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Therapeutic option for treating methicillin-resistant Staphylococcus aureus (MRSA) infection is urgently required since its resistance to a broad spectrum of currently available antibiotics. Here, we report that isoniazid is able to potentiate the killing efficacy of tigecycline to MRSA. The combination of isoniazid and tigecycline reduces the minimal inhibitory concentration of clinic MRSA strains to tigecycline. The killing activity of tigecycline is further confirmed by killing experiments and murine infection model. We further demonstrate the mechanism that isoniazid increases intracellular accumulation of tigecycline by promoting the influx but limiting the efflux of tigecycline through proton motive force. We also show that isoniazid and tigecycline synergize to increase the abundance of isoniazid-NAD adduct, which in turn damage cell membrane, possibly contributing to the disruption of PMF. Whereas phosphatidylethanolamine and cardiolipin are able to abrogate the synergistic effect of isoniazid plus tigecycline. Thus our study provides a new perspective that antibiotics, e.g. isoniazid, once recognized only to target Mycobacterium tuberculosis, can be repurposed as antibiotic adjuvant to tigecycline, expanding our choice of antibiotic-antibiotic combinations in treating bacterial infectious diseases.

Background: While severe postoperative complications (SPCs) impact cancer prognosis, their effect on locally advanced esophageal squamous cell carcinoma (ESCC) patients with varying immunonutritional statuses after minimally invasive esophagectomy (MIE) is unclear.

Methods: This retrospective study analyzed 442 patients with locally advanced ESCC who underwent MIE, investigating the relationship between SPCs and survival based on preoperative immunonutritional status, determined by the prognostic nutritional index (PNI). Nomograms were developed for patients with preserved immunonutritional status using Cox regression, and their performance was assessed.

Results: Of the patients, 102 (23.1%) experienced SPCs after MIE. Five-year overall survival (OS) and disease-free survival (DFS) were significantly different between SPCs and non-SPCs groups (p < 0.001). In the preserved immunonutritional group, SPCs significantly reduced 5-year OS (p = 0.008) and DFS (p = 0.011), but not in the poor immunonutritional group (OS p = 0.152, DFS p = 0.098). Multivariate Cox regression identified SPCs as an independent risk factor for OS (HR = 1.653, p = 0.013) and DFS (HR = 1.476, p = 0.039). A nomogram for predicting OS and DFS in preserved immunonutritional patients demonstrated excellent performance.

Conclusions: SPCs significantly affect prognosis in ESCC patients with preserved immunonutritional status after MIE. Nomograms based on SPCs can predict OS and DFS in these patients.

Purpose: Rugby sevens is a high-intensity contact sport often played in two-day tournaments. Caffeine is widely used by rugby players for its performance-enhancing effects. This study aimed to investigate the impact of caffeine supplementation on various performance metrics, including distance covered at different speeds, acceleration, deceleration, collisions, and repeated high-intensity efforts across four matches over two consecutive days in collegiate male rugby sevens players. Reactive agility, a key performance attribute in rugby sevens, was also assessed before each match.

Methods: A position-matched, double-blind, randomized crossover design was employed, with six male collegiate rugby players (mean height: 1.78 ± 0.09 m, mean weight: 81.3 ± 9.2 kg, mean age: 21.5 ± 0.8 years) participating in two trials. Each trial consisted of a two-day tournament, with two matches per day. Performance was monitored using global positioning system units to track distance covered in various speed zones, as well as total distance, frequency of acceleration, deceleration, collisions, and repeated high-intensity efforts.

Results: The results indicated that in the placebo trial, participants covered significantly more distance at a walking pace (0-6 km/h) in match 4 compared to match 3 (match 3: 480.3 ± 32.7 m; match 4: 629.4 ± 21.3 m, p < 0.001, d = 0.117). In the caffeine trial, players covered significantly more distance at a jogging pace (6-12 km/h) in match 4 compared to the placebo trial (caffeine: 405.9 ± 9.8 m; placebo: 303.6 ± 20.2 m, p = 0.015, d = 1.693). Reactive agility was significantly better in the caffeine trial before match 3 (caffeine trial: 1.80 ± 0.17 s; placebo trial: 2.07 ± 0.18 s, p = 0.038, d = 0.858).

