Presentation of the ATLETAS DA VOZ™ Conditioning Program

Objectives: To present a simple form of vocal and breathing conditioning for voice professionals based on concepts from vocal science. The vocal conditioning program called Voice Athletes Conditioning uses the principles of exercise physiology to gradually improve vocal and respiratory overload to achieve endurance, power, and flexibility. Methods: Due to our personal experience with high voice users, we synthesized a vocal conditioning program (AVCP) that combines voice science, exercise physiology, sports science and physical therapy principles. This is an 8-week program of daily vocal and breathing exercises with overload enhancement each week using different types of breathing devices and semi-occluded vocal tract exercises, designed and developed according to the specific requirements and performance of the voice professional. Reflections: Professional voice users often experience episodes of vocal fatigue that can directly affect their performance and vocal health. As with physical training for athletes, voice exercises can also contribute to improving vocal conditioning, preventing voice disorders, as well as helping to obtain better performance, greater tolerance to fatigue and shorter recovery time. Conclusions: AVCP is an approach that considers the principles of muscle training aimed objectively at the respiratory and vocal muscles, carried out with a variety of breathing devices and specific vocal exercises in search of greater performance time, less physiological stress, and shorter recovery time in the professional use of the voice.

Objetivos: Presentar una forma sencilla de acondicionamiento vocal y respiratorio para profesionales de la voz, basada en conceptos de la ciencia vocal. El programa de acondicionamiento vocal denominado Voice Athletes Conditioning utiliza los principios de la fisiología del ejercicio para mejorar gradualmente la sobrecarga vocal y respiratoria, con el fin de lograr resistencia, potencia y flexibilidad. Métodos: Debido a nuestra experiencia personal con usuarios de voz aguda, sintetizamos un programa de acondicionamiento vocal (AVCP) que combina principios de la ciencia de la voz, la fisiología del ejercicio, las ciencias del deporte y la fisioterapia. Se trata de un programa de 8 semanas de ejercicios vocales y respiratorios diarios con realce de sobrecarga cada semana utilizando diferentes tipos de dispositivos respiratorios y ejercicios semioclusivos del tracto vocal, diseñado y desarrollado de acuerdo con los requerimientos específicos y el rendimiento del profesional de la voz. Reflexiones: Los usuarios profesionales de la voz experimentan a menudo episodios de fatiga vocal que pueden afectar directamente su rendimiento y salud vocal. Al igual que ocurre con el entrenamiento físico de los deportistas, los ejercicios vocales también pueden contribuir a mejorar el acondicionamiento vocal, prevenir trastornos de la voz, además de ayudar a obtener un mejor rendimiento, una mayor tolerancia a la fatiga y un menor tiempo de recuperación. Conclusiones: El AVCP es un enfoque que considera los principios del entrenamiento muscular dirigido objetivamente a la musculatura respiratoria y vocal, realizado con diversos aparatos respiratorios y ejercicios vocales específicos en busca de un mayor tiempo de actuación, menor estrés fisiológico y menor tiempo de recuperación en el uso profesional de la voz.

The small acid-soluble proteins of spore-forming organisms: Similarities and differences in function.

The small acid-soluble proteins are found in all endospore-forming organisms and are a major component of spores. Through their DNA binding capabilities, the SASPs shield the DNA from outside insults (e.g., UV and genotoxic chemicals). The absence of the major SASPs results in spores with reduced viability when exposed to UV light and, in at least one case, the inability to complete sporulation. While the SASPs have been characterized for decades, some evidence suggests that using newer technologies to revisit the roles of the SASPs could reveal novel functions in spore regulation.

IL-22 signaling promotes sorafenib resistance in hepatocellular carcinoma via STAT3/CD155 signaling axis.

