Pediatr Allergy Immunol. 2025 Jun;36(6):e70113. doi: 10.1111/pai.70113.

ABSTRACT

BACKGROUND: Long-acting β2-agonists (LABA) are commonly used to treat asthma. Some children do not respond well to LABA, which may be due to +46G>A-/rs1042713 (Arg16 amino acid) in the ADRB2 gene encoding the β2 receptor. Arg16Gly ADRB2 genotyping to guide treatment step-up decisions in children with uncontrolled asthma despite inhaled corticosteroids (ICS) has been shown to reduce asthma exacerbations. We investigated whether ADRB2 genotype-guided treatment is cost-saving.

METHODS: Total semi-annual healthcare and indirect costs for children with and without exacerbations were calculated using PUFFIN trial data. One hundred and two Dutch and Swiss children were randomised to a genotype-guided treatment arm (adding LABA [Gly16Gly] or double dose ICS [Arg16Arg/Arg16Gly]) or a control arm, where children were again randomised to LABA or double dose ICS. We used exacerbation rates of the PUFFIN and the PACT trials to calculate asthma-related healthcare costs per treatment arm, as PACT closely matches the PUFFIN design. The PACT trial randomised 91 children from England and Scotland with uncontrolled asthma to the genotype-guided treatment arm (LABA [Gly16Gly] or montelukast [Arg16Arg/Arg16Gly]) or the control arm (routine care as per British Thoracic Society guidelines).

RESULTS: Overall mean semi-annual costs per child were €56.24 lower in the genotype-guided treatment arm compared to the control arm (€771.07 [range €616.86-€925.28, 23 of 90 children experienced exacerbations] and €827.31 [range €661.85-€992.77, 40 of 103 experienced exacerbations], respectively).

CONCLUSION: A treatment strategy that includes ADRB2 genotype-guided treatment is potentially cost-saving compared to usual care. The decreased healthcare costs associated with a reduction in asthma exacerbations more than offset the incurred genotyping costs.

PMID:40464075 | DOI:10.1111/pai.70113

Front Genet. 2025 May 20;16:1490863. doi: 10.3389/fgene.2025.1490863. eCollection 2025.

ABSTRACT

INTRODUCTION: Hypertension (HTN) is a leading risk factor for several cardiovascular diseases. While some previous studies reported that CYP3A5 variants were associated with decreased blood pressure and risk of HTN, others reported no associations. Therefore, we aimed to analyze these associations in the UK Biobank, a population large enough to have sufficient power to detect meaningful associations.

METHODS: The association of CYP3A5 variants (*3, *6, *7) and CYP3A5 activity with systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), and HTN diagnosis was analyzed in the UK Biobank (N = 487,171). Linear and logistic regression models were used, adjusting for age, sex, race, antihypertensives use, smoking status, and salt intake. Moreover, subgroup analyses were performed in Black participants, White participants, participants of East Asian and South Asian descent separately, using the same models.

RESULTS: Neither the CYP3A5 variants, nor the CYP3A5 activity showed significant associations with SBP, DBP, MAP, or HTN. In a sensitivity analysis based on different racial subgroups, only White participants showed significant associations between the CYP3A5*3 variant and slightly higher DBP (β = 0.10 mmHg, 95% CI: 0.02 to 0.18, P = 0.01), as well as between genotype-predicted CYP3A5 activity score and slightly lower DBP (β = -0.10 mmHg, 95% CI: -0.18 to -0.02, P = 0.01).

DISCUSSION: While some associations were statistically significant, the small effect sizes and lack of associations observed in the whole UK Biobank population suggest that CYP3A5 variation likely has no impact on blood pressure related phenotypes in a general population.

PMID:40463714 | PMC:PMC12129758 | DOI:10.3389/fgene.2025.1490863

Br J Clin Pharmacol. 2025 Jun 3. doi: 10.1002/bcp.70109. Online ahead of print.

