Role of epigenetics and alterations in RNA metabolism in leukodystrophies.

Leukodystrophies are a class of rare heterogeneous disorders which affect the white matter of the brain, ultimately leading to a disruption in brain development and a damaging effect on cognitive, motor and social-communicative development. These disorders present a great clinical heterogeneity, along with a phenotypic overlap and this could be partially due to contributions from environmental stimuli. It is in this context that there is a great need to investigate what other factors may contribute to both disease insurgence and phenotypical heterogeneity, and novel evidence are raising the attention toward the study of epigenetics and transcription mechanisms that can influence the disease phenotype beyond genetics. Modulation in the epigenetics machinery including histone modifications, DNA methylation and non-coding RNAs dysregulation, could be crucial players in the development of these disorders, and moreover an aberrant RNA maturation process has been linked to leukodystrophies. Here, we provide an overview of these mechanisms hoping to supply a closer step toward the analysis of leukodystrophies not only as genetically determined but also with an added level of complexity where epigenetic dysregulation is of key relevance. This article is categorized under: Regulatory RNAs/RNAi/Riboswitches > Regulatory RNA RNA in Disease and Development > RNA in Disease RNA in Disease and Development > RNA in Development.

Implementing circulating tumor DNA as a prognostic biomarker in resectable non-small cell lung cancer.

Systemic treatment of resectable non-small cell lung cancer (NSCLC) is evolving with emerging neoadjuvant, perioperative, and adjuvant immunotherapy approaches. Circulating tumor DNA (ctDNA) detection at clinical diagnosis, during neoadjuvant therapy, or after resection may discern high-risk patients who might benefit from therapy escalation or switch. This Review summarizes translational implications of data supporting ctDNA-based risk determination in NSCLC and outstanding questions regarding ctDNA validity/utility as a prognostic biomarker. We discuss emerging ctDNA capabilities to refine clinical tumor-node-metastasis (TNM) staging in lung adenocarcinoma, ctDNA dynamics during neoadjuvant therapy for identifying patients deriving suboptimal benefit, and postoperative molecular residual disease (MRD) detection to escalate systemic therapy. Considering differential relapse characteristics in landmark MRD-negative/MRD-positive patients, we propose how ctDNA might integrate with pathological response data for optimal postoperative risk stratification.

Silibinin, a commonly used therapeutic agent for non-alcohol fatty liver disease, functions through upregulating intestinal expression of fibroblast growth factor 15/19.

BACKGROUND AND PURPOSE: Silibinin is used to treat non-alcohol fatty liver disease (NAFLD) despite having rapid liver metabolism. Therefore, we investigated the role of the intestine in silibinin mechanism of action. EXPERIMENTAL APPROACH: NAFLD mice model was established by feeding them with a high-fat diet (HFD). Liver pathological were examined using H&E and oil red O staining. Tissue distribution of silibinin was detected by LC-MS/MS. SiRNA was employed for gene silencing and plasmid was used for gene overexpression. ChIP-qPCR assay was performed to detect the levels of histone acetylation. Recombinant adeno-associated virus 9-short hairpin-fibroblast growth factor (FGF)-15 and -farnesoid X receptor (FXR; NR1H4) were used to knockdown expression of FGF-15 and FXR. KEY RESULTS: Oral silibinin significantly reversed NAFLD in mice, although liver concentration was insufficient for reduction of lipid accumulation in hepatocytes. Among endogenous factors capable of reversing NAFLD, the expression of Fgf-15 was selectively up-regulated by silibinin in ileum and colon of mice. When intestinal expression of Fgf-15 was knocked down, protection of silibinin against lipid accumulation and injury of livers nearly disappeared. Silibinin could reduce activity of histone deacetylase 2 (HDAC2), enhance histone acetylation in the promoter region of FXR and consequently increase intestinal expression of FGF-15/19. CONCLUSION AND IMPLICATIONS: Oral silibinin selectively promotes expression of FGF-15/19 in ileum by enhancing transcription of FXR via reduction of HDAC2 activity, and FGF-15/19 enters into circulation to exert anti-NAFLD action. As the site of action is the intestine this would explain the discrepancy between pharmacodynamics and pharmacokinetics of silibinin.

