Therapy Research Articles

Beyond prevention: in silico designing a one-two punch novel therapeutic vaccine candidate against major oncoproteins of HPV 16, 18, 31, and 45 and subsequent cervical cancer

ABSTRACT The human papillomavirus (HPV) is the most prevalent viral sexually transmitted disease (STD). HPV 16, 18, 31 and 45 are most associated with the development of cervical cancer. Currently approved HPV vaccines are only preventive and have no therapeutic activity. With immunoinformatics approaches, we tried to design a novel vaccine against E6 and E7 oncoproteins of HPV 16, 18, 31 and 45 for the prevention and treatment of cervical cancer. The tertiary structure of the vaccine was modelled and validated. The vaccine was docked with TLR4 and TLR9 receptors, which have an undeniable anti-tumour immunity against cervical cancer. Molecular dynamic simulation indicates that the vaccine-TLR complexes were structurally stable. Immune stimulation and population coverage analysis results were much better than similar studies. Our new multi-epitope vaccine is the first HPV vaccine to target the E6 and E7 antigens of HPV 16, 18, 31 and 45. Also, this is the first study to target conserved regions of HPV and then merge the T and B cell epitopes as a regional epitope, which increases vaccine efficacy and reliability. We hope that the methodology of this study will even shed light on the design of vaccines against other viral STDs.

Modifiable Risk Factors for Subarachnoid Hemorrhage: Narrative Review With an Emphasis on Common Controversies and Epidemiologic Pitfalls.

Given the relatively low incidence, high prehospital death rate, substantial geographical differences, and complex disease origin (combination of genetic and environmental risk factors), epidemiologic research on subarachnoid hemorrhage (SAH) and its risk factors is challenging. In practice, we are more or less forced to exploit compromised study designs and nonrepresentative data in such circumstances where it is almost impossible to gather comprehensive data through an optimal design. For example, hospital-based patient cohorts, administrative data repositories, and short-term population-based studies from small geographical regions are often used to research the incidence, case fatality, and risk factors of SAH, regardless of their inherent and self-evident limitations. Since studies on the epidemiology of SAH focus largely on identifying possible risk factors that could aid in disease diagnostics, treatment, and prevention, we aimed to review recent evidence on modifiable risk factors for SAH. In this context, we also try to explain the methodological reasons behind some of the conflicting results and to discuss the primary strengths and limitations of different study designs used in the field of SAH epidemiology. Based on our findings, smoking, high blood pressure, and possibly low physical activity are the only risk factors with high-quality evidence supporting their causal role in SAH. In addition, since all 3 commonly used study designs in SAH epidemiology, namely, hospital-based, population-based, and administrative register-based studies, have their own strengths and limitations, the most robust risk factor estimates and other epidemiologic measures of SAH can likely be established by combining various overlapping and high-quality sources of information in the future.

Protective effect of Apelin-13 on oxygen and glucose deprivation induced-damage in retinal ganglion cells cultured in vitro.

Ischemic-anoxic injury plays an important role in the pathophysiology of diabetes retinopathy, optic neuropathy, even glaucoma and other ocular diseases. It may ultimately cause damage to neuronal death like retinal ganglion cells (RGCs) and subsequent visual loss. RGCs are essential elements of the retina and optic nerve that are crucial to visual formation. Ischemic-anoxic injury, inflammation, and oxidative stress are vital causes of RGC death. Thus, neuroprotection is essential for the treatment of these ocular diseases. Recent studies have shown the neuroprotective property of apelin-13 in many disease models. In this study, we isolated RGCs and found that apelin-13 promoted the viability of RGCs and increased the phosphorylation of Protein kinase B (PKB, Akt) in an in vitro oxygen-glucose deprivation model. Moreover, apelin-13 increased the expressions of glucose-6-phosphate dehydrogenase (G6PD) and nicotinamide adenine dinucleotide phosphate (NADPH) and reduced the level of reactive oxygen species (ROS). And, we also found that apelin-13 could promote the expressions of glucose transporter-1 (GLUT1) and adenosine triphosphate (ATP). These results indicated that apelin-13 could delay or stop RGC death, which might be as potential therapeutic targets for treatment of diseases mediated by ischemic-anoxic damage like diabetes retinopathy, optic neuropathy, even glaucoma.

Advances in Research on Meningeal Lymphatic Vessels in Central Nervous System Diseases.

