Preclinical Phase Research Articles

Definitions and Characteristics of Patient Digital Twins Being Developed for Clinical Use: Scoping Review

Background The concept of digital twins, widely adopted in industry, is entering health care. However, there is a lack of consensus on what constitutes the digital twin of a patient. Objective The objective of this scoping review was to analyze definitions and characteristics of patient digital twins being developed for clinical use, as reported in the scientific literature. Methods We searched PubMed, Scopus, Embase, IEEE, and Google Scholar for studies claiming digital twin development or evaluation until August 2023. Data on definitions, characteristics, and development phase were extracted. Unsupervised classification of claimed digital twins was performed. Results We identified 86 papers representing 80 unique claimed digital twins, with 98% (78/80) in preclinical phases. Among the 55 papers defining “digital twin,” 76% (42/55) described a digital replica, 42% (23/55) mentioned real-time updates, 24% (13/55) emphasized patient specificity, and 15% (8/55) included 2-way communication. Among claimed digital twins, 60% (48/80) represented specific organs (primarily heart: 15/48, 31%; bones or joints: 10/48, 21%; lung: 6/48, 12%; and arteries: 5/48, 10%); 14% (11/80) embodied biological systems such as the immune system; and 26% (21/80) corresponded to other products (prediction models, etc). The patient data used to develop and run the claimed digital twins encompassed medical imaging examinations (35/80, 44% of publications), clinical notes (15/80, 19% of publications), laboratory test results (13/80, 16% of publications), wearable device data (12/80, 15% of publications), and other modalities (32/80, 40% of publications). Regarding data flow between patients and their virtual counterparts, 16% (13/80) claimed that digital twins involved no flow from patient to digital twin, 73% (58/80) used 1-way flow from patient to digital twin, and 11% (9/80) enabled 2-way data flow between patient and digital twin. Based on these characteristics, unsupervised classification revealed 3 clusters: simulation patient digital twins in 54% (43/80) of publications, monitoring patient digital twins in 28% (22/80) of publications, and research-oriented models unlinked to specific patients in 19% (15/80) of publications. Simulation patient digital twins used computational modeling for personalized predictions and therapy evaluations, mostly for one-time assessments, and monitoring digital twins harnessed aggregated patient data for continuous risk or outcome forecasting and care optimization. Conclusions We propose defining a patient digital twin as “a viewable digital replica of a patient, organ, or biological system that contains multidimensional, patient-specific information and informs decisions” and to distinguish simulation and monitoring digital twins. These proposed definitions and subtypes offer a framework to guide research into realizing the potential of these personalized, integrative technologies to advance clinical care.

OGC SO16 - International upper GI robotic fellowship on the CMR Versius platform

Abstract Background The impetus for UGI surgery trainees to attain skills in robotic surgery is likely to increase following the global acceptance and utilisation of robotic platforms. UGI robotic fellowship programs are few in number and highly desirable providing trainees with a unique selling point when embarking on independent consultant practice. We describe the first UGI robotic surgery fellowship on the CMR Versius platform at the Gloucestershire Royal Hospital which has the largest experience of UGI robotic surgery on the CMR Versius platform in the UK, having performed over 200 cases including the first robot assisted minimally invasive oesophagectomy. Method A structured robotic training curriculum was created in collaboration with CMR Versius. It consists of a pre-clinical phase of E-learning (10 modules), simulator training (16 assessed tasks) and dry-laboratory training (a two-day course encompassing robotic system set-up, bed-side assist and assessed dry lab practical tasks). The clinical phase begins with bed-side assisting of robotic cases followed by supervised operating on the console. Operations performed on the console are recorded for review and evaluation. The videos will be scored by two independent surgeons using the modified Global Evaluation Assessment of Robotic Skills (mGEARS) score to track growth and progress. Results The E-learning modules and assessments were completed prior to commencement of the fellowship. The remainder of the pre-clinical phase of the curriculum were completed within 4 weeks of commencement followed by bed-side assisting. Once competent at bed-side assisting and able to demonstrate proficiency in set-up (selecting port site placement, docking, arm spacing and configuration), supervised console training was commenced 6 weeks into the fellowship. Console training began with robotic assisted laparoscopic assisted cholecystectomy to gain familiarity, confidence, and efficiency. After 6 cases as the only console surgeon, the surgical complexity of cases was progressed to hiatal surgery and Heller’s cardiomyotomy Conclusion A structured training curriculum with defined phases provides a feasible and effective framework for robotic fellowship training. Adherence to the pre-clinical phase of training allows safe and efficient progression to hands-on console experience. This is achievable within relatively short timeframe to allow for ample independent console surgeon experience and the development of proficiency within a 12-month fellowship period.

