Frailty Modeling using Machine Learning Methodologies: A Systematic Review with Discussions on Outstanding Questions.

Studying frailty is crucial for enhancing the health and quality of life among older adults, refining healthcare delivery methods, and tackling the obstacles linked to an aging demographic. Approaches to frailty modeling often utilise simple analytic techniques rather than available advanced machine learning methods, which may be sub-optimal. There is no large-scale systematic review on applications of machine learning methods on frailty modeling. In this study we explore the use of machine learning methods to predict or classify frailty in older persons in routinely collected data. We reviewed 181 research articles, and categorised analytic methods into three categories: generalised linear models, survival models, and non-linear models. These methods have a moderate agreement with existing frailty scores and predictive validity for adverse outcomes. Limited evidence suggests that non-linear methods outperform generalised linear methods. The top-three predictor/input variables are specific diagnosis or groups of diagnoses, functional performance (e.g., ADLs), and impaired cognition. Mortality, hospital admissions and prolonged hospital stay are the mainly predicted outcomes. Most studies utilise classical machine learning methods with cross-sectional data. Longitudinal data collected by wearable sensors have been used for frailty modeling. We also discuss the opportunities to use more advanced machine learning methods with high dimensional longitudinal data for more personalised and accessible frailty tools.

Bioactive Metal Ion-Coordinated Dynamic Hydrogel with Antibacterial, Immunomodulatory, and Angiogenic Activities for Infected Wound Repair.

The repair of infected wounds is a complex physiopathologic process. Current studies on infected wound treatment have predominantly focused on infection treatment, while the factors related to delayed healing caused by vascular damage and immune imbalance are commonly overlooked. In this study, an extracellular matrix (ECM)-like dynamic and multifunctional hyaluronic acid (HA) hydrogel with antimicrobial, immunomodulatory, and angiogenic capabilities was designed as wound dressing for the treatment of infected skin wounds. The dynamic network in the hydrogel dressing was based on reversible metal-ligand coordination formed between sulfhydryl groups and bioactive metal ions. In our design, antibacterial silver and immunomodulatory zinc ions were employed to coordinate with sulfhydrylated HA and a vasculogenic peptide. In addition to the desired bioactivities for infected wounds, the hydrogel could also exhibit self-healing and injectable abilities. Animal experiments with infected skin wound models indicated that the hydrogel dressings enabled minimally invasive injection and seamless skin wound covering and then facilitated wound healing by efficient bacterial killing, continuous inflammation inhibition, and improved blood vessel formation. In conclusion, the metal ion-coordinated hydrogels with wound-infection-desired bioactivities and ECM-like dynamic structures represent a class of tissue bionic wound dressings for the treatment of infected and chronic inflammation wounds.

Simultaneous resection of pituitary adenoma and clipping of aneurysm through endoscopic endonasal approach: a case report.

Pituitary adenomas and intracranial aneurysms are prevalent neurosurgical conditions, but their simultaneous presence is uncommon, affecting only 0.5%-7.4% of those with pituitary adenomas. The strategy of treating aneurysms endovascularly before removing pituitary adenomas is widely adopted, yet reports on addressing both conditions at once through an endoscopic endonasal approach (EEA) are scarce. We present a case involving a pituitary adenoma coupled with an anterior communicating artery aneurysm. Utilizing the EEA, we excised the adenoma and clipped the aneurysm concurrently. The patient recovered well post-surgery, with follow-up assessments confirming the successful resolution of both the adenoma and aneurysm. We proved the feasibility of the EEA in the treatment of pituitary adenomas with anterior communicating artery aneurysms under specific anatomical relationships and close intraoperative monitoring.

Enhanced Aquathermolysis of Water-Heavy Oil-Ethanol Catalyzed by B@Zn(II)L at Low Temperature.

