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Background and Aims: Accumulating data related to prevention, surveillance and treatment of chronic hepatitis B (CHB) provided the impetus for this updated guideline, using the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach. Methods: The guideline was developed in compliance with the National Academy of Medicine standards. The guideline panel developed structured questions following the Population, Intervention Comparison, Outcomes (PICO) framework. The panel addressed 6 PICO questions covering prevention (maternal to infant transmission and horizontal transmission), surveillance for liver cancer (among hepatitis B surface antigen positive (HBsAg) persons co-infected with hepatitis C virus, hepatitis D virus and/or human immunodeficiency viruses and after HBsAg loss) and treatment (HBsAg positive persons in immune-tolerant or indeterminate phases as well as withdrawal of antiviral therapy), providing evidence-based recommendations on these topics. Four systematic reviews of the literature were conducted, and two existing systematic reviews were utilized to support the recommendations in this practice guideline. Conclusions: This evidence-based guideline provides updated recommendations to optimize the care of persons with CHB.

Importance Primary brain and central nervous system cancer (collectively referred to as CNS cancer) comprises 2% of all human cancers and poses significant health and economic challenges in the United States. Objective To analyze CNS cancer burden in the US, stratified by time, location (state and division), sex, age group, and Sociodemographic Index (SDI). Design, Setting, and Participants This cross-sectional study involved a repeated analysis of Global Burden of Disease Study (GBD) 2021 data in 2024. Using data from 183 sources, CNS cancer metrics in the US were estimated across states and years. US CNS cancer metrics across all sexes and age groups were included in the GBD. Exposure CNS cancer diagnosis. Main Outcomes and Measures Overall and age-standardized estimates of the incidence, prevalence, mortality, disability-adjusted life-years (DALYs), years of life lost, and years lived with disability per 100 000 population, including 95% uncertainty intervals (UIs), and time trends. Results In 2021, for all age groups and sexes across the US, there were 31 780 incident cases (95% UI, 29971.1 to 32843.9). Age-standardized incidence, DALYs, and mortality rates per 100 000 population were 6.91 (95% UI, 6.58 to 7.12), 134.38 (95% UI, 129.83 to 137.95), and 4.1 (95% UI, 3.87 to 4.22), respectively. Despite no significant change observed in the overall incidence between 1990 and 2021, DALY and mortality rates decreased by 15.77% (95% UI, −17.75% to −13.68%) and 8.41% (95% UI, −11.09% to −6.22%), respectively. Substantial geographic variability was noted. Mississippi, Alabama, Kentucky, and Kansas (West North Central and East South Central divisions) and West Virginia faced persistently high burdens over the past 30 years. Sex differences were evident; disease burden was consistently higher in males compared with females. Age-specific estimates showed a bimodal distribution: the youngest group (<5 years) showed a significant decrease in incidence rate (−34.42% to −11.56%), whereas older age groups (>70 years) experienced increasing trends. DALYs and mortality rates were negatively correlated with SDI (ρ = −0.6860 and ρ = −0.6391; P < .001). Conclusions and Relevance These findings provide valuable insights into the CNS cancer burden across the US by age, sex, location, and SDI, enabling better public health status assessments, health care policy restructuring, and resource redistribution for improved care.

