Theory gaps in Medicine

Representative open questions

Showing 30 of 301 — one per source paper, highest-quality first.

• Heart-brain axis pathophysiological understanding and clinical impact (2026) · doi

  The inflammatory mechanisms linking macrophage activation, IL-6 production, and TGF-β/Smad-mediated cardiac fibrosis in the brain-heart axis (references 83, 90) have not been pharmacologically targeted; selective inhibition studies in stroke models are required to establish causative pathways.

• Multifunctional Lipid Polymer Hybrid Nanocarriers in Cancer Therapy: Recent Developments and Challenges (2026) · doi

  RU-loaded LPH nanoparticles with Solutol and TPGS surfactants showed enhanced brain bioavailability with highest AUC and Cmax in brain tissue, but the specific brain-targeting mechanism (receptor-mediated transcytosis, P-gp efflux inhibition, or tight junction modulation) remains unelucidated across the three surfactant formulations.

• 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 trial addresses emerging evidence that shorter treatment durations enhance patient compliance and advance to immunotherapy; however, specific predictive models identifying which stage III NSCLC patients are most likely to benefit from accelerated chemoradiotherapy schedules versus standard fractionation regimens have not been developed. Subgroup analyses stratified by PET-based metabolic heterogeneity and immune phenotype are needed.

• Activation of anti-inflammatory pathways by polyunsaturated fatty acid signaling may protect neurodevelopment in children prenatally exposed to methylmercury (2026) · doi

  Associations between anti-inflammatory oxylipins (AA-derived EETs and DiHETs) and neurodevelopmental scores were less evident at 5 years of age compared to 14 months, but the mechanistic basis for this age-dependent attenuation remains unexplored. Longitudinal follow-up studies measuring PUFA metabolites and neurodevelopmental outcomes at multiple timepoints beyond 5 years are needed to characterize the temporal dynamics of fetal PUFA signaling protection against MeHg-induced delays.

• Neurosurgery as an immune anchor point: a translational framework for perioperative immunoengineering (2026) · doi

  The framework lacks empirical evidence on how acute systemic inflammatory responses (LPS-induced perivascular CSF distribution impairment) translate to disruption of the meningeal lymphatic-venous axis in neurosurgical patients. Mechanistic studies using aquaporin-4 dysfunction models in the context of surgical stress response are needed to establish causal relationships between surgical injury and immune privilege breakdown.

• Autologous Platelet Concentrates in Sports Medicine: Mechanisms of Tissue Regeneration and Clinical Applications – A Narrative Review (2026) · doi

  Early postoperative outcomes in ligament reconstruction show only modest and inconsistent improvements with PRP despite meta-analytic data, but mechanisms underlying the inconsistency—relating to variation in platelet concentration, fibrin architecture, inflammatory profile, or rehabilitation protocol timing—have not been systematically investigated.

• What is The Effect of Early Enteral Nutrition on Mortality in Critically Ill Patients Receiving Vasopressor Support? : A Systematic Review (2026) · doi

  The paper identifies that patients with high nutritional risk (mNUTRIC ≥5) experienced increased 60-day mortality with early enteral nutrition (OR 1.52), yet no mechanistic studies have investigated whether this adverse interaction is driven by feeding-induced splanchnic ischemia, bacterial translocation, or metabolic intolerance specific to high-risk vasopressor-dependent populations.

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

  The mechanisms by which exercise training decreases whole-body and tissue iron storage in adults with obesity have been documented, but the relationship between iron metabolism modulation and exercise-induced cardioprotection in cardiovascular disease patients requires direct investigation to clarify metabolic pathways.

• Novel endogenous protein-based strategies to inhibit clinically relevant bacterial AB-type toxins including pertussis toxin (2026) · doi

  While ABPs (Angiepeptides) demonstrate dual inhibitory activity against both C. difficile bacteria and their toxins (TcdA and TcdB), the mechanism underlying this dual mode of action has not been characterized at the molecular level. Direct comparison of antibacterial efficacy versus toxin inhibition potency in the same infection model is required.

