The expansion of genomics provides opportunity to screen individuals beyond clinical indication yet the classification of genomic variants and implications for health outcomes in this context is still emerging. We investigated this further by analysing clinically relevant variants and expected clinical implications in a population with no reported medical conditions. Whole genomes from 9637 healthy unrelated research-consented participants in Singapore were analysed focusing on 1619 genes associated with severe paediatric disease. Association between causative variants and expected phenotype was assessed in correlation with participant characteristics and medical history where available. After considering protein impact, mode of inheritance and participant demographics for 110 variants, further analysis was performed for 44 variants occurring in 150 participants to understand clinical implications. Most carried variants associated with a mild phenotype (cystinuria), late onset (Fabry disease) or a potentially missed phenotype (Hajdu-Cheney syndrome). However, nine participants had variants associated with severe paediatric disease predicted to be symptomatic, such as limb-girdle muscular dystrophy and spastic paraplegia. Despite a cohort selected for absence of pre-existing health conditions, individuals were identified carrying variants associated with severe paediatric conditions. Further work is required to examine for subtle clinical symptoms or alternate genetic suppression mechanisms. This study revealed the challenge of predicting clinical outcomes from genotype-derived screening and emphasises the importance of expanding phenotype characterisation which is highly relevant in population and reproductive screening settings. Trial registration: NCT02791152.

In China, leukemia remains one of the top ten causes of death, and understanding its mortality trends is crucial for public health planning. This study analyzed the mortality trends of leukemia in China from 2004 to 2021, exploring differences by gender, age, and urban versus rural regions.

Mortality data from the "Chinese Death Cause Monitoring Results Datasets" (2004-2021) were analyzed using Joinpoint regression analysis, which identifies changes in trend slopes and provides insight into significant shifts in mortality rates. The study calculated the annual percent change (APC) and average annual percent change (AAPC) for the overall and subgroup mortality rates.

The analysis revealed a general decline in leukemia mortality over the 18-year study period. The age-standardized mortality rate (ASMR) for leukemia in China has decreased significantly from 4.492/10⁵ in 2004 to 3.517/10⁵ in 2021, representing a reduction of 21.71%. Gender-specific trends showed that while the APC for males was - 1.23% (95%CI: -1.55% to -0.97%, P < 0.001), female APC experienced a more pronounced decline of -1.33% (95% CI: -1.68% to -0.97%, P < 0.001). Regional differences were also evident: urban areas saw a sharper decline in ASMR, from 4.424/10⁵ in 2004 to 2.915/10⁵ in 2021, reflecting a 34.11% reduction, with an APC of -2.26% (95% CI: -2.87% to -1.63%, P < 0.001). By contrast, rural areas showed a slower reduction, with an APC of -0.61% (95% CI: -0.86% to -0.34%, P < 0.001), resulting in a decrease of 13.29% from 2004 to 2021. Because crude mortality rates (CMR) are influenced by changes in population age structure, the ASMR is used as the primary indicator for interpreting long-term trends in leukemia mortality. These findings highlight significant disparities in the rate of decline between urban and rural regions, as well as between genders. The overall AAPC for ASMR was - 1.26% (95% CI: -1.55% to -0.97%, P < 0.001), indicating a consistent downward trend in leukemia-related mortality.

Between 2004 and 2021, the overall leukemia mortality rate in China showed a declining trend. However, significant disparities were observed between the genders and regions. Our findings suggest that future prevention and treatment efforts may need to pay increased attention to high-risk populations, such as those in rural areas and male individuals, to further reduce leukemia mortality rates.

Adults with congenital heart disease (CHD) are at high risk of premature death, making advance care planning (ACP) crucial for aligning care with individual values and goals. Previous ACP research has focused primarily on the United States and Canada, highlighting the need for a global perspective. We aimed to describe the ACP practices, needs and preferences of adults with CHD around the globe and to investigate associations with patient-related factors.

This cross-sectional study, part of the APPROACH-IS II project, assessed ACP preferences, needs and practices using patient-reported surveys. Overall, 8,281 patients with CHD (median age 32 years; 54% women; 15% mild, 58% moderate, 27% complex CHD) from 53 centers in 32 countries, spanning 6 continents, were included.