Multi-index comprehensive evaluation of the efficacy and response mechanism of immunotherapy in non-small cell lung cancer.

OBJECTIVE: This research conducted multi-index comprehensive evaluations of the immunotherapeutic efficacy and response in non-small cell lung cancer (NSCLC). METHODS: Forty-five patients with epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK) wild-type advanced NSCLC who received immunotherapy were included. Immunohistochemistry was adopted to detect the expression levels of programmed death ligand 1 (PD-L1) with X-ray cross-complementing protein 1 (XRCC1) and excision repair cross-complementing group 1 (ERCC1) proteins in tumor tissues. Flow cytometry was utilized to measure the levels of T-cell subsets in peripheral blood before and after treatment. PCR-RELP method was employed to evaluate XRCC1 and ERCC1 gene polymorphisms in peripheral blood. According to the treatment effect, patients evaluated as complete response (CR), partial response (PR), and stable disease (SD) were categorized into the immune response group, and patients evaluated as progressive disease (PD) were categorized into the immune unresponsive group. The correlation between PD-L1 protein expression, XRCC1 and ERCC1 protein expression, gene polymorphisms, T-cell subpopulation levels, and treatment efficacy was analyzed. RESULTS: The therapeutic efficacy of patients with positive PD-L1 expression was better than that of patients with negative PD-L1 expression (P < 0.05). After treatment, peripheral blood CD3+ and CD4+ cell levels and Thl/Th2 cell levels were higher and CD8+ T cells were lower in the immune response group than in the immune unresponsive group (P < 0.05). Among the patients in the immune response group, peripheral blood CD3+ and CD4+ cell levels were higher and CD8+ T cells were lower in patients with positive PD-L1 expression than in patients with negative PD-L1 expression (P < 0.05). In the XRCC1 gene, the proportion of patients in the immune response group carrying the Arg/Trp + Trp/Trp genotype was higher than that of patients in the immune unresponsive group (P < 0.05). In the ERCC1 gene, the proportion of patients in the immune response group carrying the C/T + T/T genotype was higher than that of patients in the immune unresponsive group (P < 0.05). The positive expression rates of XRCC1 and ERCC1 in patients in the immune unresponsive group were higher than those in the immune response group (P < 0.05). CONCLUSION: PD-L1 protein expression, XRCC1 and ERCC1 protein expression, and gene polymorphisms are associated with immunotherapy outcome in EGFR/ALK wild-type advanced NSCLC patients, and may be biological indicators for predicting immunotherapy outcome in EGFR/ALK wild-type advanced NSCLC patients.

Analytical parameterization of Bragg curves for proton beams in muscle, bone, and polymethylmethacrylate.

Proton dose calculation in media other than water may be of interest for either research purposes or clinical practice. Current study aims to quantify the required parameters for analytical proton dosimetry in muscle, bone, and PMMA. Required analytical dosimetry parameters were extracted from ICRU-49 report and Janni study. Geant4 Toolkit was also used for Bragg curve simulation inside the investigated media at different proton energies. Calculated and simulated dosimetry data were compared using gamma analysis. Simulated and calculated Bragg curves are consistent, a fact that confirms the validity of reported parameters for analytical proton dosimetry inside considered media. Furthermore, derived analytical parameters for these media are different from those of water. Listed parameters can be reliably utilized for analytical proton dosimetry inside muscle, bone, and PMMA. Furthermore, accurate proton dosimetry inside each medium demands dedicated analytical parameters and one is not allowed to use the water coefficients for non-water media.

Palliative single-level selective dorsal rhizotomy for children with spastic cerebral palsy Gross Motor Function Classification System level IV and V: a case series and systematic review of the literature.

