Search

Background: Presentation of research at annual national orthopaedic conferences not only serves as a forum for the dissemination of knowledge but is also often a requirement of orthopaedic training programmes. The expected outcome is publication in a peer-reviewed journal. However, publication rates vary for a variety of reasons. The objective of this study was to determine publication rates of presentations from our local Singapore Orthopaedic Association (SOA) annual scientific meeting (ASM) and some of the potential associated factors. We also compared our findings to equivalent meetings worldwide to assess value of scientific content of various orthopaedic conferences. Methods: All presentations of six SOA ASMs were entered into a database. Using presentation titles, author names and keywords in PubMed and Google Scholar, we determined how many presentations progressed to publication in a peer-reviewed journal. Various comparisons were made to determine factors that could influence publication rates. A comparison with national orthopaedic meetings of America, United Kingdom, Ireland, Australia, Germany, Turkey and Brazil was also conducted. Results: Excluding the ASMs with less than 4 years of follow-up, the publication rate was 35.8%. Both podium and international presenters were found to have significantly higher publication rates than poster and local presenters, respectively, while basic science and clinical research were found to have equivalent rates. Publication rates from other countries' national conferences ranged between 26.6% and 58.1%. Conclusions: We suggest that the quality of a presentation is related to its subsequent publication in a peer-reviewed journal. Our findings support the general consensus that the annual meeting of the American Academy of Orthopaedic Surgeons (AAOS) is the gold standard for the dissemination of orthopaedic knowledge updates and advancements in our specialty. Each national orthopaedic association could determine the ratio of “presentations at ASM” to “publication within five years of presentation” and use this as a measure of their annual conference’s impact on the addition and advancement to the orthopaedic literature. This tool may in turn assist clinicians in determining which meetings to attend. [ABSTRACT FROM AUTHOR]

Background: Cardiovascular disease (CVD) is a leading cause of death in Canada and is a priority area for medical research. The research funding landscape in Canada has changed quite a bit over the last few decades, as have funding levels. Our objective was to estimate the magnitude of expenditures on CVD research for the public and charitable (not-for profit) sectors in Canada between 1975 and 2005. Methods: To estimate research expenditures for the public and charitable sectors, we compiled a complete list of granting agencies in Canada, contacted each agency and the Canadian Institutes of Health Research (CIHR), and extracted data from the organizations' annual reports and the Reference Lists of health research in Canada. Two independent reviewers scanned all grant and fellowship/scholarship titles (and summary/key words, when available) of all research projects funded to determine their inclusion in our analysis; only grants and fellowships/scholarships that focused on heart and peripheral vascular diseases were selected. Results: Public/charitable sector funding increased 7.5 times, from close to $13 million (in constant dollars) in 1975 to almost $96 million (in constant dollars) in 2005 (base year). The Medical Research Council of Canada (MRCC)/ CIHR and the Heart & Stroke Foundation of Canada have been the main founders of this type of research during our analysis period; the Alberta Heritage Foundation for Medical Research and the Fonds de la recherche en santé du Quebec have played major roles at the provincial level. The Indirect Costs Research Program and Canada Foundation for Innovation have played major roles in terms of funding in the last years of our analysis. Conclusion: Public/charitable-funded research expenditures devoted to CVD have increased substantially over the last three decades. By international standards, the evidence suggests Canada spends less on health-related research than the UK and the US, at least in absolute terms. However, this may not be too problematic as Canada is likely to free-ride from research undertaken elsewhere. Understanding these past trends in research funding may provide decision makers with important information for planning future research efforts. Future work in this area should include the use of our coding methods to obtain estimates of funded research for other diseases in Canada. [ABSTRACT FROM AUTHOR]

Background: Accurate and timely monitoring of influenza prevalence is essential for effective healthcare interventions. This study proposes a graph neural network (GNN)-based method to address the issue of cross-regional connectivity in predicting influenza outbreaks, aiming to achieve real-time and accurate influenza prediction. Methods: We proposed a GNN-based approach with dual topology processing, capturing both geographical and socio-economic associations among counties/cities. The model inputs consist of weekly matrices of influenza-like illness (ILI) rates at city level, along with geographical topology and functional topology. The model construction involves temporal feature extraction through 1-dimensional gated causal convolution, spatial feature embedding through graph convolution, and additional adjustments to enhance spatiotemporal interaction exploration. Evaluation metrics include four commonly used measures: root mean square error (RMSE), mean absolute percentage error (MAPE), mean absolute error (MAE), and Pearson correlation (Corr). Results: Our approach for predicting influenza outbreaks achieves competitive performance on real-world datasets (Corr = 0.8202; RMSE = 0.0017; MAE = 0.0013; MAPE = 0.0966), surpassing established baselines. Notably, our approach exhibits excellent capability in accurately and timely capturing short-term influenza outbreaks during the flu season, outperforming competitors across all evaluation metrics. Conclusion: The incorporation of dual topology processing and the subsequent fusion mechanism allows the model to explore in-depth spatiotemporal feature interactions. Demonstrating superior performance, our approach shows great potential in early detection of flu trends for facilitating public health decisions and resource optimization. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is among the most devastating neurodegenerative disorders with limited treatment options. Emerging evidence points to the involvement of lipid dysregulation in the development of AD. Nevertheless, the precise lipidomic landscape and the mechanistic roles of lipids in disease pathology remain poorly understood. This review aims to highlight the significance of lipidomics and lipid-targeting approaches in the diagnosis and treatment of AD. We summarized the connection between lipid dysregulation in the human brain and AD at both genetic and lipid species levels. We briefly introduced lipidomics technologies and discussed potential challenges and areas of future advancements in the lipidomics field for AD research. To elucidate the central role of lipids in converging multiple pathological aspects of AD, we reviewed the current knowledge on the interplay between lipids and major AD features, including amyloid beta, tau, and neuroinflammation. Finally, we assessed the progresses and obstacles in lipid-based therapeutics and proposed potential strategies for leveraging lipidomics in the treatment of AD. [ABSTRACT FROM AUTHOR]

Background: In select patients with type C esophageal atresia, primary anastomosis is not appropriate and a staged approach is required. We aim to summarize our experience in the management of type C EA using a staged approach. Methods: A retrospective chart-review of patients with type C EA admitted to Beijing Children's Hospital between July 2020 to October 2023 were conducted. Those diagnosed with type C EA who were not amendable to primary anastomosis were included for analysis. Clinical information was recorded, and follow- up was performed. Results: Seven (five boys) patients with type C EA who received staged repair were included in the study. Initial surgeries included thoracotomy and thoracoscopy. 71% (5/7) patient had complications after the initial surgery, including pyopneumothorax, pneumonia, recurrent tracheoesophageal fistula (rTEF), and anastomotic leak. Esophageal elongation techniques were applied in 3 patients. All delayed anastomosis were performed thoracoscopically, except for in one case where spontaneous fistulization occurred and no anastomosis were necessary. Complications after delayed anastomosis included recurrent esophageal pulmonary fistula (rEPF) in 50% (3/6), anastomotic leak in 33% (2/6), and esophageal stricture in all (6/6) patients. After a median follow-up of 14 months (range: 2–24), all patients were in generally good condition. Conclusion: Primary operations should be kept simple and minimal in patients diagnosed with type C EA who are not appropriate for primary anastomosis. Internal traction is an effective method that allows for subsequent anastomosis. Intraoperative indocyanine green fluorescence can aid in fistula determination and anastomosis. [ABSTRACT FROM AUTHOR]