TMOD-33. DOES PRE-CLINICAL DRUG ACTIVITY PREDICT PHASE II CLINICAL EFFICACY IN GLIOBLASTOMA? A DETAILED ANALYSIS

Abstract Despite decades of research, there are fewer than six FDA-approved therapies for glioblastoma (GBM). The drug approval process relies on studies establishing pre-clinical activity, most commonly using murine models, followed by in human studies establishing safety and then efficacy. Although murine models for GBM have allowed for insights into tumor biology, their utility in assessing the efficacy of novel anti-cancer therapies remains highly debated. Here, we sought to establish whether there was any relationship between drug activity in preclinical models and phase 2 clinical trial outcomes. Using ClinicalTrials.gov (NIH), all phase 2 trials in glioblastoma up to December 2023 were queried and downloaded. Trials that were never started, had not yet started, were withdrawn, not completed, or contained indications beyond glioblastoma were excluded. Studies examining anti-tumor effects of an investigational agent with or without bevacizumab, temozolomide, or radiation therapy in glioblastoma were included, and studies examining alternative dosing strategies, various medical devices, or drug combinations, were excluded. The corresponding preclinical studies were identified via literature review for each clinical trial. Data including the progression free and overall survival benefit, mouse models used, and sample sizes were extracted from each study. 659 trials between 1994 and 2023 were included for analysis. Of these, 272 (41%) were for monotherapies, examining 90 unique small molecules. Preclinical endpoints included murine survival and tumor weight. In comparing mouse survival and tumor size to progression free and overall survival in humans, our preliminary analysis did not reveal any clear correlation. The correlation between preclinical and clinical drug response in GBM remains uncertain. Future work will examine whether mouse genotype, immune status, or GBM cell line used affected the degree of concordance with human clinical trial data. Our analysis suggests that further investigation into preclinical models of GBM, and standardized reporting of preclinical models, are needed.

Decreased Expression of the EAAT5 Glutamate Transporter at Photoreceptor Synapses in Early, Pre-Clinical Experimental Autoimmune Encephalomyelitis, a Mouse Model of Multiple Sclerosis

Background: Multiple sclerosis is a frequent neuroinflammatory and neurodegenerative disease of the central nervous system that includes alterations in the white and gray matter of the brain. The visual system is frequently affected in multiple sclerosis. Glutamate excitotoxicity might play a role in disease pathogenesis. Methodology: In the present study, we analyzed with qualitative and quantitative immunofluorescence microscopy and Western blot analyses whether alterations in the EAAT5 (SLC1A7) glutamate transporter could be involved in the previously observed alterations in structure and function of glutamatergic photoreceptor ribbon synapses in the EAE mouse model of MS. EAAT5 is a presynaptic glutamate transporter located near the presynaptic release sites. Results: We found that EAAT5 was strongly reduced at the photoreceptor synapses of EAE retinas in comparison to the photoreceptor synapses of the respective control retinas as early as day 9 post-immunization. The Western blot analyses demonstrated a decreased EAAT5 expression in EAE retinas. Conclusions: Our data illustrate early alterations of the EAAT5 glutamate transporter in the early pre-clinical phase of EAE/MS and suggest an involvement of EAAT5 in the previously observed early synaptic changes at photoreceptor synapses. The precise mechanisms need to be elucidated by future investigations.

Preclinical study and phase 2 trial of neoadjuvant pyrotinib combined with chemotherapy in luminal/HER2-low breast cancer: PILHLE-001 study.

