The host sex contributes to the endophytic bacterial community in Sargassum thunbergii and their receptacles.

Endophytic bacteria have a complex coevolutionary relationship with their host macroalgae. Dioecious macroalgae are important producers in marine ecosystems, but there is still a lack of research on how sex influences their endophytic bacteria. In this study, the endophytic bacterial communities in male and female S. thunbergii and their reproductive tissues (receptacles) were compared using culture methods and high-throughput sequencing. The endophytic bacterial communities detected by the two methods were different. Among the 78 isolated strains, the dominant phylum, genus, and species were Bacillota, Alkalihalobacillus, and Alkalihalobacillus algicola, respectively, in the algal bodies, while in the receptacles, they were Bacillota, Vibrio, and Vibrio alginolyticus. However, 24 phyla and 349 genera of endophytic bacteria were identified by high-throughput sequencing, and the dominant phylum and genus were Pseudomonadota and Sva0996_ Marine_ Group, respectively, in both the algal body and the receptacles. The two methods showed similar compositions of endophytic bacterial communities between the samples of different sexes, but the relative abundances of dominant and specific taxa were different. The high-throughput sequencing results showed more clearly that the sex of the host alga had an effect on its endophyte community assembly and a greater effect on the endophytic bacterial community in the receptacles. Moreover, most specific bacteria and predicted functional genes that differed between the samples from the males and females were related to metabolism, suggesting that metabolic differences are the main causes of sex differences in the endophytic bacterial community. Our research is the first to show that host sex contributes to the composition of endophytic bacterial communities in dioecious marine macroalgae. The results enrich the database of endophytic bacteria of dioecious marine macroalgae and pave the way for better understanding the assembly mechanism of the endophytic bacterial community of algae.

High-Risk Hepatocellular Carcinoma: Hepatic Arterial Infusion Chemotherapy versus Transarterial Chemoembolization.

Objective: To compare the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) with transarterial chemoembolization (TACE) for the treatment of high-risk hepatocellular carcinoma (hHCC) patients. Methods: Between January 2014 and August 2022, a total of 1765 consecutive patients with hHCC who underwent initial intra-arterial therapies were reviewed and divided into a TACE group (n, 507) and a HAIC group (n, 426). The study used propensity score matching (PSM) to reduce selectivity bias. Overall survival (OS) and progression-free survival (PFS) were compared using Kaplan‒Meier curves with the Log rank test. The objective response rate (ORR), conversion surgery rate (CSR) adverse event (AE) comparison and subgroup analysis were performed between the two groups. Results: After PSM 1:1, 444 patients were divided into two groups. The patients with hHCC who received HAIC had higher median PFS (6.1 vs 3.3 months, P < 0.001) and OS (10.3 vs 8.2 months, P=0.303) than TACE. Higher ORR (24.8% vs 11.7%) and CSR (15.5% vs 8.9%) were found in the HAIC group than in the TACE group (both P < 0.05). The incidence of grade 3/4 AE was 23.9% and 8.1% in the TACE and HAIC groups, respectively. The subgroup analysis suggest that HAIC appeared to particularly benefit patients with tumor diameter of more than 10 centimeters (hazard ratio [HR], 0.6; 95% CI, 0.47-0.77; p, 0.00) and PVTT Vp4 (HR, 0.56; 95% CI, 0.39-0.8; P, 0.01) for PFS outperforming TACE. Conclusion: HAIC can provide better disease control for hHCC than cTACE, with a comparable long-term OS and safety.

Mechanical Properties of a Honeycomb Structure Dispersed with 3D-Printed Fe3O4 Nanomaterials.