In order to study the synergistic effects of exogenous catalysts and in situ minerals in the reservoir during heavy oil aquathermolysis, in this paper, a series of simple supported transition metal complexes were prepared using sodium citrate, chloride salts and bentonite, and their catalytic viscosity reduction performances for heavy oil were investigated. Bentonite complex catalyst marked as B@Zn(II)L appears to be the most effective complex. B@Zn(II)L was characterized by scanning electron microscopy (SEM), Fourier-Transform Infrared (FTIR) spectroscopy, thermo-gravimetric analysis (TGA) and N2 adsorption-desorption isotherms. Under optimized conditions, the viscosity of the heavy oil was decreased by 88.3%. The reaction temperature was reduced by about 70 °C compared with the traditional reaction. The results of the group composition analysis and the elemental content of the heavy oil indicate that the resin and asphaltene content decreases, and the saturated and aromatic HC content increases. The results of TGA and DSC of the heavy oil show that the macromolecular substances in the heavy oil were cracked into small molecules with low boiling points by the reaction. GC-MS examination of water-soluble polar compounds post-reaction indicates that B@Zn(II)L can diminish the quantity of polar substances in heavy oil and lower the aromatic nature of these compounds. Thiophene and quinoline were utilized as model compounds to investigate the reaction mechanism. GC-MS analysis revealed that C-C, C-N and C-S bonds were cleaved during the reaction, leading to a decrease in the viscosity of heavy oil.

[Inaugural Scalp Metastasis of Pulmonary Squamous Cell Carcinoma: 
A Rare Case Report and Literature Review].

Distant cutaneous metastasis of primary lung squamous cell carcinoma is an exceedingly rare event, with scalp metastasis as the initial clinical presentation even rarer. Scalp skin metastases are prone to be misdiagnosed as other scalp disorders, yet their appearance signifies the deterioration and poor prognosis of lung cancer. This case report documents a female patient presenting initially with scalp folliculitis in dermatology, who was subsequently diagnosed with malignant lung tumor through radiological imaging and referred to Department of Thoracic Surgery. Pathological examination of the excised lesion from the scalp revealed distant metastasis of lung cancer. A review of similar cases reported in literature was conducted. This article aims to enhance understanding and awareness of skin metastasis in lung cancer, to emphasize the importance of this condition, and to improve early recognition and precise diagnosis. It is crucial to prevent clinical misdiagnosis and ensure appropriate treatment, finally leading to improve the prognosis of the patients.
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Identification and validation of tryptophan metabolism-related lncRNAs in lung adenocarcinoma prognosis and immune response.

BACKGROUND: Tryptophan (Trp) is an essential amino acid. Increasing evidence suggests that tryptophan metabolism plays a complex role in immune escape from Lung adenocarcinoma (LUAD). However, the role of long non-coding RNAs (lncRNAs) in tryptophan metabolism remains to be investigated. METHODS: This study uses The Cancer Genome Atlas (TCGA)-LUAD dataset as the training cohort, and several datasets from the Gene Expression Omnibus (GEO) database are merged into the validation cohort. Genes related to tryptophan metabolism were identified from the Molecular Signatures Database (MSigDB) database and further screened for lncRNAs with Trp-related expression. Subsequently, a prognostic signature of lncRNAs related to tryptophan metabolism was constructed using Cox regression analysis, (Least absolute shrinkage and selection operator regression) and LASSO analysis. The predictive performance of this risk score was validated by Kaplan-Meier (KM) survival analysis, (receiver operating characteristic) ROC curves, and nomograms. We also explored the differences in immune cell infiltration, immune cell function, tumor mutational load (TMB), tumor immune dysfunction and exclusion (TIDE), and anticancer drug sensitivity between high- and low-risk groups. Finally, we used real-time fluorescence quantitative PCR, CCK-8, colony formation, wound healing, transwell, flow cytometry, and nude mouse xenotransplantation models to elucidate the role of ZNF8-ERVK3-1 in LUAD. RESULTS: We constructed 16 tryptophan metabolism-associated lncRNA prognostic models in LUAD patients. The risk score could be used as an independent prognostic indicator for the prognosis of LUAD patients. Kaplan-Meier survival analysis, ROC curves, and risk maps validated the prognostic value of the risk score. The high-risk and low-risk groups showed significant differences in phenotypes, such as the percentage of immune cell infiltration, immune cell function, gene mutation frequency, and anticancer drug sensitivity. In addition, patients with high-risk scores had higher TMB and TIDE scores compared to patients with low-risk scores. Finally, we found that ZNF8-ERVK3-1 was highly expressed in LUAD tissues and cell lines. A series of in vitro experiments showed that knockdown of ZNF8-ERVK3-1 inhibited cell proliferation, migration, and invasion, leading to cell cycle arrest in the G0/G1 phase and increased apoptosis. In vivo experiments with xenografts have shown that knocking down ZNF8-ERVK3-1 can significantly inhibit tumor size and tumor proliferation. CONCLUSION: We constructed a new prognostic model for tryptophan metabolism-related lncRNA. The risk score was closely associated with common clinical features such as immune cell infiltration, immune-related function, TMB, and anticancer drug sensitivity. Knockdown of ZNF8-ERVK3-1 inhibited LUAD cell proliferation, migration, invasion, and G0/G1 phase blockade and promoted apoptosis.

