Translational Research Research Articles

Toden-E: Topology-Based and Density-Based Ensembled Clustering for the Development of Super-PAG in Functional Genomics using PAG Network and LLM.

The integrative analysis of gene sets, networks, and pathways is pivotal for deciphering omics data in translational biomedical research. To significantly increase gene coverage and enhance the utility of pathways, annotated gene lists, and gene signatures from diverse sources, we introduced pathways, annotated gene lists, and gene signatures (PAGs) enriched with metadata to represent biological functions. Furthermore, we established PAG-PAG networks by leveraging gene member similarity and gene regulations. However, in practice, high similarity in functional descriptions or gene membership often leads to redundant PAGs, hindering the interpretation from a fuzzy enriched PAG list. In this study, we developed todenE (topology-based and density-based ensemble) clustering, pioneering in integrating topology-based and density-based clustering methods to detect PAG communities leveraging the PAG network and Large Language Models (LLM). In computational genomics annotation, the genes can be grouped/clustered through the gene relationships and gene functions via guilt by association. Similarly, PAGs can be grouped into higher-level clusters, forming concise functional representations called Super-PAGs. TodenE captures PAG-PAG similarity and encapsulates functional information through LLM, in characterizing network-based functional Super-PAGs. In synthetic data, we introduced a metric called the Disparity Index (DI), measuring the connectivity of gene neighbors to gauge clusterability. We compared multiple clustering algorithms to identify the best method for generating performance-driven clusters. In non-simulated data (Gene Ontology), by leveraging transfer learning and LLM, we formed a language-based similarity embedding. TodenE utilizes this embedding together with the topology-based embedding to generate putative Super-PAGs with superior performance in semantic and gene member inclusiveness.

Approachability and Sensory Changes Following Mild Traumatic Brain Injury in Pigs

Background/Objectives: Traumatic brain injury (TBI) is a global healthcare concern affecting millions, with wide-ranging symptoms including sensory and behavioral changes that can persist long-term. Due to similarities with human brain cytoarchitecture and inflammation, minipig models are advantageous for translational TBI research. However, gaps in knowledge exist regarding their behavioral and sensory sequelae following injury. Methods: Therefore, in this study, we assessed changes in approachability using a forced human approach task (FHAT) and mechanical nociception using the von Frey test in adult male and female Yucatan minipigs for up to one week following a sham or central fluid percussion injury (cFPI). Specifically, the FHAT assessed each animal’s response to a forced interaction with either a known or unknown experimenter. To evaluate changes in nociceptive sensory sensitivity, von Frey monofilaments ranging from 0.008 to 300 g of force were applied to the pinna of the ear or base of the tail. Results: We found that forced approachability was affected by experimenter familiarity as well as cFPI in a sex-specific manner at subacute timepoints. We also found reductions in sensitivity following cFPI on the ear in male minipigs and on the tail in female minipigs. Conclusion: Overall, the current study demonstrates that cFPI produces both behavioral and sensory changes in minipigs up to one-week post-injury.

Potential and challenges of clinical high-dimensional flow cytometry: A call to action.

Clinical biomarker strategies increasingly integrate translational research to gain new insights into disease mechanisms or to define better biomarkers in clinical trials. High-dimensional flow cytometry (HDFCM) holds the promise to enhance the exploratory potential beyond traditional, targeted biomarker strategies. However, the increased complexity of HDFCM poses several challenges, which need to be addressed in order to fully leverage its potential and to align with current regulatory requirements in clinical flow cytometry. These challenges include among others extended timelines for assay development and validation, the necessity for extensive knowledge in HDFCM, and sophisticated data analysis strategies. However, no guidelines exist on how to manage such challenges in adopting clinical HDFCM. Our CYTO 2024 workshop "Potential and challenges of clinical high-dimensional flow cytometry" aimed to find consensus across the pharmaceutical industry and broader scientific community on the overall benefits and most urgent challenges of HDFCM in clinical trials. Here, we summarize the insights we gained from our workshop. While this report does not provide a blueprint, it is a first step in defining and summarizing the most pressing challenges in implementing HDFCM in clinical trials. Furthermore, we compile current efforts with the goal to overcome some of these challenges. As such we bring the scientific community and health authorities together to build solutions, which will accelerate and simplify the full adoption of HDFCM in clinical trials.

