United States

Background
Molar–incisor hypomineralization (MIH) is a common developmental enamel defect in children, leading to higher risk of caries, post-eruptive enamel breakdown, and dental pain. Proper enamel formation depends on the expression and function of matrix proteins like ameloblastin (Ambn) and the protease matrix metalloproteinase 20 (Mmp20), which regulates mineral deposition and organic matrix removal during amelogenesis. We hypothesized that enamel hypomineralization caused by Ambn overexpression in mice could be rescued by increasing Mmp20 expression to
restore the correct substrate-to-enzyme ratio essential for healthy enamel.

Methods
Overexpression of Ambn and Mmp20 was achieved in separate mouse lines from transgenes (Tg). Ambn-Tg mice exhibited MIH-like phenotypes, and Mmp20-Tg mice displayed hypoplastic amelogenesis imperfecta. Crossbreeding of Ambn-Tg with Mmp20-Tg generated double-Tg mice overexpressing Ambn and Mmp20. Mandibular incisors of 7-week old mice (n=5/grp) were analyzed from the apical region to the incisal edge in sequential 1.0 mm volumes of interest (5 µm pixels) using isotropic micro-CT. Low, medium, and high thresholds were applied to quantify enamel volume and percent mineral volumes. Enamel mineral density was
calibrated to hydroxyapatite phantoms (.25 and .75 g/cm3). We compared the Ambn-Tg+Mmp20-Tg to the wildtype (WT) controls. We ran a single factor ANOVA test and a two-tailed T-test to determine if there is a significant difference between the groups.

Results
At eruption, the volumes of middle and high-density enamel in the Ambn and Mmp20 Tg’s demonstrated significant differences from the WT. Ambn-Tg had more middle density enamel volume (p=0.007). The Mmp20-Tg had significantly greater middle density (p=0.00001) and less higher density enamel (p=0.0000001) volumes compared to the WT, respectively. Ambn-Tg+Mmp20-Tg middle density and high-density enamel volumes were similar to the WT. Calculated enamel mineral densities were 38% (p=0.00001) and 8% (p=0.0005) lower in the Mmp20-Tg and Ambn-Tg groups compared to the WT, respectively. The Ambn-Tg+Mmp20-Tg
enamel mineral density was similar to the WT. Visual analysis indicated that the incisor enamel of Mmp20-Tg and Ambn-Tg groups was distributed in circular patches containing regions of lower and higher enamel density. A similar visual inspection indicated that the Ambn-Tg+Mmp20-Tg enamel was distributed like the WT.

Conclusion
These results show that enamel mineralization is highly sensitive to the balance of Ambn and Mmp20 expression. Imbalances can cause hypomineralized or hypoplastic enamel, while restoring the substrate-to-enzyme ratio can rescue normal enamel formation. This underscores the importance of maintaining balanced extracellular matrix protein and enzyme levels for healthy, functional enamel development.

AMA Research Challenge 2025 

Rebalancing the Substrate-Enzyme Ratio in Enamel Rescues Molar Incisor

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poster

Background
Despite advancements in genomic research, minoritized populations remain underrepresented, limiting the equitable distribution of benefits and contributing to ongoing health disparities. The Rare Genomes Project (RGP) at the Broad Institute of MIT and Harvard offers free whole genome sequencing to individuals in the U.S. with rare, suspected monogenic conditions who lack a genetic diagnosis. Between 2017 and 2021, enrollment was limited to English-proficient individuals. As a result, >90% of participants had some college education and >60% reported household incomes over $90,000, and no participants spoke a language other than English. Recognizing the lack of demographic diversity, RGP implemented a new diversity-focused study protocol in 2021 to address barriers to participation and increase access among historically underserved populations. 

Methods
To improve accessibility, RGP adopted strategies such as a simplified physician referral form, expanded language access (Spanish materials and interpreters), mobile phlebotomy, phone support, and extended staff hours. From 2021 to 2024, a total of 68 participants were enrolled who met at least one of six criteria for underrepresentation: non-white race, Hispanic/Latinx ethnicity, low income, limited English proficiency, rural residence, or lower educational attainment. Demographic and survey data were collected at baseline and sequencing was completed for all participants.

