RC48-Antibody-Drug Conjugate in Metastatic Urothelial Carcinoma: A Multicenter Real-World Study in China.

OBJECTIVES: RC48 is an antibody-drug conjugate (ADC) that targets HER2. In China, RC48 is approved for patients with HER-2-positive metastatic urothelial carcinoma (mUC) who have failed at least platinum-based chemotherapy. This study aimed to evaluate RC48 for mUC in a cohort of real-world patients. MATERIALS AND METHODS: We retrospectively collected data from 103 mUC patients from 12 centers between July 2021 and August 2023 in China. RC48 alone or with immunotherapy was administered until disease progression, intolerable toxicity, death, or other reasons. The objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and incidence of treatment-related adverse events (TRAEs) were evaluated. RESULTS: The median age of the patients was 68 years, and 68.0% were men. Twenty-nine (28.2%) patients received RC48 alone; 73 (70.9%) received RC48 combination therapy. The response rates were as follows: complete response in 2 (1.9%) patients, partial response in 50 (48.5%) patients, stable disease in 30 (29.1%) patients. The ORR was 50.5%. In patients with ≥80 years, Eastern Cooperative Oncology Group (ECOG) performance status ≥2 and creatinine clearance rate (CCr) <30 mL/min, the ORR was 75%, 48.6%, and 40.0%, respectively. The median PFS was 6 (3.9-8.1) months, and the median OS was not reached. The most reported TRAEs were peripheral sensory neuropathy (53.4%), alopecia (42.7%), asthenia (38.8%), decreased appetite (35.9%) and weight loss (35.9%) and TRAE did not increase in patients with poor condition or impaired renal function. CONCLUSION: Administration of RC48 for real-world patients is both effective and safe. mUC patients can benefit from RC48-based therapy, regardless of their poor condition or impaired renal function.

Cryogenic Thermal Shock Effects on Optical Properties of Quantum Emitters in Hexagonal Boron Nitride.

Solid-state quantum emitters are vital building blocks for quantum information science and quantum technology. Among various types of solid-state emitters discovered to date, color centers in hexagonal boron nitride have garnered tremendous traction in recent years, thanks to their environmental robustness, high brightness, and room-temperature operation. Most recently, these quantum emitters have been employed for satellite-based quantum key distribution. One of the most important requirements to qualify these emitters for space-based applications is their optical stability against cryogenic thermal shock. Such an understanding has, however, remained elusive to date. Here, we report on the effects caused by such thermal shock that induces random, irreversible changes in the spectral characteristics of the quantum emitters. By employing a combination of structural characterizations and density functional calculations, we attribute the observed changes to lattice strain caused by cryogenic temperature shock. Our study sheds light on the stability of the quantum emitters under extreme conditions─similar to those countered in outer space.

Superconductivity and Charge-Density-Wave-Like Transition in Th2Cu4As5.

We report the synthesis, crystal structure, and physical properties of a novel ternary compound, Th2Cu4As5. The material crystallizes in a tetragonal structure with lattice parameters a = 4.0639(3) Å and c = 24.8221(17) Å. Its structure can be described as an alternating stacking of fluorite-type Th2As2 layers with antifluorite-type double-layered Cu4As3 slabs. The measurement of electrical resistivity, magnetic susceptibility, and specific heat reveals that Th2Cu4As5 undergoes bulk superconducting transition at 4.2 K. Additionally, all these physical quantities exhibit anomalies at 48 K, accompanied by a sign change in the Hall coefficient, suggesting a charge-density-wave-like (CDW) phase transition. Drawing from both experimental data and band calculations, we propose that the superconducting and CDW-like phase transitions are, respectively, associated with the Cu4As3 slabs and the As plane in the Th2As2 layers.

Wettability and Mechanical Properties of Red Mud-Al2O3 Composites.