OBJECTIVE: Single-level selective dorsal rhizotomy (SDR), typically indicated for ambulatory patients, is a controversial topic for severe spastic cerebral palsy (CP) with Gross Motor Function Classification System (GMFCS) level IV or V. The objective of this case series and systematic literature review was to outline the indication and outcome of palliative SDR for nonambulatory patients with CP and GMFCS level IV and V, focusing on improvement of spasticity and of patient and caregiver reported quality of life assessment. METHODS: A retrospective case series of patients with CP and GMFCS level IV or V who underwent single-level SDR at the authors' institution is presented. Furthermore, two databases (PubMed and Embase) were searched and a systematic review with a search string based on the terms "selective dorsal rhizotomy," "cerebral palsy," and "outcome" was conducted. The primary outcome was the reduction of spasticity based on the modified Ashworth scale (MAS). Secondary outcomes were change on the Gross Motor Function Measure-66 (GMFM-66), evaluation of patient-reported outcome measures (PROMs), surgical morbidity, and mortality. RESULTS: Eleven consecutive children under the age of 25 years undergoing palliative single-level SDR were included. All patients showed a reduction in MAS score (mean 1.09 ± 0.66 points) and no surgical morbidity and mortality occurred. For the systematic review results from our case series, in addition to 4 reports, 274 total patients were included. Reduction of spasticity based on MAS score was noted in all studies (mean range 1.09-3.2 points). Furthermore, in 2 studies spasticity of the upper extremities showed a MAS score reduction as well (range 1.7-2.8 points). The GMFM-66 score improved in 72% of the patients, while bladder function improved in 78% of the patients. Based on the PROMs, 92% of the patients/caregivers were satisfied with the outcome and their quality of life after the procedure. Two wound infections (2.7%) and one CSF leak (1.3%) occurred, while no surgery-related deaths were described. CONCLUSIONS: This analysis showed an improvement in spasticity, daily care, and comfort for patients with CP and GMFCS levels IV and V. Larger cohorts analyzing the outcome of palliative single-level SDR, based on the MAS, GMFM-66, and PROMs, are still needed and should be the focus of future studies. Systematic review registration no.: CRD42024495762 (https://www.crd.york.ac.uk/prospero/).

Assessing the feasibility of digital keypress statistics to detect seizures and capture cognitive impairment in patients with epilepsy: A pilot study.

BACKGROUND: Efficient, non-invasive monitoring may provide a more accurate and comprehensive understanding of seizure frequency and the development of some comorbidities in people with epilepsy. Novel keyboard technology measuring digital keypress statistics has demonstrated its practical value for neurodegenerative diseases including Parkinson's Disease and Dementia. Smartphones integrated into daily life may serve as a low-burden longitudinal monitoring system for patients with epilepsy. OBJECTIVE: This study aimed to assess the feasibility of keyboard statistics as an objective measure of seizure frequency for patients with epilepsy, in addition to tracking differences between cognitively normal and cognitively impaired patients. METHODS: Six adult patients admitted to the Epilepsy Monitoring Unit (EMU) at Mayo Clinic in Rochester, Minnesota were studied. The keyboard was installed on the patient's smartphone. In the EMU, typing statistics were correlated to electroencephalogram (EEG) confirmed seizures. After discharge, participants continued using their keyboards and kept a seizure log. We also analyzed the key press/release times and usage of participants' keyboards for adherence. RESULTS: Keyboard sessions during and after seizures assessed for key press/release differences versus baseline showed no statistically significant difference (p = 0.44). Using one-way ANOVA, cognitive impairment's potential impact on keyboard statistics was explored in patients who had neuropsychological testing (N = 3). Significant differences were found between patients with and without cognitive impairment (p < 0.001). No significant difference was noted between patients with mild intellectual disability and normal cognitive function (p = 0.55).

Federated learning using model projection for multi-center disease diagnosis with non-IID data.

Multi-center disease diagnosis aims to build a global model for all involved medical centers. Due to privacy concerns, it is infeasible to collect data from multiple centers for training (i.e., centralized learning). Federated Learning (FL) is a decentralized framework that enables multiple clients (e.g., medical centers) to collaboratively train a global model while retaining patient data locally for privacy. However, in practice, the data across medical centers are not independently and identically distributed (Non-IID), causing two challenging issues: (1) catastrophic forgetting at clients, i.e., the local model at clients will forget the knowledge received from the global model after local training, causing reduced performance; and (2) invalid aggregation at the server, i.e., the global model at the server may not be favorable to some clients after model aggregation, resulting in a slow convergence rate. To mitigate these issues, an innovative Federated learning using Model Projection (FedMoP) is proposed, which guarantees: (1) the loss of local model on global data does not increase after local training without accessing the global data so that the performance will not be degenerated; and (2) the loss of global model on local data does not increase after aggregation without accessing local data so that convergence rate can be improved. Extensive experimental results show that our FedMoP outperforms state-of-the-art FL methods in terms of accuracy, convergence rate and communication cost. In particular, our FedMoP also achieves comparable or even higher accuracy than centralized learning. Thus, our FedMoP can ensure privacy protection while outperforming centralized learning in accuracy and communication cost.

