may lead to a reduction in MPO-ANCA levels, thereby potentially ameliorating the pathophysiology of ANCA-associated vasculitis. Nevertheless, the impact of avacopan on MPO-ANCA production cannot be asserted solely based on this report; therefore, further examination is necessary through subgroup analysis using data from larger-scale studies.

Bifunctional molecular probe targeting tumor PD-L1 enhances anti-tumor efficacy by promoting ferroptosis in lung cancer mouse model

PurposeImmune checkpoint inhibitors (ICIs) targeting tumor-specific PD-1/PD-L1 significantly improve the overall survival rate of patients with advanced cancer by reactivating the immune system to attack cancer cells. To explore their tumor killing effect, we used the radionuclide iodine-131 (131I) to label the anti-PD-L1 antibody Atezolizumab (131I-PD-L1 mAb). MethodWe prepared the radioimmunoassay molecular probe 131I-PD-L1 mAb by the chloramine-T method and evaluated its affinity using Lewis lung cancer (LLC) cells. The uptake of 131I-PD-L1 mAb by transplanted tumors was examined through SPECT and its in vivo distribution. We then compared the in vitro and in vivo anti-tumor efficacy of groups treated with control, PD-L1 mAb, 131I-PD-L1 mAb, and 131I-PD-L1 mAb + PD-L1 mAb combined treatment. We performed H&E staining to examine the changes in tumor, as well as the damage in major tissues and organs caused by potential side effects. The anti-tumor mechanism of 131I-PD-L1 mAb was analyzed by Western blot, RT-qPCR and immunohistochemistry (IHC). Result131I-PD-L1 mAb was highly stable and specific, and easily penetrated into tumor. 131I-PD-L1 mAb suppressed cancer cell proliferation in vitro, and inhibited tumor growth in vivo by inducing ferroptosis, thus prolonging the survival of experimental animals while demonstrating biological safety. ConclusionTherefore, our study suggested that 131I-PD-L1 mAb affected the expression of tumor-related factors through β-rays and thus promoted ferroptosis in tumor. Combined treatment showed better anti-tumor effect compared to single ICI treatment.

Prognostic significance of lymphocytic foci composition in minor salivary gland biopsies for severe disease flare and severity in Sjögren's syndrome: a 3-year follow-up cohort study.

This was an ambispective cohort study evaluating the prognostic significance of lymphocytic foci and its lymphoid composition in minor salivary gland biopsy (MSGB) for short-term disease flare and severity in Sjögren's syndrome (SS). The inclusion criteria comprised individuals meeting the ACR/EULAR 2016 criteria who underwent MSGB with an infiltration of more than 50 lymphocytes and received clinical diagnosis between September 2017 and December 2018. Patients with inadequate biopsy samples were excluded. The number of lymphocytic foci and their lymphoid composition in MSGB were assessed using immunofluorescence staining. Major organ damage and improvements in the EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) were measured. Statistical analyses, including Cox and linear regressions, were conducted. A total of 78 patients with at least one lymphocytic focus were included in the study. The presence of higher T-cell counts in lymphocytic foci in MSGB was associated with severe disease flare, and a logarithmic transformation of T-cell count indicated increased risk (HR 1.96, 95% CI 0.91-4.21). Improvements in the ESSDAI were associated with higher total lymphocyte count and T- and B-cell numbers in the lymphoid composition of the lymphocytic foci. Seropositive patients exhibited higher T CD4+ cell numbers. Correlation analysis showed negative associations between age and lymphocytic foci and the T-cell count. Positive correlations were observed between antinuclear antibody (ANA) titers and total lymphocyte numbers. Patients with a higher number of T cells in the lymphocytic infiltrates of lymphocytic foci may have a two-fold risk of severe disease flare. The number of B cells and T CD4+ cells in the lymphocytic infiltrates of lymphocytic foci showed a weak but positive relation with the ESSDAI improvement during follow-up. Age and seropositivity appeared to influence the lymphoid composition of the lymphocytic foci.

