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Viral hepatitis (VH) remains a leading cause of preventable mortality in the United States (US). Despite advancements in antiviral therapies, disparities in VH-related mortality persist across demographic, racial, and geographic groups. This study analyzes trends in VH-related mortality among US adults between 1999 and 2020 to identify high-risk subgroups and inform public health interventions. This retrospective cohort study analyzed VH-related deaths among US adults (≥25 years). Data were obtained from the CDC WONDER database, with cases identified using the International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) codes B15–B19. Age-adjusted mortality rates (AAMRs) were calculated per 1,00,000 individuals and stratified by age, gender, race and geographical location. Temporal trends in mortality were analyzed by estimating annual percentage changes (APCs) in the AAMRs using the joinpoint regression model. A total of 3,59,035 VH-related deaths were recorded among US adults during 1999 to 2020 with a cumulative overall AAMR of 7.36 (95% CI: 7.33–7.38). Overall, the AAMRs increased significantly from 1999 to 2013 (APC: +3.21; P < .01), followed by a significant decline until 2020 (APC: −5.61; P < .01). Men exhibited higher AAMRs than women, with middle-aged adults (45–64 years) most affected compared to young (25–44 years) and older adults (65 to 85+ years). Non-Hispanic (NH) American Indians/Alaska experienced the highest AAMRs followed by NH Blacks/African Americans, Hispanics, NH Asians/Pacific Islanders and NH Whites populations. Geographically, mortality rates were higher in urban areas than in rural areas, in the Western region relative to other regions and in the District of Columbia compared to other states. Significant disparities in VH-related mortality persist across demographic and geographic subgroups, with particularly higher rates among men, NH American Indian/Alaska Native population, middle-aged adults, and residents of urban and Western US regions. Targeted public health strategies are essential to address these inequities and improve outcomes.

Abstract Aims Activating transcription factor 4 (ATF4) functions as a transcriptional regulator in various cell types and tissues under both physiological and pathological conditions. While previous studies have linked ATF4 activation with promoting cardiomyocyte (CM) death in dilated cardiomyopathy (DCM), atrial fibrillation, and heart failure, its role in developing CMs remains unexplored. Methods and results We generated multiple distinct CM-specific (Atf4cKO(e2/3/pA) and Atf4cKO(e2)) and global Atf4 knockout (KO; Atf47del/7del and Atf41ins/1ins) mouse models targeting different Atf4 regions, as well as CM-specific deletion of Rps19bp1 to study cardiac phenotypes. Detailed morphological and molecular analyses were performed. Atf4cKO(e2/3/pA) [targeting exon 2–3 including the polyadenylation signal (polyA)] mice exhibited severe cardiac defects and died before E17.5, likely due to ectopic activation of the p53 signaling pathway resulting from Rps19bp1 downregulation, a potent suppressor of p53. Further investigation revealed that deleting the polyA signal of Atf4 in Atf4cKO(e2/3/pA) mice led to transcriptional readthrough, resulting in the formation of an Atf4-Cacna1i fusion transcript and Rps19bp1 downregulation. To avoid readthrough while abolishing ATF4 function, we introduced small indels into exon 3 of Atf4 in mice (Atf47del/7del and Atf41ins/1ins), which showed normal Rps19bp1 expression and cardiac morphology. Importantly, CM-specific deletion of Rps19bp1 recapitulated the cardiac defects and transcriptional change seen in Atf4cKO(e2/3/pA) mice. Conclusion We found that the downregulation of Rps19bp1, not the loss of ATF4 function, underlies the cardiac phenotypes in Atf4cKO(e2/3/pA) mice. The reduced expression of Rps19bp1 in Atf4cKO(e2/3/pA) mice is likely due to the unintentional deletion of Atf4 polyA signal and subsequent transcriptional readthrough, underscoring the essential role of RPS19BP1, not ATF4, in cardiac development. Consistent Rps19bp1 downregulation has been observed in other tissue-specific Atf4 KO models utilizing the Atf4fl(e2/3/pA) allele, suggesting that previously reported Atf4 KO phenotypes may result from Atf4 transcriptional readthrough effects. These findings reveal a locus-dependent transcriptional interference mechanism and emphasize the importance of avoiding confounding cis effects in genetically engineered models.

