Clinical Demands Research Articles

10.I. Scientific session: A National E-Infrastructure for Aging Research to Improve Public Health

Abstract Global life expectancy gains over the last half-century are remarkable. Yet the resulting demographic shift towards an older population poses substantial public health challenges, particularly in healthcare. To address these challenges, a profound and scientifically-based understanding of older adults’ health and care requirements is needed. Recognizing the need for a better understanding of the aging process and public health challenges, the National E-infrastructure for Aging Research (NEAR) was founded in 2018. NEAR seeks to promote and support aging research by facilitating longitudinal population-based data usage from 15 well-known Swedish cohort studies on aging and health. It is based on a collaboration between eight Swedish universities and includes 15 databases with individual assessments. NEAR comprises a broad range of biomedical, clinical, social, and psychological health data from more than 90,000 adults who are 50+ years old. These individuals have been followed between 12 and 52 years. The objective of this workshop is to give an overview of the NEAR infrastructure, present results from three ongoing NEAR projects, and their implications for public health: 1) Temporal trends in dementia incidence in Sweden; 2) Personality and biomarkers of neurodegeneration and Alzheimer’s disease in Swedish older adults, and 3) Characterizing risk profiles and transitions across living and care settings in Sweden. Infrastructures such as NEAR offer high-quality epidemiological data for achieving broad, interdisciplinary research goals that single databases often cannot provide. Moreover, the value added to these kinds of data includes enhanced sample sizes, variations, representativeness, and generalizability. In turn, this can address an aging society’s public and clinical health demands. Eventually, this could lead to sustainable intervention strategies for improving older persons’ health in the coming decades. Key messages • Discover new avenues in public health aging research: Gain insights into cutting-edge aging research opportunities in Sweden, exploring key NEAR projects. • Recognize the value of national infrastructures using high-quality epidemiological data in fostering collaborative and nationally representative public health research.

Ketamine and chronic treatment-resistant depression: real-world practice and after relapse

BackgroundChronic treatment-resistant depression (TRD) poses a major challenge for clinicians. Ketamine has shown a rapid but short-lived antidepressant effect in several studies involving TRD patients with different demographic and clinical profiles. Our study aimed to assess the antidepressant effect of serial infusion sessions of ketamine in patients with chronic TRD and evaluate the severity of symptoms after relapse and the general psychiatric health of the responding patients.MethodsIn this single arm open-label study, six infusions of ketamine at 0.5 mg/kg were administered to chronic TRD patients for approximately two weeks. Response and remission rates, side effects, adverse events and after-relapse symptoms were evaluated, and patients were followed for three months.Results23 patients underwent at least one infusion session, and 18 patients completed the six sessions. Twelve (66.67%) patients responded to the treatment at some point, and 11 (61.11%) patients maintained response after the end of the treatment protocol. One infusion was not sufficient to achieve a response (P > 0.9999, z = 1.81), and more than half of the responders met the response criteria after the third infusion. Only one patient (5.56%) achieved remission at the end of the infusion phase. All but one ketamine responders relapsed within one month after the end of the treatment. There was no statistical difference between baseline and after-relapse MADRS scores (P = 0.7886, 95% CI=-5.512-4.312, R2 = 0,008411). However, a high incidence of serious adverse events related to suicidality was evident; one of the non-responding patients attempted suicide and several attempts to sedate this patient with benzodiazepines failed. Two responding patients ended up with a suicidal attempt or severe suicidal thoughts.ConclusionsIntroducing rapid-acting antidepressant to manage TRD patients in clinical practice demands further investigation, and the benefit-to-harm ratio should be assessed in the light of the increased risk of suicidality.