Results
Post-implementation, RGP saw an 8% decrease in the total proportion of white participants and a 5.5% increase in Hispanic participants. The proportion of non-English speakers increased by 3.3%. However, rural enrollment declined after 2022, despite offering mobile phlebotomy and flexible contact hours. Of 437 total RGP participants, 68 comprised the new underrepresented cohort. This group was more likely to have lower education and income and greater use of government insurance (62% vs. 36%, p<0.001). At baseline, the underrepresented cohort reported higher perceived importance of a genetic diagnosis and slightly higher stress levels. While both groups agreed a diagnosis would aid understanding and preparation, the underrepresented group prioritized its role in identifying better treatments. Challenges such as limited internet or transportation and provider trust remained barriers for rural and minoritized communities.

Conclusion
The revised RGP protocol showed some success in improving access and enrollment for underrepresented populations, especially through multilingual support and flexible engagement strategies. However, limited internet access and reduced rural participation highlighted remaining gaps. Patient-provider trust also emerged as a potential barrier. Future efforts will include participant interviews and follow-up surveys to better understand values and inform long-term engagement strategies. Continued enhancements and community-centered approaches are needed to ensure equitable access to genomic medicine.


The Impact of Enhanced Recruitment and Enrollment Support
on the Diversity of a Genomic Research Study

Background
In the last century, Influenza A viruses have caused the most global pandemics. The global panzootic of Highly Pathogenic Avian Influenza A (H5N1), its expanding mammalian host range, first mammalian-to-human transmissions and rising human infections are ominous. As a leading pandemic risk, early H5N1 detection is crucial to outbreak response but currently remains limited to the CDC and state public health laboratories. Here, we present a simple, rapid, adaptable, high throughput multiplex fragment analysis test for Influenza A (H5N1, H3N2, H1N1) subtyping and Influenza A/B, RSV and SARS-CoV-2 identification.

Methods
From the most up to date viral genomes we designed novel primers targeting conserved pathogenic regions across clinically relevant Influenza subtypes and generated unique gene-specific subtype signatures for H5N1 Influenza, endemic Influenza strains, RSV and SARS-CoV-2 via fragment analysis by capillary electrophoresis. Analytic sensitivity was determined by limit of detection analysis of Influenza A viral RNA in replicate reactions for each input amount of the viral RNA genome. Inter-/intra-run variability was assessed for all gene targets. Analytical specificity was established in evaluations of H5 and non-H5 human and avian Influenza A virus genomic RNA and by in silico analysis of potential primer cross-reactivity with other pathogens using BLAST® suite analysis.

Results
We generated unique fragment size-based signatures for each targeted gene. Targeted conserved regions in the HA gene are conserved in all newly sequenced U.S. Human H5N1 cases. The generated H5 amplicon had CT-values 2-12 lower than CDC and WHO H5 primers. No confounding false positives or over-lapping non-specific amplicons were identified. 100% H5N1 detection sensitivity was observed with a lower limit of detection of 2.5 copies/uL.

Conclusion
We have applied fragment analysis to Influenza A subtyping and respiratory virus detection for the first time. The multiplex target fragment analysis test described here has 100% analytical sensitivity and no false positives. This enables total subtyping capability of all human circulating Influenza A strains in one assay. This platform also proposes an epidemiological tool for detecting possible H5 Avian strain cross-over via dual detection of the H5 and M gene without the N1 amplicon. The use of multiple gene-specific targets for each strain increases test rigor, reproducibility and confidence in the accuracy of results.

Seasonal and Avian (H5N1) Influenza Subtyping by a Multiplex Fragment Analysis Test

Background: 
Vitiligo affects an estimated 0.5–2% of individuals worldwide and is characterized by cutaneous depigmentation. Recent studies suggest that autoimmune mechanisms in vitiligo extend beyond the skin, including ocular inflammation and auditory dysfunction. Notably, a nationwide Korean cohort of over 140,000 vitiligo patients found significantly elevated risks of dry eye, cataracts, and glaucoma compared with matched controls. However, comprehensive data from diverse U.S. adult populations remain scarce.

