Early Use of Corticosteroid May Prolong SARS-CoV-2 Shedding in Non-Intensive Care Unit Patients with COVID-19 Pneumonia: A Multicenter, Single-Blind, Randomized Control Trial.

BACKGROUND: There is still no clinical evidence available to support or to oppose corticosteroid treatment for coronavirus disease 2019 (COVID-19) pneumonia. OBJECTIVE: To investigate the efficacy and safety of corticosteroid given to the hospitalized patients with COVID-19 pneumonia. METHODS: This was a prospective, multicenter, single-blind, randomized control trial. Adult patients with COVID-19 pneumonia who were admitted to the general ward were randomly assigned to either receive methylprednisolone or not for 7 days. The primary end point was the incidence of clinical deterioration 14 days after randomization. RESULTS: We terminated this trial early because the number of patients with COVID-19 pneumonia in all the centers decreased in late March. Finally, a total of 86 COVID-19 patients underwent randomization. There was no difference of the incidence of clinical deterioration between the methylprednisolone group and control group (4.8 vs. 4.8%, p = 1.000). The duration of throat viral RNA detectability in the methylprednisolone group was 11 days (interquartile range, 6-16 days), which was significantly longer than that in the control group (8 days [2-12 days], p = 0.030). There were no significant differences between the 2 groups in other secondary outcomes. Mass cytometry discovered CD3+ T cells, CD8+ T cells, and NK cells in the methylprednisolone group which were significantly lower than those in the control group after randomization (p < 0.05). CONCLUSIONS: From this prematurely closed trial, we found that the short-term early use of corticosteroid could suppress the immune cells, which may prolong severe acute respiratory syndrome coronavirus 2 shedding in patients with COVID-19 pneumonia. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04273321.

The Impact of Integrin ß2 on Granulocyte/Macrophage Progenitor Proliferation.

Previously, we reported that although the HSPC frequency in bone marrow cells (BMC) was comparable between ß2-/- and ß2+/+ mice, transplantation of ß2-/- BMC into lethally irradiated CD45.1 recipient resulted in more myeloid cell production than ß2+/+ BMC. The objective of this study is to address if integrin ß2 deficiency skews granulocyte/macrophage progenitor (GMP) proliferation. FACS analysis demonstrated that GMP frequency and cell number were higher and megakaryocyte/erythrocyte progenitor frequency and cell number were lower in ß2-/- mice than ß2+/+ mice. However, the common myeloid progenitors (CMP) frequency and cell number were similar between the two groups. The increased GMP number was due to GMP proliferation as evidenced by the percentage of BrdU-incorporating GMP. Whole genome transcriptome analysis identified increased FcεRIα expression in ß2-/- CMP compared to ß2+/+ CMP. FcεRIα expression on ß2-/- GMP was detected increased in ß2-/- mice by qRT-PCR and FACS. Although transplantation of FcεRIαhi GMP or FcεRIαlo GMP into lethally irradiated CD45.1 recipient resulted in comparable myeloid cell production, transplantation of ß2 deficient FcεRIαhi GMP generated more myeloid cells than ß2+/+ FcεRIαhi GMP. GATA2 expression was increased in ß2-/- GMP. Using a luciferase reporter assay, we demonstrated that mutation of the GATA2 binding site in the FcεRIα promoter region diminished FcεRIα transcription. In vitro, the addition of IgE, the ligand of FcεRIα, promoted GMP expansion, which was abrogated by inhibition of JNK phosphorylation. Integrin ß2 deficiency promoted GMP proliferation and myeloid cell production, which was mediated via FcεRIα/IgE-induced JNK phosphorylation in GMP. Stem Cells 2019;37:430-440.

Central hemodynamics in relation to low-level environmental lead exposure.