Background: Innovative behaviours are important for nursing postgraduates who are a significant reserve for future nursing career, thinking critically, utilizing technologies and solving complex problems. In nursing undergraduates' education, innovative behaviour is closely linked with the development of professional identity. However, there are limited studies exploring innovative behaviours, influencing factors and educational requirements of nursing postgraduates. Aim: To investigate nursing postgraduates' innovative behaviour, influencing factors, and the correlation between innovative behaviour and professional identity. Moreover, exploring nursing postgraduates' requirements for innovational education. Methods: A national descriptive cross-sectional study was conducted among postgraduate students in Chinese nursing schools between October and November 2022. A general information questionnaire, The Nurses' Innovative Behaviour Scale, the Professional Identity Questionnaire for Nurse Student, and a multiple-choice question about students' innovation education requirements were collected. The independent-sample t-test, one-way analysis of variance (ANOVA), multiple linear regression, and Pearson's correlation analyses were conducted. Results: This study recruited 426 nursing postgraduates from 44 nursing schools across China. The mean score of innovative behaviour of nursing postgraduates was 38.96 ± 4.90 (min-max 10–50). Nursing postgraduates' professional identity was positively correlated with innovative behaviour (r = 0.436, P < 0.01). Participants who read scientific literature frequently, had a high level of professional identity, and grew up in urban areas had high levels of innovative behaviour (adjusted R2 = 0.244, P < 0.001). Conclusions: It was determined that the level of innovative behaviour is associated with their professional identity and the frequence of reading scientific literature in nursing postgraduates. It is imperative for educators to foster an environment that encourages postgraduate nursing students to engage with a wider array of scholarly literature and elevates postgraduate nursing students' professional identity. Furthermore, the dissemination of advanced knowledge and the adoption of diverse pedagogical approaches are likely to meet the innovative demands of nursing postgraduates. [ABSTRACT FROM AUTHOR]

Background and aims: Previous studies have confirmed that alcohol can increase the sensitivity of the pancreas to stressors and exacerbate the severity of pancreatitis when excessive alcohol intake is combined with other causes. In the current work, this study attempted to explore how does alcohol regulate cerulein-induced acute pancreatitis, especially before inflammation occurs. Methods: Proteomics was performed to analyze the differentially expressed proteins in pancreatic tissues from a rat model of pancreatitis. The metabolite levels in the pancreatic tissue, serum of rats and serum of persons with a history of alcohol consumption were detected by LC‒MS/MS. In the present study the impact of etomoxir (a carnitine palmitoyl-transferase 1A-specific inhibitor) treatment on AR42J cells treated with alcohol and the effect of etomoxir injection on the inflammatory response in an alcohol + cerulein-induced AAP rat model was evaluated. Results: When treated with the same amount of cerulein, the rats that ingested alcohol presented with more severe pancreatitis. The proteomics results revealed that the fatty acid degradation pathway was closely related to the development of alcoholic acute pancreatitis, and CPT1A exhibited the greatest increase (approximately twofold increase). The products (acylcarnitines) of CPT1A were changed in the serum of persons with a history of alcohol consumption. Etomoxir treatment mitigates the influence of alcohol stimulation on the aberrant expression of proteins associated with oxidative stress, increased ROS production, mitochondrial ultrastructural alterations and mitochondrial dysfunction in AR42J cells. Etomoxir injection reduced the inflammatory response in the AAP rat model. Conclusion: Alcohol upregulates CPT1A protein expression in pancreatic tissue, resulting in abnormal lipid metabolism. The products of lipid metabolism, ROS, contribute to mitochondrial ultrastructural alterations and mitochondrial dysfunction. These changes act as sentinel events that regulate acute pancreatitis. [ABSTRACT FROM AUTHOR]

Background: The vascularized free fibular flap is increasingly recognized as the standard technique for the repair of complex soft tissue and hard tissue defects in oral and maxillofacial surgery. Conventionally, the vascular supply to the skin island is derived from the distal perforators of the peroneal artery. However, complications may arise if these distal perforators are either absent or damaged during surgical procedures, highlighting the necessity to employ the proximal peroneal perforators as an alternative. This study aims to investigate the anatomical characteristics—including the presence, distribution, and origin—of proximal peroneal perforators through computed tomography angiography (CTA) prior to surgical intervention. A secondary objective is to confirm their viability when distal perforators are unavailable or when dual-skin paddles are needed. Methods: A comprehensive review was conducted involving 50 patients who underwent CTA examinations. Three-dimensional reconstruction of DICOM data was utilized to document the presence, quantity, location, and variations of proximal perforators. Relative positions of the origin points were measured, and the distances from these points to the fibula were calculated. Additionally, 11 studies were included in which a proximal perforator was successfully used to prepare a free fibula chimeric myocutaneous flap for the reconstruction of maxillofacial defects. Results: Among the 100 lower limbs evaluated, a successful identification rate of 98% for proximal perforators was achieved via CTA. Of those identified, 70% were found to originate from the fibular artery, 22% branched concurrently with it, and 8% emerged prior to the point of emergence of the fibular artery. Analysis through curve fitting indicated that the origin points of proximal perforators were predominantly located approximately 13.17 mm below the origin of the fibular artery, with their endpoints projecting about 123.9 mm below the fibular head. Conclusions: The high prevalence of proximal peroneal perforators identified in this population, along with their relatively stable anatomical positions, suggests their significant surgical potential. In scenarios where the distal peroneal perforator is absent or suffers intraoperative injury, the proximal peroneal perforator can serve as a reliable alternative for preparing a free fibula osteal flap combined with a proximal peroneal perforator skin paddle. [ABSTRACT FROM AUTHOR]

Background: The potential role of Klebsiella pneumoniae (K.pn) in hypertension development has been emphasized, although the specific mechanisms have not been well understood. Bacterial extracellular vesicles (BEVs) released by Gram-negative bacteria modulate host cell functions by delivering bacterial components to host cells. Endothelial dysfunction is an important early event in the pathogenesis of hypertension, yet the impact of K.pn-secreted EVs (K.pn EVs) on endothelial function remains unclear. This study aimed to investigate the effects of K.pn EVs on endothelial function and to elucidate the underlying mechanisms. Methods: K.pn EVs were purified from the bacterial suspension using ultracentrifugation and characterized by transmission electron microscopy nanoparticle tracking analysis, and EV marker expression. Endothelium-dependent relaxation was measured using a wire myograph after in vivo or ex vivo treatment with K.pn EVs. Superoxide anion production was measured by confocal microscopy and HUVEC senescence was assessed by SA-β-gal activity. SIRT1 overexpression or activator was utilized to investigate the underlying mechanisms. Results: Our data showed that K.pn significantly impaired acetylcholine-induced endothelium-dependent relaxation and increased superoxide anion production in endothelial cells in vivo. Similarly, in vivo and ex vivo studies showed that K.pn EVs caused significant endothelial dysfunction, endothelial provocation, and increased blood pressure. Further examination revealed that K.pn EVs reduced the levels of SIRT1 and p-eNOS and increased the levels of NOX2, COX-2, ET-1, and p53 in endothelial cells. Notably, overexpression or activation of SIRT1 attenuated the adverse effects and protein changes induced by K.pn EVs on endothelial cells. Conclusion: This study reveals a novel role of K.pn EVs in endothelial dysfunction and dissects the relevant mechanism involved in this process, which will help to establish a comprehensive understanding of K.pn EVs in endothelial dysfunction and hypertension from a new scope. [ABSTRACT FROM AUTHOR]