Meningeal lymphatic vessels (mLVs), located around the dural sinuses, are considered significant participants in cerebrospinal fluid (CSF) circulation. Meningeal lymphatic vessels not only drain fluids and metabolic waste from the brain into deep cervical lymph nodes (dCLNs) but also transport immune cells from the brain to dCLNs, thus regulating the interaction between the central and peripheral immune systems. These vessels play a crucial role in maintaining normal physiological functions of the central nervous system (CNS). Meningeal lymphatic vessels are involved in the pathophysiological processes of various CNS diseases, including neurodegenerative diseases, cerebrovascular diseases, and brain tumors. In aging and various CNS diseases, damage and dysfunction of mLVs have been observed, leading to the abnormal accumulation of toxic substances and exacerbating neural damage. By transporting antigen-presenting cells that have taken up antigens within the brain to dCLNs, mLVs modulate the activation of peripheral immune cells and their migration and infiltration into brain lesions. Certain drug interventions or physical therapies can modulate the drainage function of mLVs, effectively improving the prognosis of CNS diseases. This review provides a detailed introduction to the anatomic structure, physiological roles, and research advances of mLVs in CNS diseases. In addition, we propose new strategies for targeting mLVs in the treatment of CNS diseases.

The Role of Exosomes in Myocardial Ischemia-Reperfusion Injury.

Acute myocardial infarction (AMI) is one of the critical and serious diseases in the cardiovascular system, and reperfusion therapy is the preferred treatment for AMI, but it often worsens cardiac injury and leads to myocardial ischemia reperfusion injury (MIRI), which can further result in arrhythmia, heart failure, and death. More and more studies have found that mesenchymal stem cells (MSCs)-derived exosomes play an important role in improving the cardiac injury after MIRI, and can exert anti-apoptosis, anti-inflammation, anti-fibrosis, and promotion of endothelial cells and angiogenesis functions. This review summarizes the mechanisms of action of exosomes in the treatment of MIRI and discusses exosomes as a new approach for the treatment of MIRI. 1) Exosomes play a variety of protective roles in MIRI by carrying miRNAs and other bioactive substances. 2) Exosomes can be used as carriers of drugs or active substances for the treatment of cardiovascular diseases.

Accelerated initiation of antiretroviral therapy by virtual health in service members newly diagnosed with HIV infection.

Delays in HIV antiretroviral therapy (ART) have been associated with HIV disease progression and forward transmission. We evaluated the effectiveness of an accelerated ART virtual protocol (VP) for active duty (AD) members with incident HIV diagnosis. Under the traditional protocol (TP), service members stationed worldwide were evaluated in-person at Brooke Army Medical Center (BAMC) and received comprehensive HIV care. In February 2020, a VP was adopted to initiate HIV care at the local base. Chart reviews were conducted to obtain patient demographics and clinical data. Continuous variables were compared using 2-tailed t tests, categorical variables were evaluated with Fisher's exact or Chi squared tests. Time from HIV notification to ART initiation was significantly shorter with the VP compared to the TP (15days vs 25days; p = <0.05). The VP had a shorter time to viral suppression compared to the TP (96days [SD ± 86] compared to 269 days [SD ± 300], p = <0.05). The VP was associated with a shorter time to HIV specialty evaluation, ART initiation, and viral suppression. The use of virtual health protocols for other time sensitive medical interventions and/or for access to limited specialties should be considered as these may improve quality of care.

Maintenance of Cardiac Microenvironmental Homeostasis: A Joint Battle of Multiple Cells.

Various cells such as cardiomyocytes, fibroblasts and endothelial cells constitute integral components of cardiac tissue. The health and stability of cardiac ecosystem are ensured by the action of a certain type of cell and the intricate interactions between multiple cell types. The dysfunctional cells exert a profound impact on the development of cardiovascular diseases by involving in the pathological process. In this paper, we introduce the dynamic activity, cell surface markers as well as biological function of the various cells in the heart. Besides, we discuss the multiple signaling pathways involved in the cardiac injury including Hippo/YAP, TGF-β/Smads, PI3K/Akt, and MAPK signaling. The complexity of different cell types poses a great challenge to the disease treatment. By characterizing the roles of various cell types in cardiovascular diseases, we sought to discuss the potential strategies for preventing and treating cardiovascular diseases.

