Data gaps in Medicine

Representative open questions

Showing 30 of 711 — one per source paper, highest-quality first.

• Longitudinal localization of leukaemic stem cells between the metaphysis and central marrow governs their behaviour (2026) · doi

  The study identifies N-cadherin+ vascular niche interactions with leukaemic stem cells (referenced in N-cad-tdTomato experiments), but the specific adhesion mechanisms governing metaphyseal versus central marrow localization and their differential response to N-cadherin-targeted therapy (reference 65: telmisartan/ADH-1 function) have not been systematically compared across AML subtypes.

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

  The relationship between specific insular cortex stroke locations (right dorsal anterior insula, reference 112) and myocardial injury mechanisms requires mechanistic investigation using combined neuroimaging and cardiac biomarker analysis in prospective cohorts to determine causality versus association.

• CUIDADO TRANSICIONAL HOSPITAL-DOMICÍLIO REALIZADO POR ENFERMEIRAS A PESSOAS IDOSAS COM MARCAPASSO ARTIFICIAL: PROTOCOLO DE REVISÃO DE ESCOPO (2026) · doi

  The data extraction table (Quadro 3) lacks specification of standardized instruments or validated assessment scales for measuring outcomes related to transitional nursing care quality, patient safety, and clinical outcomes in elderly pacemaker patients during hospital-to-home transition. No specific outcome measurement tools are defined for systematic comparison across included studies.

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

  Roflumilast-loaded Man-LPHFNPs with nano-in-micro (NiM) delivery strategy achieved appropriate lung deposition particle sizes, but in vivo pulmonary bioavailability, mucociliary clearance resistance, and bronchial epithelial distribution kinetics have not been quantified in animal inhalation studies.

• Integrative transcriptomic analysis reveals miR-26a-5p downregulation and a potential predictive gene signature for the progression of metabolic liver disease (2026) · doi

  Larger cohorts with longitudinal histological assessment are needed to characterize the full spectrum of transcriptomic and histological changes across the progression from diet-induced metabolic perturbation to HCC, as the in vivo HCD model demonstrated only a relatively small sample size that was underpowered to capture comprehensive disease progression phenotypes.

• 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

  Diaphragm injuries represent a diagnostic challenge in trauma patients with rib fractures, yet the relationship between diaphragmatic dysfunction and pneumonia development in the context of blunt chest trauma has not been systematically investigated with standardized diagnostic protocols.

• 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

  While the PACCELIO trial combines FDG-PET/CT-based target volume reduction with hypofractionated accelerated radiotherapy, the optimal threshold values for FDG-PET/CT uptake-based delineation and the corresponding tumor control probability thresholds specific to accelerated dose delivery schedules in stage III NSCLC remain undefined. Direct comparison of tumor recurrence patterns between volume-reduced and conventional radiotherapy planning is needed.

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

  The study measured blood glucose levels in the triple-comorbidity group (hypertension + diabetes + obesity) but reported that glucose levels showed improvement with intervention (p=0.0189); however, the paper does not specify the duration of follow-up or long-term sustainability of glycemic control, which is critical for assessing diabetes management in rural non-communicable disease prevention programs.

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

  High-quality prospective or large-sample studies on cHCC-CCA are lacking; most existing research remains retrospective or based on small sample sizes due to the tumor's low incidence and diagnostic complexity, creating a scarcity of high-quality evidence to guide clinical practice.

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

  The translational framework does not address how blood-brain barrier dysfunction varies across different neurosurgical procedures and how this impacts the pharmacokinetics of intratumoral immunotherapeutic administration in glioma resection versus vascular neurosurgery. Comparative pharmacodynamic studies are needed to determine optimal drug delivery strategies for choroid plexus-mediated immune responses in post-operative CNS patients.

• Kidney angiopoietin-like protein 4 regulates fibrotic responses in diabetic kidney disease (2026) · doi

  The comparative efficacy of ANGPTL4 inhibition versus modulation of downstream effectors (such as STAT6 or cGAS-STING signaling) for attenuating kidney inflammation and fibrosis in diabetic nephropathy has not been systematically evaluated in head-to-head preclinical studies using identical disease models and outcome measures.

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

  Knee osteoarthritis studies with PRP show symptomatic improvement in pain and function, but structural cartilage regeneration remains insufficiently demonstrated; high-quality trials specifically designed to assess structural improvement through imaging biomarkers and load-tolerance restoration in physically active patient subgroups are lacking.

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

  While the NUTRIREA-3 trial demonstrated that low-calorie enteral nutrition (6 kcal/kg/day) halved bowel ischemia risk compared to standard-calorie feeding (25 kcal/kg/day), no randomized controlled trials have directly compared gradual advancement protocols (3-7 day escalation) versus immediate full-dose feeding in patients with persistent shock receiving high-dose vasopressors (≥0.3 µg/kg/min norepinephrine equivalents) to determine long-term outcome differences.

• Decision-ready evidence for vital pulp therapy: a network meta-analysis of bioactive materials in mature permanent teeth (2026) · doi

  Evidence networks for laser-assisted vital pulp therapy, PRP/PRF, and potassium nitrate bioactive materials were sparse, reducing precision and inflating rank volatility in network meta-analysis comparisons. Direct head-to-head randomized controlled trials comparing these materials against calcium-silicate cements (MTA, Biodentine) at standardized timepoints are needed to establish reliable rankings.

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

  While SIRT1 and SIRT6 signaling pathways have been identified as protective mechanisms in cardiovascular disease, the specific role of SIRT1 gene single-nucleotide polymorphisms on exercise-induced metabolic adaptations and cardiovascular outcomes in diverse ethnic populations remains unexplored beyond the Han Chinese population study cited.

