Faculty Bibliography

BACKGROUND/AIM/OBJECTIVE:Multiple measures of health and wellness have worsened for rural communities in the last two decades. Few studies have sought to characterize the rural-urban difference in 5-year cancer survival data in a nationwide sample over that time. PATIENTS AND METHODS/METHODS:We analyzed cause-specific five-year survival data for prostate, breast, colorectal, pancreatic, lung, and liver cancers diagnosed from 2000-2016 among rural and non-rural populations using the Surveillance, Epidemiology, and End Results Database. We explored the CDC Wonder Database for drug related mortality in rural and non-rural populations. Ordinary least squares regression assessed temporal survival trends, and analysis of covariance compared the statistical significance in annual change in survival between groups. RESULTS:<0.0001) of drug related mortality disparities between rural and urban populations from the years 1999 to 2015. CONCLUSION/CONCLUSIONS:From 2000 to 2016, rural-urban disparities in cancer survival widened for five of six major cancers during the same period in which national drug overdose rates increased in rural populations.

Age is the greatest risk factor for mortality and morbidity. We previously reported premature ageing in PKP2 arrhythmogenic cardiomyopathy (PKP2-ACM). However, depiction of cardiomyocyte molecular anatomy in premature ageing remains incomplete. Furthermore, the relationship between myocyte premature ageing and the molecular components of electrical homeostasis in PKP2-deficient hearts remains understudied. Therefore, we aimed to identify molecular anatomical changes of premature ageing in PKP2-deficient adult cardiomyocytes, the corresponding gene cohort and its imprint in the human electrocardiogram (ECG). We used a murine model of cardiomyocyte-specific PKP2 knockout. Molecular anatomy was resolved by expansion and structured illumination microscopy, allowing 3D-nanometric visualization, and by serial block-face scanning electron microscopy. We used omics databases to distill a subset of genes related to ageing and PKP2 deficiency containing single nucleotide polymorphisms (SNPs) with an ECG-relevant genomic signature. We found increased DNA damage and reduced abundance of transcriptionally repressed heterochromatin at the lamin-associated domain (LAD), and disrupted mitochondria ultrastructure at the intercalated disc. Genes dysregulated in ageing hearts and PKP2-deficient cells were distilled to identify those in the PKP2 human left ventricular gene network (by GTEx) that contain SNPs with an imprint in the human ECG (based on ECG GWAS). These findings indicate that in PKP2 deficiency, transcriptionally repressed heterochromatin in the LAD is vulnerable to damage, and erasing of otherwise transcriptionally inaccessible genomic regions, consistent with premature cellular ageing and transcriptional reprogramming. Multi-omics analysis indicates that reduced PKP2 expression accelerates cardiomyocyte ageing, and the age-related gene network contributes to dysfunction of cell metabolism and arrhythmia risk in PKP2-ACM. KEY POINTS: We used advanced imaging technology to unveil DNA damage and loss of heterochromatin architecture in the lamin-associated domain (LAD), and mitochondrial remodelling at the intercalated disc, as features of premature myocyte ageing in adult PKP2-deficient murine cardiomyocytes. Multi-omics analysis identified a network of genes dysregulated by ageing and by PKP2 deficiency. Cross-correlation with the ECG GWAS database found a subset of single nucleotide polymorphisms with an imprint in the human electrocardiogram. These results provide novel insight into the mechanisms of transcriptional remodelling and take an initial step toward a better understanding of the oligogenic bases of arrhythmia risk in PKP2-deficient hearts.