Efficient type Ⅰ and type Ⅱ ROS generated aggregation-induced emission photosensitizer for mitochondria targeted photodynamic therapy

Fluorescence imaging-guided photodynamic therapy (PDT) is considered as an ideal alternative strategy to treat tumors. However, insufficient supply of oxygen in solid tumor tissue, aggregation-caused quenching (ACQ) of photosensitizers (PSs), poor targeting-specificity of cancer cells and short wavelengths of emission are representative obstacles for effective PDT. In this paper, three D-π-A structured PSs TSB-OH, TSBPy-OH, TSBPy-DNT with aggregation induced emission (AIE) properties and integrated type I and type II ROS generation were synthesized by modulating distinct acceptor units. Among them, TSBPy-OH is optimal with multiple advantages including near-infrared emission, good biocompatibility, remarkably intracellular ROS production ability, mitochondria targeting capability inducing cell apoptosis and enhancing PDT, and long-term tumor retention ability for imaging-guided photodynamic therapy. More importantly, efficient in vitro cancer cells damage, in vivo tumor ablation and ignorable damage in major organs during PDT are demonstrated, suggesting potential capability of TSBPy-OH in safe and effective fluorescence imaging-guided PDT. This successful example of AIE theranostics design would provide a reference for the modification of D-π-A structure organic AIEgens.

Reactive A1 Astrocyte-Targeted Nucleic Acid Nanoantiepileptic Drug Downregulating Adenosine Kinase to Rescue Endogenous Antiepileptic Pathway.

Resistance to traditional antiepileptic drugs is a major challenge in chronic epilepsy treatment. MicroRNA-based gene therapy is a promising alternative but has demonstrated limited efficacy due to poor blood-brain barrier permeability, cellular uptake, and targeting efficiency. Adenosine is an endogenous antiseizure agent deficient in the epileptic brain due to elevated adenosine kinase (ADK) activity in reactive A1 astrocytes. We designed a nucleic acid nanoantiepileptic drug (tFNA-ADKASO@AS1) based on a tetrahedral framework nucleic acid (tFNA), carrying an antisense oligonucleotide targeting ADK (ADKASO) and A1 astrocyte-targeted peptide (AS1). This tFNA-ADKASO@AS1 construct effectively reduced brain ADK, increased brain adenosine, mitigated aberrant mossy fiber sprouting, and reduced the recurrent spontaneous epileptic spike frequency in a mouse model of chronic temporal lobe epilepsy. Further, the treatment did not induce any neurotoxicity or major organ damage. This work provides proof-of-concept for a novel antiepileptic drug delivery strategy and for endogenous adenosine as a promising target for gene-based modulation.

Metabolic syndrome as risk factor for left ventricular hypertrophy in children with chronic kidney disease.

The metabolic syndrome (MS), a cluster of clinical and biochemical abnormalities including insulin resistance, dyslipidemia and hypertension, is often diagnosed in chronic kidney disease (CKD) children. Left ventricular hypertrophy (LVH) is a major target organ damage in hypertension and an important cardiovascular risk factor in CKD patients. We aimed to identify the most significant risk factors of LVH in children with CKD. Children with CKD stage 1-5 were enrolled in the study. MS was diagnosed according to De Ferranti (DF) as ≥3 from 5 criteria. Ambulatory blood pressure measurements (ABPM) and echocardiographic evaluation were performed. LVH was defined as ≥95th percentile of LV mass index related to height and age. Clinical and laboratory parameters included: serum albumin, Ca, HCT, cystatin C, creatinine, estimated glomerular filtration rate (eGFR) based on Schwartz formula, triglycerides, high-density lipoprotein (HDL), proteinuria, BMI standard deviation score (SDS), height SDS, waist circumference, ABPM data. 71 children (28 girls/43 boys) with median age 14.05 (25%-75%:10.03-16.30) years and median eGFR 66.75 (32.76-92.32) ml/min/1.73m2 were evaluated. CKD stage 5 was diagnosed in 11 pts (15.5%). MS (DF) was diagnosed in 20 pts (28.2%). Glucose ≥ 110 mg/dL was present in 3 pts (4.2%); waist circumference ≥75th pc in 16 pts (22.5%); triglycerides ≥ 100 mg/dL in 35 pts (49.3%); HDL < 50mg/dL in 31 pts (43.7%) and BP ≥ 90th pc in 29 pts (40.8%), respectively. LVH was detected in 21 (29.6%) children. In univariate regression the strongest risk factor for LVH was CKD stage 5 (OR 4.9, p=0.0019) and low height SDS (OR 0.43,p=0.0009). In stepwise multiple logistic regression analysis (logit model) of the most important risk factors for LVH in CKD children, only three were statistically significant predictors: 1)MS diagnosis based on DF criteria (OR=24.11; 95%CI 1.1-528.7; p=0.043; Chi2=8.38,p=0.0038); 2), high mean arterial pressure (MAP SDS) in ABPM (OR=2.812; 95%CI 1.057-7.48; p=0.038;Chi2=5.91, p=0.015) and 3) low height SDS (OR=0.078; 95%CI 0.013-0.486;p=0.006; Chi2=25.01, p<0.001). In children with chronic kidney disease LVH is associated with the cluster of multiple factors, among them the components of MS, hypertension, stage 5 CKD and growth deficit were the most significant.

