Construction of a Label-Detection Integrated Visual Probe to Reveal the Double-Edged Sword Principle of Ferroptosis in Liver Injury.

Ferroptosis has been confirmed as a potential mediator and an indicator of the severity of liver injury. Despite the fruitful results, there are still two deficiencies in the research on the association between ferroptosis and liver injury. First, iron ions are usually selected as the target bioanalyte, but its detection based on a fluorescent probe is interfered with by specific chemical reaction mechanisms, leading to low sensitivity and poor physiological stability. Second, more efforts were focused on the harmful effects of ferroptosis on liver injury and less involved in the therapeutic value of ferroptosis for liver injury. Hence, in this work, we proposed a new nonreactive analyte (mitochondrial viscosity) as an analysis marker, which can circumvent the challenges caused by specific reaction mechanisms of iron ions. Meanwhile, we constructed a novel label-detection integrated visual probe (VPF) to explore the feasibility of ferroptosis in the treatment of liver injury. As expected, we not only successfully traced the dynamic changes in mitochondrial viscosity but also visualized the changes in cell morphology during induced and inhibited ferroptosis. Conspicuously, this work revealed that liver injury can be alleviated by regulating ferroptosis, confirming the therapeutic value of ferroptosis in liver injury. In addition, a complex biological communication network between ferroptosis and liver injury was constructed by western blotting, providing an important theoretical mechanism for revealing their double-edged sword relationship. This study not only provides a new strategy for studying the complex relationship between ferroptosis and liver injury but also facilitates the future treatment of liver injury.

Preconception episodes of severe hypoglycemia and risk of adverse pregnancy outcomes in pregnant women with type 1 diabetes mellitus.

AIMS: To explore the relationship between preconception severe hypoglycemia (PSH) and pregnancy outcomes in pregnancies complicated with type 1 diabetes mellitus (T1DM). MATERIALS AND METHODS: In this multicenter prospective cohort study, women with pregestational T1DM were stratified by episodes of severe hypoglycemia within 1 year before conception: No PSH, sporadic PSH (1-6 times/year), and recurrent PSH (>6 times/year). We analysed the predictive ability of PSH for maternal and neonatal outcomes using log-binomial regression models and receiver operating characteristic (ROC) curve. RESULTS: Of the 124 women studied, 37.1% experienced at least one episode of severe hypoglycemia preconception. In the multiple adjusted regression models, recurrent PSH was significantly associated with increased incidence of preeclampsia (RR 17.59, 95% CI: 2.89-150.62, p for trend = 0.007), preterm birth (RR 6.34, 95% CI: 1.22-40.63, p for trend = 0.027), neonatal hypoglycemia (RR 4.52, 95% CI: 1.14-17.16, p for trend = 0.017), neonatal hyperbilirubinemia (RR 4.12, 95% CI: 1.11-15.56, p for trend = 0.004), and composite neonatal outcome (RR 3.85, 95% CI: 1.01-19.61, p for trend = 0.003). In the ROC analysis, PSH predicted preeclampsia, preterm birth, neonatal hypoglycemia, neonatal hyperbilirubinemia, and composite neonatal outcome with areas under the ROC curve all ≥0.6. CONCLUSIONS: Recurrent preconception severe hypoglycemia is associated with increased risks of adverse outcomes in pregnant women with T1DM.

Health-related quality of life in pregnant women with type 1 diabetes and associations with maternal and neonatal complications.