Oblique Lumbar Interbody Fusion Combined With Anterolateral Fixation and Cement Augmentation for the Treatment of Degenerative Lumbar Diseases in the Elderly Population: A Retrospective Study.

Cage subsidence is a common complication of oblique lumbar interbody fusion (OLIF), particularly in elderly patients with osteoporosis or osteopenia. While bilateral pedicle screw fixation (BPS) is effective in reducing subsidence, it is associated with longer operative times, increased blood loss, and greater tissue trauma. In contrast, anterolateral fixation (AF) is less invasive but linked to higher subsidence rates. Ensuring both minimal invasiveness and adequate stability in OLIF-assisted fixation remains a significant challenge. This study aimed to evaluate the efficacy of combining AF with cement augmentation (AF + CA) in reducing cage subsidence and improving clinical outcomes compared with AF and BPS. A retrospective analysis was conducted on 138 elderly patients with degenerative lumbar diseases treated with OLIF. Patients were divided into three groups: AF + CA (32 patients), AF (32 patients), and BPS (74 patients). Clinical and radiographic outcomes were compared among the groups, and logistic regression analyses were performed to identify risk factors for cage subsidence after OLIF. At 1 year postoperatively, the disc height of the AF + CA group was significantly greater than that of the AF group. The cage subsidence rate in the AF + CA group was 24.3%, significantly lower than that in the AF group (48.8%, p < 0.05) and comparable to the BPS group (30.4%). Survivorship curve analysis showed better outcomes in reducing cage subsidence in theAF + CA group compared with the AF group, with no significant difference between the AF + CA and BPS groups. Compared with the AF + CA and BPS groups, the AF group had significantly higher grades and severity of cage subsidence. Fusion rates at 1 year were 91.9% in the AF + CA group, 90.2% in the AF group, and 95.1% in the BPS group, with no significant differences. The AF + CA group had significantly shorter operative times, less intraoperative blood loss, lower VAS scores at 3 days and 1 year postoperatively, and lower ODI scores at 3 days and 3 months compared with the BPS group. Multivariate regression analysis revealed that AF was a significant risk factor for cage subsidence, with an odds ratio of 3.399 compared with AF + CA. AF + CA effectively reduces cage subsidence in OLIF surgeries, offering results comparable to BPS while providing advantages such as shorter surgical time, reduced blood loss, and improved early postoperative outcomes. AF + CA is a viable alternative, especially for elderly patients with comorbidities who may not tolerate the longer operative durations or greater blood loss associated with BPS.

Therapeutic mechanisms of glucocorticoids, their administration and chronotherapy

Glucocorticoids represent a cornerstone in the treatment of inflammatory and autoimmune diseases due to their potent anti-inflammatory and immunosuppressive effects. These steroid hormones, including endogenous cortisol and synthetic analogs like prednisone and dexamethasone, exert their effects through genomic and non-genomic pathways, targeting key inflammatory mediators. While genomic mechanisms regulate long-term gene expression, non-genomic pathways enable rapid modulation of immune responses, particularly at high doses. Despite their therapeutic efficacy, glucocorticoid use is often limited by significant adverse effects, including osteoporosis and metabolic disorders. Chronotherapy, which aligns medication timing with circadian rhythms, enhances therapeutic outcomes while reducing side effects, particularly in diseases like rheumatoid arthritis where inflammation peaks in the early morning. Emerging innovations, such as selective glucocorticoid receptor agonists (SEGRAs) and liposomal drug delivery systems, offer targeted anti-inflammatory effects with reduced systemic toxicity. These advancements highlight the potential for optimizing glucocorticoid therapy to achieve maximum efficacy while mitigating adverse effects. This review underscores the importance of understanding glucocorticoid mechanisms, administration methods, and novel therapeutic strategies to improve outcomes in inflammatory and autoimmune diseases.

The amino acid metabolism pathway of peripheral T lymphocytes and ketamine-induced schizophrenia-like phenotype.

