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BACKGROUND: Concomitant use of clopidogrel and proton pump inhibitor (PPI) is common, but PPI may reduce the antiplatelet effects of clopidogrel in patients undergoing percutaneous coronary intervention (PCI). We evaluated the impact of PPI use on clinical outcomes in post-PCI patients, by incorporating P2Y12 reaction unit (PRU) and CYP2C19 genotyping results. METHODS: From a multicenter registry of patients who underwent PCI with drug-eluting stent implantation and received clopidogrel-based dual antiplatelet therapy (DAPT), patients who were prescribed a PPI at the time of PCI (PPI users) were compared to those who were not (non-users). The primary outcome included all-cause death, myocardial infarction, stent thrombosis, or cerebrovascular accident at 12 months. Major bleeding (Bleeding Academic Research Consortium [BARC] types 3-5) and gastrointestinal (GI) bleeding (BARC types 3-5) were important secondary outcomes. The adjusted outcomes were compared using a 1:1 propensity-score (PS) matching and competing risk analysis. RESULTS: Of 13,160 patients, 2,235 (17.0%) were prescribed PPI, with an average age of 65.4 years. PPI users had higher on-treatment PRU levels than non-users. After PS matching, the primary outcome occurred in 51 patients who were PPI users (cumulative incidence, 4.7%) and 41 patients who were non-users (cumulative incidence, 3.7%; log-rank p = 0.27). In carriers of both CYP2C19 loss-of-function alleles, PPI use was linked to an increased risk of the primary outcome (hazard ratio, 3.22; 95% confidence interval, 1.18-8.78). The incidence of major bleeding and GI bleeding (BARC types 3-5) was comparable between PPI users and non-users in the PS-matched cohort. CONCLUSIONS: In post-PCI patients receiving clopidogrel-based DAPT, PPI use was not linked to an increased risk of adverse cardiac and cerebrovascular events, but there was a small but significant increase in on-treatment PRU. Future research using a more individualized approach would further elucidate these interactions and guide evidence-based clinical practices.
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Clopidogrel , Citocromo P-450 CYP2C19 , Stents Liberadores de Fármacos , Intervención Coronaria Percutánea , Inhibidores de Agregación Plaquetaria , Inhibidores de la Bomba de Protones , Humanos , Clopidogrel/uso terapéutico , Clopidogrel/efectos adversos , Clopidogrel/administración & dosificación , Inhibidores de la Bomba de Protones/efectos adversos , Inhibidores de la Bomba de Protones/uso terapéutico , Inhibidores de la Bomba de Protones/administración & dosificación , Masculino , Femenino , Stents Liberadores de Fármacos/efectos adversos , Anciano , Persona de Mediana Edad , Inhibidores de Agregación Plaquetaria/uso terapéutico , Inhibidores de Agregación Plaquetaria/efectos adversos , Inhibidores de Agregación Plaquetaria/administración & dosificación , Intervención Coronaria Percutánea/efectos adversos , Citocromo P-450 CYP2C19/genética , Resultado del Tratamiento , Sistema de Registros , Pueblos del Este de AsiaRESUMEN
BACKGROUND: Despite a plethora of research on the topic, there is still no solid evidence that pharmacological treatment actually reduces the risk of suicide in patients with mental illness. In this study, we aimed to assess the effect of psychotropic medications on suicidal ideation in patients with major depressive disorder (MDD) and bipolar disorder (BPD) in two age groups: less than 25 years and 25 years and older. METHODS: We analyzed 312 patients with mood disorders with current suicidal thoughts or recent suicide attempts. We followed the participants from baseline for 6 months and assessed changes in suicidal ideation with Columbia-Suicide Severity Rating Scale (C-SSRS). The effect of psychotropic drug administration on suicidal ideation over time was analyzed using a linear mixed model. RESULTS: In patients aged 25 years and older with mood disorders, suicidal ideation was more severe when using psychotropic drugs than when not using them. However, suicidal ideation decreased rapidly over time. The time-dependent reduction in suicidal ideation was accelerated when using antidepressants and sedatives/hypnotics in adult MDD, and when using mood stabilizers in adult BPD. However, this effect was not observed in participants aged less than 25 years. CONCLUSION: Adequate psychotropic medication may reduce suicidal ideation in patients with mood disorders aged 25 years and older. Additional research on psychotropic drugs is needed to effectively reduce the risk of suicide among children and adolescents with mood disorders.
