Multifaceted complications and surgical management of bronchobiliary fistula with associated pneumonia and intrahepatic stones: A case report.

Background: Bronchobiliary fistulas (BBFs), primarily stemming from choledocholithiasis, present considerable diagnostic and treatment challenges. Their prolonged nature can lead to life-threatening situations without timely management, often complicated by lung abscesses. Case presentation: A 64-year-old man, presenting with fever, chills, and a cough initially misdiagnosed as a common cold, developed severe respiratory distress and delirium upon admission. Urgent intensive care unit (ICU) admission was prompted by a computed tomography (CT) scan revealing a right lung abscess. Enhanced CT scans and elevated bilirubin levels confirmed the biliary origin of the BBFs. Comprehensive treatment included laparoscopic partial hepatectomy, choledochojejunostomy, stone extraction, choledochoscopy, T-tube drainage, and BBFs closure. The patient was discharged with a T-tube. Follow-up CT after two months showed no recurrence. Conclusions: Managing BBFs, especially with concurrent lung abscesses in choledocholithiasis patients, remains challenging but feasible. Early diagnosis and intervention are crucial to improving survival rates and quality of life, highlighting the need for vigilance. This case underscores the importance of early detection and comprehensive treatment for successful outcomes in such complex conditions.

Enhancing predictive accuracy in hypertriglyceridemia-induced acute pancreatitis: Role of red cell distribution width and prospective studies.

This letter addresses the study titled "Red cell distribution width: A predictor of the severity of hypertriglyceridemia-induced acute pancreatitis" by Lv et al published in the World Journal of Experimental Medicine. The study offers a valuable analysis of red cell distribution width (RDW) as a predictive marker for persistent organ failure in patients with hypertriglyceridemia-induced acute pancreatitis. The study results suggest that RDW, combined with the Bedside Index for Severity in Acute Pancreatitis score, could enhance the predictive accuracy for severe outcomes. Further investigation into the role of RDW in different severities of acute pancreatitis is recommended. Additionally, the need for large-scale and multicenter prospective studies to validate these findings is emphasized.

Unraveling colorectal cancer prevention: The vitamin D - gut flora - immune system nexus.

Colorectal cancer (CRC) is one of the most common cancers diagnosed in the world. Although environmental and genetic factors play a major role in the pathogenesis of CRC, extensive research has suggested that vitamin D may play a pivotal role in the development of CRC. Vitamin D, primarily obtained through sunlight exposure, dietary sources, and supplements, has long been recognized for its essential functions in maintaining health, including immune regulation. This article delves into the intricate relationship between vitamin D, the immune system, gut flora, and the prevention of CRC. It presents a synthesis of epidemiological data, experimental studies, and clinical trials, highlighting the mechanisms by which vitamin D influences immune cell function, cytokine production, and inflammation. By enhancing the immune system's surveillance and anti-tumor activity, vitamin D may offer a promising avenue for CRC prevention. Furthermore, this comprehensive review delves into the prospective clinical applications of vitamin D supplementation and delineates the forthcoming avenues of research in this dynamic domain. Additionally, the paper tentatively outlines a spectrum of prophylactic impacts of vitamin D on CRC, emphasizing its significant potential in reducing CRC risk through shedding light on its mechanisms, encompassing antineoplastic mechanisms, influences on the immune system, and modulation of the gut microbiome.

Prediction of Chinese suitable habitats of Panax notoginseng under climate change based on MaxEnt and chemometric methods.

Notoginseng saponin R1; ginsenosides Rg1, Re, Rb1, and Rd; the sum of the five saponins; and underground-part fresh weight (UPFW) of single plants were used as quality evaluation indices for Panax notoginseng (Burk.) F. H. Chen (P. notoginseng). Comprehensive evaluation of P. notoginseng samples from 30 production areas was performed using that MaxEnt model. Spatial pattern changes in suitable P. notoginseng habitats were predicted for current and future periods (2050s, 2070s, and 2090s) using SSP126 and SSP585 models. The results revealed that temperature, precipitation, and solar radiation were important environmental variables. Suitable habitats were located mainly in Yunnan, Guizhou, and Sichuan Provinces. The distribution core of P. notoginseng is predicted to shift southeast in the future. The saponin content decreased from the southeast to the northwest of Yunnan Province, which was contrary to the UPFW trend. This study provides the necessary information for the protection and sustainable utilization of P. notoginseng resources, and a theoretical reference for its application in the quality evaluation of Chinese medicinal products.