The prognosis of patients with luminal/human epidermal growth factor receptor 2 (HER2)-low early breast cancer (EBC) needs to be improved. This preclinical study and phase 2 trial (ChiCTR2100047233) aims to explore the efficacy and safety of pyrotinib (a pan-HER tyrosine kinase inhibitor) plus chemotherapy in this population. Our preclinical experiments indicate a synergistic anti-tumor effect of pyrotinib plus chemotherapy in luminal/HER2-low (immunochemistry [IHC] 2+/fluorescent in situ hybridization [FISH]-negative) breast cancer models. Furthermore, 48 women with luminal/HER2-low (IHC 2+/FISH-negative) high-risk EBC are enrolled to receive neoadjuvant pyrotinib plus chemotherapy (epirubicin-cyclophosphamide followed by docetaxel). Ultimately, 26 (54.2%; 95% confidence interval [CI] 39.2%-68.6%) patients achieve the primary endpoint (residual cancer burden [RCB] 0/I). Treatment-related adverse events of grade ≥3 occur in 21 (43.8%) patients, with the most prevalent being diarrhea (10 [20.8%]). In conclusion, neoadjuvant pyrotinib plus chemotherapy has encouraging efficacy and manageable toxicity in women with luminal/HER2-low (IHC 2+/FISH-negative) high-risk EBC. This regimen warrants to be further validated.

Zebrafish Experimental Animal Models for AD: A Comprehensive Review.

AD disease (AD) is a multifaceted and intricate neurodegenerative disorder characterized by intracellular neurofibrillary tangle (NFT) formation and the excessive production and deposition of Aβ senile plaques. While transgenic AD models have been found instrumental in unravelling AD pathogenesis, they involve cost and time constraints during the preclinical phase. Zebrafish, owing to their simplicity, well-defined behavioural patterns, and relevance to neurodegenerative research, have emerged as a promising complementary model. Zebrafish possess glutaminergic and cholinergic pathways implicated in learning and memory, actively contributing to our understanding of neural transmission processes. This review sheds light on the molecular mechanisms by which various neurotoxic agents, including okadaic acid (OKA), cigarette smoke extract, metals, and transgenic zebrafish models with genetic similarities to AD patients, induce cognitive impairments and neuronal degeneration in mammalian systems. These insights may facilitate the identification of effective neurotoxic agents for replicating AD pathogenesis in the zebrafish brain. In this comprehensive review, the pivotal role of zebrafish models in advancing our comprehension of AD is emphasized. These models hold immense potential for shaping future research directions and clinical interventions, ultimately contributing to the development of novel AD therapies.

New promising antiseptics for individual antiviral protection against seasonal infections including COVID-19

Seasonal viral infections of the upper respiratory tract are widespread throughout the world. The SARS-CoV-2 pandemic has revealed the importance of timely personalized prevention of acute viral diseases and related bacterial complications. One of the main directions in the preventing viral infections relies on the development of effective antiseptics to inactivate viruses on the hands and mucous membranes. To effectively destroy SARS-CoV-2, the WHO recommends two antiseptics: a 70% ethanol solution and sodium hypochlorite. The proposed antiseptics are outdated and have an irritating effect on the skin and mucous membranes. In connection with this, a promising research direction includes development of new antiseptics with selective toxicity, low volatility, low coefficients in the oil-water system, weak lipophilic properties, low absorption into the vacuolar skin structures and low content of toxic impurities. One of these antiseptics is anavidin. The development and selection of molecules has been carried out, the next planned stage will be assessment of the effectiveness and safety of new molecules, including preclinical and early phase clinical trials, also analyzing prevention of viral infections, e.g. COVID-19.

Bayesian modeling for analyzing heterogeneous response in preclinical mouse tumor models.

In anticancer research, tumor growth measured in mouse models is important for assessing treatment efficacy for a treatment to progress to human clinical trials. Statistical analysis of time-to-event tumor volume data is complex because of heterogeneity in response and welfare-related data loss. Traditional statistical methods of testing the mean difference between groups are not robust because they assume common responses across a population. Heterogeneity in response is also seen in the clinic, and consequently, the assessment of the treatment considers the diversity through classification of the individual's response using the RECIST (Response Evaluation Criteria in Solid Tumors). To provide a comparable and translatable assessment of in vivo tumor response, we developed a statistical method called INSPECT (IN vivo reSPonsE Classification of Tumors) for analyzing heterogeneous responses through Bayesian modeling. This method can classify individual tumor behaviors into the categories of nonresponder, modest responder, stable responder, and regressing responder. Using both published and simulated data, we show that INSPECT methodology is more accurate and sensitive than existing methods with respect to balancing false-negative and false-positive rates. A case study demonstrates the value of INSPECT in drug projects for supporting the translation of drug efficacy from the preclinical phase into clinical trials. We also provide a package, "INSPECTumours," that launches a web interface to enable users to conduct the analysis and generate reports.