Two birds with one stone: triple negative breast cancer therapy by PtCo bimetallic nanozyme coated with gemcitabine-hyaluronic acid-polyethylene glycol

For the treatment of triple-negative breast cancer (TNBC), without expression of estrogen, progesterone and HER2 receptors, specific treatment guideline is still under criticism, especially in tumor hypoxia. But assuming the molecular similarity of TNBC with breast cancer gene-1-related cancers, gemcitabine may be used in TNBC treatment on the nanozyme platform combined with photodynamic therapy (PDT). After designing the nanozyme with four components, platinum–cobalt: with catalase/peroxidase capabilities, hyaluronic acid: nanozyme targeting by interacting with CD44 receptor, poly[ethylene glycol]: water-soluble macromolecule for immune escape, and Gem: antitumor drug, its physicochemical properties was investigated by thermogravimetric, X-ray diffraction and energy dispersive X-ray, and therapeutic effects in in vitro and in vivo. The results show that platinum–cobalt@gemcitabine-hyaluronic acid-polyethylene glycol (PtCo@Gem-HA-PEG) especially synergized with PDT has high toxicity on 4T1 cells and tumor by enhancing the catalase-/peroxidase-like activities to produce O2, O2•− and •OH, and increase the intracellular free radicals. PtCo@Gem-HA-PEG inhibits tumor development by increasing drug accumulation in the tumor and enhancing apoptotic mechanisms through synergistic activity with PDT. Nevertheless, the major organ damage confirmed by the histological method in the long-term application of PtCo@Gem-HA-PEG, makes their application challenging due to permanent catalytic activity. However, results of improved drug permeability based on reduced hypoxia, higher drug retention, and enzyme-like activity that could be synergized with other therapeutic approaches like a PDT, have made their use attractive. Hence, this study provides a promising path in the TNBC treatment by nanozymes, which requires further toxicological investigations.Graphic

PREDICTORS OF SEVERE SYSTEMIC LUPUS ERYTHEMATOSUS

The aim of the study was to assess the nature of lesions and to identify risk factors of lesions in our group of patients with SLE. A retrospective review of charts and case histories in the Internal Medicine Department of the SamMU’s clinic was carried out on a group of 75 patients with SLE. 225 people were included in this study: 75 in the main group (cases) and 150 in the control group (healthy controls). The results show that the presence of neuropsychiatric manifestations is a significant risk factor for lesions. Other likely risk factors for lesions include younger age at diagnosis, more major organ damage, more exacerbations and serious infections.

Analysis of multiple organ function damage in patients with severe COVID-19 pneumonia.

This study aims to analyze the changes and significance of organ function indices in patients with severe Coronavirus Disease 2019 (COVID-19) pneumonia for prediction of major organ damages and guiding treatment schemes. 63 patients with severe COVID-19 pneumonia were selected as the severe group and 73 patients with mild syndromes were selected as the mild group. SAS9.4 software was used for statistical analysis of the data. Levels of ALT, AST, cTnI, Cr, PT, APTT and Ddimer of the severe group were significantly higher while PLT was lower than those of the mild group. The data of all quantitative variables were converted into categorical variables. Significantly higher levels of AST, ALB, D-dimer and higher proportion of bilateral lung involvement were observed from the severe group comparing to those in the mild group, while the difference in the other indices between the two groups was insignificant in statistical perspective. There are significant differences in the levels of multiple organ function indices between the severe group and the mild group of patients with COVID-19 pneumonia infection. Through examining the relevant indices, conditions of patients' multiple organ function damage could be predicted and used as guidance of treatment.