Effects of exercise on brain-derived neurotrophic factor in Alzheimer's disease models: A systematic review and meta-analysis.

A growing body of research examining effects of exercise on brain-derived neurotrophic factor (BDNF) in Alzheimer's disease (AD) models, while due to differences in gender, age, disease severity, brain regions examined, and type of exercise intervention, findings of available studies were conflicting. In this study, we aimed to evaluate current evidence regarding effects of exercise on BDNF in AD models. Searches were performed in PubMed, Web of Science, Cochrane, and EBSCO electronic databases, through July 20, 2023. We included studies that satisfied the following criteria: eligible studies should (1) report evidence on experimental work with AD models; (2) include an exercise group and a control group (sedentary); (3) use BDNF as the outcome indicator; and (4) be randomized controlled trials (RCTs). From 1196 search records initially identified, 36 studies met the inclusion criteria. There was a significant effect of exercise on increasing BDNF levels in AD models [standardized mean differences (SMD) = 0.98, P < 0.00001]. Subgroup analysis showed that treadmill exercise (SMD = 0.92, P< 0.0001), swimming (SMD = 1.79, P< 0.0001), and voluntary wheel running (SMD = 0.51, P= 0.04) were all effective in increasing BDNF levels in AD models. In addition, exercise significantly increased BDNF levels in the hippocampus (SMD = 0.92, P< 0.00001) and cortex (SMD = 1.56, P= 0.02) of AD models. Exercise, especially treadmill exercise, swimming, and voluntary wheel running, significantly increased BDNF levels in hippocampus and cortex of AD models, with swimming being the most effective intervention type.

Integrating disulfidptosis-related long noncoding RNAs in colorectal cancer prognosis: A path to precision medicine.

This commentary explores the burgeoning field of disulfidptosis-related long noncoding RNAs (lncRNAs) in the prognosis and therapeutic targeting of colorectal cancer (CRC). By evaluating recent research, including the pivotal study "Predicting colorectal cancer prognosis based on long noncoding RNAs of disulfidptosis genes" by Wang et al, this analysis underscores the critical role of lncRNAs in deciphering the molecular complexities of CRC. Highlighting the innovative methodologies and significant findings, I discuss the implications for patient survival, therapeutic response, and the potential of lncRNAs as biomarkers for precision medicine. The integration of bioinformatics, clinical databases, and molecular biology in these studies offers a promising avenue for advancing CRC treatment strategies and improving patient outcomes.

Effects of exercise on post-stroke cognitive function: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: A growing body of research examining the effect of exercise on cognitive function in stroke patients, while findings of available studies were conflicting. OBJECTIVES: We aimed to estimate the effect of exercise on cognitive function in stroke patients. METHODS: For this systematic review and meta-analysis, we searched PubMed, Web of Science, Embase, Cochrane, and Scopus electronic databases, through 13 March 2023. The three-level restricted maximum likelihood random effects model was used to synthesize the data. RESULTS: Twenty-five studies met the inclusion criteria. There was a significant effect of exercise on improving cognitive function in stroke patients (Cohen's d = 0.37, 95% CI, 0.16 to 0.58, p < 0.01, I2 = 22.12%). Subgroup analysis showed that exercise significantly improved memory. In addition, aerobic exercise, exercise conducted 12 weeks or more, 3 times or more per week, less than 60 minutes per session, less than 180 minutes per week, and up to 12 months post-stroke increased cognitive function significantly. CONCLUSIONS: Exercise improved cognitive function in stroke patients. To improve cognitive function, this meta-analysis provides clinicians with evidence to recommend that stroke patients participate in aerobic exercise at least 3 times per week for 30-60 minutes, with a goal of 180 minutes per week being achieved by increasing the frequency of exercise. Exercise initiated within 12 months post-stroke and continued for 12 weeks or more is most beneficial for improving cognitive function.

Random forest differentiation of Escherichia coli in elderly sepsis using biomarkers and infectious sites.