Background: Atrial fibrillation (AF) significantly impacts quality of life (QoL) and is often observed in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). Acoramidis achieves near-complete (≥90%) transthyretin (TTR) stabilization and is approved in the USA, the UK, Europe and Japan for the treatment of ATTR-CM in adults. In the phase 3 ATTRibute-CM study (NCT03860935), acoramidis treatment significantly reduced the time to all-cause mortality (ACM) or first cardiovascular-related hospitalization (CVH) at Month 30, and resulted in improved 6-minute walk distance (6MWD), Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) scores and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels relative to placebo. The clinical efficacy of acoramidis has not yet been reported in patients with ATTR-CM and with an AF or atrial flutter (AFL) diagnosis at baseline. Research Question: How does acoramidis treatment affect ACM or first CVH, 6MWD, KCCQ-OS scores, and NT-proBNP levels at Month 30 in participants with ATTR-CM with or without AF/AFL diagnosis at baseline? Methods: The ATTRibute-CM study design has been previously published. This post hoc analysis included participants in the modified intention-to-treat population (N=611) grouped by AF/AFL diagnosis at baseline (defined as recorded AF medical history or the presence of AF or AFL on an ECG at enrollment). The rate of ACM or first CVH at Month 30 was compared between groups using a stratified Cox proportional hazards model. Changes from baseline to Month 30 in 6MWD, KCCQ-OS scores and NT-proBNP levels were summarized descriptively. Results: Overall, 62.8% (384/611) of participants had an AF/AFL diagnosis at baseline (acoramidis: 255/409, placebo: 129/202). These participants had lower mean 6MWD and KCCQ-OS scores and higher median NT-proBNP levels than those without AF/AFL diagnosis at baseline. Treatment with acoramidis reduced ACM or first CVH, slowed the decline in 6MWD and KCCQ-OS scores and blunted the rise in NT-proBNP compared with placebo, regardless of AF/AFL diagnosis at baseline ( Table ). Conclusions: Acoramidis improved clinical outcomes (ACM, CVH), functional status, QoL and NT-proBNP levels relative to placebo in participants with ATTR-CM, regardless of AF/AFL diagnosis at baseline.

Introduction: Transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) arises from amyloidogenic aggregates of destabilized TTR protein in variant (ATTRv-CM) or acquired wild-type TTR (ATTRwt-CM). The p.V142I (V122I) variant is the most common pathogenic TTR allele in the USA and has higher mortality vs wild type. Acoramidis, an oral TTR stabilizer achieving ≥90% stabilization, is approved in USA, UK, Europe, and Japan for treating ATTR-CM in adults. In ATTRibute-CM (NCT03860935), acoramidis showed a reduction in all-cause mortality (ACM) or first cardiovascular-related hospitalization (CVH) vs placebo (PBO), with consistent benefit in ATTRwt-CM and ATTRv-CM (all variants). We report clinical outcomes in participants with p.V142I ATTRv-CM. Research Question: What was the efficacy of acoramidis for clinical outcomes (ACM, CVH) in participants with p.V142I ATTRv-CM in ATTRibute-CM? Methods: In ATTRibute-CM, 632 participants were randomized 2:1 to receive acoramidis HCl 800 mg or PBO twice daily for 30 months. All participants enrolled in open-label extension (OLE) received acoramidis only. Exploratory post hoc analyses were done in the p.V142I ATTRv-CM subgroup. Time-to-event analyses used a stratified Cox proportional hazards model using treatment group as an explanatory factor and baseline 6MWD as a covariate, stratified by randomization factors: serum NT-proBNP and eGFR. ACM was analyzed at Month 42 (ATTRibute-CM 30 months + 12 months OLE). Results: Of the 59 patients with ATTRv-CM reported at randomization, 35 (59.3%) had p.V142I (23 acoramidis, 12 PBO) with comparable baseline characteristics; 4 were homozygous for p.V142I (1 acoramidis, 3 PBO). Through Month 30, ACM/first CVH occurred in 43.5% (10/23) of acoramidis vs 83.3% (10/12) in PBO (HR 0.311; 95% CI 0.120–0.805; Figure 1 ). Through Month 42, ACM occurred in 26.1% (6/23) of continuous acoramidis vs 66.7% (8/12) in PBO to acoramidis (HR 0.307; 95% CI 0.097–0.973; Figure 2 ). Conclusions: In participants with p.V142I ATTRv-CM, acoramidis use was associated with 69% risk reduction in ACM/first CVH through Month 30 and ACM through Month 42 vs PBO. This is the first report of clinical benefit of this magnitude observed in this high-risk population. These findings have biologic plausibility and may reflect the near-complete stabilization observed experimentally with acoramidis in p.V142I ATTR fibrils. These observations require confirmation in larger cohort studies.