In 2023, the global production of new red mud is expected to reach nearly 200 million tons, but less than 10% of it is currently being utilized in an environmentally friendly manner. To reduce the sintering temperature of alumina ceramics, a sintering aid method is used, as high-purity alumina ceramics require a solid-phase sintering temperature of over 1700 °C. The metal oxides present in red mud are necessary components for high-performance composite alumina ceramics. Composites were obtained by mixing and sintering red mud and Al2O3. This study focused on the mechanical properties and wettability of these composites. The results indicated that the 10% red mud-Al2O3 composite exhibited the highest hardness (20.12 GPa) and flexural strength (346 MPa). This is attributed to the formation of a mineral phase dominated by CaAl12O19, generated by the red mud during the sintering process, which filled the pores and reduced porosity. The surface energy of the red mud-Al2O3 composite was the highest at room temperature and high temperature, reaching 49.60 mJ·m-2 and 1164.7 mJ·m-2, respectively, indicating that it has better stability at both room and high temperatures. This study provides an important fundamental basis for the application of red mud-alumina composites to replace alumina-based composites in the field of construction materials, molten metal filters, ceramic cleavers, etc.

Leptin receptor (+) stromal cells respond to periodontitis and attenuate alveolar bone repair via CCRL2-mediated Wnt inhibition.

The impaired bone healing in tooth extraction sockets due to periodontitis presents a major obstacle to restoring oral health. The mechanisms regulating the osteogenic capacity of jawbone-derived stromal cells in the periodontitis microenvironment remain elusive. Leptin receptor (LepR) expressing stromal cells, which largely overlap with Cxcl12-abundant reticular (CAR) cells in bone tissue, rapidly proliferate and differentiate into bone-forming cells during extraction socket healing to support alveolar bone repair. In this study, we identify that CCRL2 is significantly expressed and inhibits osteogenesis in LepR+/CAR cells of alveolar bones with periodontitis. The Ccrl2-KO mice exhibit significant improvements in bone healing in extraction sockets with periodontitis. Specifically, the binding of CCRL2 to SFRP1 on the surface of LepR+/CAR cells can amplify the suppressive effect of SFRP1 on Wnt signaling under inflammation, thus hindering the osteogenic differentiation of LepR+/CAR cells and resulting in poor bone healing in extraction sockets with periodontitis. Together, we clarify that the CCRL2 receptor of LepR+/CAR cells can respond to periodontitis and crosstalk with Wnt signaling to deteriorate extraction socket healing.

The impaired bone healing in tooth extraction sockets due to periodontitis presents a major obstacle to restoring oral health. Alterations in the cellular activity of LepR+/CAR cells, an essential stromal cell population for extraction socket healing, in the periodontitis microenvironment have yet to be determined. In this study, we identify that CCRL2, as a potent agent of inflammation-bone crosstalk, is significantly expressed and inhibits osteogenesis in LepR+/CAR cells of alveolar bones with periodontitis. Specifically, the binding of CCRL2 to SFRP1 on the surface of LepR+/CAR cells can amplify the suppressive effect of SFRP1 on the Wnt/ß-catenin signaling under inflammation, thus hindering the osteogenic differentiation of LepR+/CAR cells and resulting in poor bone healing in tooth extraction sockets with periodontitis.

Paired-Related Homeobox 1-Positive Cells Are Needed for Osseointegration.

PURPOSE: To explore the contribution of paired-related homeobox 1-positive cells to the implant-induced osseointegration process in adult alveolar bone and the potential underlying mechanisms. MATERIALS AND METHODS: Cre recombinase-induced lineage tracing and cell ablation were conducted in a murine dental implant model. Scratch and transwell assays were used to assess MC3T3-E1 cell migration after paired-related homeobox 1 overexpression. Single-cell RNA sequencing were applied to identify potential genes involved in pairedrelated homeobox 1-positive cells-driven osteogenesis. RESULTS: Paired-related homeobox 1- positive cells were observed to accumulate in the peri-implant area in a time-dependent manner. The number of these cells were found to reach its maximum on day 14. Osseointegration in mice were noticeably impaired after ablation of paired-related homeobox 1-positive cells. Further, it was discovered that paired-related homeobox 1 promotes MC3T3- E1 cell migration, a process which is indispensable for sound healing of peri-implant tissue. Finally, Semaphorin 3C was detected exclusively and abundantly expressed by paired-related homeobox 1-positive cells. Knockdown of semaphorin 3C in paired-related homeobox 1- positive cells significantly weakened their osteogenic potential. CONCLUSION: Our data suggest that paired-related homeobox 1-positive cells contribute to the osseointegration process under stress stimulation and semaphorin 3C may play a critical role in paired-related homeobox 1- positive cell-driven osteogenesis. Paired-related homeobox 1 could significantly promote MC3T3-E1 cell migration.