Purpose: Arterial stiffness predicts cardiovascular complications. The association between arterial stiffness and blood lead (BL) remains poorly documented. We aimed to assess the association of central hemodynamic measurements, including pulse wave velocity (aPWV), with blood lead in a Flemish population.Materials and Methods: In this Flemish population study (mean age, 37.0 years; 48.3% women), 267 participants had their whole BL and 24-h urinary cadmium (UCd) measured by electrothermal atomic absorption spectrometry in 1985-2005. After 9.4 years (median), they underwent applanation tonometry to estimate central pulse pressure (cPP), the augmentation index (AI), pressure amplification (PA), and aPWV. The amplitudes of the forward (Pf) and backward (Pb) pulse waves and reflection index (RI) were derived by a pressure-based wave separation algorithm.Results: BL averaged 2.93 µg/dL (interquartile range, 1.80-4.70) and UCd 4.79 µg (2.91-7.85). Mean values were 45.0 ± 15.2 mm Hg for cPP, 24.4 ± 12.4% for AI, 1.34 ± 0.21 for PA, 7.65 ± 1.74 m/s for aPWV, 32.7 ± 9.9 mm Hg for Pf, 21.8 ± 8.4 mm Hg for Pb, and 66.9 ± 18.4% for RI. The multivariable-adjusted association sizes for a 2-fold higher BL were: +3.03% (95% confidence interval, 1.56, 4.50) for AI; -0.06 (-0.08, -0.04) for PA; 1.02 mm Hg (0.02, 2.02) for Pb; and 3.98% (1.71, 6.24) for RI (p ≤ .045). In 206 participants never on antihypertensive drug treatment, association sizes were +2.59 mm Hg (0.39, 4.79) for cPP and +0.26 m/s (0.03, 0.50) for aPWV. Analyses adjusted for co-exposure to cadmium were consistent.Conclusion: In conclusion, low-level environmental lead exposure possibly contributes to arterial stiffening and wave reflection from peripheral sites.

Heart rate variability and peripheral nerve conduction velocity in relation to blood lead in newly hired lead workers.

OBJECTIVES: Previous studies relating nervous activity to blood lead (BL) levels have limited relevance, because over time environmental and occupational exposure substantially dropped. We investigated the association of heart rate variability (HRV) and median nerve conduction velocity (NCV) with BL using the baseline measurements collected in the Study for Promotion of Health in Recycling Lead (NCT02243904). METHODS: In 328 newly hired men (mean age 28.3 years; participation rate 82.7%), we derived HRV measures (power expressed in normalised units (nu) in the high-frequency (HF) and low-frequency (LF) domains, and LF/HF) prior to long-term occupational lead exposure. Five-minute ECG recordings, obtained in the supine and standing positions, were analysed by Fourier transform or autoregressive modelling, using Cardiax software. Motor NCV was measured at the median nerve by a handheld device (Brevio Nerve Conduction Monitoring System, NeuMed, West Trenton, NJ, USA). BL was determined by inductively coupled plasma mass spectrometry. RESULTS: Mean BL was 4.54 µg/dL (IQR 2.60-8.90 µg/dL). Mean supine and standing values of LF, HF and LF/HF were 50.5 and 21.1 nu and 2.63, and 59.7 and 10.9 nu and 6.31, respectively. Orthostatic stress decreased HF and increased LF (p<0.001). NCV averaged 3.74 m/s. Analyses across thirds of the BL distribution and multivariable-adjusted regression analyses failed to demonstrate any association of HRV or NCV with BL. CONCLUSIONS: At the exposure levels observed in our study, autonomous nervous activity and NCV were not associated with BL. TRIAL REGISTRATION NUMBER: NCT02243904.

Central hemodynamics in relation to blood lead in young men prior to chronic occupational exposure.

Background: Aortic pulse wave velocity (aPWV) predicts cardiovascular complications, but the association of central arterial properties with blood lead level (BL) is poorly documented. We therefore assessed their association with BL in 150 young men prior to occupational lead exposure, using baseline data of the Study for Promotion of Health in Recycling Lead (NCT02243904). Methods: Study nurses administered validated questionnaires and performed clinical measurements. Venous blood samples were obtained after 8-12 h of fasting. The radial, carotid and femoral pulse waves were tonometrically recorded. We accounted for ethnicity, age, anthropometric characteristics, mean arterial pressure, heart rate, smoking and drinking, and total and high-density lipoprotein serum cholesterol, as appropriate. Results: Mean values were 4.14 µg/dL for BL, 27 years for age, 108/79/28 mm Hg for central systolic/diastolic/pulse pressure, 100/10% for the augmentation ratio/index, 1.63 for pressure amplification, 5.94 m/s for aPWV, 27/11 mm Hg for the forward/backward pulse pressure height, and 43% for the reflection index. Per 10-fold BL increase, central diastolic pressure and the augmentation ratio were respectively 5.37 mm Hg (95% confidence interval [CI], 1.00-9.75) and 1.57 (CI, 0.20-2.94) greater, whereas central pulse pressure and the forward pulse pressure height were 3.74 mm Hg (CI, 0.60-6.88) and 3.37 mm Hg (CI, 0.22-6.53) smaller (p ≤ .036 for all). The other hemodynamic measurements were unrelated to BL. The reflected pulse peak time was inversely correlated with diastolic pressure (r = -0.20; p ≤ .017). Conclusion: At the exposure levels observed in our current study, aPWV, the gold standard to assess arterial stiffness, was not associated with BL. Increased peripheral arterial resistance, as reflected by higher diastolic pressure, might bring reflection points closer to the heart, thereby moving the backward wave into systole and increasing the augmentation ratio in relation to BL.