Conclusions: Caffeine supplementation at 3 mg/kg may increase jogging and reduce walking and standing in the final match of a two-day rugby sevens tournament, while also improving reactive agility on the second day. This suggests that by mitigating fatigue in the later stages of the tournament, caffeine allowed players to shift from low-intensity activities to higher-intensity efforts. These adjustments may improve both offensive and defensive performance during rugby sevens matches. Therefore, rugby sevens players could benefit from taking caffeine supplements in the later stages of 2-day tournaments to optimize their performance.

Aims: Empagliflozin confers cardioprotective benefits among patients with heart failure, across the range of ejection fraction (EF), regardless of type 2 diabetes status. The long-term cost-effectiveness of empagliflozin for the treatment of heart failure (HF) in the Philippines remains unclear. This study aims to determine the economic benefit of adding empagliflozin to the standard of care (SoC) vs the SoC alone for HF in the Philippines.

Methods: Using a Markov model, we predicted lifetime costs and clinical outcomes associated with treating HF in the Philippine setting. We used estimates of treatment efficacy, event probabilities, and derivations of utilities from the EMPEROR trials. Costs were derived from hospital tariffs and expert consensus. Separate analyses were performed for patients with left ventricular EF > 40%, categorized under mid-range ejection fraction or preserved ejection fraction (HFmrEF/HFpEF), and patients with left EF ≤ 40%, categorized under HF with reduced ejection fraction (HFrEF).

Results: Our model predicted an average of 0.09 quality-adjusted life year (QALY) gains among HFmrEF/HFpEF patients and HFrEF patients when empagliflozin was compared to SoC. The addition of empagliflozin in the treatment results in a discounted incremental lifetime cost of PHP 62,692 (USD 1,129.99) and PHP 17,215 (USD 308.67) for HFmrEF/HFpEF and HFrEF, respectively. The incremental cost-effectiveness ratio (ICER) of empagliflozin is PHP 198,270 (USD 3,570.72)/QALY and PHP 742,604 (USD 13,385.08)/QALY for HFrEF and HFmrEF/HFpEF, respectively.

Limitations: This study employed parameters derived from short-term clinical trial data, alongside metrics representative of Asian populations, which are not specific to the Philippine cohort.

Conclusions: Adding empagliflozin to the SoC in comparison to the SoC is associated with improved clinical outcomes and quality-of-life, at additional costs for both HFrEF and HFmrEF/HFpEF.

Objective: To comprehensively investigate the predictive value of thyroid hormone sensitivity parameters for cervical lymph node metastasis in patients diagnosed with differentiated thyroid cancer (DTC) undergoing total thyroidectomy and neck lymph node dissection.

Methods: A retrospective cohort study was conducted involving patients diagnosed with DTC and evaluated for cervical lymph node metastasis. Relevant demographic, tumour, lymph node and thyroid hormone sensitivity parameter data were extracted from medical records and laboratory reports. Thyroid hormone sensitivity parameters including thyroxine (T4), triiodothyronine (T3), thyroid-stimulating hormone (TSH), thyroglobulin (Tg), thyroglobulin antibodies (TgAbs), thyroid peroxidase antibody, thyroid hormone receptor α and TSH receptor antibody were assessed. Statistical analyses including descriptive statistics, comparative analysis, Pearson's correlation analysis, logistic regression analysis, receiver operating characteristic (ROC) analysis and construction of a multivariable prediction model based on machine learning using the xgbTree method were employed to evaluate the associations and predictive value of thyroid hormone sensitivity parameters for cervical lymph node metastasis.

