IDO1 promotes CSFV replication by mediating tryptophan metabolism to inhibit NF-κB signaling.

Tryptophan metabolism plays a crucial role in facilitating various cellular processes essential for maintaining normal cellular function. Indoleamine 2,3-dioxygenase 1 (IDO1) catalyzes the conversion of tryptophan (Trp) into kynurenine (Kyn), thereby initiating the degradation of Trp. The resulting Kyn metabolites have been implicated in the modulation of immune responses. Currently, the role of IDO1-mediated tryptophan metabolism in the process of viral infection remains relatively unknown. In this study, we discovered that classical swine fever virus (CSFV) infection of PK-15 cells can induce the expression of IDO1, thereby promoting tryptophan metabolism. IDO1 can negatively regulate the NF-κB signaling by mediating tryptophan metabolism, thereby facilitating CSFV replication. We found that silencing the IDO1 gene enhances the expression of IFN-α, IFN-ß, and IL-6 by activating the NF-κB signaling pathway. Furthermore, our observations indicate that both silencing the IDO1 gene and administering exogenous tryptophan can inhibit CSFV replication by counteracting the cellular autophagy induced by Rapamycin. This study reveals a novel mechanism of IDO1-mediated tryptophan metabolism in CSFV infection, providing new insights and a theoretical basis for the treatment and control of CSFV.IMPORTANCEIt is well known that due to the widespread use of vaccines, the prevalence of classical swine fever (CSF) is shifting towards atypical and invisible infections. CSF can disrupt host metabolism, leading to persistent immune suppression in the host and causing significant harm when co-infected with other diseases. Changes in the host's metabolic profiles, such as increased catabolic metabolism of amino acids and the production of immunoregulatory metabolites and their derivatives, can also influence virus replication. Mammals utilize various pathways to modulate immune responses through amino acid utilization, including increased catabolic metabolism of amino acids and the production of immunoregulatory metabolites and their derivatives, thereby limiting viral replication. Therefore, this study proposes that targeting the modulation of tryptophan metabolism may represent an effective approach to control the progression of CSF.

Amino acid profile alteration in age-related atrial fibrillation.

BACKGROUND: Amino acids (AAs) are one of the primary metabolic substrates for cardiac work. The correlation between AAs and both atrial fibrillation (AF) and aging has been documented. However, the relationship between AAs and age-related AF remains unclear. METHODS: Initially, the plasma AA levels of persistent AF patients and control subjects were assessed, and the correlations between AA levels, age, and other clinical indicators were explored. Subsequently, the age-related AF mouse model was constructed and the untargeted myocardial metabolomics was conducted to detect the level of AAs and related metabolites. Additionally, the gut microbiota composition associated with age-related AF was detected by a 16S rDNA amplicon sequencing analysis on mouse fecal samples. RESULTS: Higher circulation levels of lysine (Student's t-test, P = 0.001), tyrosine (P = 0.002), glutamic acid (P = 0.008), methionine (P = 0.008), and isoleucine (P = 0.014), while a lower level of glycine (P = 0.003) were observed in persistent AF patients. The feature AAs identified by machine learning algorithms were glutamic acid and methionine. The association between AAs and age differs between AF and control subjects. Distinct patterns of AA metabolic profiles were observed in the myocardial metabolites of aged AF mice. Aged AF mice had lower levels of Betaine, L-histidine, L-alanine, L-arginine, L-Pyroglutamic acid, and L-Citrulline compared with adult AF mice. Aged AF mice also presented a different gut microbiota pattern, and its functional prediction analysis showed AA metabolism alteration. CONCLUSION: This study provided a comprehensive network of AA disturbances in age-related AF from multiple dimensions, including plasma, myocardium, and gut microbiota. Disturbances of AAs may serve as AF biomarkers, and restoring their homeostasis may have potential benefits for the management of age-related AF.

A high level of uric acid is associated with long-term adverse cardiovascular outcomes in patients who received fractional flow reserve with coronary intermediate stenosis.