Introduction: Sorafenib is currently the first-line treatment for patients with advanced hepatocellular carcinoma (HCC). Nevertheless, sorafenib resistance remains a huge challenge in the clinic. Therefore, it is urgent to elucidate the mechanisms underlying sorafenib resistance for developing novel treatment strategies for advanced HCC. In this study, we aimed to investigate the role and mechanisms of interleukin-22 (IL-22) in sorafenib resistance in HCC. Methods: The in vitro experiments using HCC cell lines and in vivo studies with a nude mouse model were used. Calcium staining, chromatin immunoprecipitation, lactate dehydrogenase release and luciferase reporter assays were employed to explore the expression and roles of IL-22, STAT3 and CD155 in sorafenib resistance. Results: Our clinical results demonstrated a significant correlation between elevated IL-22 expression and poor prognosis in HCC. Analysis of transcriptomic data from the phase-3 STORM-trial (BIOSTORM) suggested that STAT3 signaling activation and natural killer (NK) cell infiltration may associate sorafenib responses. STAT3 signaling could be activated by IL-22 administration in HCC cells, and then enhanced sorafenib resistance in HCC cells by promoting cell proliferation and reducing apoptosis in vitro and in vivo. Further, we found IL-22/STAT3 axis can transcriptionally upregulate CD155 expression in HCC cells, which could significantly reduce NK cell-mediated HCC cell lysis in a co-culture system. Conclusions: Collectively, IL-22 could contribute to sorafenib resistance in HCC by activating STAT3/CD155 signaling axis to decrease the sensitivities of tumor cells to sorafenib-mediated direct cytotoxicity and NK cell-mediated lysis. These findings deepen the understanding of how sorafenib resistance develops in HCC in terms of IL-22/STAT3 signaling pathway, and provide potential targets to overcome sorafenib resistance in patients with advanced HCC.

Potential role of Citrus bergamia flower essential oil against oral pathogens.

BACKGROUND: Oral bacterial infections are difficult to treat due to emergence of resistance against antibiotic therapy. Essential oils are considered emerging alternate therapy against bacterial infections and biofilms. We investigated Citrus bergemia flower essential oil against oral pathogens. METHODS: The essential oil was analsyed using Gas Chromatography(GC-MS), in silico investigations, antioxidant, antimicrobial, antibiofilm and antiquorum sensing assays. RESULTS: Gas Chromatography analysis confirmed presence of 17 compounds including 1,6-Octadien-3-ol,3,7-dimethyl, 48.17%), l-limonene (22.03%) and p-menth-1-ol, 8-ol (7.31%) as major components. In silico analysis showed compliance of all tested major components with Lipinski's rule, Bioavailability and antimicrobial activity using PASS (prediction of activity spectrum of substances). Molecular docking with transcriptional regulators 3QP5, 5OE3, 4B2O and 3Q3D revealed strong interaction of all tested compounds except 1,6-Octadien-3-ol,3,7-dimethyl. All tested compounds presented significant inhibition of DPPH (2,2-diphenyl-1-picrylhydrazyl) (IC50 0.65 mg/mL), H2O2 (hydrogen peroxide) (63.5%) and high FRAP (ferrous reducing antioxidant power) value (239.01 µg). In antimicrobial screening a significant activity (MIC 0.125 mg/mL) against Bacillus paramycoides and Bacillus chungangensis was observed. Likewise a strong antibiofilm (52.1 - 69.5%) and anti-QS (quorum sensing) (4-16 mm) activity was recorded in a dose dependent manner. CONCLUSION: It was therefore concluded that C. bergemia essential oil posess strong antioxidant, antimicrobial and antibiofilm activities against tested oral pathogens.

Study of association of leptin with leukocyte telomere length in a Chinese rural population.