Over half (55%) of participants reported speaking to their physician about how their health might be in the future and 9% had preferences being documented in a plan. According to 66% of patients, the best time to initiate ACP is early in the disease trajectory. Most patients indicated being relatively comfortable talking to their physician about their future health and about death. ACP varied widely across different countries, with United States and Canada top of the class for most variables.

When looking at global ACP practices, needs and preferences, much room for improvement of ACP provision could be noticed. Also, a notable variation in ACP was observed worldwide.

Delamanid is a nitro-dihydro-imidazooxazole derivative that possesses highly potent activity against Mycobacterium tuberculosis, including strains linked to multidrug-resistant tuberculosis (MDR-TB). We conducted an all-case post-marketing surveillance to assess the real-world safety and effectiveness of delamanid in treating MDR-TB in Japan.

All patients diagnosed with MDR-TB were included if they started delamanid between September 2014 and February 2023. Case report forms were collected every 6 months during the treatment period and every 12 months during the follow-up period. Safety assessment included any adverse events that occurred during the treatment period. Effectiveness assessment included the proportion of patients with sputum-culture conversion and treatment success.

In the safety analysis set, 61.6 % of patients (114/185) were males, and the median (interquartile range) age was 48.0 (32.0, 64.0) years. During the treatment period, 54.05 % of patients (100/185) experienced adverse drug reactions (ADRs), and 8.65 % (16/185) experienced serious ADRs. Electrocardiogram QT prolongation was reported in 8.65 % of patients (16/185) but was not associated with an increased risk of cardiovascular events. In the sputum-culture conversion analysis set, sputum-culture conversion was achieved in 86.0 % of patients (80/93). In the effectiveness analysis set, treatment success was achieved in 54.1 % of patients (99/183) by the end of the treatment period.

This surveillance showed the effectiveness of ≥6 months of delamanid treatment among patients with MDR-TB in real-world settings in Japan, with no new safety issues identified.

Myocardial fibrosis (MF), a hallmark of cardiovascular diseases (CVDs) such as myocardial infarction (MI), drives progressive cardiac dysfunction and adverse remodeling. Histone acetylation is a critical epigenetic regulator in cardiovascular pathology. Anacardic acid (AA), a histone acetyltransferase inhibitor (HATi) with pleiotropic bioactivities, has been studied in various disease contexts; however, its antifibrotic efficacy and mechanisms in MF remain unclear.

In vivo, a mouse model of post-infarction MF was established by permanent left anterior descending (LAD) ligation. Using pirfenidone (PFD, an antifibrotic by inhibiting TGF-β) as a positive control, AA's effects were assessed by cardiac function, histopathology, and quantification of fibrotic burden. In vitro, primary cardiac fibroblasts (CFs) stimulated with TGF-β1 were used to delineate mechanisms, focusing on proliferation, migration, myofibroblast differentiation, and transcription of fibrosis-related genes.

In vivo, AA and PFD comparably attenuated cardiac fibrosis and collagen deposition, downregulated fibrosis-related gene expression, and improved heart failure biomarkers in MI mice. Transcriptomic profiling indicated that MAPK pathway and GATA3 expression were reduced in AA-treated MI mouse hearts but increased in CFs in human MI single-cell RNA-sequencing datasets. In vitro, AA inhibited TGF-β1-induced CF proliferation, migration, and myofibroblast differentiation by suppressing p38/JNK phosphorylation, limiting GATA3 nuclear translocation, and reducing H3K9ac levels, thereby decreasing transcription of α-SMA, Col1a1, and Col3a1.

AA protects against post-infarction MF by suppressing the p38/JNK-GATA3 pathway and downregulating H3K9ac-dependent epigenetic activation, supporting AA as a potential antifibrotic strategy and therapeutic candidate for cardiac fibrosis.