High-resolution quantitative susceptibility mapping (QSM) combined with susceptibility source decomposition provides a powerful approach for investigating the magnetic susceptibility alterations in Alzheimer's disease (AD). In this study, ex vivo three-dimensional multi-echo gradient-echo (mGRE) images of 5xFAD and

Long-acting growth hormone (LAGH) preparations have moved from development to routine clinical use over the past decade. Several products are now approved for paediatric growth hormone deficiency (GHD), selected non-GHD short-stature indications, and, in some regions, for adult GHD. The Growth Hormone Research Society convened an international workshop in October 2025 to reappraise the evidence base and refine clinical recommendations. Currently, data are available for up to 7 years of LAGH treatment in over 8,000 individuals. This remains substantially shorter and smaller than for daily GH. Across preparations, short- to mid-term efficacy appears comparable to daily somatropin, provided dosing is individualised and monitored appropriately. Approvals and pivotal trials include both, treatment initiation and switching from daily GH, depending on product and regional label. No new major safety signals have been identified in trials and real-world reports, although data on BMI trajectories require further evaluation. Injection-site reactions remain the most frequent adverse event and vary by formulation. Anti-drug-antibodies have been observed, yet evidence suggests they have limited clinical impact. Effects on glucose metabolism resemble those of daily therapy, but metabolically high-risk groups are under-represented in studies. Among cancer survivors, data on tumour recurrence and second neoplasms with LAGH are not yet available. Recommendations and practice points emphasised careful patient selection and counselling, product-specific dosing, and insulin-like growth factor-I (IGF-I) monitoring. Urgent knowledge gaps include transition care, long-term efficacy, adherence and safety in cancer survivors. Well-resourced registries are essential for addressing these gaps and supporting safe, effective, and patient-centred use of LAGH.

BACKGROUND AND OBJECTIVES/OBJECTIVE:This systematic review (SR) provides updated evidence-based conclusions regarding the use of pharmacologic migraine prevention in adults to inform a new joint American Academy of Neurology (AAN) and American Headache Society practice guideline. METHODS:A multidisciplinary panel conducted an SR following the 2017 AAN Clinical Practice Guideline Process Manual. Randomized controlled trials evaluating pharmacologic preventive treatments for adults with episodic or chronic migraine were included. Searches encompassed MEDLINE, Embase, and ClinicalTrials.gov from database inception through June 6, 2024. Studies were screened in duplicate, with dual independent risk-of-bias assessment. Outcomes included change in monthly headache days, ≥50% responder rate, and validated patient-reported quality of life (QOL) measures. Raw mean differences, standardized mean differences, and risk ratios were calculated. A modified Grading of Recommendations Assessment, Development, and Evaluation process was used to classify certainty of evidence. RESULTS:A total of 217 studies met inclusion criteria. For episodic migraine, high-confidence evidence showed that galcanezumab and erenumab are more effective than placebo in reducing headache frequency. Moderate-confidence evidence supported benefit from atogepant, eptinezumab, fremanezumab, propranolol, topiramate, and valproate. Several additional oral agents including amitriptyline, bisoprolol, flunarizine, fluoxetine, levetiracetam, metoprolol, nifedipine, pizotifen, and telmisartan had low-confidence evidence suggesting possible benefit. For chronic migraine, high-confidence evidence supported reductions in headache frequency with fremanezumab, galcanezumab, and onabotulinumtoxinA. Moderate-confidence evidence supported benefit from atogepant, eptinezumab, erenumab, topiramate and valproate. Across both episodic and chronic migraine populations, erenumab, fremanezumab, galcanezumab, eptinezumab, rimegepant, atogepant, topiramate and onabotulinumtoxinA demonstrated improvements in patient-reported QOL outcomes on validated instruments. Evidence comparing active treatments was limited and generally of low or very low confidence, restricting conclusions about comparative effectiveness. DISCUSSION/CONCLUSIONS:This SR provides a comprehensive synthesis of evidence on pharmacologic migraine prevention in adults. High- and moderate-confidence findings confirm the efficacy of several established and newer preventive therapies and demonstrate improvements in patient-reported outcomes across multiple validated measures. These conclusions informed the development of evidence-based recommendations, presented in a companion publication, to guide clinicians in selecting preventive medications for adults with episodic and chronic migraine.