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Trastorno Bipolar , Trastorno Depresivo Mayor , Psicotrópicos , Ideación Suicida , Humanos , Adulto , Masculino , Femenino , Estudios Prospectivos , Psicotrópicos/uso terapéutico , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Mayor/psicología , Trastorno Bipolar/tratamiento farmacológico , Trastorno Bipolar/psicología , Adulto Joven , Antidepresivos/uso terapéutico , Trastornos del Humor/tratamiento farmacológico , Trastornos del Humor/psicología , Persona de Mediana Edad , Intento de Suicidio/psicología , Adolescente , Factores de TiempoRESUMEN
Bacteria are ideal anticancer agents and carriers due to their unique capabilities that are convenient in genetic manipulation, tumor-specific targeting, and deep-tissue penetration. However, the specific molecular mechanisms of bacteria-mediated cancer therapy (BMCT) have not been clarified. In this study, we found that TLR4 signaling pathway is critical for Salmonella-mediated tumor targeting, tumor suppression, and liver and spleen protection. TLR4 knockout in mice decreased the levels of cytokines and chemokines, such as S100a8, S100a9, TNF-α, and IL-1ß, in tumor microenvironments (TMEs) after Salmonella treatment, which inhibited tumor cell death and nutrient release, led to reduced bacterial contents in tumors and attenuated antitumor efficacy in a negative feedback manner. Importantly, we found that S100a8 and S100a9 played a leading role in Salmonella-mediated cancer therapy (SMCT). The antitumor efficacy was abrogated and liver damage was prominent when blocked with a specific inhibitor. These findings elucidated the mechanism of Salmonella-mediated tumor targeting, suppression, and host antibacterial defense, providing insights into clinical cancer therapeutics.
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Synergistic combinations of immunotherapeutic agents can improve the performance of anti-cancer therapies but may lead to immune-mediated adverse effects. These side-effects can be overcome by using a tumor-specific delivery system. Here, we report a method of targeted immunotherapy using an attenuated Salmonella typhimurium (SAM-FC) engineered to release dual payloads: cytolysin A (ClyA), a cytolytic anti-cancer agent, and Vibrio vulnificus flagellin B (FlaB), a potent inducer of anti-tumor innate immunity. Localized secretion of ClyA from SAM-FC induces immunogenic cancer cell death and promotes release of tumor-specific antigens and damage-associated molecular patterns, which establish long-term antitumor memory. Localized secretion of FlaB promotes phenotypic and functional remodeling of intratumoral macrophages that markedly inhibits tumor metastasis in mice bearing tumors of mouse and human origin. Both primary and metastatic tumors from bacteria-treated female mice are characterized by massive infiltration of anti-tumorigenic innate immune cells and activated tumor-specific effector/memory T cells; however, the percentage of immunosuppressive cells is low. Here, we show that SAM-FC induces functional reprogramming of the tumor immune microenvironment by activating both the innate and adaptive arms of the immune system and can be used for targeted delivery of multiple immunotherapeutic payloads for the establishment of potent and long-lasting antitumor immunity.
