Journal of Internal Medicine最新文献

Editorial

Current population estimates suggest over a third of adults in the world have hepatic steatosis, and the majority would meet criteria for metabolic dysfunction-associated steatotic liver disease (MASLD) [1]. This was previously termed non-alcoholic fatty liver disease until an international multi-society consensus to change the name in 2023 [2] to facilitate a proactive diagnosis rather than being a diagnosis of exclusion.

However, only a small proportion of patients with MASLD will have a major adverse liver outcome in their lifetime, such as decompensated cirrhosis or developing a hepatocellular carcinoma (HCC). The major risk for adults with hepatic steatosis is a major adverse cardiovascular event (MACE), particularly myocardial infarction, with an increased lifetime odds of coronary artery disease rising by 33% compared to adults without steatosis [3].

The counterfactual is MASLD is a leading indication for liver transplantation across Europe and North America, in part due to the success of the Hepatitis C eradication programmes internationally. MASLD is also a rapidly rising cause of liver-related deaths in the WHO global burden of disease study, behind alcohol-related liver disease and viral hepatitis. Modelling of trajectories of liver disease–related deaths from seven international liver disease cohorts suggests MASLD related deaths will have doubled between 2015 and 2030 [4]. It is also driving the rise in HCC in non-cirrhotic liver disease across the western world, with one multicentre French cohort reporting 72% of non-cirrhotic HCC diagnoses were made incidentally over an 11-year period [5].

Crucially, fibrosis progression rates (FPRs) in MASLD are slow, and addressing cardiometabolic risk factors can halt—and even reverse—progression whilst improving all-cause morbidity and mortality from MACE. Importantly, fibrosis is the only histological feature which is known to determine the risk of liver-related events, with progressive stages of fibrosis conferring the highest risk of adverse outcomes [6, 7]. Therefore, identifying patients with MASLD with advanced fibrosis is pivotal in terms of risk stratification. Emerging data suggested that Type 2 diabetes (T2D) is one of the strongest potentiators of fibrogenesis, and FPRs in those with T2D are enhanced [8]. However, a substantial proportion of this evidence comes from clinical trials or those attending secondary care diabetes services; thus, real-world evidence, particularly from primary care settings, is to be welcomed.

In this context, Balkhed et al. provide valuable normative data when screening for MASLD amongst T2D patients in the primary care setting [9]. Steatosis prevalence in T2D has historically been reported at 50%–70% [10], and multiple societies such as the European Association for the Study of the Liver and the Ame

Cholecystokinin (CCK) is a classic gut hormone that has been known for almost a century to regulate gallbladder emptying, pancreatic enzyme secretion, and gastrointestinal motor activity. In 1968, the CCK structure was identified by Viktor Mutt and Erik Jorpes from porcine gut extracts as a peptide of 33 amino acid residues. Based on that structure, physiological, immunochemical, molecular, and cell biological research has since expanded the insight into the biology of CCK remarkably. Thus, CCK was the first identified intestinal satiety signal to the brain. Moreover, the CCK gene is now known to be expressed in different molecular forms not only in the gut, but very much so in central and peripheral neurons, in addition to extra-intestinal endocrine cells, immune cells, cardiomyocytes, spermatogenic cells, and certain fat cells. Accordingly, CCK peptides function not only as hormones. They are also neurotransmitters, paracrine growth and satiation factors, anti-inflammatory cytokines, incretins, adipokins, myokines, potential fertility factors, and tumor markers. Consequently, CCK biology has now opened windows for insights into pathophysiology with diagnostic and therapeutic possibilities in metabolic disorders (obesity, eating disorders, and diabetes mellitus), gallbladder disease, neuropsychiatric diseases (cerebral tumors, memory, and anxiety disorders), cardiac diseases (prognosis in heart failure), neuroendocrine and pediatric tumors, as well as perhaps infertility.

Extensively studied over the past four decades, the TP53 gene has emerged as a pivotal watchman in cellular defense and a key factor in cancer biology. TP53 is the most frequently mutated gene in human malignancies, 50% of which carry alterations to it. Initially, the functions of p53 were thought to be restricted to cell-cycle arrest and apoptosis. With time, however, a growing number of functions have been discovered, illustrating p53's role as a master switch between any cellular stress and cellular or multicellular responses that contribute to its anti-tumor activity. Indeed, the peculiar landscape of TP53 mutations and its high heterogeneity are linked both to the structure of the protein and its ubiquitous function in regulating cellular homeostasis. Mutations in p53 are associated with poor response to therapy and shorter survival in most cancer types, and the diagnosis of p53 mutations is currently used to improve case management in some types of leukemia and lymphoma. Although TP53 has been defined as a tumor suppressor gene, overexpressed mutated p53 variants found in human tumors are defined as dominant oncogenes with a potential gain of function, which makes the gene a very attractive target for developing new cancer treatments. Beyond its role in cancer, our review also highlights TP53's significance in non-neoplastic conditions, such as bone marrow failure syndromes and certain developmental disorders, where chronic p53 activation plays a crucial role in cellular stress responses, demonstrating its broader biological importance.

Healthcare-associated infections (HAIs) are common adverse events, and surveillance is considered a core component of effective HAI reduction programmes. Recently, efforts have focused on automating the traditional manual surveillance process by utilizing data from electronic health record (EHR) systems. Using EHR data for automated surveillance, algorithms have been developed to identify patients with (ventilator-associated) pneumonia and (catheter-related) bloodstream, surgical site, (catheter-associated) urinary tract and Clostridioides difficile infections (sensitivity 54.2%–100%, specificity 63.5%–100%). Mostly methods based on natural language processing have been applied to extract information from unstructured clinical information. Further developments in artificial intelligence (AI), such as large language models, are expected to support and improve different aspects within the surveillance process; for example, more precise identification of patients with HAI. However, AI-based methods have been applied less frequently in automated surveillance and more frequently for (early) prediction, particularly for sepsis. Despite heterogeneity in settings, populations, definitions and model designs, AI-based models have shown promising results, with moderate to very good performance (accuracy 61%–99%) and predicted sepsis within 0–40 h before onset. AI-based prediction models detecting patients at risk of developing different HAIs should be explored further. The continuous evolution of AI and automation will transform HAI surveillance and prediction, offering more objective and timely infection rates and predictions. The implementation of (AI-supported) automated surveillance and prediction systems for HAI in daily practice remains scarce. Successful development and implementation of these systems demand meeting requirements related to technical capabilities, governance, practical and regulatory considerations and quality monitoring.

Over the past decade, numerous reports have highlighted intergenerational and even transgenerational epigenetic effects resulting from parental exposure to diets, toxins, and stress. In many cases, these parentally induced phenotypes do not seem to confer an obvious benefit, making it challenging to understand the evolutionary drivers behind them. In this perspective, we discuss recent observations in humans and rodents indicating that a parental infection or vaccination can enhance the offspring's ability to cope with infections. Such parental priming of their offspring's immune system and cellular defense would provide immediate protection to the newborn, offering a clear evolutionary advantage. Here, focusing mainly on paternal effects, we propose that a parentally induced inflammatory memory in the offspring could be the underlying mechanism for many of the reported inter- and transgenerational effects. Sperm-borne RNA could be a triggering signal to initiate inflammatory pathways in early embryogenesis. This gene-regulatory state would then be maintained via epigenetic mechanisms throughout each mitosis and last for the individual's lifetime. The accumulating understanding that diet, stress, toxins, and infections affect offspring health raises important questions about public health policies. There is an urgent need to understand what consequences different exposures during sensitive time windows have on future generations.