Widefield optical coherence tomography by electro-optical modulation

Optical coherence tomography (OCT) is a unique imaging modality capable of axial sectioning with a resolution of only a few microns. Its ability to image with high resolution deep within tissue makes it ideal for material inspection, dentistry, and, in particular, ophthalmology. Widefield retinal imaging has garnered increasing clinical interest for the detection of numerous retinal diseases. However, real-time applications in clinical practice demand the contrast of swept-source OCT at scan speeds that limit their depth range. The curvature of typical samples, such as teeth, corneas, or retinas, thus restricts the field-of-view of fast OCT systems. Novel high-speed swept sources are expected to further improve the scan rate; however, not without exacerbating the already severe trade-off in depth range. Here, we show how, without the need for mechanical repositioning, harmonic images can be rapidly synthesized at any depth. This is achieved by opto-electronic modulation of a single-frequency swept source laser in tandem with tailored numerical dispersion compensation. We demonstrate experimentally how real-time imaging of highly-curved samples is enabled by extending the effective depth-range 8-fold. Even at the scan speed of a 400 kHz swept source, harmonic OCT enables widefield retinal imaging.

Gábor Transform-Based Antibody Quantitation in Serum: An Interlaboratory Liquid Chromatography/High-Resolution Mass Spectrometry Investigation.

Therapeutic monoclonal antibodies (t-mAbs) are crucial for treating various conditions, including cancers and autoimmune disorders. Accurate quantitation and pharmacokinetic monitoring of t-mAbs in serum are essential, but current methods like ligand binding assays (LBAs) and bottom-up peptide liquid chromatography-tandem mass spectrometry (LC-MS/MS) can lack the sensitivity and specificity needed to meet clinical demands. Emerging techniques using high-resolution mass spectrometry (HRMS) in top-down and middle-up approaches offer improved ability to accurately quantify mAb proteoforms apart from degradation products by keeping the sample proteins intact or minimizing digestion. This study describes the first use of Gábor transform (GT)-based iFAMS Quant+ software to quantify a t-mAb (vedolizumab) from ∼400 samples using an Agilent 6545XT AdvanceBio Q-TOF at the University of Oregon. These results are compared to a previously validated laboratory-developed test (LDT) from Mayo Clinic utilizing a Thermo Q Exactive Plus Orbitrap. The Mayo method used conventional extracted ion chromatograms (XICs) of select charge states for quantitation, while the iFAMS Quant+ method utilized GT-based charge state deconvolution, background subtraction, and signal integration. Calibration and quality control (QC) analyses and Passing-Bablok regression of 351 subject samples demonstrated excellent agreement between the two methods. The iFAMS Quant+ workflow exhibited unique advantages for characterizing interferents and analyte signal anomalies due to its deconvolution-based approach.

3D bioprinting for drug development and screening: Recent trends towards personalized medicine

Personalized medicine, leveraging patient-specific genomic data, is revolutionizing treatment paradigms by enabling tailored therapies to individual needs, thus mitigating adverse effects and enhancing clinical outcomes. One innovative application in this field is the use of 3D bioprinting technology to design, develop and screen patient-customized medicines. This technology meticulously designs and develops therapeutic drugs by depositing active pharmaceutical ingredients layer by layer, culminating in a drug delivery structure optimized for the patient's unique dosage requirements. 3D bioprinting represents an emerging confluence of biological sciences and additive manufacturing, meeting the clinical demand for functional biological tissues through the integration of printing technologies, regenerative medicine principles, and advanced material science. This review provides an overview of the current state of 3D bioprinting applications and explores the transformative potential of 3D bioprinting in personalizing medicine. Moreover, the review elucidates the capabilities of 3D bioprinting in drug design, facilitating the production of complex therapeutic regimens in specific dosage forms, such as drugs with tailored dose concentrations, controlled release kinetics, and the capacity to combine multiple therapeutic regimens into a single, easy-to-administer format. This paper also addresses the challenges and obstacles faced in integrating 3D bioprinting techniques into pharmaceutical practice, ranging from technical and regulatory hurdles to scalability. Further, the efficacy of 3D bioprinting as a tool for advancing personalized medicine helps to utilize the full potential of this technology to enhance patient healthcare regimes.