Polycystic kidney disease (PKD) is a genetic disorder characterized by progressive kidney cyst formation and eventual kidney failure. Emerging evidence suggests that plant-based diets may confer therapeutic benefits in patients with PKD by modulating mTOR and AMPK signaling, reducing oxidative stress and inflammation, while improving metabolic and cardiovascular profiles. These diets, which are low in animal protein and rich in antioxidants, may help lower uric acid levels and support blood pressure control, thereby potentially reducing fibrosis. However, careful planning is required to avoid nutritional deficiencies. Well-designed clinical trials are warranted to validate their role in ADPKD management.

Abstract BACKGROUND STELLAR was a phase III randomized, open-label trial of eflornithine (ornithine decarboxylase inhibitor) with lomustine versus lomustine alone in patients with recurrent anaplastic astrocytoma (AA). We previously reported an overall survival (OS) and progression free survival (PFS) of the combination in the patients with grade 3 IDH-mutant astrocytoma. Here we report updated OS and PFS outcomes based on additional molecular classification and blinded independent central review (BICR). METHOD Eligibility included: age ≥ 18 years, AA (2016 WHO criteria) with first recurrence ≥ 6 months after radiation, KPS ≥ 70, and no imaging findings consistent with grade 4 glioblastoma. Patients received eflornithine (2.8 g/m2 TID Q 2/3 weeks) with lomustine (90 mg/m2 Q 6 weeks) (Arm A) or lomustine alone (110 mg/m2 Q 6 weeks) (Arm B). Primary endpoint was OS. RESULTS Updated molecular data resulted in re-classification of the 343 AA patients enrolled into 3 WHO 2021 defined tumor subtypes, 196 tumors were IDHmut, CDKN2A/B intact, consistent with diagnosis of astrocytoma, IDHmut, WHO grade 3, 33 tumors had CDKN2A/B loss consistent with astrocytoma, IDHmut, WHO grade 4, 106 tumors were IDHwt consistent with diagnosis of glioblastoma, IDHwt, WHO grade 4. Updated results strengthen initial conclusion that eflornithine plus lomustine resulted in significant survival benefit in the astrocytoma, IDHmut, WHO grade 3 group (mOS 34.9 vs, 23.5 months, HR = 0.64, stratified log rank p =0.0136). PFS with eflornithine was also improved (15.8 vs, 7.2 months, HR = 0.57, stratified log rank p =0.0113). BICR demonstrated a high correlation between investigator and centrally determined PFS (p=0.0305), and high correlation between OS and PFS (p=.0001). CONCLUSION The clinically meaningful OS and PFS benefits observed with eflornithine in the molecularly defined 2021 WHO CNS grade 3 astrocytomas is further confirmed and expanded based on additional molecular classification and BICR of PFS.

Abstract Berubicin is a unique anthracycline engineered to have the ability to cross the blood-brain barrier (BBB). Herein we present the primary results from a large global trial of Berubicin vs. Lomustine randomizing patients with progressive disease after only one prior therapy, all being IDH WT and stratified for MGMT methylation. The primary endpoint was overall survival (OS), secondary endpoints included progression-free survival (PFS), overall response rates (ORR) of complete (CR) and partial (PR) responses. Eligibility was determined radiologically by central reads based on progression of disease, and in 2.5 years 252 patients were enrolled with 168 randomized to Berubicin and 84 to Lomustine. Safety assessment showed that Berubicin was well tolerated and myelosuppressive side effects were manageable with growth factors. Importantly, although anthracyclines are known to cause cardiotoxicity, evaluation with frequent troponin measurements, ECG and ECHO testing revealed no evidence of impact on cardiac function. The primary endpoint, OS, showed Berubicin and Lomustine had similar outcomes. Median overall survival for Berubicin was 8.7 months (6.7, 9.9) and for Lomustine was 9.3 months (6.7, 10.7) with a Hazard Ratio of 1.13 (p = 0.5351). PFS of Berubicin and Lomustine were also similar (1.5 vs, 1.6 months). There were no responses in the Lomustine arm and stable disease in 35.2% of patients while Berubicin had a response rate of 5.8% (PR) and stable disease of 33.6% with a combined disease control rate (DCR) of 39.4%. Additional data will be presented and discussed. Anthracyclines are characteristically used in combination for systemic therapy (e.g. leukemia, lymphoma, certain breast cancers), so there is promise that combination therapy will be the next pertinent approach to treatment of GBM. Evaluation of activity against a range of pediatric brain tumors is being pursued and preliminary results will be presented at the time of the conference.

