Application gaps in Medicine

Representative open questions

Showing 30 of 481 — one per source paper, highest-quality first.

• The impact of traumatic injury on the respiratory system; a narrative review of injury-associated and clinically-induced mechanisms of trauma-associated pneumonia (2026) · doi

  The persistent inflammation, immunosuppression, and catabolism (PIICS) syndrome has been described in trauma patients, but specific interventions targeting the compensatory anti-inflammatory response (CARS) phase to prevent secondary pneumonia in this population require clinical trial development and validation.

• FDG-PET/CT based small volume accelerated immuno chemoradiotherapy in locally advanced NSCLC (PACCELIO) – a randomized, open-label, multicenter phase II trial protocol (2026) · doi

  The hypofractionated, accelerated CRT approach has been extensively studied in breast cancer but not systematically in locally advanced unresectable NSCLC. Direct comparative effectiveness data between this condensed schedule and conventional fractionation regarding toxicity profiles in adjacent organs at risk (esophagus, heart, lungs) specific to NSCLC geometry are lacking.

• Impact of Health Education and Preventive Interventions on Non- Communicable Diseases in Rural Communities: A Community-Based Randomized Controlled Trial (2026) · doi

  Participants in the control group failed to maintain weight loss due to lack of organized support for lifestyle choices, but the paper does not identify what specific support structures, follow-up frequencies, or community-based mechanisms are needed to sustain behavioral change in rural populations with hypertension and obesity.

• From organelles to therapy: rethinking combined hepatocellular-cholangiocarcinoma (2026) · doi

  Therapeutic targeting of organelle pathways including autophagy inhibitors, mitochondrial dynamics modulators, and ER stress inducers must be evaluated in preclinical cHCC-CCA models with systematic assessment of whether treatment efficacy correlates with the predominant lineage component (hepatocellular versus cholangiocarcinoma).

• Integration of biomedical imaging and sensing technologies with AI-IoT for Materiovigilance and predictive modeling of stillbirth risk in maternal-fetal health monitoring (2026) · doi

  Multi-modal AI systems capable of combining clinical, physiological, and molecular data for real-time stillbirth risk assessment have not been developed or clinically validated. Integration of continuous IoT monitoring with biomarker-based diagnostics to create personalized treatment pathways in precision obstetrics remains unexplored.

• Exercise benefits in metabolism on cardiovascular disease (2026) · doi

  The associations between sedentary behavior and cardiovascular disease mortality have been examined in meta-analyses of over 850,000 participants, but the differential effects across varying physical activity levels and exercise intensities in specific cardiovascular disease subpopulations (heart failure, coronary artery disease) warrant targeted investigation.

• Effectiveness of screening modalities for early detection of diabetic retinopathy: a systematic review and meta-analysis of tele-ophthalmology, AI-based tools, and conventional methods (2026) · doi

  Clinical informatics tools for DR screening workflow integration in primary care have been limited to EHR-enabled clinics with fundus imaging; practical implementation and workflow efficiency outcomes of AI-assisted screening in non-EHR primary care environments need evaluation.

• Unveiling the relationship of the comorbidity between depression and type 2 diabetes mellitus: a macro analysis and micro interpretation (2026) · doi

  The integrated treatment framework combining psychological interventions with metabolic management for depression and T2DM comorbidity lacks specification regarding implementation protocols in primary health care settings. Research is needed on translating HPA axis and BDNF-targeted interventions into practical primary care workflows across different healthcare systems.

• Artificial intelligence in acute and critical care: current challenges and strategic solutions (2026) · doi

  Human-in-the-loop quality control mechanisms for AI systems in acute and critical care lack concrete specifications regarding workflow integration, decision override protocols, and clinician feedback loops. The paper mentions this requirement but does not detail what specific human-AI interaction patterns should be validated or how to measure their effectiveness in real clinical environments.

• Bioactive and Ion-releasing materials in minimum intervention dentistry: a clinical pathway from prevention to restorative treatment (2026) · doi

  Integration of AI-assisted material selection with 3D printing and bioprinting technologies for producing patient-specific bioactive restorations requires validation studies measuring clinical outcomes in deep caries management with liners and dentin substitutes under selective caries removal protocols.