ABSTRACT

Over the past decade there has been considerable and growing enthusiasm about the promise of using genomics to inform healthcare. In particular, using genetic data to inform prescribing practice has emerged as a compelling policy priority for health systems around the world, not least in the NHS. Various initiatives and strategies have been developed to explore the value of pharmacogenomics in the UK National Health Service (NHS) and identify strategies for implementation. The NHS England Network of Excellence for Pharmacogenomics and Medicines Optimisation (PGx-NoE) was launched in 2024 and held two stakeholder meetings over the year in collaboration with the UK Pharmacogenetics and Stratified Medicine Network and the British Pharmacological Society (BPS). This article describes the outputs of those meetings, which are discussed in the context of previously identified challenges and opportunities. Rather than simply identify further barriers or facilitators, outputs are contextualized around tangible recommendations and real-world implementation exercises. These are grouped into three key areas: genetics, data and service. The work of partners across the UK are highlighted, including development of the NHS England Genomic Test Directory, the proof-of-principle informatic patterns demonstrated by the PROGRESS study, and the launch of the Centre for Excellence in Regulatory Science and Innovation (CERSI) in Pharmacogenomics, which will create UK-specific guidance and clarify complex regulatory pathways. Many of the well-defined barriers to the implementation of pharmacogenomics have been addressed in recent years, and this work highlights how the UK has the opportunity to emerge as a global leader in genomics-informed healthcare.

PMID:40460990 | DOI:10.1002/bcp.70109

Virology. 2025 May 22;610:110579. doi: 10.1016/j.virol.2025.110579. Online ahead of print.

ABSTRACT

The global pandemic coronavirus disease 2019 (COVID-19) attributable to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The current study aimed at combination therapies with natural polyphenolic compounds, such as cannabidiol (CBD), green tea polyphenols (Tea-poly), epigallocatechin gallate (EGCG) and theaflavin (TF), to investigate in vitro their inhibitory effects on virus invasion and viral spike (S) protein expression. Among the compounds tested, CBD and Tea-poly exhibited the most significant inhibitory effects on virus entry, comparable to the positive control chloroquine (CQ). EGCG showed the strongest suppression of the expression of the S protein, while CBD remarkably decreased ACE2 expression. CoIP-MS revealed eleven S-protein-interacting proteins that were significantly affected by EGCG. Transcriptome analysis demonstrated similar trends of CBD and EGCG in the modulation of many SARS-CoV-2-associated genes, with CBD showing greater impact on the gene profile than EGCG. GO and KEGG functional enrichment analyses revealed overlapping pathways of EGCG and CBD, including DNA repair, cell-cycle, and ER-, spliceosome- and ribosome-related processes. The combined use of CBD and EGCG can complement each other's advantages in inhibiting the invasion and reinvasion process of the virus at multiple levels, while minimizing the adverse effects of ACE2 expression level changes. Findings in this work offer new information for developing multi-level therapeutic strategies to control SARS-CoV-2 infection and, specifically, provide a novel antiviral agent combination of CBD and EGCG for the control of COVID-19.

PMID:40460494 | DOI:10.1016/j.virol.2025.110579

Drug Metab Pers Ther. 2025 Jun 2. doi: 10.1515/dmpt-2025-0028. Online ahead of print.

NO ABSTRACT

PMID:40459564 | DOI:10.1515/dmpt-2025-0028

J Antimicrob Chemother. 2025 Jun 3:dkaf173. doi: 10.1093/jac/dkaf173. Online ahead of print.

NO ABSTRACT

PMID:40458036 | DOI:10.1093/jac/dkaf173

J Pharm Health Care Sci. 2025 Jun 2;11(1):46. doi: 10.1186/s40780-025-00453-2.

ABSTRACT

BACKGROUND: Edoxaban is used as an anti-coagulant to prevent cardioembolic infarction, deep vein thrombosis, and pulmonary embolism. Edoxaban pharmacokinetics have been reported to be affected by several factors such as renal function, age, body weight, and the concomitant use of P-glycoprotein inhibitors. However, the relationship between genetic polymorphisms in drug metabolizing enzymes and transporters and the inter-individual variability of edoxaban pharmacokinetics in patients with atrial fibrillation (AF) remains unclear. Additionally, there is little information concerning PPK analysis using real world data. In this study a population pharmacokinetic and pharmacogenomic analysis was conducted to clarify covariate factors affecting the edoxaban pharmacokinetics in Japanese adult AF patients.