Results: The study revealed significant associations between several thyroid hormone sensitivity parameters and cervical lymph node metastasis in patients with DTC. Specifically, higher levels of T4, T3, Tg, TgAbs and TSH receptor antibody were associated with lymph node metastasis. Pearson's correlation analysis, logistic regression analysis and ROC analysis further underscored the predictive performance of these parameters, with strong overall discriminative abilities. The machine learning-based prediction model demonstrated promising performance with a high area under the curve (AUC) of 0.979.

Conclusions: The findings provide compelling evidence for the predictive value of thyroid hormone sensitivity parameters, particularly T3, T4, Tg, TgAbs and TSH receptor antibody, in identifying and evaluating the likelihood of cervical lymph node metastasis in patients with DTC. These parameters hold potential implications for risk stratification, clinical decision-making and personalized management strategies, contributing to improved outcomes for patients at risk of lymph node metastasis.

Background: Chronic kidney disease (CKD) is a prevalent chronic, non-communicable disease. The long-term health effects of dietary live microbes, primarily probiotics, on CKD patients remain insufficiently understood. This study aims to investigate the association between dietary intake of live microbes and long-term health outcomes among individuals with CKD.

Methods: Utilizing the National Health and Nutrition Examination Survey (NHANES) database, Cox regression analysis assessed the association between medium and high categories dietary live microbe intake and health outcomes (all-cause, cardiovascular disease [CVD], and cancer-related mortality) in CKD patients.

Results: A total of 3,646 CKD patients were enrolled. During the follow-up period, 1,593 all-cause mortality events were recorded, including 478 CVD deaths and 268 cancer deaths. In the fully adjusted model, compared to CKD patients in the lowest quartile (quartile 1) of live microbes intake, those in quartiles 3 and 4 exhibited a 20% and 26% reduced risk of all-cause mortality, with hazard ratios (HR) of 0.80 (95% confidence interval, CI: 0.69, 0.94) and 0.74 (95% CI: 0.62, 0.90), respectively. Additionally, compared to those with low live microbe intake (quartile 1), higher live microbe intake in quartile 4 was associated with a 37% reduction in the risk of CVD mortality for CKD patients, with an HR of 0.63 (95% CI: 0.45, 0.88). Consistent results were observed in subgroup and sensitivity analyses. A significant negative association was observed between live microbe intake and the risk of all-cause mortality as well as CVD mortality in the CKD population, with a p-value for trend < 0.05.

Conclusion: Our study indicated that high dietary live microbe intake could mitigate the risk of all-cause and CVD mortality in CKD patients. These findings support the inclusion of live microbes in dietary recommendations, highlighting their significant roles in CKD.

Background: Vascular calcification is highly prevalent and associated with mortality in hemodialysis patients. However, extreme splanchnic arterial calcification in calciphylaxis with poor prognosis raises questions regarding the reliability of previous vascular calcification scoring methods. Therefore, this study aimed to examine the distribution characteristics of abdominal aortic branch calcification and identify a more reliable predictor of mortality in hemodialysis patients.

Methods: The cohort study included 237 hemodialysis patients. The distribution characteristics of abdominal aortic branch calcification were determined by quantifying the calcification volumes. The primary and secondary outcomes were all-cause mortality and new-onset cardiovascular events, respectively. We compared the prognostic values of abdominal aortic branch calcification and constructed a predictive nomogram model.

Results: The prevalence of abdominal vascular calcification in hemodialysis patients was 95.36%, with the highest prevalence in the abdominal aorta (88.61%) and internal iliac artery (85.65%). During a median follow-up period of 3.92 years, 137 patients died. Internal iliac artery and mesenteric artery calcification showed the greatest predictive values for mortality. Internal iliac artery calcification and serum albumin level were independently associated with mortality in hemodialysis patients (p < .001). The nomogram model constructed with internal iliac artery calcification, serum albumin level, age, and comorbid cardiovascular disease was well discriminative, calibrated, and clinically applicable for predicting 3-year survival.