This study addresses the challenge of accurately diagnosing sepsis subtypes in elderly patients, particularly distinguishing between Escherichia coli (E. coli) and non-E. coli infections. Utilizing machine learning, we conducted a retrospective analysis of 119 elderly sepsis patients, employing a random forest model to evaluate clinical biomarkers and infection sites. The model demonstrated high diagnostic accuracy, with an overall accuracy of 87.5%, and impressive precision and recall rates of 93.3% and 87.5%, respectively. It identified infection sites, platelet distribution width, reduced platelet count, and procalcitonin levels as key predictors. The model achieved an F1 Score of 90.3% and an area under the receiver operating characteristic curve of 88.0%, effectively differentiating between sepsis subtypes. Similarly, logistic regression and least absolute shrinkage and selection operator analysis underscored the significance of infectious sites. This methodology shows promise for enhancing elderly sepsis diagnosis and contributing to the advancement of precision medicine in the field of infectious diseases.

The effect of exercise on balance function in stroke patients: a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: A growing body of studies has examined the effect of exercise on balance function in stroke patients, with conflicting findings. This study aimed to investigate the effect of exercise on balance function in stroke patients and to determine the optimal exercise prescription for stroke patients. METHODS: We conducted an extensive search across various databases, including PubMed, Web of Science, EBSCO, Cochrane, and Scopus. The search was conducted until March 11th, 2024. Data were pooled using the weighted mean difference (WMD) and 95% confidence interval. RESULTS: Twenty-nine studies fulfilled the inclusion criteria. Exercise significantly improved Berg balance scale (BBS, WMD, 5.24, P < 0.00001) and timed up and go test (TUG, WMD, - 2.91, P < 0.00001) in stroke patients. Subgroup analyses showed that aerobic exercise (WMD, 6.71, P = 0.003), exercise conducted ≥ 8 weeks (WMD, 6.43, P < 0.00001), > 3 times per week (WMD, 6.18, P < 0.00001), ≥ 60 min per session (WMD, 6.40, P < 0.0001), and ≥ 180 min per week (WMD, 7.49, P < 0.00001) were more effective in improving BBS. CONCLUSIONS: Exercise improved balance function in stroke patients, and aerobic exercise might be the most effective intervention. To improve balance function, this meta-analysis provides clinicians with evidence to recommend that stroke patients participate in a minimum of 8 weeks of exercise at least 3 times per week for more than 60 min per session, with a goal of 180 min per week being achieved by increasing the frequency of exercise.

Exploring predictive markers for liver failure post-hepatectomy in hepatocellular carcinoma patients.

This letter to the editor addresses the study titled "Predictive value of NLR, Fib4, and APRI in the occurrence of liver failure after hepatectomy in patients with hepatocellular carcinoma" by Kuang et al in the World Journal of Gastrointestinal Surgery. The study acknowledges the comprehensive patient data analysis while suggesting that there is a need for further discussion on the clinical applicability of these markers across diverse patient populations. This letter recommends prospective studies for validation and considers the influence of confounding factors. This finding underscores the significance of this study in improving hepatocellular carcinoma management.

Mangiferin attenuates lipopolysaccharide-induced neuronal injuries in primary cultured hippocampal neurons.

Mangiferin, a naturally occurring potent glucosylxanthone, is mainly isolated from the Mangifera indica plant and shows potential pharmacological properties, including anti-bacterial, anti-inflammation, and antioxidant in sepsis-induced lung and kidney injury. However, there was a puzzle as to whether mangiferin had a protective effect on sepsis-associated encephalopathy. To answer this question, we established an in vitro cell model of sepsis-associated encephalopathy and investigated the neuroprotective effects of mangiferin in primary cultured hippocampal neurons challenged with lipopolysaccharide (LPS). Neurons treated with 20 µmol/L or 40 µmol/L mangiferin for 48 h can significantly reverse cell injuries induced by LPS treatment, including improved cell viability, decreased inflammatory cytokines secretion, relief of microtubule-associated light chain 3 expression levels and several autophagosomes, as well as attenuated cell apoptosis. Furthermore, mangiferin eliminated pathogenic proteins and elevated neuroprotective factors at both the mRNA and protein levels, showing strong neuroprotective effects of mangiferin, including anti-inflammatory, anti-autophagy, and anti-apoptotic effects on neurons in vitro.