BACKGROUND: Previous studies have demonstrated the relationship between adipocyte factors, insulin resistance, and other indicators with telomere length. However, these studies did not consider the influence of changes in different indicators on telomere length over time. Therefore, the aim of this study is to elucidate the impact of changes in adipocyte factors, HOMA-IR, and other indicators on the dynamic variation of telomere length. METHODS: The data were from a cohort study conducted in Ningxia, China. A total of 1624 subjects were analyzed. Adipokines and relative leukocyte telomere length (RLTL) were measured, and changes in Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), Homeostatic Model Assessment for ß-Cell Function (HOMA-ß), and Quantitative Insulin Sensitivity Check Index (QUICKI) were calculated. Generalized linear models evaluated associations between changes in adipokines and RLTL changes. Furthermore, univariate analyses examined the effects of changes in adipokines and insulin resistance indicators on ΔRLTL. RESULTS: The research findings indicate that females generally have shorter telomeres compared to males. In comparison to the low-level group of Δleptin (LEP), the high-level group of ΔLEP shows a negative correlation with ΔRLTL (B=-1.32, 95% CI (-2.38, -0.27)). Even after multivariable adjustments, this relationship persists (B=-1.31, 95% CI (-2.24, -0.23)). Further analysis reveals that after adjusting for ΔHOMA-IR, ΔHOMA-ß, and ΔQUICKI, the high-level group of ΔLEP still exhibits a significant negative correlation with ΔRLTL (B=-1.37, 95% CI (-2.43, -0.31)). However, the interaction effects between ΔHOMA-IR, ΔHOMA-ß, ΔQUICKI, and ΔLEP do not affect ΔRLTL. CONCLUSIONS: Elevated levels of leptin were significantly correlated with shortened telomere length. This suggests that increased leptin levels may impact overall individual health by affecting telomere length, underscoring the importance of measures to reduce leptin levels to mitigate the onset and progression of related diseases.

A reconstructed genome-scale metabolic model of Helicobacter pylori for predicting putative drug targets in clarithromycin and rifampicin resistance conditions.

BACKGROUND: Helicobacter pylori is considered a true human pathogen for which rising drug resistance constitutes a drastic concern globally. The present study aimed to reconstruct a genome-scale metabolic model (GSMM) to decipher the metabolic capability of H. pylori strains in response to clarithromycin and rifampicin along with identification of novel drug targets. MATERIALS AND METHODS: The iIT341 model of H. pylori was updated based on genome annotation data, and biochemical knowledge from literature and databases. Context-specific models were generated by integrating the transcriptomic data of clarithromycin and rifampicin resistance into the model. Flux balance analysis was employed for identifying essential genes in each strain, which were further prioritized upon being nonhomologs to humans, virulence factor analysis, druggability, and broad-spectrum analysis. Additionally, metabolic differences between sensitive and resistant strains were also investigated based on flux variability analysis and pathway enrichment analysis of transcriptomic data. RESULTS: The reconstructed GSMM was named as HpM485 model. Pathway enrichment and flux variability analyses demonstrated reduced activity in the ribosomal pathway in both clarithromycin- and rifampicin-resistant strains. Also, a significant decrease was detected in the activity of metabolic pathways of clarithromycin-resistant strain. Moreover, 23 and 16 essential genes were exclusively detected in clarithromycin- and rifampicin-resistant strains, respectively. Based on prioritization analysis, cyclopropane fatty acid synthase and phosphoenolpyruvate synthase were identified as putative drug targets in clarithromycin- and rifampicin-resistant strains, respectively. CONCLUSIONS: We present a robust and reliable metabolic model of H. pylori. This model can predict novel drug targets to combat drug resistance and explore the metabolic capability of H. pylori in various conditions.

Relationship between triglyceride-glucose index and new-onset hypertension in general population-a systemic review and meta-analysis of cohort studies.

BACKGROUND: The triglyceride-glucose (TyG) index is an alternative biomarker for insulin resistance that may be connected to incident hypertension. We performed the meta-analysis to clarify the connection between TyG index and new-onset hypertension in the general population. METHODS: We recruited cohort studies that assessed the association between TyG index and the risk of hypertension in the general population by searching the databases of PubMed, EMBASE, and Web of Science (SCI) from their inception dates until July 18, 2023. The primary focus of the study was on the hazard ratio (HR) of hypertension in relation to the TyG index. The adjusted HR and 95% confidence interval (CI) were pooled by the random-effects model. Subgroup analyzes stratified by age, sex, follow-up duration, body mass index (BMI), and ethnicity were performed. RESULTS: Our analysis comprised 35 848 participants from a total of 7 cohort studies. The highest TyG index category showed a 1.51-fold greater risk of hypertension in the general population than the lowest category (HR = 1.51, 95%CI 1.26-1.80, p < .001). Consistent results were obtained using sensitivity analysis by eliminating one trial at a time (p values all <0.001). Subgroup analysis showed that the relationship between TyG index and hypertension was not substantially influenced by age, sex, BMI, participant ethnicity, and follow-up times (P for interaction all >0.05). CONCLUSIONS: Elevated TyG index significantly increased the risk of new-onset hypertension in the general population. It is necessary to conduct the research to clarify the probable pathogenic processes underpinning the link between the TyG index and hypertension.