Doxorubicin-liposome combined with clodronate-liposome inhibits hepatocellular carcinoma through the depletion of macrophages and tumor cells

Macrophages in the liver have capacities of capturing and phagocytosing nanocarriers. Macrophages also play an important role in the inflammatory microenvironment and in the tumorigenesis, development and progression of hepatocellular carcinoma (HCC). Several studies have shown that depletion of macrophages is a viable strategy for drug delivery and tumor microenvironment regulation. We prepared liposomes containing doxorubicin and clodronate using an ammonium sulfate gradient and thin film hydration method. The repressive therapeutic effects of liposomes were compared by intrasplenic injection at different stages of a primary HCC model induced by diethylnitrosamine (DEN) in rats. Doxorubicin-liposome (DOX-LIP) and clodronate-liposome (CL-LIP) about 180–200 nm were successfully prepared and characterized. We found that DOX-LIP combined with CL-LIP could effectively inhibit the occurrence and development of liver cancer without major organ damage and side effects. The combination of doxorubicin and clodronate liposomes notably decreased hepatic CD68 + macrophages, enriched DOX in plasma and accumulated it for a long time in the liver and spleen, thus improving the tumor microenvironment, inhibiting the activation of hepatic progenitor cells (HPCs) and promoting the apoptosis of tumor cells, and finally producing the inhibitory and therapeutic effects of HCC in rats. Results of this study were expected to provide a new prospect for the chemotherapy of HCC.

Phytochemical and toxicological evaluation of Zephyranthes citrina

Drugs obtained from medicinal plants have always played a pivotal role in the field of medicine and to identify novel compounds. Safety profiling of plant extracts is of utmost importance during the discovery of new biologically active compounds and the determination of their efficacy. It is imperative to conduct toxicity studies before exploring the pharmacological properties and perspectives of any plant. The present work aims to provide a detailed insight into the phytochemical and toxicological profiling of methanolic extract of Zephyranthes citrina (MEZ). Guidelines to perform subacute toxicity study (407) and acute toxicity study (425) provided by the organization of economic cooperation and development (OECD) were followed. A single orally administered dose of 2000 mg/kg to albino mice was used for acute oral toxicity testing. In the subacute toxicity study, MEZ in doses of 100, 200, and 400 mg/kg was administered orally, consecutive for 28 days. Results of each parameter were compared to the control group. In both studies, the weight of animals and their selected organs showed consistency with that of the control group. No major toxicity or organ damage was recorded except for some minor alterations in a few parameters such as in the acute study, leukocyte count was increased and decreased platelet count, while in the subacute study platelet count increased in all doses. In the acute toxicity profile liver enzymes Alanine aminotransferase (ALT), as well as, aspartate aminotransferase (AST) were found to be slightly raised while alkaline phosphatase (ALP) was decreased. In subacute toxicity profiling, AST and ALT were not affected by any dose while ALP was decreased only at doses of 200 and 400 mg/kg. Uric acid was raised at a dose of 100 mg/kg. In acute toxicity, at 2000 mg/kg, creatinine and uric acid increased while urea levels decreased. Therefore, it is concluded that the LD50 of MEZ is more than 2000 mg/kg and the toxicity profile of MEZ was generally found to be safe.

Cardiac involvement in Fabry disease - A non-invasive assessment and the role of specific therapies.

Fabry disease is an X-linked inherited metabolic disorder due to the pathogenic mutation of the GLA gene, which codes lysosomal enzyme alpha-galactosidase A. The resultant accumulation of glycosphingolipids causes various systemic symptoms in childhood and adolescence, and major organ damage in adulthood. Cardiac involvement is important as the most frequent cause of death in Fabry disease patients. Progressive left ventricular hypertrophy with varying degrees of contractile dysfunction as well as conduction abnormalities and arrhythmias are typical cardiac features, and these findings can be evaluated in detail via non-invasive modalities, such as an electrocardiogram, echocardiography and cardiac magnetic resonance. In addition, specific therapies of enzyme replacement therapy and pharmacological chaperone therapy are available, and their beneficial effects on cardiac involvement have been reported. This minireview highlights recent evidence concerning non-invasive modalities for assessing cardiac involvement in Fabry disease and the effects of enzyme replacement therapy and pharmacological chaperone therapy on the findings of those modalities.