Synthesis and biological evaluation of 4-imidazolidinone-containing compounds as potent inhibitors of the MDM2/p53 interaction.

Inhibition of MDM2/p53 interaction with small-molecule inhibitors stabilizes p53 from MDM2 mediated degradation, which is a promising strategy for the treatment of cancer. In this report, a novel series of 4-imidazolidinone-containing compounds have been synthesized and tested in MDM2/p53 and MDM4/p53 FP binding assays. Upon SAR studies, compounds 2 (TB114) and 22 were identified as the most potent inhibitors of MDM2/p53 but not MDM4/p53 interactions. Both 2 and 22 exhibited strong antiproliferative activities in HCT-116 and MOLM-13 cell lines harboring wild type p53. Mechanistic studies show that 2 and 22 dose-dependently activated p53 and its target genes and induced apoptosis in cells based on the Western blot, qPCR, and flow cytometry assays. In addition, the antiproliferative activities of 2 and 22 were dependent on wild type p53, while they were not toxic to HEK-293 kidney cells. Furthermore, the on-target activities of 2 were general and applicable to other cancer cell lines with wild type p53. These attributes make 2 a good candidate for future optimization to discover a potential treatment of wild-type p53 cancer.

Effects of exercise in people with multiple sclerosis: a systematic review and meta-analysis.

Background: A growing body of studies have examined the effect of exercise in people with multiple sclerosis (MS), while findings of available studies were conflicting. This meta-analysis aimed to explore the effects of exercise on balance, walking ability, walking endurance, fatigue, and quality of life in people with MS. Methods: We searched PubMed, Web of Science, Scopus, and Cochrane databases, through March 1, 2024. Inclusion criteria were: (1) RCTs; (2) included an intervention and control group; (3) had people with MS as study subjects; (4) had balance, walking ability, walking endurance, fatigue, or quality of life as the outcome measures. Exclusion criteria were: (1) non-English publications; (2) animal model publications; (3) review articles; and (4) conference articles. A meta-analysis was conducted to calculate weighted mean difference (WMD) and 95% confidence interval (CI). Cochrane risk assessment tool and Physiotherapy Evidence Database (PEDro) scale were used to evaluate the methodological quality of the included studies. Results: Forty studies with a total of 56 exercise groups (n = 1,300) and 40 control groups (n = 827) were eligible for meta-analysis. Exercise significantly improved BBS (WMD, 3.77; 95% CI, 3.01 to 4.53, P < 0.00001), TUG (WMD, -1.33; 95% CI, -1.57 to -1.08, P < 0.00001), MSWS-12 (WMD, -2.57; 95% CI, -3.99 to -1.15, P = 0.0004), 6MWT (WMD, 25.56; 95% CI, 16.34 to 34.79, P < 0.00001), fatigue (WMD, -4.34; 95% CI, -5.83 to -2.84, P < 0.00001), and MSQOL-54 in people with MS (WMD, 11.80; 95% CI, 5.70 to 17.90, P = 0.0002) in people with MS. Subgroup analyses showed that aerobic exercise, resistance exercise, and multicomponent training were all effective in improving fatigue in people with MS, with resistance exercise being the most effective intervention type. In addition, a younger age was associated with a larger improvement in fatigue. Furthermore, aerobic exercise and multicomponent training were all effective in improving quality of life in people with MS, with aerobic exercise being the most effective intervention type. Conclusion: Exercise had beneficial effects in improving balance, walking ability, walking endurance, fatigue, and quality of life in people with MS. Resistance exercise and aerobic exercise are the most effective interventions for improving fatigue and quality of life in people with MS, respectively. The effect of exercise on improving fatigue was associated with the age of the participants, with the younger age of the participants, the greater the improvement in fatigue. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=371056, identifier: CRD42022371056.

Assessing the 2023 Canadian wildfire smoke impact in Northeastern US: Air quality, exposure and environmental justice.