'Facilitators and barriers to recruitment in mental health research: A survey of psychiatrists and psychiatry registrars in training'.

To explore the attitudes of Royal Australian and New Zealand College of Psychiatrists (RANZCP) consultants and registrars towards recruitment of patients in mental health research. Specifically, we aimed to measure potential barriers and facilitators for recruitment and comment on strategies for improvement. A survey was distributed to 287 consultant and trainee psychiatrists working across South Australian public mental health services. The survey was hosted via SurveyMonkey and ran for 5weeks from April to June 2023. Participant's attitudes were recorded through use of Likert scale, yes/no and free-text response. In total, 88 responses were collected, corresponding to a 30.7% response rate. Participants were interested in mental health research, with 90.7% reading articles and 61.4% reporting personal research engagement. The factors that rated most highly as recruitment barriers were unawareness of current studies, competing clinical demands and not prioritising recruitment. Factors felt most strongly to facilitate recruitment included the presence of an onsite research assistant and the clinician viewing the trial as clinically relevant. While attitudes towards research were generally positive, many barriers to recruitment were identified. Increased advertising of current studies, presence of an onsite research assistant and reduction in clinicians' workload are likely to improve clinicians' capacity to recruit.

Opportunities and challenges in the development of artificial intelligence research in spinal surgery

Artificial intelligence has emerged as a game-changer in the field of spine surgery, offering transformative diagnostic and therapeutic approaches for spinal conditions. The application of AI in spine research encompasses a diverse range of diseases, with usage scenarios becoming increasingly widespread and technological integration going deeper. AI technology shows immense promise and value in the diagnosis of spinal diseases, the formulation of treatment strategies, surgical navigation, prognostic evaluation, and postoperative rehabilitation. Through deep learning and machine learning, AI can aid doctors in enhancing diagnostic accuracy, creating personalized treatment plans, and executing precise maneuvers during surgery, thus improving operational safety. Moreover, AI can provide intelligent support for patients' postoperative recovery, facilitating the restoration of their functions. However, current research is still in its nascent stage and confronts several challenges, such as the lack of standardized databases, the simplicity of algorithmic learning models, the inadequate fusion of multi-modal clinical information, and the limited clinical applicability. By developing open-source, standardized spine databases, incorporating innovative intelligent core algorithms, and establishing normalized screening, diagnostic, and predictive models for spinal conditions, we trust that we can drive the innovation and refinement of diagnostic and treatment technologies in spine surgery. This will realize an effective conjunction between technological provision and clinical demands, continuously elevating the intelligence level of spine surgery and offering safer, more effective medical services to a vast array of patients.

Design and Improvement of Bone Adhesive in response to Clinical Needs.

Fracture represents one of the most common diagnoses in contemporary medical practice, with the majority of cases traditionally addressed through metallic device fixation. However, this approach is marred by several drawbacks, including prolonged operative durations, considerable expenses, suboptimal applicability to comminuted fractures, increased infection risks, and the inevitable requirement for secondary surgery. The inherent advantages of bone adhesives in these fields have garnered the attention of orthopedic surgeons, who have commenced utilizing biocompatible and biodegradable bone adhesives to bond and stabilize bone fragments. Regrettably, the current bone adhesives generally exhibit insufficient adhesive strength in vivo environments, and it is desirable for them to possess effective osteogenesis to facilitate fracture healing. Consequently, aligning bone adhesives with practical clinical demands remains a significant hurdle, which has catalyzed a surge in research endeavors. Within this review, the conceptual framework, characteristics, and design ideas of bone adhesives based on clinical needs are delineated. Recent advancements in this domain, specifically focusing on the enhancement of two pivotal characteristics-adhesive strength and osteogenic potential are also reviewed. Finally, a prospective analysis of the future advancements in bone adhesives, offering new insights into solutions for diverse clinical problems is presented.