Combining fecal microbiome and metabolomics reveals diagnostic biomarkers for esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is one of the most predominant subtypes of esophageal cancer. The characteristics of the gut microbiome and its metabolites from patients with ESCC have not been adequately studied and discussed. In this study, 40 fecal samples (20 from ESCC patients and 20 from healthy controls) were analyzed by 16S rRNA gene sequencing and untargeted metabolomics. The data sets were analyzed individually and synthesized using various bioinformatics methods. Alpha and beta diversity indicated significant differences in microbial diversity and abundance between ESCC and healthy control feces. At the genus level, the abundance of Phascolarctobacterium, Sutterella, and Streptococcus was significantly increased in ESCC. At the genus level, linear discriminant analysis effect size identified two biomarkers: Bacteroides_stercoris and Prevotella_copri. Untargeted metabolomics analysis revealed 307 differential metabolites between ESCC and healthy control feces, with indoles and derivatives, tropane alkaloids, lipids, and lipid-like molecules in higher relative abundance in ESCC feces than in healthy control feces. Kyoto Encyclopedia of Genes and Genomes enrichment analysis revealed that unsaturated fatty acids (FAs), ascorbate and aldarate metabolism, and hypoxia-inducible factor 1 signaling pathway were significantly associated with differential metabolite. Phenylethanolamine and despropionyl p-fluoro fentanyl could be used as reliable biomarkers to differentiate ESCC from healthy control. The correlation analysis showed that Prevotella may be involved in the synthesis of fatty acyl, carboxylic acids and derivatives, benzenes and substituted derivatives, organic oxygenates, and indoles and derivatives as metabolites. Fusicatenibacter and Lachnospira may be involved in the degradation of indoles and derivatives. Alistipes, Agathobacter, and Parabacteroides may be involved in the synthesis of indoles and derivatives with strong contributions. There is an intricate relationship between the gut microbiome and the levels of several metabolites (e.g., fatty acyls, carboxylic acids and derivatives, indoles, and derivatives). Microbial-associated metabolites can be used as diagnostic biomarkers in therapeutic exploration. Further analysis revealed that Prevotella, Alistipes, Agathobacter, and Parabacteroides might promote ESCC by regulating the synthesis of indoles and their derivatives. The results of this study provide favorable evidence for the early diagnosis of ESCC and subsequent individualized treatment and targeted interventions.IMPORTANCEWe describe for the first time the differences in fecal microbiome composition and metabolites between patients with esophageal squamous cell carcinoma (ESCC) and healthy controls by 16S rRNA gene sequencing and untargeted metabolomics. The results of this study provide a favorable basis for the early diagnosis of ESCC and subsequent targeted interventional therapy.