METHODS: One hundred and thirty-one blood samples were collected from 131 patients. The edoxaban pharmacokinetic profile was described by a one-compartment model, and pharmacogenomic data were stratified according to CYP3A5 (CYP3A5*3) and ABCB1 (ABCB1 1236 C > T, 2677G > T/A, and 3435 C > T) polymorphisms. A non-linear mixed-effects modeling software (NONMEM™) was used to evaluate the effects of patient characteristics and genetic polymorphisms on the edoxaban pharmacokinetics.

RESULTS: The apparent oral clearance (CL/F) of edoxaban was estimated, and the apparent volume of distribution was fixed at the reported value. The CL/F of edoxaban was correlated non-linearly with creatinine clearance (CLcr), wherein the population mean CL/F for a typical patient (CLcr = 61.8 mL/min) was estimated to be 28.2 L/h. Other clinical laboratory data and genetic polymorphisms, excluding CLcr, did not affect the edoxaban pharmacokinetics.

CONCLUSIONS: These results suggest that genetic polymorphisms of CYP3A5 and ABCB1 are not considered intrinsic factors affecting edoxaban pharmacokinetics in Japanese adult AF patients. Similarly to previous studies, renal function affects its pharmacokinetics. These findings may provide useful information for individualized anticoagulant therapy with edoxaban to prevent adverse events without reference to genetic polymorphisms of CYP3A5 and ABCB1.

PMID:40457359 | DOI:10.1186/s40780-025-00453-2

BMC Infect Dis. 2025 Jun 2;25(1):788. doi: 10.1186/s12879-025-11135-7.

ABSTRACT

BACKGROUND: The global HIV prevalence estimate at the end of 2022 was 39 million. This has led to mass testing to diagnose new cases, and the conduction of prognostic tests for monitoring HIV progression. This is being done to meet the targets of the 95%: 95%: 95% UN AIDS goal which is to be achieved by 2025. Therefore, there is the need to discover other diagnostic and prognostic biomarkers to be supplemented with the currently used ones. Studies indicate that micro RNAs have their levels influenced by the presence and replication of aetiologic agents, thus the micro RNA (miRNA) expression profile test may serve the dual purpose of HIV diagnosis and prognosis. Therefore, this study assessed the HIV-1 diagnostic and prognostic potential of the expression patterns of circulating miRNAs in HIV positive persons in Cape Coast, Ghana.

METHODS: A cross-sectional research design was used to assess the expression patterns of seven miRNAs - hsa-mir-146a, hsa-mir-155, hsa-mir-34a, hsa-mir-29a, hsa-mir-29b, hsa-mir-223 and hsa-mir-27a in 72 plasma samples. The samples were obtained from six antiretroviral therapy naïve persons, 37 ART-experienced persons and 29 healthy controls. Total RNA was extracted, afterwards, cDNA synthesis and RT-qPCR was done.

RESULTS: There were low levels of hsa-mir-155, and elevated levels of two miRNAs - hsa-mir-34a, and hsa-mir-27a in ART-experienced persons relative to healthy control. The sensitivities of the above miRNAs were 82.14%, 72.73% and 81.25 respectively, and specificities were 86.21%, 70.59% and 87.50% respectively. Upregulated levels of hsa-mir-223 was associated with HIV-1 infection in ART-naïve persons. Hsa-mir-223, hsa-mir-155, hsa-mir-29a and hsa-mir29b were present in quantities that distinguished between viral load categories classified as very low and high. These miRNAs were correlated with viral load. Low levels of hsa-mir-155 in HIV-1 persons with viral load of less than 7cps/ml distinguished them from HIV-negative control. Increased levels of hsa-mir-146a correlated with ART-resistance.

CONCLUSION: Decreased levels of hsa-mir-155, and elevated levels of hsa-mir-34a, hsa-mir-223 and hsa-mir-27a could be biomarkers of HIV-1. Hsa-mir-155, hsa-mir-29a, hsa-mir29b and hsa-mir-223 could be good biomarkers of HIV-1 progression and Low levels of hsa-mir-155 may possess the potential to detect minute HIV-1 RNA copies. Elevated levels of hsa-mir-146a could be a potential biomarker of ART-resistance.