Electron transferring with oxygen defects on Ni-promoted Pd/Al2O3 catalysts for low-temperature lean methane combustion.

Methane (CH4) is the second most consequential greenhouse gas after CO2, with a substantial global warming potential. The CH4 catalytic combustion offers an efficient method for the elimination of CH4. However, improving the catalytic performance of Pd-based materials for low-temperature CH4 combustion remains a big challenge. In this study, we synthesized an enhanced Pd/5NiAlOx catalyst that demonstrated superior catalytic activity and improved water resistance compared to the Pd/Al2O3 catalyst. Specifically, the T90 was decreased by over 100 °C under both dry and wet conditions. Introducing Ni resulted in an enormously enhanced number of oxygen defects on the obtained 5NiAlOx support. This defect-rich support facilitates the anchoring of PdO through increased electron transfer, thereby inhibiting the production of high-valence Pd(2+δ)+ and stimulating the generation of unsaturated Pd sites. Pd0 can effectively activate surface oxygen and PdO plays a significant role in activating CH4, resulting in high activity for Pd/5NiAlOx. On the other hand, the increased water resistance of Pd/5NiAlOx was mainly due to the generation of *OOH species and the lower accumulation of surface -OH species during the reaction process.

Wandering Spleen in a 47-year-old female treated by non-operative conservative management. Case report and literature review.

INTRODUCTION: Wandering spleen (WS) is a rare clinical condition found in less than 0.5 % of splenectomies and is characterized by ectopic location of the spleen within the abdomen or pelvis. It is always caused by excessive mobility brought on by the ligamentous laxity of its peritoneal attachments. Abdominal ultrasonography and computed tomography are the key imaging modalities for inquiry of WS. CASE PRESENTATION: We report the case of a 47-year-old woman who presented with painless abdominal swelling since the age of 6 years. An abdominal examination revealed a palpable, firm, mobile mass in the right lower abdomen approximately 15 × 15 cm in dimensions. A contrast CT scan of the abdomen revealed the absence of the spleen in the left upper quadrant. The patient was managed conservatively and followed for five years with favourable outcome. DISCUSSION: Failure of the dorsal mesogastrium to merge with the posterior abdominal wall in the second month of embryonic development is one of the reasons for WS. The nonsurgical conservative approach is limited to patients who are high-risk surgical candidates and have minimal symptoms and no complications. CONCLUSION: The good clinical outcome of our patient suggests that conservative non-surgical approach may be a reasonable alternative to unwarranted surgical intervention in selected clinically stable patients who have no evidence of splenic torsion or infarction, avoiding the possible complications of surgery.

Sucralose and stevia consumption leads to intergenerational alterations in body weight and intestinal expression of histone deacetylase 3.

OBJECTIVES: It is unclear whether parental consumption of non-nutritive sweetener (NNS) can affect subsequent generations. The aim of this study was to determine whether chronic parental consumption of sucralose and stevia in mice affects body weight gain and liver and intestinal expression of histone deacetylase 3 (Hdac3) in these animals and in the subsequent first filial (F1) and second filial (F2) generations. METHODS: Male and female mice (n = 47) were divided into three groups to receive water alone or supplemented with sucralose (0.1 mg/mL) or stevia (0.1 mg/mL) for 16 wk (parental [F0] generation). F0 mice were bred to produce the F1 generation; then, F1 mice were bred to produce the F2 generation. F1 and F2 animals did not receive NNSs. After euthanasia, hepatic and intestinal expression of Hdac3 was determined by quantitative reverse transcription polymerase chain reaction. RESULTS: Body weight gain did not differ between the three groups in the F0 generation, but it was greater in the F1 sucralose and stevia groups than in the control group. Consumption of both NNSs in the F0 generation was associated with lower Hdac3 expression in the liver and higher in the intestine. Hepatic Hdac3 expression was normalized to the control values in the F1 and F2 animals of the sucralose and stevia groups. Intestinal expression was still higher in the F1 generations of the sucralose and stevia groups but was partially normalized in the F2 generation of these groups, compared with control. CONCLUSIONS: NNS consumption differentially affects hepatic and intestinal Hdac3 expression. Changes in hepatic expression are not transmitted to the F1 and F2 generations whereas those in intestinal expression are enhanced in the F1 and attenuated in the F2 generations.