Objective: 
To determine whether adults with vitiligo have increased odds of developing ocular and auditory comorbidities compared with matched controls.

Methods: 
We conducted a retrospective, matched case–control study using de‑identified EHR data from the NIH All of Us Research Program. We identified cases based on the presence of ≥2 EHR visits with ICD‑10 L80 codes. Controls were matched 4:1 on age, sex, race/ethnicity, and duration of follow-up. We identified ocular outcomes (dry eye syndrome, uveitis, cataracts, glaucoma, retinal diseases, visual impairment) and auditory outcomes (sensorineural and sudden hearing loss, Ménière’s disease, benign paroxysmal positional vertigo, vestibular neuronitis) via validated ICD‑10 codes. Multivariate logistic regression estimated adjusted odds ratios (aORs) with 95% confidence intervals (CIs). Covariates included body mass index, Charlson Comorbidity Index (CCI), cumulative systemic steroid exposure, hypertension, diabetes, dyslipidemia, and chronic kidney disease. CCI is a validated score that assigns weighted points to chronic conditions based on ICD-10 codes in order to quantify baseline comorbidity burden.

Results: 
A total of 842 vitiligo cases and 3,368 matched controls were identified. Patients with vitiligo had lower BMI (28.91 vs 29.72 kg/m²; p=0.005), higher rates of long‑term steroid exposure (78.3% vs 56.6%; p<0.001), and higher proportions of CCI>1 (90.1% vs. 78.9%, p<0.001). Patiens with vitiligo patients exhibited higher unadjusted prevalence of any ocular comorbidity (43.2% vs 31.5%) and any auditory comorbidity (20.8% vs 15.9%). In fully adjusted models, vitiligo was associated with dry eye syndrome (aOR 1.39; 95% CI 1.13–1.71; p=0.002), anterior uveitis (aOR 3.00; 95% CI 1.18–7.64; p=0.021), cataracts (aOR 1.22; 95% CI 1.02–1.46; p=0.030), overall retinal disease (aOR 1.27; 95% CI 1.01–1.60; p=0.042), and other retinopathies (aOR 1.39; 95% CI 1.04–1.87; p=0.026). No adjusted associations persisted for any auditory comorbidity (aOR 1.04; 95% CI 0.85–1.27; p=0.703).

Conclusion: 
This large, multiethnic U.S. cohort demonstrates that vitiligo is independently associated with a spectrum of ocular comorbidities but not with auditory disorders. These findings underscore the need for routine ophthalmologic screening in patients with vitiligo and suggest that interdisciplinary care models may optimize long‑term visual health in this population.


Ocular and Auditory Comorbidities in Adults with Vitiligo: A Retrospective Case–Control Study

Background 

Shoulder injuries are common in adolescent athletes, particularly in overhead and contact sports. However, comparative data on sport-specific risk profiles remain limited. This study aimed to create risk profiles using strength and range-of-motion (ROM) of the shoulder across high school athletes in baseball, softball, female basketball, female wrestling, and male wrestling.

Methods 

We conducted a cross-sectional analysis of 247 high school athletes (159 male, 88 female) from three Utah schools between November 2023 and April 2025. Bilateral shoulder ROM and isometric strength were assessed using goniometry and handheld dynamometry. Primary outcomes included ER:IR strength ratio, internal rotation (IR) asymmetry, and total arc of motion (TROM) asymmetry. Athletes were classified as “at risk” if they met any of the following thresholds: ER:IR ratio < 0.75, IR deficit > 20°, or TROM asymmetry > 10°. Chi-square tests were used for between-group comparisons. 