BACKGROUND AND AIMS: The role of fractional flow reserve (FFR) in coronary intermediate lesions is widely recommended by guidelines. The effect of uric acid (UA) on cardiovascular events is also well known. However, the relationship between UA and long-term cardiovascular outcomes in patients who received FFR with intermediate lesions remains unknown. METHODS AND RESULTS: We retrospectively included 428 patients who underwent both coronary angiography (CAG) and FFR. Participants were stratified into two groups based on the median UA. The primary endpoint was the composite of major adverse cardiovascular and cerebrovascular events (MACCEs), including repeat revascularization, nonfatal stroke, nonfatal myocardial infarction, and all-cause death. A Cox proportional hazards model was utilized to analyze the association between UA and the prevalence of MACCEs. During a median follow-up of 5.8 years, a higher MACCEs rate occurred in the high UA group compared to the low UA group (16.8% vs. 5.1%, p log-rank<0.01). Elevated UA was independently linked to a higher incidence of MACCEs, whether UA was treated as a categorical or continuous variable (hazard ratio [HR] 2.76, 95% confidence interval [CI] 1.27-6.03 or HR 1.01, 95% CI 1.01-1.02). The restricted cubic spline (RCS) analysis illustrated that the HR for MACCEs increased with increasing UA. CONCLUSION: The present study demonstrates that UA is associated with MACCEs risk and suggests that UA is a reliable predictor of long-term cardiovascular events in coronary intermediate stenosis patients.

Triglyceride to high-density lipoprotein cholesterol ratio associated with long-term adverse clinical outcomes in patients deferred revascularization following fractional flow reserve.

BACKGROUND: Guidelines on coronary intermediate lesions strongly recommend deferred revascularization after detecting a normal fractional flow reserve (FFR). Researches about triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) on cardiovascular diseases has also been well conducted. However, the association of TG/HDL-C and long-term adverse clinical outcomes remains unknown for patients deferred revascularization following FFR. METHODS: This study retrospectively included 374 coronary artery disease (CAD) patients with non-significant coronary lesions diagnosed by coronary angiography (CAG) and FFR. The main outcome measure was the combination of major adverse cardiovascular and cerebrovascular events (MACCEs). All patients were categorized into three subgroups in terms of TG/HDL-C tertiles (T1 < 0.96, 0.96 ≤ T2 < 1.58, T3 ≥ 1.58). Three different Cox regression models were utilized to reveal the association between TG/HDL-C and prevalence of MACCEs. RESULTS: 47 MACCEs were recorded throughout a median monitoring period of 6.6 years. The Kaplan-Meier survival curves showed a higher MACCEs rate occurred in the higher TG/HDL-C group (5.6% vs. 12.9% vs. 19.4%, log-rank P < 0.01). After adjustment, patients in T3 suffered a 2.6-fold risk compared to the T1 group (T3 vs. T1: HR 2.55, 95% CI 1.05-6.21, P = 0.038; T2 vs. T1: HR 1.71, 95% CI 0.65-4.49, P = 0.075; P for trend = 0.001). The restricted cubic spline (RCS) analysis demonstrated that the HR for MACCEs rose as TG/HDL-C increased. Both the receiver operating characteristic (ROC) and time-dependent ROC proved the excellent predictive ability of TG/HDL-C. CONCLUSION: The study illustrates that TG/HDL-C correlates with the risk of MACCEs in CAD patients deferred revascularization following FFR. TG/HDL-C could serve as a dependable predictor of cardiovascular events over the long term in this population.

Physical activity, sedentary behavior, and the risk of frailty and falling: A Mendelian randomization study.