Discovery of a prominent dual-target DDR1/EGFR inhibitor aimed DDR1/EGFR-positive NSCLC.

This study aimed to develop the first dual-target small molecule inhibitor concurrently targeting Discoidin domain receptor 1 (DDR1) and Epidermal growth factor receptor (EGFR), which play a crucial interdependent roles in non-small cell lung cancer (NSCLC), demonstrating a synergistic inhibitory effect. A series of innovative dual-target inhibitors for DDR1 and EGFR were discovered. These compounds were designed and synthesized using structural optimization strategies based on the lead compound BZF02, employing 4,6-pyrimidine diamine as the core scaffold, followed by an investigation of their biological activities. Among these compounds, D06 was selected and showed micromolar enzymatic potencies against DDR1 and EGFR. Subsequently, compound D06 was observed to inhibit NSCLC cell proliferation and invasion. Demonstrating acceptable pharmacokinetic performance, compound D06 exhibited its anti-tumor activity in NSCLC PC-9/GR xenograft models without apparent toxicity or significant weight loss. These collective results showcase the successful synthesis of a potent dual-targeted inhibitor, suggesting the potential therapeutic efficacy of co-targeting DDR1 and EGFR for DDR1/EGFR-positive NSCLC.

First report of plastic and non-plastic microparticles in stomach of slandertail lanternshark and shortspine spurdog from the edge of East China Sea.

This study investigates the presence of plastic and non-plastic microparticles in the gastrointestinal tracts of two deep-sea sharks, Etmopterus molleri (n = 118) and Squalus mitsukurii (n = 6), bycatch from the East China Sea continental shelf. We found a total of 117 microparticles, predominantly fibres (67.52 %), with blue (31.62 %) and black (23.94 %) being the most prevalent colours. E. molleri contained 70 microparticles (0.63 ± 0.93 items/shark), 61.42 % non-plastics like viscose and cotton, while plastics included polyethylene, polyethylene terephthalate, and acrylic. Despite S. mitsukurii's limited sample size, the results show that it takes in a lot of microparticles (47 microparticles, 7.83 ± 2.64 items/shark), 57.44 % non-plastics (viscose, cotton, and ethyl cellulose), and 42.56 % plastics. A positive correlation between microparticle presence and total length was observed for E. molleri. These results provide initial data on microparticle ingestion by these species, highlighting potential ecological risks and trophic transfer implications in deep-sea ecosystems.

The effects of empiric antibiotic regimens in adults with non-ventilator-associated hospital-acquired pneumonia: A systematic review and network meta-analysis of randomized controlled trials.