• What is the diagnostic accuracy of different clinical diagnostic criteria (Rotterdam, NIH, and Androgen Excess Society) for identifying polycystic ovary syndrome in women of reproductive age? : A Systematic Review (2026) · doi

  Geographic variations in diagnostic accuracy for ovarian volume (Turkish women: 6.43 cm³, North African women: 9.25 mL, Iraqi women: >9.4 mL) and follicle counts cannot be fully disentangled from genetic versus environmental influences; migrant population studies comparing diagnostic marker performance between origin countries and destination countries remain largely absent from the literature.

• Deep learning-based multimodal prediction of chronic kidney disease stage (2026) · doi

  Class imbalance is explicitly mentioned as causing poor performance in support vector machine models for CKD stage prediction, but the paper does not report the actual class distribution in the dataset or evaluate whether the multimodal model's superior performance is robust to different levels of class imbalance across CKD stages G1-G5.

• Perineural invasion in solid tumors: biological foundations and the emerging integration of machine learning and artificial intelligence (2026) · doi

  The location-specific prognostic significance of perineural invasion in early-stage oral cavity squamous cell carcinoma has been identified as a factor, but quantitative mapping of invasion patterns relative to tumor depth, surgical margins, and lymph node involvement in large prospective cohorts is absent from current literature.

• 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

  Studies on telemedicine DR screening have been limited to insured populations and single healthcare systems; effectiveness in rural and uninsured populations using teleophthalmology platforms remains unvalidated, particularly for primary care integration settings.

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

  Recurrent placenta accreta risk was identified in only nine focal-occult PAS patients with subsequent pregnancies (Larish et al.), with three showing recurrence. A larger prospective cohort tracking women with prior PAS through subsequent pregnancies is needed to quantify recurrence rates, identify predictors of recurrence, and determine whether intervening pregnancy intervals or timing affects risk.

• A systematic review of sample size determination in Bayesian randomized clinical trials: full Bayesian methods are rarely used (2026) · doi

  Many trials in the review are coded as 'No Justification' for their sample size methodology (e.g., Bolinski, Banooni, Bardia), indicating that a substantial proportion of clinical trials lack explicit documentation of their sample size determination approach. There is a need to investigate whether these trials employed Bayesian, frequentist, or hybrid methods but failed to report them, versus genuinely lacking formal sample size justification.

• A behaviour and disease model of testing and isolation (2026) · doi

  The model assumes symptomatic individuals who tested negative retained the same infectiousness and behaviour as untested symptomatic individuals, despite test sensitivity being below 100%. Removing this assumption requires behavioural data collection on how negative test results affect behaviour change, infectiousness reduction, and compliance in symptomatic 'behaviour aware' individuals.

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

  The mechanisms governing osteoblast-to-osteoclast differentiation regulation via exosomal miR-503-3p/Hpse axis and estrogen deficiency-mediated osteoimmunity in postmenopausal osteoporosis have been partially characterized; comprehensive multi-omics profiling of exosomal cargo changes across disease progression stages is lacking.

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

  The analysis of home-based artificial wombs (item 5) offering aesthetically-driven solutions like colored amniotic fluids identifies a commercialization pathway, but provides no data on how such consumer customization options would interact with medical safety standards, regulatory frameworks, or long-term fetal outcomes in uncontrolled home environments.

• Treatment options for long head of biceps tendon tenodesis (2026) · doi

  While high-quality long-term comparative clinical studies are identified as necessary, the paper does not specify which specific patient populations (age groups, overhead athletes, rotator cuff tear severity) require investigation to define optimal indications for each of the nine non-subpectoral tenodesis techniques presented. Comparative outcome data stratified by these clinical parameters is absent.

• Source-stratified gut–extraintestinal organ crosstalk in sepsis-associated acute gastrointestinal injury and paralytic ileus: the gut as both driver and target (2026) · doi

  In enterogenic sepsis specifically, the dominant routes through which gut-derived inflammatory, microbial, metabolic, vascular, and extracellular vesicle signals propagate toward distant organs remain uncharacterized and require systematic mapping of directional signaling pathways to distinguish primary from secondary organ injury.

• Crosstalk between autophagy-dependent ferroptosis and PANoptosis in myocardial and cerebral ischemia-reperfusion injury: mechanisms and therapeutic implications (2026) · doi

  Clinical evidence for autophagy-dependent ferroptosis and PANoptosis in ischemia-reperfusion injury patients is entirely absent. Future research must conduct clinical sample analyses to validate expression of key molecules (ROS, NLRP3, ZBP1, NCOA4, STING) in myocardial and cerebral IRI patient tissues and develop multiplex biomarkers capable of simultaneously monitoring multiple cell death modalities for clinical efficacy assessment.

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

  AI-based adherence prediction models predominantly rely on retrospective electronic health record and administrative datasets that contain incomplete or missing data and may not capture routine real-world medication-taking behaviors. There is a critical need for adherence prediction studies utilizing prospective data collection methods and real-time monitoring technologies to validate model performance against actual adherence patterns.

• Evidence-based approaches for Empty Nose Syndrome management: a systematic review highlighting current treatments and future directions (2026) · doi

  The timing of adverse events in Empty Nose Syndrome implant-related complications is documented inconsistently across studies: most events occur within one month, but documentation extends to four years with sparse intermediate reporting, leaving critical gaps in understanding late-stage graft resorption, extrusion, and material degradation trajectories.

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

  The study examined only clinicians and former patients in the PTSD treatment sociotechnical system, but did not investigate how integrating perspectives from trusted others (family and friends) affects patient experience tracking and therapy progress monitoring in intensive outpatient PE therapy. Evans et al. examined this integration conceptually, but the situated objectivity of patient experience when social networks are incorporated into CDSS design remains unexplored.