Exploring the Pharmacogenomic Map of Croatia: PGx Clustering of 522-Patient Cohort Based on UMAP + HDBSCAN Algorithm.

Pharmacogenetics is a branch of genomic medicine aiming to personalize drug prescription guidelines based on individual genetic information. This concept might lead to a reduction in adverse drug reactions, which place a heavy burden on individual patients' health and the economy of the healthcare system. The aim of this study was to present insights gained from the pharmacogenetics-based clustering of over 500 patients from the Croatian population.

Targeting Metabolic and Epigenetic Vulnerabilities in Glioblastoma with SN-38 and Rabusertib Combination Therapy.

Glioblastoma (GBM), the most prevalent primary malignant brain tumor, remains challenging to treat due to extensive inter- and intra-tumor heterogeneity. This variability demands combination treatments to improve therapeutic outcomes. A significant obstacle in treating GBM is the expression of O-methylguanine-DNA methyltransferase, a DNA repair enzyme that reduces the efficacy of the standard alkylating agent, temozolomide, in about 50% of patients.

Diurnal timing of physical activity in relation to obesity and diabetes in the German National Cohort (NAKO).

Background: Physical activity supports weight regulation and metabolic health, but its timing in relation to obesity and diabetes remains unclear. We aimed to assess the diurnal timing of physical activity and its association with obesity and diabetes.

Methods: We cross-sectionally analyzed hip-worn accelerometry data from 61,116 participants aged 20-75 in the German National Cohort between 2015 and 2019.

Coordinated immune networks in leukemia bone marrow microenvironments distinguish response to cellular therapy.

Understanding how intratumoral immune populations coordinate antitumor responses after therapy can guide treatment prioritization. We systematically analyzed an established immunotherapy, donor lymphocyte infusion (DLI), by assessing 348,905 single-cell transcriptomes from 74 longitudinal bone marrow samples of 25 patients with relapsed leukemia; a subset was evaluated by both protein- and transcriptome-based spatial analysis. In acute myeloid leukemia (AML) DLI responders, we identified clonally expanded CD8 cytotoxic T lymphocytes with in vitro specificity for patient-matched AML.

Lifestyle scores and their potential to estimate the risk of multiple non-communicable disease-related endpoints: a systematic review.

Background: Lifestyle scores have emerged as a practical tool to assess the risk of major non-communicable diseases (NCDs). However, most of them are primarily developed for single NCDs. Given the common risk factors for some of the major NCDs, we conducted a systematic review to evaluate the potential of existing lifestyle scores in predicting the risk of multiple NCD-related endpoints.

A proteogenomic analysis of the adiposity colorectal cancer relationship identifies GREM1 as a probable mediator.

Background: Adiposity is an established risk factor for colorectal cancer (CRC). The pathways underlying this relationship, and specifically the role of circulating proteins, are unclear.

Methods: Utilizing two-sample univariable Mendelian randomization (UVMR), multivariable Mendelian randomization (MVMR), and colocalization, based on summary data from large sex-combined and sex-specific genetic studies, we estimated the univariable associations between: (i) body mass index (BMI) and waist-hip ratio (WHR) and overall and site-specific (colon, proximal colon, distal colon, and rectal) CRC risk, (ii) BMI and WHR and circulating proteins, and (iii) adiposity-associated circulating proteins and CRC risk.

Guiding the Hand to an Invisible Target.

Numerous devices are being developed to assist visually impaired and blind individuals in performing everyday tasks such as reaching out to grasp objects. Considering that the size, weight, and cost of assistive devices significantly impact their acceptance, it would be useful to know how effective various types of guiding information can be. As an initial exploration of this issue, we conducted four studies in which participants with normal vision were visually guided toward targets.

Global cellular proteo-lipidomic profiling of diverse lysosomal storage disease mutants using nMOST.

Lysosomal storage diseases (LSDs) comprise ~50 monogenic disorders marked by the buildup of cellular material in lysosomes, yet systematic global molecular phenotyping of proteins and lipids is lacking. We present a nanoflow-based multiomic single-shot technology (nMOST) workflow that quantifies HeLa cell proteomes and lipidomes from over two dozen LSD mutants. Global cross-correlation analysis between lipids and proteins identified autophagy defects, notably the accumulation of ferritinophagy substrates and receptors, especially in and mutants, where lysosomes accumulate cholesterol.

Montelukast Use and the Risk of Neuropsychiatric Adverse Events in Children.

Importance: Spontaneous reports have indicated that montelukast increases the risk of neuropsychiatric adverse events, and the US Food and Drug Administration added a boxed warning about these risks in 2020. However, the potential mechanism is not well understood, and the observational evidence is scarce, particularly in children.

Objective: To assess the potential association between the use of montelukast and the risk of neuropsychiatric adverse events in children and adolescents.

Wnt signaling drives stromal inflammation in inflammatory arthritis.

The concept that fibroblasts are critical mediators of inflammation is an emerging paradigm. In rheumatoid arthritis (RA), they are the main producers of IL-6 as well as a host of other cytokines and chemokines. Their pathologic activation also directly causes cartilage and bone degradation.

Associations of blood-based biomarkers of neurodegenerative diseases with mortality, cardio- and cerebrovascular events in persons with chronic coronary syndrome.

Background: In light of growing evidence highlighting interactions between cardiac and brain health, we investigated associations of biomarkers of neurodegenerative diseases with adverse outcomes (all-cause and cardiovascular mortality, major cardiovascular events, and stroke) in persons with chronic coronary syndrome (CCS).

