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Backgrounds and Aims: HBV-related liver disease ranks as the seventh leading cause of mortality. Despite advances in prevention and treatment, global disparities in the burden of primary liver cancer (PLC) persist. We evaluate global trends in the prevalence, incidence, and death of HBV-related liver disease. Approach and Results: Data from the Global Burden of Disease Study 2021 evaluated acute HBV infection, HBV-related cirrhosis, and HBV-related liver cancer prevalence, incidence, and death. In 2021, there were 7.30 million cases of acute HBV, 283.64 million cases of HBV-related cirrhosis, and 288,110 cases of HBV-related PLC. HBV-related PLC accounted for 39% of the global incidence of PLC; Western Pacific had the highest rates for HBV-related PLC, with an incidence of 5.24 and a death rate of 4.38 per 100,000 population. Between 2000 and 2021, age-standardized incidence, prevalence, and death rates from HBV-related liver disease decreased; however, the incidence of HBV-related PLC rose in 65 countries from 2000 to 2021. In parallel, age-standardized prevalent rates from HBV-related PLC increased in Europe (annual percent change: 0.77%, 95% CI: 0.72%–0.81%) and the Americas (annual percent change: 1.05%, 95% CI: 1.00%–1.10%). Conclusions: From 2000 to 2021, decreases in HBV-related liver disease incidence and prevalence were observed; however, more than one-third of countries showed an increase in the incidence of HBV-related PLC. These findings highlight the need for strengthened HBV treatment efforts to reduce the risk of liver cancer.

Abstract Tooth enamel, the hardest vertebrate tissue, is crucial for mastication and dental protection. Its formation depends on the enamel organ (EO), a specialized epithelial structure derived from oral epithelium. How uniform oral epithelium differentiates into diverse EO cell types remains unclear. While p63 , an ectodermal development master regulator, is essential for dental placode formation, its specific roles in EO development have been obscured by early arrest in p63 knockout mice. Using single-cell RNA sequencing from mouse incisors, we show p63 expression across all EO cell types with both shared and distinct functions. Through trajectory reconstruction, we identify p63 ’s role in regulating both amelogenic (AmG) and non-AmG lineage commitment during EO development. Comparative transcriptome analyses reveal that p63 regulates the Krt8-to-Krt5 transition during AmG cell differentiation, paralleling its function in skin development. This parallel is reinforced by comparative motif discovery showing shared transcription factor usage, particularly p63 and AP-2 family members. Chromatin accessibility analyses further illustrate that p63 mediates this transition through chromatin landscape remodeling. These findings demonstrate that p63 co-opts the Krt8-to-Krt5 transition mechanism from skin development for EO formation. Summary statement This study reveals how p63 repurposes a skin keratinization mechanism for tooth enamel formation, providing novel insights into how specialized dental tissues develop and potential therapeutic targets for enamel disorders.

Objectives To evaluate the feasibility for use of electronic health record (EHR) data in conducting adverse event surveillance among women who received mid-urethral slings (MUS) to treat stress urinary incontinence (SUI) in five health systems. Design Retrospective observational study using EHR data from 2010 through 2021. Women with a history of MUS were identified using common data models; a common analytic code was executed at each site. A manual chart review was conducted in a per-site random patient subset to establish a reference standard. Automated text processing (Text Processed Integrated (TPI)) was developed and evaluated at each site to determine the surgical approach and synthetic mesh implantation. Patients were characterized and surgical outcomes were ascertained over 730 subsequent days. Setting Five large tertiary care academic medical centers. Participants Across five health systems, 9,906 eligible patients (mean age 57–60 per site) were identified. Main outcome measures Determination of surgical approach, synthetic mesh implantation, and assessment of the duration of surveillance for mortality and reoperation rates following MUS implantation. Results In the TPI cohort analysis, 3,331 patients were identified. Surgical approach per site was retropubic (42% to 77%), transobturator (6% to 44%), single incision (0% to 24%), and adjustable sling (0% to <4%). Concordance rates for TPI using chart review were 71%–90% at each site for the surgical approach and 28%–85% for synthetic mesh implantation. Patient follow-up observation rates for mortality and reoperation ranged from 22% to 36% at 90 days, 15% to 30% at 365 days, and 8% to 19% at 730 days. Conclusion Using EHR data alone, identification of medical devices and surgical approaches was feasible among women with MUS surgery for SUI, but long-term follow-up ascertainment rates were low. Medical device surveillance using EHR data should be evaluated in the context of the clinical use case, as applicability may vary.

Abstract Background The association of body composition with checkpoint inhibitor outcomes in melanoma is a matter of ongoing debate. In this study, we aim to investigate body mass index (BMI) alongside computed tomography (CT)-derived body composition metrics in the largest cohort to date. Methods Patients treated with first-line anti-PD1 ± anti-CTLA4 for advanced melanoma were retrospectively identified from 11 melanoma centers in The Netherlands. From baseline CT scans, 5 body composition metrics were extracted: subcutaneous adipose tissue index, visceral adipose tissue index, skeletal muscle index, density, and gauge. These metrics were correlated in univariable and multivariable Cox proportional hazards analysis with progression-free survival, overall survival, and melanoma-specific survival (PFS, OS, and MSS). Results A total of 1471 eligible patients were included. Median PFS and OS were 9.1 and 38.1 months, respectively. Worse PFS was observed in underweight patients (multivariable hazard ratio [HR] = 1.86, 95% CI = 1.14 to 3.06). Furthermore, prolonged OS was observed in patients with higher skeletal muscle density (multivariable HR = 0.88, 95% CI = 0.81 to 0.97) and gauge (multivariable HR = 0.61, 95% CI = 0.82 to 0.998), whereas higher visceral adipose tissue index was associated with worse OS (multivariable HR = 1.12, 95% CI = 1.04 to 1.22). No association with survival outcomes was found for overweight, obesity, or subcutaneous adipose tissue. Conclusion Our findings suggest that underweight BMI is associated with worse PFS, whereas higher skeletal muscle density and lower visceral adipose tissue index were associated with improved OS. These associations were independent of known prognostic factors, including sex, age, performance status, and extent of disease. No significant association between higher BMI and survival outcomes was observed.