The Functional Study of Response Regulator ArlR Mutants in Staphylococcus Aureus.

Staphylococcus aureus is a major cause of hospital-associated infections worldwide. The organism's ability to form biofilms has led to resistance against current treatment options such as beta-lactams, glycopeptides, and daptomycin. The ArlRS two-component system is a crucial regulatory system necessary for S. aureus autolysis, biofilm formation, capsule synthesis, and virulence. This study aims to investigate the role of the arlR deletion mutant in the detection and activation of S. aureus. We created an arlR deleted mutant and complementary strains and characterized their impact on the strains using partial growth measurement. The quantitative real-time PCR was performed to determine the expression of icaA, and the microscopic images of adherent cells were captured at the optical density of 600 to determine the primary bacterial adhesion. The biofilm formation assay was utilized to investigate the number of adherent cells using crystal violet staining. Eventually, the Triton X-100 autolysis assay was used to determine the influence of arlR on the cell autolytic activities. Our findings indicate that the deletion of arlR reduced the transcriptional expression of icaA but not icaR in the ica operon, leading to decrease in polysaccharide intercellular adhesin (PIA) synthesis. Compared to the wild-type and the complementary mutants, the arlR mutant exhibited decreased in biofilm production but increased autolysis. It concluded that the S. aureus response regulatory ArlR influences biofilm formation, agglutination, and autolysis. This work has significantly expanded our knowledge of the ArlRS two-component regulatory system and could aid in the development of novel antimicrobial strategies against S. aureus.

Mechanistic and biophysical characterization of polymyxin resistance response regulator PmrA in Acinetobacter baumannii.

Introduction: Acinetobacter baumannii PmrAB is a crucial two-component regulatory system (TCS) that plays a vital role in conferring resistance to polymyxin. PmrA, a response regulator belonging to the OmpR/PhoB family, is composed of a C-terminal DNA-binding effector domain and an N-terminal receiver domain. The receiver domain can be phosphorylated by PmrB, a transmembrane sensor histidine kinase that interacts with PmrA. Once phosphorylated, PmrA undergoes a conformational change, resulting in the formation of a symmetric dimer in the receiver domain. This conformational change facilitates the recognition of promoter DNA by the DNA-binding domain of PmrA, leading to the activation of adaptive responses. Methods: X-ray crystallography was carried out to solve the structure of PmrA receiver domain. Electrophoretic mobility shift assay and Isothermal titration calorimetry were recruited to validate the interaction between the recombinant PmrA protein and target DNA. Field-emission scanning electron microscopy (FE-SEM) was employed to characterize the surface morphology of A. baumannii in both the PmrA knockout and mutation strains. Results: The receiver domain of PmrA follows the canonical α5ß5 response regulator assembly, which undergoes dimerization upon phosphorylation and activation. Beryllium trifluoride is utilized as an aspartate phosphorylation mimic in this process. Mutations involved in phosphorylation and dimerization significantly affected the expression of downstream pmrC and naxD genes. This impact resulted in an enhanced cell surface smoothness with fewer modifications, ultimately contributing to a decrease in colistin (polymyxin E) and polymyxin B resistance. Additionally, a conservative direct-repeat DNA PmrA binding sequence TTTAAGNNNNNTTTAAG was identified at the promoter region of the pmrC and naxD gene. These findings provide structural insights into the PmrA receiver domain and reveal the mechanism of polymyxin resistance, suggesting that PmrA could be a potential drug target to reverse polymyxin resistance in Acinetobacter baumannii.

The Impact of high-performance work system perceived by medical staff on job satisfaction: the mediating role of self-efficacy.