The honeycomb structure demonstrates exceptional stability, efficient mechanical performance, outstanding load-bearing capacity, and energy-saving and lightweight properties, rendering it extensively employed in various fields such as industrial manufacturing, radiation protection building, aerospace engineering, and wave-absorbing stealth materials. Bionic design can enhance the performance of structures, making bionic honeycomb design valuable in engineering. This study employs a bionic optimization design based on the original honeycomb size to investigate the impact of a new composite honeycomb core structure on mechanical properties. Orthogonal experiments are conducted to explore the effect of honeycomb size on mechanical properties and determine the optimal size. Combining numerical simulation and 3D printing experiments, we examine the mechanical properties of both nano-Fe3O4 particle-distributed honeycomb structure and common structures, analyzing mechanisms behind their tensile and compressive properties.

Immune Dysfunction-Associated Elevated RDW, APACHE-II, and SOFA Scores Were a Possible Cause of 28-Day Mortality in Sepsis Patients.

Objective: To explore the early predictors and their predicting value of 28-day mortality in sepsis patients and to investigate the possible causes of death. Methods: 127 sepsis patients were included, including 79 cases in the survival group and 48 cases in the death group. The results of all patients on admission were recorded. After screening the risk factors of 28-day mortality, the receiver operating characteristic curve (ROC) was used to determine their predictive value for the 28-day mortality rate on admission, and the Kaplan-Meier curve was drawn to compare the 28-day mortality rate between groups. Finally, patients with cytokine and lymphocyte subsets results were included for investigating the possible causes of death through correlation analysis. Results: APACHE II (acute physiology and chronic health evaluation II), SOFA (Sequential Organ Failure Assessment) and red blood cell distribution width (RDW) were the risk factors for 28-day mortality in sepsis patients (OR: 1.130 vs.1.160 vs.1.530, P < 0.05). The area under the curve (AUC), sensitivity and specificity of APACHE II, SOFA and RDW in predicting the mortality rate at 28 days after admission in sepsis patients were 0.763 vs 0.806 vs 0.723, 79.2% vs 68.8% vs 75.0%, 65.8% vs 89.9% vs 68.4%. The combined predicted AUC was 0.873, the sensitivity was 89.6%, and the specificity was 82.3%. The Kaplan-Meier survival curve showed that the 28-day mortality rates of sepsis patients with APACHE II≥18.5, SOFA≥11.5 and RDW≥13.8 were 58.5%, 80.5% and 59.0%, respectively. In the death group, APACHE II was positively correlated with SOFA, IL-2, and IL-10, and RDW was positively correlated with PLT, TNF-α, CD3+ lymphocyte count, and CD8+ lymphocyte count. Conclusion: Sepsis patients with high APACHE II, SOFA and RDW levels at admission have an increased 28-day mortality rate. The elevation of these indicators in dead patients are related to immune dysfunction.

Triggering Receptor Expressed on Myeloid Cells 2 Mediates the Involvement of M2-Type Macrophages in Pulmonary Tuberculosis Infection.

Background: Macrophage play a significant work in the development of tuberculosis. This study aims to investigate the relationship between TREM2 and macrophage polarization, as well as the related cytokines. Methods: This study involved 43 pulmonary tuberculosis patients and 37 healthy controls. Enzyme-linked immunosorbent assay (ELISA) was used to detect the expression levels of M1/M2 macrophage-related cytokines IL-10 and IL-12 in the peripheral blood of pulmonary tuberculosis patients. The relative mRNA expression levels of TREM2, IL-10 and IL-12 were detected using quantitative real-time PCR (qRT-PCR). Additionally, Spearman rank correlation analysis was used to preliminarily assess the correlation between TREM2 and M1 / M2 macrophages. Hematoxylin-eosin (HE) staining was performed to observe the pathological manifestations of pulmonary tuberculosis lesions. Immunohistochemical (IHC) staining was used to observe the localization of the macrophage-specific molecule CD68, the M1 specific molecule iNOS, the M2 specific molecule CD163, and TREM2. Results: The lesions of pulmonary tuberculosis patients showed Langhans multinucleated macrophages and tuberculous granulomas. The ELISA results indicated that the expression levels of IL-10 and IL-12 were significantly increased in peripheral blood of pulmonary tuberculosis patients. Additionally, the relative mRNA expression levels of TREM2, IL-10 and IL-12 were also significantly higher in the pulmonary tuberculosis group. Furthermore, a positive correlation was observed between TREM2 and IL-10, which are secreted by M2 macrophages. IHC revealed significant positivity of TREM2 and macrophage-related markers in tuberculous granuloma. Specifically, TREM2 and M2 macrophage marker CD163 were significantly expressed in the cytoplasm and membrane of Langhans multinucleated macrophages. Conclusion: The role of macrophage polarization in pulmonary tuberculosis is significant, and further investigation is needed to understand relationship between TREM2 and M2 macrophages.