Acupuncture and sleep disorders in Parkinson's disease: A systematic evaluation with meta-analysis.

BACKGROUND: Parkinson's disease (PD) patients commonly suffer from sleep disorders, significantly impacting their quality of life. Western treatments often entail adverse effects, while acupuncture (ACU) presents a safe, nonaddictive alternative. METHODS: A thorough literature search was performed across PubMed, Cochrane Library, and Embase databases. Eligible studies underwent statistical analysis via RevMan 5.4 software. RESULTS: This study synthesized data from 19 randomized controlled trials involving 1300 patients. The ACU cohort showed notable improvement in Parkinson's disease sleep scale (PDSS) scores (mean difference [MD] = 10.81, 95% confidence interval [CI]: 5.64, 15.98) relative to controls. Subgroup analysis revealed significance for ACU treatments beyond 6 weeks (MD = 15.39, 95% CI: 11.70, 19.09) but not for those 6 weeks or shorter (MD = 3.51, 95% CI: -1.20, 8.23). Notably, electroacupuncture resulted in significant PDSS score enhancements (MD = 12.39, 95% CI: 6.06, 18.71), with sensitivity analysis verifying result stability. However, without electroacupuncture, PDSS score differences were insignificant (MD = 7.83, 95% CI: -2.33, 17.99) and had lower result stability. Additionally, increased ACU session frequency may yield better improvements in PDSS scores. The ACU group also observed Improved Pittsburgh Sleep Quality Index scores (MD = -4.52, 95% CI: -6.36, -2.67). However, no significant variation was identified in Epworth Sleepiness Scale score improvement between groups (MD = -0.90, 95% CI: -3.67, 1.88). CONCLUSION: ACU therapy effectively improves nighttime sleep quality in PD patients. A treatment duration extending beyond 6 weeks is highly recommended. Additionally, increasing the frequency of ACU sessions and incorporating electroacupuncture in the treatment regimen may be essential for optimal results.

Association between Metabolically Healthy Status and Risk of Gastrointestinal Cancer.

PURPOSE: Although obesity is associated with numerous diseases, the risks of disease may depend on metabolically healthy status. Nevertheless, it is unclear to whether metabolically healthy status affects risk of gastrointestinal (GI) cancer in general Chinese population. MATERIALS AND METHODS: A total of 114,995 participants who met the criteria were included from the Kailuan Study. The study participants were divided into four groups according to body mass index (BMI)/waist circumference (WC) and metabolic status. Incident of GI cancer (esophageal cancer, gastric cancer, liver cancer, biliary cancer, pancreatic cancer, and colorectal cancer) during 2006-2020 were confirmed by review of medical records. The Cox proportional hazard regression models were used to assess the association metabolically healthy status with the risk of GI cancer by calculating the hazard ratios (HR) and 95% confidence interval (CI). RESULTS: During a mean 13.76 years of follow-up, we documented 2,311 GI cancers. Multivariate Cox regression analysis showed that compared with the metabolically healthy normal-weight group, metabolically healthy obese (MHO) participants demonstrated an increased risk of developing GI cancer (HR, 1.54; 95% CI, 1.11 to 2.13) by BMI categories. However, such associations were not found for WC category. These associations were moderated by age, sex, and anatomical site of the tumor. Individuals with metabolic unhealthy normal-weight or metabolic unhealthy obesity phenotype also have an increased risk of GI cancer. CONCLUSION: MHO phenotype was associated with increased risk of GI cancer. Moreover, individuals who complicated by metabolic unhealthy status have an increased risk of developing GI cancer. Hence, clinicians should consider the risk of incident GI cancer in people with abnormal metabolically healthy status and counsel them about metabolic fitness and weight control.

ThCr2Si2C: An Antiferromagnetic Metal with a Cr2C Square Lattice.