Background: The insulin-like growth factor 2 (IGF2) and H19 are overexpressed in hepatocellular carcinoma (HCC). IGF2-derived miR-483-5p is implicated in the development of cancers. Here, we investigated the involvement of miR-483-5p in IGF2 and H19 overexpression regulation and its role in HCC. Methods: Firstly, the effect of miR-483-5p on the expression of IGF2 and H19, and the binding of miR-483-5p to IGF2/H19 enhancer were evaluated in HCC cells. Next, miR-483-5p-mediated IGF2/H19 enhancer activation and its mechanism were investigated in HCC cells. Then, the mechanism by which active IGF2/H19 enhancer mediated by miR-483-5p activate IGF2/H19 promoters was studied in HCC cells. Finally, the effect of MED1 on the expression of IGF2/H19 as well as the malignant phenotype of HCC cells in vitro and in vivo mediated by miR-483-5p was evaluated. Results: Mir-483-5p up-regulated IGF2 P2 mRNA-P4 mRNA and H19 expression by binding to IGF2/H19 enhancer resulting in IGF2/H19 enhancer activation in HCC cells. Mechanistically, miR-483-5p increased recruitment of Ago1 and Ago2 at IGF2/H19 enhancer and then activated transcription of IGF2/H19 eRNA by RNA polymerase II and p300, which further induced chromatin loops formation between IGF2/H19 enhancer and IGF2/H19 promoters to activate IGF2/H19 promoters via IGF2/H19 eRNA-MED1-IGF2/H19 promoters complex in HCC cells. In this process, MED1 promoted chromatin loops formation as well as the malignant phenotype of HCC cells in vitro and in vivo mediated by miR-483-5p. Conclusions: miR-483-5p-mediated activating of IGF2/H19 enhancer up-regulates IGF2/H19 expression via DNA loops, thereby promoting the malignant progression of HCC. [ABSTRACT FROM AUTHOR]

Background: During the last decades, the advancements in synthetic biology opened the doors for a profusion of cost-effective, fast, and ecologically friendly medical applications priorly unimaginable. Following the trend, the genetic engineering of the baker's yeast, Saccharomyces cerevisiae, propelled its status from an instrumental ally in the food industry to a therapy and prophylaxis aid. Main text: In this review, we scrutinize the main applications of engineered S. cerevisiae in the medical field focusing on its use as a cell factory for pharmaceuticals and vaccines, a biosensor for diagnostic and biomimetic assays, and as a live biotherapeutic product for the smart in situ treatment of intestinal ailments. An extensive view of these fields' academic and commercial developments as well as main hindrances is presented. Conclusion: Although the field still faces challenges, the development of yeast-based medical applications is often considered a success story. The rapid advances in synthetic biology strongly support the case for a future where engineered yeasts play an important role in medicine. [ABSTRACT FROM AUTHOR]

Background: Namaste Care is an intervention designed to improve the quality of life for people with advanced dementia by providing individualised stimulation and personalised activities in a group setting. Current evidence indicates there may be benefits from this intervention, but there is a need to explore the practical realities of its implementation, including potential barriers, enablers, and how it is delivered within the context of nursing care homes. Objective: To systematically assess the factors involved in implementing Namaste Care for people with advanced dementia in nursing care homes. To provide pragmatic suggestions on how Namaste Care can be delivered in the context of nursing care homes. Design: Systematically constructed review using framework synthesis. Data sources: Comprehensive searches were conducted in Medline, CINAHL, and PsycINFO databases for studies published between 2018 and 2024. Search concepts included "Namaste Care," "advanced dementia," and related terms. Review methods: Studies were included if they focused on the use of Namaste Care for people with advanced dementia in nursing care homes. Data extraction and quality assessment were performed by two independent researchers using standardised forms and critical appraisal tools. A framework synthesis of the results was conducted, which involves systematically combining qualitative and quantitative data within a structured analytical framework to identify overarching themes and insights. Findings: Twenty-five studies met the inclusion criteria. Key themes identified were: (1) Frequency and duration of Namaste sessions. (2) Namaste Care environment and personalisation of care. (3) Staff engagement and training needs. (4) Involvement of family members and volunteers. Conclusions: Implementing Namaste Care in nursing care homes presents various challenges but also significant opportunities for enhancing the quality of life for residents with advanced dementia. Addressing key themes such as the frequency and duration of sessions, the environment and personalisation of care, staff engagement and training needs, and the involvement of family members and volunteers is crucial. Specifically, providing tailored training programmes for staff, creating dedicated Namaste Care spaces, and encouraging active family and volunteer participation can facilitate effective integration. By incorporating these pragmatic recommendations, Namaste Care can be sustainably integrated into daily care routines, leading to improved resident well-being, reduced behavioural symptoms, and enhanced caregiver-resident interactions. [ABSTRACT FROM AUTHOR]

Purpose: To explore possible pathogenic genes for concomitant exotropia using whole-exome sequencing. Methods: In this study, 47 individuals from 10 concomitant exotropia (including intermittent exotropia and constant exotropia) pedigrees were enrolled. Whole-exome sequencing was used to screen mutational profiles in 25 affected individuals and 10 unaffected individuals. Sanger sequencing and in silico analysis were performed for all participants. Two target genes were used to capture the sequences of 220 sporadic samples. Results: All 10 concomitant exotropia pedigrees presented autosomal dominant inheritance with childhood onset (3.35 ± 1.51 years old). Eleven different missense variants were identified among seven potential pathogenic genes (COL4A2, SYNE1, LOXHD1, AUTS2, GTDC2, HERC2 and CDH3) that cosegregated with pedigree members. All variants were predicted to be deleterious and had low frequencies in the general population. Distinct variants of COL4A2 were present in three pedigrees, and distinct variants of SYNE1 were present in two pedigrees. Fifteen variants in AUTS2 and four variants in GTDC2 were identified in 220 patients with sporadic concomitant exotropia using a target-capture sequencing approach. Conclusion: This is the first study to explore the genetic mechanism of concomitant exotropia and identify seven associated genes (COL4A2, SYNE1, LOXHD1, AUTS2, GTDC2, HERC2 and CDH3) that may be candidate genes causing concomitant exotropia. More samples and in-depth studies are needed to verify these findings. [ABSTRACT FROM AUTHOR]

Super-enhancers (SEs) represent a distinct category of cis-regulatory elements notable for their robust transcriptional activation capabilities. In tumor cells, SEs intricately regulate the expression of oncogenes and pivotal cancer-associated signaling pathways, offering significant potential for cancer treatment. However, few studies have systematically discussed the crucial role of SEs in hepatocellular carcinoma (HCC), which is one of the most common liver cancers with late-stage diagnosis and limited treatment methods for advanced disease. Herein, we first summarize the identification methods and the intricate processes of formation and organization of super-enhancers. Subsequently, we delve into the roles and molecular mechanisms of SEs within the framework of HCC. Finally, we discuss the inhibitors targeting the key SE-components and their potential effects on the treatment of HCC. In conclusion, this review meticulously encapsulates the distinctive characteristics of SEs and underscores their pivotal roles in the context of hepatocellular carcinoma, presenting a novel perspective on the potential of super-enhancers as emerging therapeutic targets for HCC. [ABSTRACT FROM AUTHOR]

Background: Postoperative delirium (POD) is the most common neurological adverse event among elderly patients undergoing surgery. POD is associated with an increased risk for postoperative complications, long-term cognitive decline, an increase in morbidity and mortality as well as extended hospital stays. Delirium prevention and treatment options are currently limited. This study will evaluate the effect of transcranial electrical stimulation (tES) on the incidence of POD. Methods: We will perform a randomized, double-blind, sham-controlled trial using single-session postoperative application of tES in the recovery room in 225 patients (> 65 years) undergoing elective major surgery. Patients will be randomly allocated (ratio 1:1:1) to one of three study groups: (1) alpha-tACS over posterior parietal cortex [2 mA, 20 min], (2) anodal tDCS over left dorsolateral prefrontal cortex [2 mA, 20 min], (3) sham [2 mA, 30 s]. Delirium will be screened twice daily with the 3-min diagnostic interview Confusion Assessment Method (3D-CAM) in the 5 days following surgery. The primary outcome is the incidence of POD defined as at least one positive screening during the five first postoperative days compared between tACS and sham groups. Secondary outcomes include delirium severity, duration, phenotype, postoperative pain, postoperative nausea and vomiting, electroencephalographic (EEG) markers, and fluid biomarkers. Discussion: If effective, tES is a novel, easily applicable, non-invasive method to prevent the occurrence of POD. The comprehensive neurophysiological and biofluid assessments for markers of (neuro-)inflammation and neurodegeneration will shed light on the pathomechanisms behind POD and further elucidate the (after-)effects of tES. The potential implications for the postoperative recovery comprise enhanced patient safety, neurocognitive outcome, perioperative manageability but also reduced healthcare costs. Trial registration: German Clinical Trial Registry DRKS00033703. Registered on February 23, 2024. [ABSTRACT FROM AUTHOR]