COVID-19 postacute care major organ damage: a systematic review

BackgroundMajor organ complications have been reported in patients hospitalised for COVID-19; most studies lacked controls.ObjectiveExamine major organ damage postdischarge among adults hospitalised for COVID-19 versus non-COVID-19 controls.Data sourcesMEDLINE, Embase and Cochrane Library from 1 January 2020 to 19 May 2021.Study eligibility criteriaEnglish language studies of adults discharged from hospital for COVID-19; reporting major organ damage. Single review of abstracts; independent dual review of full text.Study appraisal and synthesis methodsStudy quality was assessed using the Joanna Briggs Institute Appraisal Checklist for Cohort Studies. Outcome data were not pooled due to heterogeneity in populations, study designs and outcome assessment methods; findings are narratively synthesised.ResultsOf 124 studies in a full evidence report, 9 included non-COVID controls and are described here. Four of the nine (three USA, one UK) used large administrative databases. Four of the remaining five studies enrolled <600 COVID-19 patients. Mean or median age ranged from 49 to 70 years with 46%–94% male and 48%–78% White race; 10%–40% had been in intensive care units. Follow-up ranged from 4 weeks to 22 weeks postdischarge. Four used hospitalised controls, three non-hospitalised controls and two were unclear. Studies used various definitions of, and methods to assess, major organ damage outcomes. While the magnitude of effect differed across studies, incident cardiac, pulmonary, liver, acute and chronic kidney, stroke, diabetes, and coagulation disorders were consistently greater in adults hospitalised for COVID-19 compared with non-COVID-19 controls.LimitationsApplicability to subgroups (age, gender, COVID-19 severity, treatment, vaccination status) and non-hospitalised patients is unknown.Conclusions and implications of key findingsPostacute COVID-19 major organ damage is common and likely higher than controls. However, there is substantial uncertainty. More consistent reporting of clinical outcomes and pre-COVID health status along with careful selection of control groups are needed to address evidence gaps.PROSPERO registration numberCRD42020204788.

Evaluation of the 2019 EULAR/ACR classification criteria for systemic lupus erythematosus in children and adults

To evaluate the performance of the 2019 European League Against Rheumatism/American College of Rheumatology (EULAR/ACR-2019) classification criteria for systemic lupus erythematosus (SLE) compared with the ACR-1997 and Systemic Lupus International Collaborating Clinics (SLICC) 2012 criteria in childhood-onset SLE (cSLE) and adult-onset SLE (aSLE) patients. We conducted a retrospective study of SLE patients (221 children and 221 adults) and controls (214 children and 214 adults) with defined rheumatic diseases to establish each ACR-1997, SLICC-2012, and EULAR/ACR-2019 criterion fulfilled. Demographic, clinical, and laboratory features were evaluated through chart review. For cSLE, sensitivities of ACR-1997, SLICC-2012, and EULAR/ACR-2019 criteria were 63.3%, 94.6%, and 98.2%, with specificities 99.5%, 98.6%, and 93.5%, respectively. For aSLE, sensitivities of ACR-1997, SLICC-2012, and EULAR/ACR-2019 criteria were 72.9%, 96.8%, and 99.1%, with specificities 97.2%, 92.5%, and 90.2%, respectively. When including only ANA positive patients, receiver operating characteristics analysis demonstrated that the cutoff value for EULAR/ACR-2019 criteria in cSLE and aSLE patients was 13 (sensitivity, 92.2%; specificity, 93.1%) and 10 (sensitivity, 99.1%; specificity, 85.1%), respectively. Twelve cSLE patients and seven aSLE patients only met the EULAR/ACR-2019 criteria, among whom eleven and four cases had single organ involvement, respectively. The EULAR/ACR-2019 criteria showed similar sensitivity to cSLE and aSLE patients and was more sensitive than ACR-1997 and SLICC-2012 criteria, allowing earlier recognition of patients with single or major organ involvement. The adoption of a EULAR/ACR total score ≥ 13 in this study, instead of the initially proposed ≥ 10 points, could further improve the diagnostic performance of the EULAR/ACR-2019 criteria in cSLE. Key Points • Sensitivity of the EULAR/ACR-2019 criteria was high in both cSLE and aSLE patients. • The EULAR/ACR-2019 criteria allowed earlier recognition of patients with single or major organ damage. • The adoption of a EULAR/ACR total score ≥13 could further improve the diagnostic performance of the EULAR/ACR-2019 criteria in cSLE.

P822: A PHASE 1 SINGLE ASCENDING DOSE STUDY OF CAN106, A LONG-ACTING ANTI-C5 COMPLEMENT MONOCLONAL ANTIBODY IN CLINICAL DEVELOPMENT FOR PNH AND OTHER COMPLEMENT-MEDIATED DISEASES