Activation of brown adipocytes by placental growth factor.

Gestational diabetes mellitus (GDM) is a type of diabetes and occurs during pregnancy. Brown adipose tissue (BAT) improves glucose homeostasis and mitigates insulin resistance, however, its activity is reduced in GDM. Placenta growth factor (PlGF) is an angiogenic factor produced by placental trophoblasts. Nevertheless, whether and how PlGF could affect BAT function in GDM are not defined. To investigate this question, 91 non-diabetic pregnant participants and 73 GDM patients were recruited to Gynaecology and Obstetrics Centre in Lu He hospital. Serum levels of PlGF were quantified by ELISA. Skin temperature was measured by far infrared thermography in the supraclavicular region where classical BATs were located. The direct effect of PlGF on BAT function was explored using the established human preadipocyte differentiation system. Thereby, we demonstrated that serum levels of PlGF were lower in GDM patients compared with controls, which was accompanied by decreased skin temperature in the supraclavicular region. By qPCR and western blot, mRNA and protein expression of UCP1 and OXPHOS were elevated in differentiated adipocytes treated with PlGF. PlGF stimulated mitochondrion transcription and increased copy number of mitochondrial. When subjected for respirometry, PlGF-treated differentiated adipocytes showed higher oxygen consumption rates than controls. PlGF induced AMPK phosphorylation and blockade of AMPK phosphorylation blunted UCP1 and OXPHOS expression in differentiated adipocytes. PlGF administration reduced cholesterol and triglyceride content in the liver and improved insulin sensitivity in db mice compared with control. In Conclusion, PlGF could activate BAT function. Downregulation of PlGF might contribute to the reduced BAT activity in GDM.

Glomerular function in relation to circulating adhesion molecules and inflammation markers in a general population.

Background: Inflammation is a hallmark of chronic kidney disease (CKD) and stimulates glomerular expression of vascular adhesion molecules (VCAMs). We investigated in a general population whether estimated glomerular filtration rate (eGFR) is associated with circulating adhesion molecules, inflammation markers or both. Methods: We measured serum levels of five adhesion molecules [VCAM-1, intracellular adhesion molecule-1 (ICAM-1), P-selectin, E-selectin and monocyte chemoattractant protein-1 (MCP-1)] and seven inflammation markers [C-reactive protein (CRP), neutrophil gelatinase-associated lipocalin (NGAL), tumour necrosis factor receptor 1 (TNF-R1), TNF-α, interleukin 6 (IL-6), IL-8 and vascular endothelial growth factor] in 1338 randomly recruited people (50.8% women, mean age 51.7 years, eGFR 79.9 mL/min/1.73 m2). Results: In multivariable-adjusted analyses, eGFR decreased (P ≤ 0.004) with higher VCAM-1 (association size expressed in mL/min/1.73 m2 for a doubling of the marker, -2.99), MCP-1 (-1.19), NGAL (-1.19), TNF receptor 1 (-2.78), TNF-α (-2.28) and IL-6 (-0.94). The odds ratios of having eGFR <60 versus ≥60 mL/min/1.73 m2 (n = 138 versus 1200) were significant (P ≤ 0.001) for VCAM-1 (1.77), MCP-1 (1.32), NGAL (1.26), TNF-R1 (1.49), TNF-α (1.45) and IL-6 (1.20). Compared with 24-h albuminuria, VCAM-1 increased (P <0.0001) the area under the curve from 0.57 to 0.65, MCP-1 to 0.67 and TNF-R1 to 0.79, but TNF-R1 outperformed both adhesion molecules (P < 0.0001). Conclusions: In a general population, eGFR is inversely associated with circulating adhesion molecules VCAM-1 and MCP-1 and several inflammation markers, but inflammation markers, in particular TNF-R1 and TNF-α, identify patients with eGFR <60 mL/min/1.73 m2 more accurately.