Identification of human pregnane X receptor antagonists utilizing a high-throughput screening platform

Pregnane X receptor (PXR) is a xenobiotic-sensing nuclear receptor with a well-established role in regulating drug metabolism and clearance. Recent studies have shown that PXR is involved in cell proliferation, apoptosis, immune response, and energy homeostasis. It is important to identify compounds that may modulate PXR activity to prevent drug-drug interactions, distinguish chemicals which could potentially generate toxicity, and identify compounds for further development towards therapeutic usage. In this study, we have screened the National Center for Advancing Translational Sciences (NCATS) Pharmacologically Active Chemical Toolbox (NPACT) library, which consists of 5,099 unique pharmacologically active synthetic and naturally derived small molecules to identify PXR antagonists. Ninety-four compounds were identified as potential PXR antagonists through a primary screen and 66 were confirmed in a confirmation study. Of these compounds, twenty potential PXR antagonists, including gamma-secretase modulator 2 (GSM2) and fusidic acid, were selected for further study based on their efficacy, potency, and novelty. Their PXR inhibition abilities were assessed by examining their effects on cytrochrome P450 (CYP) 3A4 mRNA expression using metabolically competent HepaRG cells. Additionally, a pharmacological inhibition assay using various concentrations of rifampicin as a stimulator was performed in HepG2-CYP3A4-hPXR cells to confirm the activity of the 20 selected compounds against PXR. Finally, HepaRG cells were used to confirm PXR antagonism by verification of a concentration-dependent decrease of CYP3A4 when co-treated with the known PXR agonist, rifampicin. Additionally, the potent actives were further investigated using molecular docking to find the potential interactions of the novel ligands with the active sites of hPXR. To our knowledge from the current study, GSM2 and fusidic acid have been identified as novel PXR antagonists, which provides useful information for further investigation regarding possible drug-drug interactions, as well as the detection of potential therapeutic effects or other toxic consequences.

Future Therapeutic Strategies for Alzheimer’s Disease: Focus on Behavioral and Psychological Symptoms

Alzheimer’s disease (AD) is a progressive, degenerative brain disorder that impairs memory and thinking skills, leading to significant economic and humanistic burdens. It is associated with various neuropsychiatric symptoms (NPS) such as anxiety, agitation, depression, aggression, apathy, and psychosis. NPSs are common in patients with AD, affecting up to 97% of individuals diagnosed with AD. The severity of NPS is linked to disease progression and cognitive decline. NPS in Alzheimer’s disease leads to increased morbidity, mortality, caregiver burden, earlier nursing home placement, and higher healthcare costs. Despite their significant impact, clinical research on NPS in AD is limited. In clinical settings, accurately distinguishing and diagnosing NPS related to AD remains a challenge. Additionally, conventional treatments for NPS in AD are often ineffective, highlighting the need for new therapies that target these specific symptoms. Understanding these comorbidities can aid in early diagnosis and better management of AD. In this review, we provide a summary of the various neurological and psychiatric symptoms (NPS) associated with AD and new candidates under development for the treatment of NPS based on their therapeutic targets and mechanisms. On top of the conventional NPS studied so far, this review adds recent advancements in the understanding of social functional impairment in AD. This review also provides information that can contribute to the advancement of studies and translational research in this field by emphasizing therapeutic targets and mechanisms of action focused on AD-related NPS rather than conventional mechanisms targeted in AD drug development. Above all, considering the relative lack of research in this new field despite the importance of clinical, medical, and translational research, it may increase interest in NPS in AD, its pathophysiological mechanisms, and potential therapeutic candidates such as molecules with antioxidant potential.

Multi-scale hierarchical brain regions detect individual and interspecies variations of structural connectivity in macaque monkeys and humans

Macaques are representative animal models in translational research. However, the distinct shape and location of the brain regions between macaques and humans prevents us from comparing the brain structure directly. Here, we calculated structural connectivity (SC) with multi-scale hierarchical regions of interest (ROIs) to parcel out human and macaque brain into 8 (level 1 ROIs), 28 (level 2 ROIs), or 46 (level 3 ROIs) regions, which consist of anatomically and functionally defined level 4 ROIs (around 100 parcellation of the brain). The SC with the level 1 ROIs showed lower individual and interspecies variation in macaques and humans. SC with level 2 and 3 ROIs shows that the several regions in frontal, temporal and parietal lobe show distinct connectivity between macaques and humans. Lateral frontal cortex, motor cortex and auditory cortex were shown to be important areas for interspecies differences. These results provide insights to use macaques as animal models for translational study.