PMID:40457240 | DOI:10.1186/s12879-025-11135-7

Sci Rep. 2025 Jun 2;15(1):19347. doi: 10.1038/s41598-025-99541-4.

ABSTRACT

MET exon 14 skipping is an oncogenic driver observed in 1 to 4% of non-small cell lung cancer (NSCLC). MET exon 14 mutations affect splice sites and are highly heterogeneous which makes them difficult to detect. Because of the approval of capmatinib for patients with MET exon 14 mutated tumors and the related poor response to immunotherapy (ICI) for a subset of patients with MET mutated tumors, MET screening has become mandatory for first line treatment decision. Here we report our testing experience based on 1143 consecutive NSCLC addressed for molecular diagnosis. Two strategies using either DNA sequencing (NGS) and fragment analysis or DNA-RNA sequencing (NGS) were developed and validated to accurately detect MET exon 14 alterations including large deletions. For patients with MET tumors (n = 46), demographic characteristics, treatments and outcomes were obtained from medical records and discussed. 46 MET exon 14 alterations were identified, 4 were not called by DNA sequencing and rescued by fragment analysis or RNA sequencing. Sixty-seven percent tumors had a high PD-L1 expression > 50 and 42% of cases had co-occurring alterations, mainly TP53 mutations (24%) and PIK3CA mutations (9%). Response to MET inhibitors (Crizotinib and Capmatinib) was evaluated for 15 patients. The ORR (Objective Response Rate) and the median of PFS (Progression Free Survival) were 44% and 5.5 months [1.6-18.2 months] respectively. Thirteen patients were treated by immunotherapy, ORR and median PFS (Progression Free Survival) median were 30% and 4 months [0.7-55.5 months] respectively. The response to immunotherapy was not correlated with PD-L1 status but smokers seemed to better respond to ICIs. This study highlights that a multimodal approach may be necessary to detect MET exon 14 mutations as large deletions may not be detected by DNA sequencing. Targeted DNA-ARN sequencing strategies broadly interrogate the diverse druggable genomic variations and permits direct detection of altered splicing or gene fusions. Because patients with MET exon 14 mutated tumors, demonstrate low response to immunotherapy despite high PDL1 and because MET exon 14 is druggable the detection of MET mutations is mandatory to optimize treatment.

PMID:40456875 | DOI:10.1038/s41598-025-99541-4

J Biol Chem. 2025 May 31:110327. doi: 10.1016/j.jbc.2025.110327. Online ahead of print.

ABSTRACT

Obesity is a major risk factor for multiple metabolic diseases, including type 2 diabetes mellitus (T2DM) and metabolic dysfunction-associated steatotic liver disease (MASLD). The cholesterol sulfotransferase SULT2B1 is best known for its function in converting cholesterol to cholesterol sulfate. Here, by using the high fat diet (HFD)-induced obesity model and the genetic obese ob/ob mice, we showed that genetic ablation of Sult2b1 protected mice from developing obesity and related insulin resistance, hepatic steatosis, and adipose tissue inflammation. Loss of Sult2b1 increased energy expenditure without affecting food intake or locomotive activity. The cold exposure test revealed that loss of Sult2b1 promoted thermogenesis in brown adipose tissue, which may have contributed to increased energy expenditure. In vivo reconstitution experiments suggested that the loss of Sult2b1 in extrahepatic tissues might have been responsible for the metabolic benefit. Mechanistically, our in vivo lipid uptake and metabolomic analyses showed that the Sult2b1KO mice exhibited suppression of intestinal dietary lipid absorption and the consequent downregulation of both systemic fatty acid level and fatty acid metabolism. Our results suggest that targeting SULT2B1 may represent a novel strategy to combat obesity and related metabolic syndrome.

PMID:40456448 | DOI:10.1016/j.jbc.2025.110327

Biol Psychiatry. 2025 May 31:S0006-3223(25)01219-3. doi: 10.1016/j.biopsych.2025.05.020. Online ahead of print.