Sham or no sham control: that is the question in trials of renal denervation for resistant hypertension. A systematic meta-analysis.

BACKGROUND: Studies of renal denervation (RDN) in patients with apparent treatment resistant hypertension have been hampered by a number of patient and physician related confounders on blood pressure (BP) including poor drug adherence. It remains uncertain whether RDN lowers BP. We aimed to investigate whether the use of sham control is essential in RDN studies or whether systematic use of 24-hour ambulatory BP provides enough information thereby making an invasive sham control redundant. METHODS: We meta-analyzed randomized controlled trials of the BP response to RDN on top of continued or optimized antihypertensive drugs in patients with resistant hypertension. On top of the randomized trials reviewed earlier, we additionally included three studies, one conducted in Spain (24 patients, RDN vs. spironolactone), one conducted in Denmark (69 patients, sham controlled) and one conducted in Netherlands (139 patients, RDN vs. continued treatment). We analyzed 24-hour ambulatory BP in 3 sham controlled studies vs. 7 no sham controlled studies. RESULTS: The updated meta-analysis of 10 studies showed 3.6 mmHg (p = .45) and 1.0 mmHg (p = .54) reductions in office and in 24-hour systolic BP, respectively. Meta-analysis of 24-hour systolic BP in the 3 sham-controlled studies showed a reduction of 2.18 mmHg (95% confidence intervals (CIs) -4.70 to 0.33 mmHg, n = 396 vs. 230, p = .07). For the 7 no sham controlled studies there was no difference in 24-hour systolic BP (+0.38 mmHg; 95% CIs -5.29 to 6.04 mmHg, n = 215 vs. 245, p = .90). The test for sub-group heterogeneity showed no significant interaction (p = .69). Removing one trial at a time produced confirmatory results. CONCLUSION: The overall meta-analysis of 10 randomized and controlled studies showed no significant effect on BP of RDN in resistant hypertension. Moreover, our analysis does not support the use of sham control but rather suggests extensive use of 24-hour ambulatory BP in studies of RDN in resistant hypertension.

Different relationship between ANGPTL3 and HDL components in female non-diabetic subjects and type-2 diabetic patients.

BACKGROUND: Angiopoietin-like protein 3 (ANGPTL3) is a major lipoprotein regulator and shows positive correlation with high-density lipoprotein-cholesterol (HDL-c) in population studies and ANGPTL3 mutated subjects. However, no study has looked its correlation with HDL components nor with HDL function in patients with type 2 diabetes mellitus (T2DM). METHODS: We studied 298 non-diabetic subjects and 300 T2DM patients who were randomly recruited in the tertiary referral centre. Plasma levels of ANGPTL3 were quantified by ELISA. Plasma samples were fractionated to obtain HDLs. HDL components including apolipoprotein A-I (apoA-I), triglyceride, serum amyloid A (SAA), phospholipid and Sphingosine-1-phosphate were measured. HDLs were isolated from female controls and T2DM patients by ultracentrifugation to assess cholesterol efflux against HDLs. A Pearson unadjusted correlation analysis and a linear regression analysis adjusting for age, body mass index and lipid lowering drugs were performed in male or female non-diabetic participants or diabetic patients, respectively. RESULTS: We demonstrated that plasma level of ANGPTL3 was lower in female T2DM patients than female controls although no difference of ANGPTL3 levels was detected between male controls and T2DM patients. After adjusting for confounding factors, one SD increase of ANGPTL3 (164.6 ng/ml) associated with increase of 2.57 mg/dL cholesterol and 1.14 µg/mL apoA-I but decrease of 47.07 µg/L of SAA in HDL particles of non-diabetic females (p < 0.05 for cholesterol and SAA; p < 0.0001 for apoA-I). By contrast, 1-SD increase of ANGPTL3 (159.9 ng/ml) associated with increase of 1.69 mg/dl cholesterol and 1.25 µg/mL apoA-I but decrease of 11.70 µg/L of SAA in HDL particles of female diabetic patients (p < 0.05 for cholesterol; p < 0.0001 for apoA-I; p = 0.676 for SAA). Moreover, one SD increase of ANGPTL3 associated with increase of 2.11 % cholesterol efflux against HDLs in non-diabetic females (p = 0.071) but decrease of 1.46 % in female T2DM patients (p = 0.13) after adjusting for confounding factors. CONCLUSIONS: ANGPTL3 is specifically correlated with HDL-c, apoA-I, SAA and HDL function in female non-diabetic participants. The decrease of ANGPTL3 level in female T2DM patients might contribute to its weak association to HDL components and function. ANGPTL3 could be considered as a novel therapeutic target for HDL metabolism for treating diabetes.