Biofunctional applications of Chitosan in Dentistry – An Overview

Chitosan due to its unique properties has attracted materials scientists globally to explore it for bio-dental applications. In dentistry, chitosan is also shown wide applications. The creation of effective biomaterials for the prevention and treatment of dental disorders is a challenge for researchers in the present scenario. The natural semi-synthetic polysaccharide based biomaterial Chitosan is obtained from the marine source chitin. Due to its peculiar characteristics, chitosan offers benefits in biomedicine and can be utilized in the development of capsules (micro and nanoparticles), powders, scaffolds, films, beads, hydrogels, and bandages. Chitosan offers its benefits as an anti-microbial agent, mucoadhesive, biomimetic mineralization Teeth hardening action due to its remineralizing property which leads to the search and focus of chitosan towards dental applications. Translation of research to clinical applications is better suited for chitosan in terms of its multifactorial activities. Therefore, this article provides an overview of chitosan, which mainly covers the basic information of chitosan, with a focus on different techniques of preparation of chitosan based formulations. It also explores the usage of chitosan in the treatment of various dental disorders.

Role of Immunotherapy in Gastroesophageal Cancer with Liver Metastasis.

The role of immune checkpoint inhibitors (ICIs) for patients with gastroesophageal (GE) cancer with liver metastasis remains unclear. Our objective was to investigate if ICIs are beneficial in patients with GE cancer with liver metastasis. We searched PubMed, Embase, ESMO, and ASCO Meeting Abstracts for phase III randomized clinical trials (RCTs) testing ICIs in metastatic/advanced GE cancer from 2017 to 2023. Seven studies were included. OS was similar among all patients (HR 0.72 [0.67,0.77], p < .001), in patients without (HR 0.73 [0.67,0.81], p < .001, I2 = 0.0%), and with liver metastasis (HR 0.74 [0.67,0.81], p < .001, I2 = 0.0%). PFS was also similar among all patients (HR 0.63 [0.57,0.70], p < .001), without (HR 0.62 [0.51,0.76], p < .001), and with liver metastasis (HR 0.66 [0.57,0.76], p < .001). ICIs showed no difference in benefit in patients with GE cancer regardless of liver metastasis. Future studies could focus on deciphering the tumor microenvironment of liver metastasis as an area of translational research.

Uptake of health economic evaluations alongside clinical trials in Australia: an observational study.

Australia's clinical trials sector is highly productive with continued sector investment needed to enhance research impact. Generating economic evidence alongside trials has the potential to facilitate the implementation of trial results into practice. Ascertaining the use of health economic evaluations alongside clinical trials can assist in determining whether clinical trials fully realize and operationalize their potential to change policy and practice. The aims of this study were to ascertain the uptake of health economic evaluations alongside Australian-led clinical trials and explore associations between uptake and trial characteristics. This observational study comprised a descriptive analysis of clinical trials registries, a cross-sectional survey of Australian Clinical Trials Alliance (ACTA) networks, and a subgroup analysis of completed acute care trials. Descriptive analyses of trial registrations were conducted, with logistic regressions used to identify predictors of proposing and subsequently publishing a health economic evaluation alongside acute care trials. Few randomized Australian-led clinical trials (11% of 9251) and ACTA network trials (43% of 227) proposed a health economic evaluation. In the subgroup analysis, 22% of the 324 acute care trials and 53% of the 38 ACTA network acute care trials proposed a health economic evaluation. Acute care trials funded by government bodies were significantly more likely to propose and publish a health economic evaluation than those funded by hospitals, universities, and other funders, after adjusting for phase, registration year, primary sponsor type, and comparator. Current uptake of health economic evaluations alongside Australian-led clinical trials is low, with uptake higher among the subset of ACTA network trials. This is despite economic evidence playing an increasingly prominent role in health system management, as well as rising health expenditure, limited budgets, and competing demands. There is significant opportunity to embed health economic evaluations alongside clinical trials, particularly phase 3 trials, to increase research outputs and optimize research translation. Investing in clinical trial networks that support funding for a health economist or a health economic evaluation may be an effective strategy to increase the uptake of health economic evaluations alongside trials.