The cathepsin family comprises lysosomal proteases that play essential roles in various physiological processes, including protein degradation, antigen presentation, apoptosis, and tissue remodeling. Dysregulation of cathepsin activity has been linked to a variety of pathological conditions, such as cancer, autoimmune diseases, and neurodegenerative disorders. Understanding the functions of cathepsins is crucial for gaining insights into their roles in both health and disease, as well as for developing targeted therapeutic approaches. Emerging research underscores the significant involvement of cathepsins in immune cells, particularly T cells, macrophages, dendritic cells, and neutrophils, as well as their contribution to immune-related diseases. In this review, we systematically examine the impact of cathepsins on the immune system and their mechanistic roles in cancer, infectious diseases, autoimmune and neurodegenerative disorders, with the goal of identifying novel therapeutic strategies for these conditions. [ABSTRACT FROM AUTHOR]

Background: Thyroid hormone (T3) has an inhibitory effect on tissue/organ regeneration. It is still elusive how T3 regulates this process. It is well established that the developmental effects of T3 are primarily mediated through transcriptional regulation by thyroid hormone receptors (TRs). Here we have taken advantage of mutant tadpoles lacking both TRα and TRβ (TRDKO), the only receptor genes in vertebrates, for RNA-seq analyses to investigate the transcriptome changes underlying the initiation of tail regeneration, i.e., wound healing and blastema formation, because this crucial initial step determines the extent of the functional regeneration in the later phase of tissue regrowth. Results: We discovered that GO (gene ontology) terms related to inflammatory response, metabolic process, cell apoptosis, and epithelial cell migration were highly enriched among commonly regulated genes during wound healing at either stage 56 or 61 or with either wild type (WT) or TRDKO tadpoles, consistent with the morphological changes associated with wound healing occurring in both regenerative (WT stage 56, TRDKO stage 56, TRDKO stage 61) and nonregenerative (WT stage 61) animals. Interestingly, ECM-receptor interaction and cytokine-cytokine receptor interaction, which are essential for blastema formation and regeneration, were significantly enriched among regulated genes in the 3 regenerative groups but not the non-regenerative group at the blastema formation period. In addition, the regulated genes specific to the nonregenerative group were highly enriched with genes involved in cellular senescence. Finally, T3 treatment at stage 56, while not inducing any measurable tail resorption, inhibited tail regeneration in the wild type but not TRDKO tadpoles. Conclusions: Our study suggests that TR-mediated, T3-induced gene regulation changed the permissive environment during the initial period of regeneration and affected the subsequent patterning/outgrowth period of the regeneration process. Specifically, T3 signaling via TRs inhibits the expression of ECM-related genes while promoting the expression of inflammation-related genes during the blastema formation period. Interestingly, our findings indicate that amputation-induced changes in DNA replication-related pathways can occur during this nonregenerative period. Further studies, particularly on the regenerative microenvironment that may depend on ECM-receptor interaction and cytokine-cytokine receptor interaction, should provide important insights on the regulation of regenerative capacity during vertebrate development. [ABSTRACT FROM AUTHOR]

Taking foreign language majors with experience in innovation and entrepreneurship training program (IETP) as samples, this study investigates the influence of disciplinary expertise on entrepreneurial intention. Based on the theory of planned behavior (TPB), a model was designed to examine the relationships among entrepreneurial intentions, perceived behavioral control, attitude toward entrepreneurship, subjective norms, IETP experience, foreign language self-efficacy and cultural intelligence. The data were collected through questionnaires and Partial least squares structural equation modeling (PLS-SEM) was adopted to test the hypotheses. The results show that: (1) perceived behavioral control and attitude toward entrepreneurship are sound predictors of entrepreneurial intentions but the influence of subjective norms on entrepreneurial intentions is insignificant; (2) IETP experience is directly related with perceived behavioral control and indirectly related with entrepreneurial intentions; (3) indicators of participants' disciplinary expertise such as foreign language self-efficacy and cultural intelligence are directly related with IETP experience and indirectly related with entrepreneurial intentions. These six variables included in the research model account for 53.4% of the variance of entrepreneurial intentions. [ABSTRACT FROM AUTHOR]

The gut microbiota is a complex and dynamic ecosystem that plays a crucial role in human health and disease, including obesity, diabetes, cardiovascular diseases, neurodegenerative diseases, inflammatory bowel disease, and cancer. Chronic inflammation is a common feature of these diseases and is closely related to angiogenesis (the process of forming new blood vessels), which is often dysregulated in pathological conditions. Inflammation potentially acts as a central mediator. This abstract aims to elucidate the connection between the gut microbiota and angiogenesis in various diseases. The gut microbiota influences angiogenesis through various mechanisms, including the production of metabolites that directly or indirectly affect vascularization. For example, short-chain fatty acids (SCFAs) such as butyrate, propionate, and acetate are known to regulate immune responses and inflammation, thereby affecting angiogenesis. In the context of cardiovascular diseases, the gut microbiota promotes atherosclerosis and vascular dysfunction by producing trimethylamine N-oxide (TMAO) and other metabolites that promote inflammation and endothelial dysfunction. Similarly, in neurodegenerative diseases, the gut microbiota may influence neuroinflammation and the integrity of the blood–brain barrier, thereby affecting angiogenesis. In cases of fractures and wound healing, the gut microbiota promotes angiogenesis by activating inflammatory responses and immune effects, facilitating the healing of tissue damage. In cancer, the gut microbiota can either inhibit or promote tumor growth and angiogenesis, depending on the specific bacterial composition and their metabolites. For instance, some bacteria can activate inflammasomes, leading to the production of inflammatory factors that alter the tumor immune microenvironment and activate angiogenesis-related signaling pathways, affecting tumor angiogenesis and metastasis. Some bacteria can directly interact with tumor cells, activating angiogenesis-related signaling pathways. Diet, as a modifiable factor, significantly influences angiogenesis through diet-derived microbial metabolites. Diet can rapidly alter the composition of the microbiota and its metabolic activity, thereby changing the concentration of microbial-derived metabolites and profoundly affecting the host's immune response and angiogenesis. For example, a high animal protein diet promotes the production of pro-atherogenic metabolites like TMAO, activating inflammatory pathways and interfering with platelet function, which is associated with the severity of coronary artery plaques, peripheral artery disease, and cardiovascular diseases. A diet rich in dietary fiber promotes the production of SCFAs, which act as ligands for cell surface or intracellular receptors, regulating various biological processes, including inflammation, tissue homeostasis, and immune responses, thereby influencing angiogenesis. In summary, the role of the gut microbiota in angiogenesis is multifaceted, playing an important role in disease progression by affecting various biological processes such as inflammation, immune responses, and multiple signaling pathways. Diet-derived microbial metabolites play a crucial role in linking the gut microbiota and angiogenesis. Understanding the complex interactions between diet, the gut microbiota, and angiogenesis has the potential to uncover novel therapeutic targets for managing these conditions. Therefore, interventions targeting the gut microbiota and its metabolites, such as through fecal microbiota transplantation (FMT) and the application of probiotics to alter the composition of the gut microbiota and enhance the production of beneficial metabolites, present a promising therapeutic strategy. [ABSTRACT FROM AUTHOR]