Therapeutic targeting of the protein tyrosine kinase-7 in cancer: an overview.

The protein tyrosine kinase-7 (PTK7) is an evolutionarily conserved transmembrane receptor that has emerged as a potential therapeutic target for human tumors. PTK7 is a pseudokinase that is involved in the modulation of the Wnt signaling pathway through interactions with other receptors. These interactions result in targeted gene activation that regulates cell polarity, migration, and proliferation during embryogenesis. Aside of this role during development, PTK7 has been shown as overexpressed in numerous cancers including colon carcinoma, leukemia, neuroblastoma, hepatoma, and ovarian cancer. The activity of PTK7 and the direct correlation with poor prognosis have fostered preclinical investigations and phase I clinical trials, aiming at inhibiting PTK7 and inducing antitumoral effects. In this review, we provide an exhaustive overview of the diverse approaches that use PTK7 as a new molecular target for cancer therapy in different tumor types. We discuss current therapies and future strategies including chimeric antigen receptor-T cells, antibody-drug conjugates, aptamers, based on up-to-date literature and ongoing research progress.

A multi-national survey-based evaluation of undergraduate/predoctoral endodontic education.

To evaluate the current status of endodontic education and assessment at an undergraduate/predoctoral level in dental schools worldwide. The current survey comprised a 50-item online questionnaire related to undergraduate endodontic education. The project leaders emailed the survey's details to faculty members responsible for endodontic teaching at one dental school in every country to seek their willingness to participate in the survey. After the faculty members accepted, the survey details were sent to participants along with the survey link. Simple descriptive statistics were used to represent the data. Amongst the 44 faculty members from different countries who agreed to participate, 36 completed the survey. Endodontic training starts in 50% of dental schools from the third year of the curriculum. Each dental school employs a diverse range of educational methods. During pre-clinical training, 19.4% of the participating dental schools used only natural teeth. Stainless-steel hand instruments, syringe irrigation with a needle, resin-based sealer and the cold lateral compaction technique are the most frequently used in pre-clinical and clinical training. A significant percentage of dental institutions necessitate that students treat a predetermined quantity of canals or teeth throughout their pre-clinical and clinical education. Dental institutions conduct formative, summative or a combination of the formative and summative throughout the clinical and pre-clinical phases of endodontic training. According to the data collected from this survey, there are considerable variations in the curriculum for undergraduate/predoctoral endodontic programmes amongst the surveyed dental schools. Pre-clinical and clinical education should integrate a larger array of modern tools and procedures.

Insights in Nutrition to Optimize Type 1 Diabetes Therapy

Nutrition is an essential part of therapy for type 1 diabetes and is constantly evolving, offering growing opportunities to prevent this disease, slow down its evolution, and mitigate it. An attempt was made to bring together the current state of knowledge. In the path from the preclinical phase of the disease to its clinical onset, there is a phase known as the “honeymoon period” or partial remission, where different possible dietary options for combatting this disease have been presented. The most commonly used dietary models were compared, and the most frequent co-existing pathologies, such as overweight, non-alcoholic fatty liver disease, dyslipidemia, celiac disease, and metabolic instability, were addressed from their nutritional and dietary perspectives to provide clinicians with an updated framework of knowledge and support researchers in further investigations into the topic. Finally, a glimpse into the possible interplay between nutrition and the gut microbiome, food security, and ultra-processed food is provided. It is hoped that clinicians treating people with type 1 diabetes will be provided with further opportunities for the daily management of their patients through personalized nutrition.

Activation of a Soft Robotic Left Ventricular Phantom Embedded in a Closed-Loop Cardiovascular Simulator: A Computational and Experimental Analysis.