• The Bounded Corridor_Life as Persistence Under Joint Constraint (2026) · doi

  The paper notes that real clinical cases involve combinations of the four failure modes (e.g., autoimmune disease with concurrent chronic activation and boundary drift) but provides no framework for predicting which combinations are stable versus which trigger cascading collapse. Constructing state-space models of the coupled immune-proteostasis system would identify which multi-modal failure states lead to irreversible transitions.

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

  The HPA axis and BDNF are identified as prominent research hotspots in depression and T2DM comorbidity, but the paper does not specify which mechanisms within these pathways remain mechanistically unclear or require experimental validation in comorbid populations specifically.

• Engineered exosome biomedical technologies for precision diagnosis and therapy in orthopedic diseases (2026) · doi

  The role of immune system mechanisms in osteoarthritis progression (inflammatory mediators, matrix metalloproteinases) has been identified, but exosome-based immunomodulatory strategies targeting specific immune pathways (Th17/Treg balance, macrophage polarization) in osteoarthritis remain underdeveloped and require mechanistic investigation.

• Science fiction and the futures of artificial womb technology: towards a carrier bag theory of design fiction (2026) · doi

  The carrier bag theory framework is applied to critique the hero narrative in AWT design fictions, but the paper lacks empirical investigation of how prospective parents and healthcare providers actually conceptualize suffering, failure, and loss in relation to reproductive technologies and artificial gestation.

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

  The mechanistic roles of calcium, phosphate, and trace ions (fluoride, zinc, magnesium, silanols) in fostering enzymatic protection, pH buffering, and microbial modulation within hybrid layers require controlled long-term randomised clinical trials to establish whether these biological mechanisms translate to superior clinical performance in selective caries removal.

• Human-centered Perspectives on a Clinical Decision Support System for Intensive Outpatient Veteran PTSD Care (2026) · doi

  The three human-centered perspectives applied to this CDSS work (distributed cognition, situated learning, and infrastructural inversion) are not comprehensive for understanding psychotherapeutic contexts. Alternative theoretical lenses and their utility for designing and evaluating clinical decision support systems in intensive outpatient PTSD care have not been identified or tested.

• Adversity and Resilience in Children With Moderate-to-profound Intellectual Disabilities: A Multi-source, Multiple-case Study Across Developmental Stages (2026) · doi

  The case summaries reveal that children with identical medical complications (e.g., gastrostomy dependence, prolonged ICU admission, nocturnal epilepsy) show divergent resilience trajectories, yet the study lacks systematic quantification of the threshold or dosage of protective family factors (e.g., consistent caregiver presence, access to early intervention, household stability) required to buffer against cumulative medical adversity in children with intellectual disabilities.

• 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 collects data on physiological and mechanistic understanding of auricular stimulation's effects on blood pressure control, exercise tolerance, and wellbeing through primary and secondary objectives, but does not specify the mechanistic pathways (parasympathetic activation, baroreceptor reflex modulation, sympathetic nervous system inhibition) that will be directly measured or validated.

• 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

  Cases where ChatGPT showed less concordance with physicians were identified as potentially valuable for mutual learning and improvement of diagnostic systems, yet the paper does not systematically analyse these discordant cases to identify specific diagnostic domains, error patterns, or knowledge gaps where AI and human judgment diverge.

• Psychiatric conditions in palliative medicine (2020) · doi

  Suicidal ideation occurs in advanced cancer patients with elevated rates of post-traumatic stress disorder, panic disorder, hopelessness, and social isolation, but the mechanisms linking these psychiatric comorbidities to suicide risk in palliative care remain unclear. Longitudinal studies examining the temporal relationship and causal pathways between these psychiatric conditions and suicidal ideation in palliative oncology populations are required.

• Echocardiographic Assessment of Left Ventricular Mass Regression and Functional Changes after Bariatric Surgery (2026) · doi

  The paper documents improvements in diastolic performance (E/A ratio, e' velocity) but does not investigate the neurohormonal and metabolic mechanisms regulating these cardiac changes. Studies measuring circulating biomarkers (e.g., natriuretic peptides, inflammatory cytokines, adipokines) alongside echocardiographic diastolic parameters would elucidate the pathophysiology of obesity-induced cardiac remodeling reversal.

• Principles and ethics in medicine (2020) · doi

  While principlism is presented as a practical approach offering structure for ethical quandaries without generating definitive solutions, the paper does not address how to resolve conflicts when the four core principles (beneficence, non-maleficence, autonomy, justice) are in direct opposition in specific clinical contexts or patient populations.