The purine metabolite inosine monophosphate accelerates myelopoiesis and acute pancreatitis progression.

Hyperglycemia-induced myelopoiesis and atherosclerotic progression occur in mice with type I diabetes. However, less is known about the effects of metabolites on myelopoesis in type 2 diabetes. Here, we use fluorescence-activated cell sorting to analyze the proliferation of granulocyte/monocyte progenitors (GMP) in db/db mice. Using targeted metabolomics, we identify an increase in inosine monophosphate (IMP) in GMP cells of 24-week-old mice. We show that IMP treatment stimulates cKit expression, ribosomal S6 activation, GMP proliferation, and Gr-1+ granulocyte production in vitro. IMP activates pAkt in non-GMP cells. In vivo, using an established murine acute pancreatitis (AP) model, administration of IMP-treated bone marrow cells enhances the severity of AP. This effect is abolished in the presence of a pAkt inhibitor. Targeted metabolomics show that plasma levels of guanosine monophosphate are significantly higher in diabetic patients with AP. These findings provid a potential therapeutic target for the control of vascular complications in diabetes.

Nanomedicine for the treatment of diabetes-associated cardiovascular diseases and fibrosis.

Cardiomyopathy and fibrosis are the main causes of heart failure in diabetes patients. For therapeutic purposes, a delivery system is required to enhance antidiabetic drug efficacy and specifically target profibrotic pathways in cardiomyocytes. Nanoparticles (NPs) have distinct advantages, including biocompatibility, bioavailability, targeting efficiency, and minimal toxicity, which make them ideal for antidiabetic treatment. In this review, we overview the latest information on the pathogenesis of cardiomyopathy and fibrosis in diabetes patients. We summarize how NP applications improve insulin and liraglutide efficacy and their sustained release upon oral administration. We provide a comprehensive review of the results of NP clinical trials in diabetes patients and of animal studies investigating the effects of NP-mediated anti-fibrotic treatments. Collectively, the application of advanced NP delivery systems in the treatment of cardiomyopathy and fibrosis in diabetes patients is a promising and innovative therapeutic strategy.

Roles of Hematopoietic Stem and Progenitor Cells in Ischemic Cardiovascular Disease.

Macrophage proliferation and skewed myelopoiesis-induced monocytosis, as well as neutrophils, enhance the generation of atherogenic inflammatory cells in a lesion area, leading to plaque formation and Cardiovascular Disease (CVD). Among all risk factors, accumulated data have shown that hyperlipidemia activates Hematopoietic Stem/Progenitor Cells (HSPCs) in the Bone Marrow (BM) niche. Recently, proliferation of Granulocyte-Monocyte Progenitors (GMPs) has been demonstrated to drive skewed myelopoiesis, while HSPCs remain quiescent. In this review, we discuss how HSPCs and GMPs participate in atherosclerosis of mice in terms of proliferation and cell mobilization from BM to peripheral blood and the lesion area. We also describe how the spleen, an extramedullary organ, is involved in skewed myelopoiesis and inflammation in atherosclerosis. We further summarize the clinical evidence of the relationship of HSPCs with coronary stenoses in patients with CVD. Ultimately, this review facilitates understanding the pathological roles of HSPCs and GMPs in atherosclerosis for future treatments.

Diabetic Bone Marrow Cell Injection Accelerated Acute Pancreatitis Progression.