Introduction: Pre-alerts from paramedics to trauma centers are important for ensuring the highest quality of trauma care. Despite this, there is a paucity of data to support best practices in trauma pre-alert notifications. Within the trauma system of Ontario, Canada, the provincial critical care transport organization, Ornge, provides pre-alerts to major trauma centers, but standardization is currently lacking. This study examined the satisfaction of trauma team leaders' (TTLs) satisfaction with current trauma pre-alerts and their preferences for logistics, content, and structure. Methods: This was a quantitative survey of TTLs at adult and pediatric trauma centers across Ontario, Canada. Recruitment was through email to trauma directors, with follow-up efforts to target low-response sites to achieve good geographical representation. The survey was completed online and contained a combination of single or multiple-choice questions, Likert scales and free text options. Results: In total, 79 TTLs from adult and pediatric lead trauma centers across Ontario responded to the survey, which took place over a 120-day period. The survey achieved good geographical representation. Given the current processes, TTLs describe moderate satisfaction with room for improvement (median score 3, IQR 3–4 on a 5-point Likert scale). Their overall preference was for timely and direct communication, with some concerns about multiple channels of communication around logistics. Most TTLs agreed on the important and less important content details found in common standardized framework tools. For structure, 28/79 TTLs strongly preferred the cognitive aid ATMIST, 13/79 preferred IMIST-AMBO, and 8/79 preferred MIST or SBAR as the most useful. Conclusions: There is room for improvement through standardizing communication and streamlined pre-alert channels. Some disagreements exist between TTLs, particularly regarding logistics. Further research should examine TTL satisfaction after implementing the change in the pre-alert notification framework, which can address localized issues through stakeholder meetings with individual TTLs. [ABSTRACT FROM AUTHOR]

Non-immunoglobulin E (IgE)-mediated food allergies are characterized by delayed gastrointestinal (GI) manifestations that occur after exposure to an inciting food protein; they include food protein-induced allergic proctocolitis (FPIAP), food protein–induced enteropathy (FPE), and food protein-induced enterocolitis syndrome (FPIES). Although the exact mechanisms underlying these disorders are not well understood, non-IgE-mediated food allergies likely represent a spectrum of disease with shared pathophysiological processes. Typically, these non-IgE-mediated food allergies begin in infancy or early childhood, although FPIES can present across the lifespan, with increasing reports in adults in recent years. Diagnosing non-IgE-mediated food allergies can be challenging due to the lack of noninvasive confirmatory tests or biomarkers for most of these disorders and the non-specific nature of GI symptoms. Thus, the diagnosis is usually made clinically, and relies on a constellation of typical symptoms that improve upon removal of the culprit food. The primary approach to management of FPIAP, FPE and FPIES is avoidance of the triggering food, and a multidisciplinary management approach that includes allergy/immunology may be required to avoid unnecessary food restriction and guide food reintroduction. This review outlines the clinical manifestations, epidemiology, pathophysiology, diagnosis, management, and prognosis of these non-IgE-mediated food allergies. [ABSTRACT FROM AUTHOR]

Background: Bacillus subtilis is widely used for industrial enzyme production due to its capacity to efficiently secrete proteins. However, secretion efficiency of enzymes varies widely, and optimizing secretion is crucial to make production commercially viable. Previously, we have shown that overexpression of the xylanase XynA lowers expression of Clp protein chaperones, and that inactivation of CtsR, which regulates and represses clp transcription, increases the production of XynA. In the current study, we examined whether the same is the case for overexpression of the α-amylase AmyM from Geobacillus stearothermophilus by B. subtilis, and why XynA shows a different timing of secretion compared to AmyM. Results: Transcriptome analyses revealed that B. subtilis cells overexpressing AmyM exhibited a distinct profile compared to XynA overexpressing cells, however there were also similarities and in both cases expression of CtsR controlled genes was downregulated. In contrast to XynA, inactivation of CtsR did not improve AmyM production. Upregulation of other protein chaperones, including GroEL/ES and DnaJ/K, by inactivating their transcriptional repressor HrcA, had almost no effect on XynA yields and in fact considerably lowered that of AmyM. Despite using the same promoter, the production of XynA peaks well before AmyM reaches its optimal secretion rate. Transcriptome and ribosome profiling indicated that this is neither related to transcription nor to translation regulation. We show that the reduced secretion in the stationary phase is partially due to the activity of secreted proteases, but also due to the activity of the intracellular protease LonA. The absence of this protein resulted in a 140% and 20% increased production for XynA and AmyM, respectively. Conclusion: The combination of transcriptome and ribosome profiling offered important information to determine at which cellular level production bottlenecks occurred. This helped us to identify LonA protease as an important factor influencing enzyme production yields in B. subtilis. [ABSTRACT FROM AUTHOR]

Background: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a typical hepatic steatosis with metabolic dysfunction. The composite dietary antioxidant index (CDAI) measures individual antioxidant capacity, and the relationship with MAFLD has received little attention. Our goal is to explore the association of CDAI with MAFLD. Methods: Participants were selected from the National Health and Nutrition Examination Survey (NHANES) from 2013 to 2020. CDAI was calculated basing on six dietary antioxidants, including zinc, selenium, carotenoids, and vitamins A, C, and E. Univariate regression and multivariable logistic regression analysis were conducted to evaluate the correlation between CDAI and MAFLD. We performed subgroup analysis to study the correlation in various populations. Results: A total of 18,163 participants, including 13,969 MAFLD and 4,194 non-MAFLD, were included. CDAI was significantly negatively correlated with MAFLD. After adjusting for all confounders (including age, gender, race, marital status, poverty ratio, education level, drinking status, smoking status, and physical activity), individuals in the highest quartile of CDAI exhibited a 27% lower likelihood of developing MAFLD than those in the lowest quartile (OR = 0.73; 95% CI [0.66, 0.81], p < 0.001). Physical activity subgroup analysis showed that this negative association was significant in the moderate-intensity physical exercise population (Model 3 in Q4, OR = 0.72; 95% CI [0.58–0.89], p < 0.001). Additionally, the changes in vitamins C were independently associated with MAFLD (Model 3, OR = 0.90; 95% CI [0.86–0.93], p < 0.001). Conclusions: We found a negative relationship between higher CDAI scores and MAFLD. This study provided a new reference for exploring dietary interventions that affect MAFLD to reduce its incidence. [ABSTRACT FROM AUTHOR]

The realm of hematopoietic stem cell transplantation (HSCT) has witnessed remarkable advancements in elevating the cure and survival rates for patients with both malignant and non-malignant hematologic diseases. Nevertheless, a considerable number of patients continue to face challenges, including transplant-related complications, infection, graft failure, and mortality. Inflammasomes, the multi-protein complexes of the innate immune system, respond to various danger signals by releasing inflammatory cytokines and even mediating cell death. While moderate activation of inflammasomes is essential for immune defense and homeostasis maintenance, excessive activation precipitates inflammatory damage. The intricate interplay between HSCT and inflammasomes arises from their pivotal roles in immune responses and inflammation. This review examines the molecular architecture and composition of various types of inflammasomes, highlighting their activation and effector mechanisms within the context of the HSCT process and its associated complications. Additionally, we summarize the therapeutic implications of targeting inflammasomes and related factors in HSCT. [ABSTRACT FROM AUTHOR]

Ovarian cancer (OC) remains one of the most lethal gynecological malignancies globally. Despite the implementation of various medical imaging approaches for OC screening, achieving accurate differential diagnosis of ovarian tumors continues to pose significant challenges due to variability in image performance, resulting in a lack of objectivity that relies heavily on the expertise of medical professionals. This challenge can be addressed through the emergence and advancement of radiomics, which enables high-throughput extraction of valuable information from conventional medical images. Furthermore, radiomics can integrate with genomics, a novel approach termed radiogenomics, which allows for a more comprehensive, precise, and personalized assessment of tumor biological features. In this review, we present an extensive overview of the application of radiomics and radiogenomics in diagnosing and predicting ovarian tumors. The findings indicate that artificial intelligence methods based on imaging can accurately differentiate between benign and malignant ovarian tumors, as well as classify their subtypes. Moreover, these methods are effective in forecasting survival rates, treatment outcomes, metastasis risk, and recurrence for patients with OC. It is anticipated that these advancements will function as decision-support tools for managing OC while contributing to the advancement of precision medicine. [ABSTRACT FROM AUTHOR]