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Inmunoterapia , Salmonella typhimurium , Microambiente Tumoral , Animales , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología , Salmonella typhimurium/inmunología , Salmonella typhimurium/efectos de los fármacos , Femenino , Ratones , Humanos , Inmunoterapia/métodos , Línea Celular Tumoral , Inmunidad Innata/efectos de los fármacos , Ratones Endogámicos C57BL , Flagelina/inmunología , Vibrio vulnificus/inmunología , Vibrio vulnificus/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/efectos de los fármacos , Neoplasias/inmunología , Neoplasias/terapia , Neoplasias/tratamiento farmacológico , Antineoplásicos/farmacología , Antineoplásicos/administración & dosificaciónRESUMEN
BACKGROUND: Owing to the lack of understanding of the clinical significance of pericardial calcification during pericardiectomy, whether pericardial calcification should be considered when determining the optimal timing for pericardiectomy is debatable. We aimed to investigate the effect of pericardial calcification on early postoperative outcomes in patients who underwent pericardiectomy for constrictive pericarditis. METHODS: Altogether, 44 patients who underwent pericardiectomy for constrictive pericarditis were enrolled. After excluding three patients who underwent concurrent surgeries, a total of 41 patients were categorized into two groups based on the presence of pericardial calcification as determined by preoperative computed tomography and pathological examination. Preoperative clinical and imaging characteristics, intraoperative data, and early postoperative outcomes were compared between the two groups. A multivariable analysis was performed to identify the factors associated with postoperative complications. RESULTS: The group with and without PC comprised 21 and 20 patients, respectively. No significant differences were observed in 30-day mortality (n = 1 [5%]) in the group with pericardial calcification and no mortality in the group without pericardial calcification (p > 0.999). Other early postoperative outcome variables did not demonstrate any significant differences between the two groups. However, the use of cardiopulmonary bypass was associated with postoperative complications (p < 0.009, odds ratio: 63.5, 95% confidence interval: 5.13-3400). CONCLUSIONS: Pericardial calcification did not significantly affect the postoperative outcomes after pericardiectomy. Further comprehensive studies, including those with larger sample sizes and longitudinal designs, are necessary to determine whether pericardial calcification can significantly influence the timing of surgical intervention.
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Calcinosis , Pericardiectomía , Pericarditis Constrictiva , Pericardio , Complicaciones Posoperatorias , Humanos , Masculino , Femenino , Pericardiectomía/efectos adversos , Estudios Retrospectivos , Calcinosis/cirugía , Persona de Mediana Edad , Pericarditis Constrictiva/cirugía , Resultado del Tratamiento , Tomografía Computarizada por Rayos X , Anciano , AdultoRESUMEN
Artificial intelligence (AI) is transforming spinal imaging and patient care through automated analysis and enhanced decision-making. This review presents a clinical task-based evaluation, highlighting the specific impact of AI techniques on different aspects of spinal imaging and patient care. We first discuss how AI can potentially improve image quality through techniques like denoising or artifact reduction. We then explore how AI enables efficient quantification of anatomical measurements, spinal curvature parameters, vertebral segmentation, and disc grading. This facilitates objective, accurate interpretation and diagnosis. AI models now reliably detect key spinal pathologies, achieving expert-level performance in tasks like identifying fractures, stenosis, infections, and tumors. Beyond diagnosis, AI also assists surgical planning via synthetic computed tomography generation, augmented reality systems, and robotic guidance. Furthermore, AI image analysis combined with clinical data enables personalized predictions to guide treatment decisions, such as forecasting spine surgery outcomes. However, challenges still need to be addressed in implementing AI clinically, including model interpretability, generalizability, and data limitations. Multicenter collaboration using large, diverse datasets is critical to advance the field further. While adoption barriers persist, AI presents a transformative opportunity to revolutionize spinal imaging workflows, empowering clinicians to translate data into actionable insights for improved patient care.