BACKGROUND: Due to inconclusive evidence from observational studies regarding the impact of physical activity (PA) and sedentary behavior on frailty and falling risk, we conducted a two-sample Mendelian randomization analysis to investigate the causal associations between PA, sedentary behavior, and frailty and falls. METHODS: We extracted summary data from genome-wide association studies conducted among individuals of European ancestry, encompassing PA (n = 90 667-608 595), sedentary behavior (n = 372 609-526 725), frailty index (n = 175 226), and falling risk (n = 451 179). Single nucleotide polymorphisms associated with accelerometer assessed fraction >425 milligravities, self-reported vigorous activity, moderate to vigorous physical acticity (MVPA), leisure screen time (LST), and sedentary behavior at work were taken as instrumental variables. The causal effects were primarily estimated using inverse variance weighted methods, complemented by several sensitivity and validation analyses. RESULTS: Genetically predicted higher levels of PA were significantly associated with a reduction in the frailty index (accelerometer assessed fraction >425 milligravities: ß = -0.25, 95% CI = -0.36 to -0.14, p = 1.27 × 10-5 ; self-reported vigorous activity: ß = -0.13, 95% CI = -0.20 to -0.05, p = 7.9 × 10-4 ; MVPA: ß = -0.28, 95% CI = -0.40 to -0.16, p = 9.9 × 10-6 ). Besides, LST was significantly associated with higher frailty index (ß = 0.18, 95% CI = 0.14-0.22, p = 5.2 × 10-20 ) and higher odds of falling (OR = 1.13, CI = 1.07-1.19, p = 6.9 × 10-6 ). These findings remained consistent throughout sensitivity and validation analyses. CONCLUSIONS: Our study offers evidence supporting a causal relationship between PA and a reduced risk of frailty. Furthermore, it underscores the association between prolonged LST and an elevated risk of frailty and falls. Therefore, promoting PA and reducing sedentary behavior may be an effective strategy in primary frailty and falls prevention.

On-Demand Removable Self-Healing and pH-Responsive Europium-Releasing Adhesive Dressing Enables Inflammatory Microenvironment Modulation and Angiogenesis for Diabetic Wound Healing.

Current diabetic wound treatments remain unsatisfactory due to the lack of a comprehensive strategy that can integrate strong applicability (tissue adhesiveness, shape adaptability, fast self-healability, and facile dressing change) with the initiation and smooth connection of the cascade wound healing processes. Herein, benefiting from the multifaceted bonding ability of tannic acid to metal ions and various polymers, a family of tannin-europium coordination complex crosslinked citrate-based mussel-inspired bioadhesives (TE-CMBAs) are specially developed for diabetic wound healing. TE-CMBAs can gel instantly (< 60 s), possess favorable shape-adaptability, considerable mechanical strengths, high elasticity, considerable wet tissue adhesiveness (≈40 kPa), favorable photothermal antimicrobial activity, excellent anti-oxidant activity, biocompatibility, and angiogenetic property. The reversible hydrogen bond crosslinking and sensitive metal-phenolic coordination also confers TE-CMBAs with self-healability, pH-responsive europium ion and TA releasing properties and on-demand removability upon mixing with borax solution, enabling convenient painless dressing change and the smooth connection of inflammatory microenvironment modulation, angiogenesis promotion, and effective extracellular matrix production leveraging the acidic pH condition of diabetic wounds. This adhesive dressing provides a comprehensive regenerative strategy for diabetic wound management and can be extended to other complicated tissue healing scenarios.

Swine Enteric Coronavirus: Diverse Pathogen-Host Interactions.

Swine enteric coronavirus (SeCoV) causes acute gastroenteritis and high mortality in newborn piglets. Since the last century, porcine transmissible gastroenteritis virus (TGEV) and porcine epidemic diarrhea virus (PEDV) have swept farms all over the world and caused substantial economic losses. In recent years, porcine delta coronavirus (PDCoV) and swine acute diarrhea syndrome coronavirus (SADS-CoV) have been emerging SeCoVs. Some of them even spread across species, which made the epidemic situation of SeCoV more complex and changeable. Recent studies have begun to reveal the complex SeCoV-host interaction mechanism in detail. This review summarizes the current advances in autophagy, apoptosis, and innate immunity induced by SeCoV infection. These complex interactions may be directly involved in viral replication or the alteration of some signal pathways.

Immunogenicity and Immunoprotection of PCV2 Virus-like Particles Incorporating Dominant T and B Cell Antigenic Epitopes Paired with CD154 Molecules in Piglets and Mice.