Background: The cardiac hormone atrial natriuretic peptide is the endogenous ligand for the guanylyl cyclase A (GC-A) receptor. The ANP/GC-A/cGMP pathway is a key regulator of cardiorenal and metabolic homeostasis. Beyond its classical natriuretic and vasodilatory roles, emerging evidence reveals that ANP via GC-A stimulates lipolysis in human adipocytes and modulates insulin secretion. Notably, the ANP gene variant rs5068, which enhances ANP production, is associated with reduced risk of obesity and metabolic syndrome in humans. We recently engineered CRRL191, a novel best-in-class GC-A agonist, with superior receptor activation and greater resistance to degradation by neprilysin and insulin degrading enzyme resulting in greater blood pressure lowering and natriuretic effects than ANP. Given the metabolic properties of GC-A signaling, we investigated CRRL191’s metabolic effects on lipolysis and insulin secretion in pancreatic, including its interaction with GLP-1. Hypothesis: CRRL191 exerts potent lipolytic and insulinotropic effects and synergizes with GLP-1 to enhance insulin secretion. Methods: Human visceral adipocytes were treated with CRRL191 (10 -8 -10 -6 M) for 6 hrs. Lipolysis was assessed by measuring glycerol and non-esterified fatty acids (NEFA) in supernatants. Rat pancreatic beta cells (INS-1) were stimulated treated with CRRL191 (10 -10 -10 -6 M), GLP-1 (10 -10 -10 -6 M) alone or their combination for 1 hr. Insulin secretion was quantified by ELISA. Results: CRRL191 stimulated lipolysis in human visceral adipocytes (10 -8 -10 -6 M), increasing glycerol and NEFA release. CRRL191 induced greater glycerol release than GLP-1 across all tested doses, with low dose CRRL191 (10 -10 M) notably enhancing NEFA production. In INS-1 cells, CRRL191 dose dependently increased insulin secretion under hyperglycemic conditions, demonstrating superior potency at lower concentrations (10 -10 and 10 -8 M) compared to GLP-1. Remarkably, co-administration of CRRL191 with GLP-1 amplified insulin release beyond levels achieved by either peptide alone. Conclusion: CRRL191 is a potent GC-A agonist that robustly stimulates lipolysis in visceral adipocytes and enhances insulin secretion in pancreatic beta cells. Its synergistic interaction with GLP-1 highlights a novel therapeutic avenue targeting the GC-A/cGMP pathway for integrated treatment of cardiometabolic diseases. These findings support further evaluation of CRRL191 as a promising candidate for cardiometabolic drug development.