GLP-1 in hypothalamic paraventricular nucleus promotes sympathetic activation and hypertension.

Glucagon-like peptide-1 (GLP-1) and its analogs are widely used for treatment of diabetes. Paraventricular nucleus (PVN) is crucial for regulating cardiovascular activity. This study aims to determine the roles of GLP-1 and its receptors (GLP-1R) in PVN in regulating sympathetic outflow and blood pressure. Experiments were carried out in male normotensive rats and spontaneously hypertensive rats (SHR). Renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) were recorded. GLP-1 and GLP-1R expression was present in the PVN. PVN microinjection of GLP-1R agonist recombinant human GLP-1 (rhGLP-1) or EX-4 increased RSNA and MAP, which were prevented by GLP-1R antagonist EX9-39 or GLP-1R antagonist 1, superoxide scavenger tempol, antioxidant N-acetylcysteine, NADPH oxidase inhibitor apocynin, adenylyl cyclase inhibitor SQ22536 or protein kinase A (PKA) inhibitor H89. PVN microinjection of rhGLP-1 increased superoxide production, NADPH oxidase activity, cAMP level, adenylyl cyclase and PKA activity, which were prevented by SQ22536 or H89. GLP-1 and GLP-1R were upregulated in the PVN of SHR. PVN microinjection of GLP-1 agonist increased RSNA and MAP in both WKY and SHR, but GLP-1 antagonists caused greater effects in reducing RSNA and MAP in SHR than in WKY. The increased superoxide production and NADPH oxidase activity in the PVN of SHR were augmented by GLP-1R agonists, but attenuated by GLP-1R antagonists. These results indicate that activation of GLP-1R in PVN increased sympathetic outflow and blood pressure via cAMP-PKA-mediated NADPH oxidase activation and subsequent superoxide production. GLP-1 and GLP-1R upregulation in the PVN partially contribute to sympathetic overactivity and hypertension.Significance Statement Activation of GLP-1 receptors in paraventricular nucleus (PVN) increases sympathetic activity and blood pressure, which are mediated by cAMP-PKA-NADPH oxidase-superoxide production. Intervention of GLP-1 receptors in the PVN may play beneficial roles in attenuating sympathetic overactivity and hypertension. The central effects may have a major impact during GLP-1 receptor agonist therapy in patients with hypertension.

Salvage haploidentical transplantation for graft failure after first haploidentical allogeneic stem cell transplantation: an updated experience.

Graft failure is a fatal complication following allogeneic stem cell transplantation where a second transplantation is usually required for salvage. However, there are no recommended regimens for second transplantations for graft failure, especially in the haploidentical transplant setting. We recently reported encouraging outcomes using a novel method (haploidentical transplantation from a different donor after conditioning with fludarabine and cyclophosphamide). Herein, we report updated outcomes in 30 patients using this method. The median time of the second transplantation was 96.5 (33-215) days after the first transplantation. Except for one patient who died at +19d and before engraftment, neutrophil engraftments were achieved in all patients at 11 (8-24) days, while platelet engraftments were achieved in 22 (75.8%) patients at 17.5 (9-140) days. The 1-year OS and DFS were 60% and 53.3%, and CIR and TRM was 6.7% and 33.3%, respectively. Compared with the historical group, neutrophil engraftment (100% versus 58.5%, p < 0.001) and platelet engraftment (75.8% versus 32.3%, p < 0.001) were better in the novel regimen group, and OS was also improved (60.0% versus 26.4%, p = 0.011). In conclusion, salvage haploidentical transplantation from a different donor using the novel regimen represents a promising option to rescue patients with graft failure after the first haploidentical transplantation.