Cardiovascular simulators are used in the preclinical testing phase of medical devices. Their reliability increases the more they resemble clinically relevant scenarios. In this study, a physiologically actuated soft robotic left ventricle (SRLV) embedded in a hybrid (in silico- in vitro) simulator of the cardiovascular system is presented, along with its experimental and computational analysis. A SRLV phantom, developed from a patient's CT scan using polyvinyl alcohol (PVA), is embedded in a hybrid cardiovascular simulator. We present an activation method in which the hydraulic pressure external ( ) to the SRLV is continuously adapted to regulate the left ventricular volume ( ), considering the geometry and material behavior of the SRLV and the left ventricular pressure ( ). This activation method is verified using a finite element (FE) model of the SRLV and validated in the hybrid simulator. Different hemodynamic profiles are presented to test the flexibility of the method. Both the FE model and hybrid simulator could represent the desired in silico data ( , ) with the implemented activation method, with deviations below 8.09% in the FE model and mainly < 10% errors in the hybrid simulator. Only two measurements out of 32 exceeded the 10% threshold due to simulator setup limitations. The activation method effectively allows to represent various pressure-volume loops, as verified numerically, and validated experimentally in the hybrid simulator. This work presents a high-fidelity platform designed to simulate cardiovascular conditions, offering a robust foundation for future testing of cardiovascular medical devices under physiological conditions.

External validation of dementia prediction models in Black or African American and White older adults: A longitudinal population-based study in the United States.

Identifying people at high risk of Alzheimer's disease (AD) dementia allows for timely intervention, which, if successful, will result in preventing or delaying the onset of the disease. Utilizing data from the Chicago Health and Aging Project (CHAP; n=2130), we externally evaluated four risk-prediction models for AD dementia, including Cardiovascular Risk Factors, Aging, and Dementia (CAIDE), Australian National University Alzheimer's Disease Risk Index (ANU-ADRI), Brief Dementia Screening Indicator (BDSI), and Dementia Risk Score (DRS), in Black or African American and White adults. BDSI had the highest discriminate abilities for AD dementia (c-statistics of 0.79 in Black and 0.77 in White adults), followed by ANU-ADRI, within the age range and follow-up period of the original development cohort. CAIDE had the lowest discriminating power (c-statistic≤0.55). With increasing follow-up periods (i.e., 10-15 years), the discrimination abilities for all models declined. Because of racial disparities in AD dementia and longer preclinical and prodromal stages of disease development, race-specific models are needed to predict AD risk over 10 years. Utilizing risk-prediction models to identify individuals at higher risk of Alzheimer's disease (AD) dementia could benefit clinicians, patients, and policymakers. Clinicians could enroll high-risk individuals in clinical trials to test new risk-modifiable treatments or initiate lifestyle modifications, which, if successful, would slow cognitive decline and delay the onset of the disease. Current risk-prediction models had good discriminative power during the first 6 years of follow-up but decreased with longer follow-up time. Acknowledging the longer preclinical phase of AD dementia development and racial differences in dementia risk, there is a need to develop race-specific risk-prediction models that can predict 10 or 20 years of risk for AD and related dementias.

Mechanisms and functions of the cerebral-cognitive reserve in patients with Alzheimer's disease: a narrative review

BACKGROUND: The need for scientific knowledge about aging is predicated on the demand of modern society to extend the active life of a person. To maintain intellectual longevity, it is necessary to take into account not only the pathological, but also compensatory mechanisms that arise during aging. The cerebral-cognitive reserve (CCR) influences the rate of transition from pre-phenomenological stages to the clinical stage of the disease, thereby changing the prognosis of Alzheimer’s disease (AD). AIM: The aim of this work was to review meta-analyses from studies that have examined the principles and functions of the CCR in people with AD. METHODS: The work included 83 scientific publications devoted to the issues of the CCR in neurodegenerative diseases such as AD. The Results and Discussion sections of this article provide reviews of the results of 12 meta-analyses published from 2012 to 2024 and selected from the PubMed and eLibrary databases using the following keywords in English and Russian: “cerebral reserve”, “cognitive “reserve”, and “Alzheimer’s disease”. The scope of the definition was not limited, since the goal here was to determine the terminological boundaries of the concepts of “cognitive reserve” and “single brain reserve”. RESULTS: The modern understanding of AD as a biological continuum covering the preclinical, prodromal, and clinical phases of the disease makes it possible to infer that insufficiency of protective factors underlies the progression of AD. The cognitive reserve is involved in the sanogenetic protective mechanism during neurodegeneration. The cognitive reserve is a theoretical concept that reflects modern research’s understanding of how the integrative functioning of the brain (cerebral) and cognitive reserves extend the period of active intellectual longevity through energy-saving mechanisms. It considers these mechanisms as central to healthy mental activity and in slowing the progression of neurodegenerative diseases. At some point, an increase in excess interneuronal activity that reflects the hypercompensatory function of the reserve would accelerate the depletion of brain structures and contribute to clinical and psychopathological manifestations of AD. CONCLUSION: The concept of the CCR puts the spotlight on the need to determine the compensatory indicators of cognitive deficit in AD, assess the architecture and volume of the reserve, and develop and follow protocols for its maintenance. It appears just as crucial to adopt measures to prevent the Reserve’s depletion as early as at the preclinical stages of the disease. Elaborating protective and compensatory mechanisms that help to maintain the functional activity of the brain in conditions of neurodegeneration, that is, CCR, require further research and can form a conceptual basis for the prevention of AD, starting from the preclinical stages of the disease.