The 2025 American Joint Replacement Registry Annual Report includes 4.6 million hip and knee arthroplasty procedures, with 4,434,668 validated cases, representing a 20% increase from the prior report. Registry participation continues to expand, with contributions from over 5000 surgeons and 1200 institutions, including an increasing submission of patient-reported outcome measures. A key methodological change includes the adoption of Kaplan-Meier survivorship analysis, allowing improved assessment of time-dependent revision risk. Ongoing efforts to improve data completeness and registry infrastructure continue to support registry-driven research. The full report can be accessed at https://www.aaos.org/registries/publications/ajrr-annual-report/.

OBJECTIVE:To quantify general population prevalence, and differences by sex and BMI, in ultrasound (US) features of knee osteoarthritis (KOA), patient-reported knee symptoms (Ksx), radiographic KOA (rKOA), and symptomatic KOA (sxKOA). METHODS:Participants from the Johnston County Health Study (2019-2024; n=902) provided demographic, clinical, and imaging data. Ksx was defined as self-reported pain, aching or stiffness on most days of any one month in the past 12 months. rKOA was defined as Kellgren-Lawrence grade ≥2 (or total knee replacement (TKR)), severe rKOA as grades 3-4 (or TKR), and sxKOA as rKOA and Ksx in the same knee. Standardized US scoring was performed as previously reported. Weighted prevalence estimates and 95% confidence intervals (CI) for Ksx, rKOA, sxKOA, severe rKOA, and US features were calculated overall and by sex and BMI category. RESULTS:Among 902 participants (67% female; 66% non-Hispanic white, mean age 55 years, and BMI 33 kg/m²), the weighted prevalence of Ksx, rKOA, sxKOA, and severe rKOA were 61%, 36%, 27%, and 21%, respectively, all higher (based on non-overlapping CIs) than baseline estimates from the Johnston County Osteoarthritis Project and other cohorts. Ksx, rKOA, sxKOA, and severe rKOA were higher among females and those with obesity. Compared to females with obesity, those with severe obesity had higher prevalence of all radiographic outcomes at moderate and severe grades with non-overlapping CI. US effusion and synovitis were more prevalent in males, whereas medial and lateral cartilage damage were more common in females. With increasing obesity, osteophytes and medial cartilage damage were more prevalent, while gryescale effusion was actually less frequent. CONCLUSION/CONCLUSIONS:KOA prevalence continues to increase in the population. Sex and BMI differences in KOA prevalence and US features were most pronounced among females with severe obesity. Distinguishing between sexes and by obesity levels may improve understanding of KOA mechanisms and guide tailored prevention and treatment strategies.

BACKGROUND/UNASSIGNED:Liver cancer poses a significant global health burden, characterized by substantial regional disparities. We analyzed liver cancer incidence and mortality across 204 countries and territories from 1990 to 2021 and projected trends from 2021 to 2041. MATERIALS AND METHODS/UNASSIGNED:Data from the Global Burden of Disease (GBD) Study 2021 were used to calculate age-standardized rate (ASR), average annual percentage change (AAPC), and estimated annual percentage change (EAPC). Risk factors, human development index (HDI), and sociodemographic index (SDI) were evaluated. The Nordpred and Bayesian Age-Period-Cohort (BAPC) models projected future trends. RESULTS/UNASSIGNED:Globally, according to the analysis of AAPC, the ASR of liver cancer incidence rose by 0.115% (95% CI: 0.07-0.159) annually, while the mortality ASR trend remains stable (-0.113%, 95% CI: -0.35-0.124). Viral hepatitis B and C remained primary causes, but non-alcoholic steatohepatitis (NASH) contributions increased. The summary exposure value (SEV) for drug use increased by 12% globally, with a dramatic increase of 308% in North America. High-HDI/SDI countries exhibited higher ASR than expected, which may be attributed to aging populations and the rising incidence of metabolic diseases. Projections indicated a rising number of cases but declining ASR for both males and females by 2041. CONCLUSIONS/UNASSIGNED:Tailored prevention strategies are needed to address region-specific risk factors and mitigate the growing burden of liver cancer.