Statins are the most widely prescribed class of drugs for cardiovascular (CV) disease (CVD) prevention due to their potent lipid-lowering effects. However, accumulating evidence demonstrates additional cardioprotective properties of statins mediated through pleiotropic mechanisms unrelated to cholesterol modulation. We aimed to discuss the pleiotropic effects of statins and their relevance to clinical outcomes in 2 reviews: Part I focuses on anti-inflammatory, antioxidant and immunomodulatory effects of statins, whereas Part II on statin-induced endothelial function improvement, plaque stabilization and anti-thrombotic effects. Part II also includes a clinical applications and future directions section.

A literature search was conducted in Embase, Scopus, web of science, PubMed and Cochrane Library databases for experimental and clinical studies investigating the effects of statins on inflammation, oxidative stress and immune function. Statins exert potent anti-inflammatory, antioxidant and immunomodulatory activities that can be linked to reduced CV events. Statins confer cardio protection via diverse pleiotropic pathways distinct from cholesterol modulation. Future directions involve optimizing regimens to maximize clinical benefits, addressing controversies, and exploring statins' therapeutic potential beyond CVD through non-lipid mechanisms. A comprehensive understanding of statins' pleiotropic profile will uncover new preventive strategies and therapeutic applications.

Trastuzumab (TRZ), a monoclonal antibody targeting the ErbB2 protein, significantly improves the prognosis of patients with ErbB2-positive breast or gastric cancer; however, its cardiotoxicity substantially limits its clinical applicability in certain patient populations. TRZ-induced cardiotoxicity (TIC) primarily arises from ErbB2 signaling blockade, compromising cardiomyocyte repair mechanisms and functional integrity. This inhibition further compromises the cellular antioxidant capacity, leading to the accumulation of reactive oxygen species (ROS) and triggering a cascade of downstream events, including apoptosis, inflammatory responses, ferroptosis, autophagy dysfunction, and pyroptosis. Based on the aforementioned mechanisms, researchers have conducted in-depth investigations into the molecular pathways involved in TIC. To date, decades of research have identified several keys signaling pathways implicated in TIC, including PI3K/Akt, MAPK, STATs, AMPK, mTOR, MDM2/p53, NLRP3, and NF-κB. Furthermore, a number of potential therapeutic agents targeting key molecules in TIC have been explored. However, these findings have not yet been summarized. Therefore, this review aims to comprehensively consolidate existing knowledge on TIC, elucidate its regulatory mechanisms, and provide insights for developing novel cardioprotective strategies.

Cardiac chamber strain is associated with outcomes in various diseases. However, it remains uncertain whether left ventricular global longitudinal strain (LVGLS), left atrial reservoir strain (LASr), or right ventricular free wall longitudinal strain (RVfwLS) has the most robust association with outcomes.

The authors aimed to compare head-to-head the associations of LVGLS, LASr, and RVfwLS with major adverse cardiovascular events (MACE) using 2-dimensional speckle tracking echocardiography (2D-STE) and cardiac magnetic resonance feature tracking (CMR-FT).

Consecutive patients who underwent clinically indicated echocardiography and cardiac magnetic resonance on the same day were enrolled. Strain was derived from 2D-STE (fully automated and manually edited) and CMR-FT. The primary endpoint was MACE, including cardiac death, heart failure hospitalization, and sustained ventricular tachyarrhythmia.

We included 550 patients (age 65 ± 15 years, 361 [66%] male). Over a median follow-up of 2.2 years (Q1-Q3: 0.9-4.2 years), 78 (14.3%) patients experienced MACE. LVGLS, LASr, and RVfwLS were independently associated with MACE in separate models after adjusted for key clinical variables. Head-to-head comparisons of 3 strain parameters revealed that LASr remained significantly associated with MACE using 2D-STE (both fully automated and manually edited, HR: 0.91; 95% CI: 0.86-0.95) and CMR-FT (HR: 0.91; 95% CI: 0.86-0.96) (all P ≤ 0.001). Incremental analysis showed that LASr provided additional value beyond clinical parameters and LVGLS (all P < 0.001), while the subsequent addition of RVfwLS did not. Nomogram analyses indicated that LASr had the most significant impact on MACE compared with LVGLS and RVfwLS, as assessed by both 2D-STE and CMR.

Compared with LVGLS and RVfwLS, LASr exhibited the strongest association with MACE, regardless of the imaging modality used. Incorporating LASr as a routine measurement should therefore be considered.