Collection, Establishment and Assessment of Complex Human Osteocartilaginous Explants for Modeling Osteoarthritis.

With the increasing burden of osteoarthritis worldwide, cost efficient and reliable models are needed to enable the development of innovative therapies or therapeutic interventions. Ex vivo models have been identified as valuable modalities in translational research, bridging the gap between in vitro and in vivo models. Osteocartilaginous explants from Osteoarthritis (OA) patients offer an exquisite opportunity for studying OA progression and testing novel therapies. We describe the protocol for establishing human osteocartilaginous explants with or without co-culture of homologous synovial tissue. Furthermore, a detailed protocol for the assessment of explanted tissue in terms of protein content using Western blot and immunohistochemistry is provided. Commentaries regarding the technique of choice, possible variations and expected results are inserted.

Defining social reward: A systematic review of human and animal studies.

Social rewards are strong drivers of behavior and fundamental to well-being, yet there is a lack of consensus regarding what actually defines a reward as "social." Because a systematic overview of existing social reward operationalizations is currently absent, a review of the literature seems necessary to advance toward a unified framework and to better guide research and theory. To bridge this gap, we preregistered and conducted the first comprehensive systematic review of human and animal experimental studies that used the term "social reward" and charted existing operationalizations, revealing the implicit and explicit definitions used in the field. Stimulus characteristics and measures of social reward were extracted from a total of 384 studies encompassing 42,118 participants and subjects. We provide detailed summaries of these elements, stratified by species (human/animal) and study type (behavioral, brain imaging, pharmacological, and physiological). Two main aspects were found to account for most of the difference in operationalizations: the sensory richness of a stimulus (intimacy) and engagement in social interaction (i.e., the synchronous observation and action between at least two individuals, viz., immediacy). Drawing insights from second-person neuroscience approaches and theoretical models in the field of human-computer interaction, we propose that human and animal research can greatly benefit from considering these properties, as they have important theoretical and practical consequences for human and translational research, with far-reaching implications for neighboring research fields such as those pertaining to social media and the development of artificial intelligence. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Beta-Amyloid and Its Asp7 Isoform: Morphological and Aggregation Properties and Effects of Intracerebroventricular Administration.

One of the hallmarks of Alzheimer's disease (AD) is the accumulation of aggregated beta-amyloid (Aβ) protein in the form of senile plaques within brain tissue. Senile plaques contain various post-translational modifications of Aβ, including prevalent isomerization of Asp7 residue. The Asp7 isomer has been shown to exhibit increased neurotoxicity and induce amyloidogenesis in brain tissue of transgenic mice. The toxicity of Aβ peptides may be partly mediated by their structure and morphology. In this respect, in this study we analyzed the structural and aggregation characteristics of the Asp7 isoform of Aβ42 and compared them to those of synthetic Aβ42. We also investigated the effects of intracerebroventricular (i.c.v.) administration of these peptides, a method often used to induce AD-like symptoms in rodent models. Atomic force microscopy (AFM) was conducted to compare the morphological and aggregation properties of Aβ42 and Asp7 iso-Aβ42. The effects of i.c.v. stereotaxic administration of the proteins were assessed via behavioral analysis and reactive oxygen species (ROS) estimation in vivo using a scanning ion-conductance microscope with a confocal module. AFM measurements revealed structural differences between the two peptides, most notably in their soluble toxic oligomeric forms. The i.c.v. administration of Asp7 iso-Aβ42 induced spatial memory deficits in rats and elevated oxidative stress levels in vivo, suggesting a potential of ROS in the pathogenic mechanism of the peptide. The findings support the further investigation of Asp7 iso-Aβ42 in translational research on AD and suggest its involvement in neurodegenerative processes.

Physical activity interventions to prevent and manage type 2 diabetes in Aboriginal and Torres Strait Islander people: a systematic review.