An Innovative, Collaborative, and Transformative Program to Enhance Off-Campus Clinical Faculty Engagement.

Off-campus (volunteer, community-based) clinical faculty, upon whom medical schools heavily depend, are an integral component of medical education. However, challenges hinder their involvement in medical school governance and other activities, including inadequate communication, lack of recognition, high clinical demands that may preclude teaching, and time-consuming non-clinical tasks. While faculty appointments offer benefits like free CME, access to library resources, and email communications, faculty often prioritize potential contributions to their teaching roles over these benefits. Our medical school launched a new initiative to tackle these issues head-on. We established an Office of Faculty Engagement (OFE) that leverages engagement strategies to enhance communication, broaden access to campus resources, and provide tailored rewards for clinicians. We rebranded volunteer clinical faculty as Off-Campus Faculty (OCF) to foster a more interactive relationship and innovative measures, including personalized welcome emails, a dedicated point of contact for OCF, a user-friendly website, regular orientations, faculty development programs, recognition and appreciation events, and exclusive awards. From August 2021 to December 2023, we contacted 587 OCF members; 85 faculty members experienced improved communication. This innovative approach streamlines and personalizes interactions with OCF, enhances their satisfaction, and represents a transformative opportunity to engage and involve OCF in medical education.

A novel rural hospital/clinic-system practice-based research network: the Rural Addiction Implementation Network (RAIN) initiative and its goals, implementation, and early results

ABSTRACT Background: Rural and frontier communities face high rates of opioid use disorders (OUDs). In 2021, the Rural Addiction Implementation Network (RAIN) sought to establish a rural hospital/clinic-system practice-based research network (RH-PBRN) to facilitate implementation of evidence-based addiction-related prevention, treatment, and recovery (PTR) services to reduce the morbidity of OUD and substance use disorder (SUD) in rural communities. Objective: To describe the goals and implementation of PTR activities of RAIN, a novel RH-PBRN. Methods: RAIN identified teams of external/internal facilitators at four rural hospitals/clinic-networks to achieve at least 15 PTR activities involving OUD and other SUDs. RAIN utilized an implementation-facilitation approach: facilitators assessed the implementation environment and promoted interventions to overcome barriers to PTR implementation. Other interventions included site visits, community of learning calls, and e-communication. RAIN assessed and recorded facilitators and barriers to implementation, milestone attainment, and outcomes of PTR activities. At 18 months, we queried facilitators about the fidelity and implementation of RAIN activities. Results: RAIN established an HP-PBRN in four sites (Idaho, Montana, Utah, and Wyoming). Within the HP-PBRN, 20 PTR activities were established (p = 7, T = 10, R = 3; range 3–7 per site). Barriers to implementation of PTR activities included competing clinical demands, especially due to COVID-19, lack of dedicated effort for staff at sites, and stigma of addiction and its treatment. Facilitators of implementation included the use of trained expert facilitators and communication between the sites. Conclusions: RAIN implemented 20 addiction-related PTR activities in four rural hospitals/clinic-networks. RAIN’s intervention model could be replicated to address addiction-related harms in other rural communities.

Distribution of Certified Pelvic Health Physical Therapists Across the United States

Purpose: Pelvic floor dysfunction (PFD) describes a range of impairments affecting people of all genders. Pelvic health physical therapy (PHPT), a first-line treatment option for PFD, has been associated with improvements in myriad related conditions. This study aimed to examine the number of PHPT specialists in the United States and each state individually in order to assess distribution of care. We hypothesized that this number is low when compared with the estimated demand for services. Methods: This descriptive cross-sectional study identified PHPT specialists as those with a Certificate of Achievement in Pelvic Health Physical Therapy (CAPP-Pelvic), a Women’s Health Clinical Specialist (WCS) Board Certification, or a Pelvic Rehabilitation Practitioner Certification (PRPC), as of May 31, 2022. Researchers utilized 3 online databases to identify 1135 PHPT providers across the US and compared statewide data with current state population to determine providers per million people. Results: The number of PHPT providers per state ranged from 1 (Vermont) to 119 (California). When compared to state population, the lowest PHPT provider ratio was approximately 1 per million people (Alabama) and the highest was approximately 8 per million people (Oregon). Discussion: The data indicate that the number of PHPT providers available varies by state. The number of PHPT providers in the US is low overall and relative to states’ populations. Given the prevalence of PFD in the US, it is unlikely that the total number of providers in most states is sufficient to meet clinical demands.