PURPOSE: Preexisting type 1 diabetes is a stressful situation for women in pregnancy. We aimed to evaluate health-related quality of life (HRQoL) during pregnancy in women with type 1 diabetes and examine the association between HRQoL and pregnancy outcomes. METHODS: This multicenter prospective cohort study involved 115 pregnant women with type 1 diabetes from 11 participating centers in China. HRQoL was investigated in three trimesters using European Quality-of-life 5-Dimension 5-Level questionnaire (EQ-5D-5 L). Chinese time trade-off value method was used to calculate the EQ-5D-5 L score. Multivariable logistic regression model was used to evaluate the effect of HRQoL on maternal and neonatal outcomes. Receiver operating characteristic curves and distribution-based methods were employed to estimate minimally important differences of clinically important decline in HRQoL. RESULTS: 50.43% of the studied women with type 1 diabetes reported impaired HRQoL in pregnancy. Estimated maternal HRQoL significantly decreased from early to mid-pregnancy (mean EQ-5D-5 L score 0.97 in the first trimester and 0.91 in the second trimester) and improved slightly in late pregnancy (mean EQ-5D-5 L score 0.95). Multivariable regression model showed that women who experienced impaired HRQoL in pregnancy had higher risk of hypertensive disorder, preterm birth, and composite pregnancy outcome. The estimated minimally important difference for composite pregnancy outcome was -0.045 to -0.043. CONCLUSIONS: Experiencing impaired HRQoL during pregnancy was associated with a higher risk of hypertensive disorder and preterm birth in women with type 1 diabetes. The estimated minimally important difference of EQ-5D-5 L might serve as a clinically important tool in prenatal care. TRIAL REGISTRATION: No.ChiCTR1900025955.

Endothelial Dysfunction in Atherosclerotic Cardiovascular Diseases and Beyond: From Mechanism to Pharmacotherapies.

The endothelium, a cellular monolayer lining the blood vessel wall, plays a critical role in maintaining multiorgan health and homeostasis. Endothelial functions in health include dynamic maintenance of vascular tone, angiogenesis, hemostasis, and the provision of an antioxidant, anti-inflammatory, and antithrombotic interface. Dysfunction of the vascular endothelium presents with impaired endothelium-dependent vasodilation, heightened oxidative stress, chronic inflammation, leukocyte adhesion and hyperpermeability, and endothelial cell senescence. Recent studies have implicated altered endothelial cell metabolism and endothelial-to-mesenchymal transition as new features of endothelial dysfunction. Endothelial dysfunction is regarded as a hallmark of many diverse human panvascular diseases, including atherosclerosis, hypertension, and diabetes. Endothelial dysfunction has also been implicated in severe coronavirus disease 2019. Many clinically used pharmacotherapies, ranging from traditional lipid-lowering drugs, antihypertensive drugs, and antidiabetic drugs to proprotein convertase subtilisin/kexin type 9 inhibitors and interleukin 1ß monoclonal antibodies, counter endothelial dysfunction as part of their clinical benefits. The regulation of endothelial dysfunction by noncoding RNAs has provided novel insights into these newly described regulators of endothelial dysfunction, thus yielding potential new therapeutic approaches. Altogether, a better understanding of the versatile (dys)functions of endothelial cells will not only deepen our comprehension of human diseases but also accelerate effective therapeutic drug discovery. In this review, we provide a timely overview of the multiple layers of endothelial function, describe the consequences and mechanisms of endothelial dysfunction, and identify pathways to effective targeted therapies. SIGNIFICANCE STATEMENT: The endothelium was initially considered to be a semipermeable biomechanical barrier and gatekeeper of vascular health. In recent decades, a deepened understanding of the biological functions of the endothelium has led to its recognition as a ubiquitous tissue regulating vascular tone, cell behavior, innate immunity, cell-cell interactions, and cell metabolism in the vessel wall. Endothelial dysfunction is the hallmark of cardiovascular, metabolic, and emerging infectious diseases. Pharmacotherapies targeting endothelial dysfunction have potential for treatment of cardiovascular and many other diseases.

Investigating the Therapeutic Effects of Ferroptosis on Myocardial Ischemia-Reperfusion Injury Using a Dual-Locking Mitochondrial Targeting Strategy.

Research on ferroptosis in myocardial ischemia/reperfusion injury (MIRI) using mitochondrial viscosity as a nexus holds great promise for MIRI therapy. However, high-precision visualisation of mitochondrial viscosity remains a formidable task owing to the debilitating electrostatic interactions caused by damaged mitochondrial membrane potential. Herein, we propose a dual-locking mitochondria-targeting strategy that incorporates electrostatic forces and probe-protein molecular docking. Even in damaged mitochondria, stable and precise visualisation of mitochondrial viscosity in triggered and medicated MIRI was achieved owing to the sustained driving forces (e.g., pi-cation, pi-alkyl interactions, etc.) between the developed probe, CBS, and the mitochondrial membrane protein. Moreover, complemented by a western blot, we confirmed that ferrostatin-1 exerts its therapeutic effect on MIRI by improving the system xc-/GSH/GPX4 antioxidant system, confirming the therapeutic value of ferroptosis in MIRI. This study presents a novel strategy for developing robust mitochondrial probes, thereby advancing MIRI treatment.