As the mainstay of healthcare, the job satisfaction of medical staff deserves attention. This study aimed to explore the correlation between the perception of the high-performance work system (P-HPWS) and job satisfaction of medical staff in public hospitals and to further investigate the mediating effect of self-efficacy. From November 2019 to January 2020, a cross-sectional survey on working doctors and nurses was conducted in five tertiary public hospitals in China. A total of 520 participants were surveyed. The P-HPWS, job satisfaction, and self-efficacy were assessed using the 25-item self-administered scale, six-item job satisfaction questionnaire, and the General Self-Efficacy Scale, respectively. Linear regression and mediation effects models were used to identify the associations between primary variables. The results showed a significant positive correlation between P-HPWS and job satisfaction (P < 0.01), while self-efficacy played a mediating role between P-HPWS and job satisfaction. This finding reveals the benefits of improving employees' P-HPWS and self-efficacy on their job satisfaction, and that hospitals can improve their management systems by implementing and refining HPWS.

Management of cavernous sinus meningiomas: Clinical features, treatment strategies, and long-term outcomes.

OBJECTIVES: The purpose of this research was to summarize the clinical and prognostic features of cavernous sinus meningiomas (CSM), evaluate the treatment strategies and long-term prognosis of CSM, and improve the management of CSM and the treatment effect for patients. METHODS: We retrospectively studied the data of 54 patients who received initial surgical resection and 45 patients who received initial gamma knife radiosurgery (GKRS) for CSM at West China Hospital of Sichuan University from 2009 to 2021. Progression-free survival (PFS), Karnofsky Performance Scale (KPS) scores and neurological function recovery were adopted to assess a comprehensive management strategy for CSM. RESULTS: Gross total resection (GTR) was performed in 51.9 % of cases with 3.7 % surgical mortality. The average follow-up time was 48.7 months, with a progression rate of 29.3 %. The overall improvement rate for cranial nerve function deficits was 50.0 %. By survival analysis, the extent of resection and the histological grade were significantly related to the prognosis. The role of postoperative GKRS is uncertain. For patients who received initial GKRS, the progression rate was 17.8 %, and the overall improvement rate for cranial nerve function deficits was 61.1 %. Primary treatment with GKRS showed better long-term tumor control in patients with CSM (P = 0.046). CONCLUSIONS: Maximum safe resection of CSM can improve the neurological function and quality of life of patients, but aggressive resection will cause high perioperative mortality and complication rates. For CSM patients who are suitable for initial gamma knife treatment, choosing GKRS can achieve better long-term tumor control and neurological outcomes.

Chewing difficulties mediated association between edentulism and depressive symptoms among middle aged and older population.

BACKGROUND: Depression is a major health condition among the aging population. Previous studies indicated that edentulism was a risk factor for depression. The link between edentulism and depression has not been fully clarified. OBJECTIVES: This study aimed to estimate whether chewing difficulties play a mediating role in the association between edentulism and depression among middle-aged and older populations with national cross-sectional data. METHODS: Data were obtained from the latest fourth wave of the China Health and Retirement Longitudinal Study (CHARLS). The outcome variable was set as depression, which was measured by the Center for Epidemiologic Studies Depression Scale (CES-D-10). Independent and mediated variables were separately set as self-assessed edentulism and chewing difficulties. The nearest neighbour propensity score matching (PSM) method was used to construct a matching group to balance the basic characteristics of individuals with and without edentulism with minimised bias in the estimation. Causal mediation analysis was performed to estimate the degree of contribution of chewing difficulties to the association between edentulism and depression. Several sensitivity analyses were performed to evaluate the robustness of the primary result. RESULTS: A total of 15 853 individuals remained for analysis. After PSM, 809 individuals with edentulism and 2628 without edentulism remained for analysis. Among the matched individuals, the mean age was 66.3 ± 9.2 years, 58.5% were female, 78.8% lived in rural areas, 23.5% had edentulism, 51.1% had depressive symptoms, and 50.1% had chewing difficulties. Logistic regression results showed that a higher incidence of edentulism was associated with a higher rate of depression (OR: 1.39, 95% CI: 1.19-1.63) in the matching group. Causal mediation analysis results indicated that the average mediation effect of chewing difficulties on the association between edentulism and depression was 0.010 (95% CI: 0.005-0.015), and the average direct effect was 0.072 (95% CI: 0.036-0.11). The mediation proportion of chewing difficulties was 11.7% (95% CI: 0.079-0.21). CONCLUSION: A higher prevalence of edentulism was associated with a higher rate of depression among middle-aged and elderly populations. Chewing difficulties moderately mediated the association between edentulism and depression. Fundamental oral function should not be neglected to improve mental health among the aging population.