The intricate interplay between peripheral adaptive immune cells and the central nervous system (CNS) has garnered increasing recognition. Given that alterations in cell quantities often translate into modifications in metabolite profiles and that these metabolic changes can potentially traverse the bloodstream and enter the CNS, thereby modulating the progression of mental illnesses, we sought to explore the metabolic profiles of peripheral immune cells in a ketamine-treated mouse model of schizophrenia. We used flow cytometry to scrutinize the alterations in peripheral adaptive immune cells in a ketamine-induced schizophrenia mouse model. Subsequently, we implemented an untargeted metabolomic approach with ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) to detect the metabolite profiles of peripheral abnormal lymphocytes and identify differential metabolites present in plasma. We then employed targeted metabolomics using UPLC-MS/MS to quantify the common differential metabolites detected in mouse plasma. Flow cytometry analysis detected a notable increase in the count of peripheral CD3+ T cells in a ketamine-induced schizophrenia mouse model. Subsequent untargeted metabolomics analysis revealed that the amino acid metabolism pathway underwent substantial alterations. A detailed quantification of 22 amino acid profiles in the peripheral plasma indicated significant elevation in the levels of glycine, alanine, asparagine, and aspartic acid. Our ongoing research has yet to conclusively identify the precise amino acid metabolism pathway that serves as the pivotal factor in the manifestation of the schizophrenia-like phenotype induced by ketamine. The peripheral amino acid metabolism pathway is involved in the ketamine-induced schizophrenia-like phenotype. The metabolic profile of peripheral immune cells could provide accurate biomarkers for the diagnosis and treatment of psychiatric diseases.

Traditional Chinese medicine for cardiovascular disease: efficacy and safety

In China and other Asian nations, traditional medicine has long been utilized in the treatment of cardiovascular diseases (CVD). While Chinese authorities have incorporated traditional Chinese medicine (TCM) treatment experiences as a supplementary guide for CVD, its international recognition remains limited due to a scarcity of high-quality and reliable randomized controlled trials (RCTs) evidence. The purpose of this study was to examine the clinical outcomes with TCM for CVD after the recent publication of large trials adding &amp;gt;20,000 individuals to the published data. Here, we systematically reviewed 55 published RCTs (modified Jadad scores &amp;gt; 4) in the past 20 years, involving a total of 36,261 patients. In most studies, TCM has been associated with significant improvements in alternative endpoints such as hypertension, coronary heart disease, stroke and heart failure. A total of 19 trials reported on primary outcomes such as cardiovascular events and death events. During the follow-up period, some Chinese patent medicines can effectively reduce the “hard” endpoints of coronary heart disease, stroke, and heart failure, the overall trend of cardiovascular outcomes is lower. The risk of adverse effects was not significantly increased compared to the control group, suggesting its potential as an alternative approach for primary and secondary prevention of CVD based on the available evidence.

Long-term real-world evidence of SB5 (adalimumab biosimilar) treatment in patients with moderate-to-severe psoriasis from the British Association of Dermatologists Biologic and Immunomodulators Register (BADBIR)

Background SB5 (adalimumab-bwwd) is an adalimumab biosimilar targeting tumor necrosis factor (TNF) for the treatment of chronic inflammatory diseases, including moderate-to-severe chronic plaque psoriasis. Objectives To assess the four-year persistence associated with the effectiveness and safety of SB5 in patients with psoriasis in the UK and Ireland. Methods This prospective study included 1195 SB5-treated patients using British Association of Dermatologists’ Biologic Interventions Register (BADBIR) between 01 June 2018 and 31 August 2022. Persistence was defined as the time from biologic therapy initiation to discontinuation and Kaplan-Meier analysis was used to evaluate SB5 discontinuation rates. Cox regression was used to investigate the effect of covariates on the time-to-first-discontinuation of SB5 with the potential covariates. Results SB5 one-, two-, three-, and four-year discontinuation rates were 26.5%, 37.2%, 41.9%, and 43.3%, respectively. Tested covariates such as switching, age, sex, body mass index (BMI), and duration of psoriasis did not significantly affect the discontinuation rate of SB5. Conclusions Median persistence of SB5 in predominantly bio-naïve psoriasis patients was about 2.5 years in clinical practice. The results suggest that SB5 can be confidently used for patients with psoriasis, offering comparable outcomes to reference adalimumab.

Clinical expert consensus document on bailout algorithms for complications in percutaneous coronary intervention from the Japanese Association of Cardiovascular Intervention and Therapeutics.