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Objectives: In this functional magnetic resonance imaging study, we aimed to investigate the differences in brain activation between individuals with autism spectrum disorder (ASD) and typically developing (TD) individuals during perspective taking. We also examined the association between brain activation and empathic and interoceptive abilities. Methods: During scanning, participants from the ASD (n=17) and TD (n=22) groups were shown pain stimuli and asked to rate the level of the observed pain from both self- and other-perspectives. Empathic abilities, including perspective taking, were measured using an empathic questionnaire, and three dimensions of interoception were assessed: interoceptive accuracy, interoceptive sensibility, and interoceptive trait prediction errors. Results: During self-perspective taking, the ASD group exhibited greater activation in the left precuneus than the TD group. During other-perspective taking, relative hyperactivation extended to areas including the right precuneus, right superior frontal gyrus, left caudate nucleus, and left amygdala. Brain activation levels in the right superior frontal gyrus while taking other-perspective were negatively correlated with interoceptive accuracy, and those in the left caudate were negatively correlated with perspective taking ability in the ASD group. Conclusion: Individuals with ASD show atypical brain activation during perspective taking. Notably, their brain regions associated with stress reactions and escape responses are overactivated when taking other-perspective. This overactivity is related to poor interoceptive accuracy, suggesting that individuals with ASD may experience difficulties with the self-other distinction or atypical embodiment when considering another person's perspective.
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Background: Accurate medical advice is paramount in ensuring optimal patient care, and misinformation can lead to misguided decisions with potentially detrimental health outcomes. The emergence of large language models (LLMs) such as OpenAI's GPT-4 has spurred interest in their potential health care applications, particularly in automated medical consultation. Yet, rigorous investigations comparing their performance to human experts remain sparse. Objective: This study aims to compare the medical accuracy of GPT-4 with human experts in providing medical advice using real-world user-generated queries, with a specific focus on cardiology. It also sought to analyze the performance of GPT-4 and human experts in specific question categories, including drug or medication information and preliminary diagnoses. Methods: We collected 251 pairs of cardiology-specific questions from general users and answers from human experts via an internet portal. GPT-4 was tasked with generating responses to the same questions. Three independent cardiologists (SL, JHK, and JJC) evaluated the answers provided by both human experts and GPT-4. Using a computer interface, each evaluator compared the pairs and determined which answer was superior, and they quantitatively measured the clarity and complexity of the questions as well as the accuracy and appropriateness of the responses, applying a 3-tiered grading scale (low, medium, and high). Furthermore, a linguistic analysis was conducted to compare the length and vocabulary diversity of the responses using word count and type-token ratio. Results: GPT-4 and human experts displayed comparable efficacy in medical accuracy ("GPT-4 is better" at 132/251, 52.6% vs "Human expert is better" at 119/251, 47.4%). In accuracy level categorization, humans had more high-accuracy responses than GPT-4 (50/237, 21.1% vs 30/238, 12.6%) but also a greater proportion of low-accuracy responses (11/237, 4.6% vs 1/238, 0.4%; P=.001). GPT-4 responses were generally longer and used a less diverse vocabulary than those of human experts, potentially enhancing their comprehensibility for general users (sentence count: mean 10.9, SD 4.2 vs mean 5.9, SD 3.7; P<.001; type-token ratio: mean 0.69, SD 0.07 vs mean 0.79, SD 0.09; P<.001). Nevertheless, human experts outperformed GPT-4 in specific question categories, notably those related to drug or medication information and preliminary diagnoses. These findings highlight the limitations of GPT-4 in providing advice based on clinical experience. Conclusions: GPT-4 has shown promising potential in automated medical consultation, with comparable medical accuracy to human experts. However, challenges remain particularly in the realm of nuanced clinical judgment. Future improvements in LLMs may require the integration of specific clinical reasoning pathways and regulatory oversight for safe use. Further research is needed to understand the full potential of LLMs across various medical specialties and conditions.
