The association between low serum calcium level and new-onset atrial fibrillation after coronary artery bypass grafting.

OBJECTIVES: This study aims to investigate the relationship between serum calcium (SC) levels and the incidence of postoperative atrial fibrillation (POAF) in patients undergoing coronary artery bypass graft surgery. METHODS: This retrospective, observational cohort study consecutively enrolled patients undergoing isolated coronary artery bypass grafting in Beijing Anzhen Hospital from January 2018 to December 2021. Patients with a previous history of atrial fibrillation or atrial flutter or requiring concomitant cardiac surgery were excluded. A logistic regression model was used to determine predictors of POAF. Multivariable adjustment, inverse probability of treatment weighting and propensity score matching were used to adjust for confounders. Moreover, we conducted univariable and multivariable logistic regression analyses on preoperative and postoperative SC and ionized SC levels. RESULTS: The analysis encompassed 12 293 patients. The POAF rate was significantly higher in patients with low SC level than those without (1379 [33.9%] vs 2375 [28.9%], P < 0.001). Low SC level was associated with an increased odds ratio of POAF (odds ratio [95% confidence interval]: 1.27 [1.18-1.37], P < 0.001). Inverse probability of treatment weighting and propensity score matching analyses confirmed the results. The increased POAF rate in low SC level group still existed among subgroup analysis based on different age, sex, body mass index, hypertension, hyperlipidaemia, CHA2DS2-VASc and magnesium. CONCLUSIONS: Low SC level indicates elevated POAF risk in patients undergoing isolated coronary artery bypass graft surgery even after the adjustment for age, sex, cardiovascular risk factors, echocardiographic parameters and laboratory markers.

Recent advances in small-molecule inhibitors targeting influenza virus RNA-dependent RNA polymerase / 药学学报

Influenza virus causes serious threat to human life and health. Due to the inherent high variability of influenza virus, clinically resistant mutant strains of currently approved anti-influenza virus drugs have emerged. Therefore, it is urgent to develop antiviral drugs with new targets or mechanisms of action. RNA-dependent RNA polymerase is directly responsible for viral RNA transcription and replication, and plays key roles in the viral life cycle, which is considered an important target of anti-influenza drug design. From the point of view of medicinal chemistry, this review summarizes current advances in diverse small-molecule inhibitors targeting influenza virus RNA-dependent RNA polymerase, hoping to provide valuable reference for development of novel antiviral drugs.

Recent advances in drug screening methods of SARS-CoV-2 spike protein / 药学学报

The pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a serious impact on global public health and the economy. SARS-CoV-2 infiltrates host cells via its surface spike protein, which binds to angiotensin-converting enzyme 2 on the host cell membrane. As a result, small molecules targeting spike protein have emerged as a hotspot in anti-SARS-CoV-2 drug research. Activity screening is an important step in seeking small molecule drugs. Therefore, this article aims to review the biological activity evaluation methods of small molecule inhibitors targeting SARS-CoV-2 spike protein, with the goal of laying the foundation for the discovery of new anti-SARS-CoV-2 drugs.

Research progress of anti-gout small molecules targeting the NLRP3 inflammasome / 药学学报

Currently, clinically used drugs for the treatment of gout inflammation, such as colchicine, nonsteroidal anti-inflammatory drugs, and glucocorticoids, can only relieve the pain of joint inflammation and have severe hepatorenal toxicity and multiple organ adverse reactions. The NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome is a key complex that induces the onset of gout inflammation and has become a crucial target in the development of anti-gout drugs. This article reviews the research progress of anti-gout small molecules targeting the NLRP3 inflammasome and their bioactivity evaluation methods in the past five years, in order to provide information for the development of specific drugs for the treatment of gout inflammation.

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The main protease (Mpro) of SARS-CoV-2 is an attractive target in anti-COVID-19 therapy for its high conservation and major role in the virus life cycle. The covalent Mpro inhibitor nirmatrelvir (in combination with ritonavir, a pharmacokinetic enhancer) and the non-covalent inhibitor ensitrelvir have shown efficacy in clinical trials and have been approved for therapeutic use. Effective antiviral drugs are needed to fight the pandemic, while non-covalent Mpro inhibitors could be promising alternatives due to their high selectivity and favorable druggability. Numerous non-covalent Mpro inhibitors with desirable properties have been developed based on available crystal structures of Mpro. In this article, we describe medicinal chemistry strategies applied for the discovery and optimization of non-covalent Mpro inhibitors, followed by a general overview and critical analysis of the available information. Prospective viewpoints and insights into current strategies for the development of non-covalent Mpro inhibitors are also discussed.

Double-layer horizontal cross sutures for intra-atrial mitral valve implantation: An effective surgical method for severe mitral annular calcification.