The coupling coordination and spatiotemporal evolution of industrial water-energy-CO2 in the Yellow River Basin.

The Yellow River Basin (YRB) is an important energy, chemical, raw material, and basic industrial base in China. With economic growth, water and energy consumption in industrial industries increasing dramatically, huge pressure for CO2 emission reduction has generated. This paper constructed an industrial water-energy-CO2 (WEC) evaluation index system, analyzed the comprehensive evaluation level, coupling status and coupling coordination status, by using the comprehensive evaluation method, coupling degree model and coupling coordination degree model and used the spatial autocorrelation analysis to study the spatiotemporal evolution from 1999 to 2019 in the YRB. The results demonstrated that the integrated development level of the basin's industrial WEC system and subsystems had been improving. The basin was at a high coupling and the level of coupling had been increasing as a whole, and the industrial energy-CO2 coupling degree was bigger than the industrial water-energy and industrial water-CO2 coupling degrees in the YRB. The coupling coordination status had transitioned from forced coordination to good coordination. Spatially, the coupling coordination didn't appear a significant correlation and showed a random distribution. Accordingly, the suggestions were made to improve the level of industrial development in the basin, strengthen integrated resource management, and enhance intra-basin cooperation.

Robotic Frameless Stereotactic Aspiration with Thrombolysis for Primary Pontine Hemorrhage: A Therapeutic Evaluation of a Retrospective Cohort Study.

BACKGROUND: There is still no consensus on whether primary pontine hemorrhage (PPH) should be managed conservatively or treated promptly via surgical evacuation of the hematoma. The purpose of this study was to assess the therapeutic effect of robotic frameless stereotactic aspiration with thrombolysis in the treatment of PPH. METHODS: A total of 39 patients with PPH treated between January 2012 and November 2016 were included in the study. Sixteen patients underwent frameless stereotactic surgical treatment (ST group) and 23 patients underwent conservative treatment (CT group). Clinical and radiologic parameters were assessed, and the patient outcomes were analyzed over a 6-month follow-up period. RESULTS: Surgical treatment did not result in any intracranial infections, or complications. Baseline characteristics did not significantly differ between the two groups. At discharge, the average Glasgow Coma Scale (GCS) score and the overall Glasgow Outcome Scale (GOS) score were significantly higher in the ST group compared to the CT group (p < 0.05). The mortality rate (GOS score 1) was significantly lower in the ST group (18.75%, 3/16) than in the CT group (52.17%, 12/23). For patients with hematoma volumes of 5 to 10 mL or GCS scores of 6 to 8, following treatment, the ST group exhibited markedly higher GOS scores in comparison to the CT group. CONCLUSION: Our study suggests that robotic frameless stereotactic aspiration with thrombolysis is a safe and efficient method for the treatment of PPH. Patients with hematomas of 5 to 10 mL or GCS scores of 6 to 8 could benefit from surgery.

Rational multivalency construction enables bactericidal effect amplification and dynamic biomaterial design.