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired genetic disorder caused by clonal mutations in the PIGA gene. Deficiency of PIGA protein renders erythrocytes susceptible to complement-mediated destruction, causing intravascular and extravascular hemolysis, which can lead to anemia, fatigue, thromboembolism, major organ damage, and death. Despite the approval of one anti-C3 and two anti-C5 therapies for PNH, high treatment costs limit market access in many countries. CAN106 is a novel anti-C5 monoclonal antibody designed for optimal pH-dependent binding to C5 and enhanced binding to FcRN to increase intracellular recycling and prolong its half-life. Aims: This first-in-human Phase 1 study aimed to evaluate the single-dose safety and tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity of CAN106. Methods: This was a randomized, double-blind, placebo-controlled, single-ascending-dose study. We enrolled 31 healthy adult subjects at a single site in Singapore who received CAN106 (mg/kg) or placebo at one of the following 6 doses (mg/kg) and ratios: (0.25, n=1:0; 0.75, n=1:0; 2, n=3:2; 4, n=6:2; 8, n=6:2 or 12, n=6:2). The primary endpoint was the incidence of adverse events overall and by intensity, seriousness, type, and relatedness to study drug. Secondary endpoints were the pharmacokinetic characterization of CAN106, the pharmacodynamic effects on free C5 (target engagement) and CH50 (serum hemolytic activity), and the incidence of anti-drug antibodies. The original study duration of 196 days was shortened to 112 days based upon the observed half-life of CAN106 and the return of CH50 to normal values. Results: The mean age of subjects was 34 years, and 97% were male. All 31 subjects completed the study. Seven CAN106 subjects experienced 20 treatment-emergent adverse events (TEAEs), and three placebo subjects experienced five TEAEs. Most TEAEs were mild and not related to CAN106, and all resolved without any sequelae. Three CAN106 subjects experienced seven drug-related TEAEs at the two highest doses. Most were mild, none was serious, and all resolved without any sequelae. These events included a moderate infusion-related reaction that resolved upon discontinuing treatment; mild dizziness; and mild elevations in ALT, AST, hemoglobin, hematocrit, and RBC. CAN106 exposure (Cmax and AUC) was dose-proportional, linear, and had low inter-subject variability (<20% CV). The terminal elimination half-life was approximately 32 days. CAN106 led to dose-dependent reductions in free C5 and CH50 within 24 hours. At the 8 and 12 mg/kg doses, all subjects showed >99% reduction in free C5 and >90% inhibition of CH50, with the latter sustained for 2 to 4 weeks. Two subjects in the 4 mg/kg cohort tested positive for anti-drug antibodies at single time points (pre-dose and Day 28). Summary/Conclusion: CAN106 was safe and well-tolerated at single doses up to 12 mg/kg in healthy adult subjects. The dose-exposure relationship was linear, and the 32-day half-life in healthy subjects was similar to that of ravulizumab, which is dosed every 8 weeks in patients, suggesting the potential for an extended dosing interval. CAN106 led to rapid, dose-dependent reductions in free C5 and CH50, and at the two highest doses, achieved complete and sustained complement blockade (>90% inhibition of CH50) for up to 4 weeks. These promising results support further clinical development of CAN106 in PNH and other complement-mediated diseases.

Statutory safety quarantine and its compensation of consumer’s long-term intake of food additives

To improve the sensory properties of food, prevent deterioration and extend shelf life, increase the variety of food, enhance the convenience of food, or increase the variety of food are the functions and purposes of food additives such as Ractopamine added into fodder feeding cattle in order to produce more feed efficiency and growth promotion instead of fatty tissues. Consumers feel Ractopamine meat more delicious because of less fatty tissues, and you can spend less money if you want to buy lean meat of the same weight. However, Taiwan consumers worry about Ractopamine harmful side effect. Therefore, we have to find several medical scientific evidences to prove the causal relationship between Ractopamine and human major organ damage in order to rule out potentially many variables involved related to consumption of specific products. It will violate the desire of American farmers wishing to earn money from exporting beef and pork if excessive Ractopamine residual dosage or non-compliance with international standards. For example, the United States does not meet EU standards. For methodology, we suggest that patient’s medical record including the frequency of consumption of Ractopamine meat in hospital or at private clinic, then help patient to do Rapid Test which is provided by BALLYA. It can be the evidence to claim compensation. Concerning our paper’s contribution, although American cattle have more meat and less fat, they will certainly be rejected by the EU due to Ractopamine. Our article not only promotes food safety, but also hopes to express the concerns of foreign consumers to American farmers who may opt for different ways of food additives. We expect that concerning law not only deals with follow-up claims for compensation afterwards, but also has the function of assessing risks and preventing personal injury. • The intake of food additive by swine and cattle leads to residual in pork and beef. • Long-term intake causes adverse effects to consumers’ lung and heart. • If food additive is overdosing, the government can apply “off-shelves” precautionary measurement. • By urine test, we can find if remaining residual is overdosing. .● If the test is positive, the consumer should be compensated by law; if negative, no compensation.