The efficacy and safety of percutaneous coronary intervention (PCI) for coronary artery disease has been established, and approximately 250,000 PCI procedures are performed annually in Japan. However, various complications including life-threatening complications can occur during PCI. Although several bailout procedures have been proposed to address complications during PCI, it is critically important for operators to manage each complication in real catheter rooms with confidence even in emergent situations. Standard bailout methods including specific techniques should be clarified as algorithms and shared with inexperienced operators as well as experienced operators. The Task Force of the Japanese Society for Cardiovascular Intervention and Therapeutics (CVIT) has developed the expert consensus document on bailout algorithms for complications in PCI.

Clinical Perspectives of Managing Epilepsy Across Different Patient Populations with a Focus on Brivaracetam: A Cross-sectional Study among Indian Physicians

Objective: To evaluate clinicians' preferences, prescribing patterns, and clinical experiences with brivaracetam compared to other antiepileptic drugs, particularly levetiracetam, in the management of epilepsy across different patient populations. Methodology: This cross-sectional study used a 24-item multi-response questionnaire to gather expert opinion across different Indian settings regarding their perspectives on epilepsy and brivaracetam. Data analysis employed descriptive statistics, with results reported as frequencies and percentages. Results: The survey included 360 participants. Clinicians showed a strong preference for brivaracetam as the first-line antiepileptic drug in patients with newly diagnosed epilepsy, with 72% favoring it for younger patients and 74% for elderly. This preference was particularly notable for managing partial-onset seizures, as cited by 71% of clinicians. Additionally, 65% reported that partial-onset seizures were the primary reason for switching to brivaracetam from other antiepileptics. Behavioral and psychiatric adverse effects were cited by 60% of clinicians as the main reasons for transitioning from levetiracetam to brivaracetam. Moreover, 47% reported that 10-20% of patients experiencing behavioral changes on levetiracetam were switched to brivaracetam, with 49% noting improved efficacy and behavioral outcomes in 20-30% of these cases. The minimal psychiatric and behavioral side effects of brivaracetam were noted as its main advantage by 41% of clinicians in managing partial-onset seizures. Furthermore, 70% of clinicians preferred brivaracetam for treatment-resistant epilepsy, and approximately half of them preferred it for pediatric partial seizures. Conclusion: This study highlighted brivaracetam as a preferred antiepileptic drug in clinical practice, especially for managing partial-onset seizures. It serves as an effective alternative for patients experiencing adverse effects with levetiracetam.

Liver tumor segmentation method combining multi-axis attention and conditional generative adversarial networks.

In modern medical imaging-assisted therapies, manual annotation is commonly employed for liver and tumor segmentation in abdominal CT images. However, this approach suffers from low efficiency and poor accuracy. With the development of deep learning, automatic liver tumor segmentation algorithms based on neural networks have emerged, for the improvement of the work efficiency. However, existing liver tumor segmentation algorithms still have several limitations: (1) they often encounter the common issue of class imbalance in liver tumor segmentation tasks, where the tumor region is significantly smaller than the normal tissue region, causing models to predict more negative samples and neglect the tumor region; (2) they fail to adequately consider feature fusion between global contexts, leading to the loss of crucial information; (3) they exhibit weak perception of local details such as fuzzy boundaries, irregular shapes, and small lesions, thereby failing to capture important features. To address these issues, we propose a Multi-Axis Attention Conditional Generative Adversarial Network, referred to as MA-cGAN. Firstly, we propose the Multi-Axis attention mechanism (MA) that projects three-dimensional CT images along different axes to extract two-dimensional features. The features from different axes are then fused by using learnable factors to capture key information from different directions. Secondly, the MA is incorporated into a U-shaped segmentation network as the generator to enhance its ability to extract detailed features. Thirdly, a conditional generative adversarial network is built by combining a discriminator and a generator to enhance the stability and accuracy of the generator's segmentation results. The MA-cGAN was trained and tested on the LiTS public dataset for the liver and tumor segmentation challenge. Experimental results show that MA-cGAN improves the Dice coefficient, Hausdorff distance, average surface distance, and other metrics compared to the state-of-the-art segmentation models. The segmented liver and tumor models have clear edges, fewer false positive regions, and are closer to the true labels, which plays an active role in medical adjuvant therapy. The source code with our proposed model are available at https://github.com/jhliao0525/MA-cGAN.git.