Porcine circovirus type 2 (PCV2) is capable of causing porcine circovirus-associated disease (PCVAD) and is one of the major threats to the global pig industry. The nucleocapsid protein Cap encoded by the PCV2 ORF2 gene is an ideal antigen for the development of PCV2 subunit vaccines, and its N-terminal nuclear localization sequence (NLS) structural domain is essential for the formation of self-assembling VLPs. In the present study, we systematically expressed and characterized full-length PCV2 Cap proteins fused to dominant T and B cell antigenic epitopes and porcine-derived CD154 molecules using baculovirus and found that the Cap proteins fusing epitopes were still capable of forming virus-like particles (VLPs). Both piglet and mice experiments showed that the Cap proteins fusing epitopes or paired with the molecular adjuvant CD154 were able to induce higher levels of humoral and cellular responses, particularly the secretion of PCV2-specific IFN-γ and IL-4. In addition, vaccination significantly reduced clinical signs and the viral load of PCV2 in the blood and tissues of challenged piglets. The results of the study provide new ideas for the development of a more efficient, safe and broad-spectrum next-generation PCV2 subunit vaccine.

Historical Evolutionary Dynamics and Phylogeography Analysis of Transmissible Gastroenteritis Virus and Porcine Deltacoronavirus: Findings from 59 Suspected Swine Viral Samples from China.

Since the beginning of the 21st century, humans have experienced three coronavirus pandemics, all of which were transmitted to humans via animals. Recent studies have found that porcine deltacoronavirus (PDCoV) can infect humans, so swine enteric coronavirus (SeCoV) may cause harm through cross-species transmission. Transmissible gastroenteritis virus (TGEV) and PDCoV have caused tremendous damage and loss to the pig industry around the world. Therefore, we analyzed the genome sequence data of these two SeCoVs by evolutionary dynamics and phylogeography, revealing the genetic diversity and spatiotemporal distribution characteristics. Maximum likelihood and Bayesian inference analysis showed that TGEV could be divided into two different genotypes, and PDCoV could be divided into four main lineages. Based on the analysis results inferred by phylogeography, we inferred that TGEV might originate from America, PDCoV might originate from Asia, and different migration events had different migration rates. In addition, we also identified positive selection sites of spike protein in TGEV and PDCoV, indicating that the above sites play an essential role in promoting membrane fusion to achieve adaptive evolution. In a word, TGEV and PDCoV are the past and future of SeCoV, and the relatively smooth transmission rate of TGEV and the increasing transmission events of PDCoV are their respective transmission characteristics. Our results provide new insights into the evolutionary characteristics and transmission diversity of these SeCoVs, highlighting the potential for cross-species transmission of SeCoV and the importance of enhanced surveillance and biosecurity measures for SeCoV in the context of the COVID-19 epidemic.

Viruses Hijack ERAD to Regulate Their Replication and Propagation.

Endoplasmic reticulum-associated degradation (ERAD) is highly conserved in yeast. Recent studies have shown that ERAD is also ubiquitous and highly conserved in eukaryotic cells, where it plays an essential role in maintaining endoplasmic reticulum (ER) homeostasis. Misfolded or unfolded proteins undergo ERAD. They are recognized in the ER, retrotranslocated into the cytoplasm, and degraded by proteasomes after polyubiquitin. This may consist of several main steps: recognition of ERAD substrates, retrotranslocation, and proteasome degradation. Replication and transmission of the virus in the host is a process of a "game" with the host. It can be assumed that the virus has evolved various mechanisms to use the host's functions for its replication and transmission, including ERAD. However, until now, it is still unclear how the host uses ERAD to deal with virus infection and how the viruses hijack the function of ERAD to obtain a favorable niche or evade the immune clearance of the host. Recent studies have shown that viruses have also evolved mechanisms to use various processes of ERAD to promote their transmission. This review describes the occurrence of ERAD and how the viruses hijack the function of ERAD to spread by affecting the homeostasis and immune response of the host, and we will focus on the role of E3 ubiquitin ligase.