Understanding Adaptive Leadership in the Context of Nursing Homes.

Rapidly growing populations of older adults rely heavily on formal long-term care services such as those provided in nursing homes. Nursing home staff are confronted with complex challenges. We explored how staff (N = 88), particularly care aides, interpreted challenges and responded to them by taking adaptive leadership roles, and engaging in technical and adaptive work in nursing homes. We conducted analysis of the ethnographic case studies. In long-term care settings, staff face complex challenges in improving resident care due to contextual barriers. These include demanding work conditions and inadequate resources. Additionally, top-down communications, despite being well-intentioned, often lead to misinterpretation and a lack of staff motivation. Nonetheless, we found that certain staff managed to overcome these contextual barriers and effectively execute change initiatives by assuming adaptive leadership roles. Formal leaders have a vital role in empowering staff, including care aides, and facilitating their adaptive leadership behaviors.

Cardiovascular health metrics defined by Life's Essential 8 scores and subsequent macrovascular and microvascular complications in individuals with type 2 diabetes: A prospective cohort study.

AIM: To investigate the association between cardiovascular health metrics defined by Life's Essential 8 (LE8) scores and vascular complications among individuals with type 2 diabetes (T2D). MATERIALS AND METHODS: This prospective study included 11 033 participants with T2D, all devoid of macrovascular diseases (including cardiovascular and peripheral artery disease) and microvascular complications (e.g. diabetic retinopathy, neuropathy and nephropathy) at baseline from the UK Biobank. The LE8 score comprised eight metrics: smoking, body mass index, physical activity, non-high-density lipoprotein cholesterol, blood pressure, glycated haemoglobin, diet and sleep duration. Cox proportional hazards models were established to assess the associations of LE8 scores with incident macrovascular and microvascular complications. RESULTS: During a median follow-up of 12.1 years, we identified 1975 cases of incident macrovascular diseases and 1797 cases of incident microvascular complications. After adjusting for potential confounders, each 10-point increase in the LE8 score was associated with an 18% lower risk of macrovascular diseases and a 15% lower risk of microvascular complications. Comparing individuals in the highest and lowest quartiles of LE8 scores revealed hazard ratios of 0.55 (95% confidence interval 0.47-0.62) for incident macrovascular diseases, and 0.61 (95% confidence interval 0.53-0.70) for incident microvascular complications. This association remained robust across a series of sensitivity analyses and nearly all subgroups. CONCLUSION: Higher LE8 scores were associated with a lower risk of incident macrovascular and microvascular complications among individuals with T2D. These findings underscore the significance of adopting fundamental strategies to maintain optimal cardiovascular health and curtail the risk of developing diabetic vascular complications.

Characterization of the potential allergenicity of enzymatically hydrolyzed casein in Balb/c mouse model.

Bovine casein is a major allergen present in cow milk to induce anaphylaxis. In this study, the potential allergenicity of enzymatically hydrolyzed casein (HC) was evaluated based on in vitro and in vivo. The results showed that Alcalase and Protamex treatment (AT, PT) reduced the potential allergenicity of CN, with the greatest reductions of 68.25% and 50.75%, respectively. In addition, in vivo results showed that HC effectively alleviated allergic response symptoms of Balb/c mice; a significant tendency toward decreased serum IgG1 and mast cell tryptase levels was observed, accompanied by a decrease of Th2-associated IL-4, IL-5, and IL-13 and an increase of IFN-γ levels in spleen. Moreover, the inflammation of the lung, jejunum, and ileum was remarkably ameliorated. The findings indicated that HC induced a shift toward Th1 response and maintained the Th1/Th2 immune balance. Importantly, our results provide the basis for the production of hypoallergenic dairy products.