Influence of COVID-19 public health restrictions on community-acquired pneumonia pathogens in children in Henan, China: a multicenter retrospective study

ObjectiveTo investigate the distribution of pathogens and epidemiological changes in children hospitalized with community-acquired pneumonia (CAP) during and after the COVID-19 pandemic public health restrictive measures. aiming to provide a foundation for clinical diagnosis, treatment, and policy formulation.MethodsThis multicenter retrospective study spanned January 2019 to December 2023. The study included 78,256 children hospitalized for CAP in four hospitals in Henan, China, among which 27,580 cases (35.2%) were tested for pathogens using multiplex real-time fluorescent polymerase chain reaction (PCR). The pathogens detected include Streptococcus pneumoniae (SP), Staphylococcus aureus (SA), Haemophilus influenzae (HI), respiratory syncytial virus (RSV), influenza A virus (Flu A), influenza B virus (Flu B), and Mycoplasma pneumoniae (MP).ResultsPathogens were identified in 18,690 of the 27,580 children, resulting in a 67.8% positive detection rate. Of these cases, 15,105 (54.8%) were single pathogen infections and 3,585 (13%) were mixed pathogen infections. The pathogen positivity rate was lowest in the first year of the COVID-19 pandemic (2020), at 54.7%, and peaked at 79.1% in 2023, after public health restrictions were lifted. During the COVID-19 pandemic (2020–2022), seasonal variation in pathogen prevalence was disrupted. Post-restriction, there was a significant increase in RSV and MP cases. SP remained the leading bacterial cause of CAP, especially in young children. RSV was the predominant viral pathogen, particularly affecting infants. MP showed a rising trend with age, yet it also affected younger individuals.ConclusionThe COVID-19 pandemic altered the epidemiological characteristics of pathogens in children with CAP. This impact is likely to persist, necessitating enhanced surveillance of CAP pathogens to mitigate the healthcare burden in children.Clinical trial numberNot applicable.

Integrating Out-of-Pocket Costs Into Shared Decision-Making for Heart Failure With Reduced Ejection Fraction: A Stepped-Wedge Trial (POCKET-COST-HF).

Guideline-directed medical therapy for heart failure (HF) with reduced ejection fraction can entail high out-of-pocket (OOP) costs, prompting concerns about financial toxicity and access. OOP costs are generally unavailable during encounters. This trial assessed the impact of providing patient-specific OOP costs to patients and clinicians. This trial was conducted between June 2021 and August 2023 at 6 clinics in 2 health systems using a stepped-wedge, clinic-level cluster-randomized design. Adult patients with HF with reduced ejection fraction (left ventricular ejection fraction ≤40%) were enrolled. The intervention was built upon the EPIC-HF (Electronically Delivered, Patient-Activation Tool for Intensification of Medications for Chronic Heart Failure with Reduced Ejection Fraction) checklist of approved HF with reduced ejection fraction medications. Patients and clinicians received this checklist with (intervention) or without (control) patient-specific OOP cost estimates for higher-cost medications at the time of encounter. Estimates were obtained by providing pharmacy benefit information to a financial navigation firm. Encounters were audio-recorded, and patients were surveyed 2 weeks later. The primary outcome was cost-informed decision-making, defined by mentioning HF medication cost during the encounter. The primary analysis used a generalized linear mixed model. Secondary outcomes were assessed via transcript subcoding and analysis of survey responses. Demographic characteristics of 247 patients (mean age, 62.9 years; 29.5% female; 26.3% Black; and 3.2% Hispanic/LatinX) treated by 39 clinicians in intervention and control periods were similar. In the primary model, the rate of cost-informed decision-making was higher in the intervention group than the control group (68% versus 49%; P=0.021). Baseline rates of cost discussions and the impact of the intervention varied across sites. When cost discussions were present, fewer discussions in the intervention group involved contingency plans to address potential costs (16.5% versus 31.9%; P=0.028). Most other secondary outcomes were not significantly different. Disclosing comprehensive OOP medication costs to patients with HF with reduced ejection fraction increased cost-informed decision-making. Further work is needed to optimize implementation and assess the impact on medication choices and adherence. URL: https://www.clinicaltrials.gov; Unique identifier: NCT04793880.