Patient and care team experiences with an EHR-integrated symptom management program (eSyM) in routine oncology practice.

324 Background: Clinical trials have shown that collecting electronic patient-reported outcomes (ePROs) improves quality of life and survival in cancer patients. To bolster integration of ePROs into routine care, the SIMPRO Research Consortium developed an electronic symptom management (eSyM) program, deployed it at six cancer centers, and conducted a hybrid effectiveness-implementation study. eSyM, an ePRO toolkit integrated into the Epic EHR, enables patients to report and care teams to triage symptoms in real-time. To assess eSyM, we conducted structured qualitative interviews with patients and clinic staff, including doctors, nurses, advanced practice providers, and administrative staff. We sought to understand eSyM from the patient and staff perspectives. Methods: Using an iterative process, we developed semi-structured interview guides to query the experiences and perceptions of patients and staff exposed to eSyM. Questions were informed by the Consolidated Framework for Implementation Research. One year after eSyM was launched, sites identified and referred participants for interviews or focus groups. Participants must have either used eSyM to submit symptoms (patients) or had access to eSyM at their institution (staff). Patients provided written consent; a consent waiver was obtained for staff. Interviews were recorded and transcribed, and a common analytic codebook was developed. Transcripts were dual or triple-coded and underwent thematic analysis to identify key contexts and concepts within and across patient and staff groups. Results: From 9/28/20 to 4/14/23, 50 staff participated in individual interviews and 29 participated in focus groups (79 total). From 9/14/23 to 3/14/24, 14 patient interviews were conducted. Transcripts revealed that staff and patients held similar beliefs regarding eSyM compatibility, communication, and prioritization. 93% (13/14) of patients and 72% (57/79) of staff believed eSyM was easy to use and improved communication. Both cohorts (66% staff, 36% patients) noted that competing demands often needed to be prioritized over responding to symptom concerns. Discordance emerged in the domains of receptivity and technology; patients were more receptive and capable of using eSyM than staff perceived. Both groups believed eSyM was helpful but perceived that deeper engagement from patients and staff was necessary for sustainability. Conclusions: Most interviewees reported that eSyM added value and was easy to navigate. Competing clinical demands, however, frequently deprioritized use of eSyM. Staff tended to underestimate patients’ receptivity to use eSyM and were more likely to cite competing demands as a barrier to their own use of eSyM. Sites looking to adopt eSyM, or similar ePRO programs, will benefit from understanding the facilitators that need to be incorporated and the barriers that need to be surmounted to optimize success. Clinical trial information: NCT03850912 .

Green synthesis of neuroprotective spirocyclic chalcone derivatives and their role in protecting against traumatic optic nerve injury

For clinically prevalent traumatic optic neuropathy (TON) and other retinal and optic nerve injuries lacking effective therapeutic agents, there is an urgent clinical demand for developing highly efficient and safe neuroprotective agents. Here, we have integrated naturally sourced chalcone with isatin through a catalyst-free green synthesis method, reporting a series of spirocyclic chalcone derivatives with significantly lower cytotoxicity than chalcone itself. Following in vitro cell protection assays in models of hydrogen peroxide and glutamic acid-induced damage, multiple active compounds capable of combating both forms of damage were identified. Among these, candidate compound X38 demonstrated promising neuroprotective prospects: in vitro, it attenuated glutamate-induced cell apoptosis, while in vivo, it effectively ameliorated retinal thinning and loss of optic nerve electrophysiological function induced by optic nerve injury. Preliminary mechanistic studies suggest that X38 exerts its neuroprotective effects by mitigating intracellular ROS accumulation, inhibiting JNK phosphorylation, and alleviating oxidative stress. Additionally, acute toxicity studies (intraperitoneal injection, 500 mg/kg) underscored the favorable in vivo safety profile of X38. Taken together, this study has designed a class of safe, neuroprotective spirocyclic chalcone derivatives that can be synthesized using green methods, offering an attractive candidate for treating retinal and optic nerve injuries.