BACKGROUND: The optimal empiric antibiotic regimen for non-ventilator-associated hospital-acquired pneumonia (HAP) is uncertain. OBJECTIVES: To compare alternative empiric antibiotic regimens in HAP using a network meta-analysis (NMA). METHODS: Data sources: Medline, EMBASE, Cochrane CENTRAL, Web of Science, and CINAHL from database inception to July 06, 2023. STUDY ELIGIBILITY CRITERIA: Randomized controlled trials (RCT). PARTICIPANTS: Adults with clinical suspicion of HAP. INTERVENTION: Any empiric antibiotic regimen versus another, placebo, or no treatment. ASSESSMENT OF RISK OF BIAS: Paired reviewers independently assessed risk of bias using a modified Cochrane tool for assessing risk of bias in randomized trials. METHODS OF DATA ANALYSIS: Paired reviewers independently extracted data on trial and patient characteristics, antibiotic regimens, and outcomes of interest. We conducted frequentist random-effects NMAs for treatment failure and all-cause mortality and assessed the certainty of the evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. RESULTS: 39 trials proved eligible. 30 RCTs involving 4,807 participants found low certainty evidence that piperacillin-tazobactam (RR compared to all cephalosporins: 0.65; 95% CI: 0.42, 1.01) and carbapenems (RR compared to all cephalosporins: 0.77; 95% CI: 0.53, 1.11) might be among the most effective in reducing treatment failure. The findings were robust to the secondary analysis comparing piperacillin-tazobactam vs antipseudomonal cephalosporins or antipseudomonal carbapenems vs antipseudomonal cephalosporins. 11 RCTs involving 2,531 participants found low certainty evidence that ceftazidime and linezolid combination may not be convincingly different from cephalosporin alone in reducing all-cause mortality. Evidence on other antibiotic regimens is very uncertain. Data on other patient-important outcomes including adverse events was sparse, and we did not perform network or pairwise meta-analysis. CONCLUSIONS: For empiric antibiotic therapy of adults with HAP, piperacillin-tazobactam might be among the most effective in reducing treatment failure in HAP. Empiric MRSA coverage may not exert additional benefit in reducing mortality in HAP. REGISTRATION: PROSPERO (CRD 42022297224).

Systematic Review and Meta-Analysis: Effects of Pharmacological Treatment for Attention-Deficit/Hyperactivity Disorder on Quality of Life.

OBJECTIVE: We conducted a systematic review and meta-analysis to quantify the effect of ADHD medication on QoL, and to understand if this effect differs between stimulants and non-stimulants. METHOD: From the dataset of a published network meta-analysis (Cortese et al., 20181), updated on 27th February 2023 (https://med-adhd.org/), we identified randomized controlled trials (RCTs) of ADHD medications for individuals aged 6 or more with a diagnosis of ADHD based on DSM (from III to 5 editions) or ICD (9 or 10), reporting data on QoL (measured with a validated scale). The risk of bias for each RCTs was assessed using the Cochrane Risk of Bias tool 2. Multi-level meta-analytic models were conducted with R 4.3.1. RESULTS: We included 17 RCTs (5,388 participants in total; 56% randomized to active medication) in the meta-analyses. We found that amphetamines (Hedge's g = 0.51, 95% CI = 0.08, 0.94), methylphenidate (0.38; 0.23, 0.54), and atomoxetine (0.30; 0.19, 0.40) were significantly more efficacious than placebo in improving QoL in people with ADHD, with moderate effect size. For atomoxetine, these effects were not moderated by the length of intervention, nor differed between children/adolescents and adults. DISCUSSION: In addition to being efficacious in reducing ADHD core symptoms' severity, both stimulant and non-stimulant medications are efficacious in improving QoL in people with ADHD, albeit with lower effect sizes. Future research should explore whether and to what degree combining pharmacological and non-pharmacological interventions is likely to further improve QoL in people with ADHD. STUDY PREREGISTRATION INFORMATION: Effects of pharmacological treatment for ADHD on quality of life: a systematic review and meta-analysis; https://osf.io/; qvgps.

Predicting Concrete Strength Early Age using a Combination of Machine Learning and Electromechanical Impedance with Nano-enhanced Sensors.

To ensure the structural integrity of concrete and prevent unanticipated fracturing, real-time monitoring of early-age concrete's strength development is essential, mainly through advanced techniques such as nano-enhanced sensors. The piezoelectric-based electro-mechanical impedance (EMI) method with nano-enhanced sensors is emerging as a practical solution for such monitoring requirements. This study presents a strength estimation method based on Non-Destructive Testing (NDT) Techniques and Long Short-Term Memory (LSTM) and artificial neural networks (ANNs) as hybrid (NDT-LSTMs-ANN), including several types of concrete strength-related agents. Input data includes water-to-cement rate, temperature, curing time, and maturity based on interior temperature, allowing experimentally monitoring the development of concrete strength from the early steps of hydration and casting to the last stages of hardening 28 days after the casting. The study investigated the impact of various factors on concrete strength development, utilizing a cutting-edge approach that combines traditional models with nano-enhanced piezoelectric sensors and NDT-LSTMs-ANN enhanced with nanotechnology. The results demonstrate that the hybrid provides highly accurate concrete strength estimation for construction safety and efficiency. Adopting the piezoelectric-based EMI technique with these advanced sensors offers a viable and effective monitoring solution, presenting a significant leap forward for the construction industry's structural health monitoring practices.