To review evidence regarding the impact of physical activity interventions for preventing and managing type 2 diabetes in Aboriginal and Torres Strait Islander Australians. We searched for published reports of physical activity interventions for preventing and managing type 2 diabetes in Indigenous adults (18 years or older). There were no exclusion criteria regarding study type or duration, frequency, length, or intensity of physical activity, except that short term interventions were excluded. We assessed the quality of each study using the Joanna Briggs Institute (JBI) critical appraisal tools and the ethical and methodological quality of studies from an Indigenous Australian perspective with the Centre of Research Excellence in Aboriginal Chronic Disease Knowledge Translation and Exchange (CREATE) Critical Appraisal Tool. MEDLINE; Scopus, Embase (Elsevier); Cumulative Index to Nursing and Allied Health Literature (CINAHL), Sports Discus, PsycINFO (EBSCO); Informit Complete; ProQuest Dissertations and Theses, and ProQuest Health and Medicine; each from their inception to 30 October 2022. The database searches identified 703 potentially relevant records; after removing duplicates and initial screening, the full text of 27 articles was assessed for eligibility. Nine studies met our inclusion criteria: two randomised controlled trials, five cohort studies, one quasi-experimental study, and one repeated cross-sectional study. Eight studies were rated as being of low or medium quality (median JBI score, 54%; interquartile range [IQR], 36-64%); seven studies were rated as being of low to medium ethical and methodological quality from the Indigenous perspective (median CREATE score, 50%; IQR, 36-64%). Six studies reported changes in glycated haemoglobin (HbA1c) levels, of which two (both cohort studies) reported significantly lower mean HbA1c levels after the intervention, but only one publication provided detailed results. No randomised controlled trials that investigated the effect of a combination of physical activity and dietary change for Indigenous Australians diagnosed with type 2 diabetes were identified. Differences in study design, outcome variables, and the small number of studies precluded meta-analysis. Quality research into the impact of physical activity interventions on type 2 diabetes in Indigenous people is sparse. To improve research translation, studies that involve Indigenous community members at all levels of the research process are needed. PROSPERO CRD42021247496 (prospective).

Innovations in Drug Delivery: From Microtechnology to Targeted Therapeutics

Drug delivery systems are developed to maximize drug efficacy and minimize side effects. As drug delivery technologies improve, the drug becomes safer and more comfortable for patients to use. The study on advanced drug delivery systems aims to increase patient compliance, decrease adverse effects, and improve treatment efficacy. Furthermore, the goal of these systems is to deliver drugs to particular body tissues or cells in a targeted manner, which should enhance treatment outcomes. During the last seven decades, extraordinary progress has been made in drug delivery technologies, such as systems for long-term delivery for months and years, localized delivery, and targeted delivery. In this review, we explain the general principles of several advanced drug delivery systems, their introduction objective, components, mechanism, functioning principle, and application. The implantable polymeric drug delivery system, cardiac pacemaker, prefilled dual chamber device, closed-loop insulin delivery system, hepatic infusion pumps, MEMS devices, inhaled insulin devices, and hydrogel-forming microneedles are among the medical devices that are being discussed in this article as being at the forefront of technological innovation in medicine. For a variety of medical diseases, these devices provide minimally invasive procedures, real-time monitoring, and more accurate drug delivery. The scope of medical treatment and monitoring procedures is changing due to the integration of cutting-edge materials and technology. By increasing convenience, decreasing adverse effects, and increasing efficacy, these cutting-edge solutions directly help patients. Furthermore, the adoption of advanced drug delivery systems has demonstrated promising results in enhancing patient compliance and treatment outcomes. By increasing the bioavailability and pharmacokinetics of pharmaceuticals, these systems have the potential to transform the fields of drug delivery and personalized medicine. However, the field also faces challenges in overcoming physicochemical barriers and biological unknowns. Challenges facing the advanced drug delivery systems industry include complicated formulation requirements, regulatory obstacles, and the need for new technologies to enhance patient outcomes and therapeutic efficacy. Strict intellectual property rules and competition from generic drug manufacturers can also directly hinder the expansion and financial success of businesses in this field. To progress, the field should focus on translatable research ideas, develop realistic goals, and most importantly, diversify technologies. This emphasis on diversity will inspire new ideas and approaches, leading to the development of more effective, patient-friendly drug delivery systems.

Unlocking Success: Community Engagement for Enhanced HIV Care Outcomes.