• Evasive Eragrostis: A Unique Case of Intralingual Plant Implantation with Persistent Viability (2026) · doi

  The diagnostic delay mechanisms when plant foreign bodies present without reported trauma or ingestion history remain undefined; the paper recommends maintaining broad differential diagnoses but does not specify what clinical decision rules or diagnostic algorithms should be implemented to reduce missed diagnoses of asymptomatic plant foreign body retention.

• Comparative study on WHO Western Pacific Region and World Federation of Chinese Medicine Societies international standard terminologies on traditional medicine: Diseases in External Medicine (Part 3) (2013) · doi

  While the paper documents TCM etiological explanations and clinical treatments for six skin conditions (vitiligo, scabies, urticaria, dry ringworm, oxhide lichen, psoriasis), it does not establish systematic mapping between TCM pathophysiological mechanisms (wind-dampness, qi-blood disharmony) and modern dermatological disease mechanisms to bridge WHO Western Pacific Region and WFCMS terminology standards.

• Hypoxemia After Inferior Atrial Septal Defect Repair Due to Iatrogenic Diversion of Inferior Vena Cava to Left Atrium: A Case Report (2026) · doi

  Risk stratification criteria for which inferior or low-lying ASD patients are at highest risk for iatrogenic caval diversion (based on defect size, location, rim anatomy, or patient age) have not been formally defined. A multicenter case-control study comparing anatomical features of inferior ASDs that experienced IVC diversion versus uncomplicated repairs would enable preoperative risk assessment.

• Are Two Planes Better Than One?: A Comparative Analysis of Transverse versus Sagittal Pelvic Views in the FAST Examinations (2026) · doi

  Over one-third of sagittal-positive exams showed no corresponding free fluid on transverse imaging, and nearly one-fifth of transverse-positive exams lacked sagittal findings, indicating discordant detection between planes. Future prospective work should investigate the mechanism behind this plane-specific free fluid detection discordance—whether attributable to fluid distribution patterns, probe positioning technique, or image interpretation bias—to optimize scanning protocols for two-plane pelvic FAST examinations.

• The Impactful Weight of Treating Beyond the Scale: A Comprehensive Course to Improve Obesity Care Among Medical Students (2026) · doi

  The study documents reduced implicit bias and increased self-awareness of biases regarding obesity, but does not assess whether these attitudinal changes in medical students correlate with measurable improvements in clinical outcomes (e.g., patient satisfaction, treatment adherence, weight loss) or reduce internalized weight stigma experienced by patients with obesity receiving care from trained students.

• Do preventive medicine physicians practice medicine? (2018) · doi

  While the paper cites evidence that health systems led by physicians with clinical backgrounds show improved outcomes, it does not differentiate whether this benefit applies specifically to preventive medicine physicians in administrative roles or if outcomes vary by the type of non-clinical medical administration role (e.g., public health policy versus hospital operations management).

• Biosemiotic medicine: From an effect-based medicine to a process-based medicine (2020) · doi

  The paper argues that the blind spot (foggy interstice) in human representation of reality has implications for disease modeling, but does not specify how this epistemological limitation should be addressed methodologically when designing biosemiotic diagnostic tools or how clinicians can work within this constraint.

• Guardrails for GenAI drafted replies in patient portal messaging (2026) · doi

  The governance framework proposed aligns with EU AI Act, FDA medical device guidance, and state-level mandates (California AB 3030, Texas SB 1188, HB 149), but no research has evaluated whether these regulatory approaches create conflicting implementation requirements or gaps when applied simultaneously to GenAI patient messaging across multi-state health systems.

• Effectiveness and Feasibility of Transvaginal Ultrasound–Guided Platelet-Rich Plasma Injection for The Management of Female Stress Urinary Incontinence (2026) · doi

  The study demonstrates that PRP injection efficacy for female stress urinary incontinence decreases substantially with severity (50% efficacy in mild SUI, 20% in moderate SUI, 14.3% in severe SUI after first dose), but lacks investigation into the mechanistic reasons why periurethral PRP injections fail to generate adequate tissue regeneration or urethral sphincter strengthening in moderate-to-severe cases.