Results 

Of the 247 athletes, 57 played baseball, 38 softball, 26 girls’ basketball, 24 girls’ wrestling, and 102 male wrestling. The most prevalent risk factor was ER:IR strength ratio < 0.75, observed in 45% of male wrestlers, 42% of female wrestlers, and 27% of girls’ basketball players. TROM asymmetry > 10° was most common in softball athletes (63%), followed by girls’ basketball (35%) and girls’ wrestling (33%). IR deficits > 20° were uncommon (≤12%) across all groups. Overall, 66% of male wrestlers and 63% of female wrestlers met at least one risk criterion. Significant between-sport differences were observed for ER:IR ratio (p < 0.001) and TROM asymmetry (p = 0.011), but not for IR deficit (p = 0.83). 

Conclusion 

Distinct sport-specific shoulder risk patterns were identified among adolescent athletes. ER:IR strength imbalance was most common in wrestlers, TROM asymmetry in softball and basketball players, and IR deficits were infrequent. These findings support the need for targeted screening and individualized preventive strategies to address modifiable shoulder injury risk in youth athletes. 



Sport-Specific Shoulder Risk Profiles in Adolescent Athletes: A Cross-Sectional Study

Background: Retinal detachment (RD) is a vision-threatening emergency requiring prompt surgical intervention with pars plana vitrectomy (PPV) (first-line), and/or scleral buckling (SB). PPV removes vitreous and repairs retinal detachment internally, while SB indents the sclera externally to reattach the retina. Though primary surgery is often successful, reoperations for detachments increase risks of permanent vision loss. This study identifies key anatomical predictors for indications of adjunctive SB to optimize single-surgery success rate (SSSR).

Methods: This retrospective cohort study (2010–2023) analyzed 3,528 RD repairs, including PPV alone (n = 2,811), SB alone (n = 163), and PPV+SB (n = 554). The primary outcome was SSSR at 3 months. Anatomical predictors included detachment extent (quadrants: Q1=superior nasal, Q2=superior temporal, Q3=inferior temporal, Q4=inferior nasal), macular status, lens status, gender, and prior ocular history. Chi-square tests compared outcomes; subgroup analyses excluded SB-only cases (secondary analysis).

Results:
Overall SSSR was 86.4% for PPV alone versus 89.5% for PPV+SB (p= 0.044). SB-only achieved 89.6% SSSR (p=0.321 vs PPV+SB).

Macular status: PPV+SB significantly outperformed PPV alone in macula-on detachments (93.5% vs 87.2%, p=0.005) but not macula-off cases (86.2% vs 85.9%, p=0.886).

Lens status: Phakic eyes benefited from PPV+SB (89.7% vs 85.3%, p=0.036), while pseudophakic eyes showed no difference (88.9% vs 87.3%, p=0.489).

Regional patterns: PPV+SB superiority was present when: Q3/Q4 were involved (Q3: 89.8% vs 84.9%, p=0.014; Q4: 89.7% vs 84.0%, p=0.013) and when Q1/Q2 were spared (Q1 absent: 90.6% vs 86.0%, p=0.025; Q2 absent: 92.5% vs 86.2%, p=0.009).

Panretinal detachments showed no significant PPV+SB benefit (84.9% vs 78.8%, p=0.249), whereas limited detachments trended positively (90.5% vs 87.2%, *p* = 0.052).

Demographics: Females had higher SSSR with PPV+SB (90.7% vs 84.5%, p=0.020), unlike males (88.7% vs 87.5%, p=0.533).

Conclusion: Adjunctive SB is associated with improved SSSR in specific anatomical contexts: macula-on detachments, phakic eyes, female patients, and detachments involving inferior quadrants (Q3/Q4) or sparing superior quadrants (Q1/Q2). These findings support selective SB use in RD repair, tailored to patient-specific anatomical risk profiles to avoid reoperations and improve visual outcomes.