Clinical Features and Treatment Outcomes of Bone and Joint Nontuberculous Mycobacterial Infections According to Immune Status: a 9-year Retrospective Observational Cohort.

OBJECTIVES: Nontuberculous mycobacteria (NTM) bone and joint infections (BJIs) are uncommon. We evaluated the characteristics of BJIs and identified differences according to immune status. METHODS: We performed a multicenter retrospective study in France involving patients with documented NTM BJI over a 9-year period. We collected the clinical and microbiological characteristics, management, and clinical outcomes of the patients. RESULTS: Ninety-five patients were included, of whom 50.5% (48/95) were immunosuppressed. Tenosynovitis was more frequent in the immunocompetent group, and native arthritis more common in the immunosuppressed group. M. marinum and M. abscessus complex were significantly more frequent in the immunocompetent group, and M. avium and M. xenopi were significantly more frequent in the immunosuppressed group. The combination of antibiotherapy with surgery tended to be more frequent in the immunocompetent than the immunosuppressed group (63.8% (30/47) vs 47.8% (22/46), respectively); of the latter, 45.7% (21/46) received antimicrobial therapy alone, a higher frequency than in the immunocompetent group (23.4%, 11/47). The median duration of antimicrobial treatment was similar in the two groups (11 months). Mortality was significantly higher in the immunosuppressed group. CONCLUSIONS: Although the clinical presentations and the NTM species involved in BJI differed according to immune status, most recovered completely after treatment.

Prevalence and Predictors of Mitral Annular Disjunction and Ventricular Ectopy in Mitral Valve Prolapse.

BACKGROUND: Mitral annular disjunction (MAD) is associated with ventricular arrhythmia in mitral valve prolapse (MVP). The proportional risk from MAD and other predictors of ventricular arrhythmia in MVP have not been well characterized. OBJECTIVE: To identify predictors of complex or frequent ventricular ectopy (cfVE) in MVP and quantify risk of cfVE and mortality in MVP with MAD. METHODS: We studied 632 adult patients with MVP on transthoracic echocardiography at the University of North Carolina Medical Center from 2016-2019 (median age [IQR] 64 [52-74] years; 52.7% female; 16.3% African American). Resting and ambulatory electrocardiograms were used to identify cfVE. RESULTS: MAD was present in 94 (14.9%) patients. Independent associations of MAD were bileaflet prolapse (OR [95% CI] 4.25 [2.47-7.33], p<0.0001), myxomatous valve (2.17 [1.27-3.71], p=0.005), absence of hypertension (2.00 [1.21-3.32], p=0.007), electrocardiogram inferior or lateral lead T-wave inversion (TWI, 2.07 [1.23-3.48], p=0.006), and female sex (1.99 [1.21-3.25], p=0.006). cfVE was frequent with MAD (39 [41.5%] vs 93 [17.3%] without, p<0.0001). Independent cfVE predictors were MAD (HR [95% CI] 2.23 [1.47-3.36], p=0.0001), bileaflet prolapse (1.86 [1.25-2.76], p=0.002), heart failure (1.79 [1.16-2.77], p=0.009), lower LV ejection fraction (0.14 [0.03-0.61], p=0.009), coronary artery disease (1.60 [1.05-2.43], p=0.03), and TWI (1.51 [1.03-2.22], p=0.03). After median 40 (33-48) months, there was increased mortality with MAD (p=0.04). CONCLUSION: MAD in MVP is associated with bileaflet or myxomatous MVP, absence of hypertension, T-wave inversion, and female sex. There is increased complex and frequent ventricular ectopy and mortality with MAD, highlighting the need for closer follow-up in these patients.

Epigenetic regulation of autophagy by non-coding RNAs and exosomal non-coding RNAs in colorectal cancer: A narrative review.