The Interaction in Electrolyte Additives Accelerates Ion Transport to Achieve High-Energy Non-Aqueous Lithium Metal Batteries.

Electrolyte engineering is a feasible strategy to realize high energy density lithium metal batteries. However, stabilizing both lithium metal anodes and nickel-rich layered cathodes is extremely challenging. To break through this bottleneck, a dual-additives electrolyte containing fluoroethylene carbonate (10 vol.%) and 1-methoxy-2-propylamine (1 vol.%) in conventional LiPF6 -containing carbonate-based electrolyte is reported. The two additives can polymerize and thus generate dense and uniform LiF and Li3 N-containing interphases on both electrodes' surfaces. Such robust ionic conductive interphases not only prevent lithium dendrite formation in lithium metal anode but also suppress stress-corrosion cracking and phase transformation in nickel-rich layered cathode. The advanced electrolyte enables Li||LiNi0.8 Co0.1 Mn0.1 O2 stably cycle for 80 cycles at 60 mA g-1 with a specific discharge capacity retention of 91.2% under harsh conditions.

A pregnancy-specific Glucose management indicator derived from continuous glucose monitoring in pregnant women with type 1 diabetes.

OBJECTIVE: Glucose management indicator (GMI) is a core metric derived from continuous glucose monitoring (CGM) and is widely used to evaluate glucose control in patients with diabetes. No study has explored the pregnancy-specific GMI. This study aimed to derive a best-fitting model to calculate GMI from mean blood glucose (MBG) obtained from CGM among pregnant women with type 1 diabetes mellitus (T1DM). METHODS: A total of 272 CGM data and corresponding laboratory HbA1c from 98 pregnant women with T1DM in the CARNATION study were analysed in this study. Continuous glucose monitoring data were collected to calculate MBG, time-in-range (TIR), and glycaemic variability parameters. The relationships between the MBG and HbA1c during pregnancy and postpartum were explored. Mix-effect regression analysis with polynomial terms and cross-validation method was conducted to investigate the best-fitting model to calculate GMI from MBG obtained by CGM. RESULTS: The pregnant women had a mean age of 28.9 ± 3.8 years, with a diabetes duration of 8.8 ± 6.2 years and a mean body mass index (BMI) of 21.1 ± 2.5 kg/m2 . The HbA1c levels were 6.1 ± 1.0% and 6.4 ± 1.0% during pregnancy and at postpartum (p = 0.024). The MBG levels were lower during pregnancy than those at postpartum (6.5 ± 1.1 mmol/L vs. 7.1 ± 1.5 mmol/L, p = 0.008). After adjusting the confounders of haemoglobin (Hb), BMI, trimesters, disease duration, mean amplitude of glycaemic excursions and CV%, we developed a pregnancy-specific GMI-MBG equation: GMI for pregnancy (%) = 0.84-0.28* [Trimester] + 0.08 * [ BMI in kg/m2 ] + 0.01 * [Hb in g/mL] + 0.50 * [MBG in mmol/L]. CONCLUSIONS: We derived a pregnancy-specific GMI equation, which should be recommended for antenatal clinical care. CLINICAL TRIAL REGISTRY NUMBER: ChiCTR1900025955.

Effects of intermittently scanned continuous glucose monitoring in adult type 1 diabetes patients with suboptimal glycaemic control: A multi-centre randomized controlled trial.