Background: Though social determinants are the primary drivers of health, few studies of people living with HIV (PLWH) focus on non-clinical correlates of insecure and/or fragmented connections with the care system. Our team has used linked clinical and multisector non-clinical data to study how residential mobility and connection to social services influence the HIV care continuum. We engage a diverse group of invested patients and community members to guide and inform this research. Our objective is to generate stakeholder-informed, research-based interventions that are relevant to the community, and to share our engagement approach and findings so that other researchers can do the same. Methods: Our research team partnered with the Indiana Clinical and Translational Sciences Institute's Research Jam, to develop and implement a human-centered design research plan to engage with individuals with lived experience relevant to our research. We recruited a panel composed of PLWH as well as clinicians and individuals from agencies that provide medical and non-medical services to PLWH in Marion County, Indiana. We used a variety of human-centered design tools and activities to engage individuals during six sessions, with results informing our engagement and research activities. Results: Since the inception of the project, 48 individuals have joined the stakeholder panel. Thirty-five are actively engaged and have participated in one or more of the six sessions conducted to date. The panel helped guide and prioritize analyses, aided in identification of data missing from our ecosystem, helped interpret results, provided feedback on future interventions, and co-presented with us at a local health equity conference. Conclusions: We utilized community engagement to expand the scope of our research and found that the process provided value to both stakeholders and research team members. Human-centered design enhanced this partnership by keeping it person-centered, developing empathy and trust, increasing stakeholder retention, and empowering stakeholders to collaborate meaningfully with the research team. The use of these methods is essential to conducting relevant, impactful, and sustainable research. We anticipate that these methods will be important for academic and public health researchers wishing to engage with and integrate the ideas of community stakeholders.

Racial disparities in prostate cancer in the UK and the USA: similarities, differences and steps forwards.

In the USA, Black men are approximatelytwice as likely to be diagnosed with and to die of prostate cancer than white men. In the UK, despite Black men having vastly different ancestral contexts and health-care systems from Black men in the USA, the lifetime risk of being diagnosed with prostate cancer is two-to-three times higher among Black British men than among white British men and Black British men are twice as likely to die of prostate cancer as white British men. Examination of racial disparities in prostate cancer in the USA and UK highlights systemic, socio-economic and sociocultural factors that might contribute to these differences. Variation by ancestry could affect incidence and tumour genomics. Disparities in incidence might alsobe affected by screening guidelines and access to and uptake of screening. Disparities in treatment access, continuity of care and outcomes could contribute to survival differences. In both localized and metastatic settings, equal access could diminish the observed disparities in both the USA and the UK. An understanding of behavioural medicine, especially an appreciation of cultural beliefs about illness and treatment, could inform and improve the ways in which health systems can engage withand deliver care to patients in minoritized groups affected by prostate cancer. Methods of promotingequity include targeting systemic barriers including systemic racism,proportional recruitment of patients into clinical trials, diversifying the health-care workforce and facilitating care informed by cultural humility.Actively engaging patients and communities in research and intervention might enable the translation of research into increasingly equitable care for patients with prostate cancer in the UK, the USAand globally.

Remote Passive Sensing of Older Adults' Activities and Function: User-Centered Design Considerations for Behavioral Interventions Conducted in the Home Setting.

Behavioral intervention studies often lack sufficiently sensitive and frequent measurements to observe an effect. Remote passive sensing offers a highly sensitive, continuous, and ecologically valid method of assessment that increases the ability to detect changes in the daily activities and function of those being monitored. To be most effectively deployed in research studies, applications of remote assessment technology must be designed with the end user in mind. User-centered design (UCD) is especially important in clinical trials where the needs and characteristics of participants and research staff need to be uniquely considered to ensure the feasibility and acceptability of the study. This paper describes UCD issues in remote passive sensing that commonly arise among older adult participants-including those living with dementia-as well as any strategies that were taken to overcome them. Using exemplars from the National Institute on Aging-funded Roybal Center ORCASTRAIT (Oregon Roybal Center for Care Support Translational Research Advantaged by Integrating Technology), as well as other experimental and observational research studies conducted in community settings, this paper brings together our collective experiences with studies using remote passive sensing technology that incorporate a UCD design approach. Although passive sensing eliminates some common UCD issues that arise with higher-touch technology, issues, such as usability, trust, and aesthetic acceptability, still need to be addressed for behavioral interventions using passive sensing technology to be potent and implementable.

Bedside to bench and back again-translational research in interventional pulmonology.