The Canadian wildfires in June 2023 significantly impacted the northeastern United States, particularly in terms of worsened air pollution and environmental justice concerns. While advancements have been made in low-cost sensor deployments and satellite observations of atmospheric composition, integrating dynamic human mobility with wildfire PM2.5 exposure to fully understand the environmental justice implications remains underinvestigated. This study aims to enhance the accuracy of estimating ground-level fine particulate matter (PM2.5) concentrations by fusing chemical transport model outputs with empirical observations, estimating exposures using human mobility data, and evaluating the impact of environmental justice. Employing a novel data fusion technique, the study combines the Weather Research and Forecasting model with Chemistry (WRF-Chem) outputs and surface PM2.5 measurements, providing a more accurate estimation of PM2.5 distribution. The study addresses the gap in traditional exposure assessments by incorporating human mobility data and further investigates the spatial correlation of PM2.5 levels with various environmental and demographic factors from the US Environmental Protection Agency (EPA) Environmental Justice Screening and Mapping Tool (EJScreen). Results reveal that despite reduced mobility during high PM2.5 levels from wildfire smoke, exposure for both residents and individuals on the move remains high. Regions already burdened with high environmental pollution levels face amplified PM2.5 effects from wildfire smoke. Furthermore, we observed mixed correlations between PM2.5 concentrations and various demographic and socioeconomic factors, indicating complex exposure patterns across communities. Urban areas, in particular, experience persistent high exposure, while significant correlations in rural areas with EJScreen factors highlight the unique vulnerabilities of these populations to smoke exposure. These results advocate for a comprehensive approach to environmental health that leverages advanced models, integrates human mobility data, and addresses socio-demographic disparities, contributing to the development of equitable strategies against the growing threat of wildfires.

Epidemiological insights into seasonal, sex­specific and age­related distribution of bacterial pathogens in urinary tract infections.

Urinary tract infections (UTIs) are prevalent and recurrent bacterial infections that affect individuals worldwide, posing a significant burden on healthcare systems. The present study aimed to explore the epidemiology of UTIs, investigating the seasonal, gender-specific and age-related bacterial pathogen distribution to guide clinical diagnosis. Data were retrospectively collected from electronic medical records and laboratory reports of 926 UTIs diagnosed in Fuding Hospital (Fujian University of Traditional Chinese Medicine, Fuding, China). Bacterial isolates were identified using standard microbiological techniques. χ2 tests were performed to assess associations between pathogens and the seasons, sex and age groups. Significant associations were found between bacterial species and seasons. Enterococcus faecium exhibited a substantial prevalence in spring (χ2, 12.824; P=0.005), while Acinetobacter baumannii demonstrated increased prevalence in autumn (χ2, 16.404; P=0.001). Female patients showed a higher incidence of UTIs. Gram-positive bacteria were more prevalent in males, with Staphylococcus aureus showing significant male predominance (χ2, 14.607; P<0.001). E. faecium displayed an age-related increase in prevalence (χ2, 17.775; P<0.001), whereas Escherichia coli tended to be more prevalent in younger patients (χ2, 12.813; P=0.005). These findings highlight the complex nature of UTIs and offer insights for tailored diagnostic and preventive strategies, potentially enhancing healthcare outcomes.

Procalcitonin and C-reactive protein as diagnostic biomarkers in COVID-19 and Non-COVID-19 sepsis patients: a comparative study.