AIMS: To investigate whether intermittently scanned continuous glucose monitoring without alarms (intermittently scanned CGM (isCGM)) improves glycaemic control over capillary blood glucose monitoring (BGM) among adult type 1 diabetes mellitus (T1DM) patients with suboptimal control. MATERIALS AND METHODS: Adults with T1DM and HbA1c between 7% and 10% were 1:1 randomized to use isCGM or BGM for 24 weeks. The primary outcome was the change in HbA1c levels after intervention. The secondary outcomes were the changes in sensor-derived metrics. RESULTS: A total of 104 adults with T1DM (34.2 ± 12.2 years; M/F, 38/66) were randomized to the isCGM group (n = 54) and the BGM group (n = 50). After 24 weeks, HbA1c significantly decreased in the isCGM group (8.1 ± 0.7% to 7.5 ± 1.0%) and the BGM group (8.0 ± 0.8% to 7.7 ± 1.0%) with between-group differences of 0.3% (95% coefficient intervals, 0.0%-0.6%; P = 0.04). The percentage of HbA1c reduction over 1.0% and 1.5% was significantly higher in the isCGM group with adjusted odds ratios of 2.5 (95% CI: 1.1-5.5; P = 0.03) and 3.2 (95% CI: 1.1-9.0; P = 0.03). Mean time-in-range 70-180 mg/dl (TIR) in the isCGM group significantly increased (from 58.5 ± 13.0% to 63.0 ± 12.6%), whereas mean TIR was similar in the BGM group (from 58.0 ± 14.6% to 57.5 ± 14.5%). Time spent in hyperglycemia reduced more in the isCGM group and time spent in hypoglycemia did not change significantly in both groups. CONCLUSIONS: Among adult T1DM patients with suboptimal glycaemic control, compared with BGM, isCGM use resulted in a statistically significant improvement in glycaemic control after 24-week intervention. TRIAL REGISTRATION: Clinicaltrials.gov Identifier (NCT03522870).

Predicting the clinical outcomes and benefit from letrozole after 5 years of treatment with aromatase inhibitors for early breast cancer: analysis from CCTG MA.17R.

PURPOSE: Women with hormone receptor positive breast cancer may receive 5 years of treatment with aromatase inhibitors but the magnitude of benefit was relatively small. Our goal was to develop a tool for identification of women with limited treatment benefit. METHODS: Regression analyses were applied to women treated by placebo in CCTG MA.17R trial (NCT00754845) to identify important prognostic factors associated with distant recurrence and develop a nomogram for predicting 5-year likelihood of distant recurrence, which was internally validated using bootstrap resampling method. Differential treatment effects between risk categories derived from the nomogram were evaluated among all women enrolled through interaction test between treatment and risk category. RESULTS: A total of 1735 women were included and the final model from 866 women treated by placebo identified the following three factors associate with distant recurrence: tumor size, nodal status, and presence of cardiovascular disease. The nomogram derived from the final model exhibited good discrimination power with a bootstrap-corrected concordance index of 0.71 and, importantly, identified 64% of low risk patients in whom extended treatment has limited benefit. Interaction between treatment and risk category derived from the nomogram was significant (p = 0.04). CONCLUSION: A nomogram with good performance may be used to accurately predict distant recurrence risk and also benefits with extended treatment after 5 years of aromatase inhibitors. Future independent validation of the proposed nomogram is warranted. TRIAL REGISTRATION NUMBER: NCT00754845.

Pharmacological inhibition of IRAK1 and IRAK4 prevents endothelial inflammation and atherosclerosis in ApoE-/- mice.

Inflammation associated endothelial dysfunction represents a pivotal contributor to atherosclerosis. Increasingly, evidence has demonstrated that interleukin 1 receptor (IL1-R) / toll-like receptor (TLR) signaling participates in the development of atherosclerosis. Recent large-scale clinical trials have supported the therapeutic potential of anti-inflammatory therapies targeting IL-1ß and IL-6 in reducing atherosclerosis. The present study examined the pharmacological effects of IL-1R-associated kinase 1 and 4 inhibitors (IRAK1/4i) in regulating inflammation of the endothelium and atherosclerosis. We demonstrate that dual pharmacological inhibition of IRAK1 and IRAK4 by an IRAK1/4i is more effective against LPS induced endothelial inflammation, compared with IRAK1 inhibitor or IRAK4 inhibitor monotherapy. IRAK1/4i showed little endothelial cell toxicity at concentrations from 1 µM up to 10 µM. Inhibition of IRAK1/4 reduced endothelial activation induced by LPS in vitro as evidenced by attenuated monocyte adhesion to the endothelium. Mechanistically, blockade of IRAK1/4 ameliorated the transcriptional activity of NF-κB. To assess the pharmacological effects of IRAK1/4i on atherosclerosis in vivo, ApoE-/- mice were orally administered IRAK1/4i (20 mg/kg/d) for 8 weeks. We show that IRAK1/4i reduced atherosclerotic lesion size in the aortic sinus and increased hepatic LDLR protein levels as well as lowered LDL-C level, without affecting other lipid parameters or glucose tolerance. Taken together, our findings demonstrate that dual pharmacological inhibition of IRAK1 and IRAK4 attenuates endothelial inflammation, lowers LDL-C levels and reduces atherosclerosis. Our study reinforces the evolving standing of anti-inflammatory approaches in cardiovascular therapeutics.