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Inteligencia Artificial , Cardiología , Humanos , Cardiología/normasRESUMEN
BACKGROUND AND OBJECTIVES: Lipid lowering therapy is essential to reduce the risk of major cardiovascular events; however, limited evidence exists regarding the use of statin with ezetimibe as primary prevention strategy for middle-aged adults. We aimed to investigate the impact of single pill combination therapy on clinical outcomes in relatively healthy middle-aged patients when compared with statin monotherapy. METHODS: Using the Korean National Health Insurance Service database, a propensity score match analysis was performed for baseline characteristics of 92,156 patients categorized into combination therapy (n=46,078) and statin monotherapy (n=46,078) groups. Primary outcome was composite outcomes, including death, coronary artery disease, and ischemic stroke. And secondary outcome was all-cause death. The mean follow-up duration was 2.9±0.3 years. RESULTS: The 3-year composite outcomes of all-cause death, coronary artery disease, and ischemic stroke demonstrated no significant difference between the 2 groups (10.3% vs. 10.1%; hazard ratio (HR), 1.022; 95% confidence interval [CI], 0.980-1.064; p=0.309). Meanwhile, the 3-year all-cause death rate was lower in the combination therapy group than in the statin monotherapy group (0.2% vs. 0.4%; p<0.001), with a significant HR of 0.595 (95% CI, 0.460-0.769; p<0.001). Single pill combination therapy exhibited consistently lower mortality rates across various subgroups. CONCLUSIONS: Compared to the statin monotherapy, the combination therapy for primary prevention showed no difference in composite outcomes but may reduce mortality risk in relatively healthy middle-aged patients. However, since the study was observational, further randomized clinical trials are needed to confirm these findings.
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BACKGROUND: This study examined the efficacy of del Nido cardioplegia compared with traditional blood cardioplegia in adult cardiac surgery for isolated coronary artery bypass grafting by evaluating the early postoperative outcomes. METHODS: A total of 119 patients who underwent isolated conventional coronary artery bypass grafting were enrolled and divided into two groups (del Nido cardioplegia group [n = 36] and blood cardioplegia group [n = 50]) based on the type of cardioplegia used. This study compared the preoperative characteristics, intraoperative data, and early postoperative outcomes. Further subgroup analyses were conducted for high-risk patient groups. RESULTS: The 30-day mortality and morbidity rates were not significantly different between groups. The del Nido cardioplegia group exhibited advantageous myocardial protection outcomes, demonstrated by a significantly smaller rise in Troponin I levels post-surgery (2.8 [-0.4; 4.2] vs. 4.5 [2.9; 7.4] ng/mL, p = 0.004) and fewer defibrillation attempts during weaning off of cardiopulmonary bypass (0.0 ± 0.2 vs. 0.4 ± 1.1 times, p = 0.011) when compared to the blood cardioplegia group. Additionally, the del Nido group achieved a reduction in surgery duration, as evidenced by the reduced aortic cross-clamping time (64.0 [55.5; 75.5] vs. 77.5 [65.0; 91.0] min, p = 0.001) and total operative time (287.5 [270.0; 305.0] vs. 315.0 [285.0; 365.0] min, p = 0.008). Subgroup analyses consistently demonstrated that the del Nido cardioplegia group had a significantly smaller postoperative increase in Troponin I levels across all subgroups (p < 0.05). CONCLUSIONS: del Nido cardioplegia provided myocardial protection and favorable early postoperative outcomes compared to blood cardioplegia, making it a viable option for conventional coronary artery bypass grafting. Establishing a consensus on the protocol for Del Nido cardioplegia administration in adult surgeries is needed.