CD38: A Potential Therapeutic Target in Cardiovascular Disease.

Substantial research has demonstrated the association between cardiovascular disease and the dysregulation of intracellular calcium, ageing, reduction in nicotinamide adenine dinucleotide NAD+ content, and decrease in sirtuin activity. CD38, which comprises the soluble type, type II, and type III, is the main NADase in mammals. This molecule catalyses the production of cyclic adenosine diphosphate ribose (cADPR), nicotinic acid adenine dinucleotide phosphate (NAADP), and adenosine diphosphate ribose (ADPR), which stimulate the release of Ca2+, accompanied by NAD+ consumption and decreased sirtuin activity. Therefore, the relationship between cardiovascular disease and CD38 has been attracting increased attention. In this review, we summarize the structure, regulation, function, targeted drug development, and current research on CD38 in the cardiac context. More importantly, we provide original views about the as yet elusive mechanisms of CD38 action in certain cardiovascular disease models. Based on our review, we predict that CD38 may serve as a novel therapeutic target in cardiovascular disease in the future.

Metformin-loaded ß-TCP/CTS/SBA-15 composite scaffolds promote alveolar bone regeneration in a rat model of periodontitis.

Periodontitis is a progressive infectious inflammatory disease, which leads to alveolar bone resorption and loss of periodontal attachment. It is imperative for us to develop a therapeutic scaffold to repair the alveolar bone defect of periodontitis. In this study, we designed a new composite scaffold loading metformin (MET) by using the freeze-drying method, which was composed of ß-tricalcium phosphate (ß-TCP), chitosan (CTS) and the mesoporous silica (SBA-15). The scaffolds were expected to combine the excellent biocompatibility of CTS, the good bioactivity of ß-TCP, and the anti-inflammatory properties of MET. The MET-loaded ß-TCP/CTS/SBA-15 scaffolds showed improved cell adhesion, appropriate porosity and good biocompatibility in vitro. This MET composite scaffold was implanted in the alveolar bone defects area of rats with periodontitis. After 12 weeks, Micro-CT and histological analysis were performed to evaluate different degrees of healing and mineralization. Results showed that the MET-loaded ß-TCP/CTS/SBA-15 scaffolds promoted alveolar bone regeneration in a rat model of periodontitis. To our knowledge, this is the first report that MET-loaded ß-TCP/CTS/SBA-15 scaffolds have a positive effect on alveolar bone regeneration in periodontitis. Our findings might provide a new and promising strategy for repairing alveolar bone defects under the condition of periodontitis.

Viral Infection Modulates Mitochondrial Function.

Mitochondria are important organelles involved in metabolism and programmed cell death in eukaryotic cells. In addition, mitochondria are also closely related to the innate immunity of host cells against viruses. The abnormality of mitochondrial morphology and function might lead to a variety of diseases. A large number of studies have found that a variety of viral infections could change mitochondrial dynamics, mediate mitochondria-induced cell death, and alter the mitochondrial metabolic status and cellular innate immune response to maintain intracellular survival. Meanwhile, mitochondria can also play an antiviral role during viral infection, thereby protecting the host. Therefore, mitochondria play an important role in the interaction between the host and the virus. Herein, we summarize how viral infections affect microbial pathogenesis by altering mitochondrial morphology and function and how viruses escape the host immune response.

Identification of a nonsense mutation in TNNI3K associated with cardiac conduction disease.