Acute pancreatitis (AP) is one of the leading causes of hospital admission, 20% of which could progress to the severe type with extensive acinar cell necrosis. Clinical studies have reported that diabetes is an independent risk factor of the incidence of AP and is associated with higher severity than nondiabetic subjects. However, how diabetes participates in AP progression is not well defined. To investigate this question, wild-type (wt) and diabetic db/db mice at the age of 16 weeks were used in the study. AP was induced in wt recipients by 10 injections of 50 µg/kg caerulein with a 1 h interval. One hour after the last caerulein injection, bone marrow cells (BMC) isolated from wt and db/db mice were injected intraperitoneally into the recipients (1 × 107cells/recipient). The recipients with no BMC injection served as controls. Thirteen hours after BMC injection, serum lipase activity was 1.8- and 1.3-folds higher in mice that received db/db BMC, compared with those with no injection and wt BMC injection, respectively (p ≤ 0.02 for both). By H&E staining, the overall severity score was 14.7 for no cell injection and 16.6 for wt BMC injection and increased to 22.6 for db/db BMC injection (p ≤ 0.002 for both). In particular, mice with db/db BMC injection developed more acinar cell necrosis and vacuolization than the other groups (p ≤ 0.03 for both). When sections were stained with an antibody against myeloperoxidase (MPO), the density of MPO+ cells in pancreatitis was 1.9- and 1.6-folds higher than wt BMC and no BMC injection groups, separately (p ≤ 0.02 for both). Quantified by ELISA, db/db BMC produced more IL-6, GM-CSF, and IL-10 compared with wt BMC (p ≤ 0.04 for all). In conclusion, BMC of db/db mice produced more inflammatory cytokines. In response to acinar cell injury, diabetic BMC aggravated the inflammation cascade and acinar cell injury, leading to the progression of acute pancreatitis.

Cathepsin L plays a key role in SARS-CoV-2 infection in humans and humanized mice and is a promising target for new drug development.

To discover new drugs to combat COVID-19, an understanding of the molecular basis of SARS-CoV-2 infection is urgently needed. Here, for the first time, we report the crucial role of cathepsin L (CTSL) in patients with COVID-19. The circulating level of CTSL was elevated after SARS-CoV-2 infection and was positively correlated with disease course and severity. Correspondingly, SARS-CoV-2 pseudovirus infection increased CTSL expression in human cells in vitro and human ACE2 transgenic mice in vivo, while CTSL overexpression, in turn, enhanced pseudovirus infection in human cells. CTSL functionally cleaved the SARS-CoV-2 spike protein and enhanced virus entry, as evidenced by CTSL overexpression and knockdown in vitro and application of CTSL inhibitor drugs in vivo. Furthermore, amantadine, a licensed anti-influenza drug, significantly inhibited CTSL activity after SARS-CoV-2 pseudovirus infection and prevented infection both in vitro and in vivo. Therefore, CTSL is a promising target for new anti-COVID-19 drug development.

Glomerular function in relation to fine airborne particulate matter in a representative population sample.

From 1990 until 2017, global air-pollution related mortality increased by 40%. Few studies addressed the renal responses to ultrafine particulate [≤ 2.5 µm (PM2.5)], including black carbon (BC), which penetrate into the blood stream. In a Flemish population study, glomerular filtration estimated from serum creatinine (eGFR) and the urinary albumin-to-creatinine ratio were measured in 2005-2009 in 820 participants (women, 50.7%; age, 51.1 years) with follow-up of 523 after 4.7 years (median). Serum creatinine, eGFR, chronic kidney disease (eGFR < 60 mL/min/1.73 m2) and microalbuminuria (> 3.5/> 2.5 mg per mmol creatinine in women/men) were correlated in individual participants via their residential address with PM2.5 [median 13.1 (range 0.3-2.9) µg/m3] and BC [1.1 (0.3-18) µg/m3], using mixed models accounting for address clusters. Cross-sectional and longitudinally, no renal outcome was associated with PM2.5 or BC in models adjusted for sex and baseline or time varying covariables, including age, blood pressure, heart rate, body mass index, plasma glucose, the total-to-HDL serum cholesterol ratio, alcohol intake, smoking, physical activity, socioeconomic class, and antihypertensive treatment. The subject-level geocorrelations of eGFR change with to BC and PM2.5 were 0.13 and 0.02, respectively (P ≥ 0.68). In conclusion, in a population with moderate exposure, renal function was unrelated to ultrafine particulate.

Opportunities of Antidiabetic Drugs in Cardiovascular Medicine: A Meta-Analysis and Perspectives for Trial Design.