A quaternary compound, ThCr2Si2C, was synthesized by using the arc-melting technique. The compound adopts a tetragonal CeCr2Si2C-type crystal structure. The electronic resistivity and specific heat data exhibit metallic behavior, while the magnetic susceptibility displays a pronounced broad peak at around 370 K, indicating the antiferromagnetic phase transition. The first-principles calculations suggest A-type antiferromagnetic ordering of the Cr sublattice, which is confirmed by neutron diffraction experiments. By comparing the crystal structure of ThCr2Si2C with the isostructural Cr-based compounds, the magnetic state of Cr 3d orbital is discussed in terms of the band-filling effects and indirect spin exchange interaction.

Prognostic impact of lung ultrasound detected B-lines on hospitalised ischaemic heart failure with mildly reduced ejection fraction patients.

OBJECTIVES: Prognostic impact of lung ultrasound-derived B-lines (LUS-BL) in heart failure with mildly reduced left ventricular ejection fraction (HFmrEF) patients remains elusive. We evaluated the correlation between LUS-BL and prognosis in HFmrEF patients. METHODS: This is a subgroup analysis based on our previously published retrospective study with 1691 HFmrEF patients. This subgroup analysis involved 574 patients with LUS-BL results at admission. After discharge, patients underwent clinical follow-up for a minimum of 1 year through telephone, clinical visits or community visits. The primary endpoint was defined as cardiovascular (CV) event, including CV-related mortality or HF hospitalisation at 90 days and 1 year after discharge. RESULTS: CV event at 90 days was significantly increased with higher LUS-BL number (0, 1-2, 3-9 and ≥10: 20%, 14%, 18% and 33%, p=0.008), while CV event rate at 1 year was similar among groups (45% vs 45% vs 42% vs 50%, p=0.573). Older age, hypertension (HR=2.06, 95% CI 1.31 to 3.25), higher right ventricular diameter (>23 mm, HR=2.008, 95% CI 1.37 to 2.94), increased ratio of early transmitral flow velocity to early mitral annular velocity (>24, HR=1.79, 95% CI 1.11 to 2.26) and higher LUS-BL number (>11, HR=1.510, 95% CI 1.01 to 2.26) were identified as independent determinants associated with increased risk of CV event at 90 days after discharge. The Harrell's C-Statistic analysis, based on the Cox regression models, demonstrated a significant improvement in the predictive ability of the model that incorporated both clinical and echocardiographic risk factors along with LUS-BL (areas under the curve (AUC)=0.72) compared with the model comprising only clinical risk factors and LUS-BL (AUC=0.69, p=0.036), or to the model with echocardiographic risk factors and LUS-BL (AUC=0.68, p=0.025). CONCLUSION: In HFmrEF patients with ischaemic heart disease, admission LUS-BL>11 is independently associated with an increased risk of CV event at 90 days following discharge.

Full substitution of chemical fertilizer by organic manure decreases soil N2 O emissions driven by ammonia oxidizers and gross nitrogen transformations.

Replacing synthetic fertilizer by organic manure has been shown to reduce emissions of nitrous oxide (N2 O), but the specific roles of ammonia oxidizing microorganisms and gross nitrogen (N) transformation in regulating N2 O remain unclear. Here, we examined the effect of completely replacing chemical fertilizer with organic manure on N2 O emissions, ammonia oxidizers, gross N transformation rates using a 13-year field manipulation experiment. Our results showed that organic manure reduced cumulative N2 O emissions by 16.3%-210.3% compared to chemical fertilizer. The abundance of ammonia oxidizing bacteria (AOB) was significantly lower in organic manure compared with chemical fertilizer during three growth stages of maize. Organic manure also significantly decreased AOB alpha diversity and changed their community structure. However, organic manure substitution increased the abundance of ammonia oxidizing archaea and the alpha diversity of comammox Nitrospira compared to chemical fertilizer. Interestingly, organic manure decreased organic N mineralization by 23.2%-32.9%, and autotrophic nitrification rate by 10.5%-45.4%, when compared with chemical fertilizer. This study also found a positive correlation between AOB abundance, organic N mineralization and gross autotrophic nitrification rate with N2 O emission, and their contribution to N2 O emission was supported by random forest analysis. Our study highlights the key roles of ammonia oxidizers and N transformation rates in predicting cropland N2 O.

Optimizing cropping systems to close the gap between economic profitability and environmental health.