ABSTRACT

Bipolar disorder (BD) is a highly heritable mental disorder that affects millions of people worldwide. Our understanding of the genetic etiology and biological processes underlying BD have greatly increased in recent years. Extensive progress has been made in identifying common variant signal for BD, and the PGS from the latest GWAS may provide some clinical utility if combined with other risk factors for BD. The role of rare variation in bipolar disorder remains to be determined, although genes annotated to common variant loci are shown to be enriched for rare variation. BD subtypes are shown to differ in their genetic architecture, and as such, genetic studies across the subtypes of the BD spectrum will identify subtype-specific signals and reveal subtype-specific biological mechanisms. Despite this, subtype-specific GWAS sample sizes have not increased at the same rate as BD cases and more concerted efforts are required to obtain this information for participants included in future BD GWAS studies. Moreover, assessment of culture, geography and other systematic differences that might impact patient assessment will be necessary to ensure accurate inclusion of diverse ancestral groups and global representation in genetic studies of BD moving forward.

PMID:40456304 | DOI:10.1016/j.biopsych.2025.05.020

Adv Funct Mater. 2025 Feb 12;35(7):2411334. doi: 10.1002/adfm.202411334. Epub 2024 Sep 27.

ABSTRACT

Cancer stem cells (CSCs), harboring stem cell-like properties involving self-renewal and aberrant differentiation potential, have been known to be one of the determining factors that contribute to therapeutic resistance and tumor recurrence. However, much remains to be understood about the reprogramming network leading to the generation of CSCs driven by chemotherapy. In this study, guided by bioinformatics study, we uncover and provide deeper insight into the CSC enrichment mechanism driven by cisplatin (CDDP) treatment. We discover that CDDP can repopulate the level of CSC by activating AKT1 oncogenic pathway that is further enhanced by COX-2 inflammatory signaling. Simultaneously blocking these two pathways can synergistically restrain the number of CSCs. Under the guidance of a series of advanced hierarchical computational modeling, including molecular docking, molecular dynamics (MD) simulation and binding free energy analysis, MK-2206 is selected as the AKT1 inhibitor to achieve optimal codelivery of CDDP, MK-2206 and 5-ASA (COX-2 inhibitor) through the use of 5-ASA-derivatized dual functional immunostimulatory nanocarrier (PASA). This triple combination (PASA/CDDP/MK-2206) significantly reduces tumor burden in both orthotopic and metastatic lung cancer models. Mechanistic studies show that this improved therapeutic activity is due to elimination of CSCs and reversal of the immunosuppressive tumor microenvironment. Our study suggests that PASA/CDDP/MK-2206 may represent a simple and effective lung cancer therapy via reversing CSCs-associated chemoresistance.

PMID:40452781 | PMC:PMC12124824 | DOI:10.1002/adfm.202411334

HGG Adv. 2025 May 31:100463. doi: 10.1016/j.xhgg.2025.100463. Online ahead of print.

ABSTRACT

The human X-chromosome contains hundreds of genes and has well-established impacts on sex differences and traits. However, the X-chromosome is often excluded from many genetic analyses, limiting broader understanding of variant effects. In particular, the functional impact of rare variants on the X-chromosome is understudied. To investigate functional rare variants on the X-chromosome, we use observations of outlier gene expression from GTEx consortium data. We show outlier genes are enriched for having nearby rare variants on the X-chromosome, and this enrichment is stronger for males. Using the RIVER model, we identified 733 rare variants in 450 genes predicted to have functional differences between males and females. We examined the pharmacogenetic implications of these variants and observed that 25% of drugs with a known sex difference in adverse drug reactions were connected to genes that contained a sex-biased rare variant. We further identify that sex-biased rare variants preferentially impact transcription factors with predicted sex-differential binding, such as the XIST-modulated SIX1. Overall, we observed more within-sex variation than between-sex variation. Combined, our study investigates functional rare variants on the X-chromosome, and further details how sex-stratification of variant effect prediction improves identification of rare variants with predicted sex-biased effects, transcription factor biology, and pharmacogenomic impacts.

PMID:40452186 | DOI:10.1016/j.xhgg.2025.100463

BMC Cancer. 2025 Jun 1;25(1):974. doi: 10.1186/s12885-025-14162-4.