A global assessment of the impact of school closure in reducing COVID-19 spread.

Prolonged school closure has been adopted worldwide to control COVID-19. Indeed, UN Educational, Scientific and Cultural Organization figures show that two-thirds of an academic year was lost on average worldwide due to COVID-19 school closures. Such pre-emptive implementation was predicated on the premise that school children are a core group for COVID-19 transmission. Using surveillance data from the Chinese cities of Shenzhen and Anqing together, we inferred that compared with the elderly aged 60 and over, children aged 18 and under and adults aged 19-59 were 75% and 32% less susceptible to infection, respectively. Using transmission models parametrized with synthetic contact matrices for 177 jurisdictions around the world, we showed that the lower susceptibility of school children substantially limited the effectiveness of school closure in reducing COVID-19 transmissibility. Our results, together with recent findings that clinical severity of COVID-19 in children is lower, suggest that school closure may not be ideal as a sustained, primary intervention for controlling COVID-19. This article is part of the theme issue 'Data science approach to infectious disease surveillance'.

The First-Year Variation in Central Retinal Thickness Predicts Legal Blindness in Patients with Neovascular Age-Related Macular Degeneration.

BACKGROUND: Due to its progressive nature, early evaluation and timely prediction of legal blindness are important in patients with neovascular age-related macular degeneration (nAMD). We examined the association between early-stage variation in central retinal thickness (CRT) and long-term visual outcomes in patients with nAMD. METHODS: We included 103 nAMD patients who were administered anti-vascular endothelial growth factor (anti-VGEF). Participants were considered qualified if they were: 1) 50 years and older, 2) treatment-naïve, 3) received standard anti-VEGF treatment and had complete baseline information. We further excluded patients with less than one-year follow-up data and those who experienced best-corrected visual acuity (BCVA) ≤35. Early-stage variability in CRT was measured as the first-year coefficient of variability (CV) of CRT. Patients were then classified into the high-variability and the low-variability groups according to the X-tile. A product-limit plot was used to demonstrate the differences and tested with the log-rank test. The association between first-year variability and visual outcomes was quantified using Cox regression models. Time-to-event primary endpoint was the overall visual preservation (OVP) rate, defined as the time from the first injection to legal blindness, i.e., BCVA ≤ 35 Early Treatment Diabetic Retinopathy Study (ETDRS) letters. RESULTS: A threshold of 20% of first-year CV in CRT was used to categorized 76 qualified patients into high-variability (35, 46.1%) and low-variability (41, 53.9%). The 5- and 10-year OVPs for patients with high- vs. low-variability were 76% vs. 48%, and 59% vs. 22%, respectively. High early-stage CRT variability showed a significantly higher risk of legal blindness. Even after adjusting for the demographic and clinical features, the variability remained significant (HR=2.39, 95% CI: 1.20 to 4.78). CONCLUSIONS: First-year variability of CRT was predictive of long-term visual outcomes in patients with nAMD, and 20% of the variability could be used as a clinically convenient threshold to qualitatively classify patients into high- and low-variability groups. The current study is important for identifying high-risk populations and for long-term disease management.

Molecular landscape of DYSF mutations in dysferlinopathy: From a Chinese multicenter analysis to a worldwide perspective.