Tissue-specific inflammation and insulin sensitivity in subjects with obesity.

Obesity is associated with low-grade inflammation and insulin resistance (IR). The contribution of adipose tissue (AT) and hepatic inflammation to IR remains unclear. We conducted a study across three cohorts to investigate this relationship. The first cohort consists of six women with normal weight and twenty with obesity. In women with obesity, we found an upregulation of inflammatory markers in subcutaneous and visceral adipose tissue, isolated AT macrophages, and the liver, but no linear correlation with tissue-specific insulin sensitivity. In the second cohort, we studied 24 women with obesity in the upper vs lower insulin sensitivity quartile. We demonstrated that several omental and mesenteric AT inflammatory genes and T cell-related pathways are upregulated in IR, independent of BMI. The third cohort consists of 23 women and 18 men with obesity, studied before and one year after bariatric surgery. Weight loss following surgery was associated with downregulation of multiple immune pathways in subcutaneous AT and skeletal muscle, alongside notable metabolic improvements. Our results show that obesity is characterised by systemic and tissue-specific inflammation. Subjects with obesity and IR show a more pronounced inflammation phenotype, independent of BMI. Bariatric surgery-induced weight loss is associated with reduced inflammation and improved metabolic health.

Biofilm inhibition/eradication: exploring strategies and confronting challenges in combatting biofilm.

Biofilms are complex communities of microorganisms enclosed in a self-produced extracellular matrix, posing a significant threat to different sectors, including healthcare and industry. This review provides an overview of the challenges faced due to biofilm formation and different novel strategies that can combat biofilm formation. Bacteria inside the biofilm exhibit increased resistance against different antimicrobial agents, including conventional antibiotics, which can lead to severe problems in livestock and animals, including humans. In addition, biofilm formation also imposes heavy economic pressure on industries. Hence it becomes necessary to explore newer alternatives to eradicate biofilms effectively without applying selection pressure on the bacteria. Excessive usage of antibiotics may also lead to an increase in the number of resistant strains as bacteria employ an advanced antimicrobial resistance mechanism. This review provides insight into multifaceted technologies like quorum sensing inhibition, enzymes, antimicrobial peptides, bacteriophage, phytocompounds, and nanotechnology to neutralize biofilms without developing antimicrobial resistance (AMR). Furthermore, it will pave the way for developing newer therapeutic agents to deal with biofilms more efficiently.

Post-Transplant Fecal Carriage of Antibiotic Resistant and B-Lactamases-Producing Enterobacteriales among Renal Transplant Recipients.

BACKGROUND: The intestinal colonization and transmission of antibiotic-resistant Enterobacteriales to renal transplant recipients may pose a threat to them because they are profoundly immunocompromised and vulnerable to infection. Hence, it is crucial to identify these antibiotic-resistant fecal Enterobacteriales harboring high-risk populations. The objective of this study was to determine antibiotic resistance as well as ß-lactamases production in fecal Enterobacteriales among renal transplant recipients. METHODS: The stool samples, one collected from each transplant recipient, were processed for isolation and identification of Enterobacteriales and were tested for their antibiotic susceptibility, extended-spectrum ß-lactamase, and metallo-ß-lactamase production by standard methods. RESULTS: A total of 103 Enterobacteriales comprising of Escherichia coli (86.4%), Klebsiella species (11.7%), and Citrobacter species (1.9%) were isolated and more than 60% of the E. coli were found resistant to ceftazidime and ciprofloxacin and around half of the Klebsiella species were resistant to ceftazidime and fluroquinolones. The extended-spectrum ß-lactamase production was seen in 3.4% and 8.3% and metallo-ß-lactamase production in 24.7% and 33.3% of E. coli and Klebsiella species, respectively. The high proportion of ß-lactamase-producers were resistant to piperacillin-tazobactam, meropenem, gentamicin, and amikacin than ß-lactamases non-producers. CONCLUSION: Since the antibiotic resistance is higher in fecal Enterobacteriales, each renal transplant recipient should be screened for these highly resistant intestinal colonizers after transplantation in order to prevent infections and to reduce the rate of transplant failure due to infections.