BACKGROUND: Cardiac conduction disease (CCD) is a common cardiovascular disease which can lead to life-threatening conditions. The importance of heredity in CCD has been realized in recent years. Several causal genes have been found to be implicated in CCD such as SCN5A, TRPM4, SCN1B, TNNI3K, LMNA, and NKX2.5. To date, only four genetic mutations in TNNI3K have been identified related to CCD. METHODS: Whole-exome sequencing (WES) was carried out in order to identify the underlying disease-causing mutation in a Chinese family with CCD. The potential mutations were confirmed by Sanger sequencing. Real-time qPCR was used to detect the level of TNNI3K mRNA expression. RESULTS: A nonsense mutation in TNNI3K (NM_015978.2: g.170891C > T, c.1441C > T) was identified in this family and validated by Sanger sequencing. Real-time qPCR confirmed that the level of TNNI3K mRNA expression was decreased compared with the controls. CONCLUSIONS: This study found the first nonsense TNNI3K mutation associated with CCD in a Chinese family. TNNI3K harboring the mutation (c.1441C > T) implicated a loss-of-function pathogenic mechanism with an autosomal dominant inheritance pattern. This research enriches the phenotypic spectrum of TNNI3K mutations, casting a new light upon the genotype-phenotype correlations between TNNI3K mutations and CCD and indicating the importance of TNNI3K screening in CCD patients.

The Role of Autophagy and Autophagy Receptor NDP52 in Microbial Infections.

Autophagy is a general protective mechanism for maintaining homeostasis in eukaryotic cells, regulating cellular metabolism, and promoting cell survival by degrading and recycling cellular components under stress conditions. The degradation pathway that is mediated by autophagy receptors is called selective autophagy, also named as xenophagy. Autophagy receptor NDP52 acts as a 'bridge' between autophagy and the ubiquitin-proteasome system, and it also plays an important role in the process of selective autophagy. Pathogenic microbial infections cause various diseases in both humans and animals, posing a great threat to public health. Increasing evidence has revealed that autophagy and autophagy receptors are involved in the life cycle of pathogenic microbial infections. The interaction between autophagy receptor and pathogenic microorganism not only affects the replication of these microorganisms in the host cell, but it also affects the host's immune system. This review aims to discuss the effects of autophagy on pathogenic microbial infection and replication, and summarizes the mechanisms by which autophagy receptors interact with microorganisms. While considering the role of autophagy receptors in microbial infection, NDP52 might be a potential target for developing effective therapies to treat pathogenic microbial infections.

The impact of balance-focused attitudes on job stress: Gender differences evidenced in American and Chinese samples.

Based on gender role expectations model, we examined how balance-focused attitudes would affect job stress by influencing individuals' perceptions of family interference with work (FIW), and investigated whether a gender difference would exist in the relationships among balance-focused attitudes, FIW and job stress. Using two independent samples from the United States and China, we found support for the indirect influence of balance-focused attitudes on job stress, through FIW. Participants with balance-focused attitudes experienced lower levels of job stress as they perceived less interference from family to work. As expected, such indirect effect was more pronounce among male participants, meaning that the male participants benefited more from having balance-focused attitudes. Discussion, theoretical and practical implications are provided.

Beyond Vision Impairments: Redefining the Scope of Accessible Data Representations.

The increasing ubiquity of data in everyday life has elevated the importance of data literacy and accessible data representations, particularly for individuals with disabilities. While prior research predominantly focuses on the needs of the visually impaired, our survey aims to broaden this scope by investigating accessible data representations across a more inclusive spectrum of disabilities. After conducting a systematic review of 152 accessible data representation papers from ACM and IEEE databases, we found that roughly 78% of existing articles center on vision impairments. In this paper, we conduct a comprehensive review of the remaining 22% of papers focused on underrepresented disability communities. We developed categorical dimensions based on accessibility, visualization, and human-computer interaction to classify the papers. These dimensions include the community of focus, issues addressed, contribution type, study methods, participants, data type, visualization type, and data domain. Our work redefines accessible data representations by illustrating their application for disabilities beyond those related to vision. Building on our literature review, we identify and discuss opportunities for future research in accessible data representations. All supplemental materials are available at https://osf.io/ yv4xm/?view_only=b36a3fbf7a14b3888029966faa3def9.

Injective Programmable Proanthocyanidin-Coordinated Zinc-Based Composite Hydrogel for Infected Bone Repair.