To identify potential application of GLP1-RAs (glucagon-like peptide-1 receptor agonists) and SGLT2-Is (sodium-dependent glucose cotrasnsporter-2 inhibitors) in cardiovascular medicine, we performed PubMed search until March 31, 2020 and selected placebo-controlled randomized trials (RCTs) in patients with type 2 diabetes mellitus. Twenty-four hour ambulatory and office blood pressure (BP), major adverse cardiovascular events (MACE), progression of chronic kidney disease (CKD), and changes in glycated hemoglobin and body weight were aggregated across RCTs using random-effect models. In 2238 patients (7 RCTs), SGLT2-Is lowered 24-hour systolic/diastolic BP by 4.4/1.9 mm Hg (95% CI, 3.4-5.5/1.2-2.6 mm Hg), whereas 2 GLP1-RAs RCTs produced contradictory BP results. Over 1.3 to 5.4 years of follow-up of 56 004 patients (7 RCTs), aggregate hazard ratios associated with GLP1-RA treatment were 0.88 (0.84-0.93) for MACE, 0.84 (0.74-0.89) for CKD, and ranged from 0.84 to 0.90 for individual MACE end points (P≤0.01). Across 5 SGLT2-Is RCTs, including 43 467 patients with 1.5 to 4.2 years follow-up, hazard ratios were 0.87 (0.82-0.93) for MACE, 0.68 (0.62-0.75) for HF, 0.82 (0.72-0.93) for cardiovascular death, 0.87 (0.79-0.96) for myocardial infarction, and 0.61 (0.56-0.67) for worsening CKD. The risk of HF and CKD, but not MACE, decreased with more BP lowering. Stricter glycemic control was associated with higher HF risk, but unrelated to MACE or CKD. The aggregate effect sizes on systolic BP, body weight, and glycated hemoglobin were -1.61 mm Hg, -2.40 kg, and -0.69% for GLP1-RAs, and -2.53 mm Hg, -1.15 kg and -0.24%, for SGLT2-Is (P<0.001). In conclusion, GLP1-RAs and SGLT2-Is reduced cardiovascular risk with differential benefit profiles.

Lower Circulating Interferon-Gamma Is a Risk Factor for Lung Fibrosis in COVID-19 Patients.

Cytokine storm resulting from SARS-CoV-2 infection is one of the leading causes of acute respiratory distress syndrome (ARDS) and lung fibrosis. We investigated the effect of inflammatory molecules to identify any marker that is related to lung fibrosis in coronavirus disease 2019 (COVID-19). Seventy-six COVID-19 patients who were admitted to Youan Hospital between January 21 and March 20, 2020 and recovered were recruited for this study. Pulmonary fibrosis, represented as fibrotic volume on chest CT images, was computed by an artificial intelligence (AI)-assisted program. Plasma samples were collected from the participants shortly after admission, to measure the basal inflammatory molecules levels. At discharge, fibrosis was present in 46 (60.5%) patients whose plasma interferon-γ (IFN-γ) levels were twofold lower than those without fibrosis (p > 0.05). The multivariate-adjusted logistic regression analysis demonstrated the inverse association risk of having lung fibrosis and basal circulating IFN-γ levels with an estimate of 0.43 (p = 0.02). Per the 1-SD increase of basal IFN-γ level in circulation, the fibrosis volume decreased by 0.070% (p = 0.04) at the discharge of participants. The basal circulating IFN-γ levels were comparable with c-reactive protein in the discrimination of the occurrence of lung fibrosis among COVID-19 patients at discharge, unlike circulating IL-6 levels. In conclusion, these data indicate that decreased circulating IFN-γ is a risk factor of lung fibrosis in COVID-19.

Nanomedicine for Gene Delivery for the Treatment of Cardiovascular Diseases.