Methods: We used data from a cohort of persons with CCS for whom major adverse events were recorded over a follow-up of 20 years. We measured biomarkers of neurodegenerative diseases in baseline blood samples, using the Single-Molecule Array Technology on a HD-1 Analyzer.

Colorectal Cancer and Central Obesity.

Importance: The proportion of colorectal cancer (CRC) cases attributable to excess weight, known as population attributable fraction (PAF), has been commonly based on measures of body mass index (BMI). Central obesity metrics, such as waist circumference (WC) and waist to hip ratio (WHR), are potentially better indicators of adiposity and have demonstrated stronger associations with CRC incidence.

Objectives: To examine PAFs of CRC cases that are attributable to high WC and WHR and compare them to those attributable to high BMI.

Implications for the diagnosis of aspiration and aspergillosis in critically ill patients with detection of galactomannan in broncho-alveolar lavage fluids.

Invasive infections with Aspergillus fumigatus in ICU patients are linked to high morbidity and mortality. Diagnosing invasive pulmonary aspergillosis (IPA) in non-immunosuppressed patients is difficult, as Aspergillus antigen (galactomannan [GM]) may have other causes. This retrospective study analyzed 160 ICU surgical patients with positive GM in broncho-alveolar lavage fluid (BALF), classifying them based on AspICU criteria for suspected IPA (pIPA) or aspiration.

Pharmacologically induced proteolysis of histone deacetylase-6 attenuates influenza virus replication despite limited anti-tumor effects.

The protein deacetylase HDAC6 has been controversially linked to cancer cell proliferation and viral propagation. We analyzed whether a pharmacological depletion of HDAC6 with a recent proteolysis-targeting chimera (PROTAC) kills tumor cells. We show that low micromolar doses of the cereblon-based PROTAC TH170, but not its inactive analog TH170E, induce proteasomal degradation of HDAC6.

Voice of the nurse in paediatric intensive care: a scoping review.

Objectives: The objective was to explore how the voice of the nurse in paediatric intensive care units (PICU) is portrayed in the literature.

Design: Scoping review using the six-step scoping review framework outlined by Arksey and O'Malley.

Data Sources: PubMed, Nursing (OVID), Medline (OVID), CINHAL (EBSCO), SCOPUS and Web of Science online databases.

Improving 10-year cardiovascular risk prediction in patients with type 2 diabetes with metabolomics.

Background: Existing cardiovascular risk prediction models still have room for improvement in patients with type 2 diabetes who represent a high-risk population. This study evaluated whether adding metabolomic biomarkers could enhance the 10-year prediction of major adverse cardiovascular events (MACE) in these patients.

Methods: Data from 10,257 to 1,039 patients with type 2 diabetes from the UK Biobank (UKB) and the German ESTHER cohort, respectively, were used for model derivation, internal and external validation.

Accounting for differential exclusions in the NordICC trial discloses stronger-than-reported effects of screening colonoscopy.

Objective: Recently, results on colorectal cancer (CRC) incidence and mortality reduction by the offer of screening colonoscopy were reported for the first time from a randomized controlled trial (RCT), the Nordic-European Initiative on Colorectal Cancer (NordICC) trial. Despite randomization, there was a substantially lower proportion of post-randomization exclusions of CRC cases due to cancer registry-recorded date of diagnosis before recruitment in the invited group than in the usual-care group. We aimed to evaluate the impact of such differential exclusions on the trial's effect estimates on CRC risk.

An eCIRP inhibitor attenuates fibrosis and ferroptosis in ischemia and reperfusion induced chronic kidney disease.

Background: Chronic kidney disease (CKD) is a leading cause of death in the United States, and renal fibrosis represents a pathologic hallmark of CKD. Extracellular cold-inducible RNA-binding protein (eCIRP) is a stress response protein involved in acute inflammation, tissue injury and regulated cell death. However, the role of eCIRP in chronic inflammation and tissue injury has not been elucidated.

Ten simple rules for good model-sharing practices.

Computational models are complex scientific constructs that have become essential for us to better understand the world. Many models are valuable for peers within and beyond disciplinary boundaries. However, there are no widely agreed-upon standards for sharing models.

A Novel Technique for Inguinal Hernia Repair in Patients With Nonmalignant Ascites.

Introduction: We report a novel approach to open inguinal hernia repair in patients with known ascites in which the cord, hernia sac, and attached testicle on the affected side are repositioned into the retroperitoneum through the inguinal ring. By avoiding invasion of the peritoneum and limiting dissection of the sac off the spermatic cord, the risk of ascites leak and testicular ischemia is theoretically decreased.

Methodology: This is a retrospective case series report.

Induction of MASH in three-dimensional bioprinted human liver tissue.

Metabolic dysfunction-associated steatohepatitis (MASH), formerly known as nonalcoholic steatohepatitis (MASH), is a major risk factor for cirrhosis and hepatocellular carcinoma (HCC) and a leading cause of liver transplantation. MASH is caused by an accumulation of toxic fat molecules in the hepatocyte which leads to inflammation and fibrosis. Inadequate human "MASH in a dish" models have limited our advances in understanding MASH pathogenesis and in drug discovery.

Phase separation of initiation hubs on cargo is a trigger switch for selective autophagy.

Autophagy is a key cellular quality control mechanism. Nutrient stress triggers bulk autophagy, which nonselectively degrades cytoplasmic material upon formation and liquid-liquid phase separation of the autophagy-related gene 1 (Atg1) complex. In contrast, selective autophagy eliminates protein aggregates, damaged organelles and other cargoes that are targeted by an autophagy receptor.