Introduction: Patients with transthyretin amyloid cardiomyopathy (ATTR-CM) typically have low serum transthyretin (sTTR) levels, worsening heart failure, and increased mortality. A recent study has shown the association of sTTR levels ≥20mg/dL with reduced risk of all-cause mortality and cardiovascular mortality (CVM). It has also been shown that regardless of baseline sTTR level, greater increases in sTTR levels are associated with greater improvements in cardiovascular outcomes. Acoramidis, a near-complete (≥90%) TTR stabilizer, demonstrated a rapid and sustained increase from baseline in sTTR by Day 28 and reduced risk of cardiovascular outcomes in patients with ATTR-CM. Hypothesis: Acoramidis-mediated early increase in sTTR levels ≥20 mg/dL (lower limit of normal) at Day 28 reduces risks of CVM and cardiovascular-related hospitalizations (CVH) in patients with ATTR-CM. Methods: Analyses were conducted in the ATTRibute-CM modified intention-to-treat (mITT) population (acoramidis: 409; placebo: 202). The sTTR concentrations (normal range is 20-40 mg/dL) were assessed using an immunoturbidimetric method (Abbott ARCHITECT system) in a central laboratory. The proportion of participants with sTTR levels below normal at baseline and Day 28 were determined. The relationship between sTTR levels <20 or ≥20 mg/dL, at Day 28 across the pooled acoramidis and placebo treatment groups, and subsequent risk of CVM and of CVH over 30 months were analyzed using a stratified log-rank test. Results: At baseline about 25% of study participants had sTTR levels below normal in both treatment groups. At Day 28, less than 2% of participants had sTTR levels <20 mg/dL in the acoramidis arm compared with 26% in the placebo arm ( Table 1 ). When acoramidis and placebo treatment groups were pooled based on sTTR levels <20 or ≥20 mg/dL at Day 28, participants with sTTR ≥20 mg/dL were associated with a lower risk of the composite endpoint of CVM or first CVH at Month 30 in comparison with <20 mg/dL ( p <0.0001) ( Figure 1A ). Comparable findings were observed for the individual components (CVM, first CVH) ( Figure 1B and C ). Conclusion: Across treatment groups, sTTR levels above normal range (≥20 mg/dL) at Day 28 were associated with a lower risk of cardiovascular outcomes at Month 30, when compared with sTTR levels below normal range (<20 mg/dL). Thus, these observations demonstrate that higher sTTR levels over time may have the potential for clinical benefits in both CVM and CVH.

Background: Diabetic cardiomyopathy is a common complication of diabetes, which can progress to symptomatic heart failure. Current conventional medical therapy does not reverse the deleterious features of diabetic cardiomyopathy. The natriuretic peptide-cGMP system has been proven to provide a cardioprotective role in diabetic rats. Therefore, we developed CRRL094, a n bispecific peptide that simultaneously activates the natriuretic peptide system and glucagon-like peptide-1 (GLP-1) receptor. In this study, we aimed to characterize the cardioprotective role of CRRL094 and elucidate its downstream molecular mechanisms. Methods: In vitro, human cardiomyocytes (HCMs) were pretreated with PBS or CRRL094 (5 µM) for 6 hours, then exposed to high glucose treatment (HGT, 25 mM) for 48 hours. HCM hypertrophy was determined by assessing mRNA levels of hypertrophic gene markers (NPPA and NPPB) using real-time PCR. Lipid droplet staining was performed using BODIPY 493/503 dye and fluorescence images were analyzed. The protein levels of CIDEC (lipid droplet-related gene) and phosphorylation-AMPK and total AMPK (a key regulator of lipid metabolism) were analyzed by Western blot. In vivo, a type 2 diabetes (DM2) rat model was established by low-dose intraperitoneal Streptozotocin (STZ) injection and a high-fat diet in Wistar rats (male, 4- to 6-week-old). Diabetes was confirmed by fasting blood glucose > 350 mg/dL. Rats were then allocated to two groups: saline-treated controls (n=6) or CRRL094-treated (30 pmol/kg/min; n=6), with treatment delivered via osmotic pumps for 28 days. Heart tissues were collected and analyzed. Results: HGT in HCMs significantly increased the mRNA levels of NPPA and NPPB, whereas CRRL094 significantly attenuated markers of hypertrophy. Further, HGT increased lipid accumulation in HCMs, which was decreased with CRRL094 treatment. Moreover, CRRL094 increased p-AMPK protein levels and decreased CIDEC protein levels in HCMs under HGT. In a DM2 rat model, chronic CRRL094 therapy was associated with suppression of NPPA and NPPB, downregulation of CIDEC, and upregulation of p-AMPK expression in the heart tissue. Conclusion: CRRL094 protects against HGT-induced hypertrophy and inhibits lipid accumulation through regulating the AMPK/CIDEC pathway in vitro and in vivo . These findings support CRRL094 as a novel therapeutic candidate to prevent diabetic cardiomyopathy.