Conclusion: Abdominal aortic branch calcification, particularly internal iliac artery calcification, is a preferable prognostic predictor than abdominal aorta or coronary artery calcification in hemodialysis patients.

Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) remains the mainstay of treatment for adults with high-risk acute lymphoblastic leukemia (ALL). Due to the crucial role of measurable residual disease (MRD) before Allo-HSCT in predicting relapse and the promising anti-leukemia effect of blinatumomab, we documented a short-course, low-dose conditioning regimen incorporating blinatumomab for Allo-HSCT in three ALL patients with positive MRD. Following the administration of the blinatumomab-containing conditioning regimen, all patients attained complete remission (CR) with negative MRD status, and no severe adverse events were observed. After a 2-year follow-up, 2/3 of patients remained disease-free and attained long-term survival following transplantation. These cases indicated a short-term blinatumomab conditioning regimen may effectively prolong patient survival, improve prognosis, and offer a safe and cost-effective treatment for high-risk ALL patients with positive MRD. The addition of blinatumomab to the conditioning regimen of Allo-HSCT is feasible for high-risk ALL patients with positive MRD.

Copy number variations (CNVs) have become widely acknowledged as a significant source of genomic variability and phenotypic variance. To understand the genetic variants in horses, CNVs from six Indian horse breeds, namely, Manipuri, Zanskari, Bhutia, Spiti, Kathiawari and Marwari were discovered using Axiom^™ Equine Genotyping Array. These breeds differed in agro-climatic adaptation with distinct phenotypic characters. A total of 2668 autosomal CNVs and 381 CNV regions (CNVRs) were identified with PennCNV tool. DeepCNV was employed to re-validate to get 883 autosomal CNVs, of which 9.06% were singleton type. A total of 180 CNVRs were identified after DeepCNV filtering with the estimated length of 3.12 Kb-4.90 Mb. The functional analysis showed the majority of the CNVRs genes enriched for sensory perception and olfactory receptor activity. An Equine CNVs database, EqCNVdb (http://backlin.cabgrid.res.in/eqcnvdb/) was developed which catalogues detailed information on the horse CNVs, CNVRs and gene content within CNVRs. Also, three random CNVRs were validated with real-time polymerase chain reaction. These findings will aid in the understanding the horse genome and serve as a preliminary foundation for future CNV association research with commercially significant equine traits. The identification of CNVs and CNVRs would lead to better insights into genetic basis of important traits.

The objective of this study was to identify key secretory protein-encoding differentially expressed genes (SP-DEGs) in adipose tissue in female metabolic syndrome, thus detecting potential targets in treatment. We examined gene expression profiles in 8 women with metabolic syndrome and 7 healthy, normal body weight women. A total of 143 SP-DEGs were screened, including 83 upregulated genes and 60 downregulated genes. GO analyses of these SP-DEGs included proteolysis, angiogenesis, positive regulation of endothelial cell proliferation, immune response, protein processing, positive regulation of neuroblast proliferation, cell adhesion and ER to Golgi vesicle-mediated transport. KEGG pathway analysis of the SP-DEGs were involved in the TGF-beta signalling pathway, cytokine‒cytokine receptor interactions, the hippo signalling pathway, Malaria. Two modules were identified from the PPI network, namely, Module 1 (DNMT1, KDM1A, NCoR1, and E2F1) and Module 2 (IL-7 R, IL-12A, and CSF3). The gene DNMT1 was shared between the network modules and the WGCNA brown module. According to the single-gene GSEA results, DNMT1 was significantly positively correlated with histidine metabolism and phenylalanine metabolism. This study identified 7 key SP-DEGs in adipose tissue. DNMT1 was selected as the central gene in the development of metabolic syndrome and might be a potential therapeutic target.