BACKGROUND: This study aimed to assess and compare procalcitonin (PCT) and C-reactive protein (CRP) levels between COVID-19 and non-COVID-19 sepsis patients. Additionally, we evaluated the diagnostic efficiency of PCT and CRP in distinguishing between Gram-positive (GP) and Gram-negative (GN) bacterial infections. Moreover, we explored the associations of PCT with specific pathogens in this context. METHODS: The study included 121 consecutive sepsis patients who underwent blood culture testing during the COVID-19 epidemic. PCT and CRP were measured, and reverse transcriptase-polymerase chain reaction (RT-PCR) was employed for the detection of COVID-19 nucleic acid. The Mann-Whitney U-test was used to compare PCT and CRP between the COVID-19 and non-COVID-19 groups. Receiver operating characteristic (ROC) curves were generated to compare PCT and CRP levels in the GN group versus the GP group for assessing the diagnostic efficiency. The kruskal-Wallis H test was applied to assess the impact of specific pathogen groups on PCT concentrations. RESULTS: A total of 121 sepsis patients were categorized into a COVID-19 group (n = 25) and a non-COVID-19 group (n = 96). No significant differences in age and gender were observed between the COVID-19 and non-COVID-19 groups. The comparison of biomarkers between these groups showed no statistically significant differences. The optimal cut-off values for PCT and CRP in differentiating between GP and GN infections were 1.03 ng/mL and 34.02 mg/L, respectively. The area under the ROC curve was 0.689 (95% confidence interval (CI) 0.591-0.786) for PCT and 0.611 (95% CI 0.505-0.717) for CRP. The diagnostic accuracy was 69.42% for PCT and 58.69% for CRP. The study found a significant difference in PCT levels among specific groups of pathogens (P < 0.001), with the highest levels observed in Escherichia coli infections. The frequency of Staphylococcus spp. positive results was significantly higher (36.0%) in COVID-19 compared to non-COVID-19 sepsis patients (P = 0.047). CONCLUSION: Sepsis patients with COVID-19 revealed a significantly higher culture positivity for staphylococcus spp. than the non-COVID-19 group. Both PCT and CRP showed moderate diagnostic efficiency in differentiating between GP and GN bacterial infections. PCT showed potential utility in identifying E. coli infections compared to other pathogens.

Utility of Goal Attainment Scaling (GAS) in evaluating a multicomponent exercise programme for community-dwelling pre-frail older adults.

OBJECTIVES: This study aimed to investigate the effectiveness of Goal Attainment Scaling (GAS) in assessing an intervention for pre-frail senior citizens. Additionally, the study aimed to explain how the GAS goals were established based on the International Classification of Functioning, Disability and Health (ICF) categories, including body function, activity and participation and environmental factors. METHODS: In this study, 220 pre-frail older adults were randomly selected to participate in a controlled trial. The intervention group engaged in multicomponent exercise three times a week, once at a community health service location and twice at home. The control group received advice on physical activity but did not have supervised exercise. Participants in both groups selected individualised GAS goals from 23 goals developed based on ICF by focus group discussion. The study used generalised estimating equations to analyse the differences between the groups. RESULTS: The study included 144 participants, 72 in the exercise group and 72 in the control group. The top three individualised goals for all participants were vestibular functions (53.5%), pain management (43.1%) and lifting and carrying objects (31.9%). Both groups saw a significant increase in GAS scores at week 8 and week 24 of the intervention (p<0.05), but the exercise group showed a more significant improvement (p<0.05). The participants living alone were associated with lower postintervention improvements in the GAS scores. In contrast, the participants who were using a smartphone were likely to get higher postintervention improvements in the GAS scores. CONCLUSIONS: GAS can be a valuable tool for setting and evaluating individualised and meaningful goals in body functions, activity and participation and environmental factors. The multicomponent exercise interventions can help pre-frail older adults achieve their expected goals as measured by the GAS.

Discovery of JN122, a Spiroindoline-Containing Molecule that Inhibits MDM2/p53 Protein-Protein Interaction and Exerts Robust In Vivo Antitumor Efficacy.

MDM2 and MDM4 cooperatively and negatively regulate p53, while this pathway is often hijacked by cancer cells in favor of their survival. Blocking MDM2/p53 interaction with small-molecule inhibitors liberates p53 from MDM2 mediated degradation, which is an attractive strategy for drug discovery. We reported herein structure-based discovery of highly potent spiroindoline-containing MDM2 inhibitor (-)60 (JN122), which also exhibited moderate activities against MDM4/p53 interactions. In a panel of cancer cell lines harboring wild type p53, (-)60 efficiently promoted activation of p53 and its target genes, inhibited cell cycle progression, and induced cell apoptosis. Interestingly, (-)60 also promoted degradation of MDM4. More importantly, (-)60 exhibited good PK properties and exerted robust antitumor efficacies in a systemic mouse xenograft model of MOLM-13. Taken together, our study showcases a class of potent MDM2 inhibitors featuring a novel spiro-indoline scaffold, which is promising for future development targeting cancer cells with wild-type p53.