Enhancing pharmacogenomic data accessibility and drug safety with large language models: a case study with Llama3.1

Pharmacogenomics (PGx) holds the promise of personalizing medical treatments based on individual genetic profiles, thereby enhancing drug efficacy and safety. However, the current landscape of PGx research is hindered by fragmented data sources, time-consuming manual data extraction processes, and the need for comprehensive and up-to-date information. This study aims to address these challenges by evaluating the ability of Large Language Models (LLMs), specifically Llama3.1-70B, to automate and improve the accuracy of PGx information extraction from the FDA Table of Pharmacogenomic Biomarkers in Drug Labeling (FDA PGx Biomarker table), which is well-structured with drug names, biomarkers, therapeutic area, and related labeling texts. Our primary goal was to test the feasibility of LLMs in streamlining PGx data extraction, as an alternative to traditional, labor-intensive approaches. Llama3.1-70B achieved 91.4% accuracy in identifying drug-biomarker pairs from single labeling texts and 82% from mixed texts, with over 85% consistency in aligning extracted PGx categories from FDA PGx Biomarker table and relevant scientific abstracts, demonstrating its effectiveness for PGx data extraction. By integrating data from diverse sources, including scientific abstracts, this approach can support pharmacologists, regulatory bodies, and healthcare researchers in updating PGx resources more efficiently, making critical information more accessible for applications in personalized medicine. In addition, this approach shows potential of discovering novel PGx information, particularly of underrepresented minority ethnic groups. This study highlights the ability of LLMs to enhance the efficiency and completeness of PGx research, thus laying a foundation for advancements in personalized medicine by ensuring that drug therapies are tailored to the genetic profiles of diverse populations.

Discovery of New 1,2,4-Triazole/1,3,4-Oxadiazole-Decorated Quinolinones as Agrochemical Alternatives for Controlling Viral Infection by Inhibiting the Viral Replication and Self-Assembly Process.

Tobacco mosaic virus (TMV), a representative plant virus, is widely known and causes severe crop losses worldwide. In order to ensure the demand for crop and food security, the exploration of novel antiviral agents with outstanding activity and unique mechanisms of action is necessary. Herein, 40 new azole-quinolinone molecules were elaborately designed and systematically evaluated for their anti-TMV activity. Notably, compound A21 had significant therapeutic activity against TMV (EC50 value = 200 μg/mL), which was superior to commercial ningnanmycin (280 μg/mL). Studies on the anti-TMV mechanism showed that compound A21 could suppress the expression level of important TMV genes and affect the assembly of TMV viral particles by disrupting the self-assembly process of TMV coat protein (TMV-CP). In-depth antiviral behaviors were verified by molecular docking, fluorescence titration analysis, and TMV assembly assays, suggesting that compound A21 strongly interacted with TMV coat protein through various interactions. Overall, this promising work discloses a new paradigm for the exploitation of 2-quinolinone-based virucidal agents for hindering plant viral infection through triggering versatile antiviral behavior.

Long-term outcomes with medical therapy, transcatheter repair, or surgery for isolated tricuspid regurgitation: a systematic review and network meta-analysis.

Several transcatheter tricuspid valve (TV) repair devices for tricuspid regurgitation (TR) have emerged. However, few studies have compared transcatheter TV repair with medical therapy (MT) alone or isolated TV surgery. PubMed and EMBASE were searched in February 2024. Studies comparing at least any of the following 2 were included: MT, surgical TV repair, surgical TV replacement, or transcatheter TV repair. The primary outcome was long-term mortality (≧ 1year). The secondary outcomes were short-term mortality (30-day or in-hospital mortality) and periprocedural complications. We performed a network meta-analysis using a random effects model. A total of 25,831 patients from 22 studies (one randomized trial and 21 observational studies) were included. MT alone was associated with higher long-term mortality compared to surgical TV repair (HR [95% CI] 1.72 [1.34-2.23]), surgical TV replacement (HR [95% CI] 1.49 [1.14-1.96]), and transcatheter TV repair (HR [95% CI] 1.52 [1.30-1.78]). Long-term mortality was comparable between transcatheter and surgical interventions. Transcatheter TV repair had a lower risk of short-term mortality (versus surgical TV repair; RR [95% CI] 0.40 [0.22-0.72], versus surgical TV replacement; RR [95% CI] 0.35 [0.19-0.66]) and lower rates of periprocedural complications, including new pacemaker implantation, renal complications, cardiogenic shock than surgical interventions. MT alone for TR was associated with higher long-term mortality compared to surgical or transcatheter TV interventions. Transcatheter TV repair had better periprocedural outcomes compared to surgical interventions with similar long-term mortality. Despite the possibility of selection bias, transcatheter TV repair appears to be an attractive option for TR treatment.