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Soluciones Cardiopléjicas , Puente de Arteria Coronaria , Paro Cardíaco Inducido , Humanos , Paro Cardíaco Inducido/métodos , Puente de Arteria Coronaria/métodos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Estudios Retrospectivos , Resultado del Tratamiento , Complicaciones Posoperatorias/prevención & control , Enfermedad de la Arteria Coronaria/cirugía , Troponina I/sangre , Cloruro de Potasio , Manitol , Lidocaína , Soluciones , Electrólitos , Sulfato de Magnesio , Bicarbonato de SodioRESUMEN
Despite previous efforts to build statistical models for predicting the risk of suicidal behavior using machine-learning analysis, a high-accuracy model can lead to overfitting. Furthermore, internal validation cannot completely address this problem. In this study, we created models for predicting the occurrence of suicide attempts among Koreans at high risk of suicide, and we verified these models in an independent cohort. We performed logistic and penalized regression for suicide attempts within 6 months among suicidal ideators and attempters in The Korean Cohort for the Model Predicting a Suicide and Suicide-related Behavior (K-COMPASS). We then validated the models in a test cohort. Our findings indicated that several factors significantly predicted suicide attempts in the models, including young age, suicidal ideation, previous suicidal attempts, anxiety, alcohol abuse, stress, and impulsivity. The area under the curve and positive predictive values were 0.941 and 0.484 after variable selection and 0.751 and 0.084 in the test cohort. The corresponding values for the penalized regression model were 0.943 and 0.524 in the original training cohort and 0.794 and 0.115 in the test cohort. The prediction model constructed through a prospective cohort study of the suicide high-risk group showed satisfactory accuracy even in the test cohort. The accuracy with penalized regression was greater than that with the "classical" logistic model.
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Aprendizaje Automático , Ideación Suicida , Intento de Suicidio , Humanos , Intento de Suicidio/estadística & datos numéricos , Masculino , Femenino , República de Corea/epidemiología , Adulto , Adulto Joven , Estudios Prospectivos , Modelos Logísticos , Persona de Mediana Edad , Adolescente , Factores de RiesgoRESUMEN
BACKGROUND: Altered thyroid hormone levels have been associated with increased risk of Alzheimer's disease (AD) dementia and related cognitive decline. However, the neuropathological substrates underlying the link between thyroid hormones and AD dementia are not yet fully understood. We first investigated the association between serum thyroid hormone levels and in vivo AD pathologies including both beta-amyloid (Aß) and tau deposition measured by positron emission tomography (PET). Given the well-known relationship between Aß and tau pathology in AD, we additionally examined the moderating effects of thyroid hormone levels on the association between Aß and tau deposition. METHODS: This cross-sectional study was conducted as part of the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer's Disease (KBASE) cohort. This study included a total of 291 cognitively normal adults aged 55 to 90. All participants received comprehensive clinical assessments, measurements for serum total triiodothyronine (T3), free triiodothyronine (fT3), free thyroxine (fT4), and thyroid-stimulating hormone (TSH), and brain imaging evaluations including [11C]-Pittsburgh compound B (PiB)- PET and [18F] AV-1451 PET. RESULTS: No associations were found between either thyroid hormones or TSH and Aß and tau deposition on PET. However, fT4 (p = 0.002) and fT3 (p = 0.001) exhibited significant interactions with Aß on tau deposition: The sensitivity analyses conducted after the removal of an outlier showed that the interaction effect between fT4 and Aß deposition was not significant, whereas the interaction between fT3 and Aß deposition remained significant. However, further subgroup analyses demonstrated a more pronounced positive relationship between Aß and tau in both the higher fT4 and fT3 groups compared to the lower group, irrespective of outlier removal. Meanwhile, neither T3 nor TSH had any interaction with Aß on tau deposition. CONCLUSION: Our findings suggest that serum thyroid hormones may moderate the relationship between cerebral Aß and tau pathology. Higher levels of serum thyroid hormones could potentially accelerate the Aß-dependent tau deposition in the brain. Further replication studies in independent samples are needed to verify the current results.