Supporting food security while maintaining ecosystem sustainability is one of the most important global challenges for humanity. Optimization of cropping systems is expected to promote the ecosystem services of agroecosystems. Yet, how and why cropping system influences the trade-offs between economic profitability and multiple ecosystem services remain poorly understood. We investigate the influence of six cropping systems on trade-offs between economic profitability and multiple ecosystem services after considering 36 agricultural ecosystem properties using field experiment data from 2020 to 2022. We show that designing cropping system is a critical tool to closing the gap between ecosystem sustainability and commercial profitability. Cropping system with three harvests within 2 yr had higher performance in overall ecosystem multiple services through enhancement of supporting, regulating, and economic performance without compromising provisioning compared with four other systems. These systems diminished the trade-off among multiple services, resulting in a 'win-win' situation for economics and multiple services. By contrast, the monoculture and double cropping systems lead to a strong trade-off between pairwise services including ecosystem health and profitability. Our work illustrates the substantial potential of rotation systems with three harvests within 2 yr in enforcing ecosystem services and closing the trade-offs among multiple agricultural ecosystem services.

Spatial variation in actual and required nitrogen use efficiency and the potential to close the gap by management practices.

To boost crop production, China uses almost a third of the world's nitrogen (N) fertilizer. However, N losses due to enhanced application of N fertilizers has led to surface water and groundwater pollution. A reduction in N losses without reducing crop yields is possible by increasing nitrogen use efficiency (NUE), which is important for the effective management of local crop production and water quality. This study used two representative agricultural counties in China (Quzhou and Qiyang) to assess if it is possible to achieve N loss thresholds in surface and groundwater by optimizing N management measures while maintaining actual crop production. We used a spatially explicit N balance model to assess the spatial variation in actual N inputs to soil and N losses to water, and in critical N losses and associated agricultural N inputs. We also used this model to calculate the spatial variation in actual NUEs and the required NUE to align actual crop production with N thresholds. We then assessed the feasibility of achieving the necessary NUE changes through optimizing agricultural N management strategies. It was found that actual N input exceeded critical N input in 95 and 83 % of the agricultural area in Quzhou and Qiyang, respectively. To meet actual crop production without exceeding N loss thresholds, the NUE needs to increase with 11 to 15 % whereas the total N input needs to be reduced by 37 %. NUE gaps can be closed by reducing N rates, enhancing organic manure recycling, and using efficiency-enhancing fertilizers, with optimal combinations being dependent on site conditions.

Targeted inhibition of mTOR by BML-275 induces mitochondrial-mediated apoptosis and autophagy in prostate cancer.

Prostate cancer (PCa) is the most frequently diagnosed cancer among men and the second leading cause of death in Western countries. Clinically, screening drugs and develop developing new therapeutics to treat PCa is of great significance. In this study, BML-275 was demonstrated to exert potent antitumor effects in PCa by antagonizing mTOR activity. In cultured PCa cells, BML-275 treatment reduced the expression levels of c-Myc and survivin, promoted the activation of p53, and thereby induced p21/cyclin D1/CDK4/6-dependent cell cycle G1/S arrest. As a result, BML-275 inhibited cellular proliferation and induced mitochondrial-mediated apoptosis. In addition, BML-275 treatment triggered autophagy. Interestingly, EACC-mediated suppression of autophagy did not affect BML-275-induced proliferation and apoptosis. Nude mouse tumorigenic experiments also confirmed that BML-275 inhibited PCa growth, induced PCa cell apoptosis and autophagy. Mechanistically, the activities of PI3K/AKT and AMPK pathways were downregulated by BML-275 treatment in vitro and in vivo. Importantly, mTOR, a common downstream negative protein of PI3K/AKT and AMPK signaling, was induced to inactivate, which may be associated with the induction of apoptosis and autophagy. The pharmacological activation of mTOR by MHY1485 abolished the induction of apoptosis and autophagy of BML-275. Molecular docking results showed that BML-275 can bind to the FKRP12-rapamycin binding site on mTOR protein, and thereby may have the same inhibitory activity on mTOR as rapamycin. Thus, these findings indicated that BML-275 induces mitochondrial-mediated apoptosis and autophagy in PCa by targeting mTOR inhibition. BML-275 may be a potential candidate for the treatment of PCa.