Adjunctive Scleral Buckling with Pars Plana Vitrectomy for Retinal Detachment: Impact on Single-Surgery Success Rates by Anatomical Predictors

Chronic Shoulder Pain as a Herald of Advanced Small Cell Neuroendocrine Carcinoma
Background:
Small cell neuroendocrine carcinoma (SCNC) most commonly originates in the lung but can come from many organs. It typically presents with pulmonary symptoms such as cough, shortness of breath, or hemoptysis. We present a case of extensive-stage SCNC initially misattributed to benign shoulder pathology, ultimately requiring emergent chemotherapy intervention. Musculoskeletal pain as the sole initial manifestation presented a rare and challenging diagnostic scenario.
Case presentation:
A 51-year-old male with a 15-pack-year smoking history and family history of malignancies (mother with rectal cancer at age 48, and brother with head and neck cancer) presented with 2 months of right scapular and bilateral arm pain, initially managed with NSAIDs and chiropractic care. Symptoms progressed to right arm weakness, nocturnal pain, and 20-pound unintentional weight loss. Physical examination revealed right arm weakness (4/5) and numbness with otherwise stable vital signs apart from hypertension.
Initial CT abdomen obtained revealed extensive hepatic lesions suspicious for metastatic disease. Subsequent MRI cervical spine demonstrated osseous lesion in clivus and T1 vertebral body. Further evaluation with PET-CT showed FDG-avid metastatic involvement of the liver and numerous bones in the body, and significant neck and mediastinal lymphadenopathy. Notably, bone lesions were CT-occult, undetectable on prior imaging. Given the concerning imaging findings and rapid clinical progression, emergent chemotherapy was initiated due to the high risk of impending organ dysfunction from extensive tumor burden. Liver biopsy results demonstrate SCNC, supported by a high Ki-67 (70%) indicating rapid proliferation, positive synaptophysin confirming neuroendocrine differentiation, and elevated serum chromogranin A, further consistent with small cell neuroendocrine carcinoma. The patient demonstrated good initial tolerance to carboplatin/etoposide therapy with a plan to add immunotherapy after the first cycle.
Discussion:
This case highlights SCNC's potential to present atypically as isolated musculoskeletal pain, demonstrating how CT imaging may underestimate metastatic burden while PET-CT reveals more extensive disease. The diagnostic challenge is particularly acute in high-risk patients with significant smoking histories and familial cancer predisposition. These findings underscore the importance of maintaining clinical suspicion for malignancy even in the absence of classic symptoms, as earlier recognition can significantly impact patient outcomes.

Chronic Shoulder Pain as a Herald of Advanced Small Cell Neuroendocrine Carcinoma

Background
A massive brain abscess caused by otogenic Klebsiella pneumoniae is a neurological emergency in the United States and worldwide. We present a rare case of an otogenic massive brain abscess caused by Klebsiella pneumoniae to guide clinicians in establishing a prompt diagnosis and preventing significant morbidity and mortality.
Case Presentation
A 23-year-old male with a past medical history of uncontrolled type 1 diabetes and a recent presentation for otitis media was brought to the emergency department unresponsive. On initial examination, he was non-verbal, showed abnormal posturing to painful stimuli, and had a purulent, pinkish discharge from his left ear. He was found to be in Diabetic ketoacidosis. CT Head without contrast revealed a 5.8 cm x 4.9 cm left temporoparietal lobe abscess with significant edema, a 1.4 cm midline shift and extensive left-sided mastoiditis. Blood culture revealed Rhodotorula mucilaginosa and Aureobasidium. An emergent craniotomy evacuated 120 mL of purulent material, which grew otogenic Klebsiella pneumonia. Due to rapid pathogen identification, patient's condition stabilized with drainage of abscess, antibiotics, and comprehensive management.
Discussion
Otogenic Klebsiella pneumoniae is rarely considered as a cause of brain abscesses. A report from the Centers for Disease Control and Prevention identified only one case of Klebsiella pneumoniae as a cause of pediatric brain abscess between January 2016 and August 2022. Due to its rarity, the CDC's Active Bacterial Core surveillance system, which tracks invasive bacterial diseases, does not currently include Klebsiella pneumoniae. However, a massive brain abscess can be caused by otogenic Klebsiella pneumoniae in patients with diabetic ketoacidosis or any immunocompromised states, leading to high morbidity and mortality. 
Conclusion
This case report underscores the importance of including Klebsiella pneumoniae in the differential diagnosis of otogenic brain abscess, especially in the setting of DKA or other immunocompromised states. Early neuroimaging, prompt surgical intervention, and targeted antimicrobial therapy are critical for improving outcomes in these life-threatening infections. Clinicians should maintain a high index of suspicion for atypical pathogens to reduce diagnostic delays and prevent severe neurological sequelae.