Transcription factor 12-mediated self-feedback regulatory mechanism is required in DUX4 fusion leukaemia.

BACKGROUND: IGH::DUX4 is frequently observed in 4% B-cell acute lymphoblastic leukaemia patients. Regarding the IGH::DUX4-driven transactivation and alternative splicing, which are the main reasons behind this acute leukaemia outbreak, it remains unclear how transcriptional cofactors contribute to this oncogenic process. Further investigation is required to elucidate their specific role in leukaemogenesis. METHODS: In order to investigate the cofactors of IGH::DUX4, integrated mining of Chromatin immunoprecipitation (ChIP)-sequencing and RNA-sequencing of leukaemia cells and patient samples were conducted. Furthermore, to elucidate the synergistic interaction between transcription factor 12 (TCF12) and IGH::DUX4, knockdown and knockout experiment, mammalian two-hybridisation assay, co-immunoprecipitation and in situ proximity ligation assays were carried out. Additionally, to further investigate the direct interaction between TCF12 and IGH::DUX4, AI-based structural simulations were utilised. Finally, to validate the synergistic role of TCF12 in promoting IGH::DUX4 leukaemia, cell proliferation, apoptosis and drug sensitivity experiments were performed. RESULTS: In this study, we observed that the IGH::DUX4 target gene TCF12 might be an important cofactor/helper for this oncogenic driver. The co-expression of IGH::DUX4 and TCF12 resulted in enhanced DUX4-driven transactivation. Supportively, knockdown and knockout of TCF12 significantly reduced expression of IGH::DUX4-driven target genes in leukaemia REH (a precursor B-cell leukaemia cell line) and NALM-6 cells (a precursor B-cell leukaemia cell line). Consistently, in TCF12 knockout cells, the expression of structure-based TCF12 mutant, but not wild-type TCF12, failed to restore the TCF12-IGH::DUX4 crosstalk and the synergistic transactivation. More importantly, the breakdown in TCF12-IGH::DUX4 cooperation impaired IGH::DUX4-driven leukaemia cell survival, caused sensitivity to the chemotherapy. CONCLUSIONS: Altogether, these results helped to define a previously unrecognised TCF12-mediated positive self-feedback regulatory mechanism in IGH::DUX4 leukaemia, which holds the potential to function as a pivotal drug target for the management of this particular form of leukaemia. HIGHLIGHTS: Transcription factor 12 (TCF12) is a new novel cofactor in IGH::DUX4 transcriptional complexes/machinery. TCF12 mediates a positive self-feedback regulatory mechanism in IGH::DUX4-driven oncogenic transaction. IGH::DUX4-TCF12 structure/cooperation might represent a potent target/direction in future drug design against B-cell acute lymphoblastic leukaemia.

Correlation of procalcitonin and c-reactive protein levels with pathogen distribution and infection localization in urinary tract infections.

Aimed to explore the relationships between infection localization, bacterial species, and procalcitonin (PCT) and C-reactive protein (CRP) levels in urinary tract infections (UTIs). A retrospective study included 314 UTI hospitalized patients divided into two groups (268 with lower UTI, 46 with upper UTI) in a tertiary care hospital. PCT and CRP were performed. Bacterial isolates were identified using standard microbiological techniques, and statistical analyses were performed to assess associations between infection localization, bacterial species, PCT, and CRP levels. Age and gender showed no significant differences between the lower and upper UTIs. Escherichia coli dominated as the leading UTI pathogen. A positive correlation (r = 0.646, P < 0.001) between PCT and CRP levels was found. The subgroup with ureteritis in the upper UTI category exhibited the highest PCT and CRP levels. PCT and CRP exhibited favorable diagnostic potential in predicting upper UTIs, with AUCs of 0.644 and 0.629, respectively. The optimal cutoff values were 0.21 ng/mL for PCT and 60.77 mg/L for CRP. Sensitivities were 69.03% and 77.99%, while specificities were 56.52% and 47.83%, respectively. E. coli emerged as the predominant bacterium in UTIs. PCT and CRP demonstrated moderate diagnostic efficacy in distinguishing between upper and lower UTIs. Notably, PCT and CRP exhibited enhanced utility in identifying ureteritis.