Background: Despite a wealth of data from high-income countries, there is limited information on the distinct epidemiological patterns observed in diverse, densely populated regions within Latin America. This retrospective analysis of COVID-19's four major waves in Bogotá, Colombia, evaluates 1.77 million cases in detail. Methods: A comprehensive suite of statistical methods was employed. Transmission dynamics were assessed by estimating the instantaneous reproduction number R (t) , while variant-specific transmission advantages were estimated using multinomial logistic regression models. Disease severity was assessed through a suite of indicators: Hospitalisation Case Ratio (HCR), intensive care unit case ratio (ICU-CR), case fatality ratio (CFR), hospitalisation fatality ratio (HFR), and ICU fatality ratio (ICU-FR). Additionally, we analysed the distribution of hospitalisations, ICU admissions, and fatalities by age group and wave. We employed a Bayesian hierarchical model to capture epidemiological delays—such as onset-to-death, hospitalisation, and ICU admission durations to estimate hospital and ICU stay durations. Results: Our findings reveal substantial variation in R (t) , with peaks exceeding 2.5 during the ancestral and Omicron waves. Over the course of the pandemic, we observed a 78% reduction in CFR, underscoring shifts in clinical severity. The third wave, associated with the Mu variant, recorded the highest case and death counts, alongside a decreased CFR, an elevated HFR, and a shift in the most affected age group towards younger populations. In contrast, the fourth wave, driven by the Omicron variant, exhibited the highest reproduction number and the lowest overall severity. This wave was characterised by a significant increase in pediatric hospitalisations. The study reveals a continued decline in the mean durations of hospital and ICU stays across the four waves, with hospital stays decreasing from 10.84 to 7.85 days and ICU stays dropping from 16.2 to 12.4 days. Conclusions: This study reveals significant shifts in transmission and severity metrics—including mortality, hospitalisation, and ICU rates and stays—across age groups during Bogotá's four COVID-19 waves. These insights underscore the value of retrospective analyses to understand the pandemic's varied impact and inform public health strategies in diverse urban settings. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is the most aggressive primary brain tumor in adults, with a universally lethal prognosis despite maximal standard therapies. Here, we present a consensus treatment protocol based on the metabolic requirements of GBM cells for the two major fermentable fuels: glucose and glutamine. Glucose is a source of carbon and ATP synthesis for tumor growth through glycolysis, while glutamine provides nitrogen, carbon, and ATP synthesis through glutaminolysis. As no tumor can grow without anabolic substrates or energy, the simultaneous targeting of glycolysis and glutaminolysis is expected to reduce the proliferation of most if not all GBM cells. Ketogenic metabolic therapy (KMT) leverages diet-drug combinations that inhibit glycolysis, glutaminolysis, and growth signaling while shifting energy metabolism to therapeutic ketosis. The glucose-ketone index (GKI) is a standardized biomarker for assessing biological compliance, ideally via real-time monitoring. KMT aims to increase substrate competition and normalize the tumor microenvironment through GKI-adjusted ketogenic diets, calorie restriction, and fasting, while also targeting glycolytic and glutaminolytic flux using specific metabolic inhibitors. Non-fermentable fuels, such as ketone bodies, fatty acids, or lactate, are comparatively less efficient in supporting the long-term bioenergetic and biosynthetic demands of cancer cell proliferation. The proposed strategy may be implemented as a synergistic metabolic priming baseline in GBM as well as other tumors driven by glycolysis and glutaminolysis, regardless of their residual mitochondrial function. Suggested best practices are provided to guide future KMT research in metabolic oncology, offering a shared, evidence-driven framework for observational and interventional studies. [ABSTRACT FROM AUTHOR]

Introduction: The incidence of PCOS is notably elevated in Iran, making it crucial to examine the quality of life among these individuals. This study aimed to thoroughly evaluate the psychometric properties of the Iranian adaptations of the PCOSQoL-47 and PCOSQoL-42 questionnaires. The application of these tools is significant as they could enhance further research in in communities with similar social norms concerning marriage and sexuality. Methods: This study employed a cross-sectional design. Following the linguistic validation of the Iranian adaptation of the PCOSQoL-47 and PCOSQoL-42, a panel of experts reviewed the items through an evaluation of the content validity index (CVI) and content validity ratio (CVR). Subsequently, a semi-structured interview was carried out to evaluate face validity. Consequently, discriminant validity was assessed using the known groups comparison. Convergent validity was evaluated by assessing the correlation between similar content on the PCOSQoL-47 and PCOSQoL-42, SF-12 and body image questionnaire. Responsiveness was assessed by comparing two scales scoring in baseline and eight-week follow-up data of prescription contraceptive Daine-35. In addition, reliability analyses including internal consistency and test–retest analysis were carried out. Results: The CVR in this study for the total scale was 0.98 for two scales, indicating a satisfactory result. The CVI for the scale was found to be 0.98 and 0.99 for PCOSQoL-42 and PCOSQoL-47, respectively suggesting that it had a good content validity. Known groups comparison revealed that the two scales effectively distinguished between sub-groups of women with varying symptoms specific to PCOS, thereby supporting their discriminant validity. Additionally, convergent validity was evaluated and, as anticipated, a strong positive correlation was observed between corresponding subscales of the two instruments. The paired t-test showed significant changes in PCOSQoL-47 and PCOSQoL-42 scores (p < 0.001) indicating as a responsive outcome measure to detect significant changes over time before and after treatment. Additional analyses indicated satisfactory results of PCOSQoL-42 for internal consistency (Cronbach’s alpha ranging from 0.72 to 0.78) and intraclass correlation coefficients (ranging 0.67 to 0.92; P < 0.05). regarding PCOSQoL-47, Cronbach’s alpha ranging from 0.80 to 0.82 and intraclass correlation coefficients (ranging 0.61 to 0.73; P < 0.05). Conclusion: The PCOSQoL-47 and PCOSQoL-42 have undergone thorough testing in Iran and may be utilized as outcome measures in forthcoming studies within this demographic. [ABSTRACT FROM AUTHOR]

Medium chain fatty acids (MCFAs) are valuable platform compounds for the production of biotechnologically relevant chemicals such as biofuels and biochemicals. Two distinct pathways have been implemented in the yeast Saccharomyces cerevisiae for the biosynthetic production of MCFAs: (i) the mutant fatty acid biosynthesis (FAB) pathway in which the fatty acid synthase (FAS) complex is mutated and (ii) a heterologous multispecies-derived reverse β-oxidation (rBOX) pathway. Hexanoic acid has become of great interest as its acyl-CoA ester, hexanoyl-CoA, is required for the biosynthesis of olivetolic acid (OA), a cannabinoid precursor. Due to insufficient endogenous synthesis of hexanoyl-CoA, recombinant microbial systems to date require exogenous supplementation of cultures with hexanoate along with the overexpression of an acyl-CoA ligase to allow cannabinoid biosynthesis. Here, we engineer a recombinant S. cerevisiae strain which was metabolically optimized for the production of hexanoic acid via the FAB and rBOX pathways and we combine both pathways in a single strain to achieve titers of up to 120 mg L−1. Moreover, we demonstrate the biosynthesis of up to 15 mg L−1 OA from glucose using hexanoyl-CoA derived from the rBOX pathway. [ABSTRACT FROM AUTHOR]

In the absence of an effective vaccine or curative treatment for HIV, the global HIV/AIDS epidemic continues despite significant advances in treatment and prevention. Antiretroviral therapy (ART) drugs have transformed HIV from a terminal illness to a manageable chronic condition. Likewise, pre-exposure prophylaxis treatment (PrEP) has dramatically reduced transmission in some of the highest risk populations. However, quality of life and life expectancy in people living with HIV (PWH) still lag significantly behind the general population. The mechanisms that reduce the efficacy of PrEP and ART are multifaceted, but one factor that warrants additional attention is the impact of the microbiome on ART and PrEP efficacy, as well as pharmacokinetics more broadly. In this review, we assess the current state of research on the HIV-associated microbiome, how this impacts treatment efficacy, and how microbiome states can alter HIV susceptibility. We also explore how the mechanisms we propose could extend to the efficacy of other drugs and identify promising areas of research that remain understudied. 96-86NP6eG5MrMGBqL51qV Video Abstract [ABSTRACT FROM AUTHOR]