Effectively integrating infection control and osteogenesis to promote infected bone repair is challenging. Herein, injective programmable proanthocyanidin (PC)-coordinated zinc-based composite hydrogels (ipPZCHs) are developed by compositing antimicrobial and antioxidant PC-coordinated zinc oxide (ZnO) microspheres with thioether-grafted sodium alginate (TSA), followed by calcium chloride (CaCl2 ) crosslinking. Responsive to the high endogenous reactive oxygen species (ROS) microenvironment in infected bone defects, the hydrophilicity of TSA can be significantly improved, to trigger the disintegration of ipPZCHs and the fast release of PC-coordinated ZnOs. This together with the easily dissociable PC-Zn2+ coordination induced fast release of antimicrobial zinc (Zn2+ ) with/without silver (Ag+ ) ions from PC-coordinated ZnOs (for Zn2+ , > 100 times that of pure ZnO) guarantees the strong antimicrobial activity of ipPZCHs. The exogenous ROS generated by ZnO and silver nanoparticles during the antimicrobial process further speeds up the disintegration of ipPZCHs, augmenting the antimicrobial efficacy. At the same time, ROS-responsive degradation/disintegration of ipPZCHs vacates space for bone ingrowth. The concurrently released strong antioxidant PC scavenges excess ROS thus enhances the immunomodulatory (in promoting the anti-inflammatory phenotype (M2) polarization of macrophages) and osteoinductive properties of Zn2+ , thus the infected bone repair is effectively promoted via the aforementioned programmable and self-adaptive processes.

Advancing Guideline-Directed Medical Therapy in Heart Failure: Overcoming Challenges and Maximizing Benefits.

The delayed titration of guideline-directed drug therapy (GDMT) is a complex event influenced by multiple factors that often result in poor prognosis for patients with heart failure (HF). Individualized adjustments in GDMT titration may be necessary based on patient characteristics, and every clinician is responsible for promptly initiating GDMT and titrating it appropriately within the patient's tolerance range. This review examines the current challenges in GDMT implementation and scrutinizes titration considerations within distinct subsets of HF patients, with the overarching goal of enhancing the adoption and effectiveness of GDMT. The authors also underscore the significance of establishing a novel management strategy that integrates cardiologists, nurse practitioners, pharmacists, and patients as a unified team that can contribute to the improved promotion and implementation of GDMT.

Causal relationship between particulate matter and COVID-19 risk: A mendelian randomization study.

Background: Observational studies have linked exposure to fine (PM2.5) and coarse (PM10) particulate matter air pollution with adverse COVID-19 outcomes, including higher incidence and mortality. However, some studies questioned the effect of air pollution on COVID-19 susceptibility, raising questions about the causal nature of these associations. To address this, a less biased method like Mendelian randomization (MR) is utilized, which employs genetic variants as instrumental variables to infer causal relationships in observational data. Method: We performed two-sample MR analysis using public genome-wide association studies data. Instrumental variables correlated with PM2.5 concentration, PM2.5 absorbance, PM2.5-10 concentration and PM10 concentration were identified. The inverse variance weighted (IVW), robust adjusted profile score (RAPS) and generalized summary data-based Mendelian randomization (GSMR) methods were used for analysis. Results: IVW MR analysis showed PM2.5 concentration [odd ratio (OR) = 3.29, 95% confidence interval (CI) 1.48-7.35, P-value = 0.0036], PM2.5 absorbance (OR = 5.62, 95%CI 1.98-15.94, P-value = 0.0012), and PM10 concentration (OR = 3.74, 95%CI 1.52-9.20, P-value = 0.0041) increased the risk of COVID-19 severity after Bonferroni correction. Further validation confirmed PM2.5 absorbance was associated with heightened COVID-19 severity (OR = 6.05, 95%CI 1.99-18.38, P-value = 0.0015 for RAPS method; OR = 4.91, 95%CI 1.65-14.59, P-value = 0.0042 for GSMR method) and hospitalization (OR = 3.15, 95%CI 1.54-6.47, P-value = 0.0018 for RAPS method). No causal links were observed between particulate matter exposure and COVID-19 susceptibility. Conclusions: Our study established a causal relationship between smaller particle pollution, specifically PM2.5, and increased risk of COVID-19 severity and hospitalization. These findings highlight the importance of improving air quality to mitigate respiratory disease progression.