Depth of Cure, Surface Characteristics, Hardness, and Brushing Wear of 4 Direct Restorative Materials in Paediatric Dentistry

Aim: The study aimed to compare the depth of cure, hardness, surface roughness, and wear resistance of four restorative materials used in pediatric dentistry: FUJI IX GP FAST, RivaSilver, SDR flow+, and Vertise Flow. Materials and Methods: The depth of cure was measured per ISO 4049 standards using a digital caliper, with 15 samples of each material. Hardness was evaluated using a Vickers indenter under a 10 N load for 20 s. Surface roughness was assessed before and after acid exposure using an optical profilometer according to ISO 4288. Brushing wear resistance was analyzed by subjecting samples to 20 and 60 min of brushing, followed by roughness measurements. Statistical analysis was performed using independent sample t-tests to determine the significance of differences between the materials, with p-values < 0.05 considered significant. Results: SDR flow+ exhibited the highest depth of cure with an average of 3.5 mm (±0.2 mm), significantly higher than Vertise Flow at 2.8 mm (±0.3 mm) (p < 0.001). Hardness testing revealed SDR flow+ had the highest average hardness (85 HV ± 4 HV), while Vertise Flow had the lowest (72 HV ± 5 HV) (p < 0.001). Surface roughness increased significantly after acid exposure for RivaSilver (from 1.2 μm ± 0.12 μm to 1.6 μm ± 0.15 μm, p = 0.007) and for SDR flow+ (from 0.85 μm ± 0.08 μm to 1.3 μm ± 0.14 μm, p = 0.001). Brushing wear resistance was highest in RivaSilver (Ra increase from 1.2 μm to 1.4 μm ± 0.11 μm) and lowest in FUJI IX GP FAST (Ra increase from 1.5 μm to 1.9 μm ± 0.15 μm, p < 0.001). Conclusions: The study demonstrates significant differences in performance among the tested materials. SDR flow+ showed a superior depth of cure and hardness, making it suitable for high-stress applications. However, all materials displayed increased surface roughness following acid exposure and brushing, with FUJI IX GP FAST showing the highest wear. These findings highlight the need to select restorative materials based on the specific clinical demands of pediatric patients, considering both their mechanical properties and resistance to wear and acid.

A self-gelling alginate/chitosan based powder containing bioactive nanoparticles for non-compressible bleeding control and promoting wound healing

The challenge remains in developing hemostatic dressings that can fulfill both hemostatic and repair functions to meet clinical demands worldwide. Herein, the biodegradable powders composed of benzeneboronic acid-modified sodium alginate/catechol-modified quaternized chitosan hydrogel (SBQCC) networks and bioactive cerium oxide nanoparticles (CNPs), were prepared for hemostasis and promoting wound healing. The SBQCC/CNPs powders had good self-gelation ability, water absorption ratio, tissue adhesiveness and biocompatibility. The SBQCC/CNPs powders could not only rapidly absorb a large amount of blood to concentrate coagulation factors when applied on bleeding wounds, but also formed an adhesive hydrogel physical barrier to control bleeding in situ. Meanwhile, the aggregation and activation of red blood cells and platelets induced by the SBQCC/CNPs powders can initiate the forming of internal blood clot with fibrin to further enhance the hemostatic effect. The SBQCC/CNPs powders demonstrated excellent hemostatic performance in non-compressible rat tail vein bleeding and rabbit liver bleeding models. In addition, SBQCC/CNPs powder-derived hydrogels had antibacterial activity and multiple biological activities, including antioxidant, anti-inflammatory and promoting angiogenesis for accelerating wound healing. Therefore, the SBQCC/CNPs powders can accelerate wound healing while achieving effective hemostasis, which will be a promising hemostatic dressing.