Background: Knowledge, attitudes, and practices related to oral health among parents play a crucial role in shaping oral hygiene and preventing early childhood caries. This study was intended to determine the effect of a neuroeducational strategy in improving knowledge, attitudes, and practices related to early childhood caries among mothers or caregivers of children. Methods: A quasi-experimental study was conducted, implementing an educational strategy involving 33 mothers or female caregivers of children who met specific selection criteria. The strategy consisted of three key elements derived from neuroeducation: (1) experiment, (2) surprise and play, and (3) learn. Based on the participants' attendance at the sessions, they were categorized into two groups: those who underwent in-person intervention (G1) and those who received a combined in-person and virtual intervention (G2). The impact of the strategy was evaluated by comparing the participants' knowledge and attitudes, as well as their children's plaque index, before and after the intervention (immediate and 6-month impact). Results: The participants exhibited a favorable and statistically significant effect on the median number of correct answers related to knowledge (G1 immediate effect (IE): p = 0.03, 6-month effect (ME): p = 0.002; G2 IE p = 0.002, ME: p = 0.001), and in the children's plaque index (G1 IE: p = 0.003, ME: p = 0.003; G2 IE: p = 0.033, ME: p = 0.003). Furthermore, there was an increase in the number of participants with a high level of knowledge (G1 IE: 41.5%; ME: 75%; G2 IE: 45.5%, ME: 42.9%), and of children with a good level of oral hygiene (G1 IE: 50%; ME: 73.0%; G2 IE: 27.3%, ME: 84.6%). Finally, qualitative interviews revealed a lasting clarity in concepts and sustained knowledge and attitudes at the six-month mark. However, a slightly diminished understanding of the relationship between bacteria, sugar, and caries was observed in G2 group, and some loss of association in the G1 group, at six months. Conclusion: The implementation of this strategy resulted in significant and lasting impacts on knowledge, attitudes, and practices, especially in the G1 group. Nevertheless, there is a need for further reinforcement of the association between bacteria, sugar, and caries. [ABSTRACT FROM AUTHOR]

Background: Cognitive impairments are prevalent across mood disorders and psychosis spectrum disorders, but there is a lack of real-life-like cognitive training programmes. Fully immersive virtual reality has the potential to ensure motivating and engaging cognitive training directly relevant to patients' daily lives. We will examine the effect of a 4-week, intensive virtual reality-based cognitive remediation programme involving daily life challenges on cognition and daily life functioning in patients with mood disorders or psychosis spectrum disorders and explore the neuronal underpinnings of potential treatment efficacy. Methods: The trial has a randomized, controlled, double-blinded, parallel-group design. We will include 66 symptomatically stable outpatients with mood disorders or psychosis spectrum disorders aged 18–55 years with objective and subjective cognitive impairment. Assessments encompassing a virtual reality test of daily life cognitive skills, neuropsychological testing, measures of daily life functioning, symptom ratings, questionnaires on subjective cognitive complaints, and quality of life are carried out at baseline, after the end of 4 weeks of treatment and at a 3-month follow-up after treatment completion. Functional magnetic resonance imaging scans are performed at baseline and at the end of treatment. The primary outcome is a broad cognitive composite score comprising five subtasks on a novel ecologically valid virtual reality test of daily life cognitive functions. Two complete data sets for 54 patients will provide a power of 80% to detect a clinically relevant between-group difference in the primary outcome. Behavioural data will be analysed using linear mixed models in SPSS, while MRI data will be analysed with the FMRIB Expert Analysis Tool (FEAT). Treatment-related changes in neural activity from baseline to end of treatment will be investigated for the dorsal prefrontal cortex and hippocampus as the regions of interest. Discussion: The results will provide insight into whether virtual reality-based cognitive remediation has beneficial effects on cognition and functioning in symptomatically stable patients with mood disorders or psychosis spectrum disorders, which can aid future treatment development. Trial registration: ClinicalTrials.gov NCT06038955. Registered on September 15, 2023. [ABSTRACT FROM AUTHOR]

Background: The tree shrew (Tupaia belangeri) is a promising emerging model organism in biomedical studies, notably due to their evolutionary proximity to primates. To enhance our understanding of how DNA methylation is implicated in regulation of gene expression and the X chromosome inactivation (XCI) in tree shrew brains, here we present their first genome-wide, single-base-resolution methylomes integrated with transcriptomes from prefrontal cortices. Results: Genome-wide relationships between DNA methylation and gene expression are consistent with those in other mammals. Interestingly, we observed a clear and significant global reduction (hypomethylation) of DNA methylation across the entire female X chromosome compared to male X. Female hypomethylation does not directly contribute to the gene silencing of the inactivated X chromosome nor does it significantly drive sex-specific gene expression in tree shrews. However, we identified a putative regulatory region in the 5′ end of the X-inactive-specific transcript (Xist) gene, whose pattern of differential DNA methylation strongly relate to its sex-differential expression in tree shrews. Furthermore, differential methylation of this region is conserved across different species. We also provide evidence suggesting that the observed difference between human and tree shrew X-linked promoter methylation is associated with the difference in genomic CpG contents. Conclusions: Our study offers novel information on genomic DNA methylation of tree shrews as well as insights into the evolution of sex chromosome regulation in mammals. Specifically, we show conserved role of DNA methylation in regulation of Xist expression and propose genomic CpG contents as a factor in driving sex-differential DNA methylation of X-linked promoters. [ABSTRACT FROM AUTHOR]

Background: Globally, diabetic kidney disease (DKD) has become the leading cause of end-stage renal disease, imposing substantial social and economic costs. This meta-analysis was designed to provide valuable insights into gene-disease interactions by investigating the potential association between lipid metabolism gene polymorphisms and the risk of DKD. Methods: An electronic literature search was conducted on MEDLINE Complete, Web of Science, Embase, and PubMed. A total of 18 studies on the peroxisome proliferator-activated receptor γ (PPARγ) Pro12Ala variant and 20 publications concerning apolipoprotein E (ApoE) gene polymorphism were included in the meta-analysis. Results: Overall, the PPARγ Pro12Ala polymorphism was found to be significantly associated with a decreased DKD risk (OR = 0.74, 95% CI: 0.62–0.88). In subgroup analysis, Ala carriers were less susceptible to DKD than Pro homozygotes among Asian (OR = 0.73, 95% CI: 0.56–0.95) and Caucasian populations (OR = 0.74, 95% CI: 0.59–0.93). Subgroup analysis stratified by albuminuria categories showed that the PPARγ Pro12Ala polymorphism reduced the risk of both microalbuminuria and macroalbuminuria with corresponding ORs of 0.58 (95% CI: 0.43–0.78) and 0.68 (95% CI: 0.53–0.86). Sensitivity analysis confirmed the robustness of the meta-analysis results. However, publication bias was identified in the subgroup analysis of the Caucasian population. The primary analysis of the ApoE gene polymorphism yielded significant findings, indicating that ApoE ε2/ε2, ApoE ε2/ε3, and ApoE ε2/ε4 genotypes increase the risk of DKD (ε2/ε2 vs. ε3/ε3: OR = 1.93, 95% CI: 1.03–3.61; ε2/ε3 vs. ε3/ε3: OR = 1.63, 95% CI: 1.19–2.25; ε2/ε4 vs. ε3/ε3: OR = 1.87, 95% CI: 1.37–2.55). However, sensitivity analysis suggested that influential and Hardy-Weinberg equilibrium (HWE)-violating studies may impact the overall effect estimates. Conclusions: A meta-analysis showed that PPARγ gene polymorphism may be a protective factor for DKD, whereas the ApoE ε2/ε2, ApoE ε2/ε3, and ApoE ε2/ε4 genotypes are associated with an increased risk of DKD. However, the role of ApoE gene polymorphism in susceptibility to DKD is less certain and requires further evaluation. [ABSTRACT FROM AUTHOR]