Translational research in Interventional Pulmonology has made significant advances in recent years, ranging from novel biomarkers and imaging to practice-changing clinical trials in lung cancer and pleural disease. This review article aims to summarize key research studies in the field to understand the latest published evidence and to highlight areas of growing academic interest. In lung cancer, the role of novel imaging and biomarkers and their potential utility in early lung cancer diagnosis will be highlighted. In pleural disease, less invasive/conservative treatment in pneumothorax, early aggressive treatment in pleural infection along with novel biomarkers, and the shift beyond drainage strategies in malignant pleural effusion and mesothelioma will be discussed. This overview of translational research in the field of interventional pulmonology will ultimately help to highlight the gaps in current evidence to promote research in areas of clinical significance.

Translational research priorities for bacteriophage therapeutics.

The growing threat of antimicrobial resistant (AMR) bacterial pathogens coupled with the relative dearth of promising novel antibiotics requires the discovery and development additional medical interventions. Over the past decade bacteriophages have emerged one of the most promising new tools to combat AMR pathogens. Anecdotal clinical experiences under so-called 'compassionate use' regulatory pathways as well as a limited number of clinical trials have provided ample evidence of safety and early evidence of efficacy. For phages to reach their full potential it is critical that rigorous clinical trials be conducted that define their optimal use and that enable regulatory authorities to support the commercialization required to afford global access. The clinical development of phage therapeutics requires the design and execution of clinical trials that take full advantage of lessons learned from a century of antibiotic development and that use clinical investigation as a platform in which aspects of phage biology that are critical to therapeutics are more clearly elucidated. Translational research that elucidates phage biology in the context of clinical trials will promote highly relevant hypothesis-driven work in basic science laboratories and will greatly accelerate the development of the field of phage therapeutics.

Assessing Retrieval-Augmented Large Language Model Performance in Emergency Department ICD-10-CM Coding Compared to Human Coders.

Accurate medical coding is essential for clinical and administrative purposes but complicated, time-consuming, and biased. This study compares Retrieval-Augmented Generation (RAG)-enhanced LLMs to provider-assigned codes in producing ICD-10-CM codes from emergency department (ED) clinical records. Retrospective cohort study using 500 ED visits randomly selected from the Mount Sinai Health System between January and April 2024. The RAG system integrated past 1,038,066 ED visits data (2021-2023) into the LLMs' predictions to improve coding accuracy. Nine commercial and open-source LLMs were evaluated. The primary outcome was a head-to-head comparison of the ICD-10-CM codes generated by the RAG-enhanced LLMs and those assigned by the original providers. A panel of four physicians and two LLMs blindly reviewed the codes, comparing the RAG-enhanced LLM and provider-assigned codes on accuracy and specificity. RAG-enhanced LLMs demonstrated superior performance to provider coders in both the accuracy and specificity of code assignments. In a targeted evaluation of 200 cases where discrepancies existed between GPT-4 and provider-assigned codes, human reviewers favored GPT-4 for accuracy in 447 instances, compared to 277 instances where providers' codes were preferred (p<0.001). Similarly, GPT-4 was selected for its superior specificity in 509 cases, whereas human coders were preferred in only 181 cases (p<0.001). Smaller open-access models, such as Llama-3.1-70B, also demonstrated substantial scalability when enhanced with RAG, with 218 instances of accuracy preference compared to 90 for providers' codes. Furthermore, across all models, the exact match rate between LLM-generated and provider-assigned codes significantly improved following RAG integration, with Qwen-2-7B increasing from 0.8% to 17.6% and Gemma-2-9b-it improving from 7.2% to 26.4%. RAG-enhanced LLMs improve medical coding accuracy in EDs, suggesting clinical workflow applications. These findings show that generative AI can improve clinical outcomes and reduce administrative burdens. This work was supported in part through the computational and data resources and staff expertise provided by Scientific Computing and Data at the Icahn School of Medicine at Mount Sinai and supported by the Clinical and Translational Science Awards (CTSA) grant UL1TR004419 from the National Center for Advancing Translational Sciences. Research reported in this publication was also supported by the Office of Research Infrastructure of the National Institutes of Health under award number S10OD026880 and S10OD030463. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funders played no role in study design, data collection, analysis and interpretation of data, or the writing of this manuscript. A study showed AI models with retrieval-augmented generation outperformed human doctors in ED diagnostic coding accuracy and specificity. Even smaller AI models perform favorably when using RAG. This suggests potential for reducing administrative burden in healthcare, improving coding efficiency, and enhancing clinical documentation.