ABSTRACTBackgroundIndividuals with a germline CDKN2A pathogenic variant (PV) have an increased lifetime risk of melanoma and pancreatic cancer. It is unknown whether the CDKN2A PV impacts quality of life (QoL). Therefore we aimed to assess QoL and psychological distress in families affected by the PV.MethodsThis cross‐sectional study included confirmed carriers and those with a 50% likelihood of carrying the PV (at‐risk carriers) under cancer surveillance who were invited to complete a one‐time questionnaire. Both confirmed and at‐risk carriers are offered skin surveillance, whereas only confirmed carriers aged 40 years or older can participate in pancreatic surveillance.ResultsIn total, 59/247 (24%) individuals under skin surveillance only (skin surveillance group) and 188/290 (65%) individuals under both skin and pancreatic cancer surveillance (pancreatic surveillance group) responded. In both surveillance groups, health‐related QoL and general distress levels were within the general population norms. However, more than 40% of all study participants reported melanoma‐related distress. Pancreatic cancer‐related distress was experienced by 45% of the pancreatic surveillance group. Determinants of cancer‐related distress were a first‐degree relative with melanoma or pancreatic cancer, increased cancer risk perception, and poor general health perception. Over 80% of the participants felt that the benefits of cancer surveillance outweigh the disadvantages.ConclusionIn conclusion, confirmed and at‐risk carriers of the CDKN2A PV under cancer surveillance experienced similar levels of QoL and general distress compared to the general population. However, cancer‐related worry was substantial in this population. These findings can help identify individuals who may benefit from psychological support.

The NCCN Guidelines for Head and Neck Cancers address tumors arising in the oral cavity (including mucosal lip), pharynx, larynx, and paranasal sinuses, as well as occult primary cancer, salivary gland cancer, and mucosal melanoma (MM). The specific site of disease, stage, and pathologic findings guide treatment (eg, the appropriate surgical procedure, radiation targets, dose and fractionation of radiation, indications for systemic therapy). The NCCN Head and Neck Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel’s most recent recommendations regarding management of nasopharynx cancer and ongoing research in this area.

Abstract Objective Sex-specific differences impact vulnerability to alcohol effects, dependence (AD) and related phenotypes. Previous studies demonstrated that sex-related hormone and protein levels may contribute to those differences in sex-specific manner. However, previous studies were limited by sample size, the depths of phenotyping assessments and/or the number of hormones and proteins measured at the same time. Here, we investigated the association of the sex-related hormone (testosterone, estrogens, and progesterone) and protein (FSH, LH, SHBG, and albumin) levels with AD in males and females treated in community-based programs compared to age and sex-matched controls. We also investigated the associations of AD with the combined plasma sex-related hormone/protein “signatures” in the same groups of study subjects. Methods Sex-related hormone and protein levels were measured in plasma samples collected from 401 male and female subjects meeting DSM-IV-TR criteria for AD and 401 age and sex matched controls. Psychiatric Research Interview for Substance and Mental Disorder (PRISM) was used to capture DSM-IV diagnoses of substance use and other psychiatric disorders. All analyses were stratified by sex. Associations between each plasma sex-related hormone/protein level and AD was assessed with multivariable linear regression adjusted for age and BMI for males and age, BMI, and menopause status for females. Progesterone was defined as a continuous variable and a binary variable based on a lower laboratory detection limit of 0.1 ng/mL. We used principal component analysis to define hormone/protein signatures. Hormones and proteins with factor loadings =/&gt; |0.4| were considered important drivers for the corresponding principal components (PCs). Resulting PCs were entered into a sex-stratified logistic regression model with adjustment of age and BMI to determine which PCs were associated with AD. Results Male AD subjects had higher estradiol and albumin levels (p &lt;0.00625) as well as progesterone and LH levels (p &lt;0.05) compared to controls. Progesterone was detected in a larger proportion of AD subjects than in the controls (62.6% vs. 47.7%; p = 0.017). In females, albumin levels were significantly higher (p &lt;0.00385) while estrone and progesterone levels were lower (p &lt;0.05) in AD subjects than the controls. Total testosterone (TT) levels were relatively higher in AD subjects but differences between groups were not significant (p &gt;0.05). In males, the first PC (PC1) that accounted for the majority of data variance was significantly associated with AD (p=0.016) and was mostly driven by TT, estrone, estradiol and SHBG. PC3 (driven by albumin, progesterone and estradiol) and PC4 (driven by albumin and SHBG) were also associated with AD (p=0.007 and p&lt;0.001, respectively). In females, PC1 (driven by estrone, estradiol, SHBG) was not significantly associated with AD. However, PC3 (driven by Albumin and progesterone), PC4 (driven by TT and Albumin) and PC5 (driven by progesterone and TT), were significantly associated with AD (p=0.009, p=0.001, p=0.004, respectively). Conclusion Our findings indicate that individual hormone/protein levels as well as hormone/protein combination signatures associated with AD are different in male and female alcoholics. Future studies should investigate physiological mechanisms reflected in hormone/protein signatures captured by PC analyses.