Shared genetic basis and causality between schizophrenia and inflammatory bowel disease: evidence from a comprehensive genetic analysis.

BACKGROUND: The comorbidity between schizophrenia (SCZ) and inflammatory bowel disease (IBD) observed in epidemiological studies is partially attributed to genetic overlap, but the magnitude of shared genetic components and the causality relationship between them remains unclear. METHODS: By leveraging large-scale genome-wide association study (GWAS) summary statistics for SCZ, IBD, ulcerative colitis (UC), and Crohn's disease (CD), we conducted a comprehensive genetic pleiotropic analysis to uncover shared loci, genes, or biological processes between SCZ and each of IBD, UC, and CD, independently. Univariable and multivariable Mendelian randomization (MR) analyses were applied to assess the causality across these two disorders. RESULTS: SCZ genetically correlated with IBD (rg = 0.14, p = 3.65 × 10−9), UC (rg = 0.15, p = 4.88 × 10−8), and CD (rg = 0.12, p = 2.27 × 10−6), all surpassed the Bonferroni correction. Cross-trait meta-analysis identified 64, 52, and 66 significantly independent loci associated with SCZ and IBD, UC, and CD, respectively. Follow-up gene-based analysis found 11 novel pleiotropic genes (KAT5, RABEP1, ELP5, CSNK1G1, etc) in all joint phenotypes. Co-expression and pathway enrichment analysis illustrated those novel genes were mainly involved in core immune-related signal transduction and cerebral disorder-related pathways. In univariable MR, genetic predisposition to SCZ was associated with an increased risk of IBD (OR 1.11, 95% CI 1.07­1.15, p = 1.85 × 10−6). Multivariable MR indicated a causal effect of genetic liability to SCZ on IBD risk independent of Actinobacteria (OR 1.11, 95% CI 1.06­1.16, p = 1.34 × 10−6) or BMI (OR 1.11, 95% CI 1.04­1.18, p = 1.84 × 10−3). CONCLUSIONS: We confirmed a shared genetic basis, pleiotropic loci/genes, and causal relationship between SCZ and IBD, providing novel insights into the biological mechanism and therapeutic targets underlying these two disorders.

Mediastinal Rosai-Dorfman Disease with KRAS mutation case report and literature review.

BACKGROUND: Rosai-Dorfman Disease (RDD) is a rare self-limiting histiocytosis, more prevalent in children and young adults. It typically manifests as painless bilateral massive cervical lymphadenopathy but may also extend to extra-nodal sites, with intrathoracic RDD noted in 2% of cases. Distinguishing mediastinal RDD from thymoma on imaging poses challenges, underscoring the reliance on pathological features and immunohistochemical staining for diagnosis. CASE PRESENTATION: Patient, male, 33 years old, underwent lung a CT revealing an enlarged round soft tissue shadow in the anterior superior mediastinum, compared to a year ago. Surgical resection removed the entire mass, thymus, and part of the pericardium, confirming RDD on pathology. Genetic testing using second-generation testing technology identified a KRAS gene point mutation. CONCLUSIONS: No established treatment protocol currently exists for this disease. However, as genetic mutation research progresses, a novel therapeutic avenue is emerging: targeted therapy integrated with surgical interventions.

MiR-3682-3p promotes esophageal cancer progression by targeting FHL1 and activating the Wnt/ß-catenin signaling pathway.