ABSTRACT

AIM: To investigate the impact of tamoxifen dose, CYP2D6 inhibitors, CYP2D6*4 genotype, and non-genetic parameters on the outcomes of tamoxifen treated female breast cancer patients.

METHOD: We retrospectively included 3218 female patients who initiated tamoxifen following a diagnosis of breast cancer with long-term follow-up (median 7.5 years). A subgroup analysis of 303 genotyped patients with a median follow-up of 9.7 years was also conducted. The outcomes of interest were overall survival (OS) and breast-cancer-specific survival (BCS).

RESULTS: In the whole cohort, an additional 20 mg of tamoxifen during six-month duration was associated with a 1.6% reduction in all-cause mortality (HR: 0.984, 95% CI: 0.982-0.985, P < 0.001) and a 1.9% decrease in breast cancer mortality (HR: 0.981, 95% CI: 0.979-0.984, P < 0.001). In the genotyped subgroup, CYP2D6*4 heterozygotes had a 76% greater risk of all-cause mortality than *4 non-carriers (HR: 1.76, 95% CI: 1.07-2.9, P = 0.025). For breast cancer-specific mortality, CYP2D6*4 heterozygotes and homozygotes had increased risk by 3.7-fold (HR: 3.7, 95% CI: 1.32-10.6, P = 0.01) and 11.6-fold (HR: 11.6, 95% CI: 1.3-103.5, P = 0.03), respectively.

CONCLUSION: Our study demonstrates that carriers of CYP2D6*4 have a higher risk of both all-cause and breast cancer-specific mortality and indicates that longer follow-up time may be crucial to determining impact. The shorter follow-up in previous studies may be a key reason for the conflicting results. A large real-world pharmacogenomic study with long-term follow-up is warranted to determine the impact of CYP2D6 genotyping and its implications for clinical decision making.

PMID:40452016 | DOI:10.1186/s12885-025-14162-4

J Toxicol Sci. 2025;50(6):245-261. doi: 10.2131/jts.50.245.

ABSTRACT

Ototoxicity, or hearing loss and damage to the auditory system caused by certain medications, is a significant clinical challenge. Many commonly used drugs, including antimicrobials, cancer therapies, and loop diuretics, have the potential to induce temporary or permanent ototoxicity. The underlying mechanisms are complex, involving both genetic and environmental factors. Pharmacogenomics, the study of how an individual's genetic makeup influences their response to drugs, has emerged as a promising field for understanding and mitigating ototoxicity. Developing personalized approaches to prevent and manage ototoxicity is crucial, and this is where the pharmacogenomic basis of ototoxicity becomes crucial. This review aims to provide healthcare professionals with an updated perspective on the genetics of ototoxicity by summarizing the latest research and insights in this rapidly evolving field. It presents a comprehensive overview of the mechanisms and genetic factors associated with drug-induced ototoxicity, with a particular focus on cisplatin and aminoglycoside antibiotics.

PMID:40451854 | DOI:10.2131/jts.50.245

Cardiovasc Drugs Ther. 2025 May 31. doi: 10.1007/s10557-025-07690-5. Online ahead of print.

ABSTRACT

PURPOSE: To evaluate the impact of statin therapy on warfarin dose requirements in diabetic patients and to assess the performance of various machine learning algorithms in predicting optimal warfarin dosing.

METHODS: The datasets available for total participants of 628 (216 diabetics and 412 non-diabetic patients) were analyzed. We categorized the patients according to height, weight, gender, race, and age, plasma international normalized ratio (INR) on reported therapeutic dose of warfarin, target INR, warfarin dose, statin therapy, and indications for warfarin. Various models were tested on data of patients from the International Warfarin Pharmacogenetics Consortium (IWPC). Data preprocessing involves structuring and handling missing values. Six predictive models, including least absolute shrinkage and selection operator (LASSO), k-nearest neighbors (KNN), support vector regression (SVR), linear regression (LR), decision tree, and random forest (RF), were employed in predicting optimal warfarin dosage. The best dose for each patient will be predicted using one of the six regression models.