• Artificial intelligence approaches to predicting treatment non-adherence in chronic diseases: a narrative review (2026) · doi

  Relatively few studies have evaluated AI-based adherence prediction models prospectively in actual clinical workflows, highlighting a critical gap between methodological development and real-world implementation. Future research must assess technical success factors alongside organizational readiness, clinician engagement, governance oversight, and human-centered design considerations in resource-limited healthcare settings.

• Multimodal artificial intelligence in urologic precision oncology: from algorithm to translational medicine (a systemized narrative review) (2026) · doi

  PSMA-based imaging is advancing in localized and advanced prostate cancer (reference 28), but integration of quantitative PSMA-PET/CT radiomics features with deep learning-extracted histopathological features and clinical variables in unified multimodal AI models for treatment selection has not been thoroughly developed.

• Quercetin in metabolic diseases: mechanisms, therapeutics, and multidimensional frontiers (2026) · doi

  While the paper reviews quercetin's antidiabetic mechanisms in rodent models (streptozotocin-induced, db/db, high-fructose-fed rats), translation to human metabolic disease cohorts remains absent. Randomized controlled trials with quercetin nanoformulations in type 2 diabetic patients or obese individuals measuring insulin signaling biomarkers (phosphorylated Akt, glucose transporter expression), inflammatory cytokines (TNF-α, IL-6), and glucose homeostasis parameters are needed to establish clinical efficacy beyond animal models.

• Biochemical Markers In Seminal Plasma And Serum: A Comparative Assessment In Fertile And Infertile Men (2026) · doi

  Clinical studies directly correlating seminal plasma biomarkers with assisted reproductive technology outcomes are limited. Future longitudinal cohort studies must monitor how SP biomarkers for male fertility (Cu, SGOT, LDH, cholesterol) evolve over time and in response to different therapeutic drugs.

• Protocol for non-invasive assessment of skeletal muscle structure and function in adolescents with single ventricle heart disease: a cross-sectional, case-control study (2026) · doi

  The study aims to generate hypotheses supporting future exercise intervention trials (aerobic activation, strength training, hypertrophy) in the SV population, but no randomized controlled trials testing specific exercise interventions on skeletal muscle outcomes in SV adolescents have been designed or conducted.

• Cardiovascular Risk Prediction Using Machine Learning: Advances and Clinical Translation (2026) · doi

  Machine learning models trained on predominantly Western populations exhibit biased performance across different demographic groups in cardiovascular risk prediction, yet specific investigation is needed into which risk factors (age, blood pressure, cholesterol, comorbidities) show the greatest performance disparities and how fairness-aware algorithms should be designed for underrepresented populations.

• A sham-controlled randomised trial evaluating the safety, acceptability, and efficacy of autonomic neuromodulation using transcutaneous vagal sensory stimulation in uncontrolled hypertensive patients: rationale and study design of the SCRATCH-HTN study (2026) · doi

  The study's efficacy threshold is defined as >10 mmHg reduction in systolic blood pressure lasting >1 month post-discontinuation, but does not establish whether this criterion applies uniformly across subpopulations with different baseline hypertension severity, medication burden, or comorbidities in uncontrolled hypertensive patients.

• Medical clinical minds meet artificial intelligence: Italian physicians' knowledge, attitudes, and concordance between Italian physicians and AI-generated diagnoses. A national cross-sectional study (2026) · doi

  The study identified that excessive confidence in AI-physician concordance could lead to 'collective blindness' in atypical or rare cases, but provides no empirical framework or methodology to detect, quantify, or mitigate this risk in integrated clinical workflows. Future research must develop specific metrics to identify and prevent shared diagnostic limitations.

• Deep learning-based differential diagnosis of major depression and bipolar disorder using microglia-cellular sensors and patient-derived small extracellular vesicles (2026) · doi

  The 24-hour sEV incubation period and image acquisition pipeline have been evaluated for turnaround time feasibility, but clinical workflow integration using automated high-content imaging platforms (Opera Phenix, ImageXpress Micro Confocal) has not been prospectively validated in multi-site clinical settings for mood disorder diagnosis.