BACKGROUND: Esophageal cancer (EC) is highly ranked among all cancers in terms of its incidence and mortality rates. MicroRNAs (miRNAs) are considered to play key regulatory parts in EC. Multiple research studies have indicated the involvement of miR-3682-3p and four and a half LIM domain protein 1 (FHL1) in the achievement of tumors. The aim of this research was to clarify the significance of these genes and their possible molecular mechanism in EC. METHODS: Data from a database and the tissue microarray were made to analyze the expression and clinical significance of miR-3682-3p or FHL1 in EC. Reverse transcription quantitative PCR and Western blotting were used to detect the expression levels of miR-3682-3p and FHL1 in EC cells. CCK8, EdU, wound healing, Transwell, flow cytometry, and Western blotting assays were performed to ascertain the biological roles of miR-3682-3p and FHL1 in EC cells. To confirm the impact of miR-3682-3p in vivo, a subcutaneous tumor model was created in nude mice. The direct interaction between miR-3682-3p and FHL1 was demonstrated through a luciferase assay, and the western blotting technique was employed to assess the levels of crucial proteins within the Wnt/ß-catenin pathway. RESULTS: The noticeable increase in the expression of miR-3682-3p and the decrease in the expression of FHL1 were observed, which correlated with a negative impact on the patients' overall survival. Upregulation of miR-3682-3p expression promoted the growth and metastasis of EC, while overexpression of FHL1 partially reversed these effects. Finally, miR-3682-3p motivates the Wnt/ß-catenin signal transduction by directly targeting FHL1. CONCLUSION: MiR-3682-3p along the FHL1 axis activated the Wnt/ß-catenin signaling pathway and thus promoted EC malignancy.

Manufacturing, quality control, and GLP-grade preclinical study of nebulized allogenic adipose mesenchymal stromal cells-derived extracellular vesicles.

BACKGROUND: Human adipose stromal cells-derived extracellular vesicles (haMSC-EVs) have been shown to alleviate inflammation in acute lung injury (ALI) animal models. However, there are few systemic studies on clinical-grade haMSC-EVs. Our study aimed to investigate the manufacturing, quality control (QC) and preclinical safety of clinical-grade haMSC-EVs. METHODS: haMSC-EVs were isolated from the conditioned medium of human adipose MSCs incubated in 2D containers. Purification was performed by PEG precipitation and differential centrifugation. Characterizations were conducted by nanoparticle tracking analysis, transmission electron microscopy (TEM), Western blotting, nanoflow cytometry analysis, and the TNF-α inhibition ratio of macrophage [after stimulated by lipopolysaccharide (LPS)]. RNA-seq and proteomic analysis with liquid chromatography tandem mass spectrometry (LC-MS/MS) were used to inspect the lot-to-lot consistency of the EV products. Repeated toxicity was evaluated in rats after administration using trace liquid endotracheal nebulizers for 28 days, and respiratory toxicity was evaluated 24 h after the first administration. In vivo therapeutic effects were assessed in an LPS-induced ALI/ acute respiratory distress syndrome (ARDS) rat model. RESULTS: The quality criteria have been standardized. In a stability study, haMSC-EVs were found to remain stable after 6 months of storage at - 80°C, 3 months at - 20 °C, and 6 h at room temperature. The microRNA profile and proteome of haMSC-EVs demonstrated suitable lot-to-lot consistency, further suggesting the stability of the production processes. Intratracheally administered 1.5 × 108 particles/rat/day for four weeks elicited no significant toxicity in rats. In LPS-induced ALI/ARDS model rats, intratracheally administered haMSC-EVs alleviated lung injury, possibly by reducing the serum level of inflammatory factors. CONCLUSION: haMSC-EVs, as an off-shelf drug, have suitable stability and lot-to-lot consistency. Intratracheally administered haMSC-EVs demonstrated excellent safety at the tested dosages in systematic preclinical toxicity studies. Intratracheally administered haMSC-EVs improved the lung function and exerted anti-inflammatory effects on LPS-induced ALI/ARDS model rats.

Preoperative systemic immune-inflammation index-based nomogram for lung carcinoma following microwave ablation -a real world single center study.