RESULTS: This comparative study showed that the mean (and the standard deviation) of warfarin dose for diabetic and non-diabetic patients were 38.73 (15.37) and 34.50 (18.27) mg per week, respectively. Furthermore, the impact of various statin they use is considered and patient undergoing atorvastatin and rosuvastatin therapy against the necessity of high dose warfarin if the diabetic patients use lovastatin and fluvastatin.

CONCLUSION: Diabetic patients under statin therapy, considering the specific statin used, require different warfarin dose. Through the application of advanced machine learning, models as dosing predictors may attenuate the adverse effects of warfarin.

PMID:40448807 | DOI:10.1007/s10557-025-07690-5

EBioMedicine. 2025 May 29;117:105779. doi: 10.1016/j.ebiom.2025.105779. Online ahead of print.

ABSTRACT

BACKGROUND: Motor neuron disease (MND) leads to progressive functional decline, making reliable measures of disease progression critical for patient care and clinical trials. Current clinical outcome measures lack the ability to continuously and objectively track functional decline in daily life of patients with MND. This study assessed and validated wrist-worn accelerometry outcome measures for continuous monitoring in MND, with the potential to refine clinical trial outcomes.

METHODS: This longitudinal study included 95 patients with MND who wore an ActiGraph GT9X Link device on their non-dominant wrist for 8 days, with follow-up every 3-4 months. Accelerometer data were processed using ActiLife and GGIR. Joint models were used to simultaneously investigate the longitudinal change in ALS Functional Rating Scale-Revised (ALSFRS-R) scores and accelerometer-derived outcomes alongside their relationship with overall survival. Sample size estimates for clinical trials were generated using both accelerometer- and ALSFRS-R-based outcomes, and principal component analysis (PCA) explored outcome relationships.

FINDINGS: Accelerometer outcomes showed a slower rate of decline (-0.03 to -0.07 SD/month) compared to ALSFRS-R (-0.10 SD/month) and had stronger correlations with ALSFRS-R motor subdomains (partial r: 0.60-0.73). PCA revealed that longitudinal measures of accelerometry were distinct from the ALSFRS-R, highlighting the complementary nature of these measures. Peak 6-min activity predicted smaller clinical trial sample sizes for studies over 12 months. Accelerometer-derived outcomes were not significantly associated with survival.

INTERPRETATION: Wrist-worn accelerometry offers a practical solution for continuous monitoring in MND, complementing ALSFRS-R. Measures of peak performance, and specifically peak 6-min activity shows promise, potentially reducing sample sizes and improving disease tracking over longer duration studies. Further refinement and validation are needed to adopt actigraphy measures as clinical assessment outcomes.

FUNDING: This study was supported by Wesley Medical Research (2016-32), the Honda Foundation, Motor Neurone Disease Research Australia, and FightMND. CJH received a Higher Degree Research Scholarship from UQ. STN received support from the Scott Sullivan Fellowship (MND and Me Foundation/RBWH Foundation), a FightMND Mid-Career Fellowship, and the AIBN.

PMID:40446399 | DOI:10.1016/j.ebiom.2025.105779

Anim Microbiome. 2025 May 30;7(1):53. doi: 10.1186/s42523-025-00405-z.

ABSTRACT

Several studies have indicated that the dysregulation of microbial metabolites and the inflammatory environment resulting from microbial dysbiosis may contribute to the occurrence and progression of cardiovascular diseases. Therefore, restoring the disordered gut microbiota in patients with colorectal cancer by fecal microbiota transplantation (FMT) has the potential to reduce the incidence of cardiac disease. In this study, we identified cardiac dysfunction in azomethane and dextran sodium sulfate-induced colorectal cancer mice. Intestinal microbes from healthy mice were transferred to colorectal cancer mice, which vastly reversed the disorder of the gut microbiota and effectively alleviated cardiac dysfunction. Moreover, FMT regulated the expression of serum metabolites such as uridine triphosphate (UTP), tiamulin, andrographolide, and N-Acetyl-D-glucosamine, as well as cytokines like TGF-β, IRF5, and β-MHC in the heart. These findings uncover that the disturbed gut microbiota causes cardiac dysfunction in colorectal cancer mice by modulating the expression of serum metabolites and cytokines, which could be alleviated by treatment with FMT.