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Péptidos beta-Amiloides , Tomografía de Emisión de Positrones , Hormonas Tiroideas , Proteínas tau , Humanos , Masculino , Femenino , Anciano , Proteínas tau/sangre , Proteínas tau/metabolismo , Estudios Transversales , Hormonas Tiroideas/sangre , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/sangre , Persona de Mediana Edad , Anciano de 80 o más Años , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Encéfalo/patología , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Tiroxina/sangre , Tirotropina/sangre , Estudios de CohortesRESUMEN
Immunotherapy has revolutionized the treatment of cancer but continues to be constrained by limited response rates, acquired resistance, toxicities and high costs, which necessitates the development of new, innovative strategies. The discovery of a connection between the human microbiota and cancer dates back 4,000 years, when local infection was observed to result in tumour eradication in some individuals. However, the true oncological relevance of the intratumoural microbiota was not recognized until the turn of the twentieth century. The intratumoural microbiota can have pivotal roles in both the pathogenesis and treatment of cancer. In particular, intratumoural bacteria can either promote or inhibit cancer growth via remodelling of the tumour microenvironment. Over the past two decades, remarkable progress has been made preclinically in engineering bacteria as agents for cancer immunotherapy; some of these bacterial products have successfully reached the clinical stages of development. In this Review, we discuss the characteristics of intratumoural bacteria and their intricate interactions with the tumour microenvironment. We also describe the many strategies used to engineer bacteria for use in the treatment of cancer, summarizing contemporary data from completed and ongoing clinical trials. The work described herein highlights the potential of bacteria to transform the landscape of cancer therapy, bridging ancient wisdom with modern scientific innovation.
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Bacterias , Inmunoterapia , Neoplasias , Microambiente Tumoral , Humanos , Neoplasias/terapia , Neoplasias/inmunología , Neoplasias/microbiología , Inmunoterapia/métodos , Microambiente Tumoral/inmunología , Bacterias/inmunología , Microbiota/inmunologíaRESUMEN
Objective: The phenotypic heterogeneity and complex disease trajectory complicate the ability to predict specific clinical milestone for individual patients with amyotrophic lateral sclerosis (ALS). Here we developed individualized prediction models to estimate the time to the loss of autonomy in swallowing function. Methods: Utilizing the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database, we built three models of distinct time-to-event prediction algorithms: accelerated failure time (AFT), cox proportional hazard (COX) and random survival forest (RSF) for an individualized risk assessment of the swallowing milestone. The target variable was defined as the time to a decline in the ALSFRS-R swallowing item score to 1 or below, indicating a need for supplementary tube feeding. Results: Internal cross-validation revealed the median concordance index (C-index) of 0.851 (IQR, 0.842-0.859) for AFT, 0.850 (0.841-0.859) for COX and 0.846 (0.839-0.854) for RSF, and all models demonstrated good distributional calibration with predicted and observed event probabilities closely matched across different time intervals. For external validation with a registry dataset with characteristics different from PRO-ACT, the discriminative power was replicated with comparable C-indices for all models, whereas the calibration revealed a left-skewed distribution suggesting a bias towards overestimation of event probabilities in real-world data. While all models were effective at stratifying patients, the results of RSF model, unlike AFT and COX, did not match well with the KM curves of the corresponding risk groups, supporting the importance of nuanced understanding of data structure and algorithmic properties. Conclusion: Our models are implemented into a web application which could be applied to individualized counselling, management and clinical trial design for gastrostomy intervention. Further studies for model optimization will advance personalized care in patients with ALS.