Dysferlinopathy is one of the most common subgroup of autosomal recessive limb-girdle muscular dystrophies that is caused by mutations in DYSF gene. However, there is currently no worldwide comprehensive genetic analysis of DYSF variants. Through a national multicenter collaborative effort in China, we identified 222 DYSF variants with 40 novel variants from 245 patients. We then integrated DYSF variants from disease-related genetic databases including LOVD (n = 1020) and Clinvar (n = 1179), to depict the global landscape of disease-related DYSF variants. Normal-population-derived DSYF variants from gnomAD (n = 4318) and ChinaMAP (n = 13,330) were also analyzed in comparison. In Chinese patients, gender instead of genotype showed influence on the onset age of dysferlinopathy, with males showing an earlier age of onset. After integrative analysis, we identified two hotspot DYSF mutations, c.2997G>T in world patients and c.1375dup in Chinese patients, respectively. Both the pathogenic and likely pathogenic variants scattered on the whole gene length of DYSF. However, three specific domains (C2F-C2G-TM, DysF, and C2B-Ferl-C2C) contained variants at higher frequencies than reported in both the databases and Chinese patients. This study comprehensively collected available DYSF variant data, which may pave way for genetic counselling and future clinical trial design for gene therapies in dysferlinopathy.

HLA class I genes modulate disease risk and age at onset together with DR-DQ in Chinese patients with insulin-requiring type 1 diabetes.

AIMS/HYPOTHESIS: The study aimed to investigate the effects of HLA class I genes on susceptibility to type 1 diabetes with different onset ages, in addition to the well-established effects of HLA class II genes. METHODS: A total of 361 patients with type 1 diabetes (192 patients with onset <18 years and 169 patients with onset ≥18 years) and 500 healthy control participants from China were enrolled and genotyped for the HLA-A, -B, -C, -DQA1, -DQB1 and -DRB1 genes using next-generation sequencing. RESULTS: The susceptible DR3 (ß = -0.09, p = 0.0009) and DR4-DQ8 (ß = -0.13, p = 0.0059) haplotypes were negatively associated with onset age, while the protective DR11 (ß = 0.21, p = 0.0314) and DR12 (ß = 0.27, p < 0.0001) haplotypes were positively associated with onset age. After adjustment for linkage disequilibrium with DR-DQ haplotypes, A*11:01:01 was positively associated with onset age (ß = 0.06, p = 0.0370), while the susceptible C*15:02:01 was negatively associated with onset age (ß = -0.21, p = 0.0050). The unit for ß was double square-root (fourth root) transformed years of change in onset age associated with per copy of the HLA haplotype/allele. In addition, B*46:01:01 was protective (OR 0.41, 0.46; pc [corrected for multiple comparisons] = 0.0044, 0.0040), whereas A*24:02:01 (OR 2.71, 2.25; pc = 0.0003, 0.0002) and B*54:01:01 (OR 3.96, 3.79; pc = 0.0018, 0.0004) were predisposing in both the <18 group and the ≥18 group compared with healthy control participants. In the context of DR4-DQ4, A*11:01:01 (61.29% vs 28.26%, pc = 0.0144) was increased while the predisposing A*24:02:01 (19.35% vs 47.83%, pc = 0.0403) was decreased in patients with onset ≥18 years when compared with patients with onset <18 years. CONCLUSIONS/INTERPRETATION: In addition to DR-DQ haplotypes, novel HLA class I alleles were detected to play a role in susceptibility to type 1 diabetes with different onset ages, which could improve the understanding of disease heterogeneity and has implications for the design of future studies.

Current practice and perspectives of healthcare providers regarding preconception care for women with type 1 diabetes in China.