The multivalency of bioligands in living systems brings inspiration for not only the discovery of biological mechanisms but also the design of extracellular matrix (ECM)-mimicking biomaterials. However, designing controllable multivalency construction strategies is still challenging. Herein, we synthesized a series of well-defined multivalent antimicrobial peptide polymers (mAMPs) by clicking ligand molecules onto polymers prepared by reversible addition-fragmentation chain transfer polymerization. The multiple cationic ligands in the mAMPs could enhance the local disturbance of the anionic phospholipid layer of the bacterial membrane through multivalent binding, leading to amplification of the bactericidal effect. In addition to multivalency-enhanced antibacterial activity, mAMPs also enable multivalency-assisted hydrogel fabrication with an ECM-like dynamic structure. The resultant hydrogel with self-healing and injectable properties could be successfully employed as an antibacterial biomaterial scaffold to treat infected skin wounds. The multivalency construction strategy presented in this work provides new ideas for the biomimetic design of highly active and dynamic biomaterials for tissue repair and regeneration.

Hematoma-like dynamic hydrogelation through natural glycopeptide molecular recognition for infected bone fracture repair.

Infected bone fractures remain a major clinical challenge for orthopedic surgeons. From a tissue regeneration perspective, biomaterial scaffolds with antibacterial and osteoinductive activities are highly desired, while advanced materials capable of mimicking the pathological microenvironment during the healing process of infected tissues remain an area deserving more research. Hematoma, the gel-like blood coagulum, plays an essential role in bone fracture repair because of its ability to serve as a dynamic and temporary scaffold with cytokines for both pathogen elimination and tissue healing. In light of this, we designed a dynamic hydrogel with hematoma-like antimicrobial or reparative performance for infected bone fracture repair in this study. The proposed dynamic hydrogel network was based on the reversible recognition of a natural glycopeptide antibiotic vancomycin (Van) and its target dipeptide D-Ala-D-Ala (AA), which could serve as a hematoma-like scaffold for obliterating bacteria in the fracture region and promoting bone repair by introducing an endogenous osteogenic peptide (OGP). In vivo experiments demonstrated that the hydrogel could rapidly eradicate bacteria, improve bone regeneration and restore the local inflammatory microenvironment. Together, findings from this study imply that the use of hematoma-like dynamic hydrogel could lead to a biomimetic revolution in surgical strategies against susceptible bone fractures.

Non-Pharmacological Interventions in Patients With Heart Failure With Reduced Ejection Fraction: A Systematic Review and Network Meta-Analysis.

OBJECTIVE: To determine the effectiveness of non-pharmacologic interventions and the additional benefits of their combination in patients with heart failure with reduced ejection fraction (HFrEF). DATA SOURCES: We searched PubMed, Embase, and the Cochrane Clinical Trials Register from the date of database inception to April 22, 2023. STUDY SELECTION: Randomized controlled trials involving non-pharmacologic interventions conducted in patients with HFrEF were included. DATA EXTRACTION: Data were extracted by 2 independent reviewers based on a pre-tested data extraction form. The quality of evidence was assessed using the Cochrane Risk of Bias tool and the Grading of Recommendations Assessment, Development, and Evaluation method. DATA SYNTHESIS: A total of 82 eligible studies (4574 participants) were included. We performed a random-effects model within a Bayesian framework to calculate weighted mean differences (WMDs) and 95% credibility intervals. High or moderate certainty evidence indicated that high-intensity aerobic interval training (HIAIT) was best on improving 6-minute walk distance (6MWD; 68.55 m [36.41, 100.47]) and left ventricular ejection fraction (6.28% [3.88, 8.77]), while high-intensity aerobic continuous training (HIACT) is best on improving peak oxygen consumption (Peak VO2; 3.48 mL/kg•min [2.84, 4.12]), quality of life (QOL; -17.26 [-29.99, -7.80]), resting heart rate (-8.20 bpm [-13.32, -3.05]), and N-terminal pro-B-type natriuretic peptide (-600.96 pg/mL [-902.93, -404.52]). Moderate certainty evidence supported the effectiveness of inspiratory muscle training to improve peak oxygen consumption and functional electrical stimulation to improve QOL. Moderate-intensity aerobic continuous training (MIACT) plus moderate-intensity resistance training (MIRT) had additional benefits in Peak VO2, 6MWD, and QOL. This review did not provide a comprehensive evaluation of adverse events. CONCLUSIONS: Both HIAIT and HIACT are the most effective single non-pharmacologic interventions for HFrEF. MIACT plus MIRT had additional benefits in improving peak oxygen consumption, 6MWD, and QOL.