Antibiotic Susceptibility of Staphylococcus Aureus with VanA and MecA Genes.

BACKGROUND: Staphylococcus aureus (S.aureus) is an emerging antibiotic resistant bacterium responsible for various infections in human. Resistance to methicillin and vancomycin are of prime concern in S. aureus. The study aims to determine the minimum inhibitory concentration (MIC) of Vancomycin and evaluate the existence of mecA and vanA genes, associated with antibiotic resistance. METHODS: Clinical specimens from three Kathmandu hospitals were processed and S. aureus was identified using conventional microbiological procedures. MRSA was phenotypically identified with cefoxitin (30µg) disc diffusion, while vancomycin susceptibility was assessed using the Ezy MICTM stripes. The mecA and vanA genes were detected by polymerase chain reaction (PCR). RESULTS: Out of 266 S. aureus samples from various clinical specimen subjected for analysis, 77 (28.9%) were found methicillin-resistant (MRSA) and 10 (3.8%) were observed vancomycin-resistant (VRSA). Vancomycin resistant isolates showed a significant correlation between resistance to ampicillin, chloramphenicol, and cefoxitin. The mecA gene was found in 39 of the MRSA isolates, having 50.64% of MRSA cases, while the vanA gene was detected in 4 of the VRSA cases, constituting 40% of VRSA occurrences. CONCLUSIONS: The strains with higher vancomycin minimum inhibitory concentration values (≥ 1.5 µg/ml) displayed increased resistance rates to various antibiotics compared to strains with lower minimum inhibitory concentration values (< 1.5 µg/ml). The presence of vanA genes was strongly associated (100%) with vancomycin resistance, while the 10.3% mecA gene was identified from MRSA having resistance towards vancomycin also.

Phage-driven coevolution reveals trade-off between antibiotic and phage resistance in Salmonella anatum.

Phage therapy faces challenges against multidrug-resistant (MDR) Salmonella due to rapid phage-resistant mutant emergence. Understanding the intricate interplay between antibiotics and phages is essential for shaping Salmonella evolution and advancing phage therapy. In this study, MDR Salmonella anatum (S. anatum) 2089b coevolved with phage JNwz02 for 30 passages (60 days), then the effect of coevolution on the trade-off between phage and antibiotic resistance in bacteria was investigated. Our results demonstrated antagonistic coevolution between bacteria and phages, transitioning from arms race dynamics (ARD) to fluctuating selection dynamics (FSD). The fitness cost of phage resistance, manifested as reduced competitiveness, was observed. Bacteria evolved phage resistance while simultaneously regaining sensitivity to amoxicillin, ampicillin, and gentamicin, influenced by phage selection pressure and bacterial competitiveness. Moreover, the impact of phage selection pressure on the trade-off between antibiotic and phage resistance was more pronounced in the ARD stage than in the FSD stage. Whole genome analysis revealed mutations in the btuB gene in evolved S. anatum strains, with a notably higher mutation frequency in the ARD stage compared to the FSD stage. Subsequent knockout experiments confirmed BtuB as a receptor for phage JNwz02, and the deletion of btuB resulted in reduced bacterial competitiveness. Additionally, the mutations identified in the phage-resistant strains were linked to multiple single nucleotide polymorphisms (SNPs) associated with membrane components. This correlation implies a potential role of these SNPs in reinstating antibiotic susceptibility. These findings significantly advance our understanding of phage-host interactions and the impact of bacterial adaptations on antibiotic resistance.

Characteristics and phylogenetic distribution of megaplasmids and prediction of a putative chromid in Pseudomonas aeruginosa.