Clinical care ratios: differences in allied health roles in New Zealand.

ObjectiveAllied health workforce planning is difficult and needs to be informed by data. Clinical care ratios (CCR) are commonly used to differentiate between clinical and non-clinical demands. This study aimed to identify trends within and across allied health disciplines and determine if the CCR differed by allied health discipline within one New Zealand district.MethodsMeans of CCR data across six allied health roles over 1year were compared using a one-way ANOVA. Post hoc analysis was conducted to determine role differences.ResultsThere were statistically significant differences between the CCR of the six allied health disciplines. Both occupational therapy and physiotherapy had bimodal distributions of CCR. Allied health assistants had the lowest mean and median CCR.ConclusionsNon-clinical activity represents a significant proportion of allied health activity within the New Zealand hospital system. Insights into the CCR of allied health disciplines may support more effective workforce planning and enable service leaders to match the right task to the right profession.

Towards explainable oral cancer recognition: Screening on imperfect images via Informed Deep Learning and Case-Based Reasoning

Oral squamous cell carcinoma recognition presents a challenge due to late diagnosis and costly data acquisition. A cost-efficient, computerized screening system is crucial for early disease detection, minimizing the need for expert intervention and expensive analysis. Besides, transparency is essential to align these systems with critical sector applications. Explainable Artificial Intelligence (XAI) provides techniques for understanding models. However, current XAI is mostly data-driven and focused on addressing developers’ requirements of improving models rather than clinical users’ demands for expressing relevant insights. Among different XAI strategies, we propose a solution composed of Case-Based Reasoning paradigm to provide visual output explanations and Informed Deep Learning (IDL) to integrate medical knowledge within the system. A key aspect of our solution lies in its capability to handle data imperfections, including labeling inaccuracies and artifacts, thanks to an ensemble architecture on top of the deep learning (DL) workflow. We conducted several experimental benchmarks on a dataset collected in collaboration with medical centers. Our findings reveal that employing the IDL approach yields an accuracy of 85%, surpassing the 77% accuracy achieved by DL alone. Furthermore, we measured the human-centered explainability of the two approaches and IDL generates explanations more congruent with the clinical user demands.

Polymeric Microneedle Drug Delivery Systems: Mechanisms of Treatment, Material Properties, and Clinical Applications-A Comprehensive Review.

Our comprehensive review plunges into the cutting-edge advancements of polymeric microneedle drug delivery systems, underscoring their transformative potential in the realm of transdermal drug administration. Our scrutiny centers on the substrate materials pivotal for microneedle construction and the core properties that dictate their efficacy. We delve into the distinctive interplay between microneedles and dermal layers, underscoring the mechanisms by which this synergy enhances drug absorption and precision targeting. Moreover, we examine the acupoint-target organ-ganglion nexus, an innovative strategy that steers drug concentration to specific targets, offering a paradigm for precision medicine. A thorough analysis of the clinical applications of polymeric microneedle systems is presented, highlighting their adaptability and impact across a spectrum of therapeutic domains. This review also accentuates the systems' promise to bolster patient compliance, attributed to their minimally invasive and painless mode of drug delivery. We present forward-looking strategies aimed at optimizing stimulation sites to amplify therapeutic benefits. The anticipation is set for the introduction of superior biocompatible materials with advanced mechanical properties, customizing microneedles to cater to specialized clinical demands. In parallel, we deliberate on safety strategies aimed at boosting drug loading capacities and solidifying the efficacy of microneedle-based therapeutics. In summation, this review accentuates the pivotal role of polymeric microneedle technology in contemporary healthcare, charting a course for future investigative endeavors and developmental strides within this burgeoning field.