Structure and assembly of type VI secretion system cargo delivery vehicle.

Type VI secretion system is widely used in Gram-negative bacteria for injecting toxic effectors into neighboring prokaryotic or eukaryotic cells. Various effectors can be loaded onto the T6SS delivery tube via its core components: Hcp, VgrG, or PAAR. Here, we report 2.8-Å resolution cryo-EM structure of intact T6SS Hcp5-VgrG-PAAR cargo delivery system and crystal structure of unbound Hcp5 from B. fragilis NCTC 9343. Loading of Hcp5 hexameric ring onto VgrG causes expansion of its inner cavity and external surface, explaining how structural changes could be propagated to regulate co-polymerization and surrounding contractile sheath. High-affinity binding between Hcp and VgrG causes entropically unfavorable structuring of long loops. Furthermore, interactions between VgrG trimer and Hcp hexamer are asymmetric, with three of the six Hcp monomers exhibiting a major loop flip. Our study provides insights into the assembly, loading, and firing of T6SS nanomachine that contributes to bacterial inter-species competition and host interactions.

Mechanistic and structural insights into the bifunctional enzyme PaaY from Acinetobacter baumannii.

PaaY is a thioesterase that enables toxic metabolites to be degraded through the bacterial phenylacetic acid (PA) pathway. The Acinetobacter baumannii gene FQU82_01591 encodes PaaY, which we demonstrate to possess γ-carbonic anhydrase activity in addition to thioesterase activity. The crystal structure of AbPaaY in complex with bicarbonate reveals a homotrimer with a canonical γ-carbonic anhydrase active site. Thioesterase activity assays demonstrate a preference for lauroyl-CoA as a substrate. The AbPaaY trimer structure shows a unique domain-swapped C-termini, which increases the stability of the enzyme in vitro and decreases its susceptibility to proteolysis in vivo. The domain-swapped C-termini impact thioesterase substrate specificity and enzyme efficacy without affecting carbonic anhydrase activity. AbPaaY knockout reduced the growth of Acinetobacter in media containing PA, decreased biofilm formation, and impaired hydrogen peroxide resistance. Collectively, AbPaaY is a bifunctional enzyme that plays a key role in the metabolism, growth, and stress response mechanisms of A. baumannii.

Introducing value-based healthcare perspectives into hospital performance assessment: A scoping review.

OBJECTIVE: Value-based healthcare (VBHC) puts patient outcomes at the center of the healthcare process while optimizing the use of hospital resources across multiple stakeholders. This scoping review was conducted to summarize how VBHC had been represented in theory and in practice, how it had been applied to assess hospital performance, and how well it had been ultimately implemented. METHODS: For this review, we followed the PRISMA-ScR protocol and searched five major online databases for articles published between January 2006 and July 2022. We included original articles that used the concept of VBHC to conduct performance assessments of healthcare organizations. We extracted and analyzed key concepts and information on the dimensions of VBHC, specific strategies and methods for using VBHC in performance assessment, and the effectiveness of the assessment. RESULTS: We identified 48 eligible studies from 7866 articles. Nineteen nonempirical studies focused on the development of a VBHC performance assessment indicator system, and 29 empirical studies reported on the ways and points of introducing VBHC into performance assessment and its effectiveness. Ultimately, we summarized the key dimensions, processes, and effects of performance assessment after introducing VBHC. CONCLUSION: Current healthcare performance assessment has begun to focus on implementing VBHC as an integrated strategy, and future work should further clarify the reliability of metrics and their association with evaluation outcomes and consider the effective integration of clinical outcomes and patient-reported outcomes.