Massive Brain Abscess Caused by Otogenic Klebsiella pneumoniae in a Young Adult with Diabetic Ketoacidosis

Background:
Complex Regional Pain Syndrome (CRPS) Type I is a chronic pain condition that often follows trauma without identifiable nerve damage. It is marked by severe pain, autonomic changes, and motor dysfunction, including contractures. Diagnosis is clinical, often delayed, and management can be challenging. A multidisciplinary approach combining pharmacologic, interventional, and rehabilitative strategies is essential for optimizing outcomes.
Case Presentation:
A 32-year-old French-speaking male with latent tuberculosis presented with progressive pain, cramping, and contracture of the right upper extremity (RUE) two months after a fall. He described constant 10/10 pain, primarily from elbow to wrist, with minimal relief from medications including acetaminophen, oxycodone, baclofen, gabapentin, and duloxetine.
On examination, he had severe muscle spasms, tenderness at MCP joints, and was unable to extend his hand. Imaging (MRI of the brain, cervical/thoracic spine, and shoulder X-rays) was unremarkable. EMG suggested a possible upper motor neuron process but was limited due to contracture.
Despite corticosteroid injections and oral medications, his symptoms progressed. A stellate ganglion block on July 11 provided temporary relief (pain reduced from 10/10 to 2/10). A second block on July 16 followed by ketamine infusion and clonidine patch further reduced pain (0– 2/10) and spasms (~50%).
After an interdisciplinary meeting, the patient was found to meet the Budapest Criteria for CRPS Type I, Stage 3. As such, arm manipulation under anesthesia and interscalene catheter placement for continuous analgesia. Post-procedural methadone provided additional relief.
Discussion:
This case highlights the diagnostic and therapeutic complexity of CRPS Type I. The patient experienced chronic, disproportionate pain and progressive motor dysfunction following minor trauma. Despite comprehensive evaluation, no structural or neurologic cause was identified. Multimodal therapy—including nerve blocks, ketamine, and physical therapy—provided only temporary improvement. Functional disability and psychosocial stressors further complicated management.

Complex Regional Pain Syndrome Type I Presenting with Upper Extremity Contracture in a Young Adult

Background
Link Health is a Boston based organization that streamlines the enrollment process in financial assistance benefits, such as the Affordable Connectivity Program (ACP) and Lifeline, for low income individuals through in-person and digital enrollment. Studies from the US Government Accountability Office find that over two-thirds of individuals abandon their initial Lifeline applications. These deficits in Lifeline enrollment mirror ACP enrollment, as the same National Verifier (NV) system was used in both programs. This study seeks to explore LH’s sign-up methods (digital vs in-person), across Massachusetts and Texas to better understand the modalities of Link Health’s current success in enrollment into the ACP and Lifeline programs. 

Methods
Between November 2022 and March 2025, LH participants enrolled in-person at federally qualified health centers or remotely via text-messaging. In-person, patient navigators (PNs) educate participants on available programs, assess their eligibility, and address any questions. Demographic data is collected and stored in a Firebase dashboard. Participants are thereafter directed to the FCC NV site to complete the eligibility verification. Digital enrollments are completed through LH’s webpage and additional information is collected through SMS messages from remote navigators. Remote navigators proceed to offer step by step assistance through the NV application platform.