PMID:40448218 | DOI:10.1186/s42523-025-00405-z

PLoS One. 2025 May 30;20(5):e0309875. doi: 10.1371/journal.pone.0309875. eCollection 2025.

ABSTRACT

Kidney transplantation recipients (KTRs) represent a vulnerable population for COVID-19 infection and severe disease. Nirmatrelvir-ritonavir has demonstrated efficacy in treating COVID-19 among KTRs, and interacts with tacrolimus leading to a precipitous increase in tacrolimus blood levels when co-administered, which may potentially result in toxicity. To explore a safe strategy for the combination of nirmatrelvir-ritonavir and tacrolimus, we established a new administration strategy to restore tacrolimus after the discontinuation of nirmatrelvir-ritonavir and conducted a real-world retrospective observational cohort study to evaluate its clinical efficacy. In the experimental group, tacrolimus was initiated at 20-25% of the baseline dose 48 hours after the discontinuation of nirmatrelvir-ritonavir, with daily increments of 20-25% until the baseline dose was restored. The patients who did not follow the experimental protocol were included in the control group. Results showed that withholding tacrolimus 12 hours before starting nirmatrelvir-ritonavir maintained tacrolimus blood levels above 83% of the baseline throughout the nirmatrelvir-ritonavir treatment period. Compared with the control group, the experimental group achieved target trough concentrations of tacrolimus more quickly and maintained a higher proportion within the therapeutic range (p = 0.029), and had significantly lower rates of adverse events (p = 0.002, OR = 0.308, 95%CI:0.136-0.695). This study provides a safe and effective pharmacological strategy for KTRs infected with COVID-19, allowing the safe co-administration of nirmatrelvir-ritonavir and tacrolimus.

PMID:40445936 | DOI:10.1371/journal.pone.0309875

Alcohol Clin Exp Res (Hoboken). 2025 May 30. doi: 10.1111/acer.70052. Online ahead of print.

ABSTRACT

BACKGROUND: In two 12-week, randomized, placebo-controlled trials (RCTs) in individuals with alcohol use disorder (AUD), topiramate significantly reduced heavy drinking days (HDDs), and alcohol-related problems. In a secondary analysis of those findings, we examined four broad measures of genetic risk-polygenic scores (PGS)-of problematic alcohol use (PAU), drinks per week (DPW), and time to relapse to any drinking (TR) and heavy drinking (THR) as moderators of topiramate's effect on HDDs and alcohol-related problems.

METHODS: We analyzed data from 285 individuals with AUD (65.6% male) of European-like ancestry, who were treated with either topiramate (49.1%) or placebo (50.9%). All patients underwent genome-wide array genotyping, and PGS were calculated using summary statistics from genome-wide association studies of PAU, DPW, and TR and THR (two time-to-event outcomes among patients treated in AUD pharmacotherapy trials). We hypothesized an interaction effect in which greater genetic risk-particularly for PAU-would be associated with a greater therapeutic response to topiramate than placebo.

RESULTS: As shown previously, topiramate significantly reduced both HDDs (odds ratio [OR] = 0.50, p < 0.001) and Short Index of Problems (SIP) scores (b = -3.04, p < 0.001) more than placebo. There were nonsignificant associations of higher PGS with more HDDs (OR = 1.17, 95% CI = 0.98-1.41, p = 0.091) and a greater reduction in HDDs in the topiramate group (OR = 0.80, 95% CI = 0.62-1.03, p = 0.089). There were also significant interaction effects with treatment on SIP score by PGS for PAU (b = -1.64, SE = 0.78, p = 0.033), TR (b = -2.16, SE = 0.72, p = 0.003), and TRH (b = -2.17, SE = 0.72, p = 0.003).

CONCLUSIONS: These findings provide proof of principle for the use of alcohol-related PGS as moderators of the effects of topiramate for treating AUD. Larger RCTs of topiramate are needed to provide adequate statistical power to validate this pharmacogenetic approach to precision AUD treatment.

PMID:40445294 | DOI:10.1111/acer.70052