Global mean nitrogen recovery efficiency in croplands can be enhanced by optimal nutrient, crop and soil management practices.

An increase in nitrogen (N) recovery efficiency, also denoted as N use efficiency (NUEr), is crucial to reconcile food production and environmental health. This study assessed the effects of nutrient, crop and soil management on NUEr accounting for its dependency on site conditions, including mean annual temperature and precipitation, soil organic carbon, clay and pH, by meta-regression models using 2436 pairs of observations from 407 primary studies. Nutrient management increased NUEr by 3.6-11%, crop management by 4.4-8%, while reduction in tillage had no significant impact. Site conditions strongly affected management induced changes in NUEr, highlighting their relevance for site-specific practices. Data driven models showed that the global mean NUEr can increase by 30%, from the current average of 48% to 78%, using optimal combinations of nutrient (27%), crop (6.6%) and soil (0.6%) management. This increase will in most cases allow to reconcile crop production with acceptable N losses to water. The predicted increase in NUEr was below average in most high-income regions but above average in middle-income regions.

Impact of signs and symptoms on the prognosis of patients with HFmrEF.

BACKGROUND: Worsening of heart failure (HF) symptoms is the leading cause of medical contact and hospitalization of patients with mildly reduced ejection fraction (HFmrEF). The prognostic value of signs and symptoms for patients with HFmrEF is currently unclear. This study investigated the prognostic impact of signs and symptoms in HFmrEF patients. METHODS: A Cox proportional risk regression model analyzed the relationship between the number of signs/symptoms and outcomes in 1691 hospitalized HFmrEF patients. Ten significant signs and symptoms were included. Patients were divided into three groups (A: ≤2, B: 3-5, C: ≥6 signs/symptoms). Stratified analysis on male and female patients was performed. The primary endpoint was all-cause mortality, and the secondary outcome was a composite of cardiovascular death and heart failure readmission (CV events) post-discharge. RESULTS: After a median follow-up of 33 months, all-cause mortality occurred in 457 patients and CV events occurred in 977 patients. Incidence of all-cause mortality was 20.7%, 32.3%* and 49.4%*† in group A, B and C of male patients, (*P < 0.05 vs. A, †P < 0.05 vs. B) and 18.8%, 33.6% and 55.8%* in group A, B and C of female patients. Incidence of CV events was 64.8%, 70.1%* and 87.5%* in group A, B and C of male patients, 61.9%, 75.3%, and 86.1%* in group A, B and C of female patients. Multivariate Cox regression showed older age, renal insufficiency, higher number of signs and symptoms (≥ 3, hazard ratio [HR] 1.317, 95% confidence interval [CI] 1.070-1.621, P = 0.009; ≥6, HR 1.982, 95% CI 1.402-2.801, P < 0.001), myocardial infarction, stroke, faster heart rate on admission, and diabetes were independently associated with all-cause mortality(all P < 0.05). Similarly, higher number of signs and symptoms (≥ 3, HR 1.271, 95% CI 1.119-1.443, P < 0.001; ≥6, HR 1.955, 95% CI 1.524-2.508, P < 0.001), older age, renal insufficiency, atrial fibrillation, and diabetes were independently associated with cardiovascular events (all P < 0.05). CONCLUSIONS: Higher number of symptoms and signs is associated with increased risk of all-cause mortality and CV events in HFmrEF patients. Our results highlight the prognostic importance of careful inquiry on HF symptoms and related physical examination in HFmrEF patients.

SARS-CoV-2 Vaccine Uptake among Patients with Chronic Liver Disease: A Cross-Sectional Analysis in Hebei Province, China.