Objective: Severe mitral annular calcification (MAC) can make prosthetic implantation extremely difficult. Although intra-atrial mitral valve prosthesis implantation without annular decalcification offers a simpler approach, it poses a potential rupture risk due to high left ventricular pressure. We developed a double-layer (DL) horizontal cross-suture technique, which ensures close proximity of the valve prosthesis to the calcified annulus and segregates the left atrial wall from the left ventricle. The aim of this study was to compare the outcomes of DL suture with conventional single-layer (SL) suture in patients with severe MAC. Methods: This retrospective cohort study consecutively enrolled patients with severe MAC undergoing mitral valve replacement at Beijing Anzhen Hospital from May 2018 to December 2022. A detailed description of the DL suture method is described. Follow-up medical evaluations, including transthoracic echocardiography measurements, were obtained through outpatient chart reviews. Results: The study included 10 patients in the DL suture group and 20 in the SL suture group. All patients in the DL group and all but 3 in the SL group achieved technical success. Compared with the SL group, the DL suture technique was associated with lower rates of perivalvular leakage, stroke, new-onset atrial fibrillation, reoperation, and 30-day mortality. Follow-up was complete, with 1 late mortality in the DL group due to stroke and 4 cardiovascular deaths in the SL group. Conclusions: The DL horizontal cross-suture technique offers a more effective and safer approach for intra-atrial mitral valve implantation in severe MAC cases than the conventional SL suture method.

Rationale and design of a randomized trial of the dapagliflozin evaluation on atrial fibrillation patients followed Cox-Maze IV: the DETAIL-CMIV study.

AIMS: Dapagliflozin has been widely used for the treatment of type 2 diabetes mellitus (T2DM) and heart failure (HF). However, data concerning the association between dapagliflozin and the recurrence of atrial fibrillation (AF), especially in patients following Cox-Maze IV (CMIV), are rare. We aim to explore the effect of dapagliflozin on the recurrence of AF after CMIV with and without T2DM or HF. METHODS AND RESULTS: The study of dapagliflozin evaluation in AF patients followed by CMIV (DETAIL-CMIV) is a prospective, double-blind, randomized, placebo-controlled trial. A total of 240 AF patients who have received the CMIV procedure will be randomized into the dapagliflozin group (10 mg/day, n = 120) and the placebo group (10 mg/day, n = 120) and treated for 3 months. The primary endpoint is any documented atrial tachyarrhythmia (AF, atrial flutter or atrial tachycardia) lasting 30 s following a blanking period of 3 months after CMIV. CONCLUSION: DETAIL-CMIV will determine whether the sodium-glucose cotransporter-2 inhibitor dapagliflozin, added to guideline-recommended post-operative AF therapies, safely reduces the recurrence rate of AF in patients with and without T2DM or HF.

Broad and colossal edge supercurrent in Dirac semimetal Cd3As2 Josephson junctions.

Edge supercurrent has attracted great interest recently due to its crucial role in achieving and manipulating topological superconducting states. Proximity-induced superconductivity has been realized in quantum Hall and quantum spin Hall edge states, as well as in higher-order topological hinge states. Non-Hermitian skin effect, the aggregation of non-Bloch eigenstates at open boundaries, promises an abnormal edge channel. Here we report the observation of broad edge supercurrent in Dirac semimetal Cd3As2-based Josephson junctions. The as-grown Cd3As2 nanoplates are electron-doped by intrinsic defects, which enhance the non-Hermitian perturbations. The superconducting quantum interference indicates edge supercurrent with a width of ~1.6 µm and a magnitude of ~1 µA at 10 mK. The wide and large edge supercurrent is inaccessible for a conventional edge system and suggests the presence of non-Hermitian skin effect. A supercurrent nonlocality is also observed. The interplay between band topology and non-Hermiticity is beneficial for exploiting exotic topological matter.

Anterior cervical discectomy and fusion for the treatment of giant cervical disc herniation.

OBJECTIVE: Giant cervical disc herniation (GCDH) was defined as a herniated intervertebral disc that accounted for more than 50% of the spinal canal. The purpose of this study was to analyse the feasibility of anterior cervical discectomy and fusion (ACDF) for the treatment of GCDH. METHODS: Patient demographic and imaging data, clinical results, and perioperative complications were analysed retrospectively. RESULTS: A total of 23 patients were included in the study. Spinal cord recovery pulsation was observed under a microscope in all cases. Postoperative magnetic resonance imaging showed complete decompression of the spinal cord and no residual intervertebral disc. The patients were followed up for 12 to 18 months. The average visual analogue scale score and Neck Disability Index decreased from 8.6 ± 0.5 and 86.0 ± 2.7% to 2.2 ± 0.2 and 26.7 ± 2.0%, respectively, three days after surgery. The average Japanese Orthopedic Association score increased from 6.9 ± 2.1 to 13.9 ± 1.1. The cervical spinal cord function improvement rate was 69.3%. No neurological complications after surgery were observed. CONCLUSION: This study shows that ACDF is feasible for the treatment of GCDH disease. The results indicate that this approach can be used to safely remove herniated disc fragments, effectively relieve compression of the spinal cord, and improve neurological function.