BACKGROUND: Myocardial infarction (MI) is the most severe ischemic heart disease and directly leads to heart failure till death. Target molecules have been identified in the event of MI including increasing angiogenesis, promoting cardiomyocyte survival, improving heart function and restraining inflammation and myocyte activation and subsequent fibrosis. All of which are substantial in cardiomyocyte protection and preservation of cardiac function. METHODOLOGY: To modulate target molecule expression, virus and non-virus-mediated gene transfer have been investigated. Despite successful in animal models of MI, virus-mediated gene transfer is hampered by poor targeting efficiency, low packaging capacity for large DNA sequences, immunogenicity induced by virus and random integration into the human genome. DISCUSSION: Nanoparticles could be synthesized and equipped on purpose for large-scale production. They are relatively small in size and do not incorporate into the genome. They could carry DNA and drug within the same transfer. All of these properties make them an alternative strategy for gene transfer. In the review, we first introduce the pathological progression of MI. After concise discussion on the current status of virus-mediated gene therapy in treating MI, we overview the history and development of nanoparticle-based gene delivery system. We point out the limitations and future perspective in the field of nanoparticle vehicle. CONCLUSION: Ultimately, we hope that this review could help to better understand how far we are with nanoparticle-facilitated gene transfer strategy and what obstacles we need to solve for utilization of nanomedicine in the treatment of MI.

Fighting Type-2 Diabetes: Present and Future Perspectives.

BACKGROUND: Type-2 diabetes mellitus accounts for 80-90% of diabetic patients. So far, the treatment of diabetes mainly aims at elevating insulin level and lowering glucose level in the peripheral blood and mitigating insulin resistance. Physiologically, insulin secretion from pancreatic ß cells is delicately regulated. Thus, how insulin-related therapies could titrate blood glucose appropriately and avoid the occurrence of hypoglycemia remains an important issue for decades. Similar question is addressed on how to attenuate vascular complication in diabetic subjects. METHODS: We overviewed the evolution of each class of anti-diabetic drugs that have been used in clinical practice, focusing on their mechanisms, clinical results and cautions. RESULTS: Glucagon-like peptide-1 receptor agonists stimulate ß cells for insulin secretion in response to diet but not in fasting stage, which make them superior than conventional insulinsecretion stimulators. DPP-4 inhibitors suppress glucagon-like peptide-1 degradation. Sodium/ glucose co-transporter 2 inhibitors enhance glucose clearance through urine excretion. The appearance of these new drugs provides new information about glycemic control. We update the clinical findings of Glucagon-like peptide-1 receptor agonists, DPP-4 inhibitors and Sodium/glucose cotransporter 2 inhibitors in glycemic control and the risk or progression of cardiovascular disease in diabetic patients. Stem cell therapy might be an alternative tool for diabetic patients to improve ß cell regeneration and peripheral ischemia. We summarize the clinical results of mesenchymal stem cells transplanted into patients with diabetic limb and foot. CONCLUSION: A stepwise intensification of dual and triple therapy for individual diabetic patient is required to achieve therapeutic target.

The association of calcium channel blockers with ß-cell function in type 2 diabetic patients: A cross-sectional study.

Type 2 diabetes mellitus (T2DM) patients are often accompanied with hypertension. However, the association of antihypertensive drugs with ß-cell function has not been well studied. To investigate this question, the authors performed a cross-sectional study involving 882 hypertensive T2DM patients. To assess ß-cell function, patients were given 75g glucose orally and C-peptide levels before and 1, 2, and 3 hours after glucose intake were measured. Homa-ß was computed by Homeostasis Model Assessment model to evaluate ß-cell function using fasting C-peptide and glucose levels in the plasma. Multivariable-adjusted analysis was performed to evaluate the association of antihypertensive drugs with C-peptide levels, HbA1c, and Homa-ß. Among 882 hypertensive patients, 547 (62.0%) received antihypertensive treatment. Multivariate-adjusted analysis demonstrated that use of calcium channel blockers (CCBs) was negatively associated with HbA1c levels (CCBs: 0.95 [95% CI: 0.92-0.98], P = 0.002). Our data further illustrated that the C-peptide levels before and 1, 2, and 3 hours of OGTT were 1.10-, 1.18-, 1.19-, and 1.15-fold increase in T2DM patients taking CCBs (P = 0.084 for fasting C-peptide levels; P ≤ 0.024 for C-peptide levels at 1, 2, and 3 hours after OGTT) in comparison with non-CCB users. Nevertheless, usage of any other antihypertensive drugs did neither associated with HbA1c nor associated with C-peptide levels (P ≥ 0.11). In conclusion, CCB treatment was negatively associated with HbA1c levels but positively associated with ß-cell function in hypertensive T2DM patients, implying that CCBs could be considered to treat hypertensive T2DM patients with reduced ß-cell function.