One of the major diseases affecting people globally is colorectal cancer (CRC), which is primarily caused by a lack of effective medical treatment and a limited understanding of its underlying mechanisms. Cellular autophagy functions to break down and eliminate superfluous proteins and substances, thereby facilitating the continual replacement of cellular elements and generating vital energy for cell processes. Non-coding RNAs and exosomal ncRNAs have a crucial impact on regulating gene expression and essential cellular functions such as autophagy, metastasis, and treatment resistance. The latest research has indicated that specific ncRNAs and exosomal ncRNA to influence the process of autophagy in CRC cells, which could have significant consequences for the advancement and treatment of this disease. It has been determined that a variety of ncRNAs have a vital function in regulating the genes essential for the formation and maturation of autophagosomes. Furthermore, it has been confirmed that ncRNAs have a considerable influence on the signaling pathways associated with autophagy, such as those involving AMPK, AKT, and mTOR. Additionally, numerous ncRNAs have the potential to affect specific genes involved in autophagy. This study delves into the control mechanisms of ncRNAs and exosomal ncRNAs and examines how they simultaneously influence autophagy in CRC.

Exosomal circ_0084043 derived from colorectal cancer-associated fibroblasts promotes in vitro endothelial cell angiogenesis by regulating the miR-140-3p/HIF-1α/VEGF signaling axis.

Background: Circular RNAs (circRNAs) hold potential as diagnostic markers for colorectal cancer (CRC); however, their functional mechanisms remain incompletely elucidated. This work investigates the clinical implications of a unique set comprising six circRNAs derived from serum in CRC. Furthermore, we delve into the role of exosomal circ_0084043, originating from colorectal cancer-associated fibroblasts (CAFs), with a specific focus on its contribution to endothelial cell angiogenesis. Methods: The study analyzed circRNA levels in serum samples obtained from both CRC and control groups using qRT-PCR. Additionally, exosomes originating from colorectal CAFs and normal fibroblasts (NFs) were purified and confirmed by electron microscopy and Western blotting techniques. The proangiogenic effects of CAF-derived exosomal circ_0084043 were assessed in endothelial cells through proliferation, migration, and in vitro capillary tube formation assays. Gain- and loss-of-function experiments were employed to clarify the role of the circ_0084043/miR-140-3p/HIF-1α axis in endothelial cell angiogenesis, utilizing luciferase reporter assay, Western blotting, and ELISA for mechanism elucidation. Results: The candidate circRNAs (circ_0060745, circ_001569, circ_007142, circ_0084043, Circ_BANP, and CiRS-7) exhibited notably elevated expression in CRC patient sera compared to the levels observed in healthy individuals. Except for CiRS-7, all circRNAs showed elevated expression in CRC patients with positive lymph node metastasis and advanced tumor stages. Exosomes released by colorectal CAFs augmented endothelial cell proliferation, migration, and angiogenesis by upregulating VEGF expression and secretion. Circ_0084043 was highly detected in endothelial cells treated with CAF-derived exosomes. Silencing circ_0084043 reduced VEGFA expression and diminished CAF exosome-induced endothelial cell processes, indicating its pivotal role in angiogenesis. Circ_0084043 sponges miR-140-3p, regulating HIF-1α, and a reverse relationship was also identified between miR-140-3p and VEGFA in endothelial cells. Inhibiting miR-140-3p mitigated circ_0084043 knockdown effects in CAF exosome-treated endothelial cells. Co-transfection of si-circ_0084043 and a miR-140-3p inhibitor reversed the inhibited migration and angiogenesis caused by circ_0084043 knockdown in CAF exosome-treated endothelial cells. Inhibiting miR-140-3p rescued reduced VEGFA expression due to circ_0084043 knockdown in endothelial cells exposed to CAF-derived exosomes, indicating modulation of the circ_0084043/miR-140-3p/VEGF signaling in CAF-derived exosome-induced angiogenesis. Conclusions: This study unveiled a distinctive signature of six serum-derived circular RNAs, indicating their potential as promising diagnostic biomarkers for CRC. Importantly, exosomal circ_0084043 originating from colorectal CAFs was identified as playing a crucial role in endothelial cell angiogenesis, exerting its influence through the modulation of the miR-140-3p/HIF-1α/VEGF signaling axis.