Research on megaplasmids that contribute to the spread of antimicrobial resistance (AMR) in Pseudomonas aeruginosa strains has grown in recent years due to the now widely used technologies allowing long-read sequencing. Here, we systematically analyzed distinct and consistent genetic characteristics of megaplasmids found in P. aeruginosa. Our data provide information on their phylogenetic distribution and hypotheses tracing the potential evolutionary paths of megaplasmids. Most of the megaplasmids we found belong to the IncP-2-type, with conserved and syntenic genetic backbones carrying modules of genes associated with chemotaxis apparatus, tellurite resistance and plasmid replication, segregation, and transmission. Extensively variable regions harbor abundant AMR genes, especially those encoding ß-lactamases such as VIM-2, IMP-45, and KPC variants, which are high-risk elements in nosocomial infection. IncP-2 megaplasmids act as effective vehicles transmitting AMR genes to diverse regions. One evolutionary model of the origin of megaplasmids claims that chromids can develop from megaplasmids. These chromids have been characterized as an intermediate between a megaplasmid and a chromosome, also containing core genes that can be found on the chromosome but not on the megaplasmid. Using in silico prediction, we identified the "PABCH45 unnamed replicon" as a putative chromid in P. aeruginosa, which shows a much higher similarity and closer phylogenetic relationship to chromosomes than to megaplasmids while also encoding plasmid-like partition genes. We propose that such a chromid could facilitate genome expansion, allowing for more rapid adaptations to novel ecological niches or selective conditions, in comparison to megaplasmids.

First-Trimester Triglyceride-Glucose Index and Triglyceride/High-Density Lipoprotein Cholesterol are Predictors of Gestational Diabetes Mellitus Among the Four Surrogate Biomarkers of Insulin Resistance.

Purpose: This study seeks to assess the potential of early pregnancy Triglyceride Glucose Index (TyG), triglyceride to High-Density Lipoprotein Cholesterol ratio (TG/HDL-c), Low-Density Lipoprotein Cholesterol to High-Density Lipoprotein Cholesterol ratio (LDL-C/HDL-C), and Total Cholesterol to High-Density Lipoprotein Cholesterol ratio (TC/HDL-C) in predicting Gestational Diabetes Mellitus (GDM). Patients and Methods: A total of 1073 adults singleton pregnant women were enrolled from June 2017 to September 2019. Complete anthropometric data and lipid profiles were measured in the first trimester (before 12 weeks gestation) and a 75g oral glucose tolerance test (OGTT) at 24-28 weeks was performed. Based on OGTT results, participants were categorised into Normal Glucose Tolerance (NGT) group (n=872) and GDM group (n=201). General data, laboratory test results, and surrogate insulin resistance indicators such as TyG index, TG/HDL-C, LDL-C/HDL-C, and TC/HDL-C were documented and compared. To compare differences between the two groups, t-test was used, Spearman correlation analysis and linear regression analysis were performed to establish associations between these indicators and insulin resistance in GDM. Receiver Operating Characteristic (ROC) curves were generated to compare the thresholds of these indicators for predicting GDM during pregnancy and to quantify overall diagnostic accuracy. Results: Individuals with GDM had higher TyG, TG/HDL-C, and LDL-C/HDL-C levels (P < 0.001), but with no significant difference observed in TC/HDL-C. All four ratios were positively correlated with Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), yet only TyG emerged as an independent risk factor for HOMA-IR. The Area under the Curve (AUC) of TyG index (0.692) was comparable to that of HOMA-IR (0.703). The cut-off points for TyG index, TG/HDL-C, and HOMA-IR in predicting GDM were 7.088, 0.831, and 1.8, respectively. HOMA-IR exhibited the highest sensitivity (79.1%), while TyG index (64.3%) and TG/HDL-C ratio (64.3%) demonstrated better specificity compared to HOMA-IR (56.3%). LDL-C/HDL-C and TC/HDL-C offered no discernible predictive advantage. Conclusion: Early pregnancy TyG index and TG/HDL-C can aid in identifying pregnant women at risk for GDM, potentially facilitating early and effective intervention to improve prognosis. TyG index exhibited superior predictive capability compared to TG/HDL-C.

Prevalence, antibiotic resistance pattern for bacteriuria from patients with urinary tract infections.