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Deregulated cyclin-dependent kinase 5 (Cdk5) activity closely correlates with hyperphosphorylated tau, a common pathology found in neurodegenerative diseases. Previous postmortem studies had revealed increased Cdk5 immunoreactivity in amyotrophic lateral sclerosis (ALS); hence, we investigated the effects of Cdk5 inhibition on ALS model mice and neurons in this study. For the in vitro study, motor neuron cell lines with wild-type superoxide dismutase 1 (SOD1) or SOD1G93A and primary neuronal cultures from SOD1G93A transgenic (TG) mice or non-TG mice were compared for the expression of proteins involved in tau pathology, neuroinflammation, apoptosis, and neuritic outgrowth by applying Cdk5-small interfering RNA or Cdk5-short hairpin RNA (shRNA). For the in vivo study, SOD1G93A mice and non-TG mice were intrathecally injected with adeno-associated virus 9 (AAV9)-scramble (SCR)-shRNA or AAV9-Cdk5-shRNA at the age of 5 weeks. Weight and motor function were measured three times per week from 60 days of age, longevity was evaluated, and the tissues were collected from 90-day-old or 120-day-old mice. Neurons with SOD1G93A showed increased phosphorylated tau, attenuated neuritic growth, mislocalization of SOD1, and enhanced neuroinflammation and apoptosis, all of which were reversed by Cdk5 inhibition. Weights did not show significant differences among non-TG and SOD1G93A mice with or without Cdk5 silencing. SOD1G93A mice treated with AAV9-Cdk5-shRNA showed significantly delayed disease onset, delayed rotarod failure, and prolonged survival compared with those treated with AAV9-SCR-shRNA. The brain and spinal cord of SOD1G93A mice intrathecally injected with AAV9-Cdk5-shRNA exhibited suppressed tau pathology, neuroinflammation, apoptosis, and an increased number of motor neurons compared to those of SOD1G93A mice injected with AAV9-SCR-shRNA. Cdk5 inhibition could be an important mechanism in the development of a new therapeutic strategy for ALS.
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RATIONALE AND OBJECTIVES: Interpreting ankle stress radiographs is subjective and time-consuming. We aimed to train an AI model that efficiently screens negative cases, assess the agreement with expert with and without AI-assistance, and compare the workload reduction. MATERIAL AND METHODS: We collected anterior draw test (ADT) and talar tilt test (TTT) ankle stress radiographs from Seoul St. Mary's Hospital and St. Vincent's Hospital. Patients with prior surgery, severe joint fusion, or incomplete images were excluded. Expert measurements of tibio-talar distance (TTD) and tibio-talar angle (TTA) served as reference, defining positive labels as TTD ≥ 8.3 mm or TTA ≥ 6.2°. We trained a VGG16 model on data from hospital A and tested it on three separate test sets (testset1, 2 from St. Mary's Hospital, and testset3 from St. Vincent's Hospital). Three readers (expert, reader2, and the collective reading reports) evaluated the test sets, with and without AI-assistance (focusing only on AI-predicted positive cases). We measured agreement with the expert using Cohen's weighted Kappa and assessed the hypothetical workload reduction. RESULTS: AI-assistance did not significantly affect agreement with the expert for any reader in all test sets. Reader2 showed moderate-substantial agreement for all test sets, while collective reports reached fair agreement. The AI alone demonstrated fair to moderate agreement with the expert. AI-assistance reduced the hypothetical workload by 68.8-89.2% for ADT and 58.3-70.4% for TTT. CONCLUSION: We successfully trained an AI model for ankle stress radiography, achieving an average of 70% workload reduction while maintaining agreement with expert radiologists.
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The biogeographical range shift of insect pests is primarily governed by temperature. However, the range shift of seasonal long-distance migratory insects may be very different from that of sedentary insects. Nilaparvata lugens (BPH), a serious rice pest, can only overwinter in tropical-to-subtropical regions, and some populations migrate seasonally to temperate zones with the aid of low-level jet stream air currents. This study utilized the CLIMEX model to project the overwintering area under the climate change scenarios of RCP2.6 and RCP8.5, both in 2030s and 2080s. The overwintering boundary is predicted to expand poleward and new overwintering areas are predicted in the mid-latitude regions of central-to-eastern China and mid-to-southern Australia. With climate change, the habitable areas remained similar, but suitability decreased substantially, especially in the near-equatorial regions, owing to increasing heat stress. The range shift is similar between RCP2.6-2030s, RCP2.6-2080s, and RCP8.5-2030s, but extreme changes are projected under RCP8.5-2080s with marginal areas increasing from 27.2 to 38.8% and very favorable areas dropping from 27.5 to 3.6% compared to the current climate. These findings indicate that climate change will drive range shifts in BPH and alter regional risks differently. Therefore, international monitoring programs are needed to effectively manage these emerging challenges.