Background: The preoperative inflammatory condition significantly influences the prognosis of malignancies. We aimed to investigate the potential significance of preoperative inflammatory biomarkers in forecasting the long-term results of lung carcinoma after microwave ablation (MWA). Method: This study included patients who received MWA treatment for lung carcinoma from Jan. 2012 to Dec. 2020. We collected demographic, clinical, laboratory, and outcome information. To assess the predictive capacity of inflammatory biomarkers, we utilized the area under the receiver operating characteristic curve (AUC-ROC) and assessed the predictive potential of inflammatory biomarkers in forecasting outcomes through both univariate and multivariate Cox proportional hazard analyses. Results: A total of 354 individuals underwent MWA treatment, of which 265 cases were included in this study, whose average age was 69.1 ± 9.7 years. The AUC values for the Systemic Inflammatory Response Index (SIRI) to overall survival (OS) and disease-free survival (DFS) were 0.796 and 0.716, respectively. The Cox proportional hazards model demonstrated a significant independent association between a high SIRI and a decreased overall survival (hazard ratio [HR]=2.583, P<0.001). Furthermore, a high SIRI independently correlated with a lower DFS (HR=2.391, P<0.001). We developed nomograms utilizing various independent factors to forecast the extended prognosis of patients. These nomograms exhibited AUC of 0.900, 0.849, and 0.862 for predicting 1-year, 3-year, and 5-year OS, respectively. Additionally, the AUC values for predicting 1-year, 3-year, and 5-year DFS were 0.851, 0.873, and 0.883, respectively. Conclusion: SIRI has shown promise as a valuable long-term prognostic indicator for forecasting the outcomes of lung carcinoma patients following MWA.

Comparing survival rates and mortality in operative versus nonoperative treatment for femoral neck fractures among Alzheimer's disease patients: A retrospective cohort study.

Introduction: Addressing femoral neck fractures resulting from ground-level falls in older adults with Alzheimer's disease (AD) involves a personalized treatment plan. There is considerable ongoing debate concerning the relative advantages and disadvantages of surgical treatment (internal fixation or arthroplasty) vs nonoperative treatment for femoral neck fractures in older persons with AD. Methods: This retrospective cohort study compared the mortality, hazard ratio, and survival rate between operative and nonoperative treatments, controlling for patients' demographic information and baseline health status. The study population consisted of Optum beneficiaries diagnosed with AD who experienced an initial femoral neck fracture claim between January 1, 2012, and December 31, 2017. Kaplan-Meier survival curves were applied to compare the treatment groups' post-fracture survival rates and mortality. Cox regression was used to examine the survival period by controlling the covariates. Results: Out of the 4157 patients with AD with femoral neck fractures, 59.8% were women (n = 2487). The median age was 81 years. The 1-year survival rate for nonoperative treatment (70.19%) was lower than that for internal fixation (75.27%) and arthroplasty treatment (82.32%). Compared with the nonoperative group, arthroplasty surgical treatment had significant lower hazard risk of death (arthroplasty hazard ratio: 0.850, 95% CI: 0.728-0.991, P < 0.05). Discussion: The findings suggest that the operative treatment group experiences higher survival rates and lower mortality rates than the nonoperative group. This paper provides insights into treatment outcomes of older adults with AD receiving medical care for femoral neck fractures.

Endothelial phosphodiesterase 4B inactivation ameliorates endothelial-to-mesenchymal transition and pulmonary hypertension.

Pulmonary hypertension (PH) is a fatal disorder characterized by pulmonary vascular remodeling and obstruction. The phosphodiesterase 4 (PDE4) family hydrolyzes cyclic AMP (cAMP) and is comprised of four subtypes (PDE4A-D). Previous studies have shown the beneficial effects of pan-PDE4 inhibitors in rodent PH; however, this class of drugs is associated with side effects owing to the broad inhibition of all four PDE4 isozymes. Here, we demonstrate that PDE4B is the predominant PDE isozyme in lungs and that it was upregulated in rodent and human PH lung tissues. We also confirmed that PDE4B is mainly expressed in the lung endothelial cells (ECs). Evaluation of PH in Pde4b wild type and knockout mice confirmed that Pde4b is important for the vascular remodeling associated with PH. In vivo EC lineage tracing demonstrated that Pde4b induces PH development by driving endothelial-to-mesenchymal transition (EndMT), and mechanistic studies showed that Pde4b regulates EndMT by antagonizing the cAMP-dependent PKA-CREB-BMPRII axis. Finally, treating PH rats with a PDE4B-specific inhibitor validated that PDE4B inhibition has a significant pharmacological effect in the alleviation of PH. Collectively, our findings indicate a critical role for PDE4B in EndMT and PH, prompting further studies of PDE4B-specific inhibitors as a therapeutic strategy for PH.