Antibodies are essential to immune homeostasis due to their roles in neutralizing pathogenic agents. However, failures in central and peripheral checkpoints that eliminate autoreactive B cells can undermine self-tolerance and generate autoantibodies that mistakenly target self-antigens, leading to inflammation and autoimmune diseases. While autoantibodies are well-studied in autoimmune and in some communicable diseases, their roles in chronic conditions, such as obesity and aging, are less understood. Obesity and aging share similar aspects of immune dysfunction, such as diminished humoral responses and heightened chronic inflammation, which can disrupt immune tolerance and foster autoantigen production, thus giving rise to autoreactive B cells and autoantibodies. In return, these events may also contribute to the pathophysiology of obesity and aging, to the associated autoimmune disorders linked to these conditions, and to the development of immunosenescence, an age-related decline in immune function that heightens vulnerability to infections, chronic diseases, and loss of self-tolerance. Furthermore, the cumulative exposure to antigens and cellular debris during obesity and aging perpetuates pro-inflammatory pathways, linking immunosenescence with other aging hallmarks, such as proteostasis loss and mitochondrial dysfunction. This review examines the mechanisms driving autoantibody generation during obesity and aging and discusses key putative antigenic targets across these conditions. We also explore the therapeutic potential of emerging approaches, such as CAR-T/CAAR-T therapies, vaccines, and BiTEs, to tackle autoimmune-related conditions in aging and obesity. [ABSTRACT FROM AUTHOR]

AKT, or protein kinase B, is a central node of the PI3K signaling pathway that is pivotal for a range of normal cellular physiologies that also underlie several pathological conditions, including inflammatory and autoimmune diseases, overgrowth syndromes, and neoplastic transformation. These pathologies, notably cancer, arise if either the activity of AKT or its positive or negative upstream or downstream regulators or effectors goes unchecked, superimposed on by its intersection with a slew of other pathways. Targeting the PI3K/AKT pathway is, therefore, a prudent countermeasure. AKT inhibitors have been tested in many clinical trials, primarily in combination with other drugs. While some have recently garnered attention for their favorable profile, concern over resistance and off-target effects have continued to hinder their widespread adoption in the clinic, mandating a discussion on alternative modes of targeting. In this review, we discuss isoform-centric targeting that may be more effective and less toxic than traditional pan-AKT inhibitors and its significance for disease prevention and treatment, including immunotherapy. We also touch on the emerging mutant- or allele-selective covalent allosteric AKT inhibitors (CAAIs), as well as indirect, novel AKT-targeting approaches, and end with a briefing on the ongoing quest for more reliable biomarkers predicting sensitivity and response to AKT inhibitors, and their current state of affairs. [ABSTRACT FROM AUTHOR]

Background: Achieving sustainability in continuing medical education (CME) involves regular assessment of the evolving needs of healthcare professionals regarding their competencies and updates in educational content accordingly. This study aimed to investigate the key areas and competencies that physicians in Serbia prioritize for their professional development and to analyze the factors associated with these competencies. Method: This cross-sectional study was conducted among 2,625 physicians who are members of the medical chamber in Serbia. Besides similar studies, the Delphi process among medical experts served to create the research instruments, while obtained data were analyzed using factor analysis and robust regression analysis. Results: The results pointed to a significant association between the scores in all identified domains (management, clinical practice, communication, public health, essentials and clinical emergency) and female gender. The score in the communication domain was additionally associated with work in privately owned institutions (B = 0.563). The scores in the public health domain and the basic medical skills (essentials domain) were additionally associated with age (B = 0.077 and B = 0.100), work in a primary healthcare institution (B = 2.327 and B = 2.155) and being a specialist (B=-1.795 and B=-2.901). The score on the clinical emergency domain, besides the female gender, was associated with work in primary health care (B = 0.748), being a specialist (B=-1.592) and being a subspecialist (B=-1.023). Conclusion: This research identified gaps in CME/CPD program knowledge and design. It outlined competency groups developed with expert consensus. Proposed actions include integrating key competencies and developing online self-assessment tools for everyday practice. This can help physicians and program organizers focus on essential competencies and exclude non-evidence-based ones. [ABSTRACT FROM AUTHOR]

Nuclear clearance and cytoplasmic aggregation of TAR DNA-binding protein of 43 kDa (TDP-43) are pathological hallmarks of amyotrophic lateral sclerosis (ALS) and its pathogenic mechanism is mediated by both loss-of-function and gain-of-toxicity of TDP-43. However, the role of TDP-43 gain-of-toxicity in oligodendrocytes remains unclear. To investigate the impact of excess TDP-43 on oligodendrocytes, we established transgenic mice overexpressing the ALS-linked mutant TDP-43M337V in oligodendrocytes through crossbreeding with Mbp-Cre mice. Two-step crossbreeding of floxed TDP-43M337V and Mbp-Cre mice resulted in the heterozygous low-level systemic expression of TDP-43M337V with (Cre-positive) or without (Cre-negative) oligodendrocyte-specific overexpression of TDP-43M337V. Although Cre-negative mice also exhibit subtle motor dysfunction, TDP-43M337V overexpression in oligodendrocytes aggravated clasping signs and gait disturbance accompanied by myelin pallor in the corpus callosum and white matter of the lumbar spinal cord in Cre-positive mice. RNA sequencing analysis of oligodendrocyte lineage cells isolated from whole brains of 12-month-old transgenic mice revealed downregulation of myelinating oligodendrocyte marker genes and cholesterol-related genes crucial for myelination, along with marked upregulation of apoptotic pathway genes. Immunofluorescence staining showed cleaved caspase 3–positive apoptotic oligodendrocytes surrounded by activated microglia and astrocytes in aged transgenic mice. Collectively, our findings demonstrate that an excess amount of ALS-linked mutant TDP-43 expression in oligodendrocytes exacerbates motor dysfunction in mice, likely through oligodendrocyte dysfunction and neuroinflammation. Therefore, targeting oligodendrocyte protection, particularly through ameliorating TDP-43 pathology, could represent a potential therapeutic approach for ALS. [ABSTRACT FROM AUTHOR]

Background: Reminders via digital technology offer a novel and efficient means to address medication forgetfulness, as they are easily accessible and user-friendly for patients. In particular mobile text message reminders are more suitable for chronic patients, as they require few technical skills, can operate without internet connectivity, and are less expensive than other technologies. This study aimed to assess the intention to use mobile text message reminders for medication adherence among hypertensive patients at the Gondar City health facilities. Methods: A facility-based cross-sectional study was conducted. A simple random sampling method was used to select 423 hypertensive patients. Data was collected from April 1 to May 15, 2023. Data was collected using Kobo Toolbox, and the collected data was exported to MS Excel. Subsequently, the data was imported and analyzed using the SPSS version 20. Binary and multivariable logistic regression analysis was employed to assess factors associated with the outcome variable. Result: The finding indicates that 64.5% of the patients have an Intention to use mobile text message reminders for medication adherence. Perceived usefulness (AOR = 2.53: 95%CI: 1.41, 4.52), perceived ease of use (AOR = 3.28: 95% CI: 1.81, 5.95), forgetting to take medication (AOR = 2.20: 95%CI: 1.38, 3.50) and patient holds their mobile phone always (AOR = 1.96: 95%CI: 1.04, 3.68) were associated factors with outcome variable. Conclusion: Forget taking medication, the patient holds their mobile phone always, Perceived ease of use and Perceived usefulness were significantly associated with the outcome variable. We recommend designing and implementing user-friendly text message reminder systems and educating hypertensive patients about the system's benefits. [ABSTRACT FROM AUTHOR]