Tetrahydrocarbazoles incorporating 5-arylidene-4-thiazolinones as potential antileukemia and antilymphoma targeting tyrosine kinase and tubulin polymerase enzymes: Design, synthesis, structural, biological and molecular docking studies

Finding effective and selective anticancer agents is a top medical priority due to high clinical treatment demand. However, current anticancer agents have serious side effects and resistance development remains a big concern. This creates an urgent need for new multitarget drugs that could solve these problems. Tetrahydrocarbazoles and 5-arylidene-4-thiazolinones have always attracted researchers for their multifaced anticancer activities and the possibility to be easily derivatized. Thereby, herein we report the combination of the two scaffolds to provide compounds 9a-j and 10a-j that were fully characterized and their tautomeric form was confirmed by crystal structure. 9a-j and 10a-j wereassessedfor invitro antiproliferative activityusing SRB assay against a panel of seven human cancer cell lines with doxorubicin as the standard. The results revealed that the cell lines derived from leukemia (Jurkat) and lymphoma (U937) are the most sensitive. Compounds 9d, 10e, 10g, and 10f revealed the highest potency (IC50 = 3.11–11.89 μM) with much lower effects on normal lymphocytes cell line (IC50 > 50 µM). The results show that modifications at 6th position of the THC and the nature of the substituent at the arylidene moiety affect the activity. To exploit the mode of action, 9d, 10e, 10f, and 10g were evaluated as VEGFR-2 and EGFR inhibitors. 10e is the most potent (IC50 0.26 and 0.14 μM) against both enzymes. It also induced G0-G1-phase cell cycle arrest and apoptosis. While 10g exhibited higher potency (IC50 9.95 μM) than vincristine (IC50 15.63 μM) against tubulin. A molecular docking study was carried out to understand the interactions between 10e, 10g and their targets. This study reveals 10e and 10g as possible candidates for developing multitarget anticancer agents against leukemia and lymphoma.

GMP-compliant automated radiosynthesis of [18F] SynVesT-1 for PET imaging of synaptic vesicle glycoprotein 2 A (SV2A)

BackgroundA novel positron emission tomography (PET) imaging tracer, [18F] SynVesT-1, targeting synaptic vesicle glycoprotein 2 (SV2A), has been developed to meet clinical demand. Utilizing the Trasis AllinOne-36 (AIO) module, we’ve automated synthesis to Good Manufacturing Practice (GMP) standards, ensuring sterile, pyrogen-free production. The fully GMP-compliant robust synthesis of [18F] SynVesT-1 boosting reliability and introducing a significant degree of simplicity and its comprehensive validation for routine human use.Results[18F] SynVesT-1 was synthesized by small modifications to the original [18F] SynVesT-1 synthesis protocol to better fit AIO module using an in-house designed cassette and sequence. With a relatively small precursor load of 5 mg, [18F] SynVesT-1 was obtained with consistently high radiochemical yields (RCY) of 20.6 ± 1.2% (the decay-corrected RCY, n = 3) at end of synthesis. Each of the final formulated batches demonstrated radiochemical purity (RCP) and enantiomeric purity surpassing 99%. The entire synthesis process was completed within a timeframe of 80 min (75 ± 3.1 min, n = 3), saves 11 min compared to reported GMP automated synthesis procedures. The in-human PET imaging of total body PET/CT and time-of-flight (TOF) PET/MR showed that [18F] SynVesT-1 is an excellent tracer for SV2A. It is advantageous for decentralized promotion and application in multi-center studies.ConclusionThe use of AIO synthesizer maintains high production yields and increases reliability, reduces production time and allows rapid training of production staff. Besides, the as-prepared [18F] SynVesT-1 displays excellent in vivo binding properties in humans and holds great potential for the imaging and quantification of synaptic density in vivo.