Chronic liver disease (CLD) patients have higher mortality and hospitalization rates after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This study aimed to explore SARS-CoV-2 vaccine perceptions, side effects, factors associated with nonvaccination and attitudes toward fourth-dose vaccine among CLD patients. The differences between vaccinated and unvaccinated groups among 1491 CLD patients and the risk factors associated with nonvaccination status were analyzed. In total, 1239 CLD patients were immunized against SARS-CoV-2. CLD patients have a high level of trust in the government and clinicians and were likely to follow their recommendations for vaccination. Reasons reported for nonvaccination were mainly concerns about the vaccines affecting their ongoing treatments and the fear of adverse events. However, only 4.84% of patients reported mild side effects. Risk factors influencing nonvaccination included being older in age, having cirrhosis, receiving treatments, having no knowledge of SARS-CoV-2 vaccine considerations and not receiving doctors' positive advice on vaccination. Furthermore, 20.6% of completely vaccinated participants refused the fourth dose because they were concerned about side effects and believed that the complete vaccine was sufficiently protective. Our study proved that SARS-CoV-2 vaccines were safe for CLD patients. Our findings suggest that governments and health workers should provide more SARS-CoV-2 vaccination information and customize strategies to improve vaccination coverage and enhance vaccine protection among the CLD population.

Identification of crucial genes related to heart failure based on GEO database.

BACKGROUND: The molecular biological mechanisms underlying heart failure (HF) remain poorly understood. Therefore, it is imperative to use innovative approaches, such as high-throughput sequencing and artificial intelligence, to investigate the pathogenesis, diagnosis, and potential treatment of HF. METHODS: First, we initially screened Two data sets (GSE3586 and GSE5406) from the GEO database containing HF and control samples from the GEO database to establish the Train group, and selected another dataset (GSE57345) to construct the Test group for verification. Next, we identified the genes with significantly different expression levels in patients with or without HF and performed functional and pathway enrichment analyses. HF-specific genes were identified, and an artificial neural network was constructed by Random Forest. The ROC curve was used to evaluate the accuracy and reliability of the constructed model in the Train and Test groups. Finally, immune cell infiltration was analyzed to determine the role of the inflammatory response and the immunological microenvironment in the pathogenesis of HF. RESULTS: In the Train group, 153 significant differentially expressed genes (DEGs) associated with HF were found to be abnormal, including 81 down-regulated genes and 72 up-regulated genes. GO and KEGG enrichment analyses revealed that the down-regulated genes were primarily enriched in organic anion transport, neutrophil activation, and the PI3K-Akt signaling pathway. The upregulated genes were mainly enriched in neutrophil activation and the calcium signaling. DEGs were identified using Random Forest, and finally, 16 HF-specific genes were obtained. In the ROC validation and evaluation, the area under the curve (AUC) of the Train and Test groups were 0.996 and 0.863, respectively. CONCLUSIONS: Our research revealed the potential functions and pathways implicated in the progression of HF, and designed an RNA diagnostic model for HF tissues using machine learning and artificial neural networks. Sensitivity, specificity, and stability were confirmed by ROC curves in the two different cohorts.

Impact of atrial fibrillation on cerebro-cardiovascular outcome of heart failure with mildly-reduced ejection fraction.

AIMS: Atrial fibrillation (AF) and heart failure (HF) often co-exist and are closely intertwined. The impact of AF on the outcome of patients with heart failure with mildly-reduced ejection fraction (HFmrEF) is not fully clear. This study aimed to investigate the impact of AF on the outcomes of hospitalized HFmrEF patients. METHODS AND RESULTS: The study included 1691 consecutive patients with HFmrEF (mean 68.2 years, 64.8% male) including 296 AF patients. Patients completed 1 year and mean of 33 month clinical follow-up after discharge by telephone interview, clinical visit, or community visit. The primary endpoint was cerebro-cardiovascular events (CCE, composite of HF rehospitalization, stroke, or cardiovascular death). After propensity score matching, 296 patients were included into the AF group (mean 71.5 years) and 592 patients into the non-AF group (mean 70.6 years). After propensity score matching, CCE at 1 year (59.1% vs. 48.5%, P = 0.003) and at a mean of 33 month (77.0% vs. 70.6%, P = 0.043). AF was independently associated with increased CCE within 1 year (HR = 1.31, 95% CI 1.07 to 1.61, P = 0.010) and at 33 months (HR = 1.20, 95% CI 1.00 to 1.43, P = 0.050) post-discharge after adjusted for other clinical confounders including discharge heart rate, NT-proBNP, haemoglobin, and uric acid. CONCLUSIONS: AF is independently associated with an increased risk of CCE in HFmrEF patients within 1 year and at a mean of 33 months after discharge.