AIMS: We aimed to investigate the current practice and perspectives of healthcare providers (HCPs) regarding preconception care (PCC) for women with type 1 diabetes (T1D) in China. MATERIALS AND METHODS: A questionnaire based on in-depth interviews with HCPs involved in PCC was released online and advertised via doctor unions in China. The data were categorical variables and were analysed by multivariable logistic regression, Chi-square test, or Wilcoxon rank-sum test. RESULTS: From November 2016 to January 2017, 992 responses from 31 provinces of China were received (77.3% doctors and 22.7% nurses). Regarding the current status of PCC for T1D, 62.5% of HCPs treated ≤1 woman with T1D monthly on average. Only 16.5% thought they provided proper PCC, and 29.6% reported having sufficient knowledge. Regarding attitudes towards pregnancy with T1D, 92.2% were in favour of women with T1D getting pregnant after proper glycaemic control, and 94.7% perceived their worries regarding pregnancy. Regarding doctor-patient communication, 56.6% spent <10 min per visit, while 58.3% thought ≥20 min was required for adequate communication. HCPs emphasised the importance of multidisciplinary PCC, professional training, and social support. PCC practice was associated with hospital level (OR = 2.450, 95%CI: 1.580-3.799, p < 0.001), HCPs' experience of treating women with T1D (OR = 2.196, 95%CI: 1.516-3.180, p < 0.001), and their communication sufficiency (OR = 3.706, 95%CI: 2.550-5.387, p < 0.001). CONCLUSIONS: The current PCC practice for T1D in China was suboptimal and it was associated with hospital level, HCPs' experience and communication. It is necessary to reinforce professional training and appeal for social resources to improve PCC.

Adult-onset type 1 diabetic patients with less severe clinical manifestation have less risk DR-DQ genotypes than childhood-onset patients.

BACKGROUND: The aim of this study was to investigate differences in clinical features and HLA genotypes between adult-onset and childhood-onset patients with type 1 diabetes in a Chinese population. MATERIALS AND METHODS: This study enrolled 716 Han Chinese patients with type 1 diabetes from Guangdong (258 childhood-onset and 458 adult-onset) to compare their clinical features. Of them 214 patients with classical type 1 diabetes (100 childhood-onset and 114 adult-onset) were selected for HLA DR and DQ genotyping by next-generation sequencing. RESULTS: Adult-onset patients were characterized by longer duration of symptoms before diagnosis, lower frequency of DKA at disease onset, less frequent autoantibody positivity, higher serum C-peptide concentrations, and better glycemic control. These findings were replicated in the restricted cohort of 214 patients with classical type 1 diabetes. Compared with childhood-onset patients, adult-onset patients had a lower frequency of the DR9 haplotype, as well as lower frequency of high-risk DR3/DR4 and DR3/DR9 genotypes, but higher frequency of DR3/DR3 genotype and DR3/X, DR4/X or DR9/X (X, non-risk) genotypes. CONCLUSIONS: Adult-onset type 1 diabetic patients with susceptible haplotypes (DR3, DR4 or DR9) were more likely to carry protective DR-DQ haplotypes than childhood-onset patients, which suggested the association between less risk DR-DQ genotypes and the less severe clinical manifestation in adult-onset patients.

Targeting angiopoietin-like 3 in atherosclerosis: From bench to bedside.

Atherosclerotic cardiovascular disease (ASCVD) is the largest cause of morbidity and mortality worldwide. Lipid-lowering therapies are the current major cornerstone of ASCVD management. Statins, ezetimibe, fibrates and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors effectively reduce the plasma low-density lipoprotein cholesterol (LDL-C) level in most individuals at risk of atherosclerosis. Still, some patients (such as those with homozygous familial hypercholesterolaemia), who do not respond to standard therapies, and other patients who cannot take these agents, remain at a high risk of ASCVD. In recent years there has been tremendous progress in understanding the mechanism and efficacy of lipid-lowering strategies. Apart from the recently approved PCSK9 and ATP citrate lyase inhibitors, angiopoietin-like 3 (ANGPTL3) is another potential target for the treatment of dyslipidaemia and its clinical sequalae of atherosclerosis. ANGPTL3 is a pivotal modulator of plasma triglycerides (TG), LDL-C and high-density lipoprotein cholesterol (HDL-C) levels, achieved by inhibiting the activities of lipoprotein lipase and endothelial lipase. Familial combined hypolipidaemia is derived from the Angptl3 loss-of-function mutations, which leads to low levels of LDL-C, HDL-C and TG, and has a 34% decreased risk of ASCVD compared with non-carriers. To date, monoclonal antibodies (evinacumab) and antisense oligonucleotides against ANGPTL3 have been investigated in clinical trials for dyslipidaemia therapy. Herein, we review the biology and function of ANGPTL3, as well as the latest developments of ANGPTL3-targeted therapies. We also summarize evidence from basic research to clinical trials, with the aim of providing novel insights into the biological functions of ANGPTL3 and related targeted therapies.