Background and Aims: Antibiotic resistance presents a significant global public health challenge, particularly for urinary tract infections (UTIs), and is notably severe in developing countries. Surveillance of the antimicrobial susceptibility patterns of UTI-causing bacteria is crucial for effective treatment selection. This study aimed to analyze these patterns in bacteria isolated from the urine samples of patients at Mughda Medical College Hospital, Dhaka, Bangladesh. Methods: A retrospective study (January 2019 to December 2020) at Mugdha Medical College and Hospital, Dhaka, examined clinical and laboratory data from patients with positive urine cultures (≥105 CFU/mL). The study classified patients into four age groups: children (1-<18 years), young adults (18-<33 years), middle-aged adults (33-50 years), and old adults (>50 years). The standard Kirby-Bauer method was used to assess antibiotic sensitivity to 28 common antibiotics. Results: Among 243 positive urine cultures in both community- and hospital-acquired UTIs, Escherichia coli was the most common uropathogen (65.84%), followed by Klebsiella spp. (12.34%), Enterococcus spp. (8.23%), and other types of bacteria. Conclusion: Old adults are particularly vulnerable to UTIs, with E. coli being the predominant causative agent in the study region. The observed antimicrobial resistance patterns underscore the necessity of judicious antibiotic selection to effectively treat UTIs across different age groups.

Antibiogram of Escherichia coli Isolated from Dairy Cattle and in-Contact Humans in Selected Areas of Central Ethiopia.

Background: Antimicrobial resistance (AMR) is a global threat to public and animal health. Escherichia coli is considered an indicator organism for monitoring AMR among gram-negative Enterobacteriaceae in humans and animals. The current study aims to assess the antibiogram profile of E. coli isolated from dairy cattle and in-contact humans in central Ethiopia and to identify risk factors associated with multidrug resistance (MDR). Methods: A cross-sectional study was conducted in which 58 farms were recruited from selected districts of central Ethiopia. E. coli was isolated using standard bacteriological techniques. A total of 200 representative isolates (140 from cattle and 60 from humans in contact) were randomly selected and tested for susceptibility to a panel of 13 antimicrobials using the Kirby-Bauer disc diffusion assay. Results: The highest rate of resistance was observed for sulfamethoxazole+trimethoprim (58.6%, 82/140) and amoxicillin+clavulanic acid (70.0%, 42/60) among E. coli isolates from cattle and hmans, respectively. In contrast, resistance rates in isolates from in contact humans with the cattle were 30%, 33.3%, and 66.7%, respectively. Resistance to tetracycline (p=0.02), streptomycin (p=0.03), and sulfamethoxazole+trimethoprim (p=0.007) was significantly high in E. coli isolated from cattle on commercial dairy farms than in those isolated from cattle on smallholder farms. There was no significant difference (p>0.05) in the rate of resistance between E. coli isolated from in contact humans with smallholder and commercial dairy farms. Antimicrobial use for treatment purpose (p=0.04) and non-compliance with the drug withdrawal period (p=0.03) were significantly associated with the farm-level occurrence of MDR. Conclusion: A high rate of resistance was detected in E. coli isolated from the feces of dairy cattle and in-contact humans. This necessitates an effective intervention through a one-health approach and further molecular studies are required to establish source attribution.

Targeting the Cdc2-like kinase 2 for overcoming platinum resistance in ovarian cancer.

Platinum resistance represents a major barrier to the survival of patients with ovarian cancer (OC). Cdc2-like kinase 2 (CLK2) is a major protein kinase associated with oncogenic phenotype and development in some solid tumors. However, the exact role and underlying mechanism of CLK2 in the progression of OC is currently unknown. Using microarray gene expression profiling and immunostaining on OC tissues, we found that CLK2 was upregulated in OC tissues and was associated with a short platinum-free interval in patients. Functional assays showed that CLK2 protected OC cells from platinum-induced apoptosis and allowed tumor xenografts to be more resistant to platinum. Mechanistically, CLK2 phosphorylated breast cancer gene 1 (BRCA1) at serine 1423 (Ser1423) to enhance DNA damage repair, resulting in platinum resistance in OC cells. Meanwhile, in OC cells treated with platinum, p38 stabilized CLK2 protein through phosphorylating at threonine 343 of CLK2. Consequently, the combination of CLK2 and poly ADP-ribose polymerase inhibitors achieved synergistic lethal effect to overcome platinum resistance in patient-derived xenografts, especially those with wild-type BRCA1. These findings provide evidence for a potential strategy to overcome platinum resistance in OC patients by targeting CLK2.