Disease coverage of human genome-wide association studies and pharmaceutical research and development

BackgroundDespite the growing interest in the use of human genomic data for drug target identification and validation, the extent to which the spectrum of human disease has been addressed by genome-wide association studies (GWAS), or by drug development, and the degree to which these efforts overlap remain unclear.MethodsIn this study we harmonize and integrate different data sources to create a sample space of all the human drug targets and diseases and identify points of convergence or divergence of GWAS and drug development efforts.ResultsWe show that only 612 of 11,158 diseases listed in Human Disease Ontology have an approved drug treatment in at least one region of the world. Of the 1414 diseases that are the subject of preclinical or clinical phase drug development, only 666 have been investigated in GWAS. Conversely, of the 1914 human diseases that have been the subject of GWAS, 1121 have yet to be investigated in drug development.ConclusionsWe produce target-disease indication lists to help the pharmaceutical industry to prioritize future drug development efforts based on genetic evidence, academia to prioritize future GWAS for diseases without effective treatments, and both sectors to harness genetic evidence to expand the indications for licensed drugs or to identify repurposing opportunities for clinical candidates that failed in their originally intended indication.

Evaluation of Cardiotoxicity of Cancer Chemotherapeutics Using Daphnia magna as a Preclinical Model.

One of the major concerns following cancer treatment is cardiotoxicity. Therefore, it is important to predict potential cardiotoxicity of cancer chemotherapeutics at the preclinical phase. Current models of cardiotoxicity testing involve either cell culture models or rodent models. We developed a simple invertebrate animal model for rapid screening of cardiotoxicity of cancer chemotherapeutics. Daphnia magna (water flea, a crustacean) has a transparent body and a large myogenic heart that can be easily monitored under a microscope. Using this model, we have previously described comparative cardiotoxicity of several kinase inhibitors that were approved for the treatment of multiple cancers. In this article, we describe the step-wise protocols for evaluating the heart rate and survival of D. magna with relevant information on troubleshooting. © 2024 Wiley Periodicals LLC. Basic Protocol 1: Culturing and maintenance of D. magna Basic Protocol 2: Experimental design for evaluating heart rate of Daphnia Basic Protocol 3: Long-term effect on Daphnia survival upon drug exposure.

The effect of rituximab on patient reported outcomes in the preclinical phase of rheumatoid arthritis: 2 year data from the PRAIRI study

ObjectivesEarly treatment of individuals at risk of developing rheumatoid arthritis (RA-risk) in the preclinical phase has the potential to positively impact both patients and society by preventing disease onset and...

Advances in Drug Delivery Systems for the Treatment of Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is a common and catastrophic hematological neoplasm with high mortality rates. Conventional therapies, including chemotherapy, hematopoietic stem cell transplantation (HSCT), immune therapy, and targeted agents, have unsatisfactory outcomes for AML patients due to drug toxicity, off-target effects, drug resistance, drug side effects, and AML relapse and refractoriness. These intrinsic limitations of current treatments have promoted the development and application of nanomedicine for more effective and safer leukemia therapy. In this review, the classification of nanoparticles applied in AML therapy, including liposomes, polymersomes, micelles, dendrimers, and inorganic nanoparticles, is reviewed. In addition, various strategies for enhancing therapeutic targetability in nanomedicine, including the use of conjugating ligands, biomimetic-nanotechnology, and bone marrow targeting, which indicates the potential to reverse drug resistance, are discussed. The application of nanomedicine for assisting immunotherapy is also involved. Finally, the advantages and possible challenges of nanomedicine for the transition from the preclinical phase to the clinical phase are discussed.