Aims Heterotopic ossification (HO) is a recognized complication following periacetabular osteotomy (PAO), but its patterns, incidence, and clinical relevance remain poorly defined. The commonly used Brooker classification, developed for total hip arthroplasty, is not fully applicable to HO after PAO. This study aimed to propose a new classification system specific to HO after PAO, evaluate its clinical relevance, and report the cumulative probabilities of radiological and symptomatic HO. Methods This retrospective study included 643 patients who underwent PAO between January 2006 and July 2024. A total of 308 patients (47.9%) had concomitant arthroscopic procedures. Radiographs were analyzed to identify HO using both the Brooker classification and a newly developed system. The cumulative probabilities of radiological and symptomatic HO were calculated using Kaplan-Meier analysis. Difference of variables between patients with and without HO was analyzed. Receiver operating characteristic (ROC) curve analysis was used to compare the predictive performance of the two classification systems. Results The cumulative probabilities of radiological and symptomatic HO at five years post-PAO were 30.4% and 3.8%, respectively. The probabilities were 41.9% in males and 29.2% in females. Four patients (2.8%) required surgical excision of HO, all classified as type 3 or 4 under the new system. The ROC analysis demonstrated superior predictive performance for the new classification system (AUC = 0.928) compared to the Brooker classification (AUC = 0.697; p = 0.007). No significant differences were found between the patients with and without HO in terms of age, sex, concomitant arthroscopic procedures, or receiving prophylaxis in addition to low-dose aspirin. Conclusion This study highlighted the cumulative probabilities of HO following PAO and introduced a new classification system that improved clinical relevance and predictive accuracy. These findings have provided insights into the incidence and management of HO after PAO, and laid the groundwork for standardized reporting and future research. Cite this article: Bone Jt Open 2025;6(11):1436–1445.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder and a leading cause of kidney failure worldwide. Disease progression is driven by cyst expansion, tubular injury, and maladaptive metabolic and hemodynamic changes. Tolvaptan remains the only US Food and Drug Administration–approved disease-modifying therapy, however its tolerability and safety profile highlight the need for additional strategies. Sodium-glucose cotransporter 2 inhibitors (SGLT2is), initially developed for glycemic control, have demonstrated robust kidney-protective and cardioprotective effects across diverse patient populations, including those without diabetes. By lowering intraglomerular pressure, metabolic reprogramming, and attenuating hypoxic microenvironment and inflammation, SGLT2is target mechanisms that are relevant to ADPKD. However, concerns that SGLT2i may provoke osmotic diuresis and activate vasopressin led to systematic exclusion of patients with ADPKD from pivotal outcome trials. The 2025 Kidney Disease Improving Global Outcomes ADPKD guidelines explicitly advise against the use of SGLT2i for slowing kidney function decline in ADPKD. In this review, we examine mechanistic intersections between SGLT2i and ADPKD pathophysiology, summarize available preclinical and early clinical data, and discuss ongoing large trials designed to address safety and efficacy of SGLT2i in patients with ADPKD. We also highlight the importance of genetic heterogeneity, as most ongoing trials are enriched for rapid progressors carrying PKD1 or PKD2 pathogenic variants, while other genotypes such as DNAJB11 , ALG8 , and ALG9 , often associated with greater interstitial fibrosis, are underrepresented. Substratification of patients by genotype, risk of progression, and comorbidities will be essential to guide precision application of SGLT2i. Whether SGLT2i can ultimately be positioned as an adjunctive or standalone therapy for ADPKD remains unresolved.

The treatment landscape of invasive early-stage and metastatic breast cancer is evolving constantly. These NCCN Guidelines Insights focus on recent updates included in the most recent version (version 5.2025) of the NCCN Guidelines for Breast Cancer specific to workup, locoregional therapy, surveillance, and systemic neoadjuvant/adjuvant therapy recommendations for invasive, nonmetastatic breast cancer.