• An Ontology Driven Machine Learning Framework for Early Prediction in Children with Cerebral Palsy (2026) · doi

  Continuous monitoring and ontology evolution procedures are mentioned as necessary for model longevity in the GMFCS classification framework, but specific protocols for detecting when ontological concepts require updating based on emerging clinical evidence or distributional drift in pediatric cerebral palsy populations are not defined.

• Hyperbaric Medicine Practice, 3rd Edition (2010) · doi

  The current state-of-the-art for HBO use with skin grafts, flaps, and free tissue transfers in the context of cancer, trauma, and burn therapy is not addressed in the textbook. Specific clinical protocols and efficacy data for HBO as adjuvant therapy in reconstructive surgery involving tissue transfers require documentation.

• Psychiatric conditions in palliative medicine (2020) · doi

  Almost 50% of palliative patients cared for at home experience moderate to severe symptoms of anxiety and/or depression in the last week of life, yet specific psychological interventions tailored to end-of-life anxiety and depression management have not been systematically evaluated. Research is needed to develop and validate evidence-based psychological symptom management protocols for the final week of life in palliative care.

• Principles and ethics in medicine (2020) · doi

  The paper notes that consequentialism cannot distinguish between foreseen and intended consequences in medical decisions (using antibiotic treatment risk as an example), but provides no framework or decision-making algorithm for clinicians to systematically apply this distinction in real-world scenarios where multiple outcomes with varying probabilities are present.

• Reflections on preventive medicine (2014) · doi

  The author argues that precautionary principle implementation in environmental regulation remains limited in Canada and the European Union, but does not specify which types of environmental and behavioral risk factors lack adequate regulatory guidance or what regulatory gaps exist across different exposure categories. Concrete mapping of regulatory coverage gaps for specific environmental risk factors in preventive medicine is needed.

• The portability paradox of foundation models for clinical decision support (2026) · doi

  The paper discusses FDA regulatory pathways for AI/ML medical devices (references 34-35) but does not address how portability and performance degradation of foundation models across different healthcare settings should be evaluated and documented for 510(k) regulatory clearance, particularly when models are adapted for local deployment.

• Reflections on Medicine in Japan (2015) · doi

  Polypharmacy and adverse drug interactions are documented as increasing when multiple specialists prescribe medications without coordinated knowledge of existing prescriptions, but no systematic medication reconciliation protocols or clinical decision support systems are proposed for primary care integration.

• Evidence-based Medicine: Alternative Medicine [Non-drug Medicine, CAM] versus Pharmacological Medicine (2015) · doi

  The comparative cost-effectiveness analysis of non-drug medicine, complementary and alternative medicine (CAM), and biomedicine for all clinical conditions lacks specification of which specific clinical conditions or disease populations should be prioritized for economic evaluation, and what cost-effectiveness thresholds or willingness-to-pay metrics should be applied.

• Impact of Adjuvant Oral Care on Clinical Outcomes in Mechanically Ventilated ICU Patients: A Randomized Controlled Trial (2026) · doi

  The study does not investigate the relationship between structured oral care adherence and patient outcomes, nor does it address barriers to implementing and sustaining oral care regimens in routine ICU nursing practice. Qualitative and implementation science studies are needed to understand compliance challenges and optimize integration of oral care into ICU protocols.

• Artificial intelligence and the future of physicians: replacement or partnership? (2026) · doi

  Healthcare institutions lack standardized frameworks for measuring and rewarding human skills (communication, empathy, cultural sensitivity, shared decision-making, bedside reasoning) as distinct competencies within AI-physician hybrid workflows. Institutional reward mechanisms and performance metrics that balance AI technical indicators with human-centered care attributes remain undefined.

• Prevention Neuroscience: A new frontier for preventive medicine (2016) · doi

  While the paper argues for integrating prevention neuroscience methods into public health and health promotion education programs, it provides no cost-effectiveness analysis or implementation framework comparing the expense of neuroimaging and neuromodulation tools against their actual improvement in population-level chronic disease prevention outcomes.