Decreasing the steroid rapidly may help to improve the clinical outcomes of patients with intestinal steroid-refractory acute graft-versus-host disease receiving basiliximab treatment.

Intestinal steroid refractory acute graft-versus-host disease (SR-aGVHD) is the major cause of mortality in allogeneic hematopoietic stem cell transplantation (allo-HSCT). This retrospective cohort study aimed to identify the relationship between different steroid decreasing velocity and therapeutic response in patients with intestinal SR-aGVHD receiving basiliximab treatment, and also aimed to propose a reasonable steroid decreasing regimen for these patients. The median time for steroid dose decreasing to the 50% of initial dose and decreasing to the low-dose steroid for patients achieving ORR was 5 days and 12 days, respectively, which was both shorter than patients without achieving ORR. The ORR, NRM and survival in rapid and medium steroid decreasing group were all better than slow group. The cumulative incidence of ORR at any time was 90.4%, 78.1% and 62.3%, respectively, in rapid, medium, and slow group. The cumulative incidence of NRM at 1 year after basiliximab treatment was 18.7% (95% CI 11.3%-26.1%), 22.8% (95% CI 14.2%-31.4%) and 32.8% (95% CI 24.1%-41.5%), respectively, in rapid, medium, and slow group. The probability of OS at 1 year after basiliximab treatment was 76.9% (95% CI 68.9%-84.9%), 72.7% (95% CI 63.7%-81.7%), and 62.3% (95% CI 53.5%-71.1%), respectively, in rapid, medium, and slow group. Hence, it was helpful to decrease steroid to the 50% of initial dose ≤ 5 days and to the low-dose steroid ≤ 12 days after basiliximab treatment for intestinal SR-aGVHD patients, which may also be the reasonable steroid decrease protocol for these patients.

Binding Mode and Molecular Mechanism of the Two-Component Histidine Kinase Bos1 of Botrytis cinerea to Fludioxonil and Iprodione.

Gray mold caused by Botrytis cinerea is among the 10 most serious fungal diseases worldwide. Fludioxonil is widely used to prevent and control gray mold due to its low toxicity and high efficiency; however, resistance caused by long-term use has become increasingly prominent. Therefore, exploring the resistance mechanism of fungicides provides a theoretical basis for delaying the occurrence of diseases and controlling gray mold. In this study, fludioxonil-resistant strains were obtained through indoor drug domestication, and the mutation sites were determined by sequencing. Strains obtained by site-directed mutagenesis were subjected to biological analysis, and the binding modes of fludioxonil and iprodione to Botrytis cinerea Bos1 BcBos1 were predicted by molecular docking. The results showed that F127S, I365S/N, F127S + I365N, and I376M mutations on the Bos1 protein led to a decrease in the binding energy between the drug and BcBos1. The A1259T mutation did not lead to a decrease in the binding energy, which was not the cause of drug resistance. The biological fitness of the fludioxonil- and point mutation-resistant strains decreased, and their growth rate, sporulation rate, and pathogenicity decreased significantly. The glycerol content of the sensitive strains was significantly lower than that of the resistant strains and increased significantly after treatment with 0.1 µg/ml of fludioxonil, whereas that of the resistant strains decreased. The osmotic sensitivity of the resistant strains was significantly lower than that of the sensitive strains. Positive cross-resistance was observed between fludioxonil and iprodione. These results will help to understand the resistance mechanism of fludioxonil in Botrytis cinerea more deeply.