Longitudinal Assessment of Retinal Microvasculature in Preclinical Alzheimer's Disease.

To investigate if changes in vessel density (VD) and the foveal avascular zone (FAZ) occur in the preclinical phase of Alzheimer's disease (pAD) over time. Optical coherence tomography angiography (OCTA) was used to image VD and FAZ at baseline and for a follow-up period of 2years. Positron emission tomography (PET) was used to determine the amyloid beta (Aβ) status of participants. The VD and FAZ of 148 participants (54% female) were analyzed at baseline and follow-up (mean time between measurements, 2.24 ± 0.35years). The mean age of the participants was 68.3 ± 6.0years at baseline and 70.3 ± 5.9years at follow-up. Participants were divided into three groups: control group, participants who had negative Aβ status at both measurements (Aβ-, n = 116); converter group, participants who transitioned from negative to positive between baseline and follow-up (Aβ-+, n = 18); and participants who were consistently positive at both visits (Aβ++, n = 14). The VD of both Aβ+ groups demonstrated non-significant increases over time in both macula and optic nerve head (ONH) regions. The Aβ- group was found to be significantly higher in both ONH and macular regions. The VD of the Aβ++ group was significantly higher in the macula inner and outer rings compared to the Aβ-+ and Aβ- groups. No significant change was found in FAZ values over time. Alterations in VD seem to manifest already in pAD, exhibiting distinct variations between the ONH and macula. Further longitudinal studies with a longer follow-up design and known amyloid pathology should be undertaken to validate these observations.

EVALUATING THE DENTAL LEARNING ENVIRONMENT: A STUDENT-CENTRIC PRESPECTIVE ACROSS PRECLINICAL AND CLINICAL YEARS USING DUNDEE READY EDUCATION ENVIRONMENT MEASURE (DREEM) TOOL

Objectives: The learning environment has a profound role in students learning and success. It also has an integral role in the development of the curriculum. The aim of this study to evaluate the learning environment and compare dental students' perception of the learning environment of pre-clinical and clinical years. Materials and Methods: This cross-sectional study was conducted from October 2023 to April 2024. A total of 170 both male and female BDS students from all four years at the Bacha Khan College of Denistry were included in the study. A stratified random Sampling Method was used. Students migrated from other colleges in the middle of the sessions and students currently working as interns or house officers were excluded from the study. Dundee Ready Education Environment Measure (DREEM), a 50-item questionnaire that uses a 5-point Likert scale (4 = strongly agree to 0 = strongly disagree) was used to measure strength of agreement with statements on five domains of learning. Learning (L), Teaching (T), Academic self-perception (ASP), Atmosphere (A) and Social self-perception (SSP). Frequency distributions and descriptive statistics were tabulated in IBM SPSS (version 21). Mean scores for each dimension of learning were used for analysis. Comparative analysis was done using independent sample t test. Results: The DREEM questionnaire was completed by 147 students, 78 1st and 2nd year students (preclinical training phase) while 69 3rd and 4th year students. 34.6% of the participants were male and 66.6% were female. The mean age of the participants was 21.4 years (SD=1.72). Tukey's post hoc analysis within the participants revealed a significantly lower DREEM score of the Final year compared with the 1st year (p &lt; .003), and 3rd year (p&lt; 0.031). The items within each domain with the biggest signifi cant differences (p ≤ 0.05) was between Pre-Clinical Training Phase and Clinical training. Conclusion: This study examined the educational setting in our institution. The students of Bacha Khan College of Dentistry showed a predominantly satisfaction with their educational environment. The primary results indicated that students in the early stages of their studies, namely those in their pre-clinical years had positive opinions across all aspects of their learning environment. Overall, the findings from the study highlight the importance of understanding how students perceive their educational environment throughout diff erent stages of their dental training. By delving deeper into these differences and correlations, educators and administrators can make informed decisions to enhance the curriculum and ultimately improve the learning experience for students. This implies that a more tailored and effective approach to dental education could lead to better outcomes and preparedness for future dental professionals.