Detection of Various Microplastics in Patients Undergoing Cardiac Surgery.

Microplastics have been detected in human stool, lungs, and placentas, which have direct exposure to the external environment through various body cavities, including the oral/anal cavity and uterine/vaginal cavity. Crucial data on microplastic exposure in completely enclosed human organs are still lacking. Herein, we used a laser direct infrared chemical imaging system and scanning electron microscopy to investigate whether microplastics exist in the human heart and its surrounding tissues. Microplastic specimens were collected from 15 cardiac surgery patients, including 6 pericardia, 6 epicardial adipose tissues, 11 pericardial adipose tissues, 3 myocardia, 5 left atrial appendages, and 7 pairs of pre- and postoperative venous blood samples. Microplastics were not universally present in all tissue samples, but nine types were found across five types of tissue with the largest measuring 469 µm in diameter. Nine types of microplastics were also detected in pre- and postoperative blood samples with a maximum diameter of 184 µm, and the type and diameter distribution of microplastics in the blood showed alterations following the surgical procedure. Moreover, the presence of poly(methyl methacrylate) in the left atrial appendage, epicardial adipose tissue, and pericardial adipose tissue cannot be attributed to accidental exposure during surgery, providing direct evidence of microplastics in patients undergoing cardiac surgery. Further research is needed to examine the impact of surgery on microplastic introduction and the potential effects of microplastics in internal organs on human health.

Calcium promotes vascular smooth muscle cell phenotypic switching in Marfan syndrome.

Fibrillin 1 (Fbn1) mutations cause Marfan syndrome (MFS), with aortic root dilatation, dissection, and rupture. Few studies reported the blood calcium and lipid profile of MFS, and the effect of vascular smooth muscle cell (VSMC) phenotypic switching on MFS aortic aneurysm is unclear. Here, we aimed to investigate the role of calcium-related VSMC phenotypic switching in MFS. We retrospectively collected MFS patients' clinical data, performed bioinformatics analysis to screen the enriched biological process in MFS patients and mice, and detected markers of VSMC phenotypic switching on Fbn1C1039G/+ mice and primary aortic vascular smooth muscle cells. We found that patients with MFS have elevated blood calcium levels and dyslipidemia. Furthermore, the calcium concentration levels were increased with age in MFS mice, accompanied by the promoted VSMC phenotypic switching, and SERCA2 contributed to maintaining the contractile phenotype of VSMCs. This study provides the first evidence that the increased calcium is associated with the promoted VSMC phenotype switching in MFS. SERCA may become a novel therapeutic target for suppressing aneurysm progression in MFS.

Risk of Cardiovascular Death in Osteosarcoma.

OBJECTIVE: To assess the risk of cardiovascular mortality (CVM) in patients with osteosarcoma. STUDY DESIGN: Descriptive study. Place and Duration of the Study: Department of Orthopaedics, The People's Hospital of Baoan, Shenzhen, Guangdong, China, from 1st January 2019 to 1st January 2022. METHODOLOGY: Data on patients diagnosed with osteosarcoma, between 1975 and 2019, were obtained from the surveillance, epidemiology, and end results (SEER) database. Using the Nelson-Aalen cumulative risk curve to assess the risk of CVM in patients with osteosarcoma. Competing risk models were used for identifying and analysing independent risk factors for CVM in the patients. RESULTS: Data from a total of 1335 patients with osteosarcoma were obtained from the SEER database. The characteristics of patients with osteosarcoma independently related with a high risk of CVM were age over 65 years (HR: 2.528; 95% CI: 1.156 - 5.527), race of other categories (HR: 1.498; 95% CI: 1.044 - 2.151), and exposure radiotherapy (HR: 0.493; 95% CI: 0.244 - 0.998). Receiving chemotherapy was independently associated with a low risk of CVM (HR: 1.911; 95% CI: 1.016 - 3.593). CONCLUSION: Cardiovascular disease death from osteosarcoma was significantly associated with older age at diagnosis, race other class, receiving radiation therapy, and not undergoing chemotherapy. KEY WORDS: Osteosarcoma, Cancer risk factors, Epidemiology.

Metabolic signatures in pericardial fluid and serum are associated with new-onset atrial fibrillation after isolated coronary artery bypass grafting.