Effects of sources of social support and resilience on the mental health of different age groups during the COVID-19 pandemic.

BACKGROUND: A pandemic is a very stressful event, especially for highly vulnerable people (e.g., older adults). The purpose of the current study was to investigate the main and interactive relationships of social support and resilience on individual mental health during the COVID-19 pandemic across three age groups: emerging adults, adults, and older adults. METHODS: A survey was conducted with 23,192 participants aged 18-85. Respondents completed a questionnaire, including items on the COVID-19-related support they perceived from different sources, the abbreviated version of the Connor-Davidson Resilience Scale, and the Mental Health Inventory. RESULTS: Latent profile analysis identified five profiles of social support, and the patterns of potential profiles were similar in all groups. However, category distribution in the five profiles was significantly different among the age groups. Furthermore, analysis using the BCH command showed significant differences in mental health among these profiles. Lastly, interactive analyses indicated resilience had a positive relationship with mental health, and social support served as a buffer against the negative impact of low resilience on mental health. CONCLUSIONS: This study provides quantitative evidence for socioemotional selectivity theory (SST) and enables several practical implications for helping different age groups protecting mental health during pandemic.

Impaired Vps34 complex activity-mediated autophagy inhibition contributes to endothelial progenitor cells damage in the ischemic conditions.

AIMS: Endothelial progenitor cells (EPCs) are widely accepted to be applied in ischemic diseases. However, the therapeutic potency is largely impeded because of its inviability in these ischemic conditions. Autophagy is recognized to be vital in cell activity. Therefore, we explore the role and the mechanism of autophagy in ischemic EPCs. METHODS AND RESULTS: We applied 7d-cultured bone marrow EPCs to investigate the autophagy status under the oxygen and glucose deprivation (OGD) conditions in vitro, mimicking the in-vivo harsh ischemia and anoxia microenvironment. We found increased EPC apoptosis, accompanied by an impaired autophagy activation. Intriguingly, mTOR inhibitor Rapamycin was incapable to reverse this damped autophagy and EPC damage. We further found that autophagy pathway downstream Vps34-Beclin1-Atg14 complex assembly and activity were impaired in OGD conditions, and an autophagy-inducing peptide Tat-Beclin1 largely recovered the impaired complex activity and attenuated OGD-stimulated EPC injury through restoring autophagy activation. CONCLUSIONS: The present study discovered that autophagy activation is inhibited when EPCs located in the ischemia and anoxia conditions. Restoration of Vps34 complex activity obtains sufficient autophagy, thus promoting EPC survival, which will provide a potential target and advance our understanding of autophagy manipulation in stem cell transplantation.

Boosting the Reversibility of Sodium Metal Anode via Heteroatom-Doped Hollow Carbon Fibers.

Sodium (Na) metal anodes stand out with their remarkable capacity and natural abundance. However, the dendritic Na growth, infinite dimensional changes, and low Coulombic efficiency (CE) present key bottlenecks plaguing practical applications. Here, heteroatom-doped (nitrogen, sulfur) hollow carbon fibers (D-HCF) are rationally synthesized as a nucleation-assisting host to enable a highly reversible Na metal. The "sodiophilic" functional groups introduced by the heteroatom-doping and large surface area (≈1052 m2 g-1 ) synchronously contribute to a homogenous plating morphology with dissipated local current density. High "sodiophilicity" of the D-HCF is confirmed by first-principle calculations and experimental results, where strong adsorption energy of -3.52 eV with low Na+ nucleation overpotential of 3.2 mV at 0.2 mA cm-2 is realized. As such, highly reversible plating/stripping is achieved at 1.0 mA cm-2 with average CE approximating 99.52% over 600 cycles. The as-assembled Na@D-HCF symmetric cells exhibit a prolonged lifetime for 1000 h. A full-cell paired with Na3 V2 (PO4 )3 cathode further demonstrates stable electrochemical behavior for 200 cycles at 1 C along with excellent rate performance (102 mAh g-1 at 5 C). The results clearly show the effectiveness of the D-HCF in manipulating Na+ deposition and thus the significance of nucleation control in realizing dendrite-free metal anodes.