Results
In Massachusetts, 752 ACP sign-ups were recorded. 183 (24.30%) of those were completed digitally, 543 (72.20%) were completed in-person, and 26 (3.50%) were completed via a combination of in-person and digital sign-up methods. Lifeline enrollment in Massachusetts was much larger with 2195 sign-ups. 1178 (53.66%) were digital, 996 (45.38%) were in-person, and 21 (0.01%) used both in-person and digital sign ups. 

In Texas, a newer target state for LH, 363 ACP sign-ups were recorded. Of these enrollments, 174 (47.90%) were digital, 185 (51.00%) in-person, and 4 (1.10%) a combination of in-person and digital sign-up. There were an additional 56 sign ups for Lifeline, with 52 (92.86%) being digital and 4 (7.14%) being in-person. 

Conclusion
Link Health highlights the significant improvements in remote sign-up rates for ACP and Lifeline programs in Massachusetts and Texas. Initially, Massachusetts benefited from a higher level of in-person engagement due to a greater number of Link Health-associated clinics and a larger PN workforce. However, as remote communication methods with patients became more efficient and streamlined, digital sign-up rates soared. These results affirm that digital outreach is not only feasible but critical for expanding participation and ensuring equitable access to essential resources.

Comparing Digital and In-Person Enrollment Modalities for ACP and Lifeline: Evaluating Link Health’s Outreach in Massachusetts and Texas

Objective:
This is an observational descriptive epidemiological study. We aim to examine global patterns and trends in brain and CNS cancer incidence and mortality using GLOBOCAN 2022 data, analyzing how socioeconomic development, measured by the Human Development Index (HDI), influences these rates and identifying potential mediating factors that explain this association.

Background:
Brain and central nervous system (CNS) cancers pose a significant and complex global health challenge, despite accounting for less than 2% of all cancer diagnoses worldwide. These malignancies are particularly notable for their devastating impact, characterized by high mortality rates and significant challenges in treatment and patient care. Emerging epidemiological research suggests a compelling connection between economic development and brain cancer incidence and mortality, prompting a deeper investigation into the underlying factors, such as healthcare capacity, environmental exposures, and population health that influence these patterns.

Methods:
We obtained brain and CNS cancer incidence and mortality data for 193 countries from GLOBOCAN 2022 and classified countries according to their Human Development Index rankings from lowest to highest development levels. Analysis confirmed that countries with higher HDI scores demonstrated significantly greater brain cancer incidence and mortality rates compared to less developed nations. We hypothesized that several factors might explain this pattern, including better diagnostic capabilities, healthcare infrastructure, population health characteristics, and environmental exposures. We collected data on healthcare workforce density (neurosurgeons, pathologists), diagnostic technology availability (MRI scanners), health system factors (universal coverage, number of clinical trials, radiotherapy availability), population metrics (life expectancy, obesity prevalence, height), and environmental variables (air pollution, radon exposure). Statistical regression models were used to identify which factors best account for the observed relationship between development level and brain cancer burden.

Results:
Higher HDI rankings demonstrated significant positive correlations with both brain and CNS cancer incidence and mortality rates. Among all variables analyzed, population height, life expectancy at birth, and pathologist density showed the strongest positive correlations with both incidence and mortality of brain and CNS tumors. Healthcare system factors, including radiotherapy availability, universal health coverage, and neurosurgeon density, also demonstrated significant associations, though with slightly lower correlation strength. MRI availability was significantly correlated, but less strongly than other healthcare capacity measures. In contrast, the number of clinical trials for brain malignancies and national radon activity showed no significant correlation with incidence or mortality, and air pollution levels were weakly negatively correlated, suggesting limited relevance in this global dataset. These results suggest that both population-level demographic factors and health system capacity help explain the observed link between higher socioeconomic development and greater reported brain tumor burden, while some environmental exposures and research activity appear to play a minimal mediating role in this relationship.

Conclusion:
Healthcare infrastructure and population health indicators substantially explain the higher brain cancer burden observed in more developed countries. These findings suggest that the relationship between socioeconomic development and brain cancer incidence reflects complex interactions between diagnostic capacity, healthcare access, and population-level health characteristics rather than solely representing differences in disease occurrence.

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