Postoperative atrial fibrillation (POAF) is a common complication of coronary artery bypass grafting (CABG) procedures. However, the molecular mechanism of POAF remains poorly understood, hence the absence of effective prevention strategies. Here we used targeted metabolomics on pericardial fluid and serum samples from CABG patients to investigate POAF-associated metabolic alterations and related risk prediction of new-onset AF. Nine differential metabolites in various metabolic pathways were found in both pericardial fluid and serum samples from patients with POAF and without POAF. By using machine learning algorithms and regression models, a 4-metabolite (aceglutamide, ornithine, methionine, and arginine) risk prediction model was constructed and showed accurate performance in predicting POAF in both discovery and validation sets. This work extends the metabolic insights of the cardiac microenvironment and blood in patients with POAF and paves the way for the use of targeted metabolomics for predicting POAF in patients with CABG surgery.

Advances in the research of HIV-1 envelope glycoprotein gp120 inhibitors / 药学学报

From the process of human immunodeficiency virus-1 (HIV-1) invading cells, the combination of gp120 and CD4 is the first step for HIV-1 to invade cells. Interfering with this process can prevent HIV from recognizing target cells and inhibit virus replication. Therefore, HIV-1 gp120 is an important part of the HIV-1 life cycle. Fostesavir, a phosphatate prodrug derived from the gp120 inhibitor BMS-626529 modified by the prodrug strategy, was approved for the treatment of adult patients with multidrug resistant HIV-1 infection by the US FDA and the European Medicines Agency in 2020 and 2021, respectively. In this review, we focus on the research progress of small molecule inhibitors targeting the interaction of gp120-CD4 from the perspective of medicinal chemistry, in order to provide reference for the subsequent research of gp120 inhibitors.

Discovery of novel sulfonamide substituted indolylarylsulfones as potent HIV-1 inhibitors with better safety profiles

Indolylarylsulfones (IASs) are classical HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) with a unique scaffold and possess potent antiviral activity. To address the high cytotoxicity and improve safety profiles of IASs, we introduced various sulfonamide groups linked by alkyl diamine chain to explore the entrance channel of non-nucleoside inhibitors binding pocket. 48 compounds were designed and synthesized to evaluate their anti-HIV-1 activities and reverse transcriptase inhibition activities. Especially, compound R10L4 was endowed with significant inhibitory activity towards wild-type HIV-1 (EC50(WT) = 0.007 μmol/L, SI = 30,930) as well as a panel of single-mutant strains exemplified by L100I (EC50 = 0.017 μmol/L, SI = 13,055), E138K (EC50 = 0.017 μmol/L, SI = 13,123) and Y181C (EC50 = 0.045 μmol/L, SI = 4753) which were superior to Nevirapine and Etravirine. Notably, R10L4 was characterized with significantly reduced cytotoxicity (CC50 = 216.51 μmol/L) and showed no remarkable in vivo toxic effects (acute and subacute toxicity). Moreover, the computer-based docking study was also employed to characterize the binding mode between R10L4 and HIV-1 RT. Additionally, R10L4 presented an acceptable pharmacokinetic profile. Collectively, these results deliver precious insights for next optimization and indicate that the sulfonamide IAS derivatives are promising NNRTIs for further development.

Recent advances of antiviral drugs based on multispecific binding strategy / 药学学报

To address the continuous emergence of drug-resistant strains of viruses and the outbreaks of novel virus infections, developing new antiviral drugs based on novel strategies has become an important and urgent research topic. In recent years, the rapidly developing multi-specific binding strategy has become a focus and been widely applied in antiviral. This review summarizes the recent progress of the multi-specific binding strategy in the antiviral field from the perspective of medicinal chemistry and discusses existing challenges as well as future opportunities for antiviral drug discovery.

Recent advances of small molecule inhibitors directly targeting HBV / 药学学报

Hepatitis B virus infection is a serious threat to human life and health. The approved anti-HBV drugs including interferons and nucleos(t)ide analogues have serious adverse effect, rebound phenomena after drug withdrawal, and drug resistance. And the cccDNA cannot be completely eliminated by both of them, which is the reason why a complete cure for hepatitis B cannot be achieved. Therefore, developing anti-HBV drugs directly targeting protein or nucleic acid of HBV remains a current public health priority. Based on the analysis of representative literature from the last decade, this article reviews recent developments in small molecule inhibitors directly targeting HBV from a medicinal chemistry perspective.

Recent advances in small-molecule inhibitors targeting influenza virus glycoproteins / 药学学报

Hemagglutinin and neuraminidase, two important glycoproteins on the surface of influenza virus, play a considerable role in the entry and release stage of the viral life cycle, respectively. With in-depth investigation of influenza virus glycoproteins and the continuous innovation of drug discovery strategies, a new generation of glycoproteins inhibitors have been continuously discovered. From the point of view of medicinal chemistry, this review summarizes the current advances in seeking small-molecule inhibitors targeting influenza virus glycoproteins, hoping to provide valuable guidance for future development of novel antiviral drugs.