Theory gaps in Medicine

Representative open questions

Showing 30 of 330 — one per source paper, highest-quality first.

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

  The role of neutrophils in mediating cardiac arrhythmias through the brain-heart axis (reference 86) and their specific contribution to atrial fibrillation post-stroke have not been characterized; mechanistic studies examining neutrophil infiltration, electroimmunology, and conduction abnormalities are required.

• 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

  While neutrophil dysfunction and neutrophil extracellular trap (NET) formation have been implicated in trauma-associated pneumonia pathogenesis, the specific molecular mechanisms linking extrathoracic multiple trauma-induced neutrophil dysregulation to gram-negative pneumonia susceptibility require further mechanistic characterization in animal models of combined trauma and secondary lung infection.

• 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

  Positive associations were unexpectedly found between the pro-inflammatory oxylipin thromboxane B2 (TXB2) and neurodevelopmental scores in the moderate mercury group, potentially reflecting compensatory vascular adaptations or co-effects of elevated maternal AA substrate availability. Mechanistic studies using placental endothelial and platelet models should investigate whether MeHg-induced thromboxane A2 synthesis represents a harmful pro-inflammatory response or an adaptive vascular compensation during fish consumption.

• 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.

• The neuro-immune axis in preeclampsia: from the maternal-fetal interface to systemic dysregulation (2026) · doi

  The mechanistic link between cerebral autoregulation dysfunction and systemic cardiovascular responses through altered autonomic control is proposed but lacks direct experimental evidence establishing the causal direction and the specific brainstem or hypothalamic circuits mediating this neuro-immune-cardiovascular axis in preeclampsia.

• 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.

• The Relationship between a History of Cesarean Section and The Incidence of Placenta Accreta : A Systematic Review (2026) · doi

  The temporal increase in PAS incidence beyond what CS rate increases alone can explain has been observed but not mechanistically dissected. Studies are needed to distinguish whether this rise is driven by accumulation of women with multiple prior CS across successive cohorts, improved PAS recognition and conservative management enabling recurrence, or other healthcare system changes.

• 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.

• 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.

• Lipidomics and machine learning revealing dysregulation of specific triacylglycerol and phosphatidylglycerol as hub lipids associated with fetal growth in gestational diabetes mellitus (2026) · doi

  The role of elevated TP (total protein) levels as a marker of metabolic disturbance in GDM pathogenesis needs mechanistic investigation to clarify how TP relates to the identified lipid dysregulation and whether TP-guided interventions could complement lipid-based risk stratification strategies.

• 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.

• Reflections on preventive medicine (2014) · doi

  The author questions whether life expectancy prolongation should be a goal of preventive medicine and suggests cancer prevention extending life expectancy by two years may not be ideal, but offers no framework for determining the optimal distribution of life duration or criteria for selecting which conditions warrant prevention efforts in populations.

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

  The paper discusses consciousness as a primary determinant of global quality of life, health, and ability in the context of evidence-based holistic medicine, but does not operationalize how consciousness should be measured, assessed, or validated as a mechanistic variable in clinical studies of Traditional Hippocratic Medicine interventions.

• 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.

• Methotrexate-Associated Systemic Lymphadenopathy Exhibiting a Marked Elevation of the Serum IgG4 Concentrations (2026) · doi

  The molecular mechanisms by which methotrexate paradoxically enhances IgG4 class switch recombination in some patients (as in this case) while suppressing IgG4 responses in others (as reported for IgG4-RD maintenance therapy) require elucidation through in vitro and in vivo studies to identify patient-specific factors predicting IgG4 modulation.

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

  The paper emphasizes that taste-driven food preferences and calorie-dense food biases are present from birth in humans, but does not propose specific prevention neuroscience studies examining how early-life neuromodulation or brain-targeted interventions could modify these innate preferences before obesity develops.

• 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.

• 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.