Biofunctional study on chemoresistance in esophageal squamous carcinoma cells induced by missense mutation of NOTCH1 p.E450K.

Background: Neoadjuvant chemotherapy (nCT) combined with surgery is one of the main strategies for the treatment of resectable locally advanced esophageal squamous cell carcinoma (ESCC). However, nearly 40% of patients did not benefit from nCT, and the detection rate of NOTCH1 missense mutation was significantly increased in patients who did not respond to chemotherapy, suggesting that the missense mutation may be related to tumor chemoresistance. We aim to explore the effect of a NOTCH1 missense mutation on cell phenotype, to interpret the biofunctional changes in cell lines with a NOTCH1 missense mutation and to analyze the effect of a NOTCH1 missense mutation on drug resistance in ESCC cell lines. Methods: Sanger sequencing was used to evaluate the exon mutations in the NOTCH1 ligand binding region of candidate ESCC cell lines. After screening, KYSE450 and KYSE140 cells were selected as the research objects, and point mutation cell lines [KYSE140-mutant-type (MT) and KYSE450-MT] were constructed by CRISPR/Cas9 technology. Then, functional experiments were performed with the four cell lines [KYSE450-MT/wild-type (WT) and KYSE140-MT/WT]. The drug resistance of ESCC cell lines was assessed with a drug sensitivity test, and the proliferation, invasion and migration of ESCC lines were evaluated by proliferation test, scratch test and Transwell test. The cell cycle status of ESCC cells was assessed using flow cytometry. Results: Drug sensitivity tests showed that the NOTCH1 p.E450K point mutation caused chemotherapy resistance in KYSE140 and KYSE450 ESCC cell lines. Cell proliferation, Wound scratch and Transwell assays showed that the NOTCH1 p.E450K point mutation enhanced the proliferation, invasion and migration abilities of KYSE140 and KYSE450 cells. Flow cytometry analysis showed that the NOTCH1 p.E450K point mutation caused an increase in KYSE140 and KYSE450 cells in S phase. Conclusions: The NOTCH1 p.E450K point mutation causes chemotherapy resistance in KYSE140 and KYSE450 ESCC cells. Cell functional experiments showed that the NOTCH1 p.E450K point mutation enhanced the proliferation, migration and invasion abilities of KYSE140 and KYSE450 cells and increased the number of cells in S phase.

Triglyceride-glucose index and triglyceride to high-density lipoprotein cholesterol ratio predict the prognosis in patients with type B aortic dissection receiving thoracic endovascular aortic repair.

Background: The triglyceride-glucose (TyG) index and triglyceride to high-density lipoprotein cholesterol (TG/HDL-c) ratio are both reliable surrogate indicator of insulin resistance and have been shown to be valuable in predicting various cardiovascular diseases. However, few studies have explored its association with the prognosis of type B aortic dissection (TBAD) patients receiving thoracic endovascular aortic repair (TEVAR). Methods: A total of 1,425 consecutive patients who underwent TEVAR were included. Data from 935 patients were analyzed in the study. The endpoint was defined as 30-day and 1-year aortic-related adverse events (ARAEs), all-cause mortality, and major adverse cardiovascular and cerebrovascular events (MACCEs). Results: There were 935 patients included during a mean follow-up time of 2.8 years. After adjusting for multiple confounding factors, continuous TG/HDL-c [hazard ratio (HR) =1.07; 95% confidence interval (CI): 1.00-1.15; P=0.041] was independently associated with 1-year all-cause mortality. Both a high (Quintile 5: TG/HDL-c ratio ≥4.11) (HR =4.84; 95% CI: 1.55-15.13; P=0.007) and low TG/HDL-c ratio (Quintile 1: TG/HDL-c ratio <1.44) (HR =4.67; 95% CI: 1.46-14.94; P=0.001) were still independent risk factors for 1-year all-cause mortality. Conclusions: Elevated baseline TG/HDL-c ratio and TG/HDL-c ≥4.11 were significantly related to a higher risk of 1-year all-cause mortality among TBAD patients undergoing TEVAR. At the same time, the low TG/HDL-c ratio was also independently associated with 1-year all-cause mortality. Special attention should be paid to TBAD patients with a higher or an overly low TG/HDL-c ratio.